Manitoba Oculotrichoanal Syndrome

A number sign (#) is used with this entry because of evidence that Manitoba oculotrichoanal syndrome can be caused by homozygous or compound heterozygous mutation in the FREM1 gene (608944) on chromosome 9p22.3.

Mutation in the FREM1 gene can also cause bifid nose with or without anorectal and renal anomalies (BNAR; 608980).

Description

Manitoba-oculo-tricho-anal (MOTA) syndrome is a rare condition defined by eyelid colobomas, cryptophthalmos, and anophthalmia/microphthalmia, an aberrant hairline, a bifid or broad nasal tip, and gastrointestinal anomalies such as omphalocele and anal stenosis. Autosomal recessive inheritance was assumed because of consanguinity in the Oji-Cre population of Manitoba in which the syndrome was first described (summary by Slavotinek et al., 2011).

Clinical Features

In 3 male and 3 female Manitoba Indian children, Marles et al. (1992) observed an apparently new autosomal recessive syndrome manifested by hypertelorism and a variable combination of unilateral eye malformations, aberrant anterolateral scalp hairline, and nasal and anal anomalies. The children belonged to 4 related families. The parents and 7 other sibs were clinically unaffected. The family histories were otherwise unremarkable. Pictured were several examples of a curious finding of an anomalous wedge of scalp hair extending in the left frontotemporal region to the eyebrow. The eye malformations included unilateral clinical anophthalmia, obstruction of the nasolacrimal ducts, and coloboma of the medial half of the upper eyelid. The anus was stenotic in one, anteriorly displaced in another, and both anteriorly displaced and stenotic in a third.

Fryns (2001) described a 36-year-old woman who was born with bilateral microblepharon/ablepharon of the upper eyelids without apparent associated malformations. At 16 years of age, gynecologic examination for primary amenorrhea revealed vaginal atresia with the uterine cervix not in connection with the perineum. Laparoscopy demonstrated normal internal genital structures, and renal echography and cystography were normal. Examination in adulthood showed, in addition to microblepharon and subsequent corneal clouding, a high forehead with frontal hair upsweep, high nasal root with maxillary hypoplasia, small alae nasi with coloboma formation, short philtrum with thin upper lip, relative microstomia, and high palate. There were no clinical signs of ectodermal dysplasia.

Li et al. (2007) reported 7 new patients with clinical findings consistent with MOTA syndrome from the Cree/Ojibway kindred previously described by Marles et al. (1992). Two of the patients had bilateral rather than unilateral abnormal anterior hairline patterns, and omphalocele was present in 3 patients. The authors also reported the first case of probable MOTA syndrome outside the native population of Island Lake, Manitoba in a female Dutch infant, born of nonconsanguineous parents, who had colobomata of the upper eyelids, cloudy left cornea, some excess hair extending to the left upper eyelid, broad columella, and broad nasal tip with palpable groove. Li et al. (2007) stated that the most consistent features were hypertelorism and a broad or notched tip of the nose.

Yeung et al. (2009) described second-cousin male and female infants affected by a craniofacial abnormality similar to that seen in so-called 'Tessier number 10' clefts (Tessier, 1976) and in MOTA syndrome. The male infant, born of nonconsanguineous unaffected parents of Greek and Malaysian ancestry, was noted at birth to have bilateral symmetric upper eyelid colobomas, with absence of the medial two-thirds of the lid. There was disruption of the middle segment of the eyebrows and an unusual hairline, with a projection of hair in the temporal regions pointing toward the colobomas. There was hypertelorism and a broad nasal tip. Vision was assessed as normal. There were no anorectal anomalies, and the remainder of the examination was normal. The female infant, born to nonconsanguineous Greek parents, was noted at birth to have an extensive coloboma of the left upper eyelid, with absence of the medial two-thirds of the eyelid. An associated ipsilateral tongue of hair pointed to the coloboma, and there was also disruption of the middle part of the eyebrow. The right eye and surrounding soft tissues were normal, as was the remainder of the clinical examination. Yeung et al. (2009) noted that Tessier number 10 clefts previously had been only reported as sporadic cases and that the underlying etiology was believed to be environmental, but the familial clustering of these facial features and the variable association with other congenital anomalies supported a genetic rather than environmental cause.

