Endocrine Abstracts

JOINT2090

Background: Combined Oxidative Phosphorylation Deficiency 55 (COXPD55) is a rare mitochondrial disorder caused by mutations in the POLRMT gene, which encodes the mitochondrial RNA polymerase critical for mitochondrial gene expression and genome replication.

Case Presentation: A 17.3-year-old female presented with primary amenorrhea and a reportedly absent uterus. Anthropometric assessment indicated a height SDS of -5.31, weight SDS of -4.67, BMI SDS of -0.93, occipitofrontal circumference of 48 cm (-6.86 SD), and sitting height of 65.9 cm (-5.64 SD). She also exhibited delayed bone age (10.99 years, SDS -6.5) and minimal pubertal development (Tanner stage B2). Notable phenotypic features included microcephaly, alacrima, corneal scarring, learning difficulties, scant scalp hair, low posterior hairline, hypotelorism, hyperconvex nails, and a high-arched palate with a narrow jaw.

Endocrine Evaluation: The patient exhibited hypogonadotropic hypogonadism with low FSH (0.4 mIU/mL; Ref: 0.9-9.1) and LH (<0.3 mIU/mL; Ref: 0.4 - 25) and profoundly reduced estradiol (<18 pmol/l; Ref: 22.3 - 205.2). Thyroid function tests and cortisol levels were within normal limits. IGF-1 and IGFBP-3 were within reference ranges, at 303.0 ng/mL (Ref: 156 - 479) and 4,207 ng/mL (Ref: 3,705 - 8,065), respectively. DHEA-Sulfate was 7.79 umol/l (Ref: 1.77 - 9.99). Anti-Müllerian hormone was diminished at 0.45 ng/mL. Magnetic resonance imaging initially suggested an absent uterus, but ultrasound confirmed an infantile uterus.

Genetic Analysis: Whole exome sequencing identified a pathogenic POLRMT mutation (c.910C>T, p.Gln304Ter, NM_005035.4). The patient was heterozygous, with maternal heterozygosity and negative paternal testing. Inheritance involved both autosomal recessive and dominant patterns, with the mutation classified as likely pathogenic.

Discussion: Prior COXPD55 cases highlight developmental delay, renal dysfunction, and neuromuscular abnormalities. Bowden et al. (2013) described renal Fanconi syndrome with developmental delay and hypotonia, while Olahova et al. (2021) reported heterogeneous presentations among 8 patients, including short stature, developmental delay, and eye abnormalities, suggesting the phenotypic variability of COXPD55. However, delayed puberty as the primary clinical manifestation has not been previously reported.

Conclusion: This case is the first to document COXPD55 presenting primarily with delayed puberty and hypogonadotropic hypogonadism, expanding the clinical spectrum of the disorder. The diverse clinical manifestations underscore the importance of early genetic evaluation to facilitate accurate diagnosis and individualized therapeutic interventions.