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De Groot LJ, Chrousos G, Dungan K, et al., editors. Endotext [Internet]. South Dartmouth (MA):, Inc.; 2000-.

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Skeletal Dysplasias

, MD, FRCPC and , MD.

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Last Update: January 30, 2017.


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.


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 (, Genereviews (GR,, Orphanet (, 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 ( and their local geneticist.


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.


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


Short-ribs dysplasias (with or without polydactyly) group


Multiple epiphyseal dysplasia and pseudoachondroplasia group


Metaphyseal dysplasias


Spondylometaphyseal dysplasias (SMD)


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


Severe spondylodysplastic dysplasias


Acromelic dysplasias (extremities of the limbs)


Acromesomelic dysplasias (extremities and middle portion of the limbs)


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


Bent bones dysplasias


Slender bone dysplasia group


Dysplasias with multiple joint dislocations


Chondrodysplasia punctata (CDP) group


Neonatal osteosclerotic dysplasias


Increased bone density group (without modification of bone shape)


Increased bone density group with metaphyseal and/or diaphyseal involvement


Osteogenesis imperfecta and decreased bone density group


Abnormal mineralization group


Lysosomal storage diseases with skeletal involvement (dysostosis multiplex group)


Osteolysis group


Disorganized development of skeletal components group


Overgrowth syndromes with skeletal involvement


Genetic inflammatory/rheumatoid-like osteoarthropathies


Cleidocranial dysplasia and isolated cranial ossification defects group


Craniosynostosis syndromes


Dysostoses with predominant craniofacial involvement


Dysostoses with predominant vertebral with and without costal involvement


Patellar dysostoses


Brachydactylies (with or without extraskeletal manifestations)


Limb hypoplasia—reduction defects group


Polydactyly-Syndactyly-Triphalangism group


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)AD18760013661860FGFR3
Thanatophoric dysplasia type 2 (TD2)AD187601136693274FGFR3
Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN)AD187600145585165FGFR3
Camptodactyly, tall stature, and hearing loss syndrome (CATSHL)AD610474FGFR3

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.


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)AD20061093296COL2A1
Platyspondylic dysplasia, Torrance typeAD15121085166COL2A1
Spondyloepiphyseal dysplasia congenita (SEDC)AD18390094068COL2A1
Spondyloepimetaphyseal dysplasia (SEMD) Strudwick typeAD18425093346COL2A1
Kniest dysplasiaAD156550485COL2A1
Spondyloperipheral dysplasiaAD2717001856COL2A1
Mild SED with premature onset arthrosisADCOL2A1
SED with metatarsal shortening (formerly Czech dysplasia)AD609162137678COL2A1
Stickler syndrome type 1AD1083001302828COL2A1


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 2AD604841130290654COL11A1
Marshall syndromeAD154780560COL11A1
Otospondylomegaepiphyseal dysplasia (OSMED), recessive typeAR2151501427COL11A2
Otospondylomegaepiphyseal dysplasia (OSMED), dominant type (Weissenbacher-Zweymüller syndrome, Stickler syndrome type 3)AD2151501427COL11A2

Please also refer to Stickler syndrome type 1 in group 2


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)AR600972151693298SLC26A2
Atelosteogenesis type 2 (AO2)AR256050131756304SLC26A2
Diastrophic dysplasia (DTD)AR2226001350628SLC26A2
MED, autosomal recessive type (rMED; EDM4)AR226900130693307SLC26A2
SEMD, PAPSS2 typeAR60300593282PAPSS2
Chondrodysplasia with congenital joint dislocations, CHST3 type (recessive Larsen syndrome)AR60863762112263463CHST3
Ehlers-Danlos syndrome, CHST14 type (“musculo-skeletal variant”)AR6017762953CHST14

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


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 typeAR2244101865HSPG2
Dyssegmental dysplasia, Rolland-Desbuquois typeAR224400156731HSPG2
Schwartz-Jampel syndrome (myotonic chondrodystrophy)AR255800800HSPG2Aggrecan 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 typeAD60836193283ACAN
SEMD, Aggrecan typeAR612813171866ACAN
Familial osteochondritis dissecansAD165800251262ACAN

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 dysplasiaAD1565302635TRPV4
Spondyloepimetaphyseal dysplasia, Maroteaux type (Pseudo-Morquio syndrome type 2)AD184095263482TRPV4
Spondylometaphyseal dysplasia, Kozlowski typeAD18425293314TRPV4
Brachyolmia, autosomal dominant typeAD11350093304TRPV4
Familial digital arthropathy with brachydactylyAD60683585169TRPV4

