Arthrogryposis, Distal, Type 5

A number sign (#) is used with this entry because of evidence that distal arthrogryposis type 5 (DA5) is caused by heterozygous mutation in the PIEZO2 gene (613629) on chromosome 18p11.

Biallelic mutation in the PIEZO2 gene causes distal arthrogryposis with impaired proprioception and touch (DAIPT; 617146).

Description

Distal arthrogryposis type 5 is distinguished from other forms of DA by the presence of ocular abnormalities, typically ptosis, ophthalmoplegia, and/or strabismus, in addition to contractures of the skeletal muscles. Some cases have been reported to have pulmonary hypertension as a result of restrictive lung disease (summary by Bamshad et al., 2009).

There are 2 syndromes with features overlapping those of DA5 that are also caused by heterozygous mutation in PIEZO2: distal arthrogryposis type 3 (DA3, or Gordon syndrome; 114300) and Marden-Walker syndrome (MWKS; 248700), which are distinguished by the presence of cleft palate and mental retardation, respectively. McMillin et al. (2014) suggested that the 3 disorders might represent variable expressivity of the same condition.

For a general phenotypic description and a discussion of genetic heterogeneity of distal arthrogryposis, see DA1A (108120).

Genetic Heterogeneity of Distal Arthrogryposis 5

A subtype of DA5 due to mutation in the ECEL1 gene (605896) on chromosome 2q36 has been designated DA5D (615065). See NOMENCLATURE.

Clinical Features

Altman and Davidson (1939) reported a 9-year-old boy with what they termed 'amyoplasia congenita,' or arthrogryposis multiplex congenita, which they appear to have considered a synonymous designation. The boy had contractures of the fingers, toes, wrist, ankles, knees, and elbows with a lack of interphalangeal creases. Although the authors described bilateral ptosis, they did not report frank ophthalmoplegia. The patient subsequently had 3 children, one of whom likewise had distal contractures and ptosis. Friedman and Heidenreich (1995) provided follow-up of the father at age 63 years and the affected son at age 30 years. Both had distal joint contractures, ptosis, and limitation of extraocular movements. The son had a number of conical-shaped teeth, especially prominent in the lateral incisors; dentition could not be evaluated in the father because all secondary teeth had been extracted. Both the father and the son had an unusual pattern of hair loss with thinning over the parietotemporal areas.

Hall et al. (1982) reported 3 patients, 2 of whom were mother and daughter, with a unique form of distal arthrogryposis. In addition to the characteristic features of camptodactyly, ulnar deviation, and foot deformities, all patients had short stature and ptosis. Other features included epicanthal folds, keratoconus, prominent ears, and decreased facial expression. Hall et al. (1982) noted that similar features had been described by Krieger and Espiritu (1972) and Aase and Smith (1968); see 114300 and 147800.

Lai et al. (1991) reported a 27-year-old man with congenital distal arthrogryposis and ophthalmoplegia. He was born with bilateral clubfeet necessitating several operations. As an adult, he had a stiff trunk, mild pectus deformity, and limited movement of his knees, hips, and shoulders. He had internal rotation of the arms with overlapping fingers and wrist flexion. Eye movement was restricted both vertically and horizontally, and abnormal responses on electroretinogram (ERG) suggested tapetoretinal degeneration. An affected son was born with contractures of the hands and feet, stiff hands with long fingers, and internally rotated shoulders. At 1 year of age, he had increased chest diameter with widely spaced nipples, stiff trunk, camptodactyly, and limited wrist extension.

Schrander-Stumpel et al. (1993) described an isolated case of arthrogryposis, ophthalmoplegia, and retinopathy in a Dutch family. The patient had rigid fingers and bilateral clubfeet at birth. Deep set eyes, a triangular face, and prominent ears were evident from an early age. At age 17, he had limited horizontal and vertical eye movements, a rigid back, stiff walk, anteverted, hunched shoulders, and pectus excavatum. The fingers were long, phalangeal creases were totally absent, and flexion was limited to about 30 degrees. Abnormal pigmentation was present in both retinal maculas.

Gripp et al. (1996) reported a mother and son with multiple congenital contractures, expressionless face, blepharophimosis, microstomia, arachnodactyly, and short stature. The mother had sensorineural hearing loss. Although neither patient had ophthalmoplegia, the authors suggested that the disorder most closely resembled distal arthrogryposis type IIb, as classified by Hall et al. (1982).

Pallotta et al. (2000) described a family with DA5 spanning 3 generations. The proband was born with congenital flexion contractures at the elbows, hips, knees, fingers, and toes. At 9 years of age, she showed decreased facial expression, triangular face, ptosis, limitation of gaze, strabismus, high-arched palate, camptodactyly, lack of the distal interphalangeal flexion creases, clinodactyly of the toes, and a firm feel to the muscles. The patient's mother and brother had similar features. The proband also had Dandy-Walker anomaly, which raised the question of whether this anomaly is part of the spectrum of distal arthrogryposis type 5 or whether the Aase-Smith syndrome (147800), which has Dandy-Walker anomaly as a conspicuous feature, belongs to the distal arthrogryposis spectrum.

Sahni et al. (2004) described 4 members spanning 3 generations of a Caucasian family with distal arthrogryposis type 5. All patients had a degree of ophthalmoplegia, ptosis, astigmatism, and strabismus. Other findings included keratoconus in the index patient, which was associated with abnormal electron microscopy of the affected cornea and increased thickness of the central cornea, small axial length of the globe, and, in other members of the family, choroidal folds.

