Diab_12_Syndromes : simplebooklet.com

237CHAPTER 12SYNDROMESGeneral Considerations .....................................................238Language ......................................................................238Classiﬁcation .................................................................238Evaluation .....................................................................239Algorithm ......................................................................240Conditions in Alphabetic Order .........................................241Achondroplasia .................................................................241Acrodysostosis ..................................................................241Amniotic Band Syndrome ..................................................241Amyoplasia .......................................................................241Antley-Bixler Syndrome .....................................................241Apert Syndrome ................................................................241Arthrogryposis ..................................................................242Beals Syndrome ................................................................242Beckwith-Wiedemann Syndrome ......................................242Brachydactyly ....................................................................242Brachyolmia (Brachyrhachia) ..............................................242Bruck Syndromes ..............................................................242Caffey Disease (Infantile Cortical Hyperostosis) ..................242Camp(t)omelic Dysplasia ...................................................243Carpenter Syndrome .........................................................243Chondrodysplasia Punctata (Conradi-Hünermann) ............243Chondroectodermal Dysplasia (Ellis-van Creveld) ...............243Cleidocranial Dysplasia ......................................................243Cornelia de Lange Syndrome ............................................243Craniodiaphysial Dysplasia ................................................243Craniometaphysial Dysplasia .............................................243de Barsy Syndrome ...........................................................243Diastrophic Dysplasia ........................................................244Down Syndrome (Trisomy 21) ............................................244Dyggve-Melchior-Clausen Syndrome .................................244Dysplasia Epiphysialis Hemimelica ......................................244Ehlers-Danlos Syndromes ..................................................244Emanuel Syndrome ...........................................................245Epiphysial Dysplasia, Multiple ............................................245Escobar Syndrome ............................................................245Familial Dysautonomia ......................................................245Fanconi Anæmia ...............................................................245Femoral–Facial Syndrome ..................................................245Fibrodysplasia Ossiﬁcans Progressiva ..................................245Freeman-Sheldon Syndrome..............................................246Friedreich Ataxia ...............................................................246Gaucher Disease ...............................................................246Goldenhar Syndrome ........................................................246Guillain-Barré Syndrome ...................................................246Hand–Foot–Genital Syndrome ...........................................246Hæmophilia ......................................................................246Holt-Oram Syndrome ........................................................247Homocystinuria .................................................................247Klippel-Feil Syndrome ........................................................247Klippel-Trénaunay-Weber Syndrome ..................................247Kniest Dysplasia ................................................................247Larsen Syndrome ..............................................................247Léri-Weill Dyschondrosteosis .............................................247Lesch-Nyhan Syndrome .....................................................247Mafucci Syndrome ............................................................248Marfan Syndrome .............................................................248Marshall-Smith Syndrome .................................................249McCune-Albright Syndrome ..............................................249Meier-Gorlin Syndrome .....................................................249Melnick-Needles Syndrome ...............................................249Melorheostosis ..................................................................249Mesomelic Dysplasia .........................................................249Metachondromatosis ........................................................249Metaphysial Chondrodysplasias .........................................249Metatropic Dysplasia .........................................................250Möbius Syndrome .............................................................250Mucopolysaccharidosis ......................................................250Multiple Enchondromatosis ...............................................251Multiple Exostoses ............................................................251Multiple Synostosis Syndrome ...........................................251Nail–patella Syndrome ......................................................252Neuroﬁbromatosis ............................................................252Oculodentodigital Dysplasia ..............................................253Osteogenesis Imperfecta ...................................................253Osteopetrosis ....................................................................254Otopalatodigital Syndrome ...............................................255Poland Syndrome ..............................................................255Prader-Willi Syndrome .......................................................255Proteus Syndrome .............................................................256Pyle Disease ......................................................................256Prune Belly Syndrome .......................................................256Pseudoachondroplasia ......................................................256Pterygium Syndrome .........................................................256Pycnodysostosis ................................................................256Rickets ..............................................................................257Riley-Day Syndrome ..........................................................257Rubinstein-Taybi Syndrome ...............................................257Seckel Syndrome ...............................................................257Silver-Russell Syndrome .....................................................257Small Patella Syndrome .....................................................257Split Hand/Split Foot Malformation ...................................258Spondyloepimetaphysial Dysplasia .....................................258Spondyloepiphysial Dysplasia ............................................258Spondylometaphysial Dysplasia .........................................259Stickler Syndrome .............................................................259Streeter Dysplasia ..............................................................259Thanatophoric Dysplasia ...................................................259Thrombocytopenia–Absent Radius (TAR) Syndrome ...........259Trichorhinophalangeal Dysplasia ........................................259Turner Syndrome ..............................................................259VACTERL Association ........................................................260Velocardiofacial Syndrome ................................................260von Willebrand Disease .....................................................260Whistling Face Syndrome ..................................................260Waardenburg Syndrome ...................................................260Arthritis, Juvenile Idiopathic ..............................................261Additional Reading ...........................................................262Diab_Chap12.indd 237 9/23/2015 3:25:01 PM

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GENERAL CONSIDERATIONSThe title syndromes is used for lack of a more inclusive term. Syndromes are arranged in alphabetical order for simplicity. There is no comprehen-sive system of classiﬁcation that is complete, because of diverse causes, heterogeneity of presentation, evolution of expression with growth, as well as rapid and continual medical discovery. These are diseases ﬁrst and orthopedic problems second: most important is evaluation, because orthopedic management will not solve the primary problem and may deliver a fair outcome at best. This contrasts with disorders of the mus-culoskeletal system that occur in an otherwise normal child, where orthopedic management is the focus. All tissues of the skeleton may be affected, from bone to cartilage to surrounding soft tissues. The clinical presentation is broad, from premature osteoporotic fracture in the adult to perinatal lethal. While individually the disorders may be rare, collec-tively, their incidence may be as high as 1/5,000 births. It is important to realize that many diagnoses do not represent a single disease but rather a heterogeneous group of disorders of which only some subtypes are well characterized while others originate in single case reports.LanguageSyndrome, used by Galen as a compound of Greek συν: “with, together” and δροµοσ: “a course, race, running,” signiﬁes “a concurrence” of signs in, or the clinical presentation of, a disease.Short stature may be deﬁned as <2 standard deviations below mean height or below 2.5 percentile. An alternative guideline is height <5 ft. (150 cm). Short stature may be divided into proportionate, affecting the entire body equally, or disproportionate. Terms such as midget for the former and dwarf for the latter are not universally accepted. Little person is neutral and is aligned with the Little People of America.Disproportion of short stature may arise from the limbs, referred to as micromelia (Greek µικρος: “small” and µελος: “limb”). Disproportion-ate shortening of the “trunk” is known as microcormia (Greek κορµος) [A]. Limb shortening may be asymmetric. Alternatively, limbs may be short at the “root,” known as rhizomicromelia (Greek ριζα); at the “mid-dle” segment, known as mesomicromelia (Greek µεσος); or at the “tip,” known as acromicromelia (Greek ακρος) [B]]. This terminology comes from radiographic classiﬁcation based upon the region of bone princi-pally affected, such as epiphysis versus metaphysis versus diaphysis. The convenience of this system has led to its wide adoption; however, it is simplistic, bears no relationship to morbidity, and frequently suggests a connection between entities where there is none.Of the skeleton, dysplasia (Greek δυς: “bad” and πλασσω: “I form”) represents a generalized affection of the skeleton. Dysostosis (Greek οστεον: “bone”) refers to involvement of a single bone or a group of physically or functionally related bones. Dysmorphism (Greek Mor-pheus, God of Sleep who may take any human “form” in dreams) is applied to a “bad form” of body part, often the facies (Latin) or “face” that can distinguish a speciﬁc disorder [C].ClassificationThese disorders have been given descriptive names according to clinical presentation, pathogenesis, or radiographic appearance. Achondropla-sia emphasizes cartilage as locus of disease, while osteogenesis imper-fecta distinguishes bone as the abnormal tissue. Other skeletal dysplasia may be grouped according to whether they affect the metaphysis or the epiphysis of a long bone. Identiﬁcation of genetic mutations has allowed molecular typing. For example, the type II collagenopathies span a spec-trum from the severe Kniest dysplasia to spondyloepiphysial dysplasia and Stickler disease to the relatively mild precocious osteoarthritis. Chal-lenges of molecular classiﬁcation include: • The molecular defects are numerous and evolving.• Clinically unrelated disorders may have the same molecular defect. Achondroplasia is caused by mutation of one type (3) of ﬁbroblast 238 Syndromes / General ConsiderationsDisproportionateProportionateshort trunkAsymmetry short limbA Short stature This may proportionate or disproportionate, or it may affect a region of the body asymmetrically.Rhizo-humerusfemurMeso-radius/ulnatibia/fibulaAcro-handfoot B Micromelia Shortening may affect the “root” or proximal segment, the “middle” segment, or the “tip” of the limb.C Facies Many syndromes may be distinguished by appearance of the face.Syndrome FaciesAchondroplasia Frontal bossing, depressed nasal bridgeApert Proptosis, downsloping palpebral fissuresCamptodactyly Flat faceCantu syndrome Full lips, long philtrumCornelia de Lange Synophrys, “carp” mouthde Barsy ProgeroidDown MongoloidEmanuel Low-hanging columellaFreeman-Sheldon Whistling faceHurler GargoyleLarsen Dish facePseudoachondroplasia Normal faceProteus Elephant manRubinstein-Taybi Squinting smileSilver-Russell Triangular faceDiab_Chap12.indd 238 9/23/2015 3:25:03 PM

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Syndromes / General Considerations 239growth factor receptor, while other types produce the craniosynosto-sis syndromes of Pfeiffer (1) and Crouzon (2).• Clinically related disorders may have different molecular defects. Mutations in the gene encoding type IX collagen and the gene encod-ing cartilage oligomeric matrix protein both have been found in mul-tiple epiphysial dysplasia.• The molecular defects are heterogeneous, obscuring the biologic pathways to disease. The highest expression of ﬁbroblast growth fac-tor receptor 3 is in the brain, yet it is the expression in cartilage during endochondral ossiﬁcation that is responsible for the clinical manifes-tations of achondroplasia.Despite these limitations, knowledge of molecular biology may aid understanding of the tissue distribution of disease. Type I collagen is the principal structural protein of bone, dentin, and sclera, hence the asso-ciation (and clinical subclassiﬁcation) of osteogenesis imperfecta with dentinogenesis imperfecta and blue sclerae. Type II collagen occurs in cartilage and vitreous humor. As a result, Stickler arthroophthalmopathy may include osteoarthritis and retinal detachment.EvaluationAssess clinical features, support with imaging, and verify with histologic analysis and laboratory studies if available.Stature After facial appearance, stature is most distinguishing. Stature may be short, normal, or tall. Short stature may be proportionate, such as in endocrinopathy, or disproportionate, such as skeletal dysplasias. Few syndromes feature tall stature, such as Marfan. Neuromuscular disorders do not affect stature signiﬁcantly.Family history Many syndromes are inheritable. They may be auto-somal or X-linked and dominant or recessive. Others represent new spontaneous mutations. Neuroﬁbromatosis type 1 is transmitted as an autosomal dominant to half affected children, while in the other half, the disorder arises spontaneously.Development Some syndromes are characterized by global delay, such as Prader-Willi syndrome. Others affect cognitive or motor function sepa-rately, such as muscular dystrophy. Developmental delay may be temporal or permanent; for example, in achondroplasia, motor development may be delayed in the ﬁrst 2 years, due to macrocephaly and ligamentous laxity.System Divide conditions into those that affect the musculoskeletal system and those that affect other systems and viscera [D]. Within the musculoskeletal system, conditions may be categorized geographically according to the part affected.Pathognomonic features From Greek παθος: “disease” and γιγνωσκω: “I know,” these may form the nidus around which other ﬁndings may be assembled. This approach represents a primary focus on the disease, in contrast with the system approach, which focuses on the manifestation [E].ImagingRÖNTGENOGRAMMES These form the basis of evaluation. They may describe a disease geographically. • Part of the skeleton, for example, spondylo- for spine• Part of a long bone, for example, epiphysial, metaphysial, and diaph-ysialRöntgenogrammes may describe the skeleton qualitatively. • Increased density, for example, osteopetrosis• Reduced density, for example, osteogenesis imperfecta• Mixed, for example, stippling of epiphysis in chondrodysplasia punctataRöntgenogrammes may reveal features that, while not always present in every patient, are pathognomonic [E].Radiographic features vary according to age. Many features that may aid diagnosis in childhood disappear by adulthood, such as epiphysial stippling. These features are considered dynamic, a manifestation of abnormal bone development.D Geographical distribution Syndromes may be distinguished and grouped by anatomic part affected.Part Abnormality SyndromeSpine Kyphosis— thoracolumbarAchondroplasia; metatropic dysplasia; mucopolysaccharidosesKyphosis— cervicalDiastrophic dysplasia; LarsenAtlantoaxial instabilityDown; Dyggve—Melchior—Causen; Kniest; mucopolysaccharidoses;spondyloepiphysial dysplasiaSacrococcygeal Carpenter; caudal regressionHip Coxa vara Type II collagenopathyFoot Club Arthrogryposis; Bruck; camptomelic dysplasia; caudal regression; diastrophic dysplasia; Escobar; Freeman—Sheldon; Larsen; Melnick—Needles; Möbius; nail—patellaPolydactylyCarpenter; chondrodysplasia punctata; chondro—ectodermal dysplasia; Grebe; Rubinstein—Ta ybiSyndactyly ApertLong bone Bowing Neurofibromatosis (tibia); multiple exostosis (forearm); mesomelic dysplasiaKnee Patella Meier—Gorlin; nail—patella; Rubinstein—Taybi; small patellaElbow Radial head dislocationBeals; Cornelia de Lange; nail—patella; mesomelic dysplasia; otopalatodigitalForearm Radial anomaly Goldenhar; Holt—Oram; TAR; VACTERLWrist Supernumerary fusionApert; chondro—ectodermal dysplasia; multiple synostosis; otopalatodigitalHand Polydactylychondro—ectodermal dysplasiaSyndactyly ApertSkin structure Bruck; chondrodysplasia punctata; Ehlers—Danlos; melorheostosis; multiple synostosis; pterygium; oculodentodigital dysplasia; proteus;pterygiumpigmentation McCune—Albright; neurofibromatosis; oculodentodigitalJoint Arthrogryposis; epiphysial dysplasiaMuscle Amyoplasia; PolandNerve cerebral palsy; Friedreich ataxia; Lesch—Nyhan; oculodentodigital dysplasia; SanfilippoBlood Ehelers—Danlos; Klippel—Trénaunay—Weber; Marfan; melorheostosisNailApert; chondro—ectodermal dysplasia; multiple synostosis; nail—patella; oculodentodigital; otopalatodigital; pycnodysostosisHair Metaphysial chondrodysplasia of McKusick; oculodentodigital dysplasia; trichorhinophalangealDiab_Chap12.indd 239 9/23/2015 3:25:03 PM

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240 Syndromes / General ConsiderationsULTRASONOGRAPHY This modality may establish a prenatal diagno-sis. The fundamental ﬁnding is short limbs for gestational age. A small thorax (including reduced thoracic:abdominal ratio) is a feature of lethal skeletal dysplasias. There may be clinical expression of osseous disease, for example, fractures in osteogenesis imperfecta. There may be delayed or absent ossiﬁcation, for example, of the clavicles in cleidocranial dys-plasia. There may be regional abnormalities, for example, clubfoot in diastrophic dysplasia.OTHER IMAGING MODALITIES These are employed according to spe-ciﬁc relevance to disease. In achondroplasia, foramen magnum stenosis may be measured on computed axial tomography. Published disease-spe-ciﬁc standards are available based upon such measurements. Critical stenosis of the vertebral canal due to spine deformity may be evaluated by magnetic resonance imaging.Laboratory analysis This most commonly is performed of blood, urine, and skin. Chromosome number, size, position, and staining pattern may be determined by karyotyping blood. Hormone serum levels, for exam-ple, growth hormone, thyroxine, and thyroid stimulating hormone, iden-tify endocrinopathy. The mucopolysaccharidoses are characterized by enzyme deﬁciency leading to reduction of product and accumulation of precursor that is detected by urine assay. The clinical diagnosis of Mar-fan syndrome may be conﬁrmed by immunohistochemical staining or pulse-chase analysis of ﬁbrillin-1 protein in cultured skin cells obtained from skin biopsy. Biochemical and molecular analysis of skin and blood for type I collagen mutation aids the diagnosis and typing of osteogene-sis imperfecta. Ehlers-Danlos VI may be conﬁrmed by insufﬁciency of hydroxylysine on analysis of hydrolyzed dermis, reduced lysyl hydroxy-lase activity in cultured skin ﬁbroblasts, and altered ratio of lysyl pyrid-inoline to hydroxylysyl pyridinoline in urine.AlgorithmThe following is a singular and simpliﬁed approach to turn the key and open the door to this multidisciplinary area into which may be drawn the orthopedic surgeon at times insecure and intimidated [F].E Pathognomonic features These may offer direction in a sea of complexity.Pathognomonic feature SyndromeCaudal reduction in interpedicular distanceAchondroplasiaChampagne pelvisElephant iliaCloverleaf skull Antley-BixlerMitten hand and foot ApertMacroglossia Beckwith-WiedemannAccordion femoraOsteogenesis imperfectaSaber tibiaeWormian bonesBlue sclerae Marshall-Smith, osteogenesis imperfectaCauliflower ears—calcification of pinnaeDiastrophic dysplasiaHitch-hiker thumb—bracchydactyly of first metacarpalCervical kyphosisIliac horns Nail-patellaPatella: a-/hypo-plasia Meier-Gorlin; nail-patellaAbsent or bifid claviclesCleidocranial dysostosisHot-cross bun skullDouble hump vertebrae Dygvve-Melchior-ClausenExostoses directed away from physis hereditary multiple exostosisExostoses directed toward physis metachondromatosisAccessory calcaneal apophysis Larsen syndromeLace-border iliac crests Dyggve-Melchior-ClausenMonophalangic hallux Fibrodysplasia ossificans progressivaWhistling face Freeman-SheldonAshkenazim Familial dysautonomia; Gaucher; Tay-SachsErlenmeyer flask femur Craniometaphysial dysplasia; GaucherSwiss cheese epiphysial degenerationKniest dysplasiaCafé-au-lait patches ‘Coast of Maine’: McCune-Albright‘Cost of California’: neurofibromatosisLisch nodule NeurofibromatosisCoccyx prolongation like a tail Metatropic dysplasiaSynostosis Antley-Bixler; Apert; femoral-facial syndrome; mesomelic dysplasia; multiple synostosisMadelung deformity Leri-Weill dyschondrosteosisSandwich vertebrae, rugger jerseyspine, endobones.Osteopetrosis (of Albers-Schönberg)Tree frog feet.otopalatodigitalSecondary ossification center at baseof second metacarpal and metatarsalSecond metacarpal pseudo-epiphysis Silver-RussellF A simple algorithm for initial navigation of a syndromic patient.SYNDROMEmusculoskeletalglobalregionalunder overother systemdisproportionateproportionateendocrinopathy skeletal dysplasiatrunk limbsmicrocormia micromeliarhizo- meso- acro-urgent electivecognitionneuralmuscularvisceralC1-C2 instabilitycanal compromiseDiab_Chap12.indd 240 9/23/2015 3:25:04 PM

