NORD gratefully acknowledges Greg Cichon, MD candidate, Creighton School of Medicine and Heather Gomes, MD, Otolaryngologist, Boys Town National Research Hospital, for the preparation of this report.
Perrault syndrome is a rare genetic disorder which causes sensorineural hearing loss in both males and females and ovarian dysfunction in females. Only about 100 cases have been reported, mostly in females. Hearing loss is present at birth or early childhood and may be progressive, but the disease is usually diagnosed in females in early adulthood due to a late puberty. In females, the ovaries do not function normally to begin puberty despite having an otherwise normal set of chromosomes (46,XX karyotype). Male fertility is normal, but females may not be able to conceive naturally, depending on the severity. A diagnosis is usually made after imaging shows a uterus but no functional ovaries and the karyotype of 46,XX.
The hearing loss from birth is irreversible and may progressively get worse, warranting the need for a hearing aid or cochlear implant. Affected females may have primary ovarian insufficiency (POI), resulting in an early menopause before 40 years old, or some degree of ovary dysfunction. As a result, it may be difficult or impossible to conceive naturally and most women with Perrault syndrome will require an endocrinologist to manage hormone levels. Life expectancy is normal.
The most common symptoms of Perrault syndrome include:
Perrault syndrome is caused by changes (mutations) in six genes: CLPP, ERAL1, HARS2, HSD17B4, LARS2, or TWNK. Mutations in one of these genes have been identified in about 40% of patients. The cause is unknown in the other 60% of patients.
Perrault syndrome is an autosomal recessive genetic condition. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
Fewer than 100 cases of Perrault syndrome have been diagnosed, making it extremely rare (<1 in 1 million). A family history of this disease is the greatest known risk, particularly if the genetic mutation is identified.
The diagnosis of Perrault syndrome is based on the early hearing loss and ovarian dysfunction in females with a normal 46,XX set of chromosomes. Genetic testing for mutations in the six known causative genes can help to confirm the diagnosis, but more commonly the exact cause will be unknown. Since males with Perrault syndrome tend to only experience hearing loss, they may not receive a diagnosis unless they also have a sister with Perrault syndrome.
Clinical Testing and Work-up
Newborn infants may show the first signs of Perrault syndrome if they fail newborn hearing screening tests. Older children might be diagnosed with hearing loss based on an audiogram. Due to its rarity, clinicians would not likely suspect Perrault syndrome until they have also found ovarian dysfunction causing late puberty in a young adult woman. Clinical testing may include blood tests, hearing tests, pelvic imaging, genetic testing and neurological exams. A care team may include audiologists, otolaryngologists, endocrinologists, gynecologists, geneticists and neurologists. Once the diagnosis is made, these clinicians can help manage the hearing loss, hormone levels and fertility issues involved in Perrault syndrome.
There is no cure for Perrault syndrome and treatment focuses on remedying the symptoms of hearing loss, hormone imbalance and infertility. Depending on the severity of hearing loss, an audiologist or ENT physician may recommend hearing aids, cochlear implants or vibrotactile devices. Routine hearing checks are important to determine if the hearing loss is getting worse.
An endocrinologist can induce normal puberty in young women and then supplement the proper hormones to maintain a normal menstrual cycle. Most women with Perrault syndrome meet with their endocrinologists every three months when starting puberty, once a year when receiving hormone supplementation and every five years to check bone density changes as a result of hormone supplementation.
For women with primary ovarian insufficiency (POI), a clinician may recommend freezing their eggs since menopause happens early. Women with shrunken ovaries (ovarian dysgenesis) may not be able to conceive naturally but may be able to have children using in-vitro fertilization since they have a functioning uterus.
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