Rheumatoid arthritis is an inflammatory disease, primarily of the joints, with autoimmune features and a complex genetic component.

Mucopolysaccharidosis type VI (MPS6) is an autosomal recessive lysosomal storage disorder resulting from a deficiency of arylsulfatase B. Clinical features and severity are variable, but usually include short stature, hepatosplenomegaly, dysostosis multiplex, stiff joints, corneal clouding, cardiac abnormalities, and facial dysmorphism. Intelligence is usually normal (Azevedo et al., 2004).

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.

Mucopolysaccharidosis type I (MPS I) is a progressive multisystem disorder with features ranging over a continuum of severity. While affected individuals have traditionally been classified as having one of three MPS I syndromes (Hurler syndrome, Hurler-Scheie syndrome, or Scheie syndrome), no easily measurable biochemical differences have been identified and the clinical findings overlap. Affected individuals are best described as having either a phenotype consistent with either severe (Hurler syndrome) or attenuated MPS I, a distinction that influences therapeutic options. Severe MPS I. Infants appear normal at birth. Typical early manifestations are nonspecific (e.g., umbilical or inguinal hernia, frequent upper respiratory tract infections before age 1 year). Coarsening of the facial features may not become apparent until after age one year. Gibbus deformity of the lower spine is common and often noted within the first year. Progressive skeletal dysplasia (dysostosis multiplex) involving all bones is universal, as is progressive arthropathy involving most joints. By age three years, linear growth decreases. Intellectual disability is progressive and profound but may not be readily apparent in the first year of life. Progressive cardiorespiratory involvement, hearing loss, and corneal clouding are common. Without treatment, death (typically from cardiorespiratory failure) usually occurs within the first ten years of life. Attenuated MPS I. Clinical onset is usually between ages three and ten years. The severity and rate of disease progression range from serious life-threatening complications leading to death in the second to third decade, to a normal life span complicated by significant disability from progressive joint manifestations and cardiorespiratory disease. While some individuals have no neurologic involvement and psychomotor development may be normal in early childhood, learning disabilities and psychiatric manifestations can be present later in life. Hearing loss, cardiac valvular disease, respiratory involvement, and corneal clouding are common.

Mucopolysaccharidosis type III (MPS III) is a multisystem lysosomal storage disease characterized by progressive central nervous system degeneration manifest as severe intellectual disability (ID), developmental regression, and other neurologic manifestations including autism spectrum disorder (ASD), behavioral problems, and sleep disturbances. Disease onset is typically before age ten years. Disease course may be rapidly or slowly progressive; some individuals with an extremely attenuated disease course present in mid-to-late adulthood with early-onset dementia with or without a history of ID. Systemic manifestations can include musculoskeletal problems (joint stiffness, contractures, scoliosis, and hip dysplasia), hearing loss, respiratory tract and sinopulmonary infections, and cardiac disease (valvular thickening, defects in the cardiac conduction system). Neurologic decline is seen in all affected individuals; however, clinical severity varies within and among the four MPS III subtypes (defined by the enzyme involved) and even among members of the same family. Death usually occurs in the second or third decade of life secondary to neurologic regression or respiratory tract infections.

Mucopolysaccharidosis type III (MPS III) is a multisystem lysosomal storage disease characterized by progressive central nervous system degeneration manifest as severe intellectual disability (ID), developmental regression, and other neurologic manifestations including autism spectrum disorder (ASD), behavioral problems, and sleep disturbances. Disease onset is typically before age ten years. Disease course may be rapidly or slowly progressive; some individuals with an extremely attenuated disease course present in mid-to-late adulthood with early-onset dementia with or without a history of ID. Systemic manifestations can include musculoskeletal problems (joint stiffness, contractures, scoliosis, and hip dysplasia), hearing loss, respiratory tract and sinopulmonary infections, and cardiac disease (valvular thickening, defects in the cardiac conduction system). Neurologic decline is seen in all affected individuals; however, clinical severity varies within and among the four MPS III subtypes (defined by the enzyme involved) and even among members of the same family. Death usually occurs in the second or third decade of life secondary to neurologic regression or respiratory tract infections.

