Blepharophimosis, Ptosis, And Epicanthus Inversus

A number sign (#) is used with this entry because blepharophimosis, ptosis, and epicanthus inversus syndrome, either with premature ovarian failure (BPES type I) or without (BPES type II), is caused by autosomal dominant mutation in the FOXL2 gene (605597) on chromosome 3q22. Rare instances of homozygous mutation in the FOXL2 gene have been reported.

Clinical Features

Vignes (1889) probably first described this entity, a dysplasia of the eyelids. In addition to small palpebral fissures, features include epicanthus inversus (fold curving in the mediolateral direction, inferior to the inner canthus), low nasal bridge, and ptosis of the eyelids (Sacrez et al., 1963; Johnson, 1964; Smith, 1970). The condition should be considered distinct from congenital ptosis (178300).

Owens et al. (1960) updated the pedigree of a family that was first reported by Dimitry (1921), which had affected members in 6 generations. The patients had the classic syndrome triad of blepharophimosis, ptosis, and epicanthus inversus. Raviotta (1971), a physician who is an affected member of the pedigree studied by Owens et al. (1960), provided a first-hand description. Smith (1970) described affected mother and daughter.

Moraine et al. (1976) suggested that female infertility is a pleiotropic effect of the gene. Townes and Muechler (1979) reported a family in which all affected females had primary ovarian failure. They had a normal female karyotype and normal breast development; pubic and axillary hair was scant, but in a normal female distribution. Laparoscopy showed a small uterus and small atrophic ovaries.

Zlotogora et al. (1983) suggested that there are 2 forms of BPES: type I with infertility of affected females and type II with transmission by both males and females. The infertility is inherited as an autosomal dominant sex-limited trait. Jones and Collin (1984) reviewed 37 known cases; of the 6 females of child-bearing age, 1 had primary amenorrhea with raised gonadotropins and low estrogen and progesterone.

Oley and Baraitser (1988) provided an illustrated review of BPES. Fraser et al. (1988) and Smith et al. (1989) described 4 women from 3 families with blepharophimosis, epicanthus inversus, and ptosis who had premature ovarian failure. Two were sisters; they had another affected sister who was not investigated. Two of the 3 families had multiple affected members. Smith et al. (1989) suggested that these cases, type I in the classification of Zlotogora et al. (1983), represented a 'contiguous gene syndrome' (Schmickel, 1986) with a combination of blepharophimosis and familial precocious ovarian failure.

Temple and Baraitser (1989) reported a family in which an uncle and nephew were clearly affected. The carrier mother had no abnormality as an adult, but photographs of her as a child showed unilateral minimal ptosis without epicanthus inversus. Finley et al. (1990) studied 14 sporadic cases of this syndrome (which they abbreviated BPEI) and found an apparent maternal age effect, but no paternal age effect.

Panidis et al. (1994) described blepharophimosis in 2 sisters, a brother, and their father. The elder sister presented initially with 'resistant ovary syndrome' and thereafter true premature menopause, while the younger sister presented with resistant ovary syndrome.

Cunniff et al. (1998) reported 22 individuals referred for genetic evaluation because of blepharophimosis. The blepharophimosis syndrome was present in 14 of the 22, and was familial in 5, sporadic in 9. The other 8 children had a malformation syndrome other than the blepharophimosis syndrome. All 8 were mentally retarded or developmentally delayed. Two of the 8 had recognized disorders, branchiootorenal syndrome (113650) in one and a ring chromosome 4 in the other; the remaining 6 had unrecognized malformation syndromes, each distinctive from the others.

Cytogenetics

Fukushima et al. (1990) reported a newborn infant with BPES and a de novo balanced 3q23;4p15 reciprocal translocation. In a father and son with typical BPES, de Die-Smulders et al. (1991) found an apparently balanced translocation, t(3;11)(q21;q23). Since blepharophimosis, ptosis, and microphthalmia are consistent features in patients with an interstitial deletion of band 3q2 (Alvarado et al., 1987), the BPES gene was likely to be located at 3q2.

Williamson et al. (1981) described an 8-year-old boy with marked blepharophimosis, ptosis, sad fixed face, joint contractures, and several other anomalies associated with a del(3)(q22.1-q24), suggestive of Schwartz-Jampel syndrome (255800). Fujita et al. (1992) reported a 6-year-old boy with de novo 46,XY,del(3)(q12q23) and bilateral blepharophimosis, ptosis, epicanthus inversus, as well as multiple other anomalies, including joint contractures and a fixed facial appearance. However, in both patients, normal EMG findings and normal skeletal films excluded the diagnosis of Schwartz-Jampel syndrome. Fujita et al. (1992) suggested that the blepharophimosis sequence in these patients may represent a contiguous gene syndrome. Other relevant cases had been reported by Martsolf and Ray (1983), Al-Awadi et al. (1986), and Okada et al. (1987).

