ESPE Abstracts (2019) 92 P1-281

Virilization of a Girl at Puberty Due to a Unique Translocation of an Abnormal Duplicated Y-Chromosome to a Deleted Chromosome 9 Including the DMRT1 Gene

Stefanie Graf1, Nijas Aliu2, Mazen Zeino3, Christa E. Flueck1

1Department of Pediatrics (Division of Pediatric Endocrinology and Diabetology), Inselspital, Bern University Hospital, University of Bern, Switzerland, Bern, Switzerland. 2Department of Pediatrics (Division of Human Genetics), Inselspital, Bern University Hospital, University of Bern, Switzerland, Bern, Switzerland. 3Department of Pediatric Surgery (Division of Pediatric Urology ), Inselspital, Bern University Hospital, University of Bern, Switzerland, Bern, Switzerland

Background: Virilization at puberty in girls remains a challenge. Several differential diagnoses must be considered including disorders of sex development (DSD) and tumors.

Case Report: We report an 11.5-year-old girl who was referred to our center for progressive cliteromegaly since 6 months. Past medical history was remarkable for prematurity of 36 weeks gestation and for mild ongoing psychomotor delay. At presentation physical exam revealed normal height (P10) with slight disproportions and an overweight with BMI P90. She showed otherwise a normal systems exam and no syndromic features. Pubertal stage was P5, B1-2, A1-2 with rich bodily hair. External genitalia revealed a marked cliteromegaly of 3.5x1.5cm in size, but was otherwise normal looking female. No gonads were palpable. First line investigations revealed normal adrenals and gonads with a prepubertal uterus by ultrasound; no tumor was found. Bone age was normal. Laboratory studies showed a significant androgen excess. LH and FSH were both elevated (FSH>>LH) and E2 undetectable. Second line investigations showed normal adrenals and gonads by MRI. AMH was very low. 24h urine steroid profiling excluded any form of late-onset CAH but confirmed very high excretion of androgen metabolites. ACTH stimulation test showed normal reactivity of adrenals steroids, while dexamethasone test suppressed normally. Karyotype was 45,X.

Objective: 1)How to explain androgen excess in a 45,X girl at puberty? Where is the Y-material hidden? 2) What to do with a suspected androgen secreting gonad in 45,X at puberty?

Methods: Expanded genetic exams in search of a hidden Y-chromosome including cytogenetic SRY-FISH analysis and genomic Array-CGH. Exploration of the gonads by laparotomy and histopathological investigations.

Results: Genetic analysis (Karyotype, FISH and Array-CGH) showed 45,X.ish der(9)t(Y;9)(SRY+) plus a terminal heterozygotedeletion 9p24.3-p23 resulting in a partial monosomy 9p including 49 genes, e.g. the sex gene DMRT1explaining a complete sex reversal phenotype. Given these results, the patient underwent laparoscopic gonadectomy. A dysgenetic gonad was found on the left with normal looking Leydig cells and granular Sertoli cells, but no germ cells. A streak gonad was detected on the right. No signs of malignancy were found.

Conclusions: Virilization at puberty may be more complex than routinely thought. All efforts should be taken to find the underlying cause as ongoing virilization may result in irreversible bodily changes. Repeat and expanded biochemical and genetic workup may be necessary to solve complex cases. Multiple genetic hits can manifest with unique, unsuspected phenotypes.

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