Mucopolysaccharidosis type III (MPS III) is a multisystem lysosomal storage disease characterized by progressive central nervous system degeneration manifest as severe intellectual disability (ID), developmental regression, and other neurologic manifestations including autism spectrum disorder (ASD), behavioral problems, and sleep disturbances. Disease onset is typically before age ten years. Disease course may be rapidly or slowly progressive; some individuals with an extremely attenuated disease course present in mid-to-late adulthood with early-onset dementia with or without a history of ID. Systemic manifestations can include musculoskeletal problems (joint stiffness, contractures, scoliosis, and hip dysplasia), hearing loss, respiratory tract and sinopulmonary infections, and cardiac disease (valvular thickening, defects in the cardiac conduction system). Neurologic decline is seen in all affected individuals; however, clinical severity varies within and among the four MPS III subtypes (defined by the enzyme involved) and even among members of the same family. Death usually occurs in the second or third decade of life secondary to neurologic regression or respiratory tract infections.

Mucopolysaccharidosis type III (MPS III) is a multisystem lysosomal storage disease characterized by progressive central nervous system degeneration manifest as severe intellectual disability (ID), developmental regression, and other neurologic manifestations including autism spectrum disorder (ASD), behavioral problems, and sleep disturbances. Disease onset is typically before age ten years. Disease course may be rapidly or slowly progressive; some individuals with an extremely attenuated disease course present in mid-to-late adulthood with early-onset dementia with or without a history of ID. Systemic manifestations can include musculoskeletal problems (joint stiffness, contractures, scoliosis, and hip dysplasia), hearing loss, respiratory tract and sinopulmonary infections, and cardiac disease (valvular thickening, defects in the cardiac conduction system). Neurologic decline is seen in all affected individuals; however, clinical severity varies within and among the four MPS III subtypes (defined by the enzyme involved) and even among members of the same family. Death usually occurs in the second or third decade of life secondary to neurologic regression or respiratory tract infections.

GLB1-related disorders comprise two phenotypically distinct lysosomal storage disorders: GM1 gangliosidosis and mucopolysaccharidosis type IVB (MPS IVB). The phenotype of GM1 gangliosidosis constitutes a spectrum ranging from severe (infantile) to intermediate (late-infantile and juvenile) to mild (chronic/adult). Type I (infantile) GM1 gangliosidosis begins before age 12 months. Prenatal manifestations may include nonimmune hydrops fetalis, intrauterine growth restriction, and placental vacuolization; congenital dermal melanocytosis (Mongolian spots) may be observed. Macular cherry-red spot is detected on eye exam. Progressive central nervous system dysfunction leads to spasticity and rapid regression; blindness, deafness, decerebrate rigidity, seizures, feeding difficulties, and oral secretions are observed. Life expectancy is two to three years. Type II can be subdivided into the late-infantile (onset age 1-3 years) and juvenile (onset age 3-10 years) phenotypes. Central nervous system dysfunction manifests as progressive cognitive, motor, and speech decline as measured by psychometric testing. There may be mild corneal clouding, hepatosplenomegaly, and/or cardiomyopathy; the typical course is characterized by progressive neurologic decline, progressive skeletal disease in some individuals (including kyphosis and avascular necrosis of the femoral heads), and progressive feeding difficulties leading to aspiration risk. Type III begins in late childhood to the third decade with generalized dystonia leading to unsteady gait and speech disturbance followed by extrapyramidal signs including akinetic-rigid parkinsonism. Cardiomyopathy develops in some and skeletal involvement occurs in most. Intellectual impairment is common late in the disease with prognosis directly related to the degree of neurologic impairment. MPS IVB is characterized by skeletal dysplasia with specific findings of axial and appendicular dysostosis multiplex, short stature (below 15th centile in adults), kyphoscoliosis, coxa/genu valga, joint laxity, platyspondyly, and odontoid hypoplasia. First signs and symptoms may be apparent at birth. Bony involvement is progressive, with more than 84% of adults requiring ambulation aids; life span does not appear to be limited. Corneal clouding is detected in some individuals and cardiac valvular disease may develop.

