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Skeletal dysplasias: Specific disorders

Skeletal dysplasias: Specific disorders
Literature review current through: Jan 2024.
This topic last updated: Jun 30, 2022.

INTRODUCTION — The skeletal dysplasias are an extremely heterogeneous group of conditions that affect bone development. They encompass over 400 disorders [1]. Most are the result of genetic defects. Skeletal dysplasias can present any time from the prenatal period to adult life. The estimated incidence of skeletal dysplasias is approximately 15.7 in 100,000 births.

The classification of these disorders and the understanding of their pathophysiology have improved over time due to the advent of molecular studies and gene discoveries. This knowledge has contributed to the development of treatment options for specific skeletal dysplasias, such as achondroplasia, hypophosphatasia (HPP), X-linked hypophosphatemic rickets, and osteogenesis imperfecta (OI).

A few of the most common conditions are reviewed in brief here, with some reviewed in greater detail separately. The diagnostic evaluation of the lethal and nonlethal skeletal dysplasias is discussed separately. (See "Approach to prenatal diagnosis of the lethal (life-limiting) skeletal dysplasias" and "Skeletal dysplasias: Approach to evaluation".)

ACHONDROPLASIA AND HYPOCHONDROPLASIA — Achondroplasia is the most common skeletal dysplasia in humans and is associated with a recurrent pathogenic variant in the transmembrane domain of the fibroblast growth factor receptor 3 (FGFR3) gene (recurrent pathogenic variants are de novo variants that occur repeatedly in a population in the general vicinity of a particular gene). The most salient clinical features include disproportionate short stature, long bone shortening that predominantly affects the proximal aspects of the upper and lower extremities, and macrocephaly. Hypochondroplasia is another allelic disorder that is associated with FGFR3 pathogenic variants, although the mutations in this disorder occur in the cytoplasmic (immunoglobulin-like) domain of this gene. These patients have milder clinical manifestations than achondroplasia, with some similar radiologic findings. (See "Achondroplasia".)

DYSOSTOSIS MULTIPLEX — Skeletal changes can be seen in some storage metabolic disorders, such as the mucopolysaccharidoses, mucolipidoses, or gangliosidoses. In these conditions, the bone changes are secondary to progressive storage of complex carbohydrates (glycoproteins or glycolipids) slowly accumulating in the lysosomes and affecting cartilage and bones. This progressive accumulation leads to bone changes known as dysostosis multiplex. Dysostosis multiplex is evidenced by flattening of the vertebrae and, in some cases, anterior protrusion of the vertebral bodies. Other changes include widening of the ribs (paddle rib deformities) such as in mucolipidoses, long bone remodeling, and metacarpal proximal pointing. (See "Mucopolysaccharidoses: Clinical features and diagnosis", section on 'MPS type IV (Morquio syndrome)' and "Mucopolysaccharidoses: Clinical features and diagnosis", section on 'Hurler syndrome'.)

DISORDERS AFFECTING BONE DENSITY

Low bone density — Disorders with low bone density and associated fragility are due to abnormalities in bone formation. As examples, osteogenesis imperfecta (OI) is due to defects in collagen or molecules that affect collagen processing that affect matrix formation, and hypophosphatasia (HPP) affects the formation of hydroxyapatite, which is needed for bone mineralization.

Osteogenesis imperfecta — OI is a variable group of disorders associated with decreased bone density and is characterized by bone fragility, osteoporosis, bone deformities, and multiple fractures. The most frequent types are I through IV, which are associated with heterozygous mutations in alpha chains (alpha 1 and alpha 2) of the type I collagen gene [2]. Other less frequent but more severe forms of OI are mostly due to recessive pathogenic variants, but they may also be caused by autosomal-dominant or X-linked pathogenic variants. Many of these more severe forms involve defects in type I collagen chaperon molecules associated with processing and trafficking (eg, posttranslational modification, matrix mineralization, Wnt signaling pathway, endoplasmic reticulum stress response, retrograde vesicle transport, procollagen folding, procollagen secretion) [3,4].

The list of genes includes:

FK506-binding protein 10 (FKBP10)

Cartilage-associated protein (CRTAP)

Leprecan-like 1 (LEPRE1)

Peptidyl-prolyl isomerase B (PPIB)

Serpin peptidase inhibitor, clade F, member 1 (SERPINF1)

Serpin peptidase inhibitor, clade, H, member 1 (SERPINH1)

Transcription factor SP7 (SP7)

Prolyl 3-hydroxylase 1 (P3H1)

cAMP-responsive element-binding protein 3-like-1 (CREB3L1)

Secreted protein acidic cysteine-rich (SPARC)

KDEL endoplasmic reticulum protein retention receptor 2 (KDELR2)

Cyclophilin B (CYPB)

Coiled-coil domain-containing protein 134 (CCD134)

Terminal nucleotidyltransferase 5A (TENT5A)

Mesoderm development LRP chaperon (MESD)

Interferon-induced transmembrane protein 5 (IFITM5)

The pathogenesis, clinical manifestations, diagnosis, and management of OI are discussed in greater detail separately. (See "Osteogenesis imperfecta: An overview".)

Hypophosphatasia — HPP is a clinically variable disorder with perinatal, infantile, childhood, and adult presentations. It is due to pathogenic variants in the tissue-nonspecific alkaline phosphatase (TNSALP) gene that lead to low alkaline phosphatase activity [5]. There are two forms. The most severe forms of HPP are due to autosomal-recessive pathogenic variants, while milder and often late-presenting forms are caused by autosomal-dominant pathogenic variants of the TNSALP gene.

Patients with this disorder have abnormally low alkaline phosphatase, accumulation of inorganic pyrophosphate that inhibits bone mineralization, increased pyridoxal-5’-phosphate (PLP; active form of B6), and elevated urinary phosphoethanolamine (PEP). Patients with HPP present with poor bone mineralization and progressive bone demineralization leading to recurrent fractures, bone pain, and short stature. In addition, common features include craniosynostosis, vitamin B6-responsive seizures, hypotonia, failure to thrive, respiratory insufficiency/failure, and atraumatic early loss of primary teeth (often with the intact root). Enzyme therapy replacement has been approved for the treatment of the early presentation forms (infantile and childhood forms). (See "Epidemiology and etiology of osteomalacia", section on 'Hypophosphatasia' and "Periodontal disease in children: Associated systemic conditions", section on 'Hypophosphatasia' and "Approach to prenatal diagnosis of the lethal (life-limiting) skeletal dysplasias", section on 'Hypophosphatasia congenita'.)

