Pioneering studies on monogenic central precocious puberty

ABSTRACT Pubertal timing in humans is determined by complex interactions including hormonal, metabolic, environmental, ethnic, and genetic factors. Central precocious puberty (CPP) is defined as the premature reactivation of the hypothalamic-pituitary-gonadal axis, starting before the ages of 8 and 9 years in girls and boys, respectively; familial CPP is defined by the occurrence of CPP in two or more family members. Pioneering studies have evidenced the participation of genetic factors in pubertal timing, mainly identifying genetic causes of CPP in sporadic and familial cases. In this context, rare activating mutations were identified in genes of the kisspeptin excitatory pathway (KISS1R and KISS1 mutations). More recently, loss-of-function mutations in two imprinted genes (MKRN3 and DLK1) have been identified as important causes of familial CPP, describing novel players in the modulation of the hypothalamic-pituitary-gonadal axis in physiological and pathological conditions. MKRN3 mutations are the most common cause of familial CPP, and patients with MKRN3 mutations present clinical features indistinguishable from idiopathic CPP. Meanwhile, adult patients with DLK1 mutations present high frequency of metabolic alterations (overweight/obesity, early onset type 2 diabetes and hyperlipidemia), indicating that DLK1 may be a novel link between reproduction and metabolism. Arch Endocrinol Metab. 2019;63(4):438-44

Variações no número de cópias cromossômicas submicroscópicas como causa de baixa estatura de início pré-natal / Submicroscopic chromosomal copy number variants as a cause of prenatal onset short stature

A pesquisa de variações no número de cópias (CNVs; copy number variants) cromossômicas tem revelado o importante papel destas alterações genômicas na diversidade populacional e na etiologia de doenças humanas. O modelo de associação de CNVs a doenças envolve deleções e/ou duplicações individualmente raras, mas com segmentos cromossômicos de tamanhos relevantes. Os pacientes com baixa estatura de início pré-natal constituem um grupo heterogêneo com quadros clínicos complexos frequentemente resultantes de alterações genéticas, que, desde o período intrauterino, perturbam os mecanismos e vias de desenvolvimento e crescimento fetais. Assim sendo, aventamos a hipótese de que CNVs raras possam estar entre as causas genéticas de baixa estatura de início prénatal. Para tanto, nosso estudo visou avaliar a presença de deleções ou duplicações submicroscópicas em um grupo selecionado de pacientes nascidos pequenos para idade gestacional (PIG) com baixa estatura persistente sem causa definida. Foram avaliados 51 pacientes nascidos PIG com baixa estatura persistente após o 4º ano de vida que apresentavam dismorfismos, atraso de desenvolvimento neuropsicomotor (DNPM) ou deficiência intelectual, porém sem caracterizar síndromes conhecidas e com cariótipo normal. Amostras de DNA dos pacientes foram submetidas à hibridização genômica comparativa por microarray (aCGH; array comparative genomic hybridization) baseada em oligonucleotídeos na plataforma 60K. Os achados foram comparados com CNVs descritas em bancos de dados de controles normais. Foram identificadas 18 CNVs, ausentes em controles saudáveis, em 17 dos 51 pacientes (33%). As alterações foram avaliadas para classificação de sua patogenicidade de acordo com os seguintes critérios: 1) padrão de herança e segregação familiar; 2) sobreposição a coordenadas genômicas de síndromes conhecidas; 3) sobreposição a CNVs patogênicas descritas em banco de dados; 4) e conteúdo gênico. Quatro CNVs, encontradas em 3 pacientes, foram...

Analysis of chromosomic copy number variants (CNVs) have demonstrated the important role of these genomic imbalances in population diversity and human disease. The model of CNV disease association involves deletions and/or duplications that are individually rare but encompass chromosomal segments of relevant size. Prenatal onset short stature patients constitute a complex group characterized by clinical heterogeneity. The causes of prenatal growth impairment frequently involve genetic changes that disturb the mechanisms and the pathways of fetal growth and development. Thus, we hipothesized that rare CNVs might contribute to the genetic etiology of prenatal onset short stature. In order to evaluate this assumption, our study analyzed the presence of submicroscopic deletions and/or duplications in a selected group of patients born small for gestational age with persistent short stature but without a recognized cause. A total of 51 patients with prenatal and postnatal growth retardation associated with dysmorphic features, developmental delay and/or intellectual disability, but without criteria for known syndromes, were selected. All patients had normal G-banded karyotyping. Array-based comparative genomic hybridization (aCGH) in a whole-genome 60K platform was performed using DNA obtained from all patients. Detected CNVs were compared with CNV data from healthy controls individuals, excluding common copy number polymorphisms. In 17 of the 51 patients screened (33%), 18 rare CNVs were identified. The pathogenicity of CNVs was assessed by considering the following criteria: inheritance and familial segregation; overlap with genomic coordinates for a known genomic imbalance syndrome; overlap with CNVs previously identified in other patients with prenatal onset short stature; and gene content. Four distinct CNVs, found in three patients, were classified as pathogenic: 1) del 22q11.21; 2) dup 10q26.2-26.3 and del 10q26.3; and 3) del 4q28.2-q31.21. Five CNVs, found...

Mutações no gene do receptor do fator de crescimento insulina-símile 1 (IGF1R) como causa de retardo do crescimento pré- e pós-natal / Mutations in insulin-like growth factor receptor 1 gene (IGF1R) resulting in intrauterine and postnatal growth retardation

Aproximadamente 10 por cento das crianças nascidas pequenas para a idade gestacional (PIGs) não apresentam recuperação espontânea do crescimento. As causas desse déficit de crescimento pré-natal e sua manutenção após o nascimento ainda não são completamente conhecidas na maioria dos casos. Nos últimos oito anos, diversas mutações inativadoras e deleções do gene IGF1R em heterozigose foram relatadas, indicando o papel de defeitos no eixo IGFs/IGF1R como causa do déficit de crescimento. Postula-se que pelo menos 2,5 por cento das crianças nascidas PIGs possam apresentar defeitos no gene IGF1R. O quadro clínico desses pacientes apresenta grande variabilidade quanto à gravidade do retardo de crescimento e aos parâmetros hormonais. Nos casos mais evidentes, os pacientes apresentam microcefalia, déficit cognitivo leve e valores elevados de IGF-1, associados à baixa estatura de início pré-natal. Esta revisão abordará os aspectos clínicos, moleculares e do tratamento da baixa estatura com hrGH de crianças com mutações no IGF1R.

Approximately 10 percent of children born small-for-gestational age (SGA) do not show spontaneous growth catch-up. The causes of this deficit in prenatal growth and its maintenance after birth are not completely known, in most cases. Over the past eight years, several heterozygous inactivating mutations and deletions in IGF1R gene have been reported, indicating the role of defects in the IGFs/IGF1R axis as a cause of growth deficit. It has been hypothesized that at least 2.5 percent of children born SGA may have IGF1R gene defects. The clinical presentation of these patients is highly variable in the severity of growth retardation and hormonal parameters. In the most evident cases, patients have microcephaly, mild cognitive impairment and high levels of IGF-1, associated with short stature of prenatal onset. This review will describe the clinical, molecular and treatment of short stature with hrGH of children with mutations in the IGF1R gene.