Blepharophimosis, Ptosis, Epicanthus Inversus Syndrome: New Report with a 197-kb Deletion Upstream of FOXL2 and Review of the Literature

Abstract

Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is due to heterozygous FOXL2 intragenic mutations in about 70% of the patients, whereas total or partial gene deletions account for a minority of cases. Alteration of FOXL2 regulatory elements has been rarely described in patients with BPES. In this study, a prepubertal girl with BPES due to a 197-kb de novo deletion of the regulatory elements upstream of FOXL2 is reported. This girl presented with additional clinical features such as a soft cleft palate and microcephaly; thus, this copy number variant might have other somatic effects. The present deletion encompasses 2 coding genes (MRPS22 and COPB2), whose homozygous mutations have been associated with microcephaly. In our case, the sequences of the non-deleted allele were normal, ruling out a compound genetic defect. Normal levels of new biomarkers of ovarian reserve (anti-müllerian hormone, inhibin B) likely indicate an early diagnosis of type 2 BPES, but an evolutive gonadal damage will be excluded only by long-term follow-up. Additional reports of microdeletions upstream of FOXL2 are needed to better define the underlying genetic mechanism and the related phenotypic spectrum; the ability of the new hormonal markers to predict ovarian function in adolescence and adulthood should be confirmed.

Abnormal Expression of Mitochondrial Ribosomal Proteins and Their Encoding Genes with Cell Apoptosis and Diseases

“…MRPs are associated with a range of mitochondrial diseases, in which clinical manifestations are complex. A homozygous mutation of MRPS22 was detected in a prepubertal woman with blepharophimosis, ptosis and epicanthus inversus syndrome (BPEs), resulting in a soft palate cleft and microcephaly other than the BPEs phenotype [ 72 ]. Homozygous mutations in MRPS7 were associated with primary hypogonadism, primary adrenal failure, sensorineural deafness, as well as lactic academia [ 64 ].…”

COPB2: a transport protein with multifaceted roles in cancer development and progression

“…COPB2 is also involved in other diseases. Based on a genome-wide association study, COPB2 is a susceptibility gene for Kawasaki disease [ 56 ], and COPB2 homozygous mutations have been associated with microcephaly [ 57 , 58 ]. COPB2 has also been identified as a vitamin D-regulated gene, along with other new candidate vitamin D response elements that have demonstrated importance for transcriptional regulation, immune function, stress response, and DNA repair [ 59 ].…”

The Genetic and Clinical Features of FOXL2-Related Blepharophimosis, Ptosis and Epicanthus Inversus Syndrome

“…At least 460 patients have been reported with FOXL2 -related BPES [ 1 , 6 , 10 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 ]. The most common variants affect two intragenic regions ( Figure 1 ): (i) the poly-alanine region with c.663_6...…”

“…Deletions were shown to be conserved between different generations of affected family members, revealing meiotic stability. A number of microdeletions, such as a 197 kb deletion upstream of FOXL2 , have been correlated with BPES-like disorders associated with microcephaly and intellectual disability [ 13 ].…”