Contractures, Pterygia, And Variable Skeletal Fusions Syndrome 1a

A number sign (#) is used with this entry because of evidence that contractures, pterygia, and variable skeletal fusions syndrome-1A (CPSKF1A) is caused by heterozygous mutation in the MYH3 gene (160720) on chromosome 17p13.

Heterozygous mutation in the MYH3 gene can also cause distal arthrogryposes, including DA2A (193700) and DA2B3 (618436).

Description

Contractures, pterygia, and variable skeletal fusions syndrome-1A (CPSKF1) is characterized by contractures of proximal and distal joints, pterygia involving the neck, axillae, elbows, and/or knees, as well as variable vertebral, carpal, and tarsal fusions and short stature. Progression of vertebral fusions has been observed, and inter- and intrafamilial variability has been reported (Carapito et al., 2016; Zieba et al., 2017; Cameron-Christie et al., 2018).

An autosomal recessive form of CPSKF (CPSKF1B; 618469) is caused by compound heterozygous mutation in the MYH3 gene.

Clinical Features

McKeown and Harris (1988) described a multiple pterygium syndrome in 3 children and their mother. Great variability in severity was observed among the affected subjects. Ptosis and severe scoliosis due to hemivertebrae were present in some. The mother had vertebral fusions, and 2 of the children exhibited both vertebral and carpal fusions; radiographs of the feet were not reported. The mildest case was similar to distal arthrogryposis type IIB (108145), in which joint contractures are associated with ptosis. The most severely affected case closely resembled the autosomal recessive Escobar variant of multiple pterygium syndrome (EVMPS; 265000). The authors speculated that some isolated cases may in fact represent this dominant disorder. The most severely affected members of the family were exposed to phenobarbitone and phenytoin during pregnancy. Several of the affected members had a functional palate abnormality producing nasal speech.

Wiles et al. (1992) described a 12-year-old Australian girl with short-trunk short stature and scoliosis, who had a rigid spine and mild lumbar lordosis. Respiratory function tests showed a mild restrictive pattern. X-rays showed delayed bone age, platyspondyly, fusion of vertebral bodies in the cervical, thoracic, and lumbar spine, fusion of posterior elements in the thoracic and lumbar spine, foreshortened lordotic thoracic spine with scoliosis, kyphosis of lumbar spine, and horizontal sacrum. In addition, she had unilateral carpal coalition with fusion of the lunate and triquetrum bones. Tarsal findings were not reported. Cameron-Christie et al. (2018) restudied the girl reported by Wiles et al. (1992) and tabulated additional findings, including tarsal fusion, short webbed neck, and elbow contractures.

Prontera et al. (2006) reported a 3-year-old girl with classic clinical features of EVMPS, including vertebral fusions and multiple anterior vertebral clefts. Clinical examination of the father showed subtle minor signs of the disorder, including difficulty in opening the mouth widely, scoliosis, pectus excavatum, slight cutaneous syndactyly, malformed carpal bones, and an altered metacarpal-phalangeal pattern. The authors suggested that either this family shows autosomal dominant inheritance or the father is a manifesting heterozygote. Molecular studies were not performed.

Prontera et al. (2006) reviewed the features of mildly affected members of 3 previously reported families with dominant multiple pterygium syndrome and noted that one or more of the following features were present: ptosis, posteriorly rotated ears, webbing of the neck, axillae, elbows, or knees, vertebral anomalies such as vertebral fusion or hemivertebrae, carpal bone anomalies and carpal fusion, fusion of tarsal bones, and pelvic dysplasia.

Isidor et al. (2008) reported a 30-year-old French mother and her 9-year-old son with a clinical diagnosis of spondylocarpotarsal synostosis syndrome (SCT; 272460). Both exhibited short stature, progressive scoliosis, hearing loss, cleft palate, and short neck. The mother had fusion of cervical vertebrae in childhood that progressed to include thoracic vertebrae by age 26, abnormal segmentation of thoracic vertebrae, limited extension of both elbows, and carpal and tarsal synostosis. Evaluation of her son at age 8.5 years showed scoliosis with fusion of thoracic bodies and a carpal bone age of 3 years; no carpal bone fusion was observed, which was attributed to the major bone age delay.

Carapito et al. (2016) studied the mother and son originally reported by Isidor et al. (2008) (family 1) as well as an unrelated 27-year-old mother and her 6-year-old daughter (family 2) who had been clinically diagnosed with SCT. In family 2, both mother and daughter had carpal and tarsal fusions, but otherwise showed intrafamilial variability; the mother had normal stature and mobility, whereas the daughter was severely disabled with short stature, major orthopedic malformations, and pterygia of the neck, knees, and ankles. The daughter also had cardiovascular anomalies, including bicuspid aortic valve with mild aortic insufficiency and slight supravalvular stenosis as well as patent ductus arteriosus requiring surgery, and she experienced an episode of respiratory failure due to restrictive lung disease. Vertebral fusions had been diagnosed prenatally in the daughter and she showed severe scoliosis with diffuse vertebral segmentation abnormalities; the mother had fusions of C1-C2 and C6-C7 but did not show scoliosis. All 4 patients exhibited mild dysmorphic features, including downslanting palpebral fissures, low-set ears, and low hairline. Carapito et al. (2016) noted phenotypic overlap between SCT and multiple pterygium syndrome.

