Toe Syndactyly, Telecanthus, And Anogenital And Renal Malformations

A number sign (#) is used with this entry because of evidence that STAR syndrome (STAR) is caused by mutation in the FAM58A gene (300708) on chromosome Xq28.

Clinical Features

Green et al. (1996) described a mother and daughter with a consistent complex of malformations. The mother had anal stenosis with rectovaginal fistula, significant clitoromegaly, right pelvic kidney, hydronephrosis on the left, a narrow nose, asymptomatic ventricular septal defect, 3-5 syndactyly on the left foot, and 4-5 syndactyly on the right foot. The daughter had anal stenosis, clitoromegaly, solitary pelvic kidney, 3-5 syndactyly on the left foot, and 2-5 syndactyly on the right foot. Green et al. (1996) considered this disorder to have autosomal dominant inheritance, and pointed out that it should be distinguished from the Townes-Brocks syndrome (107480).

Unger et al. (2008) identified 4 unrelated girls with anogenital and renal malformations, dysmorphic facial features, normal intellect, and syndactyly of toes. They defined the cardinal features of the syndrome as a characteristic facial appearance with apparent telecanthus and broad tripartite nasal tip, variable syndactyly of toes 2-5, hypoplastic labia, anal atresia, and urogenital malformations. They proposed the name STAR syndrome for toe syndactyly, telecanthus, and anogenital and renal malformations.

Lefroy et al. (2017) described a 19-year-old woman with STAR syndrome due to a deletion of FAM58A. At birth she had an imperforate anus, rectovaginal fistula, cliteromegaly, single palmar creases, dysplasia of the fifth fingernail bilaterally, bilateral talipes, and bilateral toe syndactyly involving digits 3-5. Dysmorphic facial features included a wide nose with depressed bridge and telecanthus. Diagnostic studies revealed a small left kidney, cervical vertebrae with a bifid posterior arch of C2, sacral spina bifida occulta, and a bicornuate uterus. She was diagnosed in early childhood with bilateral Duane anomaly. She had a dysplastic left ankle with a ball and socket deformity, and she had impaired renal function. She retained fetal finger pads and had lax joints in her hands and elbows. Her development was reported to be normal. Her mother, who had bilateral 4-5 toe syndactyly but no other abnormalities, was found to have approximately 50% mosaicism for the same deletion.

Molecular Genetics

On the basis of phenotypic overlap with Townes-Brocks syndrome (107480), Okihiro syndrome (607323) and Feingold syndrome (164280), Unger et al. (2008) analyzed the genes that are mutant in those disorders, respectively, SALL1 (602218), SALL4 (607343), and MYCN (164840), but found no mutations in any of these genes. By genomewide high resolution oligonucleotide array comparative genomic hybridization (CGH) analysis of genomic DNA from the most severely affected individual, Unger et al. (2008) identified a heterozygous deletion on Xq28 that removed exon 1 and 2 of FAM58A (300708.0001). The deletion was absent in the unaffected parents. A de novo heterozygous deletion (300708.0002) was also identified in a second patient. The other 2 patients and the mother-daughter pair reported by Green et al. (1996) carried heterozygous FAM58A point mutations (300708.0003-300708.0005).

In a 19-year-old woman with STAR syndrome, Lefroy et al. (2017) identified a heterozygous deletion of the FAM58A gene. Her mother, who had only bilateral 4-5 toe syndactyly, was found to have approximately 50% mosaicism for the same deletion.