High bone density — The high bone density disorders are the result of defects in bone remodeling. Bone homeostasis depends upon the result of osteoblastic activity, when bone is laid out, versus osteoclastic activity, when bone is resorbed. Increased osteoblastic activity or decreased osteoclastic resorption leads to osteosclerosis/osteopetrosis (increased bone density), in which bone becomes thicker, harder, and denser. There are multiple forms and types of osteopetrosis, most of them caused by poor or abnormal osteoclastic activity.

Pyknodysostosis — Pyknodysostosis is a rare, recessive disorder caused by homozygous or compound-heterozygous pathogenic variants in the cathepsin K (CTSK) gene [6]. These patients present with an abnormal skull, delayed closure of the fontanelles that persists throughout adult life, wormian bones, midface hypoplasia, abnormal dentition, short stature, osteopetrosis, and acroosteolysis (bony resorption of the terminal tuft of the distal phalanx) manifested by short phalanges more pronounced distally [7]. Frequent fractures ensue after mild trauma. Conditions that increase bone density, such as pyknodysostosis or osteopetrosis, lead to fractures due to lack of bone flexibility. Henri de Toulouse-Lautrec, the acclaimed French painter, was affected by pyknodysostosis and was known to have suffered hundreds of fractures throughout his lifetime.

Infantile malignant osteopetrosis — Perhaps one of the best known and most severe forms of osteopetrosis is the autosomal-recessive form caused by homozygous or compound-heterozygous pathogenic variants in the carbonic anhydrase type II gene (CA2). This is also known as infantile malignant osteopetrosis and is associated with renal tubular acidosis (proximal and distal). The increase in bone density leads to progressive replacement of the bone marrow, with subsequent anemia and pancytopenia. Sclerosis of the skull may also cause compression of the cranial nerves, in particular the optic nerves. This condition is also associated with intellectual disability, short stature, and, in some cases, basal ganglia calcifications [8]. The etiology for the calcifications is unclear but is possibly related to secondary parathyroid dysfunction. High morbidity and early mortality are associated with this disorder.

Treatment is conservative and directed at managing complications such as anemia, kidney involvement, fractures, and dental abnormalities. Hypocalcemia can sometimes be present in these patients since the calcium is trapped inside the bone. This may require supplementation with calcium, phosphate, vitamin D, and, in some instances, calcitriol. High-dose calcitriol is no longer recommended [9]. Hematopoietic cell transplantation (HCT) has been used but proven ineffective, more so for those cases related to decrease in osteoclastic activity. Morbidity and mortality are significant in HCT secondary to graft-versus-host disease.

Autosomal-dominant osteopetrosis, type II — Autosomal-dominant osteopetrosis, type II (ADO II, also called Albers-Schönberg disease) is a form of osteopetrosis (increased bone density) caused by heterozygous pathogenic variants in the chloride channel 7 (CLCN7) gene [10]. This condition primarily affects the spine, the pelvis, and the base of the skull, although increased density is seen in other bones as well (image 1 and image 2 and image 3). Sclerotic rings in the iliac bones are seen in radiographs of the pelvis. Sometimes, bone-within-bone images can be seen in the pelvis and vertebral bodies on radiographs (image 1). Sclerosis of the skull may lead to optic nerve compression or hearing loss and may involve other cranial nerves, such as the facial nerve. These patients are at risk for fractures and anemia secondary to bone marrow replacement. Compound heterozygous pathogenic variants in this gene can also cause severe infantile osteopetrosis [11].

TYPE II COLLAGEN DISORDERS — Type II collagen is a homotrimer composed of three collagen alpha-1 chains (COL2A1x3). It is abundantly present in tissues such as cartilage and vitreous humor. Disorders of type II collagen range widely in severity, from lethal conditions such as hypochondrogenesis to milder disorders such as Stickler syndrome and osteoarthritis.

Kniest dysplasia — Kniest dysplasia is a type II collagen disorder that is associated with disproportionate short stature. The phenotype of this disorder varies widely, ranging from severe with poor survival to mild.

Patients with Kniest dysplasia have marked shortening of the trunk, lumbar lordosis, and kyphoscoliosis. The final height can range from 106 to 145 cm (3 ft 6 in to 4 ft 9 in) for males and females depending upon the severity. In addition, they have severe joint contractures and stiffening. On exam, the face is flat, and cleft palate is a common finding. Eye findings include progressive and severe myopia, retinal detachment, vitreoretinal degeneration, and cataracts. Radiographs show a characteristic widening of the metaphyses (dumbbell shaped), hypoplasia of the pelvic bones, and flattening of the vertebral bodies with coronal clefts. Conductive and sensorineural hearing loss is common in these patients.

Frequent funduscopic exams and hearing evaluations are recommended [12,13].

Spondyloepiphyseal dysplasia congenital — Spondyloepiphyseal dysplasia congenital (SEDC) is a dwarfing condition associated with collagen, type II, alpha 1 (COL2A1) pathogenic variants [14]. SEDC is clinically characterized by disproportionate short stature with a short trunk, short neck, small chest with a pear shape, pectus carinatum, scoliosis, micromelia (abnormally small limb[s]), congenital talipes equinovarus (clubfoot), and midface hypoplasia. The trunk in these patients is disproportionately shorter than the extremities. The final height is approximately 130 cm (4 ft 3 in). As often seen in other type II collagenopathies, they may also present with cleft palate, retinal detachment, myopia, and hearing loss. On radiographs, vertebrae have an ovoid shape with flattening and coronal clefting. Odontoid hypoplasia is also a common finding.

Follow-up of these patients includes eye exams for myopia and retinal detachment, cervical evaluations for odontoid hypoplasia that may necessitate surgery, and hearing evaluations [15,16].