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)AR225500289EVC1, ECV2, LBN
Short rib—polydactyly syndrome (SRPS) type 1/3 (Saldino-Noonan/Verma-Naumoff)AR26351093271DYNC2H1
SRPS type 1/3 (Saldino-Noonan)AR26351093271 IFT80
SRPS type 2 AAR26352093269NEK1
SRPS type 2BAR61508793269DYNC2H1
SRPS type 3 Verma-NaumoffAR26351093271DYNC2H1
SRPS type 4 (Beemer)AR26986093268
SRPS type 5AR614091WDR35
Uniparental disomy of paternal chromosome 14 (UPD14)60814996334Complete chromosome 14
Cerebrocostomandibular syndromeAR/AD1176501393SNRPB
Oral-facial-digital syndrome type 4 (Mohr-Majewski)AR2588602753TCTN3
Asphyxiating thoracic dysplasia (ATD; Jeune)AR208500474TTC21B, IFT80, WDR19, DYNC2H1, ATD
Thoracolaryngopelvic dysplasia (Barnes)AD1877603317

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)AD1771701487750COMP
Multiple epiphyseal dysplasia (MED) type 1 (EDM1)AD132400112393308COMP
Multiple epiphyseal dysplasia (MED) type 2 (EDM2)AD6002041123166002COL9A2
Multiple epiphyseal dysplasia (MED) type 3 (EDM3)AD6009691123166002COL9A3
Multiple epiphyseal dysplasia (MED) type 5 (EDM5)AD607078112393311MATN3
Multiple epiphyseal dysplasia (MED) type 6 (EDM6)AD6141351123166002COL9A1
Multiple epiphyseal dysplasia (MED), other types1123
Stickler syndrome, recessive typeAR6141341302250984COL9A1
Familial hip dysplasia (Beukes)AD14266911232114UFSP2
Multiple epiphyseal dysplasia with microcephaly and nystagmus (Lowry-Wood)AR2269601824

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)AD156500174COL10A1
Cartilage-hair hypoplasia (CHH; metaphyseal dysplasia, McKusick type)AR25025084550175RMRP
Metaphyseal dysplasia, Jansen typeAD15640033067PTHR1
Eiken dysplasiaAR60000279106PTHR1
Metaphyseal dysplasia with pancreatic insufficiency and cyclic neutropenia (Shwachman-Diamond syndrome)AR2604001756811SBDS
Metaphyseal anadysplasia type 1AD, AR6021111040MMP13
Metaphyseal anadysplasia type 2AR6130731040MMP9
Metaphyseal dysplasia, Spahr typeAR2504002501MMP13
Metaphyseal acroscyphodysplasia (various types)AR2502151240
Genochondromatosis (type 1/type 2)AD/SP13736085197
Metaphyseal chondromatosis with d-2-hydroxyglutaric aciduriaAR/SP61487599646 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)AR2715501855ACP5
Odontochondrodysplasia (ODCD)AR184260166272
Spondylometaphyseal dysplasia, Sutcliffe type or corner fractures typeAD18425593315COL2A1
SMD with severe genu valgumAD18425393316
SMD with cone-rod dystrophyAR60894085167PCYT1A
SMD with retinal degeneration, axial typeAR602271168549

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)AR223800239DYM
Immuno-osseous dysplasia (Schimke)AR24290013761830SMARCAL1
SED, Wolcott-Rallison typeAR2269801667EIF2AK3
SEMD, Matrilin typeAR608728156728MATN3
SEMD, short limb—abnormal calcification typeAR27166593358DDR2
SED tarda, X-linked (SED-XL)XLR313400114593284SEDL
Spondylo-megaepiphyseal-metaphyseal dysplasia (SMMD)AR613330228387NKX3-2
Spondylodysplastic Ehlers-Danlos syndromeAR612350157965SLC39A13
SPONASTRIME dysplasiaAR27151093357
SEMD with joint laxity (SEMD-JL) leptodactylic or Hall typeAD60354693360KIF22
SEMD with joint laxity (SEMD-JL) Beighton typeAR27164093359B3GALT6
Platyspondyly (brachyolmia) with amelogenesis imperfectaAR6012162899LTBP3
Late onset SED, autosomal recessive typeAR60922393284
Brachyolmia, Hobaek typeAR27153093301PAPSS2
Brachyolmia, Toledo typeAR27163093303PAPSS2