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Syndromes / Apert Syndrome 241ACHONDROPLASIAMost common skeletal dysplasia, with incidence ~ 1:25,000 live births.Gain-of-function ﬁbroblast growth factor receptor 3 (FGFR3) mutation on chromosome 4p16.3 codon 380 glycine. Chondrocyte activation of FGFR3 increases bone formation and accelerates fusion of ossiﬁcation centers with premature synchondrosis closure, limiting endochondral bone growth.This may be transmitted as autosomal dominant with complete pen-etrance; however, most are new spontaneous mutations. A family of FGFR3 mutations is recognized ranging from mild (hypochondroplasia) to moderate (achondroplasia) to severe (thanatophoric dysplasia).Features do not become apparent on ultrasonogram until after 16 weeks.Abnormal endochondral with spared membranous ossiﬁcation pro-duces a large head with narrow foramen magnum, “champagne pelvis” with constricted triradiate cartilage [A], long clavicles with broad shoul-ders, long ﬁbulae with varus ankles and knees [B], and short pedicles with lumbar spinal stenosis [C]. Hypotonia in infancy, rhizomicromelia [D], frontal bossing with midface hypoplasia, trident hand [E], thoraco-lumbar kyphosis, joint contractures (including at the hips exaggerating lumbar lordosis), and “chevron” metaphysis.Decompression of brainstem for foramen magnum stenosis, based upon MRI compared with normative data, somatosensory evoked potentials, and polysomnography. Spine osteotomy and fusion for thoracolumbar kypho-sis. Due to pedicle hypoplasia, decompression for lumbar spinal stenosis must include articular process excision, requiring fusion and instrumenta-tion. Osteotomy for genua vara. Physiodesis of distal ﬁbula for ankle varus.Nonsurgical treatment includes weight control, management of frequent middle ear infections and dental crowding, adenotonsillectomy and nasal mask continuous positive airway pressure for obstructive sleep apnea.Pharmacotherapy includes growth hormone (although there is no con-sensus), and BMN-111, a stabilized version of C-type natriuretic peptide that inhibits the FGFR3 pathway.CDABEFuture strategies for treatment include the following: • Chemical inhibitors of FGFR3 tyrosine kinase• Antibodies to interfere with binding of FGF ligands to FGFR3• C-type natriuretic peptide antagonism of FGFR3 downstream sig-naling by inhibition of mitogen-activated protein kinase pathway in growth plate chondrocytes, thereby recovering bone growthACRODYSOSTOSISType 1 caused by heterozygous mutation in PRKAR1A gene on chromo-some 17q24, and type 2 by mutation in PDE4D gene on chromosome 5q12.Peripheral dysostosis (short tubular bones) of hands and feet. Reduced interpedicular distance producing spinal stenosis. Stippling of cone-shaped epiphysis resolves spontaneously in the ﬁrst few years of age.AMNIOTIC BAND SYNDROMEAlso known as Streeter anomaly.Herniation of members through ruptured amnion results in constric-tion, vascular occlusion, and necrosis. ADAM (amniotic deformity, adhe-sions, mutilations) complex includes associated terminal transverse defects and cleft lip and palate. LBWD (limb body wall defect) includes associ-ated body wall and visceral defects explained by pressure on the embryo during the ﬁrst 4 weeks.AMYOPLASIASee arthrogryposis.ANTLEY-BIXLER SYNDROMEMutation of cytochrome P450 oxidoreductase on 7q11.23.Trapezoidocephaly secondary to lambdoid and coronal synostosis, radiohumeral and radioulnar synostosis, and camptodactyly.Abnormal steroidogenesis and genitourinary and cardiac anomalies.Airway obstruction may lead to demise in the neonatal period.APERT SYNDROMEMutation in ﬁbroblast growth factor receptor 2 gene (FGFR2). By contrast with dominant mutations in the FGFR3 gene, which affect endochondral ossiﬁcation resulting in achondroplasia, dominant mutations of FGFR1 and FGFR2 cause the craniosynostosis syndromes of Apert, Crouzon, and Pfeiffer, which involve bones arising by membranous ossiﬁcation.Autosomal dominant; however, most de novo mutations.Wheaton ﬁrst reported two cases of what Apert called acrocephalosyndactyly. Acrocephaly is due to coronal synostosis [A]: early decompressive craniectomy may limit mental deﬁciency. Syndactyly and synonychia produce “mitten” hand [B] and “sock” foot [C]: the former is an indication for release, and the latter for osteotomy or ostectomy to relieve pres-sure. Failure of cer-vical segmentation, broad thumbs and halluces, and carpal and tarsal coalition. Cardiac, respiratory, nervous, abdominal, and genitourinary anomalies.ABCABCDiab_Chap12.indd 241 9/23/2015 3:25:11 PM

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242 Syndromes / Caffey Disease (Infantile Cortical Hyperostosis)ARTHROGRYPOSISOriginally termed arthrogryposis multiplex congenita. Arthrogryposis refers to a heterogeneous group of disorders of which the common feature is multiple congenital joint contractures. Fetal akinesia due to maternal disease, intrauterine constraint, or vascular com-promise retards development of nerves, muscles, or connective tissues. The ear-lier and longer the loss of movement, the more severe the deformities. Muscle is replaced by ﬁbrofatty tissue. Arthro-gryposis without other system disease is subclassiﬁed as amyoplasia. Distal arthro-gryposis, affecting hands and feet, is auto-somal dominant. Intelligence is normal. Limited joint motion, medial rotation of shoulders, extension of elbows, ﬂexion and ulnar deviation of wrists, camptodac-tyly, thumb in palm, hip dislocation, knee contracture, clubfoot, and scoliosis. Loss of cutaneous creases with joint dimpling. Operative reduction of dislocated hips is controversial. Femoral shortening facilitates treatment of ﬂexion contracture. Center the arc of motion at 15 degrees: walking is easier on straight knees. Talectomy may be necessary for clubfoot. Stiffness limits correction of scoliosis.BEALS SYNDROMEBECKWITH-WIEDEMANN SYNDROMEMutations in several imprinted genes within 11p15.5 region, as well as mutation of 5q35. The former also is affected in Silver-Russell syndrome, while the latter in Sotos syndrome.Autosomal dominant with variable expressivity, as well as de novo mutation.Overgrowth, including macroglossia, exophthalmos, limb hypertro-phy, and visceromegaly. Tumor diathesis, including Wilms tumor, hepa-toblastoma, neuroblastoma, and adrenal carcinoma. Posterior helical ear pits, abdominal wall defects including umbilical hernia, and renal anom-alies. Neonatal hypoglycemia and history of hydramnios and prematurity.BRACHYDACTYLYMultiple mutations identiﬁed for different types and subtypes. Classiﬁed into groups A to E, each of which are subclassiﬁed. First syndrome in humans in which Mendelian inheritance was described.Premature physial closure; variable short stature; short metacarpals, metatarsals, and phalanges; and variable shortening of humerus, radius, and ulna. Hypersegmenta-tion with an extra ossicle producing phalan-geal deviation distinguishes type C.BRACHYOLMIA (BRACHYRHACHIA)Named from Greek βραχυς: “short” and ολµος: “trunk,” whence the syn-onym brachyrhachia, from Greek ραχις: “spine”.BRUCK SYNDROMEDeﬁciency of bone-speciﬁc telopeptide lysyl hydroxylase, resulting in aberrant cross-linking of type I collagen. Lysine residues in the triple helix are normally hydroxylated. Enzyme normal in cartilage and ligament.Fractures and Wormian bones resemble osteogenesis imperfecta. Normal sclerae and teeth. Contractures resemble arthrogryposis, hence the appellation “osteogenesis imperfecta with joint contractures.” Ptery-gia, scoliosis, and clubfoot.CAFFEY DISEASE (INFANTILE CORTICAL HYPEROSTOSIS)Mutation of 17q21.31-q22, which encodes the α-1 chain of type 1 colla-gen; however, no features of osteogenesis imperfecta.Autosomal dominant as well as de novo mutation.Onset in the ﬁrst few months of life with spontaneous resolution by 2 years with minimal sequelae. Despite its name, it has been detected by ultrasonogram in utero (prenatal form) and in adulthood.Inﬂammatory presentation, including fever and hot, tender long bones [A] and mandibles [B], which show diaphysial periosteal deposition.This is distinct among hereditary disorders in being transient and leaving no residue.Type FeaturesIKnown as auriculo–osteodysplasia.Autosomal dominant.Short stature, auricular anomalies including elonga-tion of lobe with secondary posterior lobule, radioca-pitular dysplasia with head of radius dislocation, hip dysplasia.IIKnown as congenital contractural arachnodactyly.Mutation in fibrillin-2 gene at 5q23-q31.Marfan syndrome without visceral involvement and with crumpled ear helices as the hallmark, due to expression of fibrillin-2 in auricular cartilage.Type Features1Hobaek, Toledo.Autosomal recessive.Scoliosis, endplate irregularity, intervertebral narrowing, corneal opacities (Toledo), precocious calcification of costal cartilage.2Maroteaux.Autosomal recessive.Affects the spine less, and is associated with precocious calcifica-tion of the falx cerebri.3Autosomal dominant, caused by a gain of function mutation in the gene for transient receptor potential cation channel subfamily V member 4, a Ca2+ channel. Allelic with Charcot-Marie-Tooth and spinal muscular atrophy, distal subtype.Kyphoscoliosis and flattened, irregular cervical vertebrae.4Autosomal recessive, caused by mutation in gene encod-ing enzyme bifunctional 3’-phosphoadenosine 5’-phosphosulfate synthetase 2. The enzyme synthesizes 3’-phosphoadenosine 5’-phosphosulfate from ATP and inorganic sulfate, providing the source for cellular sulfation.Type Mutation1 Mutation of FKBP10 gene on 17q21.2 Mutation of PLOD2 gene on 3q23-q24.ABDiab_Chap12.indd 242 9/23/2015 3:25:15 PM

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Syndromes / de Barsy Syndrome 243CLEIDOCRANIAL DYSPLASIAAutosomal dominant loss-of-function mutation in runt-related transcrip-tion factor 2 gene (RUNX2) on 6p21.1.Head has been likened to a “hot cross bun” due to per-sistent open sutures. The head also is known as “Arnold” head, after a Muslim Chinese progenitor from South Africa with >1,000 descendants.Midline defects, including hypoplastic or aplastic clavicles with hypermobile shoulders, short middle phalanges, coxa vara, symphysis pubis diastasis, scoliosis, and spondylolisthesis. Dental anomalies.Formerly called “dysostosis” to emphasize the regional nature of anomalies of the head and shoulder.CORNELIA DE LANGE SYNDROMEAutosomal dominant as well as de novo mutation in Nipped B-like (NIPBL) gene on 5p13.1, which encodes a component of cohesin, a protein complex that coheres sister chromatids during cell division. Characteristic facies, including synophrys, crescentic, or “carp” mouth, long philtrum, anteverted nares, and ptosis.Mental and growth retardation, “growl-ing” cry, hirsutism, and ocular, cardiac, gen-itourinary, gastrointestinal, and pulmonary anomalies. Self-injurious and autistic behav-ior. Micromelia disproportionately affecting the upper limb, including ulnar dysgenesis, radial head dislocation, oligodactyly, proxi-mally placed thumb, clinodactyly of smallest ﬁnger, and single palmar ﬂexion crease.de Lange was Professor of Pædiatrics at the University of Amsterdam, where she was followed by van Creveld. The disorder was described 17 years earlier (1916) by Brachmann, whose studies were interrupted by a call to the German Army.CRANIODIAPHYSIAL DYSPLASIAMutation in the SOST gene on 17q12-q21.Hyperostosis of skull encroaches on foramina and osseous canals leading to cranial nerve palsy and hearing loss, of face results in “leonine facies,” and of the skeleton bones produces diaphysial sclerosis and med-ullary stenosis, in particular of ribs, clavicles, and sternum.CRANIOMETAPHYSIAL DYSPLASIAAutosomal dominant form caused by mutation in the human homolog of mouse progressive ankylosis gene on 5p15.2-p14.1. Additional autoso-mal recessive form mapped to chromosome 6q21-22.Skull and facial manifestations similar though less severe than above. Metaphysial rather than diaphysial involvement is distinguished by “Erlenmeyer ﬂask” deformity in long bones.de BARSY SYNDROMEThis is one of the progeroid syndromes, which are distinguished by cutis laxa with subcutaneous paucity of fat and prominence of veins, together with “pseudohydrocephalic” head, producing an “old appearance,” from Greek γερων: “old man.”This type most affects the skeleton: multiple joint dislocations and subluxations, in particular of the hip, scoliosis, and vertical talus.Other features include corneal clouding, short stature, and mental retardation.CAMP(T)OMELIC DYSPLASIAGreek καµπη: “bending, ﬂexion, and twisting” and µελοσ: “limb,” to describe the characteristic feature of long bone bowing, especially of the tibiae, clubfoot, and hip dislocation.17q24 mutation with haploinsufﬁciency of SOX 9.Cutaneous dimpling at apex of bowing. Cleft palate, micrognathia, ﬂat face, and pterygium colli. Thoracic dysplasia, including tracheobron-chial hypoplasia, bladeless scapulae, slender or absent ribs, reduced cage volume, and sternal mineralization. Congenital heart and kidney disease. Death is frequent in infancy due to respiratory insufﬁciency.Gonadal dysgenesis may culminate in sex reversal of affected XY cases.CARPENTER SYNDROMEAutosomal recessive mutation in Ras-associated protein RAB23 gene on 6p11.Also called acrocephalopolysyndactyly. Craniosynostosis produces a “pointed head.” Brachysyndactyly of the hands and preaxial polysyndac-tyly of the feet. Correction of genu valgum to stabilize patellae. Pilonidal dimple with absent coccyx.Variable mental retardation, short stature, obesity, and eye, ear, car-diovascular, and genitourinary anomalies.CHONDRODYSPLASIA PUNCTATA (CONRADI-HÜNERMANN)Dominant mutation in the gene encoding delta(8)-delta(7) sterol isomerase emopamil-binding protein on Xp11.23-p11.22, an enzyme essential to cholesterol biosynthesis. Rhizomicromelic dwarﬁsm characterized by asymmetry of involvement and by calciﬁc stippling of tra-chea, thorax, spine, pelvis, coracoid process, and glenoidal cavity. The latter typically resolves after ﬁrst year of life. Kyphoscolio-sis and clubfoot. Cutaneous disease, includ-ing striated ichthyosiform hyperkeratosis, whorled pigmentation, cicatricial alopecia, and “orange-peel” skin. Ocular anomalies, including cataracts, nystagmus, and glau-coma. Warfarin teratogenicity, by inhibition of synthesis of gamma-car-boxyglutamic acid, which is involved in both clotting and calciﬁcation, may lead to chondrodysplasia punctata.CHONDROECTODERMAL DYSPLASIA (ELLIS-VAN CREVELD)Mutation in Ellis-van Creveld gene on 4p16. Micromelic dwarﬁsm characterized by postaxial polydactyly, capitate–hamate fusion, genua valga, clubfoot, nail dystro-phy, and rib hypoplasia with narrow chest. Upper lip anomaly described as “lip-tie” [A] and tooth eruption at birth described as “natal teeth.” Cardiac and male genitourinary anomalies and variable mental retardation. Largest pedigree in the Old Order Amish of Lancaster County, Pennsylvania, whose members were described as hav-ing “six-ﬁngered dwarﬁsm.” On the way to a pædiatric conference in England (1938), the Scott Ellis met the Dutchman van Creveld while sitting in the same compartment of a train, where they discussed a case they each had seen independently.Diab_Chap12.indd 243 9/23/2015 3:25:17 PM

