Patient Demographics
Search for other papers by Rahim Karim Damji in
Google Scholar
PubMed
Department of Biochemistry, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania
Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands
Tanzania Human Genetics Organization, Dar es Salaam, Tanzania
Search for other papers by Mohamed Zahir Alimohamed in
Google Scholar
PubMed
Search for other papers by Hedi L Claahsen-van der Grinten in
Google Scholar
PubMed
Search for other papers by Dineke Westra in
Google Scholar
PubMed
Search for other papers by Ben Hamel in
Google Scholar
PubMed
Summary
Pathogenic variants in the nuclear receptor subfamily 5 group A member 1 gene (NR5A1), which encodes steroidogenic factor 1 (SF1), result in 46,XY and 46,XX differences of sex development (DSD). In 46,XY individuals with a pathogenic variant in the NR5A1 gene a variable phenotype ranging from mild to severe is seen, including adrenal failure, testis dysgenesis, androgen synthesis defects, hypospadias and anorchia with microphallus and infertility. We report the clinical, endocrinological and genetic characteristics of a patient with 46,XY DSD with a novel likely pathogenic missense variant in the NR5A1 gene. A retrospective evaluation of the medical history, physical examination, limited endocrinological laboratory analysis and genetic analysis with DSD gene panel testing was performed. A 1.5-month-old individual was referred with ambiguous genitalia. The karyotype was 46,XY. The endocrinological analyses were within normal male reference including a normal response of cortisol within an adrenocorticotropic hormone test. A novel heterozygous missense variant c.206G>C p.(Arg69Pro) in the NR5A1 gene was detected. This variant was present in mosaic form (~20%) in his unaffected father. Because another missense variant at the same position and other missense variants involving the same highly conserved codon have been reported, we consider this NR5A1 variant in this 46,XY DSD patient as likely pathogenic in accordance with the ACMG/AMP 2015 guidelines causing ambiguous genitalia but no adrenal insufficiency. This variant was inherited from the apparently unaffected mosaic father, which might have implications for the recurrence risk in this family.
Learning points
-
The importance of performing trio (patient and parents) sequencing is crucial in pointing out the origin of inheritance.
-
In a 46,XY differences of sex development patient, a normal adrenal function does not rule out an NR5A1 mutation.
-
With the support of a dedicated overseas institute partnership, we could solve this complex clinical case by molecular diagnosis in a resource-limited setting.
