Chiara Guzzetti1, Carla Bizzarri2, Elisa Pisaneschi3, Mafalda Mucciolo3, Emanuele Bellacchio4, Anastasia Ibba1, Letizia Casula1, Antonio Novelli3, Sandro Loche1, Marco Cappa5. 1. Pediatric Endocrine Unit, Pediatric Hospital Microcitemico "Antonio Cao," AO Brotzu, Cagliari, Italy. 2. Endocrinology Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italycarla.bizzarri@opbg.net. 3. Medical Genetics Laboratory, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. 4. Genetic and Rare Diseases, Research Division, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. 5. Endocrinology Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
Abstract
BACKGROUND: The development of gonadotropin-independent (peripheral) precocious puberty in male children with primary adrenal insufficiency (PAI) is consistent with a defect in the genes encoding for the enzymes involved in steroid hormone biosynthesis. METHODS: Two young boys presented with peripheral precocious puberty followed by PAI. In both patients, the analysis of CYP21A2 gene encoding 21-hydroxylase was normal. As a second step, a targeted next-generation sequencing (NGS) was performed in both patients using a customized panel of congenital endocrine disor ders. RESULTS: Case 1 had a new homozygous variant in the CYP11B1 gene (c.1121+5G>A). Mutations of this gene cause congenital adrenal hyperplasia due to 11β-hydroxylase deficiency, an essential enzyme in the cortisol biosynthesis pathway. Case 2 showed a new hemizygous mutation in the NR0B1 gene (c.1091T>G), which encodes for DAX1 (dosage-sensitive sex reversal, adrenal hypoplasia congenita [AHC] and critical region on the X chromosome gene 1). NR0B1 mutations cause X-linked AHC and hypogonadotropic hypogonadism. Pathogenicity prediction software defined both mutations as probably damaging. CONCLUSIONS: Peripheral precocious puberty was the atypical presentation of 2 rare genetic diseases. The use of NGS made the characterization of these 2 cases with similar clinical phenotypes caused by 2 different genetic defects possible.
BACKGROUND: The development of gonadotropin-independent (peripheral) precocious puberty in male children with primary adrenal insufficiency (PAI) is consistent with a defect in the genes encoding for the enzymes involved in steroid hormone biosynthesis. METHODS: Two young boys presented with peripheral precocious puberty followed by PAI. In both patients, the analysis of CYP21A2 gene encoding 21-hydroxylase was normal. As a second step, a targeted next-generation sequencing (NGS) was performed in both patients using a customized panel of congenital endocrine disor ders. RESULTS: Case 1 had a new homozygous variant in the CYP11B1 gene (c.1121+5G>A). Mutations of this gene cause congenital adrenal hyperplasia due to 11β-hydroxylase deficiency, an essential enzyme in the cortisol biosynthesis pathway. Case 2 showed a new hemizygous mutation in the NR0B1 gene (c.1091T>G), which encodes for DAX1 (dosage-sensitive sex reversal, adrenal hypoplasia congenita [AHC] and critical region on the X chromosome gene 1). NR0B1 mutations cause X-linked AHC and hypogonadotropic hypogonadism. Pathogenicity prediction software defined both mutations as probably damaging. CONCLUSIONS: Peripheral precocious puberty was the atypical presentation of 2 rare genetic diseases. The use of NGS made the characterization of these 2 cases with similar clinical phenotypes caused by 2 different genetic defects possible.
Authors: Michelle Cerutti C Vargas; Felipe Scipião Moura; Cecília P Elias; Sara R Carvalho; Nelson Rassi; Ilda S Kunii; Magnus R Dias-da-Silva; Flavia Amanda Costa-Barbosa Journal: BMC Endocr Disord Date: 2020-02-06 Impact factor: 2.763