Six Novel Variants in the MKRN3 Gene Causing Central Precocious Puberty.

Context: Idiopathic central precocious puberty (iCPP) is defined by the premature reactivation of the hypothalamic-pituitary-gonadal axis with normal magnetic resonance imaging scan of the central nervous system, causing the development of secondary sexual characteristics before age 8 years in girls and 9 years in boys. MKRN3 loss of function variants now represent the most common genetic cause of iCPP. Objective: This work aims to document the clinical course of puberty in 8 families harboring pathogenic MKRN3 variants. Methods: This is an observational case series study of patients with CPP due to MKRN3 variants followed in a single center. Results: Genetic analysis of MKRN3 was carried out in 28 unrelated patients with iCPP and a family history of paternal inheritance or no/unavailable maternal inheritance, particularly in case of very early and rapidly evolving CPP. We identified 6 novel and 2 recently described variants in the MKRN3 gene in 9 girls, 1 boy, and their family members. These mutations were all predicted to be deleterious by in silico prediction programs. Conclusion: We have identified 6 novel MKRN3 mutations in children with CPP. An MKRN3 loss of function should be considered after careful history pinpointing paternally inherited CPP. A family segregation study allowed the detection of an MKRN3 variant in 2 young brothers still prepubertal, raising the question of screening and management of asymptomatic prepubertal family members.

Homozygous p.R31H GNRH1 mutation and normosmic congenital hypogonadotropic hypogonadism in a patient and self-limited delayed puberty in his relatives.

Objectives Congenital hypogonadotropic hypogonadism (CHH) is a rare condition resulting from GnRH deficiency. Gonadotropin Releasing Hormone 1 (GNRH1) homozygous mutations are an extremely rare cause of normosmic CHH (nCHH). Most heterozygous individuals are asymptomatic, with the notable exception of individuals heterozygous for a p.R31C GNRH1 mutation. Case presentation The patient is an index case from a consanguineous family, presenting with severe CHH and his parents presenting with late puberty and normal fertility. The index case is homozygous for a p.R31H GNRH1 variant, both parents being heterozygous. The analysis of a panel of genes implicated in CHH does not show any other clinically relevant variant in any other gene tested. Conclusions GNRH1 mutations are a rare cause of nCHH. Five different mutations have been reported so far in homozygous individuals. Most are frameshift in nature but the one reported here causes an amino acid change in the Gonadotropin-releasing hormone (GnRH) decapeptide. Both independently reported patients with the p.R31H mutation are from Turkish origin. The question of the possible role of this mutation in the late puberty of the heterozygous parents needs further documentation. An analogy is made with the heterozygous individuals carrying the p.R31C and displaying partial CHH. No nonreproductive disorder is noted.

ROHHAD(NET) Syndrome: Systematic Review of the Clinical Timeline and Recommendations for Diagnosis and Prognosis.

CONTEXT: Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, autonomic dysregulation and neural crest tumor (ROHHHAD[NET]) is a rare and potentially fatal disease. No specific diagnostic biomarker is currently available, making prompt diagnosis challenging. Since its first definition in 2007, a complete clinical analysis leading to specific diagnosis and follow-up recommendations is still missing. OBJECTIVE: The purpose of this work is to describe the clinical timeline of symptoms of ROHHAD(NET) and propose recommendations for diagnosis and follow-up. DESIGN: We conducted a systematic review of all ROHHAD(NET) case studies and report a new ROHHAD patient with early diagnosis and multidisciplinary care. METHODS: All the articles that meet the definition of ROHHAD(NET) and provide chronological clinical data were reviewed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis individual patient data guidelines. The data were grouped into 7 categories: hypothalamic dysfunction, autonomic dysregulation, hypoventilation, NET, psychiatric symptoms, other clinical manifestations, and outcome. RESULTS: Forty-three individual patient data descriptions were analyzed. The timeline of the disease shows rapid-onset obesity followed shortly by hypothalamic dysfunction. Dysautonomia was reported at a median age of 4.95 years and hypoventilation at 5.33 years, or 2.2 years after the initial obesity. A NET was reported in 56% of the patients, and 70% of these tumors were diagnosed within 2 years after initial weight gain. CONCLUSION: Because early diagnosis improves the clinical management and the prognosis in ROHHAD(NET), this diagnosis should be considered for any child with rapid and early obesity. We propose guidance for systematic follow-up and advise multidisciplinary management with the aim of improving prognosis and life expectancy.