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Skeletal Dysplasias

, MD, FRCPC and , MD.

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Last Update: January 30, 2017.

ABSTRACT

Skeletal dysplasias form a complex group of more than 400 conditions with extraordinary clinical and molecular heterogeneity. Their classification changes as we learn about their molecular bases. After a brief introduction to the evaluation of the short child, this chapter is structured according to the 2010 nosology and classification of genetic skeletal disorders and is not intended to detail each rare skeletal dysplasia. Rather, it aims to familiarize the reader with this classification, so that the clinician will be able to determine in which category of conditions to place an affected individual and thus establish a differential diagnosis. We then describe the clinical and radiological manifestations of some of the more common skeletal dysplasias in each group.

Introduction

Skeletal dysplasias form a complex group of more than 400 conditions with extraordinary clinical and molecular heterogeneity. Their classification changes as we learn about their molecular bases. After a brief introduction to the evaluation of the short child, this chapter is structured according to the 2010 nosology and classification of genetic skeletal disorders (1) and is not intended to detail each rare skeletal dysplasia. Rather, it aims to familiarize the reader with this classification, so that the clinician will be able to determine in which category of conditions to place an affected individual and thus establish a differential diagnosis. In the following chapter, we describe the clinical and radiological manifestations of some of the more common skeletal dysplasias in each group. The table for each section lists, when available, the inheritance pattern, the gene, and the OMIM number. General references used include OMIM (www.omim.org), Genereviews (GR, www.ncbi.nlm.nih.gov/books/1116/), Orphanet (www.orpha.net), and chapters or manuscripts by Dr. Spranger (2, 3) and Dr. Lachman (4). For genetic testing, clinicians are encouraged to refer to the Genetic Testing Registry (http://www.ncbi.nlm.nih.gov/gtr/) and their local geneticist.

EVALUATION OF THE SHORT CHILD

The first step is to analyze the growth curve of the child, compare it to an ethnicity-appropriate reference and the growth history of the parents. After a thorough familial and clinical history and examination, treatable endocrine and common conditions should be considered. Namely, if there is proportionate short stature with increased weight-for-height ratio, one needs to consider growth hormone deficiency or insensitivity, hypothyroidism, or glucocorticoid excess. Work-up could include measuring bone age, IGF1, IGFBP3, T4, TSH. A karyotype, GH, GHBP, GHRH and ACTH may be indicated. If there is proportionate short stature with decreased weight-for-height ratio, one needs to consider undernutrition or malnutrition, malabsorption, or a chronic systemic disease. Work-up depends on history and physical examination, but may include a complete blood count with sedimentation rate (for inflammatory bowel disease) and serum tissue transglutaminase (for celiac disease), serum electrolytes and a first-void morning urinalysis (for renal tubular acidosis or nephrogenic diabetes insipidus). A more detailed discussion can be found in a review by Rose et al.(5) and other chapters in Endotext.

SKELETAL DYSPLASIA CLASSIFICATION

The first 8 groups of conditions in the 2010 nosology are separated according to the molecular basis of the disease: FGFR3, type 2 collagen, type 11 collagen, sulfation disorders, perlecan, aggrecan, filamin, and TRPV4. The other 32 groups are organized according to their clinical and radiographic presentation. The prefix acro- refers to the extremities (hands and feet), meso- to the middle portion (ulna and radius, tibia and fibula), rhizo- to the proximal portion (femur and humerus), spondylo- to the spine, epi- to the epiphyses, and meta- to the metaphyses. For example, if only the hands and feet are shorter, one would consult the acromelic group of conditions, whereas if the spine and metaphyses are affected, one would consult the spondylometaphyseal dysplasias. Listed below are the 40 groups of conditions to be detailed in this chapter.

Groups of conditions organized according to their molecular bases

  1. FGFR3 chondrodysplasia group
  2. Type 2 collagen group and similar disorders
  3. Type 11 collagen group
  4. Sulfation disorders group
  5. Perlecan group
  6. Aggrecan group
  7. Filamin group and related disorders
  8. TRPV4 group

Groups of conditions organized according to their clinical presentations

9.

Short-ribs dysplasias (with or without polydactyly) group

10.

Multiple epiphyseal dysplasia and pseudoachondroplasia group

11.

Metaphyseal dysplasias

12.

Spondylometaphyseal dysplasias (SMD)

13.

Spondylo-epi-(meta)-physeal dysplasias (SE(M)D)

14.

Severe spondylodysplastic dysplasias

15.

Acromelic dysplasias (extremities of the limbs)

16.

Acromesomelic dysplasias (extremities and middle portion of the limbs)

17.

Mesomelic and rhizo-mesomelic dysplasias (proximal and middle portions of the limbs)

18.

Bent bones dysplasias

19.

Slender bone dysplasia group

20.

Dysplasias with multiple joint dislocations

21.

Chondrodysplasia punctata (CDP) group

22.

Neonatal osteosclerotic dysplasias

23.

Increased bone density group (without modification of bone shape)

24.

Increased bone density group with metaphyseal and/or diaphyseal involvement

25.

Osteogenesis imperfecta and decreased bone density group

26.

Abnormal mineralization group

27.

Lysosomal storage diseases with skeletal involvement (dysostosis multiplex group)

28.

Osteolysis group

29.

Disorganized development of skeletal components group

30.

Overgrowth syndromes with skeletal involvement

31.

Genetic inflammatory/rheumatoid-like osteoarthropathies

32.

Cleidocranial dysplasia and isolated cranial ossification defects group

33.

Craniosynostosis syndromes

34.

Dysostoses with predominant craniofacial involvement

35.

Dysostoses with predominant vertebral with and without costal involvement

36.

Patellar dysostoses

37.

Brachydactylies (with or without extraskeletal manifestations)

38.

Limb hypoplasia—reduction defects group

39.

Polydactyly-Syndactyly-Triphalangism group

40.

Defects in joint formation and synostoses

1. FGFR3 chondrodysplasia group

Thanatophoric dysplasia (thus named because it often results in early death) is characterized by micromelia with bowed femurs, short ribs, narrow thorax, macrocephaly, distinctive facial features, brachydactyly, hypotonia. Radiographically, there is rhizomelic shortening of the long bones with irregular metaphyses, platyspondyly, small foramen magnum with brain stem compression, bowed femurs (TD type I) and cloverleaf skull (always in TD type II; sometimes in TD type I). CNS abnormalities include temporal lobe malformations, hydrocephaly, brain stem hypoplasia and neuronal migration abnormalities.

Image skeletal-dysplasias_Figure-1-Thanatophoric-dysplasia-1024x642.jpg

Figure 1. Thanatophoric dysplasia type 1. Severe platyspondyly, very short ribs narrow thorax, short broad pelvis, large skull, very short and bent long bones.

Achondroplasia is characterized by small stature with rhizomelia and redundant skin folds, limitation of elbow extension and genu varum, short fingers with trident configuration of the hands. Craniocervical junction compression is a major complication which may occur and requires surveillance for early detection and management. There is also thoracolumbar kyphosis, lumbar lordosis, and a large head with frontal bossing with midface hypoplasia. The radiographic findings include short tubular bones with metaphyseal flaring, narrowing of the interpediculate distance of the lumbar spine, rounded ilia and horizontal acetabula, narrow sacrosciatic notch and proximal femoral radiolucency. In hypochondroplasia, there are similar but milder clinical and radiological findings, the head is large but there is no midface hypoplasia.

Image skeletal-dysplasias_Figure-2-Achondroplasia-1024x762.jpg

Figure 2. Achondroplasia. Small rounded iliac bones, horizontal acetabula, decreasing interpediculate distance, normal vertebral body height, short ribs.

Image skeletal-dysplasias_Figure-3-Hypochondroplasia-1024x367.jpg

Figure 3. Hypochondroplasia. decreased interpediculate distance, short broad long bones , short wide femoral necks, relative elongation of the distal fibula compare to tibia.

Group/name of disorderInher.OMIMGROrphaGene
Thanatophoric dysplasia type 1 (TD1)AD 187600 1366 1860 FGFR3
Thanatophoric dysplasia type 2 (TD2)AD 187601 1366 93274 FGFR3
Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN)AD 187600 1455 85165 FGFR3
AchondroplasiaAD 100800 1152 15 FGFR3
HypochondroplasiaAD 146000 1477 429 FGFR3
Camptodactyly, tall stature, and hearing loss syndrome (CATSHL)AD 610474 FGFR3

Please also refer to group 33 for craniosynostoses syndromes linked to FGFR3 mutations, as well as LADD syndrome in group 39 for another FGFR3-related phenotype.

2. TYPE 2 COLLAGEN GROUP

Stickler syndrome is characterized by ocular findings of myopia, cataract, and retinal detachment, sensorineural and conductive hearing loss, flat mala and cleft palate (alone or as part of the Robin sequence), mild spondyloepiphyseal dysplasia and early-onset arthritis (6).

Image skeletal-dysplasias_Figure-4-Stickler-1024x331.jpg

Figure 4. Stickler syndrome. small epiphyses, wide femoral neck, hypoplastic iliac wings, flat epiphyses, schmorl’s nodules.

Spondyloepiphyseal dysplasia congenita (SEDC) presents with disproportionate short stature (short trunk), abnormal epiphyses, and flattened vertebral bodies. Some features of Stickler syndrome include myopia and/or retinal degeneration with retinal detachment and cleft palate.

Image skeletal-dysplasias_Figure-5-SED-Congenita-1024x375.jpg

Figure 5. sed congenita. platyspondyly, delayed epiphyseal ossification (especially femoral heads), dens hypoplasia.

Group/name of disorderInher.OMIMGROrphaGene
Achondrogenesis type 2 (ACG2; Langer-Saldino)AD 200610 93296 COL2A1
Platyspondylic dysplasia, Torrance typeAD 151210 85166 COL2A1
HypochondrogenesisAD 200610 93296 COL2A1
Spondyloepiphyseal dysplasia congenita (SEDC)AD 183900 94068 COL2A1
Spondyloepimetaphyseal dysplasia (SEMD) Strudwick typeAD 184250 93346 COL2A1
Kniest dysplasiaAD 156550 485 COL2A1
Spondyloperipheral dysplasiaAD 271700 1856 COL2A1
Mild SED with premature onset arthrosisAD COL2A1
SED with metatarsal shortening (formerly Czech dysplasia)AD 609162 137678 COL2A1
Stickler syndrome type 1AD 108300 1302 828 COL2A1

3. TYPE 11 COLLAGEN GROUP

Marshall syndrome resembles Stickler syndrome but is characterized by a flat or retracted midface, thick calvaria, abnormal frontal sinuses with shallow orbits, intracranial calcifications, and ectodermal abnormalities including abnormal sweating and teeth.