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244 Syndromes / Ehlers-Danlos SyndromesDIASTROPHIC DYSPLASIAMutation in the solute carrier family 26 (sulfate transporter), member 2, gene (SLC26A2) on 5q32-q33.1. Allelic to epiphysial dysplasia, multi-ple. Greek δια-, an emphatic preﬁx, and στρεφω, “I twist,” describe the “severely twisted” clubfeet and spine. The latter includes thoracolumbar kyphoscoliosis and cervical kyphosis [A]. Short ﬁrst metacarpal produc-ing “hitchhiker thumb” [B] and calciﬁcation of pinnae producing “cauli-ﬂower ear.” The former permits diagnosis on ultrasonogram at 16 months in utero. Multiple joint contractures and malformations, in particular of the hips, which show ﬂattening and a “double-hump” deformation.Other features include cleft palate, collapse of the tracheobronchial tree, and restrictive pulmonary disease.DOWN SYNDROME (TRISOMY 21)Genomic dosage imbalance at 21q22.3 producing phenotypic variabil-ity. Diagnosis by Quad test (serum α-fetoprotein, estriol, β-HCG, and inhibin A) in second trimester of pregnancy: a positive test is followed by amniocentesis.Risk increases with maternal age: 9-fold from 30 years to 40 years. Incidence is 1:1,000.“Mongoloid” facies; simian (Latin simia: “ape”) crease (single trans-verse palmar); hypotonia; ligamentous laxity; instability of C1-C2 [A], hips [B], and patella; ﬂat feet; and scoliosis.Screen for C1-C2 instability in symptomatic patient, including local signs, such as torticollis and neck stiffness, and global signs, such as myelopathy. Asymptomatic or general screening is contraindicated: • Symptoms and signs precede neural injury.• Radiographic instability may alternate with stability without clinical correlation.• Atlantoaxial fusion has a high complication rate.Cognitive impairment; hearing loss, usually conductive; hypothyroid-ism; and congenital malformation of heart, in particular atrioventricular septal defect; gut, such as duodenal atresia; blood, in particular leukemia; and brain, including senile plaques and neuroﬁbrillary tangles leading to premature Alzheimer disease.The disorder was ﬁrst described by John Langdon Haydon Down of London, whose Observations on an Ethnic Classiﬁcation of Idiots (1866) included a description of the “Mongoloid” type. While this study has been condemned as racist, the ﬁnal sentence suggests no such intention, as Down regarded the “degeneracy” across racial barriers “to furnish some arguments in favour of the unity of the human species.”Down also ﬁrst described a mentally delayed obese girl whose hands and feet remained small as a hypogonadal adult, seven decades before the report of Prader, Labhart, and Willi.DYGGVE-MELCHIOR-CLAUSEN SYNDROMEMutation in dymeclin gene at 18q21.1.Dymeclin is necessary for correct organization of Golgi apparatus. Allelic with Smith-McCort dysplasia. Psychomotor retardation, hip insta-bility with waddling gait, odontoid hypoplasia with C1-C2 instability, platyspondyly, vertebral anterior beaking and kyphoscoliosis, hypo-plasia of scapula and glenoid cavity, epiphysial/apophysial irregularity manifesting as “lace-border” iliac crests, widening of sacroiliac joints and symphysis pubis, and camptodactyly.DYSPLASIA EPIPHYSIALIS HEMIMELICAAlso known as Trevor disease. Non- Mendelian and nonfamilial. Boys more than thrice girls. Osteocartilaginous tumors arising from epiphysis, often lower limb, multilevel, and ipsilateral. Lesions cause pain, swelling, and deformity, starting during infancy or early childhood. Radiolucency of lesions delays diagnosis. Manage by excision and osteotomy for deformity correction. Recurrence is common, necessitating repeat operation(s).EHLERS-DANLOS SYNDROMESA group of hereditable disorders characterized by: • Skin hyperextensibility. Acrogeria. Collagen ﬁbers seen on electron microscopy of skin have been likened to hieroglyphics.• Articular hypermobility. Instability of hip, patella, elbow, and shoulder.• Tissue fragility. Prematurity in 50% due to premature rupture of fetal membranes. Vascular and visceral rupture. Bruisable skin that heals with “cigarette paper” scars. Hernia and pneumothorax.• Skeletal deformity. Kyphoscoliosis, spondylolisthesis, atlantoaxial rotatory displacement, ﬂatfoot, and pectus deformity. Tendency to recurrent deformity after correction.The disorder may be classiﬁed into 10 subtypes, but V, VIII, and X may not be distinct entities. The subtypes have distinguishing features, with variable overlap. Most have autosomal dominant transmission.Type MutationIType V collagen α-1 chain on 9q34.3. Type V collagen α-2 chain on 2q32.2. Type I collagen α-1 chain on 17q21.33. IIType V collagen α-1 chain on 9q34.3. IIITenascin-XB on 6p21.3.Type III collagen α-1 chain on 2q32.2. IVType III collagen α-1 chain on 2q32.2. VAbnormal collagen cross-linking due to deficiency of lysyl hydroxylase.VI Lysyl hydroxylase on 1p36.22. VII Type I procollagen N-proteinase on 5q35.3.VIII 12p13.IXCu(2+)-transporting ATPase, alpha polypeptide on Xq21.1. Allelic to Menkes syndrome.X Fibronectin.ABABDiab_Chap12.indd 244 9/23/2015 3:25:20 PM

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Syndromes / Fibrodysplasia Ossificans Progressiva 245EMANUEL SYNDROMEMalsegregation of the t(11;22)(q23;q11.2) translocation, a rare example in humans of reciprocal (non-Robertsonian) exchange of genetic material between chromosomes.Kyphosis and scoliosis and hip dislocation.Ear: preauricular tag and sinus, low set, hearing loss, and otitis media.Eyes: hooded eyelids, strabismus, and myopia.Psychomotor delay; seizures; cardiovascular anomalies, including aortic and pulmonary stenosis and septal defects; and genitourinary anomalies, including absent kidney and cryptorchidism.EPIPHYSIAL DYSPLASIA, MULTIPLEGenetic heterogeneity manifested by six types, designated EDM1-6.Type Features1Mutation in the gene for cartilage oligomeric matrix protein on 19p13.11. Includes milder form (Ribbing) and more severe form (Fairbank). Allelic to pseudoachondroplasia.Diagnosis aided by reduced serum levels of cartilage oligomeric matrix protein2Mutation in gene encoding type 9 collagen α-2 chain on 1p33-p32.2, which also has been implicated in susceptibility to inter-vertebral disc disease with sciatica.3Mutation in gene encoding type 9 collagen α-3 chain on 20q13.33.Myopathy may distinguish this type.4Mutation in the solute carrier family 26 (sulfate transporter), member 2 gene (SLC26A2) on 5q32-q33.1. Allelic to diastrophic dysplasia, atelosteogenesis II, achondrogenesis IB. Distinguished by clubfoot and double-layered patella (red arrows).5Mutation in matrilin-3 gene on 2p24.1.Allelic to one form of spondylo-epimetaphysial dysplasia.6Mutation in gene encoding type 9 collagen α-1 chain on 6q13.Normal to moderate short stature. Delayed and irregular epiphysial formation leads to long bone deformity, in particular coxa vara, genua vara or valga, and brachydac-tyly as well as premature osteoarthritis.Multiple epiphysial involvement distin-guishes this disorder from Legg-Calvé-Perthes disease. Sparing of the spine distinguishes it from spondyloepiphysial dysplasia.ESCOBAR SYNDROMESee pterygium syndrome.FAMILIAL DYSAUTONOMIAAlso known as Riley-Day syndrome, congenital insensitivity to pain, and hereditary sensory and autonomic neuropathy type III.Mutations in the inhibitor of kappa light polypeptide gene enhancer in B cells, kinase complex-associated protein (IKBKAP) gene on 9q31.3.Diminished pain and temperature perception leads to self-inﬂicted inju-ries. Vasomotor instability often triggered by stress, hyperhidrosis, alac-rima, cutaneous blotching, and absence of fungiform papillae on tongue. Lack of axon ﬂare after intradermal injection of histamine. Gastrointestinal and renal dysfunction. Increased prevalence in Ashkenazi Jewish descent.Orthopedic problems include fracture, autoamputation, osteomyeli-tis, septic arthritis, neuropathic arthropathy, vibratory loss, areﬂexia, and scoliosis.Emotional lability and absence of pain dictate conservative management.FANCONI ANÆMIAGenetically heterogeneous with 15 complementation groups. Common feature is abnormal DNA breakage, cross-linking, and repair.Myelophthisis with pancytopenia requires bone marrow transplant.Short stature. Radial defects, including hypoplastic/absent/biﬁd thumb as well as absent radius, require reconstruction.Genitourinary anomalies, including hypoplastic/absent/horseshoe/ectopic kidney, hypogonadism, cardiac septal defects, hyperpigmentation with café au lait spots, and malignant diathesis.FEMORAL–FACIAL SYNDROMEFacies characterized by long philtrum, thin upper lip, hypoplastic alae nasi, and microretrognathia.Femoral hypoplasia/aplasia with acetabular dysplasia. Radioulnar and radiohumeral synostosis. Congenital scoliosis. Sacral dysplasia may resemble caudal regression syndrome. Feet with preaxial polysyndactyly and clubfoot. Sprengel anomaly.Cardiac and genitourinary anomalies.One-third of patients have a prenatal history of maternal diabetes.FIBRODYSPLASIA OSSIFICANS PROGRESSIVADistinguish myositis ossiﬁcans, a general term for heterotopic ossiﬁca-tion that may be subclassiﬁed as traumatica when it follows injury and is not hereditable.Mutation in activin A receptor type I gene on 2q24.1 results in abnor-mal signal transduction in response to bone morphoge-netic protein type I.Episodic and unpredict-able heterotopic ossiﬁcation of striated muscle, in craniocau-dad, axial to appendicular, and proximal to distal directions.Only signs at birth are halluceal deformation and monophalangism. Clinodac-tyly, digital reduction defects, vertebral fusion, hearing loss, and alopecia.Pain and ankylosis, which may be exacerbated by trauma (both acci-dental and iatrogenic).Mean age of onset 5 years; conﬁnement to wheelchair by third decade.Restrictive pulmonary disease may lead to respiratory failure.Eighty percent of patients receive an incorrect initial diagnosis. Diag-nosis is clinical: while lesions may be confused with malignancy, avoid biopsy as it exacerbates condition.Type FeaturesI Classic gravis: “severe”.IIClassic mitis: “mild”. Mildness may delay or preclude diagnosis.III Hypermobility without skeletal deformity.IVVascular. Autosomal dominant or recessive. Spontaneous rupture of major vessels and viscera. Aneurysm, fistula.V X-linked.VIOcular-scoliotic. Kyphoscoliosis from infancy. Retinal detachment, scleral fragility, rupture of ocular globe.VIIDermatosparaxis (“skin tearing”) due to abnormal type I collagen in skin. Autosomal recessive.VIIIPeri-odontitis: gingival recession, premature loss of teeth, resorption of alveolar bone.IXSkull. Occipital horns adjacent foramen magnum directed caudad. Wormian bones. Coarse hair.XStriae distensae. Petechiae due to defect in platelet aggregation.Diab_Chap12.indd 245 9/23/2015 3:25:22 PM

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246 Syndromes / HæmophiliaFREEMAN-SHELDON SYNDROMEAlso known as whistling face–windmill vane hand syndrome and cranio-carpotarsal dystrophy.Mutation in embryonic skeletal muscle myosin heavy chain 3 gene on 17p13.1.A type of distal arthrogryposis.Small mouth with pursed lips resembles whistling. Camptodactyly with ulnar deviation has been likened to a windmill vanes. Kyphoscolio-sis. Contractures of hips (without or with dislocation), knees, and shoul-ders. Clubfoot and vertical talus.Myopathy and seizure. Malignant hyperthermia may impact operation.FRIEDREICH ATAXIAMutation in frataxin gene on 9q21.11. Second locus on 9p reﬂects genetic heterogeneity. Frataxin is involved in mitochondrial iron homeostasis.Autosomal recessive. Most common inherited ataxia.Ataxia, absent deep tendon reﬂexes, impaired proprioception and vibra-tory sense, dysarthria, extensor plantar response (Babinski), and nystagmus.Pes cavus and scoliosis.Preadolescent onset; conﬁnement to wheelchair by fourth decade.Hypertrophic cardiomyopathy: death most frequently from heart failure.GAUCHER DISEASEMutation in gene encoding acid β-glucosidase on 1q22.Autosomal recessive lysosomal storage disease cerebroside lipidosis.Cells of mononuclear phagocyte origin (such as macrophages) laden with glucosylceramide (glucosylcerebroside), known as Gaucher cells, accumulate in bone marrow, spleen, liver, lung, ocular limbus, and skin, leading to pancytopenia, hepatosplenomegaly, interstitial restrictive lung disease, pingueculae, and cutaneous pigmentation.Continuum and wide spectrum of severity: perinatal lethal to asymptomatic adult.Osteolysis, bone crises, and pathologic fractures. Widening of distal metaphysis of femur likened to “Erlenmeyer ﬂask” (orange). Osteone-crosis of head of femur managed by hip arthroplasty.Partial splenectomy for thrombocytopenia, to balance risk of sepsis.Multifaceted treatment includes enzyme replacement, chemical chap-erone, substrate reduction, and bone marrow transplantation.Increased prevalence in Ashkenazi Jewish descent.GOLDENHAR SYNDROMELinked to 14q32.Also known as oculoauriculovertebral dysplasia and hemifacial mic-rosomia.Anomalies of ﬁrst and second branchial arch derivatives.Facial reconstruction for asymmetric eye and ear anomalies.Spine fusion for congenital scoliosis. Reconstruction for radial ray anomalies, which are ipsilateral to facial anomalies.Congenital heart disease, including tetralogy of Fallot and coarctation of aorta. Central nervous system lesions, including hydrocephalus and cerebellar hypoplasia. Genitourinary anomalies, including multicystic or ectopic kidney.Type Features1 Non-neuropathic.2Neuropathic—acute.Perinatal or infantile lethal.3Neuropathic—chronic.Later onset, slower progression.GUILLAIN-BARRÉ SYNDROMEFamilial type caused by mutation in the peripheral myelin protein 22 gene on 17p12. Allelic with Charcot-Marie-Tooth disease type 1.Acute demyelinating polyneuropathy resulting from aberrant immune mechanism suggested by preceding upper respiratory infection or Cam-pylobacter jejuni enteritis.Ascending symmetric ﬂaccid paralysis, proximal muscles more affected, ophthalmoplegia, and dysphagia. Variable sensory involve-ment, including loss of proprioception, and autonomic dysfunction, such as arrhythmia.Involvement of respiratory muscles may necessitate ventilator support.Cerebrospinal ﬂuid analysis shows albuminocytologic dissociation: elevated protein without elevated cell count, in contrast with infection.Treat with plasmapheresis or immunoglobulin per venam.HAND–FOOT–GENITAL SYNDROMEMutation in the homeobox A13 gene on 7p15.2.Genitourinary anomalies, including double uterus and biﬁd scrotum.Short ﬁrst metacarpal and metatarsal result in proximal location of hypoplastic thumbs and halluces. Smallest ﬁnger clinodactyly–brachy-dactyly. Carpal and tarsal fusions.HÆMOPHILIALaboratory tests show normal platelet count and prothrombin time (PT), but a prolonged activated partial thromboplastin time (aPTT).Hemorrhage into joints and muscles, in contrast with bleeding disor-ders due to platelet defects or von Willebrand disease, in which mucosal bleeding predominates.Hemarthrosis begins after walking and is characterized by swelling, pain, stiffness, and inﬂammatory arthritis. Muscle hemorrhage causes necrosis, contractures, and neuropathy by entrapment.Chronic synovitis unresponsive to factor replacement is associated with HLA-B27 allele, which prevents downregulation of inﬂammatory mediators after hemarthrosis.Orthopedic management includes synovectomy, arthroplasty, and radial head resection.Medical treatment consists of factor VIII infusion. Add gamma glob-ulin and cyclophosphamide to induce tolerance in 10% of patients who develop antibodies to factor VIII.Heterozygous female carriers have 50% factor levels, reducing coag-ulability without clinical signs. Mortality is reduced 20% due to reduc-tion in ischemic heart disease.Hæmophilia affected the Romanov imperial dynasty of Russia and Queen Victoria of England, who was a carrier.Type FeaturesAMutation in gene encoding coagulation factor VIII on Xq28.Recessive affects boys.Mild (40% of cases): 6–30% factor level, hæmorrhage after trauma.Moderate (10%): 1–5%.Severe (50%): <1%, at least monthly spontaneous hæmorrhage.1:10000BChristmas diseaseMutation in gene encoding coagulation factor XI on Xq27.1. Recessive.1:30,000Named after patient Stephen Christmas (1947–1993).B(M): inhibition of factor VII by abnormal factor IX pro-longs PT.B Leyden: factor IX increases after puberty to eliminatehæmorrhagic diathesis.Diab_Chap12.indd 246 9/23/2015 3:25:23 PM

