Perrault Syndrome Overview
Tianyi Li, MD, PhD, Rabia Faridi, PhD, William G Newman, MD, PhD, and Thomas B Friedman, PhD.
Author Information and AffiliationsInitial Posting: September 25, 2014; Last Update: May 8, 2025.
Estimated reading time: 26 minutes
1. Clinical Characteristics of Perrault Syndrome
Perrault syndrome, a rare multisystem disorder, has been reported in more than 170 individuals to date. Perrault syndrome was initially defined 70 years ago as bilateral sensorineural hearing loss (SNHL) and ovarian dysfunction in females with a normal 46,XX karyotype [Perrault et al 1951]. However, with the widespread use of molecular genetic testing to identify the cause of Perrault syndrome, this definition now needs to be broadened to accommodate the finding that males can be affected and that many affected individuals have associated neurologic findings. Thus, the classifications of type 1 Perrault syndrome and type 2 Perrault syndrome have been proposed [Pierce et al 2010].
Type 1 Perrault syndrome can be considered the mild end of the phenotypic spectrum and type 2 Perrault syndrome can be considered the severe end of the spectrum.
Type 1 Perrault Syndrome
SNHL is bilateral and ranges in severity from profound with prelingual (congenital) onset that can be detected through newborn hearing screening (NBHS) to moderate with early-childhood onset. The increase in the hearing threshold can vary. When presenting in early childhood, hearing loss can be progressive.
Audiograms typically initially show steeply sloping threshold elevations (>40 dB hearing loss [HL]) at 4-8 kHz that later extend to lower frequencies (0.5-2 kHz).
Progression to profound SNHL (70-100 dB HL) can occur with absent otoacoustic emissions (OAEs), indicating outer hair cell dysfunction and abnormal auditory brain stem responses (ABRs) with absent waveforms / prolonged latency indicating cochlear or auditory nerve pathology.
While MRI in most individuals shows structurally normal inner ears, up to 10% of individuals have cochlear nerve hypoplasia.
Middle ear function is normal based either in young children on acoustic immittance testing (i.e., normal tympanograms [type A] with absent/elevated stapedial reflexes) or in older children on an audiogram that shows similar hearing thresholds for both bone and air conduction.
Vestibular function in individuals with Perrault syndrome is largely unexplored.
This distinct audiologic profile aids in differentiation from other causes of genetic hearing loss and underscores the need for early intervention such as cochlear implantation to improve acquisition of speech and language.
Variability in age of onset and degree of hearing loss do not depend on the sex of the affected individual.
Females with Perrault syndrome
Ovarian dysfunction, resulting from a developmental disorder of the ovaries, encompasses a spectrum ranging from ovarian dysgenesis (absent or streak gonads) manifesting as primary amenorrhea to premature ovarian insufficiency (POI), defined as cessation of menses before age 40 years.
Ovarian dysgenesis is characterized by loss of germ and supportive cells (e.g., granulosa and theca cells, respectively). The ovaries are dysplastic, streak, or absent. Blood concentration of estrogen is decreased with a consequent elevation in blood concentrations of the two gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) (i.e., hypergonadotropic hypogonadism). The uterus is rudimentary and appears to be prepubertal on ultrasound examination.
POI presents as secondary amenorrhea, with raised blood FSH concentrations and reduced blood estrogen concentrations. Rarely women with Perrault syndrome have had children prior to the onset of premature menopause [
Jenkinson et al 2013].
Males with Perrault syndrome. Fertility in males with PRLTS is usually reported as normal; however, azoospermia and undervirilization have been described [Demain et al 2017, Adam et al 2025]. More data are needed, as the number of reported males is limited, with most diagnoses made prepubertally at the time of the diagnosis of hearing loss.
Type 2 Perrault Syndrome
Neurologic features have been reported in each of the genes associated with Perrault syndrome (see Section 2). The frequency of these features varies by the genetic cause; for example, HARS2-related Perrault syndrome is rarely associated with neurologic features, whereas HSD17B4-related Perrault syndrome and TWNK-related Perrault syndrome have neurologic features.
2. Genetic Causes of Perrault Syndrome
Perrault syndrome, caused by biallelic pathogenic (or likely pathogenic) variants in at least 12 genes, is inherited in an autosomal recessive manner (see Table 1). Approximately 80% of Perrault syndrome is attributed to pathogenic variants in these genes.
Note: There is significant interfamilial and intrafamilial variability in the 12 genes listed in Table 1 [Jenkinson et al 2013].
Table 1.
Perrault Syndrome: Associated Genes
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- 1.
Genes are listed in alphabetic order.
