Endocrine Abstracts

Case history: A 39 year old lady was being investigated and managed for premature ovarian insufficiency (onset aged 29y) associated with an unusual constellation of symptoms. Following normal childhood and pubertal development, she subsequently developed fatigue, multiple gastrointestinal symptoms and was underweight with evidence of weight loss, and a most recent BMI of 17 kg/m². She had previously been reviewed due to marked absence of subcutaneous fat in the lower extremities with acanthosis nigricans. A possible diagnosis of acquired partial lipodystrophy was made, although the cause was unclear (genetic analysis was negative for commoner causes (LMNA, PPARG and PLIN1)). HbA1c was normal but pioglitazone was commenced in view of the marked insulin resistance. She had no other medical problems. She was the oldest child of consanguineous first-cousin parents of Pakistani origin. She had 5 younger siblings. They were all reported to be well apart from one brother who died age 21y, with a history of generalised weakness and failure to thrive throughout childhood.

Investigations: Hormone profile at diagnosis confirmed POI (FSH 81.5 IU/ low oestradiol 40 pmol/l). Autoantibody screen was negative and karyotype was normal (46,XX), with a normal repeat size for FMR1. Ultrasound pelvis demonstrated a thin endometrium and small ovaries. Latest DEXA scan from 2022 showed osteoporosis; T score of -3.4 total hip. Concurrent gastroenterology investigations showed oesophageal dysmotility and severe gastroparesis. Cross-sectional imaging highlighted a 9.9mm angiomyolipoma of the right kidney, prompting MRI head to exclude tuberous sclerosis which incidentally demonstrated symmetrical abnormal diffuse T2/FLAIR hyperintensities in the white matter suggestive of a leukodystrophy.

Management: In light of the diagnostic uncertainty, history of consanguinity and features of leukodystrophy on MRI, she underwent whole genome sequencing which identified homozygosity for the c.559C>T; P.(Gin187*) variant in the thymidine phosphorylase gene (TYMP). This was a novel variant not previously reported in the literature which was considered to be pathogenic and associated with Mitochondrial DNA depletion syndrome 1 (MNGIE type).

Conclusion and points for discussion: Mitochondrial DNA depletion syndrome 1 (MNGIE type) is a rare autosomal recessive progressive degenerative disease. Cardinal features are gastrointestinal dysmotility, cachexia, peripheral neuropathy, ocular signs, hearing loss and leukoencephalopathy. Although there are no reports of POF associated with this disorder in the literature, ovarian function is known to be affected in other mitochondrial conditions, and we postulate that this is the cause of her amenorrhoea.