GNPTAB-related disorders comprise the phenotypes mucolipidosis II (ML II) and mucolipidosis IIIa/ß (ML IIIa/ß), and phenotypes intermediate between ML II and ML IIIa/ß. ML II is evident at birth and slowly progressive; death most often occurs in early childhood. Orthopedic abnormalities present at birth may include thoracic deformity, kyphosis, clubfeet, deformed long bones, and/or dislocation of the hip(s). Growth often ceases in the second year of life; contractures develop in all large joints. The skin is thickened, facial features are coarse, and gingiva are hypertrophic. All children have cardiac involvement, most commonly thickening and insufficiency of the mitral valve and, less frequently, the aortic valve. Progressive mucosal thickening narrows the airways, and gradual stiffening of the thoracic cage contributes to respiratory insufficiency, the most common cause of death. ML IIIa/ß becomes evident at about age three years with slow growth rate and short stature; joint stiffness and pain initially in the shoulders, hips, and fingers; gradual mild coarsening of facial features; and normal to mildly impaired cognitive development. Pain from osteoporosis becomes more severe during adolescence. Cardiorespiratory complications (restrictive lung disease, thickening and insufficiency of the mitral and aortic valves, left and/or right ventricular hypertrophy) are common causes of death, typically in early to middle adulthood. Phenotypes intermediate between ML II and ML IIIa/ß are characterized by physical growth in infancy that resembles that of ML II and neuromotor and speech development that resemble that of ML IIIa/ß.

Mucopolysaccharidosis type VII (MPS7) is an autosomal recessive lysosomal storage disease characterized by the inability to degrade glucuronic acid-containing glycosaminoglycans. The phenotype is highly variable, ranging from severe lethal hydrops fetalis to mild forms with survival into adulthood. Most patients with the intermediate phenotype show hepatomegaly, skeletal anomalies, coarse facies, and variable degrees of mental impairment (Shipley et al., 1993). MPS VII was the first autosomal mucopolysaccharidosis for which chromosomal assignment was achieved.

Kniest dysplasia is characterized by skeletal and craniofacial anomalies. Skeletal anomalies include disproportionate dwarfism, a short trunk and small pelvis, kyphoscoliosis, short limbs, and prominent joints and premature osteoarthritis that restrict movement. Craniofacial manifestations include midface hypoplasia, cleft palate, early-onset myopia, retinal detachment, and hearing loss. The phenotype is severe in some patients and mild in others. There are distinct radiographic changes including coronal clefts of vertebrae and dumbbell-shaped femora. The chondrooseous morphology is pathognomonic with perilacunar 'foaminess' and sparse, aggregated collagen fibrils resulting in an interterritorial matrix with a 'Swiss-cheese' appearance (summary by Wilkin et al., 1999).

Dyggve-Melchior-Clausen disease (DMC) is an autosomal recessive disorder characterized by progressive spondyloepimetaphyseal dysplasia and impaired intellectual development. Short-trunk dwarfism and microcephaly are present, and specific radiologic appearances most likely reflect abnormalities of the growth plates, including platyspondyly with notched end plates, metaphyseal irregularities, laterally displaced capital femoral epiphyses, and small iliac wings with lacy iliac crests (summary by El Ghouzzi et al., 2003).

The dyssegmental dysplasias are lethal forms of neonatal short-limbed dwarfism. Handmaker et al. (1977) coined the term 'dyssegmental dysplasia' because of the marked differences in size and shape of the vertebral bodies (anisospondyly), which he attributed to errors in segmentation. Fasanelli et al. (1985) proposed that there are different forms of dyssegmental dwarfism, a lethal Silverman-Handmaker type (224410) and a less severe Rolland-Desbuquois type. The Rolland-Desbuquois form is lethal in about 40% of patients. Although many patients survive beyond the newborn period, all exhibit neonatal distress (summary by Hennekam et al., 2010).

A rare primary bone dysplasia characterized, radiologically, by short, stubby long bones, severely angulated femurs and lesser bowing of other long bones (mild, moderate or no bowing), short and wide iliac wings with horizontal acetabular roofs, platyspondyly and a narrow thorax, clinically manifesting with severe, disproportionate short stature. Regression of femora angulation is observed with advancing age.

Cockayne syndrome (referred to as CS in this GeneReview) spans a continuous phenotypic spectrum that includes: CS type I, the "classic" or "moderate" form; CS type II, a more severe form with symptoms present at birth; this form overlaps with cerebrooculofacioskeletal (COFS) syndrome; CS type III, a milder and later-onset form; COFS syndrome, a fetal form of CS. CS type I is characterized by normal prenatal growth with the onset of growth and developmental abnormalities in the first two years. By the time the disease has become fully manifest, height, weight, and head circumference are far below the fifth percentile. Progressive impairment of vision, hearing, and central and peripheral nervous system function leads to severe disability; death typically occurs in the first or second decade. CS type II is characterized by growth failure at birth, with little or no postnatal neurologic development. Congenital cataracts or other structural anomalies of the eye may be present. Affected children have early postnatal contractures of the spine (kyphosis, scoliosis) and joints. Death usually occurs by age five years. CS type III is a phenotype in which major clinical features associated with CS only become apparent after age two years; growth and/or cognition exceeds the expectations for CS type I. COFS syndrome is characterized by very severe prenatal developmental anomalies (arthrogryposis and microphthalmia).