CLPP-related Perrault syndrome. Thirty-one individuals reported to date [Jenkinson et al 2013, Faridi et al 2022, Bayanova et al 2024, Faridi et al 2024, Shokouhian et al 2025]
Sensorineural hearing loss (SNHL). Congenital and usually severe to profound
Ovarian dysfunction. Ovarian dysgenesis to premature ovarian insufficiency (POI)
Type 2 findings. Learning difficulties, autism spectrum disorder, epilepsy, spastic-ataxic gait, dystonia
DAP3-related Perrault syndrome. Five individuals reported to date [Smith et al 2025]
SNHL. Congenital profound hearing loss
Ovarian dysfunction. POI
Fertility in males. Not reported
Type 2 findings. Mild-to-severe intellectual disability, epilepsy, diffuse leukodystrophy
ERAL1-related Perrault syndrome. Four individuals reported to date [Chatzispyrou et al 2017]
SNHL. Congenital and profound; early-childhood onset and progressive with varying degrees of severity
Ovarian dysfunction. Ovarian dysgenesis to POI
Fertility in males. Not reported
Type 2 findings. Not reported
GGPS1-related Perrault syndrome. Fourteen individuals reported to date [Foley et al 2020, Tucker et al 2020, Kaiyrzhanov et al 2022]
SNHL. Congenital hearing loss with slow progression
Ovarian dysfunction. Absent ovaries to normal
Fertility in males. Not reported
Type 2 findings. Early-onset, progressive proximal or generalized muscular dystrophy
HARS2-related Perrault syndrome. Twenty-four individuals reported to date [Souissi et al 2021, Faridi et al 2022, Lei et al 2023, Domínguez-Ruiz et al 2024]
SNHL. Can be
congenital and profound; usually early-childhood onset and progressive with varying severity
Ovarian dysfunction. Ovarian dysgenesis to normal
Fertility in males. Not reported
Type 2 findings. Rare; cerebellar ataxia reported
HSD17B4-related Perrault syndrome. Twelve individuals reported to date [Faridi et al 2022, Idyahia et al 2024, Kapil et al 2024, Özkan Kart et al 2024]
SNHL. Congenital and profound; mild with a progressive course in childhood
Ovarian dysfunction. Ovarian dysgenesis to POI
Fertility in males. Not reported
Type 2 findings. All reported individuals have neurologic findings including retinitis pigmentosa, spastic diplegic cerebral palsy, progressive sensory and motor peripheral neuropathy, cerebellar ataxia, and learning disability.
LARS2-related Perrault syndrome. Thirty-six individuals reported to date [Faridi et al 2022, Lei et al 2023, Domínguez-Ruiz et al 2024, Idyahia et al 2024, Adam et al 2025, Lu et al 2025]
SNHL. Can be
congenital and profound; onset usually in early childhood and can be progressive with varying degrees of severity
Ovarian dysfunction. Ovarian dysgenesis to POI
Fertility in males. Not reported, but undervirilization noted
Type 2 findings. Seizures, progressive cognitive impairment, leukodystrophy
MRPL49-related Perrault syndrome. Fourteen individuals reported to date [Thomas et al 2025]
SNHL. Childhood-onset bilateral profound hearing loss
Ovarian dysfunction. Ovarian dysgenesis to POI
Fertility in males. Not reported
Type 2 findings. Retinal dystrophy, learning disability; cerebellar atrophy and leukodystrophy especially in the globus pallidus
PEX6-related Perrault syndrome. One individual reported to date [Tucker et al 2020]
SNHL. Childhood onset; degree not reported
Ovarian dysfunction. POI
Fertility in males. Not reported
Type 2 findings. Retinal dystrophy, peripheral neuropathy, leukodystrophy
PRORP-related Perrault syndrome. Eleven individuals reported to date [Hochberg et al 2021, Smith et al 2023]
SNHL. Mild-to-severe hearing loss; not in all affected individuals
Ovarian dysfunction. POI to normal
Fertility in males. Not reported
Type 2 findings. Learning disability, leukodystrophy
RMND1-related Perrault syndrome. Six individuals reported to date [Boros et al 2022, Faridi et al 2022, Rioux et al 2023, Du et al 2024]
SNHL. Moderate-to-severe hearing loss
Ovarian dysfunction. POI
Fertility in males. Not reported
Type 2 findings. Learning disability, leukodystrophy
TWNK-related Perrault syndrome. Eleven individuals reported to date [Faridi et al 2022, Chang et al 2024, Shimanuki et al 2024, Shokouhian et al 2025, Tufatulin et al 2025]
3. Differential Diagnosis of Perrault Syndrome
For individuals with a clinical diagnosis of Perrault syndrome in whom a molecular diagnosis has not been established, other causes of sensorineural hearing loss (SNHL) and ovarian dysfunction need to be excluded before a clinical diagnosis of Perrault syndrome can made with confidence.