Otospondylomegaepiphyseal dysplasia (OSMED) is characterized by sensorineural hearing loss, enlarged epiphyses, skeletal dysplasia with disproportionately short limbs, vertebral body anomalies, midface hypoplasia, a short nose with anteverted nares and a flat nasal bridge, a long philtrum, cleft palate/bifid uvula, micrognathia, and hypertelorism.

Group/name of disorderInher.OMIMGROrphaGene
Stickler syndrome type 2AD 604841 1302 90654 COL11A1
Marshall syndromeAD 154780 560 COL11A1
FibrochondrogenesisAR 228520 2021 COL11A1
Otospondylomegaepiphyseal dysplasia (OSMED), recessive typeAR 215150 1427 COL11A2
Otospondylomegaepiphyseal dysplasia (OSMED), dominant type (Weissenbacher-Zweymüller syndrome, Stickler syndrome type 3)AD 215150 1427 COL11A2

Please also refer to Stickler syndrome type 1 in group 2

4. SULFATION DISORDERS GROUP

Achondrogenesis type 1B (ACG1B) is characterized extremely short limbs with short fingers and toes, hypoplasia of the thorax, protuberant abdomen, and hydropic fetal appearance. There is a normal-sized skull with a flat facies. There is a lack of ossification of the vertebral bodies (except for pedicles), short and thin ribs, and ossification of the upper part of iliac bones giving crescent-shaped appearance. Shortening of the tubular bones with metaphyseal spurring ("thorn apple" appearance) is seen.

The clinical features of diastrophic dysplasia (DTD) include limb shortening with hitchhiker thumbs, ulnar deviation of the fingers, a gap between the first and second toes, clubfeet, contractures of large joints, early-onset osteoarthritis and radial dislocation. The skull is normal-sized. There is some trunk shortening, a small chest with a protuberant abdomen and spinal deformities (scoliosis, exaggerated lumbar lordosis, cervical kyphosis). Non-skeletal findings include a cleft palate, cystic ear swelling in the neonatal period, and flat hemangiomas of the forehead.

Group/name of disorderInher.OMIMGROrphaGene
Achondrogenesis type 1B (ACG1B)AR 600972 1516 93298 SLC26A2
Atelosteogenesis type 2 (AO2)AR 256050 1317 56304 SLC26A2
Diastrophic dysplasia (DTD)AR 222600 1350 628 SLC26A2
MED, autosomal recessive type (rMED; EDM4)AR 226900 1306 93307 SLC26A2
SEMD, PAPSS2 typeAR 603005 93282 PAPSS2
Chondrodysplasia with congenital joint dislocations, CHST3 type (recessive Larsen syndrome)AR 608637 62112 263463 CHST3
Ehlers-Danlos syndrome, CHST14 type (“musculo-skeletal variant”)AR 601776 2953 CHST14

Please also refer to groups 7 and 26 for other conditions with multiple dislocations

5. PERLECAN GROUP

Schwartz-Jampel syndrome manifests with myotonia (characteristic facies with blepharophimosis and a puckered facial appearance) and osteoarticular abnormalities with progressive joint stiffness. There is also a flattening of the vertebral bodies, short stature, hip dysplasia, bowing of the diaphyses and irregular epiphyses.

Group/name of disorderInher.OMIMOrphaGene
Dyssegmental dysplasia, Silverman-Handmaker typeAR 224410 1865 HSPG2
Dyssegmental dysplasia, Rolland-Desbuquois typeAR 224400 156731 HSPG2
Schwartz-Jampel syndrome (myotonic chondrodystrophy)AR 255800 800 HSPG2Aggrecan group

6. AGGRECAN GROUP

These conditions have been each described in one family and will not be discussed in detail here.

Group/name of disorderInher.OMIMOrphaGene
SED, Kimberley typeAD 608361 93283 ACAN
SEMD, Aggrecan typeAR 612813 171866 ACAN
Familial osteochondritis dissecansAD 165800 251262 ACAN

8. TRPV4 group

Metatropic dysplasia is a severe spondyloepimetaphyseal dysplasia characterized in infancy by a long trunk and short limbs with limitation and enlargement of joints and usually severe kyphoscoliosis. The term metatropic comes from the Greek metatropos, and refers to the changing pattern of the skeletal anomalies. Indeed, there is progressive kyphoscoliosis which leads to a shortened trunk. Radiologic features include platyspondyly, metaphyseal enlargement, and shortening of long bones.

Spondylometaphyseal dysplasia, Kozlowski type is characterized by short-trunked short stature, metaphyseal abnormalities in the femur (prominent in the femoral neck and trochanteric area) with coxa vara, scoliosis and platyspondyly.

Group/name of disorderInher.OMIMGROrphaGene
Metatropic dysplasiaAD 156530 2635 TRPV4
Spondyloepimetaphyseal dysplasia, Maroteaux type (Pseudo-Morquio syndrome type 2)AD 184095 263482 TRPV4
Spondylometaphyseal dysplasia, Kozlowski typeAD 184252 93314 TRPV4
Brachyolmia, autosomal dominant typeAD 113500 93304 TRPV4
Familial digital arthropathy with brachydactylyAD 606835 85169 TRPV4

9.Short-ribs dysplasias (with or without polydactyly) group

The short rib-polydactyly syndromes (SRPS) are ciliopathies characterized by short ribs, short limbs, polydactyly, and multiple anomalies of major organs, including heart, intestines, genitalia, kidney, liver, and pancreas. In SRPS I (Saldino-Noonan type), the long bones are torpedo-shaped; in SRPS III (Verma-Naumoff type) they are banana-peel shaped. In SRPS II (Majewski syndrome) the tibiae are short and oval, and in SRPS VI (Beemer type), the tibiae are not as short and polydactyly is rare (7).

In asphyxiating thoracic dystrophy (Jeune syndrome), there is a severely constricted thoracic cage, short-limbed short stature, polydactyly, retinal degeneration and pancreatic cysts.

Image skeletal-dysplasias_Figure-6-Asphyxiating-Thoracic-Dystrophy-1024x419.jpg

Figure 6. asphyxiating thoracic dystrophy. short ribs long and narrow chest, small pelvis, trident acetabula, no platyspondyly (helps differentiate from thanatophoric dysplasia), cystic renal disease.

Ellis-van Creveld syndrome is characterized by short limbs, short ribs, postaxial polydactyly, and dysplastic nails and teeth.

Image skeletal-dysplasias_Figure-7-Chondroectodermal-Dysplasia-1024x231.jpg

Figure 7. chondroectodermal dysplasia (or Ellis-van Creveld syndrome). short ribs, early ossification of femoral head, polydactyly cone-shaped epiphyses, no platyspondyly (helps differentiate from thanatophoric dysplasia), flatening of lateral aspect of proximal tibial epiphysis.

In uniparental disomy of paternal chromosome 14, there is a narrow, bell-shaped thorax with caudal bowing of the anterior ribs and cranial bowing of the posterior ribs (coat hanger appearance) (8), and flaring of the iliac wings. There are also joint contractures, dysmorphic facial features, and developmental delay/intellectual deficiency.

Group/name of disorderInher.OMIMOrphaGene
Chondroectodermal dysplasia (Ellis-van Creveld)AR 225500 289 EVC1, ECV2, LBN
Short rib—polydactyly syndrome (SRPS) type 1/3 (Saldino-Noonan/Verma-Naumoff)AR 263510 93271 DYNC2H1
SRPS type 1/3 (Saldino-Noonan)AR 263510 93271 IFT80
SRPS type 2 AAR 263520 93269 NEK1
SRPS type 2BAR 615087 93269 DYNC2H1
SRPS type 3 Verma-NaumoffAR 263510 93271 DYNC2H1
SRPS type 4 (Beemer)AR 269860 93268
SRPS type 5AR 614091 WDR35
Uniparental disomy of paternal chromosome 14 (UPD14) 608149 96334 Complete chromosome 14
Cerebrocostomandibular syndromeAR/AD 117650 1393 SNRPB
Oral-facial-digital syndrome type 4 (Mohr-Majewski)AR 258860 2753 TCTN3
Asphyxiating thoracic dysplasia (ATD; Jeune)AR 208500 474 TTC21B, IFT80, WDR19, DYNC2H1, ATD
Thoracolaryngopelvic dysplasia (Barnes)AD 187760 3317

10. Multiple epiphyseal dysplasia and pseudoachondroplasia group

Multiple epiphyseal dysplasia is usually not recognizable before 1-2 years of age (9). Then, joint pain at the hips and knees is noted after physical exercise. Mild to moderate short stature is seen by 5-6 years of age. Radiologically, there is bilateral necrosis of the femoral heads, and the epiphyses of tubular bones, (including metacarpals, metatarsals and phalanges) show maturational delay. Femoral and phalangeal epiphyses are rounded (COMP) or flat (SCL26A2, see group 4). Double-layered patellae can be seen (SCL26A2). The most frequently mutated genes are COMP and SCL26A2, then the genes encoding type 9 collagen and Matrillin 3.

Image skeletal-dysplasias_Figure-8-MED-1024x353.jpg

Figure 8. Multiple epiphyseal dysplasia. Flattened epiphyses, normal spine (no platyspondyly).

Image skeletal-dysplasias_Figure-9-Pseudoachondroplasia-1024x409.jpg

Figure 9. pseudoachondroplasia. small femoral head, irregular epiphyses, platyspondyly with anterior tongues of vertebral bodies, irregular acetabula.

