BACKGROUND The onset of puberty is first detected as an increase in pulsatile secretion of gonadotropin-releasing hormone (GnRH). Early activation of the hypothalamic–pituitary–gonadal axis results in central precocious puberty. The timing of pubertal development is driven in part by genetic factors, but only a few, rare molecular defects associated with central precocious puberty have been identified. METHODS We performed whole-exome sequencing in 40 members of 15 families with central precocious puberty. Candidate variants were confirmed with Sanger sequencing. We also performed quantitative real-time polymerase-chain-reaction assays to determine levels of messenger RNA (mRNA) in the hypothalami of mice at different ages. RESULTS We identified four novel heterozygous mutations in MKRN3, the gene encoding makorin RING-finger protein 3, in 5 of the 15 families; both sexes were affected. The mutations included three frameshift mutations, predicted to encode truncated proteins, and one missense mutation, predicted to disrupt protein function. MKRN3 is a paternally expressed, imprinted gene located in the Prader–Willi syndrome critical region (chromosome 15q11–q13). All affected persons inherited the mutations from their fathers, a finding that indicates perfect segregation with the mode of inheritance expected for an imprinted gene. Levels of Mkrn3 mRNA were high in the arcuate nucleus of prepubertal mice, decreased immediately before puberty, and remained low after puberty. CONCLUSIONS Deficiency of MKRN3 causes central precocious puberty in humans. (Funded by the National Institutes of Health and others.)

Findings of increased CIMT, BMI, and SBP in young patients with 21-OHD indicate the need for early identification and intervention regarding cardiovascular risk. Validating these findings might result in improved therapeutic approaches for children with 21-OHD in the future.

RESUMOCom o objetivo de conhecer a estatura final de indivíduos com diabetes mellitus do tipo 1 (DM1) e possíveis fatores intervenientes sobre o crescimento foram avaliados 72 pacientes, diagnosticados na infância ou iní-cio da adolescência. O grupo foi acompanhado no Serviço de Endocrinologia do HC/UFMG. A idade média (±DP) era 21,2±3,2 anos e o tempo de doença 11,9±5,7 anos. A estatura final foi 159,5±8,1cm (escore z= -1,23±1,05), sendo 156,7±6,0cm para o sexo feminino (n= 53) e 167,5±8,2cm para o sexo masculino (n= 19). O escore z foi -1,16±0,99 para o sexo feminino e -1,42±1,25 para o masculino. A estatura final dos pacientes comparada à curva de referência do NCHS mostrou que 88,9% deles se apresentavam, anormalmente, com estatura abaixo da média. Houve, também, redução de 0,5 escore z na estatura final (-1,08±1,23) em relação à estatura do ano de diagnóstico (-0,53±0,77), num subgrupo de 23 pacientes (p= 0,01). Em outro subgrupo (n= 22), 15 apresentavam mau controle metabólico com hemoglobina glicosilada de 13,1±1,0% e sete, controle satisfatório, com hemoglobina glicosilada de 10±0,8%. Houve comprometimento da estatura final desse primeiro grupo (mau controle) em relação ao segundo (escore z= -1,83±0,78 vs. -0,83±1,07; p= 0,02). Concluímos que nossos resultados são compatíveis com prejuízo na estatura final dos pacientes diabéticos avaliados em relação à população geral e parecem estar, também, relacionados ao controle metabólico ruim. ABSTRACTThe final height of 72 patients with DM1 followed in the Endocrine Service at Hospital das Clínicas of Universidade Federal de Minas Gerais was evaluated. DM1 began before puberty was completed. Mean age was 21.2±3.2 years and they had 11.9±5.7 years of disease. Mean final height of the group was 159.5±8.1cm (z score= -1.23±1.05), 156.7± 6.0cm for female (n= 53) and 167.5±8.2cm for male (n= 19). The z scores were -1.16±0.99 for female and -1.42±1.25 for male. The comparison of patients final height curve with that from the NCHS shows that the stature of 88.9% of diabetics was abnormally below the mean reference. A reduction of 0.5 SD was observed in final height (-1.08±1.23) in relation to height at the year of diagnosis (-0.53±0.77) in a subset of 23 patients (p= 0.01). A group with poor metabolic control (n= 15; glycosylated hemoglobin of 13.1±1.0%) showed impaired final height results (z score= -1.83±0.78 vs. -0.83±1.07; p= 0.02) when compared to the better-controlled group (n= 7; glycosylated hemoglobin = 10±0.83%). We conclude that our results support the notion that DM1 has a detrimental effect on the final stature of these patients, which is also related to the status of metabolic control.

Introduction: Loss-of-function mutation of MKRN3 represents the most frequent genetic cause of familial central precocious puberty (CPP). The outcomes of gonadotropin-releasing hormone analog (GnRHa) treatment in CPP patients with MKRN3 defects are unknown. Objective: To describe the clinical and hormonal features of patients with CPP with or without MKRN3 mutations after GnRHa treatment. Anthropometric, metabolic and reproductive parameters were evaluated. Patients and Methods: Twenty-nine female patients with CPP due to loss-of-function mutations in the MKRN3 and 43 female patients with idiopathic CPP were included. Their medical records were retrospectively evaluated for clinical, laboratory, and imaging study, before, during,