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)AR20060093299TRIP11
Schneckenbecken dysplasiaAR2692503144SLC35D1
Spondylometaphyseal dysplasia, Sedaghatian typeAR25022093317GPX4
Severe spondylometaphyseal dysplasia (SMD Sedaghatian-like)ARSBDS

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 1/3AD19035077258TRPS1
Trichorhinophalangeal dysplasia type 2 (Langer-Giedion)AD150230502TRPS1 andEXT1
Acrocapitofemoral dysplasiaAR60777863446IHH
Cranioectodermal dysplasia (Levin-Sensenbrenner) type 1AR2183301515IFT122
Cranioectodermal dysplasia (Levin-Sensenbrenner) type 2AR6136101515WDR35
Geleophysic dysplasiaAR231050111682623ADAMTSL2
Geleophysic dysplasia, other typesAR614185111682623FBN1
Acromicric dysplasiaAD102370969SMAD4
Acrodysostosis type 1AD101800950 PRKAR1A
Acrodysostosis type 2AD614613950PDE4D
Angel-shaped phalango-epiphyseal dysplasia (ASPED)AD10583563442
Saldino-Mainzer dysplasiaAR266920140969IFT140
Myhre syndromeAD1392102588SMAD4
Weill-Marchesani syndrome type 1AR27760011143449ADAMTS10
Weill-Marchesani syndrome type 2AD60832811142084FBN1

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)AR60287540NPR2
Grebe dysplasiaAR2007002098GDF5
Fibular hypoplasia and complex brachydactyly (Du Pan)AR2289002639GDF5
Acromesomelic dysplasia with genital anomaliesAR609441BMPR1B
Acromesomelic dysplasia, Osebold-Remondini typeAD11291093382
Acromesomelic dysplasia, Hunter-Thomson typeAR201250968GDF5

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-AD1273001215240SHOX
Langer type (homozygous dyschondrosteosis)Pseudo-AR24970012152632SHOX
Robinow syndrome, recessive typeAR26831012401507ROR2
Robinow syndrome, dominant typeAD1807003107WNT5A
Mesomelic dysplasia, Korean typeAD
Mesomelic dysplasia, Kantaputra typeAD1562321836
Mesomelic dysplasia, Nievergelt typeAD1634002633
Mesomelic dysplasia, Kozlowski-Reardon typeAR2497102631
Mesomelic dysplasia with acral synostoses (Verloes-David-Pfeiffer type)AD6003832496SULF1, SLCO5A1
Mesomelic dysplasia, Savarirayan type (Triangular Tibia-Fibular Aplasia)SP60527485170

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)AD1142901760140SOX9
Stüve-Wiedemann dysplasiaAR6015593206LIFR
Kyphomelic dysplasia, several forms2113501801

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)AR27375014812616CUL7
3-M syndrome (3M2)AR61292114812616OBSL1
Kenny-Caffey dysplasia type 1AR24446093324TBCE
Kenny-Caffey dysplasia type 2AD12700093325FAM111A
Microcephalic osteodysplastic primordial dwarfism type 1/3 (MOPD1)AR2107102636RNU4ATAC
Microcephalic osteodysplastic primordial dwarfism type 2 (MOPD2; Majewski type)AR2107202637PCNT2
IMAGE syndrome (intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia, and genital anomalies)XL/AD61473285173CDKN1C
Hallermann-Streiff syndromeAR2341002108GJA1

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)AR2514501425CANT1
Desbuquois dysplasia with short metacarpals and elongated phalanges (Kim type)AR2514501425CANT1
Desbuquois dysplasia (other variants with or without accessory ossification center)AR
Pseudodiastrophic dysplasiaAR26418085174

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)XLD3029605506235173EBP
CDP, X-linked recessive, brachytelephalangic type (CDPX1)XLR302950154479345ARSE
Congenital hemidysplasia, ichthyosis, limb defects (CHILD)XLD30805051754139NSDHL
Congenital hemidysplasia, ichthyosis, limb defects (CHILD)XLD308050139EBP
Greenberg dysplasiaAR2151401426LBR
Rhizomelic CDP type 1AR2151001270177PEX7
Rhizomelic CDP type 2AR222765177DHPAT
Rhizomelic CDP type 3AR600121177AGPS
CDP tibial-metacarpal typeAD/AR11865179346
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 dysplasiaAR21504550945PTHR1
Caffey disease (including infantile and attenuated forms)AD114000991681310COL1A1
Caffey disease (severe variants with prenatal onset)AR114000991681310COL1A1
Raine dysplasia (lethal and non-lethal forms)AR2597751832FAM20C