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Syndromes / Lesch-Nyhan Syndrome 247HOLT-ORAM SYNDROMEAutosomal dominant mutation in T-box 5 gene on chromosome 12q24.21. T-box 5 is a transcription factor involved in heart development and limb identity.Also known by the descriptive appellations heart–hand syndrome and atriodigital dysplasia.Congenital cardiac defects, includ-ing atrial septal defect and hypoplastic left heart.Preaxial upper limb anomalies, including absent, biﬁd, or triphalangeal ﬁngerlike thumb (arrow), proximal and distal thumb metacarpal epiphysis, radial club hand and hypoplasia, radi-oulnar synostosis, and carpal abnor-mality.Anomalies of shoulder girdle and thorax. Asymmetric involvement of upper limbs, left greater than right, consistent with cardiac link.HOMOCYSTINURIAAutosomal recessive mutation in gene encoding cystathionine β-synthase on chromosome 21q22.3. Cystathionine β-synthase converts homocys-tine to cystathionine. Elevated homocystine and by-product methionine, diagnosed in urine.Developmental delay, seizures, and ocular anomalies in particular ectopia lentis within the ﬁrst decade, which requires operative treatment.Thromboembolism is the major cause of morbidity and early death. Prophylactic anticoagulation for high-risk periods such as pregnancy.Osteoporosis by second decade manifested by “codﬁsh” vertebrae on lumbar röntgenogramme. Kyphoscoliosis and dolichostenomelia, but limited joint mobility, which distinguishes this disorder from Marfan syndrome.Treat with dietary restriction of protein, betaine therapy, and pyridox-ine (B6). Responsiveness to pyridoxine distinguishes a milder phenotype from the more severe nonresponsive phenotype.KLIPPEL-FEIL SYNDROMESee Spine chapter.KLIPPEL-TRÉNAUNAY-WEBER SYNDROMEMutation of 8q22.3, or gain-of-function translocation of 8q22;14q13, possibly involving gain of function of the gene encoding the angiogenic factor VG5Q.Also known as angioosteohypertro-phy syndrome.Klippel-Trénaunay syndrome refers to cutaneous hæmangiomata, slow-ﬂow venous and lymphatic malformations, and limb hypertrophy (white). When arteriovenous ﬁstulae are present, the cutaneous manifestations are more dif-fuse and more pink, and the name of Weber is appended.Visceral dysfunction due to vascular malformations, such as thrombocytope-nia, pulmonary embolus, high-output cardiac insufﬁciency, and seizure.Length equalization by physiodesis of affected limb may be neces-sary. Synovial vascular hypertrophy may elicit pain and beneﬁt from arthroscopic débridement. Surgical debulking is controversial.Compression stockings reduce blood and lymph pooling and thereby pain, swelling, and ulceration. Sclerotherapy thickens and ultimately blocks abnormal vascular channels.KNIEST DYSPLASIAMutation of a-1 chain of type II collagen on 12q13.11.Severe type II collagenopathy.Phenotype reﬂects distri-bution of type II collagen in cartilage and vitreous humor.Disproportionate short stat-ure, kyphoscoliosis, hypoplasia/aplasia of dens axis producing atlantoaxial instability, “dumbbell” long bones with splayed metaphysis/epiphysis, “Swiss cheese” epiphysial degeneration, coxa vara, joint narrowing, and contractures.Myopia, retinal detachment, cataracts, and lens dislocation.LARSEN SYNDROMEAutosomal dominant mutation of ﬁlamin B gene on 3p14.3. Filamin B cross-links protein actin to regulate communication between cell mem-brane and cytoskeletal network. This is allelic with atelosteogenesis type I.Autosomal recessive mutation in β-1,3-glucuronyltransferase 3 gene on 11q12.3. The enzyme catalyzes glycosaminoglycan–protein linkage in proteoglycans.Cluster island of La Reunion (Indian Ocean off east coast of Africa).1:1,500 compared with 1:100,000 in Western countries.Dislocations of large joints, in particular hip, knee, and elbow.Accessory calcaneal (green) and carpal ossiﬁcation centers, equinovarus and equinovalgus, “spatula” ﬁngers, brachydactyly, congenital scoliosis, and cervical kyphosis.“Dish” facies due to prominent forehead with ﬂat midportion.Stabilize spine, reconstruct dislocations, and correct foot deformity.LÉRI-WEILL DYSCHONDROSTEOSISPseudo–autosomal dominant mutation in the short stature homeobox gene on Xp22.33 and Yp11.32, or deletion of the SHOX downstream regulator. Allelic with Langer mesomelic dysplasia, of which the phenotype is more severe.Mesomicromelia with bowing and Madelung deformity. Madelung deformity represents a growth distur-bance of the volar ulnar part of the dis-tal physis of radius, which results in volar translation of wrist and hand and dorsal displacement of the normally growing distal ulna. It is characterized by lucency (orange) at the locus of growth disturbance, triangular dis-tortion of the distal epiphysis (green), and pyramidalization (red) of the wrist as it falls into the defect.Girls more severely affected than boys.LESCH-NYHAN SYNDROMEX-linked recessive mutation in hypoxanthine guanine phosphoribosyl-transferase gene on Xq26.2-q26.3. The enzyme salvages purines from degraded DNA to reintroduce into purine synthetic pathways. While complete or severe (<1% activity) deﬁciency is the feature of Lesch-Ny-han syndrome, mild deﬁciency causes hyperuricemia and gout.Hyperuricemia and hyperuricosuria causing nephrolithiasis.Neural signs predominate: psychomotor delay, choreiform move-ments, athetosis and spasticity, dysarthria, and dysphagia.Short stature, hip dysplasia, scoliosis, fractures, self-mutilation and digital autoamputations, and infections.Diab_Chap12.indd 247 9/23/2015 3:25:24 PM

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248 Syndromes / Marfan SyndromeMAFUCCI SYNDROMESee Ollier disease.MARFAN SYNDROMEMutation of ﬁbrillin-1 gene on 15q21.1.Fibrillin-1 is the major constitutive element of extracellular microﬁ-brils, distributed in elastic and nonelastic connective tissue. The microﬁ-brils store in an inactivated form transforming growth factor-β (TGF-β); abnormal microﬁbrillar architecture results in increased release and thereby activation of TGF-β for cellular proliferation, differentiation, motility, and apoptosis. Thus, the effect of ﬁbrillin-1 mutation is both primarily structural and secondary to hyperactivity of TGF-β.Fibrillin-1 provides force-bearing structural support, its synthesis cor-relating with late morphogenesis and appearance of well-deﬁned organ structures. Synthesis of ﬁbrillin-2, of which mutation causes congenital contractural arachnodactyly (of Beals q.v.), coincides with early mor-phogenesis and the beginning of elastogenesis, during which it regulates elastic ﬁber assembly. Fibrillin is distributed in the periosteum, aortic media, and suspensory ligament of the lens, hence the three principal systems affected.Puberty onset 2 years premature.Trisomy 8, of which most cases are mosaic hence mildness of presen-tation, resembles skeletal features of Marfan syndrome.Cardiovascular disease accounts for mortality. Treatment is phar-macologic, including β-adrenergic blockade and angiotensin II receptor antagonists, and surgical, such as aortic valve and root graft.Orthopedic care is focused upon deformity of the spine (q.v.). Triradi-ate physiodesis has been advocated for protrusio acetabuli.The condition ﬁrst was described by Giovanni Morgagni (1682–1771), at autopsy of a prostitute distinguished by her tall stature and long, grac-ile limbs (in particular the ﬁngers), who died in coitu of aortic dissection.Tissue FeaturesSkeletaldisproportionate tall stature upper:lower segment < 0.85 arm span:height > 1.05 mean adult male height 190 cm mean adult female height 175 cmdolichocephalymicro-/retro-gnathiapectus: carinatum, excavatum, asymmetrydural ectasiascoliosis + kyphosisspondylolisthesisprotrusio acetabulidolichostenomeliaarachnodactylyarticular hypermobility or contracturepes planusCardiacaortic root dilatation: regurgitation + dissectionaortic aneurysmpulmonary artery dilatationOcularectopia lentismyopiaretinal detachmentcataractOtherhigh arched palatedental crowdingpneumothoraxstriae distensaeabdominal herniaAntoine Marfan (1858–1942) described the condition in a 5-year-girl as dolichostenomelia, from Greek δολιχος: “long,” στενοσ: “thin,” and µελοσ: “limb.” Niccolò Paganini (1782–1840), whose death was attributed to internal hemorrhage, is believed to have been affected by Marfan syndrome, including the arachnodactyly and articular hypermo-bility that aided his virtuosity at violin. Abraham Lincoln (1809–1865) probably had multiple endocrine neoplasia type 2B, which mimics the skeletal features of Marfan syndrome.Diagnosis is based upon family history and a systemic score.Family history No family historyAortic root dilatationEctopia lentissystemic score ≥ 7Aortic root dilatation AND  fibrillin-1 mutation ectopia lentis systemic score ≥ 7Systemic scoreWrist and thumb sign3Dural ectasia2Protrusio acetabuli 2Pes planus 2Pectus carinatum 2Pectus excavatum, asymmetry 1Scoliosis or kyphosis1Elbow contracture 1Craniofacial dysmorphia 1Myopia 1Mitral valve prolapse 1Striae distensae 1Arachnodactyly Thumb sign is defined as thumb interphalangeal joint reaching ulnar border of hand (green). Wrist sign is defined as ringing of the wrist by thumb reaching distal interphalangeal joint of smallest finger.Disproportionate tall stature.Diab_Chap12.indd 248 9/23/2015 3:25:27 PM

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Syndromes / Metaphysial Chondrodysplasia 249MARSHALL-SMITH SYNDROMEMutation in nuclear factor 1 X–type gene on 19p13.3.Accelerated or disharmonic skeletal maturation. Osseous fragility may result in “nontraumatic” fractures and secondary deformity. Absence of osteopenia suggests a qualitative rather than a quantitative defect in bone. Orthopedic management includes bisphosphonates and fracture sta-bilization.Characteristic facies includes promi-nent forehead, micrognathia, exophthal-mos, and blue sclerae.Osseous fragility and blue sclerae resemble osteogenesis imperfecta.Psychomotor delay and failure to thrive.Respiratory compromise accounts for the majority of mortality.MCCUNE-ALBRIGHT SYNDROMEGain-of-function or constitutively activating postzygotic somatic cell mutation of guanine nucleotide–binding pro-tein α-stimulating activity polypeptide 1 gene (GNAS1) on 20q13.32.Clinical triad: • Polyostotic ﬁbrous dysplasia of long and craniofacial bones• Café au lait cutaneous patches with irregu-lar or “coast of Maine” borders• Precocious pubertyDeformity, such as Shepherd crook femur, and morbid fracture produced by ﬁbrous dysplasia require orthopedic intervention, including bis-phosphonate and operation.Craniofacial hyperostosis may produce deafness and blindness due to neural foraminal compression.Cutaneous patches are asymmetric and often end abruptly at the body midline. They may be distinguished from those of neuroﬁbromatosis, which have smooth or “coast of California” borders, are smaller, and include axillary freckling.Signs of puberty, such as vaginal bleeding and spermatogenesis, may be seen in the ﬁrst half of the ﬁrst decade.Endocrinopathy is variable in type and extent, including in addition to hyperthyroidism, pituitary gigantism, and Cushing syndrome due to hyperadrenocorticism.MEIER-GORLIN SYNDROMEFive types caused by mutations in ORC1 gene on 1p32.3 (1), ORC4 gene on 2q22.3 (2), ORC6 gene on 16q11.2 (3), CDT1 gene on 16q24.3 (4), and CDC6 gene on 17q21.2 (5).Also known as ear–patella–short stature syndrome.Microtia, auditory canal atresia, hearing loss, micrognathia, and cleft palate.Thoracic dysplasia with pulmonary compromise and genital anom-alies.Aplastic/hypoplastic patellae, congenital spine deformity, articular laxity, clubfoot, and camptodactyly–clinodactyly.MELNICK-NEEDLES SYNDROMESee otopalatodigital syndromes.MELORHEOSTOSISMutation in the LEMD3 gene on 12q14.3. LEMD3 is a protein integral to the inner nuclear membrane that is involved in gene expression.The term is derived from Greek µελος: “limb,” ρεω: “I ﬂow,” and οστεον: “bone” to describe longi-tudinal ﬂowing hyperostosis along the cortex of long bones resembling wax dripping along a candlestick. Bones are affected asymmetrically and may corre-spond with a sclerotome.Involvement of surrounding soft tissues leads to painful and deforming contractures, muscle atrophy, and scleroderma. Associated vascular anomalies such as hæmangiomata, lymphangiectasis, vascular nevi, glomus tumors, stenosis, and aneurysms.MESOMELIC DYSPLASIAMesomicromelia and synostosis are the cardinal features. Radioulnar, carpal, tarsal, and metatarsal synostosis, radial capital subluxation, and bowing of long bones, including “rhomboid” tibiae and ﬁbulae.Four types may be distinguished.METACHONDROMATOSISAutosomal dominant mutation in protein tyrosine phosphatase nonrecep-tor type 11 gene on 12q24. The protein tyrosine phosphatase family are signaling proteins.The disorder is allelic with Noonan syndrome (q.v.).Combines features of enchondromato-sis (of Ollier q.v.) and hereditary multiple exostoses (q.v.). Distinguished by:• Direction of exostoses toward adja-cent joints• Predominance in hands and feet• Potential for spontaneous regression• Lack of malignant potentialInvolvement of the hip may resemble.Legg-Calvé-Perthes disease.METAPHYSIAL CHONDRODYSPLASIAMetaphysial involvement contrasts with epiphysial sparing and results in contractures rather than primary osteoarthritis.Bowing of long bones produces varus deformity in lower limbs.Stature varies from mild (Schmid) to moderate (McKusick) to severe (Jensen).Type FeaturesKantapura Mutation on 2q24-q32.LangerMutation in short stature homeo box gene.Allelic with Léri-Weill dyschondrosteosis.Distinguished by mandibular hypoplasia.NievergeltAutosomal dominant mutation of α−1 chain of type 10 collagen on 6q22.1.Mild short stature.Savarirayan Mutation of LAF4 gene on 2q11.2.Diab_Chap12.indd 249 9/23/2015 3:25:29 PM

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250 Syndromes / MucopolysaccharidosesMETATROPIC DYSPLASIAMutation in the transient receptor potential cation channel subfamily V member 4 gene on 12q24.11. TRPV4 is a Ca2+ channel.Allelic with brachyolmia type 3, spondy-loepiphysial dysplasia (Maroteaux), spon-dylometaphysial dysplasia (Kozlowski), and Charcot-Marie-Tooth type 2C.The term describes a “change” (Greek τροπη) in clinical presentation of severity of deformity from limbs (resembling achondropla-sia) to trunk (resembling Morquio syndrome) with growth. At birth, the limbs are markedly affected with relative sparing of the trunk; with advancing age, progressive and severe kypho-scoliosis becomes the predominant feature.Prolongation of the coccyx or the presence of a cutaneous fold over the posterior aspect of the pelvis gives the appearance of a tail.Deformity of the iliac alae results in a “halberd” pelvis. The ends of fem-ora and humeri are said to be “trumpeted,” rather than “dumbbell” in Kniest dysplasia. Microcalciﬁcation of epiphysis, hyoid, and cricoid cartilages.MÖBIUS SYNDROMEGene locus on 13q12.2-q13.Congenital cranial neuropathy, most frequently facial and abducens, leading to facial paralysis and impaired ocular abduction.Arthrogryposis, digital anomalies, clubfoot, scoliosis with increased sagittal plane spine deformity.Absence of pectoralis muscles reﬂects association with Poland syndrome.MUCOPOLYSACCHARIDOSESCharacterized by intracellular accumulation and urinary excretion of muco-polysaccharides [A] due to deﬁciency in degradative lysosomal enzymes. Mucopolysaccharide is the historical term for glycosaminoglycan (GAG). Proteoglycans, formerly known as protein polysaccharides or mucopro-teins, refers to a molecule of “protein and sugar.” It has three components: • Glycosaminoglycan (GAG). This represents an unbranched chain of repeating disaccharide units of which one is an amino sugar. With the exception of hyaluronic acid, the GAGs carry a high negative charge on the account of sulfate and carboxyl groups added to their sugar residues.• Core protein, to which GAGs are covalently bonded at a serine resi-due by a tetrasaccharide bridge.• Link protein, which noncovalently attaches proteoglycan to hyal-uronic acid, the principal carbohydrate polymer of the extracellular matrix.Proteoglycan monomers interact speciﬁcally though noncovalently with hyaluronic acid to form very high molecular weight “aggregates.” The major proteoglycan of cartilage is aggrecan, of which the core protein may have covalently attached as many as 100 chondroitin sulfate and 50 keratan sulfate GAGs. Cartilage also contains small, nonaggregating proteoglycans, including decorin, which “decorates” the surface of type II collagen ﬁbrils, and biglycan, of which the core protein bears “two” chondroitin sulfate GAGs. The molecular structure and negative charge of proteoglycans enable them to occupy a large volume for mass and to attract water according to the Gibbs-Donnan equilibrium. They form a porous hydrated gel, which resists compression and regulates the passage of molecules and cells through the extracellular matrix. By contrast, col-lagen ﬁbrils form a scaffold, which maintains the structural integrity of the extracellular matrix and primarily resists tensile forces.There are several types of mucopolysaccharidoses. Type II is X-linked. Type III is predominantly a neural disease. Type IV is most common. Types VI and IX may have normal intelligence.Type FeaturesJansenMutation in parathyroid hormone receptor 1 gene on 3p21.31. Ligand-independent activation disrupts endochondral ossification.Cranial sclerosis leading to deafness, choanal steno-sis or atresia.Skeletal manifestations resemble hyperparathyroid-ism, including osteopenic fractures.Hypercalcæmia and hypercalcuria with nephrocalci-nosis.Hypophosphatæmia, hyperphosphaturia, elevated 1,25 dihydroxy vitamin D and alkaline phosphatase.McKusickAutosomal recessive mutation of RNA component of mitochondrial RNA processing endoribonuclease on 9p13.3.Appellation ‘cartilage-hair hypoplasia’ reflects distin-guishing feature of sparse, small caliber hair.Immune deficiency manifested as susceptibility to infection and increased risk of malignancy.Hæmocytopenia.Clustered in Old Order Amish and in Finland.SchmidAutosomal dominant mutation of a-1 chain of type 10 collagen on 6q22.1.Type FeaturesIh (Hurler)Is (Scheie)Autosomal recessive mutation in α−L-iduronidase gene on 4p16.3.Scheie was formerly type V.Appear normal at birth, manifesting after 6 months.Developmental and growth retardation after 2 years.Gargoyle facies, with exophthalmos, corneal clouding, thick eye-brows and large tongue.Odontoid hypoplasia with atlanto-axial instability, ‘cod-fish’ vertebrae, lumbar gibbus, kyphoscoliosis.‘Oar-shaped’ ribs, epiphysial deformation including hip dysplasia and genua valga.Cardiopulmonary anomalies, including myopathy and arrhythmia, hernias, hepatosplenomegaly.Dermal melanocytosis, hypertrichosis.II (Hunter)X-linked recessive mutation in iduronidate 2-sulfatase on Xq28.Urinary excretion of chondroitin sulfate B (dermatan sulfate) and heparitin (heparan) sulfate.III (Sanfilippo)Autosomal recessive mutation in N-sulfoglucosamine sulfohydrolase gene on 17q25.3 resulting in impaired degradation of heparan sulfate, excreted in urine.Severe nervous system disease with relative sparing of skeleton.IV (Morquio)Autosomal recessive mutation in β−galactosidase gene on 3p22.3.Urinary excretion of keratan sulfate.VI (Maroteaux-Lamy)Autosomal recessive mutation in arylsulfatase B gene on 5q14.1.VII (Sly)Autosomal recessive mutation in β−glucuronidase gene on 7q11.21.Hydrops fœtalis.IXMutation in hyaluronidase gene on 3p21.31.Multiple peri-arthric masses representing hyaluronan-induced aggregation of histiocytes resulting form failure of catabolism of hyaluronan by hyaluronidase.Diab_Chap12.indd 250 9/23/2015 3:25:30 PM

