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Male LH-Independent Sexual Precocity in a 3.5-Year-Old Boy Caused by a Somatic Activating Mutation of the LH Receptor in a Leydig Cell Tumor

Department of Hematology/Oncology and Endocrinology, University Children’s Hospital (A.R.-U., H.T.W., K.S.-O., S.T., B.P.H.), 45122 Essen, Germany; University Children’s Hospital (U.M.), 44791 Bochum, Germany; Department of Veterinary Anatomy, Justus Liebig University (M.B.), 35392 Giessen, Germany; and Department of Radiology, University Hospital (J.S.), 45122 Essen, Germany

Address all correspondence and requests for reprints to: Dr. Annette Richter-Unruh, Department of Hematology/Oncology and Endocrinology, University Children’s Hospital Hufelandstrasse 55, 45122 Essen, Germany. E-mail: . annette.richter-unruh{at}uni-essen.de

Abstract

We describe the clinical features of severe sexual precocity in a 3.5-yr-old boy. Hormonal evaluation showed LH-independent T hypersecretion. Initial examination of the adrenals and testes revealed no evidence of congenital adrenal hyperplasia, hCG- or androgen-secreting tumors, or McCune-Albright syndrome. In the coding sequence of the LH receptor gene no activating mutation was found. Spironolactone (5.7 mg/kg·d) and testolactone (40 mg/kg·d) were unsuccessful in suppressing the elevated concentration of T. To further determine the origin of the elevated serum T, a selective venous sampling procedure was planned. However before the sampling procedure, high resolution ultrasound examination showed a small tumor in the left testis, which was removed. Histology proved the tumor to be a Leydig cell adenoma. Sequencing of the tumor LH receptor gene revealed a heterozygous mutation in exon 11 encoding a replacement of aspartic acid at position 578 with histidine, which has been shown to be a constitutively activating mutation.

These findings indicate that in male patients with gonadotropin-independent sexual precocity, the presence of small testicular Leydig cell tumors harboring a somatic mutation of the LH receptor gene should be considered.

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