Group/name of disorderInher.OMIMGROrphaGene
Pseudoachondroplasia (PSACH)AD 177170 1487 750 COMP
Multiple epiphyseal dysplasia (MED) type 1 (EDM1)AD 132400 1123 93308 COMP
Multiple epiphyseal dysplasia (MED) type 2 (EDM2)AD 600204 1123 166002 COL9A2
Multiple epiphyseal dysplasia (MED) type 3 (EDM3)AD 600969 1123 166002 COL9A3
Multiple epiphyseal dysplasia (MED) type 5 (EDM5)AD 607078 1123 93311 MATN3
Multiple epiphyseal dysplasia (MED) type 6 (EDM6)AD 614135 1123 166002 COL9A1
Multiple epiphyseal dysplasia (MED), other types 1123
Stickler syndrome, recessive typeAR 614134 1302 250984 COL9A1
Familial hip dysplasia (Beukes)AD 142669 1123 2114 UFSP2
Multiple epiphyseal dysplasia with microcephaly and nystagmus (Lowry-Wood)AR 226960 1824

Please also refer to multiple epiphyseal dysplasia, recessive type (rMED; EDM4) in sulfation disorders (group 4), familial osteochondritis dissecans in the aggrecan group, as well as ASPED in the Acromelic group

11. Metaphyseal dysplasias

Cartilage-hair hypoplasia manifests with severe disproportionate short-limbed short stature with short hands, bowed femorae and tibiae, joint hypermobility and often metaphyseal dysplasia and large, round epiphyses during childhood, bullet-shaped middle phalanges and vertebral dysplasia. Non-skeletal findings include fine silky slow growing hair, immunodeficiency manifested by an increased rate of infections, anemia, gastrointestinal dysfunction, and an increased risk for malignancy.

Image skeletal-dysplasias_Figure-10-Cartilage-Hair-Hypoplasia-1024x548.jpg

Figure 10. cartilage-hair hypoplasia. widening of the growth plate (often focal), metaphyseal cupping and irregularity with cyst-like lucencies, short metacarpals and phalanges with cupping and cone-shaped epiphyses.

Shwachman-Diamond syndrome manifests with exocrine pancreatic insufficiency with malabsorption, malnutrition, and growth failure, hematologic abnormalities, including increased risk of malignant transformation, and skeletal abnormalities which include short stature, generalized osteopenia, with delayed appearance of secondary ossification centers (delayed bone age) metaphyseal chondrodysplasia (metaphyses wide and irregular) and finally thickening and irregularity of the growth plates.

Schmid type of metaphyseal chondrodyplasia manifests with short stature, widened growth plates, bowing of the long bones and resembles a milder form of Jansen type metaphyseal chondrodysplasia. Radiological signs include enlarged capital femoral epiphysis in early childhood, coxa vara, greater involvement of the distal femoral metaphysis than the proximal (these disappear after epiphyseal fusion), anterior rib changes and a normal spine.

Group/name of disorderInher.OMIMGROrphaGene
Metaphyseal dysplasia, Schmid type (MCS)AD 156500 174 COL10A1
Cartilage-hair hypoplasia (CHH; metaphyseal dysplasia, McKusick type)AR 250250 84550 175 RMRP
Metaphyseal dysplasia, Jansen typeAD 156400 33067 PTHR1
Eiken dysplasiaAR 600002 79106 PTHR1
Metaphyseal dysplasia with pancreatic insufficiency and cyclic neutropenia (Shwachman-Diamond syndrome)AR 260400 1756 811 SBDS
Metaphyseal anadysplasia type 1AD, AR 602111 1040 MMP13
Metaphyseal anadysplasia type 2AR 613073 1040 MMP9
Metaphyseal dysplasia, Spahr typeAR 250400 2501 MMP13
Metaphyseal acroscyphodysplasia (various types)AR 250215 1240
Genochondromatosis (type 1/type 2)AD/SP 137360 85197
Metaphyseal chondromatosis with d-2-hydroxyglutaric aciduriaAR/SP 614875 99646 IDH1

12. Spondylometaphyseal dysplasias (SMDSpondylometaphyseal dysplasias (SMD)

SMD Sutcliffe type presents with proportional mild short stature. The spine shows odontoid hypoplasia, hyperconvex vertebral body endplates (lower thoracic and upper lumbar) with an appearance of anterior wedging and no platyspondyly or kyphoscoliosis. Hips show progressive coxa vara with short femoral necks leading to a waddling gait. Metaphyseal abnormalities include flakelike, triangular, or curvilinear ossification centers at the edges of the metaphyses simulating “corner fractures” of long tubular bones, distal tibial metaphyses on the ulnar aspect of the distal radius and in the proximal humerus. Some patients have been reported to have COL2A1 mutations.

Group/name of disorderInher.OMIMOrphaGene
Spondyloenchondrodysplasia (SPENCD)AR 271550 1855 ACP5
Odontochondrodysplasia (ODCD)AR 184260 166272
Spondylometaphyseal dysplasia, Sutcliffe type or corner fractures typeAD 184255 93315 COL2A1
SMD with severe genu valgumAD 184253 93316
SMD with cone-rod dystrophyAR 608940 85167 PCYT1A
SMD with retinal degeneration, axial typeAR 602271 168549
DysspondyloenchondromatosisSP 85198 COL2A1
Cheiro-spondyloenchondromatosisSP 99647

Please also refer to SMD Kozlowski (group TRPV4) disorders in group 11 as well as SMD Sedaghatian type in group 12; there are many individual reports of SMD variants

13. Spondylo-epi-(meta)-physeal dysplasias (SE(M)D)

Spondyloepiphyseal dysplasia tarda manifests with disproportionately short stature and a short trunk. Affected males exhibit retarded growth from about six years of age. Progressive joint and back pain with osteoarthritis follows, involving the larger joints more than the small joints. Radiologically, there are multiple epiphyseal abnormalities, platyspondyly, narrow disc spaces, scoliosis, hypoplastic odontoid process, short femoral necks and coxa vara.

Group/name of disorderInher.OMIMGROrphaGene
Dyggve-Melchior-Clausen dysplasia (DMC)AR 223800 239 DYM
Immuno-osseous dysplasia (Schimke)AR 242900 1376 1830 SMARCAL1
SED, Wolcott-Rallison typeAR 226980 1667 EIF2AK3
SEMD, Matrilin typeAR 608728 156728 MATN3
SEMD, short limb—abnormal calcification typeAR 271665 93358 DDR2
SED tarda, X-linked (SED-XL)XLR 313400 1145 93284 SEDL
Spondylo-megaepiphyseal-metaphyseal dysplasia (SMMD)AR 613330 228387 NKX3-2
Spondylodysplastic Ehlers-Danlos syndromeAR 612350 157965 SLC39A13
SPONASTRIME dysplasiaAR 271510 93357
SEMD with joint laxity (SEMD-JL) leptodactylic or Hall typeAD 603546 93360 KIF22
SEMD with joint laxity (SEMD-JL) Beighton typeAR 271640 93359 B3GALT6
Platyspondyly (brachyolmia) with amelogenesis imperfectaAR 601216 2899 LTBP3
Late onset SED, autosomal recessive typeAR 609223 93284
Brachyolmia, Hobaek typeAR 271530 93301 PAPSS2
Brachyolmia, Toledo typeAR 271630 93303 PAPSS2

Please also refer to Brachyolmia (group 8), Opsismodysplasia (group 14), SEMDs (group 11), mucopolysaccharidosis type 4 (Morquio syndrome) and other conditions in group 26, as well as PPRD (SED with progressive arthropathy) in group 31

14. Severe spondylodysplastic dysplasias

In opsismodysplasia, there is a large anterior fontanelle, anteverted nostrils, pelvic bone anomalies, metaphyseal cupping, delayed ossification, shortened digits, hypotonia, and early death.

Group/name of disorderInher.OMIMOrphaGene
Achondrogenesis type 1A (ACG1A)AR 200600 93299 TRIP11
Schneckenbecken dysplasiaAR 269250 3144 SLC35D1
Spondylometaphyseal dysplasia, Sedaghatian typeAR 250220 93317 GPX4
Severe spondylometaphyseal dysplasia (SMD Sedaghatian-like)AR SBDS
OpsismodysplasiaAR 258480 2746 INPPL1

Please also refer to Thanatophoric dysplasia, types 1 and 2 (group 1); ACG2 and Torrance dysplasia (group 2); Fibrochondrogenesis (group 3); Achondrogenesis type 1B (ACG1B, group 4); and Metatropic dysplasia (TRPV4 group).

15. Acromelic dysplasias

In Trichorhinophalangeal syndromes, skeletal abnormalities include a short stature, cone-shaped epiphyses at the phalanges, hip malformations, and short stature. All phalanges, metacarpals and metatarsal bones are shortened. Non-skeletal features include sparse scalp hair, bulbous tip of the nose, long flat philtrum, thin upper vermilion border, and protruding ears.

Image skeletal-dysplasias_Figure-11-Trichorhynophalangeal-907x1024.jpg

Figure 11. Trichorhinophalangeal syndrome. shortened phalanges and metacarpals, cone-shaped epiphyses.

In Geleophysic dysplasia, there is short stature, short hands and feet, progressive joint limitation and contractures, distinctive facial features ("smiling" round and full face, small nose with anteverted nostrils, a broad nasal bridge, hypertelorism, long flat philtrum, and a thin upper lip), progressive cardiac valvular disease, and thickened skin.

Group/name of disorderInher.OMIMGROrphaGene
Trichorhinophalangeal dysplasia types 1/3AD 190350 77258 TRPS1
Trichorhinophalangeal dysplasia type 2 (Langer-Giedion)AD 150230 502 TRPS1 andEXT1
Acrocapitofemoral dysplasiaAR 607778 63446 IHH
Cranioectodermal dysplasia (Levin-Sensenbrenner) type 1AR 218330 1515 IFT122
Cranioectodermal dysplasia (Levin-Sensenbrenner) type 2AR 613610 1515 WDR35
Geleophysic dysplasiaAR 231050 11168 2623 ADAMTSL2
Geleophysic dysplasia, other typesAR 614185 11168 2623 FBN1
Acromicric dysplasiaAD 102370 969 SMAD4
Acrodysostosis type 1AD 101800 950 PRKAR1A
Acrodysostosis type 2AD 614613 950 PDE4D
Angel-shaped phalango-epiphyseal dysplasia (ASPED)AD 105835 63442
Saldino-Mainzer dysplasiaAR 266920 140969 IFT140
Myhre syndromeAD 139210 2588 SMAD4
Weill-Marchesani syndrome type 1AR 277600 1114 3449 ADAMTS10
Weill-Marchesani syndrome type 2AD 608328 1114 2084 FBN1

Please also refer to the short rib dysplasias group

16. Acromesomelic dysplasias

In Acromesomelic dysplasia, type Maroteaux, there is disproportionate shortening the middle segments (forearms and forelegs) and distal segments (hands and feet) of the appendicular skeleton. There are short broad fingers, shortening of the middle long bones with a bowed radius, and wedging of vertebral bodies.

