Double heterozygous PROK2 p.(Ile55Ter)-PROKR2 p.(Arg85Leu) variants: case report of an oligogenic case of congenital hypogonadotropic hypogonadism with anosmia
- Journal
- Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation (Q1)
- Published
- 4 August 2026
- Study design
- Case series / case report
- Evidence level
- Level 4, Very Low (CEBM 4)
- Authors
- Mariela Urrutia, Franco Gino Brunello, Lorena Minaberry, Gabriela Sansó, Lourdes Correa Brito, Romina P Grinspon, et al.
- PMID
- 42550786
- DOI
- 10.1159/sxd/aerag002
Why clinicians should know about it
- Picked for Embryology (paper of the day, 5 August 2026).
Abstract
INTRODUCTION: Delayed puberty in males requires differentiation between self-limited delay and congenital hypogonadotropic hypogonadism (CHH), including Kallmann syndrome (KS). CASE PRESENTATION: We report an adolescent male presenting with delayed puberty and anosmia, consistent with KS. Hormonal evaluation confirmed CHH, and MRI demonstrated olfactory bulb agenesis. Targeted next-generation sequencing identified two heterozygous variants in functionally related genes: a pathogenic nonsense variant in PROK2 and a missense variant in PROKR2 classified as a variant of uncertain significance. Given their ligand-receptor relationship, oligogenic analysis was performed. The variant combination was prioritized as highly likely disease-causing by ORVAL/VarCoPP and further supported by OLIDA-based interpretation, providing objective evidence for digenic inheritance. Parental segregation confirmed trans inheritance. CONCLUSION: To our knowledge, this is the first report with objective support for the high likelihood of the existence of a digenic etiology in a patient with CHH, based on the use of OLIDA, which provides a standardized framework for the interpretation of oligogenic combinations. These findings highlight the contribution of multilocus variation to CHH and underscore the need for standardized approaches to interpret oligogenic mechanisms in clinical practice.
Abstract as published, via PubMed.
For healthcare professionals. The summary is generated by AI from the published abstract, and the evidence level is assigned automatically from the study design on the Oxford CEBM hierarchy. Neither is medical advice. Read the full paper before changing practice.