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Syndromes / Multiple Synostosis Syndrome 251Hurler and Scheie represent a spectrum of severe to mild disease. Scheie may be so mild that diagnosis is in adulthood. The other disorders are subtyped by letter according to disease severity.Carpal tunnel syndrome is a common feature of the mucopolysaccha-ridoses, due in part to excessive lysosomal storage in the ﬂexor retinacu-lum. Spine [B] and hip [C] are the other foci of orthopædic care.Anteoperative assessment must include cardiac evaluation and cervi-cal spine imaging.Medical treatment includes enzyme replacement and bone marrow transplantation. The latter, performed before age 2 years, prolongs sur-vival and, while they may delay or halt extraskeletal disease progression, they may not affect skeletal manifestations.A form of mucopolysaccharidosis, claimed to be due to glucos-amine-6-sulfate sulfatase deﬁciency, named Di Ferrante syndrome, and given the designation VIII, was found to be erroneous and retired after the discovery of type IX.MULTIPLE EXOSTOSESAlso known as multiple osteochondromata and diaphysial aclasis, describing a lesion of “bone” capped by “cartilage” showing “lack of an interruption” of the “diaphysis” from the primary bone.There are three types, distinguished genetically.Lesions arise from physis, grow away from adjacent joint, and affect long bones, ﬂat bones (except skull), and vertebrae.This contrasts from the solitary form of the disease: • The exostoses are deforming, including bowing, shortening, and joint dysplasia.• Mild short stature.• Malignant transformation is approx-imately 1%. Symptoms and signs include pain and rapid growth.Restraint is fundamental to ortho-pedic management.Indications for operation include:• Pain, such as at prominent lesions that may be struck.• Dysfunction, such as compression of tibial nerve producing denerva-tion of tibialis posterior muscle (red).• Deformity, such as tethering by a shortened ulna , which may lead to radial bowing, ulnad displacement of the wrist, and head of radius dislocation.• Unacceptable appearance.• Concern for malignant transformation.MULTIPLE SYNOSTOSIS SYNDROMEThree subtypes are distinguished by mutation.The alternate appellation facioaudiosymphalangism syndrome describes the principal clinical manifestations.Narrow face, nasal hypoplasia, and conductive deafness due to mid-dle ear ankylosis.Multiple synostoses, including carpal and tarsal coalitions, brachy-dactyly, radial head (sub)luxation, vertebral fusion and hypoplasia pro-ducing stenosis, and pectus deformity.Absent cutaneous creases over interphalangeal joints, aplastic/ hypoplastic nails.Type FeaturesIAutosomal dominant mutation in exostosin-1 (EXT1) gene on 8q24, resulting in activation of the hedgehog signaling pathway.70% of all cases, most morbid form.II Autosomal dominant mutation in exostosin-2 gene on 11p11.2.III Mapped to locus on 19.Type Features1 Mutation in homolog of mouse Noggin gene on 17q22.2Mutation in growth/differentiation factor-5 on 20q11.22.GDF5 belongs to the transforming growth factor −β superfamily.Allelic with several disorders, including brachydactyly types A and C.3Mutation in fibroblast growth factor 9 gene on 13q12.11.FGF9 is a member of fibroblast growth factor family.hyaluronic acidGAGlink proteincore proteinA Extracellular matrix Proteoglycans are glycosylated proteins consisting of a core protein to which one or more types of glycosaminoglycan are covalently linked.B Lumbar gibbus in Hurler syndrome Failure of formation of upper lumbar vertebra allows the superjacent vertebra to fall forward into the deficiency space.C Hip dysplasia in Morquio syndrome Untreated hip dysplasia may lead to severe coxarthritis.MULTIPLE ENCHONDROMATOSISBenign tumors of cartilage located in metaphysis of long bones, where lesions are asymmetric and deforming.Hands and feet most involved.Orthopedic management focuses on limb equalization and realignment osteotomy.Type FeaturesOllier Malignant transformation to chondrosarcoma 10-30%.MafucciAssociated with hæmangiomata.Higher rate of malignant transformation, including of extraskeletal tissue.Diab_Chap12.indd 251 9/23/2015 3:25:32 PM

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252 Syndromes / NeurofibromatosisNAIL–PATELLA SYNDROMEAutosomal dominant mutation in LIM homeobox transcription factor 1-b on q34.1. LMX1B plays a role in dorsoventral patterning of thevertebrate limb and renal development. Absence or hypoplasia/dysplasia of nails and patellae, as well as of pectoralis, biceps, and quadriceps muscles, represents ventral pattern-ing of the dorsal aspects of the limbs.Short stature, iliac horns, limited elbow motion with radial head hypoplasia and disloca-tion, scapular anomaly, scoliosis, and clubfoot.Renal disease, including glomerulonephritis with proteinuria and hematuria, ends in renal failure in 10% of patients.Sensorineural deafness, glaucoma, cataract, and cleft lip and palate.NEUROFIBROMATOSISSimple neuroﬁbromata, made up of Schwann cells and ﬁbrous tissue, rarely produce deﬁcit. Plexiform neuroﬁbromata, which are highly vascular, lead to disﬁgurement and gigantism, which may require limb equalization.Café au lait patches have smooth or “coast of California” borders, in distinction from the rough or “coast of Maine borders” in McCune- Albright syndrome.Type Features1 - PeripheralAutosomal dominant mutation in neurofibromin gene on 17q11.2.Neurofibromin is a tumor suppressor inhibiting p21 rasoncoprotein.Also known as von Recklinghausen disease.90% of cases with a 1:4000 incidence.Diagnosis requires 2 of the following:Diagnosis - 2 featuresCafé-au-lait patches 6> 5 mm before puberty> 15 mm after pubertyNeurofibromata > 2 subcutaneous 1 plexiformFreckling axillary or inguinalOsseous lesion sphenoid dysplasiascoliosiscongenital pseudarthrosisFamily history First-degree relative with NF1Lisch nodule hamartoma of irisOptic glioma2 - CentralAutosomal dominant mutation in merlin (neurofibromin 2) gene on 22q12.2.Sensorineural hearing loss, ocular anomalies but no Lisch nodules, central and peripheral neuropathy, neu-ral tumors including vestibular schwannoma (of ves-tibulocochlear cranial nerve VIII), meningioma, epen-dymoma, astrocytoma.Central affection delays diagnosis.Stereotactic radiosurgery or microsurgical resection of vestibular schwannoma.Scoliosis may be idiopathic or “dystrophic.” The former behaves and is treated as such. The latter is characterized by short and sharp angula-tion, osseous erosion by intraspinal lesions and dural ectasia, and spinal instability. Bracing plays no role, and early anterior together with poste-rior fusion is indicated because of the risk of pseudarthrosis. Neural risk is signiﬁcant, untreated or treated.Pseudarthrosis may involve any bone, though most often the tibia, presenting as an anterolateral bow. This is treated by prophylactic brac-ing to avoid fracture, and operative treatment after fracture, including compressive external ﬁxation or medullary nailing with autogenous osseous graft or vascularized ﬁbula transference. Bone morphogenetic protein as adjuvant is controversial.Other features include cognitive impairment, macrocephaly without hydrocephalus, seizures, and vascular anomalies. Neuroﬁbromatosis 1 carries an increased tumor risk, including leukemia and pheochromocy-toma.While the Irish surgeon Robert W. Smith (1849) was ﬁrst to report two men with “a vast number of neuromatous tumors in the subcutane-ous cellular tissues,” von Recklinghausen’s description in tribute to his professor Rudolph Virchow gave the enduring eponym for neuroﬁbro-matosis 1.Feature %Café-au-lait patches 95Lisch nodules 90Axillary freckling80Cutaneous neurofibromata 60Cognitive impairment60Family history 50Scoliosis 40Pseudarthrosis15Malignancy 10Spinal neurofibromata 2Pseudarthrosis of radius Deformity begets dysfunction.Lisch nodules These represent a yellow to brown pigmented hamartoma of the iris, consisting of dendritic melanocytes. They do not affect vision, but aid diagnosis.Diab_Chap12.indd 252 9/23/2015 3:25:35 PM

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Syndromes / Osteogenesis Imperfecta 253OCULODENTODIGITAL DYSPLASIAAutosomal dominant and recessive mutations in the gap junction α-1 protein gene on 6q22.31. The protein is a member of the connexin family and is a component of gap junctions, which form intercellular channels for diffusion.Ocular: microphthalmos, glaucoma, and cataract.Dental: hypoplastic enamel, microdontia, and premature tooth loss.Digital: camptodactyly, syndactyly of ring and smallest ﬁngers as well as of toes, and aphalangia.Hip dysplasia and hyperostosis, in particular of vertebrae and skull, which can result in neural compression. Osseous involvement other than digits has given rise to the alternate appellation oculodentoosseous dys-plasia.Neural features include spasticity, dysarthria, and hearing loss.Fine, sparse hair and orange–yellow palmoplantar keratoderma.OSTEOGENESIS IMPERFECTAThe Dutch anatomist W. Vrolik named the condition osteogenesis imper-fecta. It also is known as fragilitas ossium: “brittleness of bones.”Mutation of gene encoding type I collagen α-1 chain on 17q21.33 or α-2 chain on 7q21.3.Collagen, derived from Greek κολλα: “glue”, and the sufﬁx -γεν: “giving rise to,” is the name given to a family of proteins that comprise the principal constituents of the extracellular matrix of tissues of the mus-culoskeletal system. The collagen molecule is composed of three poly-peptide chains, two α-1 and one α-2, and is therefore a trimer. Although the primary structure of each polypeptide chain differs among collagen types, repeating three amino acid motifs are strictly preserved, repre-sented by the formula -(GLY-X-Y)n-. Every third residue is a glycine (Gly). X and Y can vary; however, a high proportion of amino acids at the X position tends to be proline (Pro), and a high proportion at the Y posi-tion tends to be hydroxyproline (Hyp). Those portions of a collagen chain, which follow this typical motif, are helical and are known as col-lagenous domains; those that do not are termed noncollagenous domains. The individual chains may be identical, encoded by the same gene, in which case they form a homotrimer, or they may be different gene prod-ucts, forming a heterotrimer. Cleavage of amino terminal and carboxyl terminal propeptides during or after secretion converts procollagen to col-lagen. The tertiary structure of each collagen chain is a left-handed helix, and the three chains wrap around one another to form a right-handed super helical molecule.Mutations may result in exclusion or inclusion of an allelic product. In heterozygous-excluded mutations (haploinsufﬁciency), failure of secretion and incorporation into a protein trimer, or of synthesis (null alleles), of a polypeptide chain, produce mild disease due to a quantita-tive reduction of normal molecules. In the homozygote, the severity of disease is proportional to the amount of allelic product excluded. Included mutations (dominant negative), such as deletions, insertions, duplica-tions, point mutations, rearrangements, and exon-skipping mutations, result in a more morbid phenotype because the abnormal allelic product N-terminal propeptideC-terminal propeptideα−1α−1α−2mature collagen moleculeN-terminal telopeptideN-terminal telopeptidetriple helixmarkers of turnovermarkers of synthesisis expressed in the extracellular matrix where it “poisons” all molecules into which it is incorporated. Severe phenotypes result from glycine mutations, because this is the smallest and only amino acid (lacking a side chain) that can ﬁt in the center of the triple helix. Assembly of the collagen molecule commences at the carboxyl terminus. This produces a “phenotypic gradient”: mutations in the carboxyl terminal region pro-duce more severe phenotypes based upon a greater potential for disrup-tion of the triple helix. Exceptions to these principles exist: for example, certain mutations are lethal, which do not involve glycine and regardless of location.Osteogenesis imperfecta is the most common lethal skeletal dyspla-sia. Phenotype reﬂects distribution of type I collagen.Increased turnover, woven to lamellar bone ratio, and hypercellularity conspire to weaken bone. Fracture healing and postoperative union are unretarded, often with “luxuriant” callus, although the quality of the new bone remains poor. Fracture rate is bimodal: childhood, decreases after puberty, and rises after menopause.Hearing loss, which affects 50% of patients, begins in second decade as conductive, from osseous fragility in the middle ear, and evolves with age to sensorineural. Otosclerosis also produces vertigo.Ole Worm, Professor of Anatomy at Copenhagen (1558 to 1654), described intrasutural bones, which may be more numerous in disease states characterized by delayed or deﬁcient ossiﬁcation.Mechanism of operative malignant hyperthermia remains unclear.Four clinical types are distinguished. They are subtyped as A or B based upon absence or presence, respectively, of dentinogenesis imper-fecta.Ambulatory potential proportional directly to age of onset and inversely to deformity.Tissue distributionFeatureBone Dentin     SkinConnective tissue“W  Type I II (Vrolik) III IVMutationα−1 or α−2 chain of type I collagen Inheritance dominant new mutation recessive dominantFrequency 50%5%25% 20%Severity mild lethalprogressive deformingvariableSclerae blue blue blue or white whiteHearing loss 50%— yes noAmbulation yes — wheel-chair yesStature normal — very short shortDiab_Chap12.indd 253 9/23/2015 3:25:36 PM

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254 Syndromes / OsteopetrosisSeveral additional types have been distinguished that are character-ized by brittle bones but that are caused by mutations other than of type I collagen.Types V, VI, and XI may phenotypically be likened to type IV. Type XV may have features of both type III and type IV. The other types resemble type III. Discovery of additional mutations and typing represents an area of ﬂux.Diagnosis is aided by analysis of type I collagen production by cul-tured dermal ﬁbroblasts.Osteogenesis imperfecta leads the differential diagnosis of nonacci-dental trauma.Minimize type and duration of immobilization for fracture in order to reduce sequelae of exacerbated osteopenia, stiffness, and weakness. Recurrent fractures and progressive deformity may be addressed by cor-rective osteotomy and ﬁxation with either solid or telescoping medul-lary nails. Scoliosis is treated with early fusion because natural history is progression despite bracing and bone fragility undermines ﬁxation. Symptomatic basilar invagination is treated by posterior with or without anterior decompression followed by posterior fusion.Audiologic examination and electronystagmography are indicated for hearing loss.Bisphosphonates are synthetic analogs of pyrophosphate, a natural inhibitor of osteoclastic bone resorption. Cyclic intravenous adminis-tration decreases bone turnover; increases bone mineral density, cortical width, and trabecular number; delays onset and reduces number of frac-tures; improves ambulation; and increases height. Physis are unaffected.Osteogenesis imperfecta has been described in an Egyptian mummy of the twenty-ﬁrst dynasty (1,000 BC). The nineteenth-century Viking king and invader of England Ivar Benløs (Ivar the Boneless), who had Type FeaturesVMutation of interferon -induced transmembrane protein-5 on 11p15.5.Moderate.Normal sclerae, normal teeth.Calcification of interosseous membrane of forearm, dislocation of head of radius, radiodense metaphysialbands.Osseous histology shows ‘mesh-like’ pattern.VIMutation of pigment epithelium-derived factor (serine protease inhibitor F1) on 17p13.3.‘Fish scale’ lamellæ and hyperosteoidosis suggest defect of mineralization.VIIMutation of cartilage associated protein on 3p22.3.First Nations community of northern Quebec.VIIIMutation of leprecan on 1p34.2.Concentration in cases of West African origins.IXMutation of peptidylprolyl isomerase B (cyclophilin B) on 15q22.31.Overhydroxylation suggests overmodification of type I collagen.X Mutation of serine protease inhibitor H on 11q13.5.XIMutation of FKBP10 member of peptidyl-prolyl cis/ trans isomerase family on 17q21.2.XIIMutation of C2H2-type zinc finger transcription factor SP7 on 12q13.13.XIIIMutation of bone morphogenetic protein 1 on 8p21.3.Resembles type III.XIV Mutation of transmembrane protein 38B on 9q31.2.XVMutation of wingless-type MMTV integration site family, member 1, on 12q13.12.Intermediate between type III and type IV.blue eyes and was carried into battle seated on a shield of bronze, is said to have had “gristle in the limbs where other men had bones.”OSTEOPETROSISAutosomal recessive also may be referred to as infantile malignant, to describe presentation in childhood and severity of clinical presentation, including death from myelophthisis. Autosomal dominant forms are more benign and typically present in adulthood. Several subtypes have been distinguished, principally based upon mutation. Autosomal domi-nant 2 was described by Albers-Schönberg and is known as “marble bone disease” after the radiographic appearance.Osteoclast dysfunction leads to defective resorption of immature bone.Encroachment upon bone marrow results in pancytopenia and infec-tion, which of the jaw results in dental caries.Cranial nerve compression results in blindness, deafness, and facial palsy.Extramedullary hematopoiesis leads to hepatosplenomegaly.Abnormal bone turnover results in morbid fractures and deformity, which are the foci of orthopedic management. Complication rate is high. Osteosynthesis may be hindered by sclerosis. Arthroplasty is compli-cated by loosening and infection. Osseous union may be delayed.Mainstay of medical treatment is bone marrow transplantation. Recombinant human interferon gamma-1b to increase superoxide gen-eration by leukocytes and bone-resorbing agent calcitriol are indicated while awaiting, or for patients who are not candidates for, bone marrow transplantation.Blue sclerae Subjacent vascular plexus tinges thinned connective tissue.Wormian bones Multiple intrasutural bones of the skull.Spine and operative treatment Biconcave vertebral end plates resemble “codfish” (red ). Telescoping Bailey-Dubow rod (blue) strengthens femur against fracture and corrects deformity while allowing for longitudinal growth.Deformity of long bones Multiple fractures of the femur with hypertrophic callus give the appearance of an accordion (green). Bowing of the tibia due to microfragility has been likened to a saber (orange). Note migration of Rush rod out of femur (pink).Diab_Chap12.indd 254 9/23/2015 3:25:38 PM