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)AR259700667TCIRG1
Osteopetrosis, severe neonatal or infantile forms (OPTB4)AR6114901127667CLCN7
Osteopetrosis, infantile form, with nervous system involvement (OPTB5)AR259720667OSTM1
Osteopetrosis, intermediate form, osteoclast-poor (OPTB2)AR259710667TNFSF11
Osteopetrosis, infantile form, osteoclast-poor with immunoglobulin deficiency (OPTB7)AR612301667TNFRSF11A
Osteopetrosis, intermediate form (OPTB6)AR611497210110PLEKHM1
Osteopetrosis, intermediate form (OPTA2)AR2597101127667CLCN7
Osteopetrosis with renal tubular acidosis (OPTB3)AR2597302785CA2
Osteopetrosis, late-onset form type 1 (OPTA1)AD6076342783LRP5
Osteopetrosis, late-onset form type 2 (OPTA2)AD16660053CLCN7
Osteopetrosis with ectodermal dysplasia and immune defect (OLEDAID)XL30030169088IKBKG
Osteopetrosis, moderate form with defective leucocyte adhesion (LAD3)AR6128402968KIND3
Melorheostosis with osteopoikilosisAD1559502485LEMD3
Osteopathia striata with cranial sclerosis (OSCS)XLD3003732780WTX
Osteopetrosis with infantile neuroaxonal dysplasiaAR?60032985179

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 typeAD12300014611522ANKH
Diaphyseal dysplasia Camurati-EngelmannAD13130011561328TGFB1
Hematodiaphyseal dysplasia GhosalAR2310951802TBXAS1
Hypertrophic osteoarthropathyAR2591001525HPGD
Pachydermoperiostosis (hypertrophic osteoarthropathy, primary, autosomal dominant)AD1671002796
Oculodentoosseous dysplasia (ODOD) mild typeAD1642002710GJA1
Oculodentoosseous dysplasia (ODOD) severe typeAR2578502710GJA1
Osteoectasia with hyperphosphatasia (juvenile Paget disease)AR2390002801OPG
Endosteal hyperostosis, van Buchem typeAR23910012283416SOST
Trichodentoosseous dysplasiaAD1903203352DLX3
Craniometaphyseal dysplasia, autosomal recessive typeAR2184001522GJA1
Diaphyseal medullary stenosis with bone malignancyAD11225085182MTAP
Craniodiaphyseal dysplasiaAD12286012281513SOST
Craniometadiaphyseal dysplasia, Wormian bone typeAR61511885184
Endosteal sclerosis with cerebellar hypoplasiaAR21300285186
Lenz-Majewski hyperostotic dysplasiaSP1510502658PTDSS1
Metaphyseal dysplasia, Braun-Tinschert typeXL60594685188
Pyle diseaseAR2659003005SFRP4


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)AD1662001295216796COL1A1,COL1A2
Osteogenesis imperfecta, perinatal lethal form (OI type II)AD, AR1662101295216804COL1A1,COL1A2,CRTAP,LEPRE1,PPIB
Osteogenesis imperfecta, progressively deforming type (OI type III)AD, AR2594201295216812COL1A1,COL1A2,CRTAP,LEPRE1,PPIB,FKBP10,SERPINH1 , WNT1, TMEM38B
Osteogenesis imperfecta, moderate form (OI type IV)AD, AR1662201295216820COL1A1,COL1A2,CRTAP,FKBP10,SP7
Osteogenesis imperfecta with calcification of the interosseous membranes and/or hypertrophic callus (OI type V)AD610967216828 IFITM5
Osteogenesis imperfecta, type VIAR613982216812SERPINF1
Osteogenesis imperfecta, type VIIAR610682216804CRTAP
Bruck syndrome type 1 (BS1)AR2594502771FKBP10
Bruck syndrome type 2 (BS2)AR6092202771PLOD2
Osteoporosis-pseudoglioma syndromeAR2597702788LRP5
Calvarial doughnut lesions with bone fragilityAD12655085192
Idiopathic juvenile osteoporosisSP25975085193
Cole-Carpenter dysplasia (bone fragility with craniosynostosis)SP1122402050P4HB
Spondylo-ocular dysplasiaAR60582285194XYLT2
Osteopenia with radiolucent lesions of the mandibleAD16626053697ANO5
Ehlers-Danlos syndrome, progeroid formAR13007075496B4GALT7
Geroderma osteodysplasticumAR2310702078GORAB
Cutis laxa, autosomal recessive form, type 2B (ARCL2B)AR61294090350PYCR1
Cutis laxa, autosomal recessive form, type 2A (ARCL2A) (Wrinkly skin syndrome)AR219200520090350ATP6VOA2
Wrinkly skin syndromeAR27825052002834ATP6VOA2
Singleton-Merten dysplasiaAD18225085191IFIH1