Mucopolysaccharidosis type I (MPS I) is a progressive multisystem disorder with features ranging over a continuum of severity. While affected individuals have traditionally been classified as having one of three MPS I syndromes (Hurler syndrome, Hurler-Scheie syndrome, or Scheie syndrome), no easily measurable biochemical differences have been identified and the clinical findings overlap. Affected individuals are best described as having either a phenotype consistent with either severe (Hurler syndrome) or attenuated MPS I, a distinction that influences therapeutic options. Severe MPS I. Infants appear normal at birth. Typical early manifestations are nonspecific (e.g., umbilical or inguinal hernia, frequent upper respiratory tract infections before age 1 year). Coarsening of the facial features may not become apparent until after age one year. Gibbus deformity of the lower spine is common and often noted within the first year. Progressive skeletal dysplasia (dysostosis multiplex) involving all bones is universal, as is progressive arthropathy involving most joints. By age three years, linear growth decreases. Intellectual disability is progressive and profound but may not be readily apparent in the first year of life. Progressive cardiorespiratory involvement, hearing loss, and corneal clouding are common. Without treatment, death (typically from cardiorespiratory failure) usually occurs within the first ten years of life. Attenuated MPS I. Clinical onset is usually between ages three and ten years. The severity and rate of disease progression range from serious life-threatening complications leading to death in the second to third decade, to a normal life span complicated by significant disability from progressive joint manifestations and cardiorespiratory disease. While some individuals have no neurologic involvement and psychomotor development may be normal in early childhood, learning disabilities and psychiatric manifestations can be present later in life. Hearing loss, cardiac valvular disease, respiratory involvement, and corneal clouding are common.

FLNA deficiency is associated with a phenotypic spectrum that includes FLNA-related periventricular nodular heterotopia (Huttenlocher syndrome), congenital heart disease (patent ductus arteriosus, atrial and ventricular septal defects), valvular dystrophy, dilation and rupture of the thoracic aortic, pulmonary disease (pulmonary hypertension, alveolar hypoplasia, emphysema, asthma, chronic bronchitis), gastrointestinal dysmotility and obstruction, joint hypermobility, and macrothrombocytopenia.

Buschke-Ollendorff syndrome (BOS) is an autosomal dominant connective tissue disorder manifest by multiple subcutaneous nevi or nodules. They may be either elastin-rich (elastoma) or collagen-rich (dermatofibrosis lenticularis disseminata) on histologic examination. The lesions are usually nontender and firm. Affected individuals also have osteopoikilosis (OPK), literally meaning 'spotted bones,' which are osteosclerotic foci that occur in the epiphyses and metaphyses of long bones, wrist, foot, ankle, pelvis, and scapula. Some individuals have both skin and bone manifestations, whereas others may lack skin or bone manifestations. Some individuals may also have melorheostosis (155950), which is characterized by 'flowing' hyperostosis of the cortex of tubular bones. Most reported cases of BOS and OPK are benign, and the bone lesions are found incidentally, although some patients may have joint pain (reviews by Hellemans et al., 2004 and Zhang et al., 2009).

GLB1-related disorders comprise two phenotypically distinct lysosomal storage disorders: GM1 gangliosidosis and mucopolysaccharidosis type IVB (MPS IVB). The phenotype of GM1 gangliosidosis constitutes a spectrum ranging from severe (infantile) to intermediate (late-infantile and juvenile) to mild (chronic/adult). Type I (infantile) GM1 gangliosidosis begins before age 12 months. Prenatal manifestations may include nonimmune hydrops fetalis, intrauterine growth restriction, and placental vacuolization; congenital dermal melanocytosis (Mongolian spots) may be observed. Macular cherry-red spot is detected on eye exam. Progressive central nervous system dysfunction leads to spasticity and rapid regression; blindness, deafness, decerebrate rigidity, seizures, feeding difficulties, and oral secretions are observed. Life expectancy is two to three years. Type II can be subdivided into the late-infantile (onset age 1-3 years) and juvenile (onset age 3-10 years) phenotypes. Central nervous system dysfunction manifests as progressive cognitive, motor, and speech decline as measured by psychometric testing. There may be mild corneal clouding, hepatosplenomegaly, and/or cardiomyopathy; the typical course is characterized by progressive neurologic decline, progressive skeletal disease in some individuals (including kyphosis and avascular necrosis of the femoral heads), and progressive feeding difficulties leading to aspiration risk. Type III begins in late childhood to the third decade with generalized dystonia leading to unsteady gait and speech disturbance followed by extrapyramidal signs including akinetic-rigid parkinsonism. Cardiomyopathy develops in some and skeletal involvement occurs in most. Intellectual impairment is common late in the disease with prognosis directly related to the degree of neurologic impairment. MPS IVB is characterized by skeletal dysplasia with specific findings of axial and appendicular dysostosis multiplex, short stature (below 15th centile in adults), kyphoscoliosis, coxa/genu valga, joint laxity, platyspondyly, and odontoid hypoplasia. First signs and symptoms may be apparent at birth. Bony involvement is progressive, with more than 84% of adults requiring ambulation aids; life span does not appear to be limited. Corneal clouding is detected in some individuals and cardiac valvular disease may develop.