Stickler syndrome — Stickler syndrome, often referred to as hereditary ophthalmoarthropathy or arthro-ophthalmopathy, is mostly due to defects in type II collagen. Molecularly, COL2A1 variants are found in 80 to 90 percent of patients. Most of the other 10 to 20 percent of patients have variants in COL11A1 (a type XI collagen chain), but other rare variants reported include COL11A2, COL9A1, COL9A2, and COL9A3 (type XI and type IX collagens). (See "Syndromes with craniofacial abnormalities", section on 'Stickler and Marshall syndromes'.)

The disorder may be associated with cleft palate, micrognathia, midface hypoplasia, retinal detachment, hearing loss, and late-onset spondyloarthropathy [17]. At birth, these patients are often diagnosed with Pierre Robin sequence (cleft palate, micrognathia, glossoptosis), and they typically have a flat midface. Stature is typically normal. Radiographs may show spine changes with platyspondyly and sometimes scoliosis. (See "Syndromes with craniofacial abnormalities", section on 'Pierre Robin sequence'.)

Patients with suspected and confirmed Stickler syndrome require careful funduscopic exams every 6 to 12 months due to the high risk for retinal detachment and myopia. In addition, hearing evaluations are recommended due to the presence of variable and often progressive sensorineural hearing loss. Mitral valve prolapse occurs in up to 50 percent of patients with Stickler; therefore, serial echocardiographs are recommended.

METAPHYSEAL DYSPLASIAS

Cartilage-hair hypoplasia — Cartilage-hair hypoplasia (CHH) is an autosomal-recessive disorder caused by homozygous or compound-heterozygous pathogenic variants in the mitochondrial ribonucleic acid (RNA) processing endoribonuclease gene (RMRP or RNaseMRP) [18]. Clinically, CHH is characterized by disproportionate short stature with short limbs (short-limbed dwarfism), genu varum deformities (outward bowing of the leg), loose joints, long fibula compared with tibia, and poor hair growth or sparse hair [19]. Some of these children may have infrequent haircuts due to their hypotrichosis. Delays in early motor development are common due to joint laxity. In addition, late sitting and standing due to hip hypoplasia is sometimes observed. Median adult height is 130 cm (4 ft 3 in). Radiographs show generalized irregularities involving the long bone metaphyses with mild widening. Patients with CHH may have impaired cellular immunity and lymphopenia. An exaggerated reaction to chickenpox infections has been reported. These patients should be referred for immunologic evaluations, and live vaccines should be avoided. Other medical complications include Hirschsprung disease. (See "Cartilage-hair hypoplasia".)

Schmid metaphyseal chondrodysplasia — Schmid metaphyseal chondrodysplasia is predominantly a metaphyseal dysplasia that results in short stature with short limbs (short-limbed dwarfism). These patients show leg bowing and a waddling gait after they start walking. Thus, this disorder is typically detected after the second year of age. Coxa vara (decreased femoral neck shaft angle) and genu varum abnormalities are common. Radiographs show metaphyseal changes with cupping, splaying, and fraying [20]. The lower extremities often appear more affected. It is caused by heterozygous pathogenic variants in the collagen type X alpha 1 chain (COL10A1) gene [21]. Final height is variable, but the deficit is often greater than three standard deviations below the mean. The differential diagnosis for this disorder includes severe rickets, hypophosphatemic rickets, and CHH.

Jansen type metaphyseal chondrodysplasia — Jansen type metaphyseal chondrodysplasia is a severe dysplasia with metaphyseal involvement. It is caused by heterozygous pathogenic variants in the parathyroid hormone receptor 1 (PTHR1) gene [22]. This mutation causes independent activation of the G protein–coupled receptor for the PTH hormone in chondrocytes. Clinically, it presents with short-limb dwarfism with a final height that does not exceed 130 cm (4 ft 3 in). In addition, the joints are widened and have restricted mobility. Other clinical findings include prominent forehead, micrognathia, high arched palate, choanal atresia, and clubfeet [23]. Laboratory findings include hypercalcemia and hypercalciuria. Radiologic findings include shortening of the long bones with severely widened metaphyses, irregular edges with fragmentation, and partial calcification of cartilage that extends into the diaphysis. (See "Etiology of hypercalcemia", section on 'Metaphyseal chondrodysplasia'.)

Shwachman-Diamond syndrome — Shwachman-Diamond syndrome is a metaphyseal dysplasia with associated neutropenia and pancreatic exocrine insufficiency. Patients have short stature that typically becomes apparent after two years of age and is due to both the bone dysplasia and pancreatic insufficiency. The exocrine structures of the pancreas are replaced by fatty tissue. Some patients also have lymphopenia, anemia, and/or thrombocytopenia. It is caused by autosomal-recessive homozygous or compound heterozygous pathogenic variants in the Shwachman-Bodian-Diamond syndrome (SBDS) gene in 80 percent of patients [24]. This gene is apparently involved in RNA metabolism. Biallelic variants in another gene, DnaJ heat shock protein family (Hsp40) member C21 (DNAJC21), a gene involved in ribosome biogenesis, have been found in a group of patients with a clinical diagnosis of SBDS but no variants in the SBDS gene [25].

Radiographs of these patients show irregularities of the long bone metaphyses. Ultrasound exams of the pancreas reveal fatty replacement. These patients require close follow-up by hematology due to their high incidence of neutropenia and lymphopenia, as well as increased risk for infections. (See "Shwachman-Diamond syndrome".)

OTHER SKELETAL DYSPLASIAS

Spondyloepiphyseal dysplasia tarda — Spondyloepiphyseal dysplasia (SED) tarda is an X-linked recessive disorder and, as such, typically presents in males. It is caused by pathogenic variants in the trafficking protein particle complex 2 (TRAPPC2) gene that encodes a protein involved in intravesicular trafficking (endoplasmic reticulum to Golgi transport) [26]. This disorder affects the spine and is characterized by disproportionate short stature with short trunk. It presents late in childhood or adolescence. Radiographs reveal platyspondyly and ovoid-shaped vertebra with a hump superiorly and inferiorly over the central and dorsal aspects of the vertebral plates [27]. There are also changes in the articular surfaces of the joints (more so hips and shoulders), leading to premature osteoarthritis.