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 formsAR2415001150436ALPL
Hypophosphatasia, adult formAD1463001150436ALPL
Hypophosphatemic rickets, X-linked dominantXLD3078008398589936PHEX
Hypophosphatemic rickets, autosomal dominantAD19310089937FGF23
Hypophosphatemic rickets, autosomal recessive, type 1 (ARHR1)AR241520289176DMP1
Hypophosphatemic rickets, autosomal recessive, type 2 (ARHR2)AR613312289176ENPP1
Hypophosphatemic rickets with hypercalciuria, X-linked recessiveXLR3005541652ClCN5
Hypophosphatemic rickets with hypercalciuria, autosomal recessive (HHRH)AR241530157215SLC34A3
Neonatal hyperparathyroidism, severe formAR239200417CASR
Familial hypocalciuric hypercalcemia with transient neonatal hyperparathyroidismAD145980405CASR
Calcium pyrophosphate deposition disease (familial chondrocalcinosis) type 2AD1186001416ANKH

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/1SAR607014116293473IDUA
Mucopolysaccharidosis type 2XLR3099001274580IDS
Mucopolysaccharidosis type 3AAR252900581SGSH
Mucopolysaccharidosis type 3BAR252920581NAGLU
Mucopolysaccharidosis type 3CAR252930581HSGNAT
Mucopolysaccharidosis type 3DAR252940581GNS
Mucopolysaccharidosis type 4AAR253000148668582GALNS
Mucopolysaccharidosis type 4BAR253010582GLB1
Mucopolysaccharidosis type 6AR253200583ARSB
Mucopolysaccharidosis type 7AR253220584GUSB
GMI Gangliosidosis, several formsAR230500354GLB1
Sialidosis, several formsAR256550812NEU1
Sialic acid storage disease (SIASD)AR269920834SLC17A5
Galactosialidosis, several formsAR256540351CTSA
Multiple sulfatase deficiencyAR272200585SUMF1
Mucolipidosis II (I-cell disease), alpha/beta typeAR2525001828576GNPTAB
Mucolipidosis III (Pseudo-Hurler polydystrophy), alpha/beta typeAR2526001875577GNPTAB
Mucolipidosis III (Pseudo-Hurler polydystrophy), gamma typeAR25260524701577GNPTG

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 osteolysisAD17481085195TNFRSF11A
Mandibuloacral dysplasia type AAD24837090153LMNA
Mandibuloacral dysplasia type BAR60861290154ZMPSTE24
Progeria, Hutchinson-Gilford typeAD1766701121740LMNA
Torg-Winchester syndromeAR2596003460MMP2
Hajdu-Cheney syndromeAD102500955 NOTCH2
Multicentric carpal-tarsal osteolysis with and without nephropathyAD1663002774 MAFB
Lipomembraneous osteodystrophy with leukoencephalopathy (presenile dementia with bone cysts; Nasu-Hakola)AR22177011972770TREM2
Lipomembraneous osteodystrophy with leukoencephalopathy (presenile dementia with bone cysts; Nasu-Hakola)AR22177011972770TYROBP

