ESPE Abstracts

Introduction: Mandibular hypoplasia, Deafness, Progeroid features, Lipodystrophy (MDPL) syndrome is a rare autosomal dominant disorder caused by mutation in POLD1 gene, which encodes the catalytic subunit of the DNA polymerase delta (Polδ) enzyme.

Case: a 6.5-year-old boy presented to the outpatient clinic due to severe thinness (BMI -4.86 SDS, WHO 2006 growth charts). Examination of his medical history revealed normal growth parameters at birth, with little weight gain from the age of 1 and a progressive decline in BMI. Dysmorphic phenotypic traits were identified during clinical assessment: triangular face, thin nose with slightly deviated tip, nasal wings and malar hypoplasia, protruding and folded ears, high and narrow palate, slight retrognathia, drumstick fingers. Limited subcutaneous fat, hypotrophic testes and micropenis were detected. Routine blood tests ruled out major causes of low weight. Given the limited representation of adipose tissue, leptin was measured, revealing normal values (3.0 ng/mL, range 2.7-6.7). The patient started a behavioural and nutritional support plan and gained 3.1 kg in 1 year, reaching a BMI of -2.39 SDS. Notably, fat mass predominantly accumulated in the truncal region, alongside blood exam recorded elevation of non-HDL cholesterol, triglycerides and transaminases. Genetic analysis revealed a de novo mutation in POLD1 gene, confirming the diagnosis of MDPL syndrome. Patient’s mutation consists of a single in-frame codon deletion (c.1812_1814delCTC) resulting in Serine-605 loss, with consequent total impairment of polymerase and proof-reading activity and a mild reduced exonuclease action of Polδ. Despite the first normal value, leptin was subsequently monitored, with progressive decrease.

At 10-years-old, the patient presented elevated gonadotropins (FSH 21.3 mUI/mL, LH 2.4 mUI/mL,) with undetectable testosterone and persistent hypotrophic testes; he underwent GnRH and bHCG stimulation tests, which confirmed a hypergonadotropic hypogonadism state.

Conclusion: as already known, hypoleptinemia causes central hypogonadism by reducing gonadotropin release from hypothalamic-pituitary axis. In our patient, elevated FSH-LH values suggest primary testicular damage as the cause of testicular hypotrophy. Albeit below the reference range, patient’s leptinaemia may be sufficient to maintain hypothalamic-pituitary function, while the impaired Polδ activity may alter testicular development itself. The case highlights the significant dysmetabolic state associated with lipodystrophy. Increased caloric intake resulted in exclusively truncal weight gain, along with elevated non-HDL cholesterol, increased triglycerides and hypertransaminasemia. Lastly, a single normal leptin value does not allow to exclude a diagnosis of lipodystrophy.