Cleidocranial dysplasia — Cleidocranial dysplasia (CCD) is caused by heterozygous autosomal-dominant pathogenic variants in the runt-related transcription factor 2 (RUNX2)/core binding factor 1 (CBFA1) gene, a transcription factor involved in osteoblast development [28]. It is characterized by delayed closure of the cranial sutures, distinctive craniofacial features, poor dentition, and hypoplastic clavicles.

The skull sutures may take years to close or, in some cases, may never close. Patients with CCD have a broad forehead, midface hypoplasia, and significant dental anomalies that require very close surveillance, including supernumerary teeth, lack of eruption of permanent teeth, and abnormal deciduous dentition. These problems often lead to dental crowding, abnormal bite, and malocclusion. Late sitting and walking are common issues in these patients due to pelvic abnormalities. Other features of CCD include short, tapered fingers; broad thumbs; narrow chest; and scoliosis. Adult patients may develop osteoporosis.

Radiographs of the head show open sutures, partial calvaria ossification, and wormian bones. Radiographic evaluation of the body reveals hypoplastic clavicles that are absent on rare occasions, absent ossification of pubic bones in infancy, wide pubic symphysis, and large pseudoepiphyses of the metacarpals and metatarsal bones.

Long-term follow-up includes dental care for removal of deciduous or supernumerary teeth, prosthesis, orthotics, and dentures. Prevention and surveillance for osteoporosis should be initiated in early adults. Helmets are suggested when engaging in certain physical activities and contact sports.

Leri-Weill dyschondrosteosis — Leri-Weill dyschondrosteosis is a skeletal dysplasia associated with short stature and mesomelic (middle or intermediate portion of the limb) shortening of the arms (radius/ulna) and legs (tibia/fibula) [29]. It is frequently seen in association with Madelung deformities in the distal radius (triangle shape of the distal radial epiphysis) (picture 1 and image 4). Most of these patients have deletions in the distal pseudoautosomal region of the X chromosome involving the short stature homeobox (SHOX) gene [30]. Homozygous deletions of the SHOX gene gives rise to a more severe form of mesomelic dysplasia and short stature known as Langer mesomelic dysplasia.

Robinow syndrome — There are several forms of Robinow syndrome. The most severe is a recessive form caused by homozygous or compound heterozygous pathogenic variants of the receptor tyrosine kinase-like orphan receptor 2 (ROR2) gene [31]. These patients have short stature, mesomelic or acromesomelic (includes hands and feet) shortening of the limbs, radioulnar synostosis, brachydactyly (shortening of the bones in the fingers and toes), syndactyly (fused fingers or toes), ectrodactyly (split/cleft hand or foot due to missing central digits), and vertebral anomalies such as hemivertebrae or fusion of the thoracic vertebrae. Craniofacial features include macrocephaly, hypertelorism, depressed nasal bridge with upturned nose, and micrognathia. Facial features have been referred to as fetal facies. Genitourinary anomalies may include micropenis and penoscrotal transposition; females may have clitoris hypoplasia. Kidney anomalies may include hydronephrosis.

The autosomal-dominant form of Robinow has similar but milder features than the recessive form and is caused by heterozygous pathogenic variants of the wingless-type MMTV integration site family, member 5A (WNT5A) gene [32]. Variants in WNT5A, however, only account for 30 percent of the dominant forms. Variants in different genes involved in the WNT signaling pathway have been reported in Robinow including dishevelled segment polarity protein 1 (DVL1), dishevelled segment polarity protein 3 (DVL3), and frizzled class receptor 2 (FZD2) [33].

Heterozygous pathogenic variants in ROR2 are associated with a different disorder, brachydactyly type B1, affecting mostly the fourth and fifth digits, with shortened middle and distal phalanges [31].

Pseudoachondroplasia — Pseudoachondroplasia is a generalized bone dysplasia that is typically recognized at two years of age and older. It is caused by heterozygous pathogenic variants in the cartilage oligomeric protein (COMP) gene [34,35]. Normal length at birth is followed by progressive joint enlargement and joint pain. These patients develop disproportionate short stature, waddling gait, prominent knees, and kyphoscoliosis [36]. The joints suffer from progressive degeneration, and most patients will require hip and other joint replacements. Odontoid hypoplasia is common and requires surveillance and ultimately C1 to C2 fusion. Radiologic findings include flattening of the vertebral bodies with anterior tonguing, small epiphyses, irregular metaphyses and epiphyses, and brachydactyly. Treatment involves orthopedic surveillance and pain management for joint deterioration.

Multiple epiphyseal dysplasia — There are several forms of multiple epiphyseal dysplasia (MED), including dominant and recessive forms. The autosomal-dominant form can be caused by pathogenic variants in one of several genes, including COMP, matrilin 3 (MATN3), COL9A1, COL9A2, and COL9A3 [35]. The autosomal-recessive form is caused by homozygous or compound heterozygous pathogenic variants in the solute carrier family 26 (anion exchanger), member 2 (SLC26A2) gene. Different variants in this gene, however, cause the autosomal-recessive disorder known as diastrophic dysplasia. (See 'Diastrophic dysplasia' below.)

MED is characterized by joint pain that may start in late childhood. The dominant form is the most common and presents in early childhood with hip and knee pain after activities, walking, and exercises. These patients have waddling gait, shortened limbs, and progressive involvement of the joints with progressive degenerative arthritis. Radiologic findings include small, delayed, and irregular epiphyses. The recessive form usually manifests at birth with clubfeet and digital abnormalities.

Diastrophic dysplasia — Diastrophic dysplasia is also caused by homozygous or compound heterozygous pathogenic variants in the SLC26A2 gene (see 'Multiple epiphyseal dysplasia' above) and is inherited as an autosomal-recessive disorder [37]. This dwarfing condition can be diagnosed at birth or even prenatally. It is characterized by short stature, small chest, scoliosis, exaggerated lumbar lordosis, brachydactyly with ulnar deviation of the fingers, radial dislocation, hitchhiker's thumb, clubfeet, separation of the first and second toes, and contractures of the large joints. A typical finding at birth includes cystic swelling of the ears present neonatally that subsides with time [38,39]. Cleft palate is seen in one-third of patients. The trachea can be abnormally soft, leading to collapse that may complicate respiratory issues due to lung hypoplasia in the neonatal period. The joints are enlarged and have contractures. In addition, these patients have early onset of degenerative osteoarthritis. Cervical instability with kyphosis can be part of this diagnosis and requires monitoring in some cases to prevent cord compression.