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 1AD1337001235321EXT1
Multiple cartilaginous exostoses 2AD1337011235321EXT2
Multiple cartilaginous exostoses 3AD600209321
Fibrous dysplasia, polyostotic form,
McCune-Albright syndrome
Progressive osseous heteroplasiaAD1663502762GNAS
Gnathodiaphyseal dysplasiaAD16626053697TMEM16E
Osteoglophonic dysplasiaAD16625014552645FGFR1
Fibrodysplasia ossificans progressiva (FOP)AD, SP135100337ACVR1
Neurofibromatosis type 1 (NF1)AD1622001109636NF1
Carpotarsal osteochondromatosisAD1278202767
Cherubism with gingival fibromatosis (Ramon syndrome)AR2662703019
Dysplasia epiphysealis hemimelica (Trevor)SP1278001822
Enchondromatosis (Ollier)SP166000296IDH1, IDH2, and PTH1R
Enchondromatosis with hemangiomata (Maffucci)SP166000296DH1, 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/AD2775903447EZH2
Sotos syndromeAD1175501479821NSD1
Marshall-Smith syndromeSP602535561NFIX
Proteus syndromeSP17692099495744AKT1
Marfan syndromeAD1547001335558FBN1
Congenital contractural arachnodactylyAD1210501386115FBN2
Loeys-Dietz syndrome types 1A and 2AAD609192,610168,1133TGFBR1
Loeys-Dietz syndrome types 1B and 2BAD608967, 6103801133TGFBR2
Loeys-Dietz syndrome, type 3AD6137951133284984SMAD3
Loeys-Dietz syndrome, type 4AD614816113391387TGFB2
Overgrowth syndrome with 2q37 translocationsSPNPPC
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)AR2082301159WISP3
Chronic infantile neurologic cutaneous articular syndrome (CINCA)/neonatal onset multisystem inflammatory disease (NOMID)AD6071151451CIAS1
Sterile multifocal osteomyelitis, periostitis, and pustulosis (CINCA/NOMID-like)AR612852210115IL1RN
Chronic recurrent multifocal osteomyelitis with congenital dyserythropoietic anemia (CRMO with CDA; Majeed syndrome)AR609628197477297LPIN2
Tumoral calcinosis, hyperphosphatemic, familialAR21190053715GALNT3, FGF23, KL
Infantile systemic hyalinosis/Juvenile hyaline fibromatosis (ISH/JHF)AR23649015252176ANTXR2
camptodactyly-arthropathy-coxa vara-pericarditis syndrome (non-inflammatory)AR2082502848PRG4

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 dysplasiaAD11960015131452RUNX2
CDAGS syndrome (craniosynostosis, delayed fontanel closure, parietal foramina, imperforate anus, genital anomalies, skin eruption)AR60311685199
Yunis-Varon syndromeAR2163403472FIG4
Parietal foramina (isolated)AD168500112860015ALX4
Parietal foramina (isolated)AD168500112860015MSX2

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)AD1016001455710FGFR1
Pfeiffer syndrome (FGFR2-related)AD1016001455710FGFR2
Apert syndromeAD101200145587FGFR2
Craniosynostosis with cutis gyrata (Beare-Stevenson)AD12379014551555FGFR2
Crouzon syndromeAD1235001455207FGFR2
Crouzon-like craniosynostosis with acanthosis nigricans (Crouzonodermoskeletal syndrome)AD612247145593262FGFR3
Craniosynostosis, Muenke typeAD602849145553271FGFR3
Antley-Bixler syndromeAR201750141963269POR
Craniosynostosis Boston typeAD6047571541MSX2
Saethre-Chotzen syndromeAD1014001189794TWIST1
Shprintzen-Goldberg syndromeAD18221212772462SKI
Baller-Gerold syndromeAR21860012041225RECQL4
Carpenter syndromeAR20100065759RAB23

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)AD1545001532861TCOF1
Mandibulo-facial dysostosis (Treacher-Collins, Franceschetti-Klein)AD1545001532861POLR1D
Mandibulo-facial dysostosis (Treacher-Collins, Franceschetti-Klein)AR1545001532861POLR1C
Oral-facial-digital syndrome type I (OFD1)XLR3112002750CXORF5
Weyer acrofacial (acrodental) dysostosisAD193530952EVC1
Endocrine-cerebro-osteodysplasia (ECO)AR612651199332ICK
Craniofrontonasal syndromeXLD3041101520EFNB1
Frontonasal dysplasia, type 1AR136760250ALX3
Frontonasal dysplasia, type 2AR613451228390ALX4
Frontonasal dysplasia, type 3AR613456306542ALX1
Hemifacial microsomiaSP/AD1642105199374
Miller syndrome (postaxial acrofacial dysostosis)AR263750246DHODH
Acrofacial dysostosis, Nager typeAD/AR154400245SF3B4
Acrofacial dysostosis, Rodriguez typeAR2011701788