Slavotinek et al. (2011) reported another Oji-Cre family in which the eldest affected sister had a bifid nasal tip and a V-shaped wedge of hair on her left forehead. She had 2 younger sisters who were also affected, 1 with anophthalmia of the left eye and a similar V-shaped wedge of hair, and 1 with bifid nasal tip and prominent central vein. Another sister was unaffected. A male second cousin had bilateral cryptophthalmos with abnormal ocular globes, frontal extension of his hairline bilaterally, broad nasal bridge with mildly widened nasal tip, omphalocele, and anal stenosis. Ultrasound in the newborn period showed mild renal pelviectasis. At 4.75 years of age, he had mild to moderate delays but could walk and speak in sentences. There was no history of consanguinity, and this family was not known to be related to the Cree/Ojibway kindred previously reported by Li et al. (2007).

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. However, although these findings enabled distinction between BNAR and MOTA in some patients, Slavotinek et al. (2011) stated that other patients exhibited more clinical overlap and could be diagnosed with either syndrome.

Mapping

Slavotinek et al. (2011) performed genomewide SNP array hybridization in 3 Oji-Cre sisters with MOTA syndrome and identified 71 SNPs that were inherited from heterozygous parents and thus represented likely loss of heterozygosity/autozygosity; 44 of the SNPs were also present in their affected male cousin, of which 4 mapped to the FREM1 gene (608944) on chromosome 9p22.3.

Molecular Genetics

Noting phenotypic overlap between Fraser syndrome (219000) and MOTA, Slavotinek et al. (2006) analyzed the FRAS1 gene (607830) in 2 patients with MOTA (patients 3 and 4 of Li et al. (2007)) but did not identify any mutations.

In a male patient from an Oji-Cre family with MOTA syndrome mapping to the FREM1 gene (608944) and 2 patients from the Cree/Ojibway kindred previously described by Li et al. (2007), Slavotinek et al. (2011) identified homozygosity for a 60.1-kb deletion including exons 8 to 23 of the FREM1 gene (608944.0004). In 3 affected sisters, second cousins to the male Oji-Cre patient, Slavotinek et al. (2011) identified compound heterozygosity for 16-exon deletion and a splice site mutation that led to skipping of exon 31. However, the same splicing pattern was seen in cDNA from a control fibroblast cell line, thus the authors concluded that this sequence variant was not pathogenic and stated that the second mutation in the 3 sisters remained undetected. In a woman with bilateral eyelid coloboma and vaginal atresia, originally reported by Fryns (2001), Slavotinek et al. (2011) identified homozygosity for a 4-bp deletion in the FREM1 gene (608944.0005), and in another MOTA patient, originally reported by Li et al. (2007), they identified compound heterozygosity for missense mutations in FREM1 (608944.0006 and 608944.0007). However, analysis of the FREM1 gene in the 2 cousins with MOTA reported by Yeung et al. (2009) revealed no mutation, and segregation analysis indicated that the affected children did not share a FREM1 allele from a common ancestor, making a causative role of FREM1 very unlikely in that family.

Animal Model

Slavotinek et al. (2011) examined Frem1-mutant mice and identified a small but statistically significant proportion of homozygous mutant animals with anal prolapse, which was not observed in heterozygous or wildtype littermates. Examination of Frem1-mutant eyes at birth showed that although the majority of animals presented with frank cryptophthalmos, a subset exhibited defects strikingly similar to the eyelid coloboma seen in MOTA, seemingly affecting only 1 part of the eyelid. Histologic analysis demonstrated that these defects were associated with a number of ocular malformations including failure of eyelid formation, defects in the formation of the conjunctiva, and absence of corneal epithelium leading to fibrosis. Slavotinek et al. (2011) proposed that defects in the development or adhesion of the corneal epithelium contribute to the opacity apparent in some MOTA patients.