Blepharocheilodontic Syndrome 1

A number sign (#) is used with this entry because of evidence that blepharocheilodontic syndrome-1 (BCDS1) is caused by heterozygous mutation in the CDH1 gene (192090) on chromosome 16q22.

Genetic Heterogeneity of Blepharocheilodontic Syndrome

BCD syndrome-2 (BCDS2; 617681) is caused by mutation in the CTNND1 gene (601045) on chromosome 11q12.

Description

The blepharocheilodontic syndrome is a rare autosomal dominant disorder characterized by lower eyelid ectropion, upper eyelid distichiasis, euryblepharon, bilateral cleft lip and palate, and conical teeth. An additional rare manifestation is imperforate anus (summary by Weaver et al., 2010).

Clinical Features

An association of ectropion of the lower eyelids, hypertelorism, and cleft lip and palate was described by Elschnig (1912), although it is not clear that Elschnig recognized the clinical constellation as a distinct entity. Allanson and McGillivray (1985) reported a family in which many members of 4 generations had a syndrome of cleft lip and/or palate, ectropion of the lower eyelids with ocular hypertelorism, and conical teeth with variable expression consistent with autosomal dominant inheritance. The ectropion suggested Treacher Collins syndrome (154400). Gorlin et al. (1976) noted that Zellweger had observed mother and son with clefting, ectropion, and limb reduction defects, and that about 4 sporadic cases have been reported. Falace and Hall (1989) presented a 5-generation kindred in which of 12 affected persons, 8 had abnormal teeth, 4 had euryblepharon (eyelids with abnormally wide lid opening), and 2 had clefts.

Peters (1915) described congenital lagophthalmia in 4 generations. Pico (1959) reported a family in which 18 members in 3 generations had lagophthalmia, 11 of whom had congenital ectropion, with associated distichiasis in 8. Korula et al. (1995) reported several individuals with bilateral cleft lip and palate, lagophthalmia (incomplete closure of the eyelids), megaloblepharon (large eyelids), distichiasis (double row of eyelashes), and ectropion of the lower eyelids. Eight cases, 3 from 1 family, were identified in a cleft palate clinic and all presented with bilateral cleft lip and palate and lagophthalmia. Distichiasis was present in 5 of the 8 cases, and 5 cases had ectropion in various degrees. Dental findings consisted of hypodontia in 5 cases and delayed dentition in 1. Hypoplastic nails and clinodactyly were confined to the 3 familial cases (father, son, and daughter).

Gorlin et al. (1996) reported 2 mother-child pairs and 4 sporadic cases of this syndrome, one of which was first reported by Piper (1957). Among the patients reported by Gorlin et al. (1996), ectropion of the lower lids and bilateral cleft lip/palate were among the most common findings; distichiasis of the upper eyelids was a less common observation. Gorlin et al. (1996) proposed the term blepharo-cheilo-dontic (BCD) syndrome for this autosomal dominant condition and suggested that affected persons reported by Korula et al. (1995) actually had the same syndrome. Similar manifestations were found in a girl described by Martinez et al. (1987), although she also had syndactyly.

Guion-Almeida et al. (1998) described 4 Brazilian patients with this disorder. Two were sporadic cases and 2 were familial, i.e., a mother and her equally affected son. The patients also showed lagophthalmos, a condition in which the eye cannot be completely closed.

Valdez-de la Torre et al. (1999) described 2 unrelated patients with bilateral cleft lip/palate and lagophthalmia. One of these 2 patients had familial cleft lip/palate in 2 generations, probably as a variable expression of an autosomal dominant gene. The other patient also had euryblepharon.

Gil da Silva Lopes et al. (2003) identified BCDS in 3 successive generations of a Brazilian family and in a sporadic case, also Brazilian. In addition to the cardinal signs, the sporadic case included hypothyroidism and imperforate anus, which had been previously observed in 1 patient. In the family with multiple cases, male-to-male transition was observed.

Because of phenotypic overlap with EEC syndrome, a form of which (EEC3; 604292) is caused by mutation in the P63 gene (603273), as well as overlap with the AEC syndrome (106260), which is caused by mutations in the same gene, Gil da Silva Lopes et al. (2003) suggested that mutation in the P63 gene should be sought in BCD syndrome. Some phenotypic overlap was also seen between BCD syndrome and van der Woude syndrome (119300), suggesting that the interferon regulatory factor-6 gene (IRF6; 607119) should be investigated also in BCDS.

Martinhago and Ramos (2004) reported a Brazilian child with lagophthalmia, ectropion of lower lids, euryblepharon, bilateral cleft lip and palate, and oligodontia with reduced crown formation who was born with agenesis of the thyroid. Martinhago and Ramos (2004) suggested that the phenotype should be broadened to include thyroid disorders.