SNHL. To date, more than 125 genes are known to be associated with nonsyndromic hearing loss. A regularly updated, comprehensive list of identified nonsyndromic and syndromic hearing loss genes is available at the Hereditary Hearing Loss Homepage. See also the Genetic Hearing Loss Overview for review of the causes and differential diagnosis of genetic hearing loss.
Note: Perrault syndrome is associated with a distinct audiologic profile (see Clinical Characteristics) that aids in the differentiation of Perrault syndrome-related hearing loss from other causes of genetic hearing loss and underscores the need for early intervention (such as cochlear implantation) to improve acquisition of speech and language.
Ovarian dysfunction. Ovarian dysgenesis (also referred to as 46,XX gonadal dysgenesis) and primary ovarian insufficiency (POI) are genetically heterogeneous (see Table 2). For individuals with primary ovarian failure, defined by primary amenorrhea with low estrogen and raised gonadotropins, Turner syndrome (45,X) or other abnormalities of the X chromosome should be considered (note that all females with Perrault syndrome have a normal 46,XX karyotype). Hearing loss is present in the majority of women with Turner syndrome; 78% of affected adults have progressive, high-tone SNHL [Hultcrantz & Sylven 1997, King et al 2007, Makishima et al 2009] and 60%-80% of affected children have recurrent acute otitis media [Verver et al 2011, Kubba et al 2017].
Table 2.
Genes Associated with Ovarian Dysfunction in the Differential Diagnosis of Perrault Syndrome
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| Gene(s) | Disorder | MOI | Comment |
|---|
|
AIRE
| Polyglandular autoimmune syndrome type 1 (OMIM 240300) | AD
AR | Autoimmune condition characterized by at least 2 of the following: candidiasis, hypoparathyroidism, &/or adrenal insufficiency. Many affected women experience ovarian dysfunction. 1 |
BMP15
ESR2
FSHR
HROB
MCM9
MRPS22
NUP107
PSMC3IP
SOHLH1
SPIDR
ZSWIM7
| Ovarian dysgenesis (OMIM PS233300) | AD
AR
XL | Nonsyndromic |
|
CYP17A1
| Congenital adrenal hyperplasia due to 17-alpha-hydroxylase deficiency (OMIM 202110) | AR | Can be excluded from differential diagnosis by measurement of 11-deoxycorticosterone & androstenedione levels |
|
FMR1
| Fragile X-assoc primary ovarian insufficiency (FXPOI) (See FMR1-Related Disorders.) | XL | FXPOI is observed in ~16%-20% of females heterozygous for a premutation allele (~55-200 CGG repeats in the 5' UTR of FMR1), compared to 3.5% in the general population. 2 |
|
FOXL2
| Blepharophimosis, ptosis, & epicanthus inversus syndrome type I | AD | Characterized by complex eyelid malformation & POI |
|
MRPL50
| Syndromic POI | AR | Single affected person also has kidney & heart dysfunction. 3 |
ZP1
ZP2
| Oocyte maturation defect (OMIM 615774, 618353) | AR | Characterized by primary infertility due to oocyte maturation defect of zona pellucida 4 |
|
ZP3
| Oocyte maturation defect (OMIM 617712) | AD | Characterized by empty follicle syndrome & female infertility 5 |
A Perrault syndrome-like phenotype was reported in a female with SNHL and POI who did not have pathogenic variants in any of the known Perrault syndrome-related genes [Faridi et al 2017]. Homozygous pathogenic variants were identified on molecular genetic testing in each of two distinct, unlinked genes: CLDN14 and SGO2. SNHL in this individual was attributed to the involvement of CLDN14 (an established autosomal recessive SNHL-related gene), while POI was attributed to inactivating variants in SGO2 (a gene not known to cause any human disorder but essential for meiosis and strongly implicated in infertility by studies in murine models).
4. Evaluation Strategies to Identify the Genetic Cause of Perrault Syndrome in a Proband
Genomic/Genetic Testing
The diagnosis of Perrault syndrome is molecularly confirmed by the presence of biallelic pathogenic (or likely pathogenic) variants in one of 12 genes: CLPP, DAP3, ERAL1, GGPS1, HARS2, HSD17B4, LARS2, MRPL49, PEX6, PRORP, RMND1, and TWNK (Table 1).
