Arthrogryposis, Distal, Type 3

A number sign (#) is used with this entry because of evidence that distal arthrogryposis type 3 (DA3) is caused by heterozygous mutation in the PIEZO2 gene (613629) on chromosome 18p11.

Description

DA3, or Gordon syndrome, is distinguished from other distal arthrogryposes by short stature and cleft palate (summary by Bamshad et al., 2009).

There are 2 syndromes with features overlapping those of DA3 that are also caused by heterozygous mutation in PIEZO2: distal arthrogryposis type 5 (DA5; 108145) and Marden-Walker syndrome (MWKS; 248700), which are distinguished by the presence of ocular abnormalities and mental retardation, respectively. McMillin et al. (2014) suggested that the 3 disorders may represent variable expressivity of the same condition.

For a phenotypic description and a discussion of genetic heterogeneity of distal arthrogryposis, see DA1 (108120).

Clinical Features

Gordon et al. (1969) described 6 affected persons (3 males, 3 females) in 3 generations. All 3 anomalies were present in 2 persons, whereas the other 4 persons had 1 or 2 of the 3 anomalies. Among the 6 affected, clubfoot occurred in 5, camptodactyly in 4, and cleft palate in 3. A useful list of camptodactyly syndromes was provided. Higgins et al. (1972) studied a father and 2 children with the same syndrome. The oldest affected son had several holes in the palate, camptodactyly, and minor foot deformity, while the youngest child had a bifid uvula, camptodactyly, and foot anomaly, but no cleft palate; the father had camptodactyly and foot anomaly without cleft palate. The syndrome was validated by the report of a 5-generation kindred by Halal and Fraser (1979). Penetrance was reduced more in females than in males, and cleft palate was the least frequently manifested trait. Say et al. (1980) described a sporadic case. Robinow and Johnson (1981) reported affected mother and daughter.

Hall et al. (1982) referred to Gordon syndrome as 'distal arthrogryposis, type IIA'; they suggested that the first report was that of Moldenhauer (1964) and that the same disorder may have been present in the case of Krieger and Espiritu (1972). Moldenhauer (1964) described 4 females of 3 generations of a family with a condition he called Nielson syndrome. The features were short stature, ptosis, cleft palate, camptodactyly, pterygium colli, and vertebral anomalies. Fertility was normal. Ioan et al. (1993) reported a kindred with affected members in 5 generations. They pointed to reduced penetrance and carrier females as a cardinal feature of the Gordon syndrome.

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.

Becker and Splitt (2001) reported a mother and 2 affected children with distal arthrogryposis and cleft palate and suggested a clinical overlap between Gordon syndrome and Aase-Smith syndrome (147800). None of the affected family members had Dandy-Walker malformation, but Becker and Splitt (2001) suggested that it may be a variable feature of Gordon syndrome.

Alisch et al. (2017) reported a father and 2 sons who exhibited multiple contractures that involved the metacarpophalangeal and interphalangeal joints as well as the elbow, shoulder, knee, and ankle joints, who also had clubfeet, short stature, bifid uvula or cleft palate, and a distinct facial phenotype including ptosis. In addition, mild intellectual disability and delay in psychomotor development were present. In the younger son, arthrogryposis multiplex was evident on prenatal ultrasound at 13 weeks' gestation, which revealed flexed wrists and elbows as well as bilateral clubfeet.

Li et al. (2018) reported 4 affected members of a 3-generation Chinese family segregating distal arthrogryposis. The proband (II5) was a 37-year-old man with congenital bilateral and symmetric contractures of fingers 2 through 5. The other 3 affected members had mild contractures restricted to the distal phalanges. All had short stature and clubfeet. None had cleft palate or ocular/facial abnormalities. Li et al. (2018) clinically diagnosed the phenotype in this family as DA1 (see 108120).

Molecular Genetics

McMillin et al. (2014) studied 12 families with DA3 that were negative for mutation in genes associated with distal arthrogryposis or other congenital contracture disorders, including TPM2 (190990), TNNT3 (600692), TNNI2 (191043), MYH3 (160720), and CHRNG (100730). Exome sequencing in 5 families revealed heterozygosity for a recurrent missense mutation in the PIEZO2 gene (R2686H; 613629.0003) in 4 of them, including the family originally reported by Becker and Splitt (2001). The fifth proband was heterozygous for an 8-bp deletion in PIEZO2 (613629.0005). Using molecular inversion probes for targeted sequencing in an additional 7 DA families revealed another 5 families that were heterozygous for the recurrent R2686H mutation. In addition, 2 probands who had been diagnosed with DA5, 1 of whom was the Dutch patient described by Schrander-Stumpel et al. (1993), were heterozygous for R2686H. Neither proband had cleft palate or bifid uvula; however, given the reduced penetrance of cleft palate in DA3, McMillin et al. (2014) suggested that the correct diagnosis in the 2 cases was DA3 rather than DA5. 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.

In a father and 2 sons with DA3, Alisch et al. (2017) sequenced the PIEZO2 gene and identified heterozygosity for the recurrent R2686H mutation. The authors noted that affected individuals in this family exhibited mild intellectual disability and psychomotor delay, suggesting phenotypic overlap between DA3 and MWKS.

In affected members of a Chinese family segregating distal arthrogryposis type 3, Li et al. (2018) identified heterozygosity for a missense mutation in the PIEZO2 gene (R2718Q; 613629.0017). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in several public variant databases.

Nomenclature

Hall et al. (1982) referred to Gordon syndrome as distal arthrogryposis type IIA (DAIIA); Bamshad et al. (1996) presented a revised and extended classification of the distal arthrogryposes, and referred to DAIIA as DA3.

DAIIA is distinct from DA2A (193700), which is also known as Freeman-Sheldon syndrome.