Group/name of disorderInher.OMIMOrphaGene
Acromesomelic dysplasia type Maroteaux (AMDM)AR 602875 40 NPR2
Grebe dysplasiaAR 200700 2098 GDF5
Fibular hypoplasia and complex brachydactyly (Du Pan)AR 228900 2639 GDF5
Acromesomelic dysplasia with genital anomaliesAR 609441 BMPR1B
Acromesomelic dysplasia, Osebold-Remondini typeAD 112910 93382
Acromesomelic dysplasia, Hunter-Thomson typeAR 201250 968 GDF5

17. Mesomelic and rhizo-mesomelic dysplasias

Leri-Weill dyschondrosteosis is characterized by short stature, mesomelia, and Madelung wrist deformity (abnormal alignment of the radius, ulna, and carpal bones at the wrist - more common and severe in females).

Group/name of disorderInher.OMIMGROrphaGene
Dyschondrosteosis (Leri-Weill)Pseudo-AD 127300 1215 240 SHOX
Langer type (homozygous dyschondrosteosis)Pseudo-AR 249700 1215 2632 SHOX
OmodysplasiaAR 258315 93329 GPC6
Robinow syndrome, recessive typeAR 268310 1240 1507 ROR2
Robinow syndrome, dominant typeAD 180700 3107 WNT5A
Mesomelic dysplasia, Korean typeAD
Mesomelic dysplasia, Kantaputra typeAD 156232 1836
Mesomelic dysplasia, Nievergelt typeAD 163400 2633
Mesomelic dysplasia, Kozlowski-Reardon typeAR 249710 2631
Mesomelic dysplasia with acral synostoses (Verloes-David-Pfeiffer type)AD 600383 2496 SULF1, SLCO5A1
Mesomelic dysplasia, Savarirayan type (Triangular Tibia-Fibular Aplasia)SP 605274 85170

18. Bent bones dysplasias

Campomelic dysplasia is characterized by bowed, short and fragile long bones, clubfeet, pelvis and chest abnormalities and eleven pairs of ribs. Non-skeletal anomalies include a flat face, laryngotracheomalacia, Pierre Robin sequence with cleft palate, ambiguous genitalia in males, and brain, heart and kidney malformations.

Image skeletal-dysplasias_Figure-12-Campomelic-Dysplasia-1024x370.jpg

Figure 12. Campomelic dysplasia. bell-shaped thorax, hypoplastic scapula, bowed femurs, widely-spaced ischial bones.

Group/name of disorderInher.OMIMGROrphaGene
Campomelic dysplasia (CD)AD 114290 1760 140 SOX9
Stüve-Wiedemann dysplasiaAR 601559 3206 LIFR
Kyphomelic dysplasia, several forms 211350 1801

Bent bones at birth can be seen in osteogenesis imperfecta, Antley-Bixler syndrome, cartilage-hair hypoplasia, Cummings syndrome, hypophosphatasia, dyssegmental dysplasia, TD, ATD, and other conditions.

19. Slender bone dysplasia group

In Three M (3M) syndrome, there is severe prenatal and postnatal growth retardation, distinctive facial features (large head, triangular face, hypoplastic midface, full eyebrows, fleshy nose tip, long philtrum, prominent mouth and lips, and pointed chin), and normal mental development. The main skeletal anomalies are slender long bones and ribs, foreshortened vertebral bodies, and delayed bone age. Joint hypermobility, joint dislocation, winged scapulae, and pes planus can also be seen.

Group/name of disorderInher.OMIMGROrphaGene
3-M syndrome (3M1)AR 273750 1481 2616 CUL7
3-M syndrome (3M2)AR 612921 1481 2616 OBSL1
Kenny-Caffey dysplasia type 1AR 244460 93324 TBCE
Kenny-Caffey dysplasia type 2AD 127000 93325 FAM111A
Microcephalic osteodysplastic primordial dwarfism type 1/3 (MOPD1)AR 210710 2636 RNU4ATAC
Microcephalic osteodysplastic primordial dwarfism type 2 (MOPD2; Majewski type)AR 210720 2637 PCNT2
IMAGE syndrome (intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia, and genital anomalies)XL/AD 614732 85173 CDKN1C
OsteocraniostenosisSP 602361 2763 FAM111A
Hallermann-Streiff syndromeAR 234100 2108 GJA1

Please also see Cerebro-arthro-digital dysplasia.

20. Dysplasias with multiple joint dislocations

Desbuquois dysplasia is characterized by short stature of prenatal onset affecting the rhizomelic and mesomelic portion of the limbs, marked joint laxity, kyphoscoliosis and facial dysmorphisms (round flat face, prominent eyes, and midface hypoplasia)

Group/name of disorderInher.OMIMOrphaGene
Desbuquois dysplasia (with accessory ossification center in digit 2)AR 251450 1425 CANT1
Desbuquois dysplasia with short metacarpals and elongated phalanges (Kim type)AR 251450 1425 CANT1
Desbuquois dysplasia (other variants with or without accessory ossification center)AR
Pseudodiastrophic dysplasiaAR 264180 85174

Please also refer to SED with congenital dislocations, CHST3 type (group 4); Atelosteogenesis type 3 and Larsen syndrome (group 6); SEMDs with joint laxity (group 11)

21. Chondrodysplasia punctata (CDP) group

The more severe, classic rhizomelic chondrodysplasia punctata type 1 can manifest in neonates with cataracts, rhizomelia, metaphyseal abnormalities, and punctate calcifications in the epiphyseal cartilage at the knee, hip, elbow, and shoulder, involving the hyoid bone, larynx, costochondral junctions, and vertebrae (chondrodysplasia punctata). In addition, unossified cartilage in the vertebral bodies show as radiolucent coronal clefts.

Image skeletal-dysplasias_Figure-13-Rhizomelic-CDP-1024x453.jpg

Figure 13. rhizomelic chondrodysplasia punctate type 1. punctate epitphyses, very small humeri less shortening of femurs, coronal clefts in vertebral bodies.

Group/name of disorderInher.OMIMGROrphaGene
CDP, X-linked dominant, Conradi-Hünermann type (CDPX2)XLD 302960 55062 35173 EBP
CDP, X-linked recessive, brachytelephalangic type (CDPX1)XLR 302950 1544 79345 ARSE
Congenital hemidysplasia, ichthyosis, limb defects (CHILD)XLD 308050 51754 139 NSDHL
Congenital hemidysplasia, ichthyosis, limb defects (CHILD)XLD 308050 139 EBP
Greenberg dysplasiaAR 215140 1426 LBR
Rhizomelic CDP type 1AR 215100 1270 177 PEX7
Rhizomelic CDP type 2AR 222765 177 DHPAT
Rhizomelic CDP type 3AR 600121 177 AGPS
CDP tibial-metacarpal typeAD/AR 118651 79346
Astley-Kendall dysplasiaAR? 85175

Note that stippling can occur in several syndromes such as Zellweger, Smith-Lemli-Opitz and others. Please also refer to desmosterolosis as well as SEMD short limb—abnormal calcification type in group 11.

22. Neonatal osteosclerotic dysplasias

Caffey disease manifests with subperiosteal new bone formation (long bones, ribs, mandible, scapulae, and clavicles) associated with fever, joint swelling and pain. Onset is around age two months and the episodes stop by age two years.

Group/name of disorderInher.OMIMGROrphaGene
Blomstrand dysplasiaAR 215045 50945 PTHR1
DesmosterolosisAR 602398 35107 DHCR24
Caffey disease (including infantile and attenuated forms)AD 114000 99168 1310 COL1A1
Caffey disease (severe variants with prenatal onset)AR 114000 99168 1310 COL1A1
Raine dysplasia (lethal and non-lethal forms)AR 259775 1832 FAM20C

Please also refer to Astley-Kendall dysplasia and CDPs in group 21

23. Increased bone density group (without modification of bone shape)

Osteopetrosis can manifest with increased bone density, diffuse and focal sclerosis, modelling defects at metaphyses, pathological fractures, osteomyelitis, tooth eruption defects and dental caries. Other complications include cranial nerve compression, hydrocephalus, pancytopaenia, extramedullary haematopoiesis, hepatosplenomegaly, and hypocalcaemia (10).

Image skeletal-dysplasias_Figure-14-Osteopetrosis-1024x352.jpg

Figure 14. osteopetrosis. thick dense bones, alternating bands of sclerosis and normal density bone in long bones, rugger jersey spine, dense base of skull.

Group/name of disorderInher.OMIMGROrphaGene
Osteopetrosis, severe neonatal or infantile forms (OPTB1)AR 259700 667 TCIRG1
Osteopetrosis, severe neonatal or infantile forms (OPTB4)AR 611490 1127 667 CLCN7
Osteopetrosis, infantile form, with nervous system involvement (OPTB5)AR 259720 667 OSTM1
Osteopetrosis, intermediate form, osteoclast-poor (OPTB2)AR 259710 667 TNFSF11
Osteopetrosis, infantile form, osteoclast-poor with immunoglobulin deficiency (OPTB7)AR 612301 667 TNFRSF11A
Osteopetrosis, intermediate form (OPTB6)AR 611497 210110 PLEKHM1
Osteopetrosis, intermediate form (OPTA2)AR 259710 1127 667 CLCN7
Osteopetrosis with renal tubular acidosis (OPTB3)AR 259730 2785 CA2
Osteopetrosis, late-onset form type 1 (OPTA1)AD 607634 2783 LRP5
Osteopetrosis, late-onset form type 2 (OPTA2)AD 166600 53 CLCN7
Osteopetrosis with ectodermal dysplasia and immune defect (OLEDAID)XL 300301 69088 IKBKG
Osteopetrosis, moderate form with defective leucocyte adhesion (LAD3)AR 612840 2968 KIND3
PyknodysostosisAR 265800 763 CTSK
OsteopoikilosisAD 155950 2485 LEMD3
Melorheostosis with osteopoikilosisAD 155950 2485 LEMD3
Osteopathia striata with cranial sclerosis (OSCS)XLD 300373 2780 WTX
MelorheostosisSP 155950 2485 LEMD3
DysosteosclerosisAR 224300 1782 SLC29A3
OsteomesopyknosisAD 166450 2777
Osteopetrosis with infantile neuroaxonal dysplasiaAR? 600329 85179

24. Increased bone density group with metaphyseal and/or diaphyseal involvement

Camurati-Engelmann manifests with bilateral cortical thickening (hyperostosis) of the diaphyses of the long bones starting with the femora and tibiae. The metaphyses and the skull base may be affected as well, but the epiphyses are spared. Limb pain, muscle weakness, a waddling gait, and easy fatigability can also occur.

