Cardiospondylocarpofacial Syndrome

A number sign (#) is used with this entry because of evidence that cardiospondylocarpofacial syndrome (CSCF) is caused by heterozygous mutation in the MAP3K7 gene (602614) on chromosome 6q15.

Frontometaphyseal dysplasia-2 (FMD2; 617137), which encompasses features overlapping those of CSCF, is also caused by mutation in the MAP3K7 gene.

Description

Cardiospondylocarpofacial syndrome is characterized by growth retardation, dysmorphic facial features, brachydactyly with carpal-tarsal fusion, extensive posterior cervical vertebral synostosis, cardiac septal defects with valve dysplasia, and deafness with inner ear malformations (Le Goff et al., 2016).

Clinical Features

In a mother and 2 daughters, Forney et al. (1966) observed congenital mitral regurgitation, congenital perceptive deafness due to stapes footplate fixation, fusion of cervical vertebrae and of carpal and tarsal bones, striking freckling of the face and iris, and short stature (mother less than 5 feet). The maternal grandfather was short of stature and his father was both short and deaf. Thus, the condition may have passed through 4 generations.

Sousa et al. (2010) reported a 9.6-year-old Moroccan-Algerian girl and a 7.9-year-old French girl, both born to nonconsanguineous parents, with a similar clinical presentation: hypotonia since the neonatal period, severe failure to thrive, postnatal growth retardation, facial dysmorphism, congenital cardiac defects (septal defect and nonprogressive multiple valve dysplasia), shortened extremities, carpal/tarsal and extensive vertebral synostosis, delayed carpal bone age, deafness, and inner ear malformation. Despite the initial hypotonia and language delay, probably related to the deafness, psychomotor development was normal in both cases. Sousa et al. (2010) proposed the designation of cardiospondylocarpofacial (CSCF) syndrome and suggested that the family reported by Forney et al. (1966) probably represents its first description.

Inheritance

Based on nonconsanguinity and the absence of family history in their 2 patients and on the family described by Forney et al. (1966), Sousa et al. (2010) suggested autosomal dominant inheritance of this disorder.

Molecular Genetics

Le Goff et al. (2016) studied DNA from 6 patients with CSCF, including a father, daughter, and son, an unrelated woman, and the 2 unrelated girls originally reported by Sousa et al. (2010), who all fulfilled inclusion criteria consisting of short stature, short hands, carpal-tarsal fusion, vertebral synostosis, facial dysmorphism, and cardiac defects. By exome sequencing in the 2 girls and the father and son, Le Goff et al. (2016) identified heterozygosity for 3 different mutations in the MAP3K7 gene: an in-1frame 6-bp deletion in the Moroccan-Algerian girl (602614.0005), a missense mutation in the French girl (G110C; 602614.0006), and an in-frame 3-bp deletion in the father and son (602614.0007). Direct sequence analysis of MAP3K7 in the remaining patient revealed heterozygosity for another missense mutation (W241R; 602614.0008). Le Goff et al. (2016) noted that although somatic MAP3K7 mutations had been observed in human cancers and TAK1 is also involved in regulation of innate and adaptive immunity, none of the CSCF patients developed cancer, and immunologic evaluation, performed in 3 of the patients, was normal.

Exclusion Studies

By molecular sequence analysis, Sousa et al. (2010) excluded mutation in the NOG gene (602991) in 1 of their patients and in the FLNB gene (603381) in the other.