Cockayne syndrome (referred to as CS in this GeneReview) spans a continuous phenotypic spectrum that includes: CS type I, the "classic" or "moderate" form; CS type II, a more severe form with symptoms present at birth; this form overlaps with cerebrooculofacioskeletal (COFS) syndrome; CS type III, a milder and later-onset form; COFS syndrome, a fetal form of CS. CS type I is characterized by normal prenatal growth with the onset of growth and developmental abnormalities in the first two years. By the time the disease has become fully manifest, height, weight, and head circumference are far below the fifth percentile. Progressive impairment of vision, hearing, and central and peripheral nervous system function leads to severe disability; death typically occurs in the first or second decade. CS type II is characterized by growth failure at birth, with little or no postnatal neurologic development. Congenital cataracts or other structural anomalies of the eye may be present. Affected children have early postnatal contractures of the spine (kyphosis, scoliosis) and joints. Death usually occurs by age five years. CS type III is a phenotype in which major clinical features associated with CS only become apparent after age two years; growth and/or cognition exceeds the expectations for CS type I. COFS syndrome is characterized by very severe prenatal developmental anomalies (arthrogryposis and microphthalmia).

Homocystinuria caused by cystathionine ß-synthase (CBS) deficiency is characterized by involvement of the eye (ectopia lentis and/or severe myopia), skeletal system (excessive height, long limbs, scolioisis, and pectus excavatum), vascular system (thromboembolism), and CNS (developmental delay/intellectual disability). All four ? or only one ? of the systems can be involved; expressivity is variable for all of the clinical signs. It is not unusual for a previously asymptomatic individual to present in adult years with only a thromboembolic event that is often cerebrovascular. Two phenotypic variants are recognized, B6-responsive homocystinuria and B6-non-responsive homocystinuria. B6-responsive homocystinuria is usually milder than the non-responsive variant. Thromboembolism is the major cause of early death and morbidity. IQ in individuals with untreated homocystinuria ranges widely, from 10 to 138. In B6-responsive individuals the mean IQ is 79 versus 57 for those who are B6-non-responsive. Other features that may occur include: seizures, psychiatric problems, extrapyramidal signs (e.g., dystonia), hypopigmentation of the skin and hair, malar flush, livedo reticularis, and pancreatitis.

Myhre syndrome is a connective tissue disorder with multisystem involvement, progressive and proliferative fibrosis that may occur spontaneously or following trauma or surgery, mild-to-moderate intellectual disability, and in some instances, autistic-like behaviors. Organ systems primarily involved include: cardiovascular (congenital heart defects, long- and short-segment stenosis of the aorta and peripheral arteries, pericardial effusion, constrictive pericarditis, restrictive cardiomyopathy, and hypertension); respiratory (choanal stenosis, laryngotracheal narrowing, obstructive airway disease, or restrictive pulmonary disease), gastrointestinal (pyloric stenosis, duodenal strictures, severe constipation); and skin (thickened particularly on the hands and extensor surfaces). Additional findings include distinctive craniofacial features and skeletal involvement (intrauterine growth restriction, short stature, limited joint range of motion). To date, 55 individuals with molecularly confirmed Myhre syndrome have been reported.

Leri pleonosteosis is an autosomal dominant skeletal disorder characterized by flexion contractures of the interphalangeal joints, limited movement of multiple joints, and short, broad metacarpals, metatarsals, and phalanges. Additional features may include chronic joint pain, short stature, bony overgrowths, spinal cord compression, scleroderma-like skin changes, and blepharophimosis. The clinical features overlap with several other musculoskeletal conditions, including Myhre syndrome (MYHRS; 139210) and geleophysic dysplasia (GPHYSD1; 231050) (summary by Banka et al., 2015).

Czech dysplasia is an autosomal dominant skeletal dysplasia characterized by early-onset, progressive pseudorheumatoid arthritis, platyspondyly, and short third and fourth toes (Marik et al., 2004; Kozlowski et al., 2004).