Beals and Weleber (2004) reported a 4-generation family with DA5. Ocular findings included ptosis, epicanthal folds, astigmatism, keratoglobus, pigmentary maculopathy, macular retinal folds, and dysplastic optic nerve heads. All had restrictive limitations involving all ocular muscles, which the authors attributed to fibrosis and contracture. The limb muscles felt firm, and some patients had scoliosis and/or restrictive lung function. Beals and Weleber (2004) commented that ophthalmoplegia in DA5 is a misleading term because the ocular movement abnormalities are not neurologic in origin.

Williams et al. (2007) described 4 affected members in 3 generations of a family with DA5 and an apparent autosomal dominant pattern of inheritance. In addition to the typical features of DA5, the propositus had pulmonary hypertension attributed to chronic hypoxia from severe restrictive chest disease (forced vital capacity and total lung capacity were 30% and 51% of predicted, respectively) and alveolar hypoventilation, exacerbated by residence at high altitude. Her affected brother and son demonstrated active use of accessory muscles of respiration and had evidence of limited chest excursion strongly suggestive of restrictive chest disease, but declined further evaluation. Her mother died at 50 years of age from congestive heart failure that was diagnosed at age 23; she reportedly had the same pattern of contractures as other affected members of the family. Williams et al. (2007) concluded that restrictive chest disease is a component of DA5.

Castori et al. (2009) reported a 19-year-old man who presented with restricted forearm pronation/supination and juvenile macular dystrophy, in whom examination revealed short stature, firm muscles, stiff spine with lumbar hyperlordosis, generalized mild limitation of the large joints, external rotation of the hips, unilateral ptosis, exophoria, and abnormal photopic and scotopic responses on ERG. Examination of the proband's father and paternal grandfather revealed restricted range of movement of the small joints together with ulnar deviation of the fingers, consistent with DA5. Castori et al. (2009) suggested that DA5 may have a very mild musculoskeletal phenotype and that it should be considered in the differential diagnosis of congenital contracture syndromes even in the absence of obvious distal joint involvement.

Coste et al. (2013) studied a mother and son and an unrelated woman who had generalized arthrogryposis associated with ptosis and ophthalmoplegia as well as restrictive lung disease. In addition, the mother had recurrent knee subluxations due to absence of the anterior cruciate ligament (ACL) bilaterally, and her son exhibited similarly unstable knees compatible with absence of the ACL. Other features present in all 3 patients included reduced ability to open the mouth, hypermetropia, hypermobile first metacarpophalangeal joint, and weak or absent tendon reflexes in the knees and ankles. Coste et al. (2013) noted that absence of the ACL had previously been reported in a father and son with arthrogryposis by Kwan and Ross (2009); no eye involvement or restrictive lung disease was reported in the father or son, however.

Molecular Genetics

In a woman with generalized arthrogryposis associated with ptosis and ophthalmoplegia as well as restrictive lung disease and absence of the anterior cruciate ligament, Coste et al. (2013) performed whole-exome sequencing and identified heterozygosity for a de novo missense mutation in the PIEZO2 gene (I802F; 613629.0001). The mutation was confirmed by Sanger sequencing in the patient and her similarly affected son. Independently, Coste et al. (2013) performed whole-genome sequencing in an unrelated woman with generalized arthrogryposis associated with ptosis, ophthalmoplegia, and restrictive lung disease, and identified heterozygosity for an in-frame 3-bp deletion in PIEZO2 (613629.0002). Functional analyses demonstrated that both mutations cause changes in kinetics that result in increased channel activity in response to a given mechanical stimulus, suggesting that DA5 is caused by PIEZO2 gain-of-function mutations.

McMillin et al. (2014) used molecular inversion probes and Sanger sequencing to screen the PIEZO2 gene in 29 families with a diagnosis of DA5, and identified heterozygous mutations in affected individuals from 24 (83%) of the families (see, e.g., 613629.0006-613629.0009), including the families originally reported by Altman and Davidson (1939), Lai et al. (1991), and Sahni et al. (2004). Ten (42%) of the 24 mutation-positive families carried the same recurrent 3-bp deletion (Glu2727del; 613629.0002), including the families originally reported by Pallotta et al. (2000) and Williams et al. (2007). In the Dutch patient described by Schrander-Stumpel et al. (1993) and another patient diagnosed with DA5, McMillin et al. (2014) identified heterozygosity for a recurrent DA3-associated mutation in the PIEZO2 gene, R2686H (613629.0003), and suggested that the correct diagnosis in those patients was DA3 (Gordon syndrome). Noting that 3 syndromes with overlapping features, DA3, DA5, and MWKS, are all caused by heterozygous mutation in the PIEZO2 gene, McMillin et al. (2014) proposed that they share a common developmental mechanism and may represent variable expressivity of the same condition.

Nomenclature

In a revised classification scheme of the distal arthrogryposes, Bamshad et al. (1996) renamed the disorder referred to as DAIIB by Hall et al. (1982) as DA5. This disorder is distinct from DA2B (601680).

Bamshad et al. (2009) stated that 2 DA5 families had been found to have mutations in the MYH2 (160740) and MYH13 (603487) genes. McMillin et al. (2011) stated that based on linkage results and screening of candidate genes, they had 'tentatively' divided DA5 into various subtypes, with MYH2-associated DA5 being designated as 'DA5A,' MYH13-associated DA5 as 'DA5B,' and DA5 mapping to chromosome 11 as 'DA5C;' thus they designated a new autosomal recessive form of DA5 as 'DA5D' (615065). However, no supporting evidence regarding MYH2-, MYH13-, or chromosome 11-associated DA5 subtypes was provided by Bamshad et al. (2009) or McMillin et al. (2011).