ESPE Yearbook of Paediatric Endocrinology

Metabolism 168 (2025) 156256.

Brief Summary: This case report describes endocrine and neurological dysfunction in a male patient with a de novo mutation in FASN (p.Ala2132Val). He displayed hypopituitarism, hypoparathyroidism, sensorineural deafness, retinal dystrophy, developmental delay, and growth failure. This work suggests that perturbing the fatty acid synthase enzyme can disrupt hypothalamo pituitary development and endocrine homeostasis.

This paper from Dattani’s laboratory introduces a human syndrome linking FASN-dependent lipogenesis to pituitary and endocrine system development. This work elegantly bridges metabolism, development, and endocrine dysfunction, positioning FASN as a novel CH-causing gene. They used clinical phenotyping and genetics to present a correlation between a novel FASN variant (FASN p.Ala2132Val) with robust exclusion of many other CH-causing genes in humans. Moreover, they use biochemical assays in fibroblast to demonstrate that FASN p.Ala2132Val markedly reduces the novo lipogenesis to confirm FASN pathogenic impact. They show that FASN is expressed in the HP-axes during human development. The report aligns with rodent studies showing that de novo lipogenesis in neural stem and progenitor cells (NSPCs) is essential for proliferation and brain development. Here, reduced FASN activity disrupted human hypothalamo pituitary development, as evidenced by persistent prepuberty, panhypopituitarism, and lack of growth response. FASN expression in parathyroids and retina neatly explains the co-occurrence of hypoparathyroidism and retinal dystrophy. This supports the notion that lipogenesis is a cross-tissue developmental requirement for normal physiology leading to multi-organ failure.

This study has broader clinical relevance and opens to further research to test if patients with FASN variants have similar presentation to that reported here. Moreover, screening in congenital hypopituitarism cohorts should clarify the prevalence of FASN variants in CH. This study seeds new inquiries into metabolic regulation of endocrine ontogeny and underscores the need to consider metabolic defects in unexplained hypopituitarism. It is poised to reshape our understanding of congenital endocrine disorders and opens avenues for targeted diagnostic and therapeutic strategies.