Perrault syndrome

Perrault syndrome presents with bilateral sensorineural hearing loss and, in 46,XX females, ovarian dysfunction. Hearing loss is typically congenital or manifests in early childhood, ranging from profound prelingual deafness detectable by newborn hearing screening to moderate early-childhood onset; audiograms initially show steeply sloping threshold elevations (>40 dB) at 4-8 kHz that later extend to lower frequencies (0.5-2 kHz).

Ovarian dysfunction encompasses a spectrum from with primary amenorrhoea to premature ovarian insufficiency, defined as cessation of menses before age 40 years. Fertility in males is usually reported as normal, although azoospermia and undervirilisation have been described.

Two clinical forms of Perrault syndrome are distinguished: Type 1, the classic phenotype, represents the milder end of the spectrum; Type 2 additionally includes neurologic features such as developmental delay, intellectual disability, ataxia, and motor/sensory neuropathies, and, in some individuals, metabolic crises with raised blood lactate.

The estimated prevalence is <1/1,000,000.

Perrault syndrome is genetically heterogeneous; biallelic germline pathogenic variants in at least 12 genes have been reported as causative. The major contributors are LARS2 (~21% of cases), CLPP (~18%), HARS2 (~14%), GGPS1 (~8%), and MRPL49 (~8%); the remaining cases are attributable to HSD17B4, PRORP, TWNK, RMND1, DAP3, ERAL1, and PEX6. The implicated proteins converge on mitochondrial function (aminoacyl-tRNA synthetases, ribosomal components, the matrix protease CLPP, the mtDNA helicase, and assembly factors), with additional roles in peroxisomal biology and isoprenoid biosynthesis. Approximately 80% of cases are explained by pathogenic variants in these 12 genes.

Perrault syndrome is inherited in an autosomal recessive manner. When both parents are heterozygous for a pathogenic variant in the same gene, the recurrence risk for each pregnancy is 25%. Once the familial pathogenic variants have been identified, prenatal molecular testing is technically possible.

The diagnosis of Perrault syndrome is established primarily by molecular genetic testing. Clinical findings supporting the diagnosis include bilateral sensorineural hearing loss on audiometry with steeply sloping high-frequency threshold elevations, hypergonadotropic hypogonadism in females (raised follicle-stimulating hormone and luteinising hormone with decreased oestrogen), and pelvic imaging showing dysplastic, streak, or absent ovaries. Brain MRI may demonstrate white-matter changes and cochlear-nerve hypoplasia.

Main differential diagnoses include:

• Turner syndrome (45,X): primary ovarian failure with high-tone sensorineural hearing loss; chromosomal (45,X karyotype), not single-gene
• 46,XX / primary ovarian insufficiency: ovarian dysfunction without sensorineural hearing loss; BMP15, ESR2, FSHR, NUP107, MCM9
• (FXPOI): premutation-related ovarian insufficiency without hearing loss; FMR1

• Establishing the diagnosis: Molecular genetic testing confirms the clinical diagnosis and identifies the specific pathogenic variants underlying the condition.
• Specific and individualised surveillance and clinical management: A confirmed molecular diagnosis is the prerequisite for targeted medical care; surveillance for hearing-loss progression, ovarian function, and neurological manifestations can then be coordinated by the treating physicians in consultation with the affected individual.
• Family member testing: Knowledge of the familial pathogenic variants enables carrier testing of at-risk relatives and informs reproductive decision-making.

• Li T, Faridi R, Newman WG, Friedman TB. Perrault syndrome overview. 2025 May 8. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: PMID:25254289.
• Wei L, Hou L, Ying YQ, Luo XP. A novel missense mutation in TWNK gene causing Perrault syndrome type 5 in a Chinese family and review of the literature. Pharmacogenomics Pers Med. 2022;15:1-8. doi:10.2147/PGPM.S341172. PMID:; PMCID: PMC8754503.
• Long X, Yang B, Wang W, Peng W, Wang X, Xiong W, et al. CLPP gene variants causing Perrault syndrome type 3 in Han Chinese families: a genotype-phenotype study. Hum Genomics. 2025;19(1):60. doi:10.1186/s40246-025-00762-5. PMID:; PMCID: PMC12102955.
• Bayanova M, Abilova A, Nauryzbayeva A, Turarbekova Z. Delayed diagnosis of Perrault syndrome: a rare genetic disorder. Case Rep Med. 2024;2024:5319443. doi:10.1155/2024/5319443. PMID:; PMCID: PMC10798831.