Precocious Puberty in a Boy With Bilateral Leydig Cell Tumors due to a Somatic Gain-of-Function Variant

Chelsi Flippo, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, Maryland 20892, USA.
Vipula Kolli, National Institutes of Health Clinical Center, Bethesda, Maryland 20892, USA.
Melissa Andrew, Division of Endocrinology, Children's National Hospital, Washington, DC 20010, USA.
Seth Berger, Center for Genetic Medicine Research & Rare Disease Institute, Children's National Hospital, Washington, DC 20012, USA.
Tricia Bhatti, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia and The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Alison M. Boyce, Metabolic Bone Disorders Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, USA.
Daniel Casella, Division of Pediatric Urology, Children's National Hospital, Washington, DC 20010, USA.
Michael T. Collins, Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, USA.
Emmanuèle Délot, Center for Genetic Medicine Research, Children's National Research Institute and Department of Genomics and Precision Medicine, George Washington University, Washington, DC 20012, USA.
Joseph Devaney, GeneDx, Gaithersburg, Maryland 20877, USA.
Stephen M. Hewitt, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20814, USA.
Thomas Kolon, Children's Hospital of Philadelphia, Perelman School of Medicine at University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Ashwini Mallappa, National Institutes of Health Clinical Center, Bethesda, Maryland 20892, USA.
Perrin C. White, Division of Pediatric Endocrinology, UT Southwestern Medical Center, Dallas, Texas 75230, USA.
Deborah P. Merke, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, Maryland 20892, USA.
Andrew Dauber, Division of Endocrinology, Children's National Hospital, Washington, DC 20010, USA.

Document Type

Journal Article

Publication Date

10-1-2022

Journal

Journal of the Endocrine Society

Volume

6

Issue

10

DOI

10.1210/jendso/bvac127

Keywords

LHCGR; LHR; Leydig cell tumor; luteinizing hormone-chorionic gonadotropin receptor; precocious puberty

Abstract

Context: Autosomal dominant and rarely de novo gain-of-function variants in the gene are associated with precocious male puberty, while somatic variants have been found in isolated Leydig cell adenomas and Leydig cell hyperplasia. Bilateral diffuse Leydig cell tumor formation in peripheral precocious male puberty has not been reported. Case Description: We present a boy with gonadotropin-independent precocious puberty and rapid virilization beginning in infancy resistant to standard therapy. Treatment with abiraterone in addition to letrozole and bicalutamide proved effective. Bilateral diffuse Leydig cell tumors were identified at age 5 years. Results: Whole-genome sequencing of tumor and blood samples was performed. The patient was confirmed to have bilateral, diffuse Leydig cell tumors harboring the somatic, gain-of-function p.Asp578His variant in the gene. Digital droplet polymerase chain reaction of the variant performed in tumor and blood samples detected low levels of this same variant in the blood. Conclusion: We report a young boy with severe gonadotropin-independent precocious puberty beginning in infancy who developed bilateral diffuse Leydig cell tumors at age 5 years due to a somatic gain-of-function p.Asp578His variant in . The gain-of-function nature of the variant and the developmental timing of the somatic mutation likely play a role in the risk of tumor formation. Abiraterone (a CYP17A1 inhibitor), in combination with an antiandrogen, aromatase inhibitor, and glucocorticoid, appears to be an effective therapy for severe peripheral precocious puberty in boys.

Department

Pediatrics

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