Group/name of disorderInher.OMIMGROrphaGene
Craniometaphyseal dysplasia, autosomal dominant typeAD 123000 1461 1522 ANKH
Diaphyseal dysplasia Camurati-EngelmannAD 131300 1156 1328 TGFB1
Hematodiaphyseal dysplasia GhosalAR 231095 1802 TBXAS1
Hypertrophic osteoarthropathyAR 259100 1525 HPGD
Pachydermoperiostosis (hypertrophic osteoarthropathy, primary, autosomal dominant)AD 167100 2796
Oculodentoosseous dysplasia (ODOD) mild typeAD 164200 2710 GJA1
Oculodentoosseous dysplasia (ODOD) severe typeAR 257850 2710 GJA1
Osteoectasia with hyperphosphatasia (juvenile Paget disease)AR 239000 2801 OPG
SclerosteosisAR 269500 1228 3152 SOST
Endosteal hyperostosis, van Buchem typeAR 239100 1228 3416 SOST
Trichodentoosseous dysplasiaAD 190320 3352 DLX3
Craniometaphyseal dysplasia, autosomal recessive typeAR 218400 1522 GJA1
Diaphyseal medullary stenosis with bone malignancyAD 112250 85182 MTAP
Craniodiaphyseal dysplasiaAD 122860 1228 1513 SOST
Craniometadiaphyseal dysplasia, Wormian bone typeAR 615118 85184
Endosteal sclerosis with cerebellar hypoplasiaAR 213002 85186
Lenz-Majewski hyperostotic dysplasiaSP 151050 2658 PTDSS1
Metaphyseal dysplasia, Braun-Tinschert typeXL 605946 85188
Pyle diseaseAR 265900 3005 SFRP4
25.

25.

25. Osteogenesis imperfecta and decreased bone density

Osteogenesis imperfect (OI) manifests with low bone mineral density and bone fragility with frequent fractures, bone deformities and short stature, dentinogenesis imperfecta (fragile grey or brown somewhat translucent teeth), and progressive hearing loss. In type I, stature is normal or slightly short, there is no bone deformity, the sclerae can be blue and there is no dentinogenesis imperfecta. Type II is the most severe with multiple rib and long bone fractures at or before birth, marked deformities, broad long bones, low density on skull X-rays, and dark sclera. OI type III presents with very short stature, a triangular face, severe scoliosis, gray sclera, and dentinogenesis imperfecta. In Type IV, the phenotype is milder with moderately short stature, mild to moderate scoliosis, grayish or white sclera, and dentinogenesis imperfecta. Type V is characterized by mild to moderate short stature, calcification of the forearm interosseous membrane, radial head dislocation and hyperplastic callus formation following fractures, and no dentinogenesis imperfecta.

Image skeletal-dysplasias_Figure-15-OI-Type-II-1024x671.jpg

Figure 15. oi type ii. wormian bones, thick short crumpled long bones, rectangular wavy femora, thick beaded ribs.

Group/name of disorderInher.OMIMGROrphaGene
Osteogenesis imperfecta, non-deforming form (OI type I)AD 166200 1295 216796 COL1A1,COL1A2
Osteogenesis imperfecta, perinatal lethal form (OI type II)AD, AR 166210 1295 216804 COL1A1,COL1A2,CRTAP,LEPRE1,PPIB
Osteogenesis imperfecta, progressively deforming type (OI type III)AD, AR 259420 1295 216812 COL1A1,COL1A2,CRTAP,LEPRE1,PPIB,FKBP10,SERPINH1 , WNT1, TMEM38B
Osteogenesis imperfecta, moderate form (OI type IV)AD, AR 166220 1295 216820 COL1A1,COL1A2,CRTAP,FKBP10,SP7
Osteogenesis imperfecta with calcification of the interosseous membranes and/or hypertrophic callus (OI type V)AD 610967 216828 IFITM5
Osteogenesis imperfecta, type VIAR 613982 216812 SERPINF1
Osteogenesis imperfecta, type VIIAR 610682 216804 CRTAP
Bruck syndrome type 1 (BS1)AR 259450 2771 FKBP10
Bruck syndrome type 2 (BS2)AR 609220 2771 PLOD2
Osteoporosis-pseudoglioma syndromeAR 259770 2788 LRP5
Calvarial doughnut lesions with bone fragilityAD 126550 85192
Idiopathic juvenile osteoporosisSP 259750 85193
Cole-Carpenter dysplasia (bone fragility with craniosynostosis)SP 112240 2050 P4HB
Spondylo-ocular dysplasiaAR 605822 85194 XYLT2
Osteopenia with radiolucent lesions of the mandibleAD 166260 53697 ANO5
Ehlers-Danlos syndrome, progeroid formAR 130070 75496 B4GALT7
Geroderma osteodysplasticumAR 231070 2078 GORAB
Cutis laxa, autosomal recessive form, type 2B (ARCL2B)AR 612940 90350 PYCR1
Cutis laxa, autosomal recessive form, type 2A (ARCL2A) (Wrinkly skin syndrome)AR 219200 5200 90350 ATP6VOA2
Wrinkly skin syndromeAR 278250 5200 2834 ATP6VOA2
Singleton-Merten dysplasiaAD 182250 85191 IFIH1

26. Abnormal mineralization group

Hypophosphatasia results from low alkaline phosphatase (TNSALP) activity. Inorganic pyrophosphate (PPi), an inhibitor of mineralization, and pyridoxal 5′-phosphate (PLP), are substrates that accumulate. The types include the prenatal benign form which spontaneously improves, perinatal (lethal), infantile (respiratory complications, premature craniosynostosis, widespread demineralization and rachitic changes in the metaphyses), childhood (skeletal deformities, short stature, and waddling gait), and adult (stress fractures, thigh pain, chondrocalcinosis and marked osteoarthropathy). Two other forms include odontohypophosphatasia (no clinical changes in long bones are present, only biochemical and dental manifestations such as premature exfoliation of fully rooted primary teeth and/or severe dental caries) and pseudohypophosphatasia (indistinguishable from infantile hypophosphatasia, but serum alkaline phosphatase activity is normal). Enzyme replacement is now available.

Hypophosphatemic rickets is discussed in detail in the section on bone and mineral metabolism of Endotext. Rickets manifests with bowing of the weight bearing bones. Other frequent manifestations are growth failure with disproportionate short stature, frontal bossing, and swelling of wrists, knees, and ankles. A rachitic rosary arises due to expansion of the costo-chondral junctions, and an inward diaphragmatic pull of soft rib cage leads to Harrison's sulcus (groove). Dentition may be delayed and enamel development can be impaired.

Image skeletal-dysplasias_Figure-16-Rickets-1024x384.jpg

Figure 16. rickets. widened growth plates, cupping fraying of metaphyses, demineralization , widened anterior rib ends.

Group/name of disorderInher.OMIMGROrphaGene
Hypophosphatasia, perinatal lethal and infantile formsAR 241500 1150 436 ALPL
Hypophosphatasia, adult formAD 146300 1150 436 ALPL
Hypophosphatemic rickets, X-linked dominantXLD 307800 83985 89936 PHEX
Hypophosphatemic rickets, autosomal dominantAD 193100 89937 FGF23
Hypophosphatemic rickets, autosomal recessive, type 1 (ARHR1)AR 241520 289176 DMP1
Hypophosphatemic rickets, autosomal recessive, type 2 (ARHR2)AR 613312 289176 ENPP1
Hypophosphatemic rickets with hypercalciuria, X-linked recessiveXLR 300554 1652 ClCN5
Hypophosphatemic rickets with hypercalciuria, autosomal recessive (HHRH)AR 241530 157215 SLC34A3
Neonatal hyperparathyroidism, severe formAR 239200 417 CASR
Familial hypocalciuric hypercalcemia with transient neonatal hyperparathyroidismAD 145980 405 CASR
Calcium pyrophosphate deposition disease (familial chondrocalcinosis) type 2AD 118600 1416 ANKH
27.

27. Lysosomal storage diseases with skeletal involvement (dysostosis multiplex group).

Several lysosomal storage diseases manifest with dysostosis multiplex (11). Clinically, there is evolving joint contractures without inflammation. Radiologically, the skull shows an abnormal J-shaped sella turcica and a thickened diploic space. The ribs are oar-shaped ribs (widened anteriorly and tapered posteriorly) and clavicles are short and thickened. The spine shows multiple superiorly notched (inferiorly beaked) vertebrae and posterior scalloping. The pelvis shows rounded iliac wings and inferior tapering of the ilea. The long bones can have mildly hypoplastic epiphyses. The capital femoral epiphyses can be fragmented, and there can be proximal humeral notching, long and narrow femoral necks, hypoplastic distal ulnae, and thickened short diaphyses. In the hands, proximally pointed metacarpals are short and thick with thin cortices.

Image skeletal-dysplasias_Figure-17-Mucopolysaccharidoses-1024x803.jpg

Figure 17. mucopolysaccharidoses. wide ribs, glenoid hypoplasia, steep acetabula with constricted iliac wings, flat/irregular femoral head , spearhead metacarpals, platyspondyly, central anterior vertebral body beaking, hypoplastic odontoid.

