Endocrine Abstracts

Background: POLR3-related leukodystrophy is an autosomal recessive hypo-myelinating leukodystrophy characterized by specific features on MRI and varying combinations of four major clinical findings¹. The latter include neurological dysfunction, abnormal dentition, endocrine dysfunction, and myopia¹. Endocrine dysfunction in POLR3-related leukodystrophy includes hypogonadotropic-hypogonadism (HH), short stature, growth hormone deficiency, and less commonly thyroid dysfunction.

Case report: A 27-year-old lady recently diagnosed with POLR3B-related leukodystrophy was referred to endocrinology to screen for endocrine dysfunction. She gave a longstanding history of ataxia, myopia, and delayed puberty. During childhood and adolescence, she had a short stature compared to her peers. She had very minimal breast development and never had spontaneous menstrual bleeding. She was reviewed by several healthcare professionals and was prescribed the combined oral contraceptive pill (COCP). This led to a growth spurt but had to be discontinued because of worsening mental state. At the time of review, she had been off the COCP for four years. She complained of frequent episodes of hot flushes and sweating. She also sustained nontraumatic vertebral fractures. She denied hyposmia or anosmia. She had a stable weight and appetite. She denied galactorrhoea and was on no medications. On physical examination, she was at Tanner Stage 2. She had grossly normal visual fields to confrontation. Laboratory investigations revealed FSH of 4.5IU/l and LH of 2.9IU/l with an oestradiol of <91.8 pmol/l, indicating HH. The rest of her pituitary profile including IGF-1 level was unremarkable. A DEXA scan revealed normal bone density. An MRI head showed atrophic cerebellar hemispheres and a low-volume pituitary gland. Transvaginal ultrasound had previously shown no abnormal anatomic disorders of the genital outflow tract. DNA sequencing performed previously revealed that she is a compound heterozygote for POLR3B mutations, specifically c.1244T>C (p. Met415Thr) and c.1263+2T>C. The patient was prescribed low-dose transdermal oestradiol (escalating dose) and progesterone soon after, to enhance the development of secondary sexual characteristics.

Discussion: The differential diagnosis of patients presenting with a combination of neurodegenerative disorders and HH is extensive. This case highlights the importance of maintaining a high level of clinical suspicion for the diagnosis of POLR3–related leukodystrophy in patients presenting with delayed/arrested puberty, particularly in the presence of concurrent cerebellar manifestations. Early diagnosis and timely management can improve the patient’s quality of life and avoid complications of untreated hypogonadism.

Reference: 1. Bernard G, et al. POLR3-Related Leukodystrophy. 2012 Aug 2 [updated 2017 May11]. In: Adam MP et al. GeneReviews®. University of Washington, Seattle; 1993–2023. PMID:22855961.