ESPE Abstracts

Introduction: Perrault syndrome is a rare autosomal recessive (AR) disorder (<1:1.000.000). Mutations in several genes, including HSD17B4, HARS2, CLPP, LARS2, TWNK, and ERAL1 have been associated with it, reflecting the genetic and clinical heterogeneity of this condition. It is characterized by bilateral mild to severe sensorineural hearing loss (SNHL) in both sexes and gonadal dysgenesis in 46,XX karyotype females. Ovarian dysfunction ranges from underdeveloped, streak, or absent gonads, leading to primary ovarian insufficiency (POI), and presenting as primary amenorrhoea and infertility. Males typically have no reproductive anomalies. Neurological manifestations can also be present with variable severity ranging from learning difficulties, developmental delay, cerebellar ataxia, and motor and sensory peripheral neuropathy.

Case report: We present a 15-year-old female referred to the Paediatric Endocrinology Unit for secondary amenorrhoea. At 2 years old she was diagnosed with bilateral SNHL and treated with cochlear implant. She also presented learning impairment and intellectual disability. Personal and family history was otherwise uneventful. Menarche presented at 12 years old, with irregular menstrual pattern for 7 months followed by amenorrhoea. Marfanoid habitus was noted in the first visit without any other dysmorphic features. Workup confirmed POI: FSH 65.5mUI/mL, LH 16.7mUI/mL, and oestradiol <10pg/mL. Ovaries were not visible in the pelvic ultrasound. As MRI was contraindicated by cochlear implant use, a pelvic CT exhibited small ovaries with atrophic parenchyma. Whole exome sequencing revealed 2 mutations in the LARS2 gene (c.1237G>A; 1987C>T) confirming Perrault Syndrome 4. Segregation studies were performed and both parents were asymptomatic carriers confirming an AR inheritance. Her two male brothers were healthy and without any mutation. She started combined oral oestradiol (2 mg) /dydrogesterone (10 mg), followed by menstrual cycle regularization, and normalization of gonadotropins and oestradiol values. However, uterus dimensions remained similar 10 months after therapy (61x35x24mm). She keeps her multidisciplinary follow-up in Endocrinology, Gynecology, Neurology, Psychology, and ENT.

Discussion: Perrault Syndrome is a rare condition affecting female patients in higher proportion (2:1). Nevertheless, it is probably underdiagnosed, especially in males where the presentation is less evident for the absence of testicular dysgenesis. In females, prognosis depends on clinical severity and the effectiveness of supportive interventions. However, infertility is common due to POI. Treatment includes hormone replacement therapy for symptom control, and in the future, if desired it requires medically assisted procreation. Regular audiological assessments are essential for hearing management. Given its hereditary nature, genetic counseling is advised for both affected individuals and their families.