From the Research
Kallmann syndrome is primarily associated with mutations in genes involved in the development and migration of GnRH neurons, with the most common mutations found in the ANOS1 gene, as identified in a recent study 1. The ANOS1 gene, also known as KAL1, is responsible for approximately 10-15% of cases, particularly in males with X-linked inheritance. Other frequently mutated genes include FGFR1, PROKR2, PROK2, CHD7, FGF8, NSMF, and WDR11.
- These mutations disrupt the normal migration of GnRH neurons from the olfactory placode to the hypothalamus during embryonic development, resulting in both hypogonadotropic hypogonadism and anosmia (loss of smell) 2.
- The pattern of inheritance varies depending on the specific gene affected, with X-linked recessive (KAL1), autosomal dominant (FGFR1), and autosomal recessive (PROKR2, PROK2) patterns all observed 3.
- Genetic testing is recommended for diagnosis confirmation and family planning, as the specific mutation can influence treatment approaches and potential associated features such as midline defects, hearing loss, or renal abnormalities that may require additional monitoring 4.
- A recent study identified three novel ANOS1 mutations and two novel FGFR1 variations in Chinese KS families, expanding the spectrum of mutations associated with KS and providing diagnostic evidence for patients who carry the same mutation in the future 1.
- Another study found that mutations in PROKR2 and PROK2 genes can also lead to Kallmann syndrome, with insufficient prokineticin-signaling through PROKR2 resulting in abnormal development of the olfactory system and reproductive axis in man 5.