Group/name of disorderInher.OMIMGROrphaGene
Mucopolysaccharidosis type 1H/1SAR 607014 1162 93473 IDUA
Mucopolysaccharidosis type 2XLR 309900 1274 580 IDS
Mucopolysaccharidosis type 3AAR 252900 581 SGSH
Mucopolysaccharidosis type 3BAR 252920 581 NAGLU
Mucopolysaccharidosis type 3CAR 252930 581 HSGNAT
Mucopolysaccharidosis type 3DAR 252940 581 GNS
Mucopolysaccharidosis type 4AAR 253000 148668 582 GALNS
Mucopolysaccharidosis type 4BAR 253010 582 GLB1
Mucopolysaccharidosis type 6AR 253200 583 ARSB
Mucopolysaccharidosis type 7AR 253220 584 GUSB
FucosidosisAR 230000 349 FUCA1
alpha-MannosidosisAR 248500 1396 61 MAN2B1
beta-MannosidosisAR 248510 118 MANBA
AspartylglucosaminuriaAR 208400 93 AGA
GMI Gangliosidosis, several formsAR 230500 354 GLB1
Sialidosis, several formsAR 256550 812 NEU1
Sialic acid storage disease (SIASD)AR 269920 834 SLC17A5
Galactosialidosis, several formsAR 256540 351 CTSA
Multiple sulfatase deficiencyAR 272200 585 SUMF1
Mucolipidosis II (I-cell disease), alpha/beta typeAR 252500 1828 576 GNPTAB
Mucolipidosis III (Pseudo-Hurler polydystrophy), alpha/beta typeAR 252600 1875 577 GNPTAB
Mucolipidosis III (Pseudo-Hurler polydystrophy), gamma typeAR 252605 24701 577 GNPTG
28.

28. Osteolysis group

Hajdu-Cheney syndrome is characterized by short stature, bowing of the long bones, vertebral anomalies, progressive focal bone destruction, acroosteolysis and generalized osteoporosis. Facial features are coarse and can include hypertelorism, bushy eyebrows, micrognathia, a small mouth with dental anomalies, low-set ears, and short neck.

Group/name of disorderInher.OMIMGROrphaGene
Familial expansile osteolysisAD 174810 85195 TNFRSF11A
Mandibuloacral dysplasia type AAD 248370 90153 LMNA
Mandibuloacral dysplasia type BAR 608612 90154 ZMPSTE24
Progeria, Hutchinson-Gilford typeAD 176670 1121 740 LMNA
Torg-Winchester syndromeAR 259600 3460 MMP2
Hajdu-Cheney syndromeAD 102500 955 NOTCH2
Multicentric carpal-tarsal osteolysis with and without nephropathyAD 166300 2774 MAFB
Lipomembraneous osteodystrophy with leukoencephalopathy (presenile dementia with bone cysts; Nasu-Hakola)AR 221770 1197 2770 TREM2
Lipomembraneous osteodystrophy with leukoencephalopathy (presenile dementia with bone cysts; Nasu-Hakola)AR 221770 1197 2770 TYROBP

Please also refer to Pycnodysostosis, cleidocranial dysplasia, and Singleton-Merten syndrome. Note: several neurologic conditions may cause acroosteolysis

29. Disorganized development of skeletal components group

Multiple hereditary exostoses are characterized by projections of bone capped by cartilage, in the metaphyses and the diaphyses of long bones.

Fibrodysplasia ossificans progressiva (FOP) is characterized by malformation of the hallux during embryonic skeletal development and by progressive heterotopic endochondral ossification later in life. In the first decade, episodes of painful soft tissue swellings precipitated by soft tissue injury, intramuscular injections, viral infection, muscular stretching, falls or fatigue lead to heterotopic bone formation. The heterotopic bone forms in the skeletal muscles, tendons, ligaments, fascia, and aponeuroses. This phenomenon is seen first in the dorsal, axial, cranial and proximal regions of the body, and later in the ventral, appendicular, caudal and distal regions.

Image skeletal-dysplasias_Figure-18-Fibrodysplasia-Ossificans-Progressiva-1024x427.jpg

Figure 18. fibrodysplasia ossificans progressive. trapezoid-shaped proximal phalanx of the great toe, soft tissue ossification, exostosis-like structures at sites of ligamentous attachment.

Fibrous dysplasia, polyostotic form, or McCune-Albright syndrome is characterized by polyostotic fibrous dysplasia, cafe au lait cutaneous spots and endocrinopathies (peripheral precocious puberty, thyroidopathies, acromegaly, etc.). The skeletal manifestations are asymmetric fibrous dysplasia affecting any bone. Pathologic fracture, pseudarthrosis, bone deformity such as the shepherd's crook of the proximal femurs are characteristic.

Group/name of disorderInher.OMIMGROrphaGene
Multiple cartilaginous exostoses 1AD 133700 1235 321 EXT1
Multiple cartilaginous exostoses 2AD 133701 1235 321 EXT2
Multiple cartilaginous exostoses 3AD 600209 321
CherubismAD 118400 1137 184 SH3BP2
Fibrous dysplasia, polyostotic form,
McCune-Albright syndrome
SP 174800 562 GNAS
Progressive osseous heteroplasiaAD 166350 2762 GNAS
Gnathodiaphyseal dysplasiaAD 166260 53697 TMEM16E
MetachondromatosisAD 156250 2499 PTPN11
Osteoglophonic dysplasiaAD 166250 1455 2645 FGFR1
Fibrodysplasia ossificans progressiva (FOP)AD, SP 135100 337 ACVR1
Neurofibromatosis type 1 (NF1)AD 162200 1109 636 NF1
Carpotarsal osteochondromatosisAD 127820 2767
Cherubism with gingival fibromatosis (Ramon syndrome)AR 266270 3019
Dysplasia epiphysealis hemimelica (Trevor)SP 127800 1822
Enchondromatosis (Ollier)SP 166000 296 IDH1, IDH2, and PTH1R
Enchondromatosis with hemangiomata (Maffucci)SP 166000 296 DH1, IDH2, and PTH1R

Please also refer to Proteus syndrome in group 30.

30. Overgrowth syndromes with skeletal involvement

Marfan syndrome manifests with skeletal, ocular and cardiovascular features. Skeletal features include joint laxity, scoliosis and extremities that are disproportionately long for the size of the trunk. Overgrowth of the ribs can cause pectus excavatum or carinatum. Ocular features include myopia and displacement of the lens from the center of the pupil. Cardiovascular features include dilatation of the aorta, susceptibility to aortic tear and rupture, mitral or tricuspid valve prolapse, and enlargement of the proximal pulmonary artery.

Group/name of disorderInher.OMIMGROrphaGene
Weaver syndromeSP/AD 277590 3447 EZH2
Sotos syndromeAD 117550 1479 821 NSD1
Marshall-Smith syndromeSP 602535 561 NFIX
Proteus syndromeSP 176920 99495 744 AKT1
Marfan syndromeAD 154700 1335 558 FBN1
Congenital contractural arachnodactylyAD 121050 1386 115 FBN2
Loeys-Dietz syndrome types 1A and 2AAD 609192,610168, 1133 TGFBR1
Loeys-Dietz syndrome types 1B and 2BAD 608967, 610380 1133 TGFBR2
Loeys-Dietz syndrome, type 3AD 613795 1133 284984 SMAD3
Loeys-Dietz syndrome, type 4AD 614816 1133 91387 TGFB2
Overgrowth syndrome with 2q37 translocationsSP NPPC
Overgrowth syndrome with skeletal dysplasia (Nishimura-Schmidt, endochondral gigantism)SP?

Please also refer to Shprintzen-Goldberg syndrome in Craniosynostosis group

31. Genetic inflammatory/rheumatoid-like osteoarthropathies

Familial hyperphosphatemic tumoral calcinosis is characterized by the progressive deposition of calcium phosphate crystals in periarticular spaces, soft tissues, and bones (periosteal reaction and cortical hyperostosis). It is caused by increased renal absorption of phosphate secondary to loss-of-function mutations in FGF23 or GALNT3.

Group/name of disorderInher.OMIMGROrphaGene
Progressive pseudorheumatoid dysplasia (PPRD; SED with progressive arthropathy)AR 208230 1159 WISP3
Chronic infantile neurologic cutaneous articular syndrome (CINCA)/neonatal onset multisystem inflammatory disease (NOMID)AD 607115 1451 CIAS1
Sterile multifocal osteomyelitis, periostitis, and pustulosis (CINCA/NOMID-like)AR 612852 210115 IL1RN
Chronic recurrent multifocal osteomyelitis with congenital dyserythropoietic anemia (CRMO with CDA; Majeed syndrome)AR 609628 1974 77297 LPIN2
Tumoral calcinosis, hyperphosphatemic, familialAR 211900 53715 GALNT3, FGF23, KL
Infantile systemic hyalinosis/Juvenile hyaline fibromatosis (ISH/JHF)AR 236490 1525 2176 ANTXR2
camptodactyly-arthropathy-coxa vara-pericarditis syndrome (non-inflammatory)AR 208250 2848 PRG4

32. Cleidocranial dysplasia and isolated cranial ossification defects group

Cleidocranial dysplasia manifests with large, wide-open fontanels at birth which may remain open with bulging calvaria, mid-face hypoplasia, hypoplasia or aplasia of the clavicles permitting apposition of the shoulders, wide pubic symphysis, brachydactyly, tapering fingers, and short, broad thumbs, dental anomalies (delayed eruption of secondary dentition, failure to shed the primary teeth, supernumerary teeth with dental crowding, and malocclusion).

Image skeletal-dysplasias_Figure-19-CCD-1024x245.jpg

Figure 19. Cleidocranial dysplasia. wormian bones, partial (or rarely complete) absence of clavicle, widened symphysis pubis, tall femoral head ossification centers, cone-shaped epiphyses.