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Syndromes / Prader-Willi Syndrome 255OTOPALATODIGITAL SYNDROMEGain-of-function mutation in ﬁlamin A gene on Xq28.Skeletal Short stature; pectus excavatum; “coat hanger” wavy, short ribs; scoliosis; hip dysplasia; joint contractures; radial head dislocation; long bone bowing; carpal and tarsal fusion; brachydactyly; secondary ossiﬁcation cen-ter at base of second metacarpal and metatarsal; wide spacing between broad toes with persistent fetal pads creates “tree frog” feet; and nail dystrophy.Craniofacial Cleft palate, conductive deafness caused by ossicular anomalies, and dental dysplasia.Four disorders are distinguished, representing a phenotypic spectrum of a single entity. Frontometaphysial dysplasia adds urogenital anomalies, including hydronephrosis/hydroureter, hypospadias, and cryptorchidism.Perinatal lethal due to cardiopulmonary insufﬁciency.POLAND SYNDROMEMost sporadic, though autosomal dominant pedigrees have been reported.Ipsilateral aplasia/hypoplasia of pectoralis major and/or minor muscle, which may be associated with Sprengel anomaly; hypoplastic or fused ribs; aplasia/ hypoplasia of nipple; symbrachydactyly or oligodactyly, including of thumb; and aplasia/hypo-plasia of other shoulder muscles. Anteoperative MRI aids assessment of reconstructive options.Association with Klippel-Feil syndrome (q.v.) and Möbius syndrome (q.v.) has led to the hypothesis that a vascular insult during embryogenesis is causative, termed subclavian artery supply disruption sequence.Boys thrice as common as girls. 75% of cases are right-sided. Left-sided anomalies may be associated with dextrocardia. One bilateral case has been reported, which may be better classiﬁed as a type of thoracic dysplasia.Unilateral gluteal hypoplasia and symbrachydactyly of the foot, due to in utero external iliac artery supply disruption sequence, may represent the lower limb equivalent of the Poland syndrome.PRADER-WILLI SYNDROMEMicrodeletion of paternal copies of imprinted small nuclear ribonucleop-rotein polypeptide N and necdin within region 15q11-q13.Most cases are sporadic. Paternal hydrocarbon exposure has been implicated.Prenatal delayed onset of fetal activity.Neonatal poor suck and swallow reﬂexes lead to failure to thrive, which is followed by hyperphagia and obesity and ultimately alimentary diabetes. Psychomotor delay with behavioral problems such as anger, picking, and related to food.Hypersalivation, hypotonia, hypopigmentation, hypogonadism, reduced bifrontal diameter, ocular anomalies, cardiac insufﬁciency, hypoventila-tion, intracranial morphologic abnormalities on MRI, and dysthermia.Kyphoscoliosis, which is the focus of orthopedic surgery, and small hands and feet with clinodactyly–syndactyly, in particular thumb adduc-tion over index.Medical treatment includes psychotherapy, dietary control, and growth hormone to improve growth, tone, and respiration and to reduce fat.otopalatodigital syndrome-1otopalatodigital syndrome-2frontometaphysial dysplasiaMelnick-Needles syndromeSEVERITYperinatal lethalType FeaturesAD 1Mutation of low density lipoprotein receptor-related protein 5 on 11q13.2, with full penetrance.Osteosclerosis predominates in craniofacial skeleton.Only type not associated with fractures.AD 2Mutation of chloride channel-7 protein on 16p13.3, with incomplete penetrance.Same mutation as AR 4.Osteosclerosis predominates in axial and appendicular skeleton.Sclerosis of upper and lower end-plates described as ‘sandwich vertebrae’ and ‘rugger jersey spine’.Differential osteosclerosis produces ‘bone within bone’ or ‘endobones’ in the limbs.Confirm diagnosis by elevated serum levels of tartrate-resistant acid phosphatase and BB isoenzyme of creatine kinase.50% patients require orthopædic surgery.AR 1Mutation of V-type proton ATPase subunit of the vacuolar proton pump on 11q13.2.Impairment in calcium homeostasis results in tetanic seizureand secondary hyperparathyroidism.AR 2Mutation of receptor activator of nuclear factor kappa-B ligand (RANKL) on 13q14.11.RANKL is an osteoclast cell surface receptor that binds RANK.Clinical mildness resembles dominant forms.AR 3Mutation of carbonic anhydrase II, which is expressed in kidney and brain, on 8q21.1.Renal tubular acidosis.The appellation ‘marble brain disease’ describes mental retardation associated with intracranial calcifications.Originated in Arabian peninsula.AR 4Mutation of chloride channel-7 protein on 16p13.3.Same mutation as AD 2.AR 5Mutation of osteopetrosis-associated transmembrane protein-1, which prevents acidification of osteoclast resorption lacuna, on 6q21.AR 6Mutation of pleckstrin homology domain-containing family M member 1 on 17q21.31.Intermediate form.AR 7Mutation of receptor activator of nuclear factor kappa-B (RANK) on 18q21.33.Hypogammaglobulinæmia.AR 8 Mutation of sorting nexin 10 on 7p15.2.Wrist Bone within bone, or endobones.Spine Endplate sclerosis leads to sandwich vertebrae that give the appearance of a rugger jersey.Marble bone Despite the epithet, osseous fragility manifests as morbid fracture.Diab_Chap12.indd 255 9/23/2015 3:25:40 PM

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256 Syndromes / PycnodysostosisPROTEUS SYNDROMEMosaicism for a somatic-activating mutation in the protein kinase AKT1 gene on 14q32.3.Sporadic occurrence and progressive course.Variable asymmetric, disproportionate, localized tissue hypertrophy leading to gigantism of trunk and/or limbs.Lymphatic and vascular tumors in skin and subcu-taneous tissue, including characteristic “cerebriform” connective tissue nevi having grooves and gyrations.Hyperostosis of craniofacial skeleton, in par-ticular of external auditory meatus.Limb equalization for hemihypertrophy.Fusion for spine deformity and decompression for spine stenosis, which may be due to kyphosco-liosis or tumor inﬁltration.The disorder is named after the ancient Greek Sea God Proteus, “the polymorphous,” who could change his shape like the ever-changing nature of the sea.Joseph Carey Merrick (1862–1890), advertized as “Half a Man and Half an Elephant” by his show-men, may have been affected by this condition.PYLE DISEASEThis also is known as metaphysial dysplasia.Autosomal recessive.The distinguishing feature is bizarre röntgenographic changes, includ-ing “unremodeled” appearance of long bones, with minimal clinical con-sequences. Erlenmeyer ﬂask deformity of proximal tibia and distal femur and genu valgum.PRUNE BELLY SYNDROMEAutosomal recessive mutation in cholinergic receptor, muscarinic 3 gene on 1q43.The disorder is named for absence of abdominal muscles with overly-ing skin, which is thin and lax with multiple creases due to redundancy.Urogenital anomalies, including mega-cystis with disorganized detrusor muscle, hydronephrosis, and cryptorchidism.Urinary obstruction in the fetus may produce distension and maldevelopment of abdominal wall.Musculoskeletal manifestations include hip dysplasia with dislocation due to laxity, segmentation defects of the spine producing congenital scoliosis and of the chest such as costal fusion, clubfoot, and vertical talus.Other management includes self-cathe-terization or vesicostomy, orchiopexy, and potentially dialysis and renal transplantation.PSEUDOACHONDROPLASIAAutosomal dominant mutation of cartilage oligomeric matrix protein gene on 19p31.11.Allelic with epiphysial dysplasia, multiple, of Fairbanks, which is milder.The appellation derives from a resemblance to achondroplasia, including rhizomicromelia, trident hand, and lumbar hyperlordosis.Distinguishing features are:• Normal presentation at birth, with diagnosis rarely before 2 years.• Normocephaly, including calvaria and face.• Epiphysial involvement leading to premature osteoarthritis, with arthroplasty common by the fourth decade.• Odontoid hypoplasia producing cervical spine instability and myelop-athy, requiring stabilization.• Absence of lumbar spine stenosis.PTERYGIUM SYNDROMEThe term derives from Greek πτερυξ: “wing,” after the appearance of the skin as it stretches across a joint.Pterygia result in primary growth disturbance and secondary physical distortion:Musculoskeletal Kyphoscoliosis due to vertebral anomaly; articular contracture with (sub)luxation in particular of hip, knee (white), and elbow; hypoplasia of patellae and innominate bones; clubfoot; vertical talus; syndactyly and synostosis of feet more than hands; cutaneous dim-ples over extension side of elbows and knees; and pyramidal cutaneous overgrowth of halluceal nails.Craniofacial Cleft lip and palate, paramedian mucous cyst of lower lip, syngnathia, ankyloblepharon ﬁliforme adnatum, and hearing loss.Genitourinary Biﬁd scrotum (blue), cryptorchidism, and hypo-plasia.Visceral Cardiopulmonary anom-aly and diaphragmatic, abdominal, and inguinal hernias.Three principal types are distin-guished, with broader involvement and increasing severity.Early pterygium release because neurovascular structures limit extent and rate of recurrence is high. Add external ﬁxator for gradual correction after index release.Phenotypic overlap with arthrogryposis and Freeman-Sheldon syn-drome.PYCNODYSOSTOSISFrom Greek πυκνος: “close-packed, dense, thick,” after the radiodensity of bone.Autosomal recessive mutation of cathepsin K on 1q21.3. Cathepsin K belongs to the papain cysteine protease superfamily, among which it is unique in having an expression restricted to a speciﬁc cell type, the osteoclast.Abnormal proteolysis in the organic matrix leads to bone sclerosis and fragility, resulting in phenotypic overlap with osteopetrosis.Delayed suture closure, hypodontia, and caries.Aplasia or hypoplasia of clavicle, scoliosis, spondylolysis and spondylolisthesis, brachydac-tyly and acroosteolysis of distal phalanges, and onychodysplasia.Type FeaturesPopliteal -faciogenitopoplitealsyndromeAutosomal dominant mutation in interferon regulatory factor-6 gene on 1q32-q41.Pterygium may extend from ischium to calcaneus as it crosses the popliteal fossa.Multiple - Escobar syndromeAutosomal recessive mutation in the gene encoding the gamma subunit of acetylcholine receptor on 2q37.1.Dysmorphology caused by transient inactivation of neuromuscular end-plate.Pterygium colli distinctive.Lethal - Bartsocas-Papas syndromeAutosomal recessive mutation in receptor-interacting serine-threonine kinase-4 gene on 21q.22.3.Clustering in Mediterranean ancestry.Death from pulmonary hypoplasia and insufficiency.Diab_Chap12.indd 256 9/23/2015 3:25:42 PM

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Syndromes / Small Patella Syndrome 257RICKETSNamed after involvement of the spine, from Greek ραχις: “spine.”Defective bone mineralization due to hypocalcemia and hypophos-phatemia.In the liver, vitamin D 25-hydroxylase adds -OH to vitamin D at car-bon 25. In the kidney, 1-alpha-hydroxylase adds a second -OH to produce the active metabolite 1,25(OH)2D3, which binds and activates the nuclear vitamin D receptor.Four types are distinguished.Rickets also may result from malnutrition, including inadequate consumption of vitamin D2 ( ergocalciferol) in plants and lack of sunlight, of which ultraviolet radiation is necessary for synthesis of vitamin D3 (cholecalciferol), the inactive precursor.Short stature; osteomalacia; “soft” fracture, for example, greenstick (red); long bone bowing, physial widening with metaphysial irregularity; bone and joint pain; calciﬁcation of entheses; spinal stenosis; and craniotabes (soft skull).“Bulging” epiphysis lead to artic-ular enlargement, and hypertrophic costochondral junctions produce the “rachitic” rosary (white).Indentation of soft ribs at the insertion of the diaphragm is known as “Harrison groove.”Muscle weakness, alopecia, and caries.Hypocalcemia may result in seizure, hypercalciuria in nephrocalcinosis, and secondary hyperparathyroidism in subperiosteal erosions.Type FeaturesHypophosphatæmic - autosomal12p13.6q22-q23.Hypophosphatæmic - X-linkedXp22.11.Xp11.22.Vitamin D-deficient in:D3-1-12q14.11p15.2.Vitamin D-resistant in:12q13.1insensitivity.receptor.RILEY-DAY SYNDROMESee familial dysautonomia.RUBINSTEIN-TAY BI SYNDROMEAutosomal dominant mutation of the transcriptional coactivator cAmp response element-binding (CREB) protein on 16p13.3.Also known as broad thumb–hallux syndrome, after these features and the characteristic facies (heavy high-arched eyebrows, long eye-lashes, low ears, grimacing smile) emphasized in the original report.Congenital scoliosis, slipped capital femoral epiphysis, patellar and other joint instability, single palmar and plantar creases, and polydactyly.Psychomotor delay; ocular (glaucoma, cataract), cardiac (valvular regurgitation, septal defect, pulmonic stenosis, aortic coarctation), and genitourinary (cryptorchidism) anomalies; and hirsutism. Five percent of patients develop a tumor, including neural, rhabdomyosarcoma, leuke-mia, and pheochromocytoma. The rate is similar to neuroﬁbromatosis I.Floating-Harbor syndrome (named for Boston Floating Hospital and Harbor General Hospital in Torrance where the ﬁrst two cases were observed) is caused by mutation in SNF2-related CBP-activator protein, which is a coactivator of CREB protein. Its features resemble the cranio-facial features of Rubinstein-Taybi syndrome.SECKEL SYNDROMEAutosomal recessive mutation in ataxia–telangiectasia and Rad3-related protein gene on 3q22.1 (type 1). Six other subtypes distinguished by mutation.The German pathologist and polymath Rudolph Carl Virchow (1821 to 1902) called this “bird-headed” dwarﬁsm, after the characteristic microcephaly, large eyes, prominent sharp nose, and small chin and ears.Scoliosis, hip dysplasia, hypoplasia of proximal radius and proximal ﬁbula, and ﬂexion contractures.Central nervous system anomalies result in psychomotor delay and seizures.SILVER-RUSSELL SYNDROMEDNA hypomethylation at the telomeric imprinting control region on 11p15.5, involving adult skeletal muscle and insulin-like growth factor 2 genes. Ten percent represent maternal uniparental disomy, in which child receives two copies of chromosome 7 from mother.Characteristic triangular facies with broad forehead (“pseudohydro-cephalic”), wide mouth, and small chin.Body asymmetry, including hemihypertrophy; hand and foot anoma-lies, including second metacarpal pseudoepiphysis; congenital scoliosis; and hip dysplasia.Genital malformations and gastrointestinal symptoms.Tumor risk, including Wilms (nephroblastoma), hepatocellular, and craniopharyngioma.Opposite epimutations, in which the same chromosomal region is hypermethylated, are associated with Beckwith-Wiedemann syndrome and Wilms tumor type 2.Associated with assistive reproductive technologies.SMALL PATELLA SYNDROMEAlso called ischiopatellar dysplasia and coxopodopatellar syndrome, which are more inclusive descriptors.Autosomal dominant mutation in T-box 4 on 17q23.2. T-box 4 encodes a transcription factor with a DNA-binding T-box domain that plays a role in lower limb development.Patellar aplasia/hypoplasia and instability, ischial hypoplasia with delayed ossiﬁcation of ischiopubic junction, wide and ﬂat proximal fem-oral epiphysis, infra-acetabular notching, and widened ﬁrst to second web spaces in the feet.Nails are normal, and while the pelvis is signiﬁcantly involved, iliac horns are absent, which distinguish this from nail–patella syndrome.Diab_Chap12.indd 257 9/23/2015 3:25:43 PM

