Clinical Characteristics
Ocular Features
This is primarily a dysplasia of the eyelids and adnexae. The acronym is derived from the longer title sometimes used: blepharophimosis, ptosis, and epicanthus inversus syndrome. The palpebral fissures are small and the curve of the epicanthal fold is mediolateral, but below the medial canthus. The nasal bridge is flat or at least low, and the lids are ptotic. Telecanthus may be present as well. Refractive errors, strabismus, nystagmus, and amblyopia are often associated. Entropion with trichiasis may require surgical attention. Mutations in the FOX family of genes are associated with a wide variety of ocular anomalies including microcornea, trabecular dysgenesis, optic nerve hypoplasias and colobomas that are sporadically present in BPES syndrome.
Alacrima is a feature in many cases, caused by hypoplasia or aplasia of the major lacrimal gland.
Systemic Features
This condition is sometimes associated with ovarian failure although breast development is often normal. The resultant infertility is an example of a sex-limited autosomal trait. The syndrome can result from cytogenetic aberrations as well but individuals with these usually have other malformations such as contractures, mental defects, microcephaly, growth retardation, etc.
Some authors have considered individuals with the typical features of BPES who also have genitourinary malformations and cognitive deficits as examples of BPES plus syndrome. A recent report, for example, describes two sibs, a male and a female, with some features of this syndrome plus posteriorly rotated ears, hypertelorism, telecanthus, micrognathia and severe psychomotor retardation. The responsible mutation was not identified and its relationship to BPES remains unknown. Another individual with typical ocular and systemic features of BPES in addition to cryptorchidism, developmental delay, and syndactyly, was found to have a mutation in the gene KAT6B in the absence of mutations in FOXL2.
The phenotypic spectrum of this condition is extensive and it is likely that multiple mutations are collectively responsible for the clinical heterogeneity.
Genetics
Inheritance
This is an autosomal dominant condition with sex-limited characteristics in females (infertility, small uterus, atrophic ovaries). The karyotype in females is normal. It is one of the rare conditions with an apparent maternal age effect, at least in sporadic cases which are not uncommon.
Mutations in the FOXL2 gene at 3q23 seem to be responsible for at least some familial cases. It codes for a gene active in the mesenchyme of the eyelids and in the ovarian follicle, at least in mice. About 12% of patients do not have a FOXL2 mutation though. Numerous mutations have been found, some of which cause premature ovarian failure (sometimes labeled BPES type I) while others cause only lid maldevelopment (BPES type II).
A mutation in KAT6B (10q22.2) has been found in a single individual with features typical of BPES in whom no FOXL2 mutations were present. It has been suggested that BPES patients without mutations in FOXL2 should be sequenced for mutations in KAT6B.
Pedigree
Autosomal dominant
Autosomal dominant disorders require only one mutation for the disease to be expressed. Since an affected parent has two chromosomes, only one of which has the mutant gene, parents can expect that half (50%) of their children will receive that one and inherit the disease. It is common for individuals that inherit the mutation, however, to not have evidence of the disease (nonpenetrance).
Autosomal dominant inheritance leads to a vertical pattern of transmission