Bifid Nose With Or Without Anorectal And Renal Anomalies

A number sign (#) is used with this entry because of evidence that bifid nose with or without anorectal and renal anomalies (BNAR) is caused by homozygous mutation in the FREM1 gene (608944) on chromosome 9p22.

Mutation in FREM1 can also cause Manitoba oculotrichoanal (MOTA; 248450) syndrome.

Clinical Features

Al-Gazali et al. (2002) reported a consanguineous Egyptian Arab family in which 4 sibs had bifid nose associated with renal and anorectal malformations. All had median nose clefts, wide bulbous nasal tip, short philtrum, but no hypertelorism. All had renal agenesis, which was unilateral in 3 and bilateral in 1. One of the children, born at 28 weeks' gestation, died during the first hour of life. The other 3 children had anorectal malformations ranging form anteriorly placed anus with stenosis to rectal atresia associated with rectovaginal fistula. The 3 also had hoarse, low-pitched cry, short and thick oral frenula, overlapping toes, and normal development. The authors suggested autosomal recessive inheritance.

Alazami et al. (2009) reported 2 consanguineous families of Afghan and Pakistani origin, with a similar phenotype but more variable renal involvement: all 5 affected individuals had a bifid nose, but only 1 of 3 affected members of the Afghan family and 1 of 2 affected members of the Pakistani family had renal agenesis. None of the 5 had anorectal malformations.

Clinical Variability

Slavotinek et al. (2011) noted that eye defects occurred consistently in patients with MOTA syndrome but had not been reported in BNAR patients, and that conversely, renal agenesis appeared to be characteristic of BNAR but had not been observed in MOTA syndrome. Slavotinek et al. (2011) stated, however, that although these findings enabled distinction between BNAR and MOTA in some patients, others exhibited more clinical overlap and could be diagnosed with either syndrome.

Mapping

Alazami et al. (2009) performed genomewide multipoint parametric linkage analysis in 3 consanguineous families with BNAR, 1 of which had been previously reported by Al-Gazali et al. (2002), and obtained a maximum lod score of 6.62 between SNP markers rs10124106 and rs10963391, a 4.4-Mb interval on chromosome 9p23-p22.2 encompassing 28 annotated genes.

Molecular Genetics

In affected members of 3 consanguineous families with bifid nose with or without anorectal and renal anomalies mapping to chromosome 9p23-p22.2, including the Egyptian Arab family originally reported by Al-Gazali et al. (2002), Alazami et al. (2009) sequenced the candidate gene FREM1 (608944) and identified homozygosity for a 1-bp deletion and 2 missense mutations, respectively (608944.0001-608944.0003). The authors noted that FREM1 is part of a ternary complex that includes 2 other extracellular matrix proteins, FRAS1 (607830) and FREM2 (608945), mutations in either of which result in Fraser syndrome (219000), a recessive condition involving cryptophthalmos, syndactyly, abnormal genitalia, and/or renal agenesis. None of the 9 patients with mutation in FREM1 displayed cryptophthalmos, syndactyly, or abnormal genitalia.