Zieba et al. (2017) studied 3 probands clinically diagnosed with SCT from the International Skeletal Dysplasia Registry: a 3-year-old boy (R06-109A) and 2 adult women (R07-183B and R12-336A). There were vertebral fusions in the cervical, thoracic, lumbar, and sacral regions of the spine, as well as carpal and tarsal coalitions. X-rays demonstrated the progressive nature of the vertebral fusions, ranging from mild disc space narrowing in the boy to vertebral fusions and severe scoliosis in the women. All 3 patients had bilateral fifth-finger clinodactyly. The boy had a cleft palate. One woman (R07-183B) had mild hand contractures with syndactyly as well as elbow and knee dislocations, and underwent surgery as a child to correct overlapping fifth toes. She was a member of a large family in which her brother, father, 2 paternal uncles, and her son were also affected. Most affected relatives reported only scoliosis and vertebral fusions, some had mild hand contractures, and the proband's son had cleft palate. None of the affected individuals were reported to have congenital pterygium, severe camptodactyly, or equinovarus deformities.

Scala et al. (2018) studied an 8.5-year-old Italian boy who exhibited severely limited extension of the elbows, wrists, knees, and ankles, as well as facial features consistent with Sheldon-Hall syndrome (see DA2B3, 618436), including triangular face, prominent nasolabial folds and chin, low-set ears with uplifted earlobes, downslanting palpebral fissures, and wide philtrum. In addition, he had unilateral carpal bone fusion, multiple cervical and thoracic vertebral fusions, and mild thoracolumbar scoliosis. The authors stated that this was the first report of a typical Sheldon-Hall syndrome phenotype accompanied by vertebral and carpal fusions.

Cameron-Christie et al. (2018) reported 4 patients from 3 families, including the Australian girl (family 9) originally described by Wiles et al. (1992), who were heterozygous for mutations in the MYH3 gene. All of the patients exhibited vertebral fusions with scoliosis, carpal/tarsal fusions, and variable joint contractures. Other features included facial dysmorphism, short neck, absent finger flexion creases, and webbing of the neck and fingers. In a Dutch family (family 2), an affected brother and sister had inherited the mutation from their mother, who exhibited only camptodactyly.

Molecular Genetics

By exome sequencing in 3 families in which affected individuals had contractures, pterygia of the knees and neck, and vertebral fusions, which Bamshad et al. (1996) had classified as distal arthrogryposis-8 (DA8), Chong et al. (2015) excluded mutation in 8 genes previously identified in patients with multiple pterygium syndromes and identified heterozygous mutations in the MYH3 gene (160720.0009-160720.0011). The mutations, which segregated with disease in the respective families, involved highly conserved residues and were not found in public databases.

In a French mother and son (family 1) with joint mobility limitation and vertebral and carpal fusions, who were previously studied by Isidor et al. (2008) and found to be negative for mutation in the FLNB (603381) and NOG (602991) genes, Carapito et al. (2016) performed exome sequencing and identified heterozygosity for a missense mutation in the MYH3 gene (T333R; 160720.0013). An unrelated mother and daughter (family 2) with multiple pterygia and vertebral, carpal, and tarsal fusions were found to be heterozygous for a different missense mutation in MYH3 (L1344P; 160720.0014).

By exome sequencing in 3 probands from the International Skeletal Dysplasia Registry who had vertebral, carpal, and tarsal fusions, Zieba et al. (2017) identified heterozygosity for mutations in the MYH3 gene (see, e.g., 160720.0011).

In an 8.5-year-old Italian boy with multiple joint contractures and facial dysmorphism reminiscent of DA2B3, as well as wide neck, mild scoliosis, and vertebral and carpal fusions, who was negative for mutation in Noonan syndrome (see 163950)-associated genes, Scala et al. (2018) sequenced the MYH3 gene and identified heterozygosity for a missense mutation (F287V; 160720.0015).

From a cohort of 16 patients with multiple contractures, pterygia, vertebral fusions, and variable carpal and/or tarsal fusions, who were known to be negative for mutation in the FLNB gene, Cameron-Christie et al. (2018) identified 4 patients from 3 families with heterozygous mutations in the MYH3 gene, including the Australian girl described by Wiles et al. (1992) (see, e.g., 160720.0016). In another 6 patients from 4 unrelated families from the same cohort, Cameron-Christie et al. (2018) identified compound heterozygosity for MYH3 mutations (see CPSKF1B, 618469).

Exclusion Studies

In a family diagnosed with distal arthrogryposis-8, in which an affected father and daughter lacked popliteal or antecubital pterygia as well as vertebral fusions and had ventricular septal defects, Chong et al. (2015) found no mutation in the MYH3 gene. The authors suggested that the phenotype in this family might represent a distinct mendelian condition.