SUN-155 - Perrault and LARS2 Variants: Clinical, Hormonal and Genetic Characterization of A Female Patient

Background: Perrault syndrome (PS) is a rare autosomal recessive disorder characterized by bilateral sensorineural hearing loss, premature ovarian insufficiency (POI), and variable neurological involvement. More than 10 genes have been associated with PS. Biallelic pathogenic variants LARS2, encoding mitochondrial leucyl-tRNA synthetase, account for a subset of cases, particularly associated with cognitive and neurological manifestations.

Objective: To describe the clinical, hormonal, and molecular findings of a girl with suspected Perrault syndrome.

Methods: Genomic DNA was analyzed by whole-exome sequencing with enrichment of nuclear and mitochondrial regions), using the Illumina platform. Sequence alignment and variant calling were based on the GRCh37 human genome and the NC_012920.1 mitochondrial reference. Bioinformatic analysis was conducted using a customized germline pipeline. Variants were annotated according to HGVS nomenclature and interpreted using American College of Medical Genetics and Genomics criteria.

Results: A 13-yr-old girl presented with arrested puberty, early onset bilateral sensorineural hearing loss and mild cognitive impairment, with persistent language and learning difficulties. Thelarche began at 10.5 years, followed by pubarche, and a single episode of vaginal bleeding at 11.5 yrs, followed by secondary amenorrhea. Physical examination revealed a height of 156 cm, weight of 42.5 kg, pubertal Tanner stage M4P3, with no dysmorphic features. Laboratory evaluation showed markedly elevated FSH (144 mIU/mL) and LH (38.6 mIU/mL) and low estradiol concentrations (23.2 pg/mL), consistent with POI. Other hormonal parameters were normal, and karyotype was 46,XX. Bone age was compatible with chronological age (13 yrs). Pelvic ultrasound showed a small uterus and non-visualized ovaries. Central nervous system MRI was unremarkable. Genetic analysis identified compound heterozygous LARS2 rare variants: a likely pathogenic frameshift variant (p.Val32*) and a missense variant of uncertain significance (p.Glu413Lys), which has been previously described in association with PS.

Conclusions: The clinical, hormonal, and genetic findings are consistent with the phenotypic spectrum of Perrault syndrome type 4. This case highlights the importance of molecular investigation in patients with sensorineural hearing loss associated with delayed puberty or POI, and reinforces the relevance of LARS2 in genotype–phenotype correlations.

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