NORD gratefully acknowledges James Grindley, NORD Editorial intern from the University of Connecticut, and Hannah Verdin, MSc, PhD, Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium, for assistance in the preparation of this report.
The four major features that are characteristic symptoms of BPES are present at birth: narrowing of the eye opening (blepharophimosis), droopy eyelids (ptosis), formation of an upward fold of the inner lower eyelid (epicanthus inversus) and increased distance between the eyes (telecanthus). There are two types of BPES, BPES type I and type II, which are both characterized by the typical eyelid malformation. However, BPES type I is also associated with loss of ovarian function or premature ovarian insufficiency (POI). Menstrual periods in women with POI become less frequent over time and stop before the age of 40 thus leading to either difficulty (subfertility) or inability to conceive (infertility). Other minor facial features frequently observed in both types include “lazy” eye (amblyopia), crossed eyes (strabismus), low-set ears, a short distance between the upper lip and nose, and a broad nasal bridge.
FOXL2 is the only gene known to cause BPES. This gene controls the production of the FOXL2 protein, which is involved in the development of the muscles in the eyelid as well as the growth and development of ovarian cells. Disease-causing changes (mutations) in the FOXL2 gene result in the signs and symptoms described above.
This syndrome is almost always inherited in an autosomal dominant manner. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an altered gene is necessary to cause a particular disease. The altered gene can be inherited from either parent or can be the result of a new mutation in the affected individual. The risk of passing the altered gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. In some individuals, the disorder is due to a spontaneous (de novo) genetic mutation that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents.
The prevalence of BPES is unknown, but there are no differences in prevalence based on ethnicity, sex, race or age.
The diagnosis of BPES is based on four clinical findings which are present at the time of birth. The first of these findings is narrowing of the eyelids (blepharophimosis). The second finding is drooping of the upper eyelid (ptosis). With this condition, affected individuals usually compensate by tilting their heads backward with their chin up and wrinkling their foreheads to pull the eyebrows upward to maintain full vision. These compensatory mechanisms result in a characteristic facial appearance. The third clinical finding is a skin fold that arises from the lower eyelid and runs inwards and upwards (epicanthus inversus). The final clinical finding used for diagnosis is widely set eyes (telecanthus). There are two types of BPES. Type I is diagnosed based on the four major features mentioned as well as premature ovarian insufficiency causing infertility or subfertility in females. Type II is diagnosed based on the presence of the four major features alone.
Clinical Testing and Work-Up
Female BPES patients can also be tested for premature ovarian insufficiency. Clinical signs of this are endocrinologic or hormonal, including elevated serum levels of FSH and LH and decreased serum concentrations of estradiol and progesterone (important hormones in the female reproductive system). In addition, the size of the uterus and clinical features observable upon pelvic ultrasound can be telltale signs of POI.
To confirm the clinical diagnosis on the molecular level, several genetic tests can be performed. Molecular genetic testing of FOXL2, includes sequence analysis and deletion/duplication analysis. In addition, chromosome analysis may be performed to screen for cytogenetic rearrangements involving 3q23 (band 23 on short arm of chromosome 3).
Treatment for BPES needs to address both the eyelid malformation and the premature ovarian insufficienty in type I patients. To manage the eyelid malformation, surgery is performed with the purpose of correcting the blepharophimosis, epicanthis inversus, telecanthus and ptosis. These procedures are traditionally done in two stages, though it is possible to do them simultaneously. Traditionally, correction of blepharophimosis, epicanthus inversus and telecanthus is done between the ages of three to five years, followed by ptosis correction after about one year. Timing of surgery is important, as this determines the balance of maintaining visual function while also producing the best cosmetic outcome.
To manage premature ovarian insufficiency associated with BPES type I, hormone replacement therapy is recommended. More specific, estrogen replacement is given to manage the insufficiency of hormones experienced with POI. It should however be noted that no therapies have been shown to restore fertility or ovarian function thus far. As such, other reproductive options may be explored including adoption, foster parenthood, embryo donation, and egg donation.
Follow-up is important in the management of BPES. Ophthalmic follow-up is individualized based on the affected individual’s visual acuity testing results, past procedures and age. Females who have BPES (type I especially) are encouraged for endocrinologic and gynecologic follow up to monitor ovarian function. This may include procedures such as pelvic ultrasounds, measuring serum FSH levels and menstrual pattern assessment.
A therapy under investigation for BPES type I is ovarian transplantation. This procedure has been performed for women who have an affected twin sister with normal ovarian function. Though successful, this treatment is only done in rare circumstances.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov . All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
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Verdin H, De Baere E. Blepharophimosis, Ptosis, and Epicanthus Inversus. 2004 Jul 8 [Updated 2015 Feb 5]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1441/ Accessed April 5, 2017.
Blepharophimosis, ptosis, and epicanthus inversus syndrome. Genetics Home Reference. Reveiwed October 2013.Available at: https://ghr.nlm.nih.gov/condition/blepharophimosis-ptosis-and-epicanthus-inversus-syndrome. Accessed April 5, 2017.
BPES Family Support. http://www.bpes.org.uk/
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