Winship and Aftimos (2005) described a 3-year-old boy who had dysmorphic features consistent with blepharocheilodontic syndrome but who also had features previously reported by Korula et al. (1995) in cases of lagophthalmia, including hypoplastic nails and a dermoid cyst of the lateral eyebrow. Winship and Aftimos (2005) stated that the significant clinical overlap in their patient further supported the proposal that lagophthalmia and blepharocheilodontic syndrome represent a continuum of a single syndrome.

Weaver et al. (2010) studied a 3-generation family segregating autosomal dominant BCDS in which the proband was a 6-week-old girl who was born with unilateral cleft lip and palate (CLP), imperforate anus, and ectropion of the lower eyelids. Her 4-year-old sister had repaired bilateral CLP as well as ectropion of the lower eyelids, eyelid insufficiency, conical teeth, and webbed digits. An older brother had repaired imperforate anus and ocular features of BCDS, and their mother had CLP, ectropion of the lower eyelids, bilateral syndactyly between fingers 3 and 4 and toes 2 and 3, and a history of imperforate anus. The mother reported additional affected family members, including 2 brothers and 2 children of 1 of the brothers, as well as her father and a paternal uncle and aunt. Noting that this was the fourth report of BCDS associated with imperforate anus, Weaver et al. (2010) concluded that imperforate anus should be considered a feature of the BCDS phenotype.

Ababneh et al. (2014) reported a Saudi boy with the common eyelid, lip, and tooth abnormalities of BCD syndrome who also had imperforate anus, thyroid agenesis, and lumbosacral meningomyelocele. The parents were consanguineous, but a comprehensive review of the family failed to reveal similar cases or even rare features of the syndrome, indicating sporadic occurrence.

Nishi et al. (2016) reported a 2-year-old Japanese girl with cleft lip and palate, right choanal atresia, tetralogy of Fallot, absent corpus callosum, and a mass in the frontal region of the cranial base compressing the right optic nerve and causing blindness in the right eye. Tumor resection revealed the mass to be a meningoencephalocele. The patient had facial dysmorphism, including posteriorly rotated ears with overfolded helices, hypertelorism, and upslanted palpebral fissures, as well as cloudy corneas and lumbar vertebral fusion. Ghoumid et al. (2017) noted that the photographs provided in the article showed eyelid anomalies consistent with ectropion and euryblepharon, making it possible to retrospectively diagnose BCDS.

Ghoumid et al. (2017) studied 11 patients from 8 families with 'typical' BCD syndrome, with variable expression severity. All patients had eyelid anomalies, including ectropion, euryblepharon, lagophthalmia, and distichiasis, and all patients exhibited features of ectodermal dysplasia, including hair anomalies, conical teeth, and tooth agenesis. All showed typical dysmorphism, with hypertelorism, flat face, and high forehead, and some had an asymmetric face. CLP was observed in 9 of the 11 patients. Less common but previously reported features included thyroid gland hypoplasia or agenesis in 3 patients, anal atresia in 2, syndactyly in 2, and neural tube defects in 2.

Inheritance

The blepharocheilodontic syndrome is inherited as an autosomal dominant trait (Allanson and McGillivray, 1985; Weaver et al., 2010).

Molecular Genetics

By whole-exome or candidate gene sequencing in 8 families with BCDS, Ghoumid et al. (2017) identified 5 heterozygous mutations in the CDH1 gene (see, e.g., 192090.0024-192090.0026) and 3 in the CTNND1 gene (601045.0001-601045.0003; see BCDS2 617681). In 2 families, the mutations occurred de novo; in 2, the mutations segregated with disease; in 2, the mutations were inherited from an asymptomatic parent, suggesting incomplete penetrance; and in the remaining 2, parental DNA was unavailable. Ghoumid et al. (2017) stated that although the series was too small to establish genotype-phenotype correlations, they observed that eyelid anomalies were more severe in patients with CDH1 mutations than in those with CTNND1 mutations. In addition, they noted that a previously reported Japanese girl (Nishi et al., 2016) who had cleft lip and palate, choanal atresia, tetralogy of Fallot, and a neural tube defect, and who upon exome sequencing was found to carry a missense mutation in CDH1 (D676E; 192090.0027), also exhibited eyelid anomalies characteristic of BCDS.

Exclusion Studies

In 3 families with blepharocheilodontic syndrome, Freitas et al. (2007) screened 5 candidate genes, including P63 and IRF6, but found no mutations. In the proband of a 3-generation family segregating autosomal dominant BCDS, Weaver et al. (2010) also found no mutations in the P63 and IRF6 genes.