Group/name of disorderInher.OMIMGROrphaGene
Cleidocranial dysplasiaAD 119600 1513 1452 RUNX2
CDAGS syndrome (craniosynostosis, delayed fontanel closure, parietal foramina, imperforate anus, genital anomalies, skin eruption)AR 603116 85199
Yunis-Varon syndromeAR 216340 3472 FIG4
Parietal foramina (isolated)AD 168500 1128 60015 ALX4
Parietal foramina (isolated)AD 168500 1128 60015 MSX2

Please also refer to pycnodysostosis, wrinkly skin syndrome, and several others

33. Craniosynostosis syndromes

Craniosynostosis is often secondary to mutations in one of the FGFR genes (12). In Apert syndrome (FGFR2) there is midface hypoplasia and symmetrical syndactyly of hands and feet. In Crouzon syndrome there is maxillary hypoplasia, shallow orbits, ocular proptosis, and normal extremities. It is caused by FGFR2 mutations unless there is acanthosis nigricans (FGFR3). In Muenke syndrome (FGFR3), there is unilateral or bilateral coronal synostosis, and absent or minimal hand/foot anomalies. In Pfeiffer syndrome there is high forehead, maxillary hypoplasia, mild syndactyly of hands and/or feet, broad thumbs and/or great toe (FGFR2, rarely FGFR1). In Saethre-Chotzen syndrome there is brachycephaly/plagiocephaly, a high forehead, facial asymmetry, maxillary hypoplasia, brachydactyly, partial cutaneous syndactyly in some cases, and thumb/great toe anomalies (TWIST gene, occasionally FGFR3).

Group/name of disorderInher.OMIMGROrphaGene
Pfeiffer syndrome (FGFR1-related)AD 101600 1455 710 FGFR1
Pfeiffer syndrome (FGFR2-related)AD 101600 1455 710 FGFR2
Apert syndromeAD 101200 1455 87 FGFR2
Craniosynostosis with cutis gyrata (Beare-Stevenson)AD 123790 1455 1555 FGFR2
Crouzon syndromeAD 123500 1455 207 FGFR2
Crouzon-like craniosynostosis with acanthosis nigricans (Crouzonodermoskeletal syndrome)AD 612247 1455 93262 FGFR3
Craniosynostosis, Muenke typeAD 602849 1455 53271 FGFR3
Antley-Bixler syndromeAR 201750 1419 63269 POR
Craniosynostosis Boston typeAD 604757 1541 MSX2
Saethre-Chotzen syndromeAD 101400 1189 794 TWIST1
Shprintzen-Goldberg syndromeAD 182212 1277 2462 SKI
Baller-Gerold syndromeAR 218600 1204 1225 RECQL4
Carpenter syndromeAR 201000 65759 RAB23

Please also refer to Cole-Carpenter syndrome in group 24, CDAGS syndrome in group 29, and Craniofrontonasal syndrome in group 34

34. Dysostoses with predominant craniofacial involvement

Treacher Collins syndrome manifests with fdownslanting eyes, coloboma of the eyelids, micrognathia, microtia and other deformity of the ears, hypoplastic zygomatic arches, macrostomia, conductive hearing loss and cleft palate.

Group/name of disorderInher.OMIMGROrphaGene
Mandibulo-facial dysostosis (Treacher Collins, Franceschetti-Klein)AD 154500 1532 861 TCOF1
Mandibulo-facial dysostosis (Treacher-Collins, Franceschetti-Klein)AD 154500 1532 861 POLR1D
Mandibulo-facial dysostosis (Treacher-Collins, Franceschetti-Klein)AR 154500 1532 861 POLR1C
Oral-facial-digital syndrome type I (OFD1)XLR 311200 2750 CXORF5
Weyer acrofacial (acrodental) dysostosisAD 193530 952 EVC1
Endocrine-cerebro-osteodysplasia (ECO)AR 612651 199332 ICK
Craniofrontonasal syndromeXLD 304110 1520 EFNB1
Frontonasal dysplasia, type 1AR 136760 250 ALX3
Frontonasal dysplasia, type 2AR 613451 228390 ALX4
Frontonasal dysplasia, type 3AR 613456 306542 ALX1
Hemifacial microsomiaSP/AD 164210 5199 374
Miller syndrome (postaxial acrofacial dysostosis)AR 263750 246 DHODH
Acrofacial dysostosis, Nager typeAD/AR 154400 245 SF3B4
Acrofacial dysostosis, Rodriguez typeAR 201170 1788

Please also refer to Oral-facial-digital syndrome type IV in the Short Rib Dysplasias group

35. Dysostoses with predominant vertebral with and without costal involvement

In spondylocostal dysostosis, there are multiple segmentation defects of the vertebrae, malalignment of the ribs with variable points of intercostal fusion, and a reduction in rib number. Clinically there is scoliosis, a short neck and trunk.

Group/name of disorderInher.OMIMGROrphaGene
Currarino triadAD 176450 1552 HLXB9
Spondylocostal dysostosis type 1 (SCD1)AR 277300 8828 2311 DLL3
Spondylocostal dysostosis type 2 (SCD2)AR 608681 8828 2311 MESP2
Spondylocostal dysostosis type 3 (SCD3)AR? 609813 8828 2311 LFNG
Spondylocostal dysostosis type 4 (SCD4)AR 613686 8828 2311 HES7
Spondylothoracic dysostosisAR 122600 8828 1797 MESP2
Klippel-Feil anomaly with laryngeal malformationAD 118100 2345 GDF6
Spondylocostal/thoracic dysostosis, other formsAD/AR
Cerebro-costo-mandibular syndrome (rib gap syndrome)AD/AR 117650 1393 SNRPB
Cerebro-costo-mandibular-like syndrome with vertebral defectsAR 611209 263508 COG1
DiaphanospondylodysostosisAR 608022 66637 BMPER

Please also refer to Spondylocarpotarsal dysplasia in group 7 and spondylo-metaphyseal-megaepiphyseal dysplasia in group 13

36. Patellar dysostoses

Nail-patella syndrome presents with patella hypoplasia, nail hypoplasia or dystrophy, elbow and knee deformities (limitation of elbow extension, pronation, and supination; cubitus valgus; and antecubital pterygia), iliac horns (bilateral, conical bony processes projecting posteriorly and laterally from the central part of the iliac bones of the pelvis), nephropathy (nephrotic syndrome which may progress to end-stage renal disease), and ocular defects (cloverleaf appearance of the iris, primary open angle glaucoma).

Image skeletal-dysplasias_Figure-20-Nail-Patella-syndrome-1024x302.jpg

Figure 20. Nail-patella syndrome. absent patella, iliac horns, radial head dislocation, spondylolysthesis.

Group/name of disorderInher.OMIMGROrphaGene
Ischiopatellar dysplasia (small patella syndrome)AD 147891 1509 TBX4
Small patella—like syndrome with clubfootAD 119800 293150 PITX1
Nail-patella syndromeAD 161200 1132 2614 LMX1B
Genitopatellar syndromeAR? 606170 114806 85201 KAT6B
Ear-patella-short stature syndrome (Meier-Gorlin)AR 224690 2554 ORC1, ORC1L, ORC4, ORC4L, ORC6, ORC6L, CDT1, CDC6, CDC18L

Please also refer to MED group for conditions with patellar changes as well as ischio-pubic-patellar dysplasia as mild expression of campomelic dysplasia

37. Brachydactylies (with or without extraskeletal manifestations)

Coffin-Siris syndrome (CSS) is characterized by aplasia or hypoplasia of the distal phalanx or nail of the fifth digit (or more digits), distinctive facial features (wide mouth with thick, everted upper and lower lips, broad nasal bridge with broad nasal tip, thick eyebrows and long eyelashes), and moderate to severe developmental/cognitive delay.

Thorough discourses on the genes involved in each condition can be found in papers by Schwabe and Mundlos (13), Temtamy and Aglan (14), and Mundlos (15).

Group/name of disorderInher.OMIMGROrphaGene
Brachydactyly type A1AD 112500 93388 IHH
Brachydactyly type A1AD 5p13.3-p13.2
Brachydactyly type A2AD 112600 93396 BMPR1B
Brachydactyly type A2AD 112600 93396 BMP2
Brachydactyly type A2AD 112600 93396 GDF5
Brachydactyly type A3AD 112700 93393
Brachydactyly type BAD 113000 93383 ROR2
Brachydactyly type B2AD 611377 140908 NOG
Brachydactyly type CAD, AR 113100 93384 GDF5
Brachydactyly type DAD 113200 93385 HOXD13
Brachydactyly type EAD 113300 93387 PTHLH
Brachydactyly type EAD 113300 93387 HOXD13
Brachydactyly—mental retardation syndromeAD 600430 1001 HDAC4
Hyperphosphatasia with mental retardation, brachytelephalangy, and distinct faceAR 239300 247262 PIGV
Brachydactyly-hypertension syndrome (Bilginturian)AD 112410 1276
Brachydactyly with anonychia (Cooks syndrome)AD 106995 1487 SOX9
Microcephaly-oculo-digito-esophageal-duodenal syndrome (Feingold syndrome)AD 164280 7050 1305 MYCN
Hand-foot-genital syndromeAD 140000 1423 2438 HOXA13
Brachydactyly with elbow dysplasia (Liebenberg syndrome)AD 186550 1275 PITX1
Keutel syndromeAR 245150 85202 MGP
Albright hereditary osteodystrophy (AHO)AD 103580 665 GNAS1
Rubinstein-Taybi syndromeAD 180849 1526 783 CREBBP
Rubinstein-Taybi syndromeAD 180849 1526 783 EP300
Catel-Manzke syndromeXLR? 302380 1388
Brachydactyly, Temtamy typeAR 605282 CHSY1
Christian type brachydactylyAD 112450 1278
Coffin-Siris syndromeAR 135900 131811 1465 SMARCA2, SMARCA4, SMARCB1, SMARCE1, ARID1A, ARID1B
Mononen type brachydactylyXLD? 301940 2565
Poland anomalySP 173800 2911

Please also refer to group 20 for other conditions with brachydactyly as well as brachytelephalangic CDP

38. Limb hypoplasia—reduction defects group

Fanconi anemia can present with bone marrow failure, developmental delay and central nervous system malformation, short stature, skeletal anomalies often involving the radial ray, anomalies of the eyes, kidneys and urinary tract, ears (including deafness), heart, gastrointestinal system, abnormal skin pigmentation, and hypogonadism. There is an increased risk of malignancy.