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic variants of uncertain significance (or of one known pathogenic variant and one variant of uncertain significance) in one of the genes in Table 1 does not establish or rule out the diagnosis. (3) To date, biallelic pathogenic variants in these 12 genes do not account for all individuals with clinically diagnosed Perrault syndrome [Faridi et al 2022, Smith et al 2025].
Molecular genetic testing approaches can include gene-targeted testing (multigene panel) and comprehensive
genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas comprehensive genomic testing does not.
A multigene panel that includes the genes in
Table 1 and other genes of interest (see
Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of pathogenic variants and variants of
uncertain significance in genes that do not explain the underlying
phenotype. Note: (1) The genes included in the panel and the diagnostic
sensitivity of the testing used for each
gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this
GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused
exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include
sequence analysis,
deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click
here. More detailed information for clinicians ordering genetic tests can be found
here.
Comprehensive
genomic testing does not require the clinician to determine which
gene is likely involved.
Exome sequencing is most commonly used;
genome sequencing is also possible.
For an introduction to comprehensive
genomic testing click
here. More detailed information for clinicians ordering genomic testing can be found
here.
5. Management
No clinical practice guidelines for Perrault syndrome have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Perrault syndrome, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.
Table 3.
Perrault Syndrome: Recommended Evaluations Following Initial Diagnosis
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| System/Concern | Evaluation | Comment |
|---|
|
Hearing 1
| Audiologic assessment | To define degree & frequency range of hearing impairment by audiometry & physiologic tests (summarized in Genetic Hearing Loss Overview) |
|
Neurologic 1
| Neurologic assessment | Determine if ataxia, peripheral neuropathy, &/or learning disability is present. Brain MRI to determine if evidence of white matter changes is present.
|
|
Endocrine 2
| Blood estrogen concentration & gonadotropin (LH & FSH) concentrations | In women w/relatively intact ovarian function, blood anti-müllerian hormone concentrations may provide evidence of incipient ovarian insufficiency. 3 |
| Pelvic imaging | Ultrasound exam or MRI to define presence of ovaries & antral follicle count |
|
Urology
| Physical exam for evidence of undervirilization | |
|
Genetic counseling
| By genetics professionals 4 | To obtain a pedigree & inform affected persons & their families re nature, MOI, & implications of Perrault syndrome to facilitate medical & personal decision making |
Family support
& resources
| By clinicians, wider care team, & family support organizations | Assessment of family & social structure to determine need for:
|
- 1.
- 2.
- 3.
- 4.
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
Treatment of Manifestations
There is no cure for Perrault syndrome.
No pharmacologic therapies are available. Although the pathogenic mechanism in most of the genetic causes of Perrault syndrome is mitochondrial dysfunction, therapies used in most known mitochondrial disorders aimed at improving metabolism (such as complex B vitamins, coenzyme Q10, idebenone, and antioxidant vitamin E) have been considered but their clinical effectiveness is uncertain.
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 4).
Table 4.
Perrault Syndrome: Treatment of Manifestations
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Manifestation/
Concern | Treatment | Considerations/Other |
|---|
|
Hearing loss
| Possible interventions incl:
Hearing aids Vibrotactile devices Cochlear implantation 1
| Assessment & treatment by multidisciplinary team incl audiologist, otolaryngologist, & speech therapist Provide for any special educational needs. Early intervention for young children w/profound hearing loss improves cognitive & language development (summarized in Genetic Hearing Loss Overview).
|
| Consultation w/developmental pediatrician &/or neuropsychologist/psychologist |
|
|
Ovarian insufficiency
| In adolescent females presenting w/primary amenorrhea, induction of puberty w/incremental doses of estrogen | In consultation w/pediatric endocrinologist If puberty is complete, administer cyclic estrogen & progesterone to mimic menstrual cycle & trigger withdrawal bleeding. Estrogen replacement therapy (if no contraindications) until age ≥50 yrs to ↓ risks of cardiovascular disease & osteoporosis
|
|
Infertility
| Assisted reproduction through in vitro fertilization | In females:
For females w/ovarian dysgenesis: consider assisted reproduction through in vitro fertilization using donor eggs. For females at risk for POI: consider oocyte cryopreservation if ovarian function is sufficient to allow successful harvesting of oocytes. Consider use of donor eggs. Before considering pregnancy, assess uterine size (ideally 7-9 cm in length).