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 triadAD1764501552HLXB9
Spondylocostal dysostosis type 1 (SCD1)AR27730088282311DLL3
Spondylocostal dysostosis type 2 (SCD2)AR60868188282311MESP2
Spondylocostal dysostosis type 3 (SCD3)AR?60981388282311LFNG
Spondylocostal dysostosis type 4 (SCD4)AR61368688282311HES7
Spondylothoracic dysostosisAR12260088281797MESP2
Klippel-Feil anomaly with laryngeal malformationAD1181002345GDF6
Spondylocostal/thoracic dysostosis, other formsAD/AR
Cerebro-costo-mandibular syndrome (rib gap syndrome)AD/AR1176501393SNRPB
Cerebro-costo-mandibular-like syndrome with vertebral defectsAR611209263508COG1

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)AD1478911509TBX4
Small patella—like syndrome with clubfootAD119800293150PITX1
Nail-patella syndromeAD16120011322614LMX1B
Genitopatellar syndromeAR?60617011480685201KAT6B
Ear-patella-short stature syndrome (Meier-Gorlin)AR2246902554ORC1, 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 A1AD11250093388IHH
Brachydactyly type A1AD5p13.3-p13.2
Brachydactyly type A2AD11260093396BMPR1B
Brachydactyly type A2AD11260093396BMP2
Brachydactyly type A2AD11260093396GDF5
Brachydactyly type A3AD11270093393
Brachydactyly type BAD11300093383ROR2
Brachydactyly type B2AD611377140908NOG
Brachydactyly type CAD, AR11310093384GDF5
Brachydactyly type DAD11320093385HOXD13
Brachydactyly type EAD11330093387PTHLH
Brachydactyly type EAD11330093387HOXD13
Brachydactyly—mental retardation syndromeAD6004301001HDAC4
Hyperphosphatasia with mental retardation, brachytelephalangy, and distinct faceAR239300247262PIGV
Brachydactyly-hypertension syndrome (Bilginturian)AD1124101276
Brachydactyly with anonychia (Cooks syndrome)AD1069951487SOX9
Microcephaly-oculo-digito-esophageal-duodenal syndrome (Feingold syndrome)AD16428070501305MYCN
Hand-foot-genital syndromeAD14000014232438HOXA13
Brachydactyly with elbow dysplasia (Liebenberg syndrome)AD1865501275PITX1
Keutel syndromeAR24515085202MGP
Albright hereditary osteodystrophy (AHO)AD103580665GNAS1
Rubinstein-Taybi syndromeAD1808491526783CREBBP
Rubinstein-Taybi syndromeAD1808491526783EP300
Catel-Manzke syndromeXLR?3023801388
Brachydactyly, Temtamy typeAR605282CHSY1
Christian type brachydactylyAD1124501278
Coffin-Siris syndromeAR1359001318111465SMARCA2, SMARCA4, SMARCB1, SMARCE1, ARID1A, ARID1B
Mononen type brachydactylyXLD?3019402565
Poland anomalySP1738002911