GLB1-related disorders comprise two phenotypically distinct lysosomal storage disorders: GM1 gangliosidosis and mucopolysaccharidosis type IVB (MPS IVB). The phenotype of GM1 gangliosidosis constitutes a spectrum ranging from severe (infantile) to intermediate (late-infantile and juvenile) to mild (chronic/adult). Type I (infantile) GM1 gangliosidosis begins before age 12 months. Prenatal manifestations may include nonimmune hydrops fetalis, intrauterine growth restriction, and placental vacuolization; congenital dermal melanocytosis (Mongolian spots) may be observed. Macular cherry-red spot is detected on eye exam. Progressive central nervous system dysfunction leads to spasticity and rapid regression; blindness, deafness, decerebrate rigidity, seizures, feeding difficulties, and oral secretions are observed. Life expectancy is two to three years. Type II can be subdivided into the late-infantile (onset age 1-3 years) and juvenile (onset age 3-10 years) phenotypes. Central nervous system dysfunction manifests as progressive cognitive, motor, and speech decline as measured by psychometric testing. There may be mild corneal clouding, hepatosplenomegaly, and/or cardiomyopathy; the typical course is characterized by progressive neurologic decline, progressive skeletal disease in some individuals (including kyphosis and avascular necrosis of the femoral heads), and progressive feeding difficulties leading to aspiration risk. Type III begins in late childhood to the third decade with generalized dystonia leading to unsteady gait and speech disturbance followed by extrapyramidal signs including akinetic-rigid parkinsonism. Cardiomyopathy develops in some and skeletal involvement occurs in most. Intellectual impairment is common late in the disease with prognosis directly related to the degree of neurologic impairment. MPS IVB is characterized by skeletal dysplasia with specific findings of axial and appendicular dysostosis multiplex, short stature (below 15th centile in adults), kyphoscoliosis, coxa/genu valga, joint laxity, platyspondyly, and odontoid hypoplasia. First signs and symptoms may be apparent at birth. Bony involvement is progressive, with more than 84% of adults requiring ambulation aids; life span does not appear to be limited. Corneal clouding is detected in some individuals and cardiac valvular disease may develop.

A rare genetic disease characterized by childhood onset of bilateral progressive sensorineural hearing loss, ocular anomalies (myopia, cataract, retinitis pigmentosa), central and peripheral nervous system features (dementia, epilepsy, ataxia, peripheral neuropathy), ectodermal features (skin atrophy, alopecia, dental caries), and skeletal anomalies (bone cysts, joint stiffness, scoliosis, kyphosis). Laboratory examination may reveal elevated cerebrospinal fluid protein.

Mild spondyloepiphyseal dysplasia due to COL2A1 mutation with early-onset osteoarthritis is a type 2 collagen-related bone disorder characterized by precocious, generalized osteoarthritis (with onset as early as childhood) and mild, dysplastic spinal changes (flattening of vertebrae, irregular endplates and wedge-shaped deformities) resulting in a mildly short trunk.

Progressive pseudorheumatoid dysplasia (PPD) is a skeletal dysplasia characterized by predominant involvement of articular cartilage with progressive joint stiffness and enlargement in the absence of inflammation. Onset – typically between ages three and six years – begins with the involvement of the interphalangeal joints. Over time, involvement of large joints and the spine causes significant joint contractures, gait disturbance, and scoliosis and/or kyphosis, resulting in abnormal posture and significant morbidity. Despite the considerable arthropathy, pain is not a major presenting feature of this condition. Initially height is normal; however, short stature (<3rd centile) becomes evident in adolescence as the skeletal changes progress.

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).

