ESPE Abstracts (2014) 82 P-D-3-2-969

A Challenging Diagnosis in Three 46,XY Females from Two Related Families

Raffaella Di Masea, Nicola Improdaa, Manuela Cerbonea, Lucia De Martinoa, Donatella Capalboa, Lilia Baldazzib & Mariacarolina Salernoa


aDepartment of Medical Traslational Sciences, Federico II University, Naples, Italy; bDepartment of Gynaecologic, Obstetric and Paediatric Sciences, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy


Background: Mutations in the 17β-hydroxysteroid dehydrogenase (17βHSD 3) result in 46,XY disorder of sex development (DSD). Biochemical hallmark of 17βHSD 3 deficiency is a Testosterone/Androstenedione ratio (T/A ratio) <0.8. 17βHSD 3 mutations have been associated with a wide spectrum of phenotypes, ranging from under-virilized male to a female appearance of genitalia at birth. Indeed, 17βHSD 3 deficiency in prepubertal patients is often clinically indistinguishable from androgen insensitivity syndrome (AIS) and its diagnosis can be extremely challenging.

Objective and hypotheses: Three females from the same pedigree (two siblings and their first cousin) were suspected to be affected by 46,XY DSD because of clitoromegaly and inguinal masses.

Method: Basal and dynamic hormonal assessment as well as genetic tests have been performed in all subjects.

Results: The two sisters were admitted at the age of 2 and 6 years respectively, their cousin at the age of 10 years. Their karyotype was 46,XY. They were suspected to be affected by androgen insensitivity and thus they underwent gonadectomy. Molecular analysis of androgen receptor gene did not reveal any mutation. A low T/A ratio (<0.8) in one of the patient raised the suspicion of 17βHSD 3 deficiency. Molecular analysis of the HSD17B3 gene (which encodes for the 17βHSD 3 enzyme) revealed a compound heterozygous mutation in all three girls. The two sisters inherited a novel mutation IVS3+1 G<T from the mother and the rare mutation IVS3-1 G<C from their father. Their cousin inherited the RW80 mutation from the father and IVS3-1 G<C from the mother.

Conclusion: Our cases suggest that 17βHSD 3 deficiency should be considered in 46,XY DSD cases with female appearance of external genitalia. Moreover, we reported a novel mutation of 17βHSD 3, causing 46,XY DSD in two out of three related subjects.

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