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Last updated: September 09, 2021
Years published: 2021
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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Demain LA, Urquhart JE, OโSullivan J, et al. Expanding the genotypic spectrum of Perrault syndrome. Clin Genet. 2017;91:302โ12.
De Vos M, Devroey P, Fauser BC. Primary ovarian insufficiency. Lancet. 2010;376:911โ21.
Faridi R, Rehman AU, Morell RJ, et al. Mutations of SGO2 and CLDN14 collectively cause coincidental Perrault syndrome. Clin Genet. 2017;91:328โ32.
Zerkaoui M, Demain LAM, Cherkaoui Jaouad I, et al. Marfanoid habitus is a nonspecific feature of Perrault syndrome. Clin Dysmorphol. 2017;26:200โ4.
Lerat J, Jonard L, Loundon N, et al. An application of NGS for molecular investigations in Perrault syndrome: study of 14 families and review of the literature. Hum Mutat. 2016;37:1354โ62.
Theunissen TE, Szklarczyk R, Gerards M, et al. Specific MRI abnormalities reveal severe Perrault syndrome due to CLPP defects. Front Neurol. 2016;7:203.
Jenkinson EM, Rehman AU, Walsh T, et al. Perrault syndrome is caused by recessive mutations in CLPP, encoding a mitochondrial ATP-dependent chambered protease. Am J Hum Genet. 2013;92:605โ13.
Jenkinson EM, Clayton-Smith J, Mehta S, et al. Perrault syndrome: further evidence for genetic heterogeneity. J Neurol. 2012;259:974โ6.
Pierce SB, Chisholm KM, Lynch ED, et al. Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome. Proc Natl Acad Sci USA. 2011;108:6543โ8.
Pierce SB, Walsh T, Chisholm KM, et al. Mutations in the DBP-deficiency protein HSD17B4 cause ovarian dysgenesis, hearing loss, and ataxia of Perrault Syndrome. Am J Hum Genet. 2010;87:282โ8.
King KA, Makishima T, Zalewski CK, et al. Analysis of auditory phenotype and karyotype in 200 females with Turner syndrome. Ear Hear. 2007;28:831โ41.
Meyers CM, Boughman JA, Rivas M, Wilroy RS, Simpson JL. Gonadal (ovarian) dysgenesis in 46,XX individuals: frequency of the autosomal recessive form. Am J Med Genet. 1996;63(4):518-24.
Nishi Y, Hamamoto K, Kajiyama M, Kawamura I. The Perrault syndrome: clinical report and review. Am J Med Genet. 1988;31(3):623-9.
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Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.
The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
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