Jewett et al. (1992) reported a child with classic features of BPES with developmental delay and an interstitial deletion of a single band within 3q: del(3)(q21.3-q22.3). De Almeida et al. (1993) described an apparently balanced translocation, t(3;8)(q23;p21.1), in a child with mild mental retardation, blepharophimosis, ptosis, telecanthus, and epicanthus inversus. The patient was microcephalic with mild dysmorphism and minor anomalies.

Reinforcement of the suggestion that the BPES gene is located at 3q2 was provided by Fryns et al. (1993), who described a 6-year-old mentally retarded boy, born to normal parents, who had typical signs of the disorder and a de novo interstitial deletion of chromosome 3: del(3)(q22.3-q23). Ishikiriyama and Goto (1993) described a girl with BPES, microcephaly of postnatal onset, mild developmental retardation, and a de novo deletion del(3)(q22.2q23). Jewett et al. (1993) described an interstitial deletion of 3q22. From a review of the other reported cases, they concluded that a locus for eyelid development is situated at the interface of bands 3q22.3 and 3q23. Wolstenholme et al. (1994) reported a sporadic case of BPES associated with prenatally diagnosed diaphragmatic hernia and interstitial deletion of the long arm of chromosome 3, del(3)(q21q23). Ishikiriyama and Goto (1994) suggested that the association of BPES with microcephaly or other manifestations of 'general hypoplasia of the CNS' such as hypotrophy of the cerebellar vermis may represent a contiguous gene syndrome because of the observed association with interstitial deletions.

Boccone et al. (1994) described a de novo, apparently balanced, reciprocal translocation between the long arms of chromosomes 3 and 7 in a 2-year-old male with BPES; the breakpoints were 3q23 and 7q32. Warburg et al. (1995) described 3 unrelated, mentally retarded boys with typical BPES, each of whom had chromosomal aberrations. One of them was thought to have a deletion of 3p25 and a second was thought to have a loss of band 3q23. The third patient, however, had a del(7)(q34). The phenotypes of the 2 patients with the chromosome 3 aberrations were similar, but the third had, in addition to features of BPES, genital malformations resembling those of the Smith-Lemli-Opitz syndrome (SLO; 270400), which maps to 7q34-qter. The patient had a palatal ridge as well as a single mesial maxillary tooth, suggesting the holoprosencephaly sequence, but CT scans of the brain were normal. Fryns (1995) described a patient in whom BPES was associated with the Langer type of mesomelic dwarfism (249700). He suggested that a submicroscopic deletion of 3q22.3-q23 was responsible for the concurrence of the 2 disorders. Karimi-Nejad et al. (1996) reported a sporadic translocation t(X;3)(p22;q21) in a girl with typical manifestations of BPES.

Common clinical features of patients with 3q23 deletion include BPES, growth and mental retardation, microcephaly, ear and nose dysmorphism, and joint and digital abnormalities. Chandler et al. (1997) described a 3-year-old girl with BPES, mental retardation, facial dysmorphism, and camptodactyly. In addition, she had a congenitally small larynx and severe, chronic feeding difficulties. Chromosome studies revealed an interstitial deletion, del(3)(q23-q25). Cai et al. (1997) reported a 3.5-year-old girl with an unbalanced translocation 46,XX,der(7)t(3;7)(q26-qter;q+) resulting in trisomy 43q26-qter. The child had blepharophimosis, unilateral ptosis, high forehead, microcephaly, and mental retardation, but did not have epicanthus inversus. Cai et al. (1997) suggested that BPES is genetically heterogeneous and may be the result of a contiguous gene defect.

Mapping

Small et al. (1995) studied 2 BPES families with autosomal dominant inheritance and obtained a maximum lod score of 3.23 using the markers rhodopsin (180380), located at 3q21-q24; prostate acid phosphatase (171790), located at 3q21-q23; and D3S1238. No evidence of genetic heterogeneity was observed. In a large French pedigree, Amati et al. (1995) also mapped the BPES gene to 3q23. With linkage studies in 2 large families, Harrar et al. (1995) confirmed the assignment of BPES to 3q21-q24 (lod score of 3.2 at D3S1237).

Amati et al. (1996) showed that the form of BPES associated with premature ovarian failure (type I of Zlotogora et al. (1983)) maps to 3q22-q23, the same chromosomal region as does the form without POF (type II).

Lawson et al. (1995) mapped a translocation breakpoint associated with BPES to the D3S1316-D3S1615 interval. The markers in this region were subsequently shown to lie in a different order, with the BPES locus mapping to the 1-cM D3S1576 and D3S1316 interval. Toomes and Dixon (1998) constructed a physical map, consisting of 60 YAC clones and 1 bacterial artificial chromosome, that spanned this region. YAC end isolation led to the creation of novel STSs that were used to reduce the size of the BPES critical region to a 280-kb interval, which was cloned in 2 nonchimeric YACs.