Limb-girdle muscular dystrophies resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239) represent the mildest end of the phenotypic spectrum of muscular dystrophies collectively known as dystroglycanopathies. The limb-girdle phenotype is characterized by onset of muscular weakness apparent after ambulation is achieved; mental retardation and mild brain anomalies are variable (Balci et al., 2005; review by Godfrey et al., 2007). The most severe end of the phenotypic spectrum of dystroglycanopathies is represented by congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A; see MDDGA1, 236670), previously designated Walker-Warburg syndrome (WWS) or muscle-eye-brain disease (MEB), and the intermediate range of the spectrum is represented by congenital muscular dystrophy-dystroglycanopathy with or without mental retardation (type B; see MDDGB1, 613155). Genetic Heterogeneity of Limb-Girdle Muscular Dystrophy-Dystroglycanopathy (Type C) Limb-girdle muscular dystrophy due to defective glycosylation of DAG1 is genetically heterogeneous. See also MDDGC2 (613158), caused by mutation in the POMT2 gene (607439); MDDGC3 (613157), caused by mutation in the POMGNT1 gene (606822); MDDGC4 (611588), caused by mutation in the FKTN gene (607440); MDDGC5 (607155), caused by mutation in the FKRP gene (606596); MDDGC7 (616052), caused by mutation in the ISPD gene (CRPPA; 614631); MDDGC8 (618135), caused by mutation in the POMGNT2 gene (614828); MDDGC9 (613818) caused by mutation in the DAG1 gene (128239); MDDGC12 (616094), caused by mutation in the POMK gene (615247); MDDGC14 (615352) caused by mutation in the GMPPB gene (615320); and MDDGC15 (612937), caused by mutation in the DPM3 gene (605951).

Permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome is characterized by neonatal diabetes mellitus associated with cerebellar and/or pancreatic agenesis.

Spondylometaphyseal dysplasia with cone-rod dystrophy (SMDCRD) is characterized by postnatal growth deficiency resulting in profound short stature, rhizomelia with bowing of the lower extremities, platyspondyly with anterior vertebral protrusions, progressive metaphyseal irregularity and cupping with shortened tubular bones, and early-onset progressive visual impairment associated with a pigmentary maculopathy and electroretinographic evidence of cone-rod dysfunction (summary by Hoover-Fong et al., 2014). Yamamoto et al. (2014) reviewed 16 reported cases of SMDCRD, noting that all affected individuals presented uniform skeletal findings, with rhizomelia and bowed lower limbs observed in the first year of life, whereas retinal dystrophy had a more variable age of onset. There was severe disproportionate short stature, with a final height of less than 100 cm; scoliosis was usually mild. Visual loss was progressive, with stabilization in adolescence.

Autosomal dominant multiple epiphyseal dysplasia (MED) presents in early childhood, usually with pain in the hips and/or knees after exercise. Affected children complain of fatigue with long-distance walking. Waddling gait may be present. Adult height is either in the lower range of normal or mildly shortened. The limbs are relatively short in comparison to the trunk. Pain and joint deformity progress, resulting in early-onset osteoarthritis, particularly of the large weight-bearing joints.

Mucolipidosis III gamma (ML III?) is a slowly progressive inborn error of metabolism mainly affecting skeletal, joint, and connective tissues. Clinical onset is in early childhood; the progressive course results in severe functional impairment and significant morbidity from chronic pain. Cardiorespiratory complications (restrictive lung disease from thoracic involvement, and thickening and insufficiency of the mitral and aortic valves) are rarely clinically significant. A few (probably <10%) affected individuals display mild cognitive impairment.

Poikiloderma with neutropenia (PN) is characterized by an inflammatory eczematous rash (ages 6-12 months) followed by post-inflammatory poikiloderma (age >2 years) and chronic noncyclic neutropenia typically associated with recurrent sinopulmonary infections in the first two years of life and (often) bronchiectasis. There is increased risk for myelodysplastic syndrome and, rarely, acute myelogenous leukemia. Other ectodermal findings include nail dystrophy and palmar/plantar hyperkeratosis. Most affected individuals also have reactive airway disease and some have short stature, hypogonadotropic hypogonadism, midfacial retrusion, calcinosis cutis, and non-healing skin ulcers.

