Abstract
Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is a craniofacial disorder caused by heterozygous variants of the forkhead box L2 (FOXL2) gene. It shows autosomal dominant inheritance but can also occur sporadically. Depending on the mutation, two phenotypic subtypes have been described, both involving the same craniofacial features: type I, which is associated with premature ovarian failure (POF), and type II, which has no systemic features. The genotype–phenotype correlation is not fully understood, but it has been hypothesised that type I BPES involves more severe loss of function variants spanning the whole gene. Type II BPES has been linked to frameshift mutations that result in elongation of the protein rather than complete loss of function. A mutational hotspot has been identified within the poly-alanine domain, although the exact function of this region is still unknown. However, the BPES subtype cannot be determined genetically, necessitating informed genetic counselling and careful discussion of family planning advice in view of the associated POF particularly as the patient may still be a child. Following puberty, female patients should be referred for ovarian reserve and response assessment. Oculofacial features can be managed with surgical intervention and regular monitoring to prevent amblyopia.
Highlights
Accepted: 25 February 2021Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES; OMIM #110100)is a rare autosomal dominant disease, with an estimated prevalence of 1 in 50,000 births, primarily affecting the development of the mid-face structures [1]
It is highly conserved among species, with 100% of homology for human, mouse, rat, cow, goat, pig, and rabbit, and consists of a 110 amino acid forkhead DNA-binding domain at position 54 to 148 [9]. It contains a strictly conserved poly-alanine tract of 14 amino acids between position 221 and 234, whose role remains unknown; it is a hotspot for expansions from 14 to 24 alanine residues accounting for ≈30% of all intragenic forkhead box L2 (FOXL2) pathogenic variants leading to predominantly BPES-II [6,9]
L2 L2 (FOXL2), up- and genomic position, proteinprotein structure, and hotspot hotspot located in the poly-alanine domain. (A) Chromosomal deletions were reported in at least 84 blepharophimosis, located in the poly-alanine domain. (A) Chromosomal deletions were reported in at least 84 blepharophimosis, ptosis, and ptosis, and epicanthus inversus syndrome (BPES) patients, with the largest encompassing 3q22.3 to 3q24 (12 Mb) and the epicanthus inversus syndrome (BPES) patients, with the largest encompassing 3q22.3 to 3q24 (12 Mb) and the smallest smallest encompassing FOXL2 or PIRST1 genes (UCSC: hg19:chr3:133,064,629-153,716,375). (B) FOXL2 is composed of encompassing
Summary
Is a rare autosomal dominant disease, with an estimated prevalence of 1 in 50,000 births, primarily affecting the development of the mid-face structures [1]. BPES can be caused by heterozygous variants involving the forkhead box L2 (FOXL2). Gene, which encodes for a transcription factor expressed predominantly in the developing mesenchyme of eyelids and ovaries [2]. Foxl expression is localised to the protruding ridges of the developing eyelids and in ovarian follicular cells. Up to 75% of affected individuals may have detectable FOXL2 mutation, leading to haploinsufficiency [3,4,5,6]. Transmission of BPES-I is usually by affected males as fertility in affected females is reduced. BPES-II can have transmission occurring through both males and females. FOXL2 gene will be detailed with respect to the two types of BPES and the most common variants in the poly-Alanine tract will be reported. Clinical features and management of patients at different stages of life, including referral for ovarian reserve, will be described
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