Uruguay Faciocardiomusculoskeletal Syndrome

A number sign (#) is used with this entry because of evidence that Uruguay faciocardiomusculoskeletal syndrome (FCMSU) is caused by hemizygous mutation in the FHL1 gene (300163) on chromosome Xq27. One such family has been reported.

Mutation in the FHL1 gene can cause several phenotypes with overlapping features; see particularly X-linked myopathy with postural muscle atrophy (XMPMA; 300696).

Clinical Features

Quadrelli et al. (2000) reported a family from Uruguay in which 6 males in 4 sibships in 3 generations, connected through females, had a syndrome of brachyturricephaly, 'pugilistic' facial appearance, a muffled voice, cardiomyopathy, muscular hypertrophy, broad hands, wide feet with progressive pes cavus deformities, dislocation of toes, variable congenital hip dislocation, and scoliosis. Three of the males were studied; 3 others had died from cardiac disease, consisting of ventricular hypertrophy. Muscle biopsy of the proband showed no abnormal findings. The mother of the propositus had milder signs of the syndrome, including an elongated face with prominent maxilla, everted lips, and a muffled voice. Her muscular development was prominent with little subcutaneous fat. The family was descended from European immigrants, probably Portuguese or Italian, who settled in Uruguay between 1850 and 1870.

Xue et al. (2016) provided follow-up of the family reported by Quadrelli et al. (2000). The proband graduated from college and was employed; his hypertrophic cardiomyopathy remained stable on a beta-blocker. One of the proband's affected uncles died at age 48 from heart failure.

Inheritance

The transmission pattern of FCMSU in the family reported by Quadrelli et al. (2000) was most consistent with X-linked recessive inheritance; however, some carrier females may have subtle manifestations.

Molecular Genetics

In 3 affected males and 2 obligate female carriers from the family with FCMSU originally reported by Quadrelli et al. (2000), Xue et al. (2016) identified a hemizygous or heterozygous splice site mutation in the FHL1 gene (300163.0018). The mutation, which was found by a combination of hemizygosity mapping and candidate gene exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient myoblasts showed skipping of exon 6, with the resulting primary structure of the protein identical to that of the FHL1C isoform. Western blot and immunohistochemical analysis of patient muscle showed almost complete absence of the FHL1A protein, and RT-PCR analysis showed a 4-fold increase in the expression of FHL1C. Xue et al. (2016) postulated that the imbalance of FHL1 isoforms contributed to the unique features in this family. There was some phenotypic similarity to XMPMA, but the authors considered these to be distinct disorders and delineated the differences.