Praphanphoj et al. (2000) identified another case of BPES associated with a de novo reciprocal translocation involving 3q23. By fluorescence in situ hybridization analysis using an assortment of probes, they found that the breakpoint in their patient lay proximal to that in the patient studied by De Baere et al. (1999), within a 10.5-kb interval.

Inheritance

The transmission pattern of BPES in the original family described by Dimitry (1921) was consistent with autosomal dominant inheritance (Owens et al., 1960). Crisponi et al. (2001) found that BPES types I and II are autosomal dominant traits.

Nallathambi et al. (2007) and Kaur et al. (2011) described an Indian family with autosomal recessive inheritance of BPES type I and type II, respectively.

Molecular Genetics

By positional cloning, Crisponi et al. (2001) identified the FOXL2 gene and identified mutations resulting in truncated proteins in affected individuals with both types I and II BPES (605597.0001 and 605597.0002). Consistent with an involvement in those tissues, FOXL2 was found to be selectively expressed in the mesenchyme of developing mouse eyelids and in adult ovarian follicles; in adult humans, it appeared predominantly in the ovary.

In 2 sporadic patients and 2 families with BPES, Beysen et al. (2005) identified 4 overlapping extragenic microdeletions 230 kb upstream of the FOXL2 gene. The shortest region of deletion overlap contains several conserved nongenic sequences harboring putative transcription factor-binding sites and representing potential long-range cis-regulatory elements. Affected females in the 2 families had BPES type II; BPES type could not be assessed in the sporadic patients. In another family with BPES, Beysen et al. (2005) identified an approximately 188-kb microdeletion downstream of the FOXL2 gene. The father of the 2 affected half-sisters was unaffected, suggestive of germinal mosaicism; quantitative analysis using 3 SNPs located in the deletion showed that about 10% of paternal germ cells and 5% of somatic peripheral blood lymphocytes carried the mutation.

Vincent et al. (2005) reported an 18-month-old girl with sporadic BPES and bilateral type 1 Duane syndrome (see 126800), in whom they identified a heterozygous duplication of 10 alanine residues in the FOXL2 gene (605597.0002).

In 3 affected males and 1 affected female of a consanguineous Indian family with BPES type I, Nallathambi et al. (2007) identified a homozygous duplication in the FOXL2 gene (605597.0018), resulting in a polyalanine expansion from 14 to 19 residues (Ala19). Several unaffected relatives were heterozygous for the mutation, indicating autosomal recessive inheritance in this family. The affected 30-year-old woman had amenorrhea and impaired fertility, consistent with ovarian dysfunction. Nallathambi et al. (2007) noted that ala19 is the shortest polyalanine expansion (+5) described in the FOXL2 gene and may confer residual enzyme activity.

In an Indian cohort comprising 6 familial and 2 sporadic cases of BPES type I or type II, Kaur et al. (2011) identified 6 heterozygous mutations in the FOXL2 gene, 3 of which were novel (see, e.g., E69K; 605597.0020). In the family with BPES type II and the E69K mutation (family BPES6), some patients were heterozygous and others homozygous; patients homozygous for the mutation had more a more severe phenotype. In another family, an affected female also had polycystic ovarian disease. Kaur et al. (2011) noted that mutations in the region downstream of the forkhead domain were predominantly responsible for BPES among Indian patients.

Animal Model

Using piggyBac (PB) insertional mutagenesis, Shi et al. (2014) created a line of mice with a modest yet significant reduction in Foxl2 expression. Homozygous PB/PB mice began to lose weight approximately 2 weeks after birth, and most died within the first month of life. At 3 weeks of age, they showed significant overgrowth of mandibular incisors with malocclusion, and some showed palpebral anomalies and periocular hair loss. Surviving female PB/PB mice were subfertile, with smaller than normal ovaries and uteri. Shi et al. (2014) concluded that PB/PB mice recapitulated the craniofacial and ovarian conditions of type I BPES patients. The authors mapped the PB insertion site to a region approximately 160 kb upstream of the Foxl2 transcription start site and approximately 10 kb upstream of an element, ECF1, that showed a high degree of conservation among goat, mouse, and human. ECF1 functioned as an enhancer in reporter gene assays and interacted directly with the Foxl2 promoter in chromosome conformation capture assays. Shi et al. (2014) noted that BPES patients with balanced translocations and chromosome breakpoints 130, 160, or 171 kb upstream of FOXL2 have been reported. The authors hypothesized that these translocations may isolate transcription regulatory elements, including the human ECF1 ortholog, leading to FOXL2 misregulation.

History

So-called 'BPES3,' which had been mapped in an Indian family to 7p, has been shown to be part of the phenotypic spectrum of Saethre-Chotzen syndrome (SCS; 101400) and to result from mutation in the TWIST1 gene (601622) on 7p21. This finding supported locus homogeneity of BPES at 3q22 (Dollfus et al., 2001).