Genetic Variability of -Related Disorders within an Italian Family: Straddling the Line between Kallmann and Waardenburg Syndrome.

INTRODUCTION

Kallmann syndrome (KS) is a genetically heterogeneous developmental disorder that most often manifests hypogonadotropic hypogonadism (HH) and hypo-/anosmia due to early embryonic impairment in the migration of gonadotropin-releasing hormone neurons. (SRY-Box 10; MIM*602229), a key transcriptional activator involved in the development of neural crest cells, has been associated with KS and is identified as one of the causative genes of Waardenburg syndrome (WS).

CASE PRESENTATION

A 28-year-old female patient, who was clinically diagnosed with KS in her childhood, presented with HH and anosmia, mild bilateral sensorineural hearing loss (SNHL), and pigmentation abnormalities. Next-generation sequencing analysis detected a missense heterozygous pathogenic variant (NM_006941.4:c.506C>T) in the proposita and in her mother, whose phenotype included exclusively anosmia and hypopigmented skin patches. The same variant has been described by Pingault et al. [Clin Genet. 2015;88(4):352-9] in a patient with apparently isolated bilateral severe SNHL.

CONCLUSION

Our finding substantiates the extreme phenotypic variability of -related disorders, which range from classical KS and/or WS to contracted endophenotypes that could share a common pathway in the development of neural crest cells and highlights the need for careful evaluation and long-term follow-up of patients, with special focus on atypical/additional and/or late-onset phenotypic traits.