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258 Syndromes / Spondyloepiphysial DysplasiaSPLIT HAND/SPLIT FOOT MALFORMATIONThis also is known as ectrodactyly, from Greek εκτρωσις: “wound resulting in loss, abortion.”Designated a malformation to emphasize a primary structural lesion, in comparison with deformity, which is secondary.Aplasia/hypoplasia of central rays produce clefts in hands and feet resembling a “lobster claw” or “ostrich foot.” Preaxial loss may produce monodactyly.Preaxial upper limb involvement is a locus discriminator, affecting approximately 50% of types 3 and 5 and <5% of others.Va ri ab le o ro f ac i al c l ef t in g an d m e nt al retardation.Six types are distinguished.SPONDYLOEPIMETAPHYSIAL DYSPLASIADysplasia of long bones, both epiphysis and metaphysis, and spine, after Greek σπονδυλοι = Latin vertebra.Skeletal Metaphysial ﬂaring and cupping, epiphysial irregularity, kyphoscoliosis, and anterior vertebral “tongues.”Hip, knee, and head of radius dislocation and clubfoot.Ocular Blue sclerae, dislocation of lens, and cleft palate.Cardiac anomalies account for demise.Other “Doughy” skin and variable mental retardation.Type Features1 Mutation in distal-less homeobox 5 on 7q21.3.Sensorineural hearing loss.2 Linkage to Xq26.3 Contiguous gene duplication linked to 10q24 trisomy.Renal hypoplasia.4 Mutation in tumor protein p63 on 3q28.5 Mutation in 2q316 Mutation in wingless-type MMTV integration site family member 10B on 12q13.Type FeaturesJoint laxity type 1 (Beighton)Autosomal recessive mutation in β−1,3 galactosyltransferase 6 on 1p36.33.Allelic to progeroid form of Ehlers-Danlos.Joint laxity type 2 (Hall)Autosomal dominant mutation in kinesin family member 22 on 16p11.2.Distinguished by leptodactyly.Strudwick Autosomal dominant mutation in type II collagen on 12q13.11.Allelic to spondyloepiphysial dysplasia, form which it may be distinguished by ‘dappled’ metaphysis due to alternating regions of osteosclerosis and osteopenia.Dens axis hypoplasia with C1-C2 instability.Missouri Mutation in matrix metalloproteinase 13 on 11q22.2.Spontaneous improvement by 2nd decade.Shohat Hepatosplenomegaly distend abdomen.Aggrecan Mutation in aggrecan on 15q.26.1.Abnormal dentition Oligodontia with discoloration.Genevieve Autosomal recessive.Hirsutism, ataxia.Irapa Described in Yukpa tribe of Irapa, Venezuela.SPONDYLOEPIPHYSIAL DYSPLASIAHeterogeneous group affecting spine and epiphysis.Congenita results from mutation of COL2A1 gene, which produces both α-1 chain of type II collagen and the α-3 chain of type XI collagen. Type II collagen is a homotrimer of polypeptide chains encoded by the COL2A1. The principal tissues of distribution are cartilage and vitreous humor, hence the phenotypic expression in bone (by morbid endochondral ossiﬁcation), joint, and eye. This subtype is allelic with Kniest dysplasia and Stickler syndrome, which bound a spectrum from severe to mild, respectively.Skeletal Microcormia. Abnormal epiphysial ossiﬁcation leads to premature osteoarthritis. Dens hypoplasia risks atlantoaxial instability. Thoracic kyphoscoliosis, lumbar hyperlordosis, and platyspondyly with anterior body “tongue” (red). Coxa vara produces a waddling gait (green). Articular contractures, genua valga and vara, clubfoot, and brachydactyly.Ocular Myopia, retinal detachment, vitreoretinal degeneration, and corneal dystrophy.Craniofacial Cleft palate and sensorineural hearing loss.Type FeaturesX-linked Without or with central nervous system anomalies, psychomotor dysfunction.Matrilin-3 Linkage to 2p24.1.Allelic to epiphysial dysplasia, multiple, type 5.Hypotrichosis (Whyte)Congenital absence of hair follicles, tarda skeletal involvement.Sponastrime Term derived from ‘spondylar and nasal alterations with striated metaphysis’, to emphasize distinguishing features.Micromelia Sub-type with most severe skeletal involvement.Coxa vara Capital femoral epiphysis are severely deformed. Proximal femoral physial–shaft angles >60 degrees.Spinal deformity Vertebral bodies give rise to projections, which have been likened to a “tongue.”Type FeaturesCongenita Mutation in α−1 chain of collagen type II on 12q13.11. Tarda(onset > 5 years)Mutation in tracking protein particle complex, subunit 2 on Xp22.2.Autosomal dominant and recessive forms identified.Maroteaux Mutation in transient receptor potential cation channel subfamily V member 4 on 12q24.11.Allelic to brachyolmia type 3, metatropic dysplasia and spondylometaphysial dysplasia of Kozlowski.Kimberley Mutation in aggrecan-1 on 15q26.1.Omani type Mutation in carbohydrate sulfotransferase-3 on 10q22.Multiple joint dislocations.Congenital heart disease.Diab_Chap12.indd 258 9/23/2015 3:25:46 PM

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Syndromes / Turner Syndrome 259SPONDYLOMETAPHYSIAL DYSPLASIAHeterogeneous group characterized by spinal and metaphysial changes of variable pattern and severity.Kyphoscoliosis, dens hypoplasia with atlantoaxial instability, and vertebral bodies extend beyond pedicles like an “open staircase.” Flaring of long bone metaphysis results in articular deformity such as coxa vara and may resemble rickets.STICKLER SYNDROMEThe descriptive alternate appellation “arthroophthalmopathy” reﬂects tis-sue distribution of types II, IX, and XI collagens in cartilage and vitreous humor.Mildest spondyloepiphysial dysplasia, including normal stature, with ocular disease most prominent.Marfanoid habitus.Type FeaturesKozlowski Autosomal dominant mutation in transient receptor potential cation channel subfamily V member 4 on 12q24.11.Allelic to brachyolmia type 3, Charcot-Marie-Tooth type IIc, metatropic dysplasia, spondylo-epiphysial dysplasia (Maroteaux), spinal muscular atrophy.Carpal and tarsal ossification delay.Sedaghatian Autosomal recessive.Cardiorespiratory insufficiency.Central nervous system anomalies.Perinatal demise.Richmond X-linked.Sclerosis of skull base.Sutcliffe Autosomal dominant.Corner and bucket handle fractures.Mild spine involvement.Goldblatt Dentinogenesis imperfecta.Joint laxity.Axial Autosomal recessive.Retinitis pigmentosa.Cone-rod dystrophyWithout or with central nervous system anomalies, psychomotor dysfunction.A4 Severe changes in neck of femur.East African Similar to A4 without anterior vertebral tongues.Algerian Severe genu valgum.Bowed forearms and facial dysmorphismType FeaturesIAutosomal dominant mutation in α-1 chain of type II collagen on 12q13.11.IIAutosomal dominant mutation in α-1 chain of type XI collagen on 1p21.1.Allelic to Marshall syndrome.IIIAutosomal dominant mutation in α-2 chain of type XI collagen on 6p21.3.Allelic to otospondylomegaepiphysial dysplasia and Weissenbacher-Zweymuller syndrome.IVAutosomal recessive mutation in α-1 chain of type IX collagen on 6q13.VAutosomal recessive mutation in α-2 chain of type IX collagen on 1p34.2.STREETER DYSPLASIASee amniotic band syndrome.THANATOPHORIC DYSPLASIAThe term, derived from Greek θανατος: “death” and φορεω: “I bring,” describes a neonatal lethal skeletal dysplasia in the family of FGFR3 receptor mutations. See achondroplasia.THROMBOCYTOPENIA–ABSENT RADIUS (TAR) SYNDROMEAutosomal recessive mutation of RNA-binding motif protein 8A on 1q21.1.Thrombocytopenia is critical in ﬁrst 2 years, when it can be lethal, is managed with platelet transfusion, and improves with age.Radial aplasia and clubhand (red) with preservation of thumb (white).Variable involvement of lower limbs, including hip dysplasia, patellar instability, absent ﬁbula, carpal hypoplasia, and synostosis.Cardiovascular, renal, and central nervous system anomalies.Distinguished from Fanconi syndrome by absence of panmyelopathy, leukemia, thumb anomalies, and pigmentary changes.TRICHORHINOPHALANGEAL DYSPLASIACraniofacial Thin “hair” (Greek θριξ, τριχο-), piriform “nose” (Greek ρις, ρινο-) with bulbous tip, and dental dysgenesis.Skeletal Conoid phalangeal epiphysis with brachydactyly, scoliosis, hip dysplasia, pes planus, and koilonychia/leukonychia.Three types are distinguished.TURNER SYNDROMEOne type of gonadal dysgenesis, characterized by amenorrhea, sterility, and delayed sexual development.Partial (p deletion or mosaicism) or complete absence of X chromo-some (45X, XO).Mild psychomotor delay, lymphedema, low hairline and ears, webbed neck, and “shield chest” with broadly spaced nipples.Short stature, cubitus valgus, patellofemoral instability, scoliosis, Madelung deformity, and fourth and ﬁfth brachydactyly.Cardiac and renal anomalies, hypothyroidism, otitis media, and celiac disease.Type FeaturesI Autosomal dominant haplo-insufficiency in zinc finger transcription factor on 8q23.3.II(Langer-Giedion)Autosomal dominant loss of functional copies of zinc finger transcription factor gene and exostosin 1 gene on 8q24.11.Phenotype combines trichorhinophalangeal syndrome and multiple exostosis.III(Sugio-Kajii)Autosomal dominant haplo-insufficiency in zinc finger transcription factor on 8q23.3. Distinguished from type I by severity of phalangeal and metacarpal involvement.Distinguished from Ruvalcaba syndrome by absence of mental retardation and microcephaly.Diab_Chap12.indd 259 9/23/2015 3:25:48 PM

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260 Syndromes / Waardenburg SyndromeVACTERL ASSOCIATIONExpanded acronym from VATER, representing a nonrandom association of independent disorders rather than a single etiologic entity. Diagnosis requires three anomalies.Vertebral Hemivertebrae produce congenital scoliosis and spinal dys-rrhaphism.Anal atresiaCardiac Septal defects, patent ductus arteriosus, tetralogy of Fallot, and transposition of the great arteries.Tracheoesophageal ﬁstulaRenal Renal aplasia/dysplasia, vesicoureteral reﬂux, and ureteropel-vic obstruction.Limb Radial aplasia/hypoplasia, radioulnar synostosis, thumb hypo-plasia, polysyndactyly, and tibial ﬁeld defects.Three types are distinguished.VACTERL may be a feature of Fanconi anæmia.VELOCARDIOFACIAL SYNDROMEAlso known as Shprintzen syndrome.Autosomal dominant mutation in T-box 1 on 22q11.21. Allelic to DiGeorge syndrome.Craniofacial Pierre Robin sequence including cleft palate, microg-nathia, and velopharyngeal insufﬁciency. Most common palatal anomaly syndrome. Ocular anomalies include tortuous retinal vessels and posterior embryotoxon. “Hooded” eyelids and asymmetric crying are characteristic.Cardiac Septal defects and conotruncal anomalies.Skeletal Arachnodactyly, scoliosis, Sprengel anomaly, and articular laxity.Other Psychiatric disorders and hypocalcemia.von WILLEBRAND DISEASEMutation in von Willebrand factor on 12p13.31.vWF binds platelets, which it promotes to adhere, and factor VIII, which degrades when not bound.Treat with the vasopressin analog desmopressin acetate (1-deami-no-8-D-arginine vasopressin; dDAVP).Orthopedic management focuses on hemarthropathy—compare hæmophilia.WHISTLING FACE SYNDROMESee Freeman-Sheldon syndrome.Type FeaturesVACTERL Mutation in the Homeobox D13 gene on 2q31.1 identi-fied in 1 patient.VACTERL-X X-linked.Mutation in zinc finger protein of cerebellum 3 on Xq26.3.VACTERL-HAssociated with hydrocephalus.Mutation in the phosphatase and tensin homolog on 10q23.31 identified in 1 patientType Features1 Quantitative partial (5-30% normal levels) deficiency. 75% of cases.2 Qualitative abnormality of von Willebrand factor.20% of cases.Further subdivided according to whether platelet function is affected or whether there is a defect in factor VIII binding. 3 Quantitative severe (< 1% normal levels) deficiency. < 5% of casesWAARDENBURG SYNDROMEAutosomal dominant mutation of paired box gene 3 on 2q36.1.The gene product is a transcription factor essential to ear, eye, and pig-mentary development.Craniofacial Sensorineural hearing loss. Dystopia canthorum giving appearance of wide-set eyes due to lateral displacement of inner canthi (W index > 2), heterochromia iridis, and synophrys.Pigmentary Albinism, including poliosis.Skeletal Spina biﬁda, winged or elevated scapulae.Subtypes reﬂect heterogeneity.Type Features1 Craniofacial malformations.2 Absence of dystopia canthorum.3 Upper limb anomalies.4 Visceral involvement such as Hirschsprung disease.Diab_Chap12.indd 260 9/23/2015 3:25:49 PM

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Syndromes / Arthritis, Juvenile Idiopathic 261ARTHRITIS, JUVENILE IDIOPATHICDisease of a joint is termed arthritis, from Greek αρθρον: “joint.” Arthralgia, from Greek αλγος: “pain,” is used when pain is the pre-dominant feature, in contrast with swelling. Arthrosis, from Greek sufﬁx -ωσις: “condition of,” originated in anatomy in the work of Galen, who distinguished different types of articulations as diarthrosis (“in all direc-tions”), amphiarthrosis (“in two directions or planes”), and synarthrosis (when bones are “joined together” such as at a suture). The term has been adopted into pathology to distinguish noninﬂammatory disease of joints, reserving arthritis for joint inﬂammation, which is indicated by Greek sufﬁx -ιτις. Inﬂammation at a site of “insertion” of a ligament or a tendon is referred to as enthesitis, from Green εν-: “in” and τιθεναι: “to place.”The term juvenile idiopathic arthritis is an inclusive term. “Rheuma-toid” has been abandoned because most subtypes lack this factor.Oligo-, from Greek ολιγος: “few,” is deﬁned as <5 joints. It has replaced pauci-, from Latin paucus: “few,” to be consistent with poly-, from Greek πολυς: “much, many,” and after the convention that Greek is the language of disease.Chronic iridocyclitis (inﬂammation of the anterior uvea) often is asymptomatic, necessitating referral to an ophthalmologist for slit-lamp examination. Early-onset disease and positive ANA are at greatest risk.Psoriasis is characterized by a dry, silvery, scaly rash, from Greek ψαω: “I rub (away), crumble.”Chronic juxta-articular inﬂammation may produce hyperemic osse-ous overgrowth in early-onset disease and premature physial closure in late-onset disease. Discrepancy does not exceed 5 cm.Orthopedic management includes: • Arthrocentesis. This is the best step to diagnosis.• Physiotherapy and bracing for contracture and weakness.• Limb equalization by physiodesis, in up to half of patients.• Arthroplasty. Overall, disease burden limits activity and prolongs implant survival.Medical treatment includes:• Nonsteroidal anti-inﬂammatory agents• Articular injection of corticosteroid• Disease-modifying antirheumatic drugs, such as methotrexate• Biologics, such as tumor necrosis factor-α blockers and anti-interleu-kin-6 inhibitorsJUVENILE IDIOPATHIC ARTHRITISCurrentFormer“Rheumatoid”Oligo-articularPauciarticularPoly-articularRheumatoid factor positivePolyarticularRheumatoid factor negativeSystemic Still diseaseEnthesitis associatedSpondyloarthropathy, including ankylosing spondylitisReiter syndromePsoriaticPsoriasisUndifferentiatedOLIGOARTICULAR POLYARTICULAR SYSTEMIC ENTHESITIS associatedFrequency60% 30% 10%Gender=Age (years)< 5 Early < 5 Late > 10 All > 10JointsLarge (e.g., knee) > small Small (e.g., fingers) > large all (including hip) ‘‘Spondylo-arthropathy’’:spine + sacro-iliac + otherPresentation Joint, iridocyclitis Unhappy: morning stiffness, fatigue, poor appetite, weight loss, anæmia.Systemic:‘‘saw-tooth’’ fever (daily rapid return to normal temperature);‘‘salmon-colored’’ migratory rash,lymphadenopathy,visceral involvement including serositis, hepatosplenomegaly,disseminated intravascular coagulation.Syndesmophytes create a ‘‘bamboo’’ appearance of the spine, and reduce excursion during maximal respira-tion and flexion (Schober sign). Inflammatory bowel disease.Bath Ankylosing Spondylitis Disease Activity Index assesses fatigue, pain, enthesitis and morning stiffness.ESRCRPANA 60% 30% 15%RF 50% (late onset) 5%HLA-B27+-Iridocyclitis Irregular pupil (white) and cataract (green)Diab_Chap12.indd 261 9/23/2015 3:25:51 PM