Larsen syndrome — There are two forms of Larsen syndrome, autosomal dominant and autosomal recessive. The dominant form is caused by heterozygous pathogenic variants in the filamin B (FLNB) gene [40], while the recessive form is caused by homozygous or compound heterozygous variants in the carbohydrate sulfotransferase 3 (CHST3) gene [41]. This condition is associated with multiple joint dislocations, flat facies, hypertelorism, and cleft palate [42]. The dominant form presents with dislocations of the large joints, cervical instability with kyphosis that could lead to C2 through C4 subluxation, midface hypoplasia, cleft palate, cleft uvula, short distal phalanges, and clubfeet. The recessive entity is slightly different, with significant short stature and severe joint dislocations that are associated with a significant reduction in range of motion, progressive kyphosis, and scoliosis.

Acromesomelic dysplasia Maroteaux type — Acromesomelic dysplasia Maroteaux type is an autosomal-recessive disorder caused by homozygous or compound heterozygous pathogenic variants in the natriuretic peptide receptor 2 (NRP2) gene that encodes the transmembrane receptor for the cartilage natriuretic peptide (CNP) [43]. The diagnosis is evident in the first year or two of age. This dysplasia is characterized by disproportionate short stature, large head with prominent forehead, micromelia (shortened and abnormally formed extremities) with striking mesomelic and acromelic shortening, as well as kyphosis. The joints are lax, which may contribute to early delay of motor skills. The final adult height averages 122 cm (4 ft) [44].

Chondrodysplasia punctata — There are three different forms of chondrodysplasia (CDP). The autosomal-recessive, so-called rhizomelic form is caused by homozygous or compound heterozygous mutations in the peroxin 7 (PEX7) gene, a receptor that interacts with a number of peroxisomal enzymes. The other two forms are X linked: the X-linked dominant form known as Conradi-Hünermann type [45] and the X-linked recessive form (CDPX1) caused by pathogenic variants in the aryl-sulfatase E (ARSE) gene or deletions or rearrangements of the short arm of the X chromosome that include the ARSE gene [46]. (See "Peroxisomal disorders", section on 'RCDP spectrum disorders'.)

The autosomal-recessive form is characterized by severe short stature, distinctive craniofacial features with low nasal bridge and midface hypoplasia, rhizomelic (proximal) shortening of the limbs, wide joints, multiple joint contractures, and abnormal spine with coronal clefts [47,48]. A typical finding is the presence of punctate calcifications (stippling) in a number of joints at the growth plates and spine. These represent multiple additional epiphyseal calcifications that decrease with time as they incorporate into the epiphyses. The metaphyses near the large joints are cupped and frayed. Other features include intellectual disability, microcephaly, and congenital cataracts.

The X-linked dominant form of CDP occurs almost exclusively in females. The limbs are short and often asymmetric, with extra-epiphyseal punctate calcifications and variable joint contractures. These patients also have a low nasal bridge and midface hypoplasia. Scoliosis is commonly seen and is often associated with multiple calcifications. Other anomalies include severe skin erythroderma and ichthyosis that may follow the Blaschko lines.

The X-linked recessive form occurs in males and is characterized by stippled epiphyses (as seen in the other forms of CDP), brachytelephalangy (shortening of the distal phalanges), and nasal and midface hypoplasia. Children born to mothers with systemic lupus erythematous or to women who were exposed to warfarin therapy during gestation can present with clinical features similar to the X-linked recessive form of CDP.

Acrodysostosis — Acrodysostosis is an autosomal-dominant condition caused by pathogenic variants in the phosphodiesterase 4D (PDE4D) gene [49] or the protein kinase, cAMP-dependent, regulatory, type I alpha (PRKAR1A) gene [50]. It is characterized by short hands; a small, flat, upturned nose; and mild-to-moderate intellectual disability. Hypoplastic genitalia and cryptorchidism are common findings. In addition, these patients have resistance to parathormone with normal calcium and phosphorus, as well as resistance to thyroid-stimulating hormone and growth hormone releasing hormone. Hand radiographs show shortened metacarpals with cone epiphyses. The spine may also be affected with loss of caudal widening of interpedicular distance, which may correlate with stenosis of the spinal canal [51].

The features are similar to those seen in Albright hereditary osteodystrophy (pseudohypoparathyroidism type IA) caused by loss of function of the guanine nucleotide binding protein, alpha stimulating (GNAS) gene on the maternally contributed allele (paternally imprinted), except that patients with acrodysostosis have more severe skeletal findings.

Chondroectodermal dysplasia (Ellis-van Creveld syndrome) — Chondroectodermal dysplasia is an autosomal-recessive disorder caused by homozygous or compound heterozygous pathogenic variants in the EvC ciliary complex subunit 1 (EVC) or EVC2 gene. It is characterized by a narrow chest, short ribs, postaxial polydactyly with a complete extra metacarpal, ectodermal dysplasia with hypoplastic nails and teeth, and structural heart disease (most commonly an atrial septal defect) [52,53].

Sensenbrenner syndrome — Sensenbrenner syndrome is a ciliopathy caused by a pathogenic variant in one of several different genes (IFT122, WDR35, WDR19, and IFT43) that encode intraflagellar transport (IFT) proteins that are members of the tryptophan-aspartate (WD) repeat domain protein family. This disorder affects many systems, including the skeletal system. It is characterized by a narrow thorax, rhizomelic shortening of the limbs, polydactyly, hypodontia, sparse hair, skin laxity, liver fibrosis, retinal dystrophy, and kidney disease. Many of these patients die secondary to end-stage kidney disease (ESKD). They have distinctive craniofacial features including dolichocephaly (head long relative to width) that can be due to sagittal synostosis, frontal bossing, telecanthus (increased distance between the medial corners of the eyes), epicanthal folds and upslanting palpebral fissures, low-set ears, and everted lips. Global developmental delay is a common clinical feature.