GNPTAB-related disorders comprise the phenotypes mucolipidosis II (ML II) and mucolipidosis IIIa/ß (ML IIIa/ß), and phenotypes intermediate between ML II and ML IIIa/ß. ML II is evident at birth and slowly progressive; death most often occurs in early childhood. Orthopedic abnormalities present at birth may include thoracic deformity, kyphosis, clubfeet, deformed long bones, and/or dislocation of the hip(s). Growth often ceases in the second year of life; contractures develop in all large joints. The skin is thickened, facial features are coarse, and gingiva are hypertrophic. All children have cardiac involvement, most commonly thickening and insufficiency of the mitral valve and, less frequently, the aortic valve. Progressive mucosal thickening narrows the airways, and gradual stiffening of the thoracic cage contributes to respiratory insufficiency, the most common cause of death. ML IIIa/ß becomes evident at about age three years with slow growth rate and short stature; joint stiffness and pain initially in the shoulders, hips, and fingers; gradual mild coarsening of facial features; and normal to mildly impaired cognitive development. Pain from osteoporosis becomes more severe during adolescence. Cardiorespiratory complications (restrictive lung disease, thickening and insufficiency of the mitral and aortic valves, left and/or right ventricular hypertrophy) are common causes of death, typically in early to middle adulthood. Phenotypes intermediate between ML II and ML IIIa/ß are characterized by physical growth in infancy that resembles that of ML II and neuromotor and speech development that resemble that of ML IIIa/ß.

Geleophysic dysplasia, a progressive condition resembling a lysosomal storage disorder, is characterized by short stature, short hands and feet, progressive joint limitation and contractures, distinctive facial features, progressive cardiac valvular disease, and thickened skin. Intellect is normal. Major findings are likely to be present in the first year of life. Cardiac, respiratory, and lung involvement result in death before age five years in approximately 33% of individuals with ADAMTSL2-related geleophysic dysplasia.

X-linked spondyloepiphyseal dysplasia tarda is a condition that impairs bone growth and occurs almost exclusively in males. The name of the condition indicates that it affects the bones of the spine (spondylo-) and the ends of long bones (epiphyses) in the arms and legs. "Tarda" indicates that signs and symptoms of this condition are not present at birth, but appear later in childhood, typically between ages 6 and 10.\n\nMales with X-linked spondyloepiphyseal dysplasia tarda have skeletal abnormalities and short stature. Affected boys grow steadily until late childhood, when their growth slows. Their adult height ranges from 4 feet 6 inches (137 cm) to 5 feet 4 inches (163 cm). Impaired growth of the spinal bones (vertebrae) primarily causes the short stature. Spinal abnormalities include flattened vertebrae (platyspondyly) with hump-shaped bulges, progressive thinning of the discs between vertebrae, and an abnormal curvature of the spine (scoliosis or kyphosis). These spinal problems also cause back pain in people with this condition. Individuals with X-linked spondyloepiphyseal dysplasia tarda have a short torso and neck, and their arms are disproportionately long compared to their height.\n\nOther skeletal features of X-linked spondyloepiphyseal dysplasia tarda include an abnormality of the hip joint that causes the upper leg bones to turn inward (coxa vara); multiple abnormalities of the epiphyses, including a short upper end of the thigh bone (femoral neck); and a broad, barrel-shaped chest. A painful joint condition called osteoarthritis that typically occurs in older adults often develops in early adulthood in people with X-linked spondyloepiphyseal dysplasia tarda and worsens over time, most often affecting the hips, knees, and shoulders.

Any Smith-McCort dysplasia in which the cause of the disease is a mutation in the DYM gene.

Autosomal recessive primary hypertrophic osteoarthropathy-1 (PHOAR1) is a rare familial disorder characterized by digital clubbing, osteoarthropathy, and acroosteolysis, with variable features of pachydermia, delayed closure of the fontanels, and congenital heart disease (summary by Uppal et al., 2008; Radhakrishnan et al., 2020). Secondary hypertrophic osteoarthropathy, or pulmonary hypertrophic osteoarthropathy, is a different disorder characterized by digital clubbing secondary to acquired diseases, most commonly intrathoracic neoplasm (Uppal et al., 2008). Touraine et al. (1935) recognized pachydermoperiostosis as a familial disorder with 3 clinical presentations or forms: a complete form characterized by periostosis and pachydermia; an incomplete form with bone changes but without pachydermia; and a 'forme fruste' with pachydermia and minimal skeletal changes. Genetic Heterogeneity Autosomal recessive primary hypertrophic osteoarthropathy-2-enteropathy syndrome (PHOAR2E; 614441) is caused by mutation in the SLCO2A1 gene (601460) on chromosome 3q22. Families with an autosomal dominant form of primary hypertrophic osteoarthropathy, in which patients may also experience gastrointestinal symptoms, have been reported (PHOAD; 167100).

The Ain-Naz type of rhizomelic dysplasia (RHZDAN) is characterized by severe short stature with marked rhizomelic shortening of the limbs, platyspondyly, and large hands and feet relative to height (Ain et al., 2021).