Blepharophimosis, ptosis, and epicanthus inversus syndrome

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Age of onset

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ICD-10

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Inheritance

Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is inherited in an autosomal dominant pattern.^[1] All individuals inherit two copies of each gene. Autosomal means the gene is found on one of the numbered chromosomes found in both sexes. Dominant means that only one altered copy of a gene is necessary to have the condition. The variant can be inherited from either parent. Sometimes an autosomal dominant condition occurs because of a new genetic variant (de novo) and there is no history of this condition in the family.

Each child of an individual with an autosomal dominant condition has a 50% or 1 in 2 chance of inheriting the variant and the condition. Typically, children who inherit a dominant variant will have the condition, but they may be more or less severely affected than their parent. Sometimes a person may have a gene variant for an autosomal dominant condition and show no signs or symptoms of the condition. Both types of BPES can be caused by the same variant in the FOXL2 gene, two individuals in the same family may have different types.^[4]

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease.

Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype.

X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder.

Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

Not applicable

Summary

Blepharophimosis, ptosis and epicanthus inversus syndrome (BPES) is present at birth and mainly involves the development of the eyelids. Symptoms of BPES include a narrow eye opening (blepharophimosis), droopy eyelids (ptosis), an upward fold of the lower eyelid (epicanthus inversus), and an increased distance between the inner corners of the eyes (telecanthus). Because the eyelids cannot open fully, vision may be limited. There are two types of BPES. Type 1 includes the eye involvement and premature ovarian failure (POF). In type 2, only the eyes are involved. BPES is caused by variants in the FOXL2 gene and is inherited in an autosomal dominant pattern. Diagnosis is based on the symptoms, clinical exam, and confirmed by the results of genetic testing. Treatment is based on managing the symptoms and involves eyelid surgery. BPES, type 1 may also be treated with hormone replacement therapy.^[1]^[2]^[3]^[4]

Symptoms

The following list includes the most common signs and symptoms in people with blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES). These features may be different from person to person. Some people may have more symptoms than others and symptoms can range from mild to severe. This list does not include every symptom or feature that has been described in this condition.

Symptoms may include:

Narrow eye opening (blepharophimosis)
Droopy eyelids (ptosis)
Upward fold of the lower eyelid (epicanthus inversus)
Increased distance between the inner corners of the eyes (telecanthus)
Vision problems

These symptoms are present at birth. Other less common features may include wide nose and low set ears. In women with BPES type 1, the ovaries stop working at an early age (premature ovarian failure) which can cause decreased fertility. People with BPES have average intelligence.^[1]^[2]^[4]

Cause

Blepharophimosis, ptosis, and epicanthus inversus syndrome is caused by by the FOXL2 gene not working correctly. DNA changes known as pathogenic variants are responsible for making genes work incorrectly or sometimes, not at all.^[1] It is difficult to predict which type of BPES a person has based on the specific gene variant.^[4]

Diagnosis

Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is diagnosed based on the symptoms, clinical exam, and can be confirmed by the results of genetic testing.^[1]^[2]

Treatment

Treatment of blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is focused on managing the symptoms. Typically, eye surgery is done to correct the eyelid abnormalities. Women with BPES type 1 who have premature ovarian failure may be treated with hormone replacement therapy.^[1]^[2]^[4]

Specialists who may be involved the care of someone with BPES include:

Medical geneticist
Ophthalmologist
Eye plastic (oculoplastic) surgeon
Reproductive endocrinologist
Gynecologist

References

De Baere E, Verdin H. Blepharophimosis, Ptosis, and Epicanthus Inversus. GeneReviews. Updated Feb 5, 2015; https://www.ncbi.nlm.nih.gov/books/NBK1441/.
Hu J, Ke H, Luo W, Yang Y, Liu H, Li G, Qin Y, Ma J, Zhao S. A novel FOXL2 mutation in two infertile patients with blepharophimosis-ptosis-epicanthus inversus syndrome. J Assist Reprod Genet. Jan 2020; 37(1):223-229. https://pubmed.ncbi.nlm.nih.gov/31823134/.
Yang XW, He WB, Gong F, Li W, Li XR, Zhong CG, Lu GX, Lin G, Du J, Tan YQ. Novel FOXL2 mutations cause blepharophimosis-ptosis-epicanthus inversus syndrome with premature ovarian insufficiency. Mol Genet Genomic Med. Mar 2018; 6(2):261-267. https://pubmed.ncbi.nlm.nih.gov/29378385/.
Bunyan DJ, Thomas NS. Screening of a large cohort of blepharophimosis, ptosis, and epicanthus inversus syndrome patients reveals a very strong paternal inheritance bias and a wide spectrum of novel FOXL2 mutations. Eur J Med Genet. Jul 2019; 62(7):103668. https://pubmed.ncbi.nlm.nih.gov/31077882/.

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Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease.

Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype.

X-linked dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

X-linked recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder.

Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

Not applicable

Summary

Symptoms

Cause

Diagnosis

Treatment

References

X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder.