LARS2-Related perrault syndrome in siblings with 46,XY differences of sex development

Adam AP; O; Peterson A; Yabumoto M; Merguerian P; Adam MP

doi:10.1530/ey.22.6.9

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ESPE Yearbook of Paediatric Endocrinology (2025) 22 6.9 | DOI: 10.1530/ey.22.6.9

ESPEYB25 6. DSD and Gender Incongruence DSD Papers: DSD associated with Rare Mitochondrial Disorders (3 abstracts)

6.9. LARS2-Related perrault syndrome in siblings with 46,XY differences of sex development

Adam AP , O’Sullivan L , Peterson A , Yabumoto M , Merguerian P & Adam MP

Am J Med Genet A. 2025 Mar 22:e64064. doi: 10.1002/ajmg.a.64064

Brief summary: This case report describes 2 brothers with a 46,XY karyotype who exhibit LARS2-related Perrault syndrome, a condition traditionally defined by sensorineural hearing loss and ovarian dysgenesis in 46,XX individuals. The brothers presented with bilateral hearing loss, bilaterally undescended testes, and hypospadias with chordee in the younger brother. Trio exome sequencing identified biallelic pathogenic variants in LARS2, a mitochondrial leucyl-tRNA synthetase gene previously linked to Perrault syndrome. No other genetic variants were found, strongly implicating LARS2 mutations as the cause of both their hearing loss and undervirilized genital phenotype, which extends the phenotypic spectrum of Perrault syndrome to include 46,XY DSD.

The findings suggest that LARS2, being expressed in gonadal tissue, plays a role in testis development or function. Although the full mechanisms remain undefined, defects in mitochondrial translation due to LARS2 dysfunction may impair testicular differentiation, resulting in undervirilization. The authors recommend including LARS2 in the gene panel for DSDs, particularly for 46,XY individuals with hearing loss and mild external genital anomalies.