Weill-Marchesani syndrome (WMS) is a connective tissue disorder characterized by abnormalities of the lens of the eye, short stature, brachydactyly, joint stiffness, and cardiovascular defects. The ocular problems, typically recognized in childhood, include microspherophakia (small spherical lens), myopia secondary to the abnormal shape of the lens, ectopia lentis (abnormal position of the lens), and glaucoma, which can lead to blindness. Height of adult males is 142-169 cm; height of adult females is 130-157 cm. Autosomal recessive WMS cannot be distinguished from autosomal dominant WMS by clinical findings alone.

Stickler syndrome is a connective tissue disorder that can include ocular findings of myopia, cataract, and retinal detachment; hearing loss that is both conductive and sensorineural; midfacial underdevelopment and cleft palate (either alone or as part of the Robin sequence); and mild spondyloepiphyseal dysplasia and/or precocious arthritis. Variable phenotypic expression of Stickler syndrome occurs both within and among families; interfamilial variability is in part explained by locus and allelic heterogeneity.

Any osteoarthritis in which the cause of the disease is a mutation in the ASPN gene.

Weill-Marchesani syndrome (WMS) is a connective tissue disorder characterized by abnormalities of the lens of the eye, short stature, brachydactyly, joint stiffness, and cardiovascular defects. The ocular problems, typically recognized in childhood, include microspherophakia (small spherical lens), myopia secondary to the abnormal shape of the lens, ectopia lentis (abnormal position of the lens), and glaucoma, which can lead to blindness. Height of adult males is 142-169 cm; height of adult females is 130-157 cm. Autosomal recessive WMS cannot be distinguished from autosomal dominant WMS by clinical findings alone.

Nestor-Guillermo progeria syndrome (NGPS) is an autosomal recessive disorder characterized by lipoatrophy, osteoporosis, and very severe osteolysis. Patients have no cardiovascular impairment, diabetes mellitus, or hypertriglyceridemia, but suffer profound skeletal abnormalities that affect their quality of life. Onset is after 2 years of age, and lifespan is relatively long (summary by Cabanillas et al., 2011).

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.

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.

Weill-Marchesani syndrome (WMS) is a connective tissue disorder characterized by abnormalities of the lens of the eye, short stature, brachydactyly, joint stiffness, and cardiovascular defects. The ocular problems, typically recognized in childhood, include microspherophakia (small spherical lens), myopia secondary to the abnormal shape of the lens, ectopia lentis (abnormal position of the lens), and glaucoma, which can lead to blindness. Height of adult males is 142-169 cm; height of adult females is 130-157 cm. Autosomal recessive WMS cannot be distinguished from autosomal dominant WMS by clinical findings alone.

Pontocerebellar hypoplasia type 8 is an autosomal recessive neurodevelopmental disorder characterized by severe psychomotor retardation, abnormal movements, hypotonia, spasticity, and variable visual defects. Brain MRI shows pontocerebellar hypoplasia, decreased cerebral white matter, and a thin corpus callosum (summary by Mochida et al., 2012). For a general phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1 (607596).

STING-associated vasculopathy with onset in infancy is an autoinflammatory vasculopathy causing severe skin lesions, particularly affecting the face, ears, nose, and digits, and resulting in ulceration, eschar formation, necrosis, and, in some cases, amputation. Many patients have interstitial lung disease. Tissue biopsy and laboratory findings show a hyperinflammatory state, with evidence of increased beta-interferon (IFNB1; 147640) signaling (summary by Liu et al., 2014).

Spondyloepiphyseal dysplasia with accumulation of glycoprotein in chondrocytes has been designated the 'Stanescu type.' Clinical hallmarks include progressive joint contracture with premature degenerative joint disease, particularly in the knee, hip, and finger joints. Interphalangeal joints of the hands are swollen due to osseous distention of the metaphyseal ends of the phalanges. Affected individuals may be relatively tall despite the presence of a short trunk. Radiologically, there is generalized platyspondyly with mild modification of the endplates, hypoplastic pelvis, epiphyseal flattening with metaphyseal splaying of the long bones, and enlarged phalangeal epimetaphyses of the hands. In addition, the proximal femora are characteristically broad and elongated with striking coxa valga (summary by Nishimura et al., 1998).

Erythrokeratodermia variabilis et progressiva-5 (EKVP5) is an autosomal recessive skin disorder characterized by progressive development of symmetrically distributed hyperkeratotic plaques with palmoplantar hyperkeratosis and nail thickening (Shah et al., 2017).