In males:
|
|
Undervirilization
| Standard therapy per urologist | May incl orchidopexy &/or hypospadias repair |
|
Neurologic
| Per treating neurologist &/or developmental pediatrician | For pain mgmt (as needed): gabapentin, pregabalin |
|
Musculoskeletal/ADL
| Orthopedics / physical medicine & rehab / PT & OT incl stretching to help avoid contractures & falls | Consider need for positioning & mobility devices to prevent falling, disability parking placard. |
ADL = activities of daily living; OT = occupational therapy; POI = primary ovarian insufficiency; PT = physical therapy
- 1.
Cochlear implantation can be considered in children age >12 months who have severe-to-profound hearing loss.
Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 5 are recommended.
Table 5.
Perrault Syndrome: Recommended Surveillance
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| System/Concern | Evaluation | Frequency |
|---|
|
Hearing loss
| Routine audiologic assessments for possible progressive hearing impairment 1 | Annually |
|
Endocrine
|
| Per treating endocrinologist |
| Women on maintenance estrogen replacement therapy: assessment of withdrawal bleeding & well being | Annually or per treating endocrinologist |
| Assessment of bone density | Every ~5 yrs |
|
Family/Community
| Assess family need for social work support (e.g., palliative/respite care, home nursing in individuals with severe neurologic involvement) or follow-up genetic counseling if new questions arise (e.g., family planning). | At each visit |
- 1.
Not required for individuals with profound hearing loss
Agents/Circumstances to Avoid
For individuals with hearing loss, avoid:
Ototoxic medication such as aminoglycosides if alternatives are available;
Exposure to loud noise, which may contribute to deterioration of hearing.
Evaluation of Relatives at Risk
It is appropriate to evaluate older and younger sibs of a proband in order to identify as early as possible those who would benefit from prompt diagnosis and early intervention for hearing loss and/or ovarian insufficiency.
6. Genetic Counseling
Genetic counseling is the process of providing individuals and families with
information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
make informed medical and personal decisions. The following section deals with genetic
risk assessment and the use of family history and genetic testing to clarify genetic
status for family members; it is not meant to address all personal, cultural, or
ethical issues that may arise or to substitute for consultation with a genetics
professional. —ED.
Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the Perrault syndrome-related pathogenic variants in the family.
Prenatal Testing and Preimplantation Genetic Testing
If the Perrault syndrome-related pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
Resources
GeneReviews staff has selected the following disease-specific and/or umbrella
support organizations and/or registries for the benefit of individuals with this disorder
and their families. GeneReviews is not responsible for the information provided by other
organizations. For information on selection criteria, click here.
Alexander Graham Bell Association for the Deaf and Hard of Hearing
Phone: 202-337-5220
Email: info@agbell.org
American Society for Deaf Children
Phone: 800-942-2732 (ASDC)
Email: info@deafchildren.org
INCIID
InterNational Council on Infertility Information Dissemination
Email: INCIIDinfo@inciid.org
National Association of the Deaf
Phone: 301-587-1788 (Purple/ZVRS); 301-328-1443 (Sorenson); 301-338-6380 (Convo)
Fax: 301-587-1791
Email: nad.info@nad.org
RESOLVE: The National Infertility Association
Phone: 703-556-7172
Email: info@resolve.org
Chapter Notes
Author Notes
William Newman (ku.ca.retsehcnam@namwen.mailliw) is actively involved in clinical research regarding individuals with Perrault syndrome. He would be happy to communicate with persons who have any questions regarding diagnosis of Perrault syndrome or other considerations.
Rabia Faridi (vog.hin@idiraf.aibar), William Newman, and Thomas Friedman (vog.hin.dcdin@namdeirf) are also interested in hearing from clinicians treating families affected by Perrault syndrome in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.
Contact Rabia Faridi, William Newman, and Thomas Friedman to inquire about review of variants of uncertain significance in genes associated with Perrault syndrome.
Acknowledgments
William Newman is supported by the Medical Research Council (MR/W019027/1), Action on Hearing Loss (S60_Newman), and NIHR Manchester Biomedical Research Centre (NIHR203308). Rabia Faridi and Thomas Friedman are supported by the Intramural Research Program of the NIDCD at the NIH (DC000039).
Author History
Gerard S Conway, MD; University College London (2014-2025)
Leigh AM Demain, PhD; University of Manchester (2018-2025)
Rabia Faridi, PhD (2025-present)
Thomas B Friedman, PhD (2014-present)
Tianyi Li, MD, PhD (2025-present)
William G Newman, MD, PhD (2014-present)
Revision History
8 May 2025 (bp) Comprehensive update posted live; scope changed to overview
6 September 2018 (bp) Comprehensive update posted live
25 September 2014 (me) Review posted live
10 March 2014 (wn) Original submission
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