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262 Syndromes / Additional ReadingAlbers–Schönberg H. Roentgenbilder einer seltenen kno-chenerkrankung. Münch. Med. Wschr. 51:365, 1904.Albright F, Butler AM, Hampton AO, Smith P. Syndrome characterized by osteitis ﬁbrosa disseminata, areas of pigmentation and endocrine dysfunction, with precocious puberty in females: report of ﬁve cases. N. Eng. J. Med. 216:727–746, 1937.Apert ME. De l’acrocephalosyndactylie. Bull. Mem. Soc. Med. Hôp. Paris 23:1310–1330, 1906.Bartsocas CS, Papas CV. Popliteal pterygium syndrome: evidence for a severe autosomal recessive form. J. Med. Genet. 9:222–226, 1972.Beals RK, Hecht F. Delineation of another heritable disorder of connective tissue. J. Bone Joint Surg. 53A:987, 1971.Beals RK. Auriculo–osteodysplasia, a syndrome of multiple osseous dysplasia, ear anomaly, and short stature. J. Bone Joint Surg. 49-A:1541, 1967.Beckwith JB. Macroglossia, omphalocele, adrenal cyto-megaly, gigantism, and hyperplastic visceromegaly. Birth Defects Orig. Art. Ser. V(2):188–196, 1969.Bick EM. The classic: on hereditary cleidocranial dysostosis (transl.). Clin. Orthop. 58:5–7, 1968.Biggs R, Douglas AS, Macfarlane RG, Dacie JV, Pitney WR, Merskey C, O’Brien JR. Christmas disease: a con-dition previously mistaken for haemophilia. Brit. Med. J. 2:1378–1382, 1952.Bruck A. Über eine seltene Form von Erkrankung der Kno-chen und Gelenke. Dtsch. Med. Wsch. 23:152–155, 1897.Byers PH. Osteogenesis imperfecta. In: Royce PM, Stein-mann B. Connective Tissue and Its Heritable Disorders: Molecular, Genetic, and Medical Aspects. New York: Wiley-Liss; 1993.Caffey J, Silverman W. Infantile cortical hyperostosis, preliminary report on new syndrome. Am. J. Roentgen. 54:1–16, 1945.Canton E. Arrest of development of the left perpendicular ramus of the lower jaw, combined with malformation of the external ear. Trans. Path. Soc. London. 12:237, 1861.Carpenter G. Two sisters showing malformation of the skull and other congenital abnormalities. Rep. Soc. Study Dis. Child (London). 1:110, 1901.Conradi EJ. Vorzeitges Auftreten von Kochen und eigenar-tigen Verkalkungskernen bei Chondrodystrophia fötalis hypoplastica, Histologische und Röntgenuntersuchungen. Kinderheilk. 80:86, 1914.De Barsy AM, Moens E, Dierckx L. Dwarﬁsm, oligophrenia and degeneration of the elastic tissue in skin and cornea. A new syndrome? Helv. Paediatr. Acta 23:305–313, 1968.De Lange C. Sur un type nouveau de dé–génération (typus Amstelodamensis). Arch. Med. Enfant. 36:713, 1933.Diab M, Raff M, Gunther DF. Osseous fragility in Mar-shall-Smith syndrome. Am. J. Med. Genet. 119-A:218–222, 2003.Down JL. Mental Affections of Childhood and Youth. Lon-don, UK: Churchill; 1887:172.Down JLH. Observations on an ethnic classiﬁcation of idi-ots. Clin. Lect. Rep. London Hosp. 3:259–262, 1866.Dyggve HV, Melchior JC, Clausen J. Morquio–Ulrich’s dis-ease; An inborn error or metabolism? Arch. Dis. Child. 37:525, 1962.Eagle JF Jr, Barrett GS. Congenital deﬁciency of abdominal musculature with associated genitourinary abnormalities: a syndrome: report of nine cases. Pediatrics 6:721–736, 1950.Ehlers E. Curtis laxa, Neigung zu Haemorrhagien in der Haut lockering meherer Artikulationen. Dermatol. Z. 8:173, 1901.Ellis RBW, Van Creveld S. A syndrome characterized by ectodermal dysplasia, polydactyly, chondrodysplasia, and congenital morbus cordis: report of three cases. Arch. Dis. Child. 15:65, 1940.Escobar V, Bixler D, Gleiser S, Weaver DD. Gibbs T. Multi-ple pterygium syndrome. Am. J. Dis. Child. 132:609–611, 1978.Fairbank HAT. Dysplasia epiphysealis multiplex. Proc. Roy. Soc. Med. 39:315–317, 1945.Farabee WC. Hereditary and Sexual Inﬂuence in Meristic Variation: A Study of Digital Malformations in Man. PhD thesis. Cambridge, MA: Harvard University; 1903.Foulkes GD, Rienker K. Congenital constriction band syn-drome: a seventy-year experience. J. Pediatr. Orthop. 14:242, 1994.Freeman EA, Sheldon JH. Cranio-carpotarsal dystrophy: undescribed congenital malformation. Arch. Dis. Child. 13:277–283, 1938.Friedreich N. Über degenerative Atrophie der spinalen, Hin-terstränge. Arch. Anat. Physiol. 26:391, 1863.Frölich F. Der Mangel der Muskeln, insbesondere der Seitenbauchmuskeln. Dissertation. Germany: Wurzburg; 1839.Gaucher PCE. De l’epithelioma primitif de la rate, hyper-trophie idiopathique de la rate sans leucemie. Thesis, Fac-ulte-de Medicine Paris; 1882.Giedion A. Das Tricho-rhino-phalangeal Syndrom. Helv. Paediatr. Acta. 21:475–482, 1966.Goldenhar M. Associations malformatives de l’oeil et de l’oreille: en particulier, le syndrome: dermoide epibul-baire-appendices auriculaires—ﬁstula auris congenita et ses relations avec la dysostose mandibulo-faciale. J. Genet. Hum. 1:243-282, 1952.Golding FC. Chondro-osteodystrophy. Brit. J. Radiol. 8:457, 1935.Gorlin RJ, Cervenka J, Moller K, Horrobin M, Witkop CJ Jr. Malformation syndromes: a selected miscellany. Birth Defects Orig. Art. Ser. 11:39–50, 1975.Gross H, Groh C, Weippl G. Kongenitale hypoplastische thrombopenie mit radius-aplasie, ein syndrom multipler Abartungen. Neue Oest Z Kinderheilk. 1:574, 1956.Guillain G, Barré JA, Strohl A. Le réﬂexe médico–plantaire: Étude de ses caracteres graphiques et de son temps perdu. Bull. Soc. Med. Hôp. Paris. 40:1459, 1915.Hall JB, Reed SD, Dricoll EP. Amyoplasia: a common, spo-radic condition with congenital contractures. Am. J. Med. Genet. 15:571, 1983.Hernandez RM, Miranda A, Kofman-Alfaro S. Acrodys-ostosis in two generations: an autosomal dominant syn-drome. Clin. Genet. 39:376, 1991.Holt M, Oram S. Familial heart disease with skeletal malfor-mations. Br. Heart J. 22:236, 1960.Horton WA. Molecular genetic basis of the human chondro-dysplasias. Endocrinol. Metab. Clin. N. Am. 25:683, 1996.Hünermann CZ. Chondrodystrophia calciﬁcans congenita als abortive form der chondrodystrophie. Kinderheilk. 51:1, 1931.Hunter C. A rare disease in two brothers. Proc. R. Soc. Med. 10:104–106, 1917.Hunter J. The Works of John Hunter. Vol 1. London, UK: Longman, Rees, 1835.Jackson WPU, Albright F. Metaphyseal dysplasia, epiph-yseal dysplasia, diaphyseal dysplasia, and related conditions. I. Familial metaphyseal dysplasia and craniometaphyseal dysplasia: their relation to leontiasis ossea and osteopetrosis: disorders of ‘bone remodeling’. Arch. Intern. Med. 94:871, 1954.Jansen M. Über atypische Chondrodystrophie (Achondro-plasie) und ueber eine noch nicht beschriebene angeborene Wachstumsstoerung des Knochensystems: Metaphysaere Dysostosis. Z. Orthop. Chir. 61:253–286, 1934.Kantaputra PN, Gorlin RJ, Langer LO Jr. Dominant mesomelic dysplasia, ankle, carpal, and tarsal synostosis type: a new autosomal dominant bone disorder. Am. J. Med. Genet. 44:730–737, 1992.Kaplan FS, Xu M, Seemann P, Connor JM, Glaser DL, Car-roll L, Delai P, Fastnacht-Urban E, Forman SJ, Gilless-en-Kaesbach G, Hoover-Fong J, Koster B, Pauli RM,Reardon W, Zaidi S-A, Zasloff M, Morhart R, Mundlos S, Groppe J, Shore EM. Classic and atypical ﬁbrodysplasia ossiﬁcans progressiva (FOP) phenotypes are caused by mutations in the bone morphogenetic protein (BMP) type I receptor ACVR1. Hum. Mutat. 30:379–390, 2009.Kitoh H. Antley-Bixler syndrome: a disorder characterized by congenital synostosis of the elbow joint and the cranial suture. J. Pediatr. Orthop. 16:243, 1996.Klippel M, Feil A. Un cas d’absence des vertebres cervi-cales avec cage thoracique remontant jusqua à la base du crane (cage thoracique cervicale). Nouv. Icon. Salpetière. 25:223, 1912.Klippel M, Trenaunay P. Du naevus variqueux osteo-hyper-trophique. Arch. Gen. Med. 185:641–672, 1900.Kniest W. Zur Abgrenzung der Dysostosis enchondralis von der Chondrodystrophie. Z. Kinderheilk. 43:633–640, 1952.Kozlowski K, Maroteaux P, Spranger JW. La dysostose spondylo-metaphysaire. Presse Med. 75:2769–2774, 1967.Lamy M, Maroteaux P. Le nanisme diastrophique. Presse Med. 68:1977, 1960.Larsen LJ, Schottstaedt ER, Bost FC. Multiple congenital dislocations associated with characteristic facial abnor-mality. J. Pediatr. 37:574, 1950.Léri A, Weill J. Une affection congenitale et symetrique du developpement osseux: la dyschondrosteose. Bull. Mem. Soc. Med. Hôp Paris. 53:1491–1494, 1929.Lesch M, Nyhan WL. A familial disorder of uric acid metab-olism and central nervous system function. Am. J. Med. 36:561–570, 1964.Lewis T. Hereditary malformations of the hands and feet. IIa. Hereditary split foot. Treasury of Human Inheritance 1:6–17, 1912.Lohmann W. Beitrag zur Kenntnis des reinen Mikrophthal-mus. Arch. Augenheilk. 86:136–141, 1920.Marfan AB. Un cas de deformation congenitale des quatre membres, plus prononcee aux extremites, caracterisee par l’allongement des os avec un certain degre d’amin-cissement. Bull. Mem. Soc. Med. Hôp. Paris. 13:220–226, 1896.Maroteaux P, Bouvet JP, Briard ML. La maladie des syn-ostoses multiples. Nouv. Presse Med. 1:3041–3047, 1972.Maroteaux P, Leveque B, Marie J, Lamy M. Une nouvelle dysostose avec elimination urinaire de chondroitine-sul-fate B. Presse Med. 71:1849–1852, 1963.Maroteaux P, Spranger JW, Wiedemann H-R. Der metatro-pische Zwergwuchs. Arch. Kinderheilk. 173:211–226, 1966.Maroteaux P. La metachondromatose. Z. Kinderheilk. 109:246–261, 1971.Maroteaux P. Le syndrome campomelique. Presse Med. 22:1157–1162, 1971.Marshall RE, Graham CB, Scott CR, Smith DW. Syndrome of accelerated skeletal maturation and relative failure to thrive: a newly recognized clinical growth disorder. J. Pediatr. 78:95–101, 1971.McCune DJ. Osteitis ﬁbro–cystica: The case of a nine year old girl who also exhibits precocious puberty, multiple pigmentation of the skin and hyperthyroidism. Am. J. Dis. Child. 52:743, 1936.McKusick VA, Eldridge R, Hosteler JA, Ruangwit U, Ege-land JA. Dwarﬁsm in the Amish. II. Cartilage-hair hypo-plasia. Bull. Johns Hopkins Hosp. 116:285–326, 1965.Meier Z, Rothschild M. Ein Fall von Arthrogryposis mul-tiplex congenita kombiniert mit Dysostosis mandibulo-facialis (Franceschetti-Syndrom). Helv. Paediatr. Acta 14:213–216, 1959.Melnick JC, Needles CF. An undiagnosed bone dysplasia: a two family study of 4 generations and 3 generations. Am. J. Roentgen. 97:39–48, 1966.Möbius PJ. Über angeborene doppelseitige Abducens-Fa-cialis-Laehmung. Münch. Med. Wschr. 35: 91–94 and 108–111, 1888.Nievergelt K. Positiver Vaterschaftsnachweis auf grund erblicher Missbildungen der Extremitaeten. Arch. Klaus Stift Vererbungsforsch. 19:157, 1944.Nowaczyk MJ, Huggins MJ, Fleming A, Mohide PT. Fem-oral-facial syndrome: prenatal diagnosis and clinical features. Report of three cases. Am. J. Med. Genet. 152-A:2029–2033, 2010.Otto JC. An account of an hemorrhagic disposition existing in certain families. M. Repository 6:1, 1803.Penttinen RP, Lichtenstein JR, Martin GR, McKusick VA. Abnormal collagen metabolism in cultured cells in Diab_Chap12.indd 262 9/23/2015 3:25:51 PM

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Syndromes / Additional Reading 263 osteogenesis imperfecta. Proc. Nat. Acad. Sci. 72:586–589, 1975.Poland A. Deﬁciency of the pectoral muscle. Guys Hosp. Rep. 6:191, 1841.Prader A, Labhart A, Willi H. Ein Syndrom von Adiposi-tas, Kleinwuchs, Kryptorchismus und Oligophrenie nach Myatonieartigem Zustand im Neugeborenenalter. Sch-weiz. Med. Wschr. 86:1260–1261, 1956.Prockop DJ, Kivirikko KI. Heritable diseases of collagen. N. Eng. J. Med. 311:376–386, 1984.Pyle E. Case of unusual bone development. J. Bone Joint Surg. 13:874–876, 1931.Quan L, Smith DW. The VATER association: vertebral defects, anal atresia, tracheoesophageal ﬁstula with esoph-ageal atresia, radial dysplasia. Birth Defects Orig. Art. Ser. 8(2):75–78, 1972.Ribbing S. Studien ueber hereditaere, multiple Epiphysens-toerungen. Acta Radiol. Suppl. 34:7–107, 1937.Riley CM, Day RL, Greeley DM, Langford WS. Central autonomic dysfunction with defective lacrimation: report of ﬁve cases. Pediatrics 3:468–478, 1949.Rock MJ, Prenen J, Funari VA, Funari TL, Merriman B, Nelson SF, Lachman RS, Wilcox WR, Reyno S, Quadrelli R, Vaglio A, Owsianik G, Janssens A, Voets T,Ikegawa S, Nagai T, Rimoin DL, Nilius B, Cohn DH. Gain-of-function mutations in TRPV4 cause autosomal domi-nant brachyolmia. Nat. Genet. 40:999–1003, 2008.Rubinstein JH, Taybi H. Broad thumbs and toes and facial abnormalities. Am. J. Dis. Child. 105:588–608, 1963.Russell A. A syndrome of intra-uterine-dwarﬁsm recogniz-able at birth with cranio-facial dysostosis, disproportionate short arms, and other anomalies (5 examples). Proc. Roy. Soc. Med. 47:1040–1044, 1954.Scheie HG, Hambrick GW Jr, Barness LA. A newly recog-nized forme fruste of Hurler’s disease (gargoylism). Am. J. Ophthal. 53:753–769, 1962.Schmid F. Beitrag zur Dysostosis enchondralis metaphys-area. Mschr. Kinderheilk. 97:393–397, 1949.Shprintzen RJ, Goldberg RB, Young D, Wolford L. The velo-cardio-facial syndrome: a clinical and genetic anal-ysis. Pediatrics 67:167–172, 1981.Sillence DO, Senn A, Danks DM. Genetic heterogeneity in osteogenesis imperfecta. J. Med. Genet. 16:101–116, 1979.Silver HK, Kiyasu W, George J, Deamer WC. Syndrome of congenital hemihypertrophy, shortness of stature, and elevated urinary gonadotropins. Pediatrics 12:368–376, 1953.Sly WS, Quinton B, McAlister WH, Rimoin DL. Beta-glu-curonidase deﬁciency: report of clinical, radiologic, biochemical features of a new mucopolysaccharidosis. J. Pediatr. 82:249–257, 1973.Stern AM, Gall JC Jr, Perry BL, Stimson CW, Weitkamp LR, Poznanski AK. The hand-foot-uterus syndrome: a new hereditary disorder characterized by hand and foot dyspla-sia, dermatoglyphic abnormalities, and partial duplication of the female genital tract. J. Pediatr. 77:109–116, 1970.Streeter GL. Focal deﬁciencies in fetal tissues and their relation to intra-uterine amputation. Contrib. Embryol. 22(126):1–144, 1930.Trélat V. Sur un vice conformation trés-rare de la lévre inférieure. J. Med. Chir. Pract. 40:442, 1869.Trevor D. Tarso-epiphysial aclasis: a congenital error of epiphysial development. J. Bone Joint Surg. 32-B:204–213, 1950.Turner HH. A syndrome of infantilism, congenital webbed neck, and cubitus valgus. Endocrinology 23:566–74, 1938.Turner JW. An hereditary arthrodysplasia associated with hereditary dystrophy of the nails. JAMA 100:882–884, 1933.von Recklinghausen F. Über die multiplen Fibrome der Haut und ihre Beziehung zu den multiplen Neuromen. Berlin, Germany: August Hirschwald; 1882.Waardenburg P. A new syndrome combining developmental anomalies of the eyelids, eyebrows and nose root with pig-mentary defects of the iris and head hair and with congeni-tal deafness. Am. J. Hum. Genet. 3:195–253, 1951.Weber FP. Angioma formation in connection with hyper-trophy of limbs and hemihypertrophy. Brit. J. Derm. 19:231–235, 1907.Wheaton SW. Two specimens of congenital cranial defor-mity in infants associated with fusion of the ﬁngers and toes. Trans. Path. Soc. Lon. 45:238–241, 1894.Wiedemann H-R, Burgio GR, Aldenhoff P, Kunze J, Kaufmann HJ, Schirg E. The Proteus syndrome: partial gigantism of the hands and/or feet, nevi, hemihypertrophy, subcutaneous tumors, macrocephaly or other skull anom-alies and possible accelerated growth and visceral affec-tions. Europ. J. Pediatr. 140:5–12, 1983.Wood VE, Peppers TA, Shook J. Cleft-foot closure: a sim-pliﬁed technique and review of the literature. J. Pediatr. Orthop. 17:501, 1997.Diab_Chap12.indd 263 9/23/2015 3:25:51 PM

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