Weill-Marchesani syndrome (WMS) is a connective tissue disorder characterized by abnormalities of the lens of the eye, short stature, brachydactyly, joint stiffness, and cardiovascular defects. The ocular problems, typically recognized in childhood, include microspherophakia (small spherical lens), myopia secondary to the abnormal shape of the lens, ectopia lentis (abnormal position of the lens), and glaucoma, which can lead to blindness. Height of adult males is 142-169 cm; height of adult females is 130-157 cm. Autosomal recessive WMS cannot be distinguished from autosomal dominant WMS by clinical findings alone.

JABELS is an autosomal recessive neurodevelopmental disorder characterized by developmental delay and intellectual disability with additional variable features. Patients have onset of symptoms in infancy, but the severity is highly variable. Some patients have social interaction and learn to walk but have an ataxic gait and abnormal movements, such as tremor or dystonia, whereas others do not achieve any motor control and are unable to speak. Additional features may include retinal anomalies, visual impairment, microcephaly, abnormal foot or hand posturing, and kyphoscoliosis; some patients have dysmorphic facial features or seizures. Brain imaging typically shows cerebellar atrophy and hypoplasia of the corpus callosum (summary by et al., 2016 and Bertoli-Avella et al., 2018).

Osteochondrodysplasia, brachydactyly, and overlapping malformed digits (OCBMD) is characterized by bilateral symmetric skeletal defects that primarily affect the limbs. Affected individuals have mild short stature due to shortening of the lower leg bones, as well as hand and foot malformations, predominantly brachydactyly and overlapping digits. Other skeletal defects include scoliosis, dislocated patellae and fibulae, and pectus excavatum (Shabbir et al., 2018).

Individuals with PPP1R12A-related urogenital and/or brain malformation syndrome (UBMS) usually present with multiple congenital anomalies, commonly including brain and/or urogenital malformations. The brain abnormalities are variable, with the most severe belonging to the holoprosencephaly spectrum and associated with moderate-to-profound intellectual disability, seizures, and feeding difficulties. In individuals without brain involvement, variable degrees of developmental delay and/or intellectual disability may be present, although normal intelligence has been seen in a minority of affected individuals. Eye abnormalities and skeletal issues (kyphoscoliosis, joint contractures) can also be present in individuals of either sex. Regardless of the presence of a brain malformation, affected individuals with a 46,XY chromosome complement may have a disorder of sex development (DSD) with gonadal abnormalities (dysgenetic gonads or streak gonads). Individuals with a 46,XX chromosome complement may have varying degrees of virilization (clitoral hypertrophy, posterior labial fusion, urogenital sinus).

Mandibuloacral dysplasia with type A lipodystrophy (MADA) is an autosomal recessive disorder characterized by growth retardation, craniofacial anomalies with mandibular hypoplasia, skeletal abnormalities with progressive osteolysis of the distal phalanges and clavicles, and pigmentary skin changes. The lipodystrophy is characterized by a marked acral loss of fatty tissue with normal or increased fatty tissue in the neck and trunk. Some patients may show progeroid features. Metabolic complications can arise due to insulin resistance and diabetes (Young et al., 1971; Simha and Garg, 2002; summary by Garavelli et al., 2009). See also MAD type B (MADB; 608612), which is caused by mutation in the ZMPSTE24 gene (606480).

Mandibuloacral dysplasia progeroid syndrome (MDPS) is an autosomal recessive severe laminopathy-like disorder characterized by growth retardation, bone resorption, arterial calcification, renal glomerulosclerosis, and hypertension (Elouej et al., 2020).

Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies-2 (SSFSC2) is characterized by thin and short long bones, distinctive facial dysmorphism, and dental and skeletal abnormalities, in the absence of developmental delay or intellectual disability. Cardiac anomalies have been reported in some patients (Lin et al., 2021). For a discussion of genetic heterogeneity of SSFSC, see SSFSC1 (617877).

Neurodevelopmental disorder with dysmorphic facies and ischiopubic hypoplasia (NEDFIH) is an autosomal recessive disorder characterized by these features and moderate to severe global developmental delay. Affected individuals show episodic regression during periods of stress, including seizures or infection, the latter of which may be associated with lymphopenia. Brain imaging shows diminished white matter volume, enlarged ventricles, and thin corpus callosum (Muffels et al., 2023).