Clinical and Genetic Characterization of a Constitutional Delay of Growth and Puberty Cohort

Priscila Sales Barroso; Alexander Augusto Lima Jorge; Antonio Marcondes Lerario; Luciana Ribeiro Montenegro; Gabriela Andrade Vasques; Lorena Guimarães Lima Amato; Leticia Ferreira Gontijo Silveira; Berenice Bilharinho Mendonca; Ana Claudia Latronico

doi:10.1159/000504783

Clinical and Genetic Characterization of a Constitutional Delay of Growth and Puberty Cohort

Neuroendocrinology. 2020;110(11-12):959-966. doi: 10.1159/000504783. Epub 2019 Nov 15.

Affiliations

¹ Unidade do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM42, Divisão de Endocrinologia e Metabologia, Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
² Unidade de Endocrinologia Genética, Laboratório de Endocrinologia Celular e Molecular LIM25, Divisão de Endocrinologia e Metabologia, Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil.
³ Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
⁴ Departamento de Clínica Médica, Faculdade de Medicina da Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
⁵ Unidade do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM42, Divisão de Endocrinologia e Metabologia, Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil, anacl@usp.br.

PMID: 31726455
DOI: 10.1159/000504783

Abstract

Introduction: Constitutional delay of growth and puberty (CDGP) is the most prevalent cause of delayed puberty in both sexes. Family history of delayed puberty (2 or more affected members in a family) has been evidenced in 50-75% of patients with CDGP and the inheritance is often consistent with autosomal dominant pattern, with or without complete penetrance. However, the molecular basis of CDGP is not completely understood.

Objective: To characterize the clinical and genetic features of a CDGP cohort.

Methods: Fifty-nine patients with CDGP (48 boys and 11 girls) underwent careful and long-term clinical evaluation. Genetic analysis was performed using a custom DNA target enrichment panel designed to capture 36 known and candidate genes implicated with pubertal development.

Results: All patients had spontaneous or induced pubertal development (transient hormonal therapy) prior to 18 years of age. The mean clinical follow-up time was 46 ± 28 months. Male predominance (81%), short stature (91%), and family history of delayed puberty (59%) were the main clinical features of this CDGP -cohort. Genetic analyses revealed 15 rare heterozygous missense variants in 15 patients with CDGP (25%) in seven different genes (IGSF10, GHSR, CHD7, SPRY4, WDR11, SEMA3A,and IL17RD). IGSF10 and GHSR were the most prevalent affected genes in this group.

Conclusions: Several rare dominant variants in genes implicated with GnRH migration and metabolism were identified in a quarter of the patients with familial or sporadic CDGP, suggesting genetic heterogeneity in this frequent pediatric condition.

Keywords: Delayed puberty; Human genetics; Hypogonadism; Next-generation sequencing; Sexual maturation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Brazil
Child
Female
Follow-Up Studies
Genetic Predisposition to Disease
Genetic Testing
Growth Disorders / diagnosis*
Growth Disorders / genetics*
Humans
Male
Puberty, Delayed / diagnosis*
Puberty, Delayed / genetics*