Novel PNPLA6 Variants: Hypogonadotropic Hypogonadism, Pituitary Hypoplasia, Anosmia, and Cerebellar Atrophy in Siblings
Year: 2025
Type: article
Study design: Case Report
Abstract: Hypogonadotropic hypogonadism can stem from many different genetic factors, and the list of implicated genes keeps expanding. PNPLA6-related disorders encompass a spectrum of neuroendocrine and neurodegenerative conditions arising from pathogenic variants of PNPLA6. Two male siblings, aged 22 and 21 years, presented with delayed puberty and absent secondary sexual characteristics. Both had low serum gonadotropin levels and testosterone levels, consistent with hypogonadotropic hypogonadism. Olfactory testing confirmed severe hyposmia. Magnetic resonance imaging (MRI) of the brain showed severely thinned anterior pituitary and superior cerebellar vermis atrophy in both siblings and asymmetric cerebral hemisphere in one sibling although neither exhibited overt cerebellar dysfunction. Genetic testing identified novel compound heterozygous missense variants in PNPLA6: c.2953G>A (p.Gly985Arg) inherited from the father and c.4046G>A (p.Arg1349Gln) inherited from the mother thus confirming the diagnosis through parental segregation analysis. Treatment with human menopausal gonadotropin (hMG) and human chorionic gonadotropin (hCG) showed a poor response, requiring switch to testosterone therapy. This report underscores PNPLA6 pathogenic variants as a rare genetic cause of hyposmic hypogonadotropic hypogonadism associated with pituitary and cerebellar abnormalities and highlights the importance of awareness for timely diagnosis, genetic counseling, and long-term surveillance for neurodegenerative progression and value of early molecular diagnosis for guiding personalized treatment.
Source: JCEM Case Reports
Language: English
Subfield: Reproductive Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $930
OpenAlex ID: W4417017035