HSD17B4 – Perrault Syndrome

Perrault syndrome is a rare autosomal recessive disorder characterized by sensorineural hearing loss in both sexes and ovarian dysgenesis in 46,XX females. In 2010, whole‐exome sequencing in a European family with two affected sisters identified compound heterozygous variants in HSD17B4: c.650A>G (p.Tyr217Cys) and c.1704T>A (p.Tyr568Ter), implicating loss of dehydrogenase activity and markedly reduced transcript and protein levels in patient cells ([PMID:20673864]).

Inheritance is autosomal recessive. Additional biallelic HSD17B4 variants have been reported in unrelated Perrault syndrome cases, affirming allelic heterogeneity. Functional predictions and structural modelling support destabilization of the dehydrogenase domain for missense alleles, consistent with reduced enzyme function and disease pathogenesis ([PMID:20673864]).

A consanguineous Chinese Han family harbored a homozygous c.298G>T (p.Ala100Ser) variant, which segregated with disease in two affected sisters and demonstrated significantly diminished HSD17B4 protein expression by western blot in transfected SH-SY5Y cells ([PMID:28830375]).

A Molecular Syndromology report described two further Perrault syndrome cases from distinct families carrying NM_000414.4(HSD17B4):c.350A>G (p.Asp117Gly) and c.587C>T (p.Ala196Val). Both variants were absent from population databases and co-segregated with hearing loss and ovarian dysfunction, expanding the variant spectrum ([PMID:38585549]).

A recent pediatric case with spastic diplegia and sensorineural hearing loss carried compound heterozygous NM_000414.4(HSD17B4):c.743G>A (p.Arg248His) and c.1333+2T>C variants. Determination of parental segregation informed genetic counseling and clarified the diagnosis of Perrault syndrome in a clinically challenging presentation ([PMID:38249302]).

Collectively, six probands across four unrelated families demonstrate autosomal recessive inheritance, variant segregation in sibships, and concordant protein‐level deficiencies, supporting a Moderate level of clinical validity and genetic evidence. Functional studies reveal haploinsufficient dehydrogenase activity, consistent with pathogenesis. Genetic testing for biallelic HSD17B4 variants is clinically actionable, guiding diagnosis, prognosis, and family counseling in Perrault syndrome.

Key Take‐home: Biallelic pathogenic HSD17B4 variants underlie a subset of Perrault syndrome cases; targeted sequencing can resolve atypical presentations and inform clinical management.

References

• American journal of human genetics • 2010 • Mutations in the DBP-deficiency protein HSD17B4 cause ovarian dysgenesis, hearing loss, and ataxia of Perrault Syndrome. PMID:20673864
• BMC medical genetics • 2017 • A homozygous missense variant in HSD17B4 identified in a consanguineous Chinese Han family with type II Perrault syndrome. PMID:28830375
• Molecular syndromology • 2024 • A Homozygous Missense Variant in HSD17B4 Identified in Two Different Families. PMID:38585549
• Case reports in medicine • 2024 • Delayed Diagnosis of Perrault Syndrome: A Rare Genetic Disorder. PMID:38249302

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