Geleophysic dysplasia — The genes involved in this disorder are a disintegrin-like and metalloproteinase with thrombospondin [ADAMTS] like protein 2 (ADAMTSL2) and fibrillin 1 (FBN1), causing geleophysic type I (autosomal recessive) and type II (autosomal dominant), respectively. FBN1 is also the gene involved in Marfan syndrome; however, patients with type II geleophysic dysplasia have mutations confined to exons 41 and 42 of this gene [54,55].

Geleophysic dysplasia is associated with postnatal growth deficiency that is mostly symmetric. Patients with this disorder have a round, full face; short, anteverted nose; and large mouth. These features have been described as happy or pleasant, hence the geleophysic name (the Greek word for happy is "gelios"). They develop coarse features later on and have a stocky appearance. Patients have involvement of heart valves (progressive thickening) and liver enlargement [56]. Radiographs show short long bones, joint contractures, cone-shaped distal phalanges, and J-shaped sella turcica.

Nail-patella syndrome — Nail-patella syndrome is caused by heterozygous pathogenic variants in the LIM homeobox transcription factor 1, beta (LMX1B) gene and is transmitted as an autosomal-dominant disorder [57]. This skeletal disorder is characterized by absence or hypoplasia of the nails, typically affecting the first, second, and third digits; absent or hypoplastic patellae; and abnormal extension and pronation of the elbows (radioulnar dysplasia and radial head dislocation) [58,59]. Stature is normal in these patients. Complications include kidney disease, manifesting as nephrotic syndrome, in up to 50 percent of affected individuals that in some patients may progress to ESKD. Another well-known complication is open-angle glaucoma.

Metatropic dysplasia — Metatropic dysplasia is an autosomal-dominant disorder caused by pathogenic variants in the transient receptor potential cation channel, subfamily V, member 4 (TRPV4) gene [60]. Patients with this disorder are born with short limbs but a longer, narrow chest, which gives them a normal birth length. However, they have progressively worsening kyphoscoliosis that leads to short-trunk dwarfism. The spine anomalies also involve the cervical C1 to C2 region, with resulting odontoid hypoplasia and potential subluxation [61]. Radiographic abnormalities include short ribs and short limbs with metaphyseal widening and flaring, as well as epiphyseal irregularities. The joints are quite prominent on radiographs and physical exam.

Paternal uniparental disomy 14 — Although not strictly a skeletal dysplasia, paternal uniparental disomy (UPD) 14 is often mistaken as one. UPD 14 is the result of monosomy rescue after maternal nondisjunction (loss of maternal chromosome 14). In this instance, only the paternal chromosome 14 is present and duplicated. These patients present with a rather unique skeletal phenotype characterized by very narrow chest, bell-shaped thorax, and angulated ribs often described as the "coat-hanger" sign [62]. The rib findings improve as they grow. Other features seen in this entity including craniofacial dysmorphisms with full cheeks, myopathic facies, and prominent philtrum. These children all have intellectual disabilities and moderate developmental delay [63].

SUMMARY

Overview – The skeletal dysplasias are an extremely heterogeneous group of conditions that affect bone development. They encompass over 400 disorders, most of which are the result of genetic defects. Skeletal dysplasias can present any time from the prenatal period to adult life. (See 'Introduction' above.)

Achondroplasia – Achondroplasia is the most common skeletal dysplasia in humans and is associated with a recurrent pathogenic variant in the transmembrane domain of the fibroblast growth factor receptor 3 (FGFR3) gene. The most salient clinical features include disproportionate short stature, long bone shortening that predominantly affects the proximal aspects of the upper and lower extremities, and macrocephaly. Hypochondroplasia is another allelic disorder that is caused by mutations in a difference region of FGFR3 that lead to milder clinical manifestations than achondroplasia. (See "Achondroplasia".)

Dysostosis multiplex – Bone changes secondary to progressive storage of complex carbohydrates (glycoproteins or glycolipids) slowly accumulating in the lysosomes and affecting cartilage and bones can occur in certain storage metabolic disorders, such as the mucopolysaccharidosis, mucolipidoses, or gangliosidoses. These bone changes are termed dysostosis multiplex. (See "Mucopolysaccharidoses: Clinical features and diagnosis", section on 'MPS type IV (Morquio syndrome)' and "Mucopolysaccharidoses: Clinical features and diagnosis", section on 'Hurler syndrome'.)

Low bone density disorders/abnormalities in bone formation – Disorders with low bone density and associated fragility are due to abnormalities in bone formation. These disorders include osteogenesis imperfecta (OI), which is due to defects in collagen that affect matrix formation and hypophosphatasia (HPP), which affects the formation of hydroxyapatite needed for bone mineralization. (See 'Low bone density' above.)

High bone density disorders/abnormalities in bone remodeling – The high bone density group of disorders are the result of bone-remodeling abnormalities. Patients with these disorders have an increased risk of fractures due to lack of bone flexibility. There are multiple forms and types of osteopetrosis, most of them caused by defects in osteoclastic activity. Examples include pyknodysostosis, infantile malignant osteopetrosis, and autosomal-dominant osteopetrosis, type II. (See 'High bone density' above.)

Disorders of type II collagen – Disorders of type II collagen range widely in severity, from lethal conditions such as hypochondrogenesis to milder disorders such as Stickler syndrome and osteoarthritis. (See 'Type II collagen disorders' above.)

Metaphyseal dysplasias – Patients with metaphyseal dysplasias have disproportionate short stature with short limbs (short-limbed dwarfism). Each metaphyseal dysplasia has its own unique features. Examples of these disorders include cartilage-hair hypoplasia (CHH), Schmid metaphyseal chondrodysplasia, Jansen type metaphyseal chondrodysplasia, and Shwachman-Diamond syndrome. (See 'Metaphyseal dysplasias' above.)

Management – Although there are specific recommendations for many of these disorders, the management of most skeletal dysplasias is conservative and aimed at handling the orthopedic complications, bone deformities, and fractures. (See disease-specific topic reviews.)