Group/name of disorderInher.OMIMGROrphaGene
Ulnar-mammary syndromeAD 181450 3138 TBX3
de Lange syndromeAD 122470 1104 199 NIPBL
Fanconi anemiaAR 227650 1401 84 Several genes, see OMIM
Thrombocytopenia-absent radius (TAR)AR?/AD? 274000 23758 3320 Several
Thrombocythemia with distal limb defectsAD 329319 THPO
Holt-Oram syndromeAD 142900 1111 392 TBX5
Okihiro syndrome (Duane—radial ray anomaly)AD 607323 1373 959 SALL4
Cousin syndromeAR 260660 93333 TBX15
Roberts syndromeAR 268300 1153 3103 ESCO2
Split-hand-foot malformation with long bone deficiency (SHFLD1)AD 119100 3329
Split-hand-foot malformation with long bone deficiency (SHFLD2)AD 610685 3329
Split-hand-foot malformation with long bone deficiency (SHFLD3)AD 612576 3329
Tibial hemimeliaAR 275220 93322
Tibial hemimelia-polysyndactyly-triphalangeal thumbAD 188770 3332
AcheiropodiaAR 200500 931 LMBR1
Tetra-ameliaXL 301090 1276 3301
Tetra-ameliaAR 273395 1276 3301 WNT3
Ankyloblepharon-ectodermal dysplasia-cleft lip/palate (AEC)AD 106260 43797 1071 TP63
Ectrodactyly-ectodermal dysplasia cleft-palate syndrome Type 3 (EEC3)AD 604292 1896 TP63
Ectrodactyly-ectodermal dysplasia cleft-palate syndrome type 1 (EEC1)AD 129900 1896
Ectrodactyly-ectodermal dysplasia-macular dystrophy syndrome (EEM)AR 225280 1897 CDH3
Limb-mammary syndrome (including ADULT syndrome)AD 603543 43797 69085 TP63
Split hand-foot malformation, isolated form, type 4 (SHFM4)AD 605289 43797 2440 TP63
Split hand-foot malformation, isolated form, type 1 (SHFM1)AD 183600 2440
Split hand-foot Malformation, isolated form, type 2 (SHFM2)XL 313350 2440
Split hand-foot malformation, isolated form, type 3 (SHFM3)AD 246560 1307 FBXW4
Split hand-foot malformation, isolated form, type 5 (SHFM5)AD 606708 2440
Split-hand/foot malformation 1 with sensorineural hearing lossAR 220600 71271 DLX5
Split-hand/foot malformation 6AR 225300 2440 WNT10B
Al-Awadi Raas-Rothschild limb-pelvis hypoplasia-aplasiaAR 276820 2879 WNT7A
Fuhrmann syndromeAR 228930 2854 WNT7A
RAPADILINO syndromeAR 266280 1204 3021 RECQL4
Adams-Oliver syndromeAD/AR 100300 974 ARHGAP31, DOCK6, RBPJ, EOGT
Femoral hypoplasia-unusual face syndrome (FHUFS)SP/AD? 134780 1988
Femur-fibula-ulna syndrome (FFU)SP? 228200 2019
Hanhart syndrome (hypoglossia-hypodactylia)AD 103300 989
Scapulo-iliac dysplasia (Kosenow)AD 169550 2839

Please also refer to CHILD in group 20 and the mesomelic and acromesomelic dysplasias

39. Polydactyly-Syndactyly-Triphalangism group

Pallister-Hall syndrome manifests with hypothalamic hamartoma, pituitary dysfunction, bifid epiglottis, laryngotracheal cleft, central polydactyly, and visceral malformations.

Meckel syndrome presents with variable combinations of renal cysts, developmental anomalies of the central nervous system (occipital encephalocele), hepatic ductal dysplasia and cysts, and polydactyly.

Group/name of disorderInher.OMIMGROrphaGene
Preaxial polydactyly type 1 (PPD1)AD 174400 93339 SHH
Preaxial polydactyly type 1 (PPD1)AD 174400 93339 Other locus
Preaxial polydactyly type 2 (PPD2)/triphalangeal thumb (TPT)AD 174500 2950 SHH
Preaxial polydactyly type 3 (PPD3)AD 174600 93337 Other locus
Preaxial polydactyly type 4 (PPD4)AD 174700 93338 GLI3
Greig cephalopolysyndactyly syndromeAD 175700 1446 380 GLI3
Pallister-Hall syndromeAD 146510 1465 672 GLI3
Synpolydactyly (complex, fibulin1—associated)AD 608180 295197 FBLN1
SynpolydactylyAD 186000 295195 HOXD13
Townes-Brocks syndrome (Renal-Ear-Anal-Radial syndrome)AD 107480 1445 857 SALL1
Lacrimo-auriculo-dento-digital syndrome (LADD)AD 149730 2363 FGFR2, FGFR3, FGF10
Acrocallosal syndromeAR 200990 36 KIF7
Acro-pectoral syndromeAD 605967 85203
Acro-pectoro-vertebral dysplasia (F-syndrome)AD 102510 957
Mirror-image polydactyly of hands and feet (Laurin-Sandrow syndrome)AD 135750 2378 SHH
Mirror-image polydactyly of hands and feet (Laurin-Sandrow syndrome) Other locus
Cenani-Lenz syndactylyAR 212780 3258 LRP4
Cenani-Lenz like syndactylySP (AD?) GREM1, FMN1
Oligosyndactyly, radio-ulnar synostosis, hearing loss, and renal defects syndromeSP (AR?) FMN1
Syndactyly, Malik-Percin typeAR 609432 157801 BHLHA9
STAR syndrome (syndactyly of toes, telecanthus, ano-, and renal malformations)XL 300707 140952 FAM58A
Syndactyly type 1 (III-IV)AD 185900 93402
Syndactyly type 3 (IV-V)AD 185900 93402 GJA1
Syndactyly type 4 (I-V) Haas typeAD 186200 93405 SHH
Syndactyly type 5 (syndactyly with metacarpal and metatarsal fusion)AD 186300 93406 HOXD13
Syndactyly with craniosynostosis (Philadelphia type)AD 601222 1527
Syndactyly with microcephaly and mental retardation (Filippi syndrome)AR 272440 3255 CKAP2L
Jawad syndromeAR 251255 313795 RBBP8
Meckel syndrome type 1AR 249000 564 MKS1
Meckel syndrome type 2AR 603194 564 TMEM216
Meckel syndrome type 3AR 607361 564 TMEM67
Meckel syndrome type 4AR 611134 564 CEP290
Meckel syndrome type 5AR 611561 564 RPGRIP1L
Meckel syndrome type 6AR 612284 564 CC2D2A

Note: the Smith-Lemli-Opitz syndrome can present with polydactyly and/or syndactyly. Please also refer to the SRPS group.

40. Defects in joint formation and synostoses

Proximal symphalangism is characterized by fusion of the proximal interphalangeal joints, but can also involve the elbows, ankles and wrists leading to ankylosis. Conductive deafness secondary to fusion of the ossicles is also seen.

Group/name of disorderInher.OMIMOrphaGene
Multiple synostoses syndrome type 1AD 186500 3237 NOG
Multiple synostoses syndrome type 2AD 186500 3237 GDF5
Multiple synostoses syndrome type 3AD 612961 3237 FGF9
Proximal symphalangism type 1AD 185800 3250 NOG
Proximal symphalangism type 2AD 185800 3250 GDF5
Radio-ulnar synostosis with amegakaryocytic thrombocytopeniaAD 605432 71289 HOXA11

Please also refer to Spondylo-Carpal-Tarsal dysplasia; mesomelic dysplasia with acral synostoses; and others.

References

  1. M. L. Warman et al., Nosology and classification of genetic skeletal disorders: 2010 revision. American journal of medical genetics. Part A 155A, 943 (May, 2011).
  2. R. E. Stevenson, J. G. Hall, R. M. Goodman, Human malformations and related anomalies. (Oxford University Press, New York, 1993).
  3. J. r. W. Spranger, Bone dysplasias : an atlas of genetic disorders of skeletal development. (Oxford University Press, Oxford ; New York, ed. 3rd, 2012), pp. xxiii, 802 p.
  4. Y. Alanay, R. S. Lachman, A review of the principles of radiological assessment of skeletal dysplasias. Journal of clinical research in pediatric endocrinology 3, 163 (2011).
  5. S. R. Rose, M. G. Vogiatzi, K. C. Copeland, A general pediatric approach to evaluating a short child. Pediatrics in review / American Academy of Pediatrics 26, 410 (Nov, 2005).
  6. J. Spranger, A. Winterpacht, B. Zabel, The type II collagenopathies: a spectrum of chondrodysplasias. European journal of pediatrics 153, 56 (Feb, 1994).
  7. N. H. Elcioglu, C. M. Hall, Diagnostic dilemmas in the short rib-polydactyly syndrome group. American journal of medical genetics 111, 392 (Sep 1, 2002).
  8. S. Naik, I. K. Temple, Coat hanger appearances of the ribs: a useful diagnostic marker of paternal uniparental disomy of chromosome 14. Archives of disease in childhood 95, 909 (Nov, 2010).
  9. S. Unger, L. Bonafe, A. Superti-Furga, Multiple epiphyseal dysplasia: clinical and radiographic features, differential diagnosis and molecular basis. Best practice & research. Clinical rheumatology 22, 19 (Mar, 2008).
  10. Z. Stark, R. Savarirayan, Osteopetrosis. Orphanet journal of rare diseases 4, 5 (2009).
  11. R. Lachman et al., Radiologic and neuroradiologic findings in the mucopolysaccharidoses. Journal of pediatric rehabilitation medicine 3, 109 (2010).
  12. K. Chun, A. S. Teebi, C. Azimi, L. Steele, P. N. Ray, Screening of patients with craniosynostosis: molecular strategy. American journal of medical genetics. Part A 120A, 470 (Aug 1, 2003).
  13. G. C. Schwabe, S. Mundlos, Genetics of congenital hand anomalies. Handchirurgie, Mikrochirurgie, plastische Chirurgie : Organ der Deutschsprachigen Arbeitsgemeinschaft fur Handchirurgie : Organ der Deutschsprachigen Arbeitsgemeinschaft fur Mikrochirurgie der Peripheren Nerven und Gefasse 36, 85 (Apr-Jun, 2004).
  14. S. A. Temtamy, M. S. Aglan, Brachydactyly. Orphanet journal of rare diseases 3, 15 (2008).
  15. S. Mundlos, The brachydactylies: a molecular disease family. Clinical genetics 76, 123 (Aug, 2009).
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