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 syndromeAD1814503138TBX3
de Lange syndromeAD1224701104199NIPBL
Fanconi anemiaAR227650140184Several genes, see OMIM
Thrombocytopenia-absent radius (TAR)AR?/AD?274000237583320Several
Thrombocythemia with distal limb defectsAD329319THPO
Holt-Oram syndromeAD1429001111392TBX5
Okihiro syndrome (Duane—radial ray anomaly)AD6073231373959SALL4
Cousin syndromeAR26066093333TBX15
Roberts syndromeAR26830011533103ESCO2
Split-hand-foot malformation with long bone deficiency (SHFLD1)AD1191003329
Split-hand-foot malformation with long bone deficiency (SHFLD2)AD6106853329
Split-hand-foot malformation with long bone deficiency (SHFLD3)AD6125763329
Tibial hemimeliaAR27522093322
Tibial hemimelia-polysyndactyly-triphalangeal thumbAD1887703332
Ankyloblepharon-ectodermal dysplasia-cleft lip/palate (AEC)AD106260437971071TP63
Ectrodactyly-ectodermal dysplasia cleft-palate syndrome Type 3 (EEC3)AD6042921896TP63
Ectrodactyly-ectodermal dysplasia cleft-palate syndrome type 1 (EEC1)AD1299001896
Ectrodactyly-ectodermal dysplasia-macular dystrophy syndrome (EEM)AR2252801897CDH3
Limb-mammary syndrome (including ADULT syndrome)AD6035434379769085TP63
Split hand-foot malformation, isolated form, type 4 (SHFM4)AD605289437972440TP63
Split hand-foot malformation, isolated form, type 1 (SHFM1)AD1836002440
Split hand-foot Malformation, isolated form, type 2 (SHFM2)XL3133502440
Split hand-foot malformation, isolated form, type 3 (SHFM3)AD2465601307FBXW4
Split hand-foot malformation, isolated form, type 5 (SHFM5)AD6067082440
Split-hand/foot malformation 1 with sensorineural hearing lossAR22060071271DLX5
Split-hand/foot malformation 6AR2253002440WNT10B
Al-Awadi Raas-Rothschild limb-pelvis hypoplasia-aplasiaAR2768202879WNT7A
Fuhrmann syndromeAR2289302854WNT7A
RAPADILINO syndromeAR26628012043021RECQL4
Adams-Oliver syndromeAD/AR100300974ARHGAP31, DOCK6, RBPJ, EOGT
Femoral hypoplasia-unusual face syndrome (FHUFS)SP/AD?1347801988
Femur-fibula-ulna syndrome (FFU)SP?2282002019
Hanhart syndrome (hypoglossia-hypodactylia)AD103300989
Scapulo-iliac dysplasia (Kosenow)AD1695502839

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)AD17440093339SHH
Preaxial polydactyly type 1 (PPD1)AD17440093339Other locus
Preaxial polydactyly type 2 (PPD2)/triphalangeal thumb (TPT)AD1745002950SHH
Preaxial polydactyly type 3 (PPD3)AD17460093337Other locus
Preaxial polydactyly type 4 (PPD4)AD17470093338GLI3
Greig cephalopolysyndactyly syndromeAD1757001446380GLI3
Pallister-Hall syndromeAD1465101465672GLI3
Synpolydactyly (complex, fibulin1—associated)AD608180295197FBLN1
Townes-Brocks syndrome (Renal-Ear-Anal-Radial syndrome)AD1074801445857SALL1
Lacrimo-auriculo-dento-digital syndrome (LADD)AD1497302363FGFR2, FGFR3, FGF10
Acrocallosal syndromeAR20099036KIF7
Acro-pectoral syndromeAD60596785203
Acro-pectoro-vertebral dysplasia (F-syndrome)AD102510957
Mirror-image polydactyly of hands and feet (Laurin-Sandrow syndrome)AD1357502378SHH
Mirror-image polydactyly of hands and feet (Laurin-Sandrow syndrome)Other locus
Cenani-Lenz syndactylyAR2127803258LRP4
Cenani-Lenz like syndactylySP (AD?)GREM1, FMN1
Oligosyndactyly, radio-ulnar synostosis, hearing loss, and renal defects syndromeSP (AR?)FMN1
Syndactyly, Malik-Percin typeAR609432157801BHLHA9
STAR syndrome (syndactyly of toes, telecanthus, ano-, and renal malformations)XL300707140952FAM58A
Syndactyly type 1 (III-IV)AD18590093402
Syndactyly type 3 (IV-V)AD18590093402GJA1
Syndactyly type 4 (I-V) Haas typeAD18620093405SHH
Syndactyly type 5 (syndactyly with metacarpal and metatarsal fusion)AD18630093406HOXD13
Syndactyly with craniosynostosis (Philadelphia type)AD6012221527
Syndactyly with microcephaly and mental retardation (Filippi syndrome)AR2724403255CKAP2L
Jawad syndromeAR251255313795RBBP8
Meckel syndrome type 1AR249000564MKS1
Meckel syndrome type 2AR603194564TMEM216
Meckel syndrome type 3AR607361564TMEM67
Meckel syndrome type 4AR611134564CEP290
Meckel syndrome type 5AR611561564RPGRIP1L
Meckel syndrome type 6AR612284564CC2D2A

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 1AD1865003237NOG
Multiple synostoses syndrome type 2AD1865003237GDF5
Multiple synostoses syndrome type 3AD6129613237FGF9
Proximal symphalangism type 1AD1858003250NOG
Proximal symphalangism type 2AD1858003250GDF5
Radio-ulnar synostosis with amegakaryocytic thrombocytopeniaAD60543271289HOXA11

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


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