  1. Mortier GR, Cohn DH, Cormier-Daire V, et al. Nosology and classification of genetic skeletal disorders: 2019 revision. Am J Med Genet A 2019; 179:2393.
  2. Byers PH, Steiner RD. Osteogenesis imperfecta. Annu Rev Med 1992; 43:269.
  3. Byers PH, Pyott SM. Recessively inherited forms of osteogenesis imperfecta. Annu Rev Genet 2012; 46:475.
  4. Claeys L, Storoni S, Eekhoff M, et al. Collagen transport and related pathways in Osteogenesis Imperfecta. Hum Genet 2021; 140:1121.
  5. Whyte MP. Hypophosphatasia - aetiology, nosology, pathogenesis, diagnosis and treatment. Nat Rev Endocrinol 2016; 12:233.
  6. Gelb BD, Shi GP, Chapman HA, Desnick RJ. Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. Science 1996; 273:1236.
  7. MAROTEAUX P, LAMY M. [Pyknodysostosis]. Presse Med 1962; 70:999.
  8. Whyte MP. Carbonic anhydrase II deficiency. Clin Orthop Relat Res 1993; :52.
  9. Wu CC, Econs MJ, DiMeglio LA, et al. Diagnosis and Management of Osteopetrosis: Consensus Guidelines From the Osteopetrosis Working Group. J Clin Endocrinol Metab 2017; 102:3111.
  10. Pangrazio A, Pusch M, Caldana E, et al. Molecular and clinical heterogeneity in CLCN7-dependent osteopetrosis: report of 20 novel mutations. Hum Mutat 2010; 31:E1071.
  11. Besbas N, Draaken M, Ludwig M, et al. A novel CLCN7 mutation resulting in a most severe form of autosomal recessive osteopetrosis. Eur J Pediatr 2009; 168:1449.
  12. Siggers CD, Rimoin DL, Dorst JP, et al. The Kniest syndrome. Birth Defects Orig Artic Ser 1974; 10:193.
  13. Mortier GR, Wilkin DJ, Wilcox WR, et al. A radiographic, morphologic, biochemical and molecular analysis of a case of achondrogenesis type II resulting from substitution for a glycine residue (Gly691-->Arg) in the type II collagen trimer. Hum Mol Genet 1995; 4:285.
  14. Murray LW, Bautista J, James PL, Rimoin DL. Type II collagen defects in the chondrodysplasias. I. Spondyloepiphyseal dysplasias. Am J Hum Genet 1989; 45:5.
  15. Spranger JW, Wiedemann HR. Dysplasia spondyloepiphysaria congenita. Helv Paediat Acta 1966; 21:598.
  16. Anderson IJ, Goldberg RB, Marion RW, et al. Spondyloepiphyseal dysplasia congenita: genetic linkage to type II collagen (COL2AI). Am J Hum Genet 1990; 46:896.
  17. STICKLER GB, BELAU PG, FARRELL FJ, et al. HEREDITARY PROGRESSIVE ARTHRO-OPHTHALMOPATHY. Mayo Clin Proc 1965; 40:433.
  18. Ridanpää M, van Eenennaam H, Pelin K, et al. Mutations in the RNA component of RNase MRP cause a pleiotropic human disease, cartilage-hair hypoplasia. Cell 2001; 104:195.
  19. MCKUSICK VA, ELDRIDGE R, HOSTETLER JA, et al. DWARFISM IN THE AMISH. II. CARTILAGE-HAIR HYPOPLASIA. Bull Johns Hopkins Hosp 1965; 116:285.
  20. Lachman RS, Rimoin DL, Spranger J. Metaphyseal chondrodysplasia, Schmid type. Clinical and radiographic delineation with a review of the literature. Pediatr Radiol 1988; 18:93.
  21. Warman ML, Abbott M, Apte SS, et al. A type X collagen mutation causes Schmid metaphyseal chondrodysplasia. Nat Genet 1993; 5:79.
  22. Schipani E, Kruse K, Jüppner H. A constitutively active mutant PTH-PTHrP receptor in Jansen-type metaphyseal chondrodysplasia. Science 1995; 268:98.
  23. Gordon SL, Varano LA, Alandete A, Maisels MJ. Jansen's metaphyseal dysostosis. Pediatrics 1976; 58:556.
  24. Boocock GR, Morrison JA, Popovic M, et al. Mutations in SBDS are associated with Shwachman-Diamond syndrome. Nat Genet 2003; 33:97.
  25. Dhanraj S, Matveev A, Li H, et al. Biallelic mutations in DNAJC21 cause Shwachman-Diamond syndrome. Blood 2017; 129:1557.
  26. Gedeon AK, Colley A, Jamieson R, et al. Identification of the gene (SEDL) causing X-linked spondyloepiphyseal dysplasia tarda. Nat Genet 1999; 22:400.
  27. Bannerman RM, Ingall GB, Mohn JF. X-linked spondyloepiphyseal dysplasia tarda: clinical and linkage data. J Med Genet 1971; 8:291.
  28. Mundlos S. Cleidocranial dysplasia: clinical and molecular genetics. J Med Genet 1999; 36:177.
  29. LANGER LO Jr. DYSCHONDROSTEOSIS, A HEREDITABLE BONE DYSPLASIA WITH CHARACTERISTIC ROENTGENOGRAPHIC FEATURES. Am J Roentgenol Radium Ther Nucl Med 1965; 95:178.
  30. Gatta V, Antonucci I, Morizio E, et al. Identification and characterization of different SHOX gene deletions in patients with Leri-Weill dyschondrosteosys by MLPA assay. J Hum Genet 2007; 52:21.
  31. Bacino C. ROR2 Related Robinow Syndrome. In: GeneReviews, Pagon RA, Adam MP, Ardinger HH, et al (Eds), University of Washington, Seattle 2005.
  32. Roifman M, Marcelis CL, Paton T, et al. De novo WNT5A-associated autosomal dominant Robinow syndrome suggests specificity of genotype and phenotype. Clin Genet 2015; 87:34.
  33. White JJ, Mazzeu JF, Coban-Akdemir Z, et al. WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome. Am J Hum Genet 2018; 102:27.
  34. Hecht JT, Nelson LD, Crowder E, et al. Mutations in exon 17B of cartilage oligomeric matrix protein (COMP) cause pseudoachondroplasia. Nat Genet 1995; 10:325.
  35. Briggs MD, Hoffman SM, King LM, et al. Pseudoachondroplasia and multiple epiphyseal dysplasia due to mutations in the cartilage oligomeric matrix protein gene. Nat Genet 1995; 10:330.
  36. MAROTEAUX P, LAMY M. [Pseudo-achondroplastic forms of spondylo-epiphyseal dysplasias]. Presse Med 1959; 67:383.
  37. Hästbacka J, de la Chapelle A, Mahtani MM, et al. The diastrophic dysplasia gene encodes a novel sulfate transporter: positional cloning by fine-structure linkage disequilibrium mapping. Cell 1994; 78:1073.
  38. LAMY M, MAROTEAUX P. [Diastrophic nanism]. Presse Med 1960; 68:1977.
  39. Gustavson KH, Holmgren G, Jagell S, Jorulf H. Lethal and non-lethal diastrophic dysplasia. A study of 14 Swedish cases. Clin Genet 1985; 28:321.
  40. Robertson S. FLNB-Related Disorders. In: GeneReviews, RA, Adam MP, Ardinger HH, et al (Eds), University of Washington, Seattle 2005.
  41. Hermanns P, Unger S, Rossi A, et al. Congenital joint dislocations caused by carbohydrate sulfotransferase 3 deficiency in recessive Larsen syndrome and humero-spinal dysostosis. Am J Hum Genet 2008; 82:1368.
  42. LARSEN LJ, SCHOTTSTAEDT ER, BOST FC. Multiple congenital dislocations associated with characteristic facial abnormality. J Pediatr 1950; 37:574.
  43. Bartels CF, Bükülmez H, Padayatti P, et al. Mutations in the transmembrane natriuretic peptide receptor NPR-B impair skeletal growth and cause acromesomelic dysplasia, type Maroteaux. Am J Hum Genet 2004; 75:27.
  44. Maroteaux P. Acromesomelic dwarfism. In: ntrinsic Diseases of Bone: Progress in Pediatric Radiology, Kaufmann HJ (Ed), S. Karger, Basel 1973. p.563.
  45. Braverman N, Lin P, Moebius FF, et al. Mutations in the gene encoding 3 beta-hydroxysteroid-delta 8, delta 7-isomerase cause X-linked dominant Conradi-Hünermann syndrome. Nat Genet 1999; 22:291.
  46. Maroteaux P. Brachytelephalangic chondrodysplasia punctata: a possible X-linked recessive form. Hum Genet 1989; 82:167.
  47. Spranger JW, Opitz JM, Bidder U. Heterogeneity of Chondrodysplasia punctata. Humangenetik 1971; 11:190.
  48. White AL, Modaff P, Holland-Morris F, Pauli RM. Natural history of rhizomelic chondrodysplasia punctata. Am J Med Genet A 2003; 118A:332.
  49. Michot C, Le Goff C, Goldenberg A, et al. Exome sequencing identifies PDE4D mutations as another cause of acrodysostosis. Am J Hum Genet 2012; 90:740.
  50. Linglart A, Menguy C, Couvineau A, et al. Recurrent PRKAR1A mutation in acrodysostosis with hormone resistance. N Engl J Med 2011; 364:2218.
  51. Robinow M, Pfeiffer RA, Gorlin RJ, et al. Acrodysostosis. A syndrome of peripheral dysostosis, nasal hypoplasia, and mental retardation. Am J Dis Child 1971; 121:195.
  52. MCKUSICK VA, EGELAND JA, ELDRIDGE R, KRUSEN DE. DWARFISM IN THE AMISH I. THE ELLIS-VAN CREVELD SYNDROME. Bull Johns Hopkins Hosp 1964; 115:306.
  53. Ruiz-Perez VL, Ide SE, Strom TM, et al. Mutations in a new gene in Ellis-van Creveld syndrome and Weyers acrodental dysostosis. Nat Genet 2000; 24:283.
  54. Le Goff C, Morice-Picard F, Dagoneau N, et al. ADAMTSL2 mutations in geleophysic dysplasia demonstrate a role for ADAMTS-like proteins in TGF-beta bioavailability regulation. Nat Genet 2008; 40:1119.
  55. Le Goff C, Mahaut C, Wang LW, et al. Mutations in the TGFβ binding-protein-like domain 5 of FBN1 are responsible for acromicric and geleophysic dysplasias. Am J Hum Genet 2011; 89:7.
  56. Spranger JW, Gilbert EF, Tuffli GA, et al. Geleophysic dwarfism--a "focal" mucopolysaccharidosis? Lancet 1971; 2:97.
  57. Vollrath D, Jaramillo-Babb VL, Clough MV, et al. Loss-of-function mutations in the LIM-homeodomain gene, LMX1B, in nail-patella syndrome. Hum Mol Genet 1998; 7:1091.
  58. FONG EE. Iliac horns (symmetrical bilateral central posterior iliac processes). Radiology 1946; 47:517.
  59. Sweeney E, Fryer A, Mountford R, et al. Nail patella syndrome: a review of the phenotype aided by developmental biology. J Med Genet 2003; 40:153.
  60. Krakow D, Vriens J, Camacho N, et al. Mutations in the gene encoding the calcium-permeable ion channel TRPV4 produce spondylometaphyseal dysplasia, Kozlowski type and metatropic dysplasia. Am J Hum Genet 2009; 84:307.
  61. Beck M, Roubicek M, Rogers JG, et al. Heterogeneity of metatropic dysplasia. Eur J Pediatr 1983; 140:231.
  62. Miyazaki O, Nishimura G, Kagami M, Ogata T. Radiological evaluation of dysmorphic thorax of paternal uniparental disomy 14. Pediatr Radiol 2011; 41:1013.
  63. Kagami M, Kurosawa K, Miyazaki O, et al. Comprehensive clinical studies in 34 patients with molecularly defined UPD(14)pat and related conditions (Kagami-Ogata syndrome). Eur J Hum Genet 2015; 23:1488.
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References

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