Objective: Isolated central precocious puberty (CPP) includes sporadic, familial and adoption-related forms, and the characterization of its etiology is challenging. This study investigated the prevalence and clinical characteristics of isolated CPP. Design and Methods: This observational cohort study included all patients (n=395) with CPP included in the database of a single academic pediatric care center over a period of 11.5 years. Results: In total, 332 of the 395 patients (84%) had isolated forms of CPP; the proportion of male patients was lower in this group than for non-isolated CPP (4 vs. 33%, p<0.0001). These patients had sporadic (n = 228, 68.5%), familial (n = 82, 25%) or adoption-related (n= 22, 6.5%) forms. Clinical characteristics at diagnosis were similar between groups, but girls with sporadic CPP were older at referral than those with familial or adoption-related CPP (p<0.02), and birth weight SDS was lower in adopted patients than in those from the sporadic and familial groups (p<0.01). In the 72 families containing patients with familial forms, both recessive and dominant transmissions were observed between first-degree relatives. Potential maternal or paternal transmission was identified in two thirds of the studied families, in similar proportions. An autosomal dominant mode of transmission with low penetrance was suggested by the high proportion of affected parents (33 of the 72 families, 46%). Clinical presentation was similar whatever the mode of inheritance. Conclusion: These findings highlight the need for careful monitoring of the various forms of CPP. Future studies should explore pathophysiological mechanisms, particularly for familial forms.

A few hundred hypothalamic neurons form a complex network that controls reproduction in mammals by secreting gonadotropin-releasing hormone (GnRH). Timely postnatal changes in GnRH secretion are essential for pubertal onset. During the juvenile period, GnRH neurons undergo morphological remodeling, concomitantly achieving an increased responsiveness to kisspeptin, the main secretagogue of GnRH. However, the link between GnRH neuron activity and their morphology remains unknown. Here, we show that brain expression levels of Dmxl2, which encodes the vesicular protein rabconnectin-3α, determine the capacity of GnRH neurons to be activated by kisspeptin and estradiol. We also demonstrate that Dmxl2 expression levels control the pruning of GnRH dendrites, highlighting an unexpected role for a vesicular protein in the maturation of GnRH neuronal network. This effect is mediated by rabconnectin-3α in neurons or glial cells afferent to GnRH neurons. The widespread expression of Dmxl2 in several brain areas raises the intriguing hypothesis that rabconnectin-3α could be involved in the maturation of other neuronal populations.

BackgroundMEGDEL (3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome) syndrome is a mitochondrial disorder associated with recessive mutations in SERAC1.ObjectivesTo report transient neonatal renal findings in MEGDEL syndrome.ResultsThis 7 year-old girl was the first child of consanguineous Turkish parents. She exhibited an acute neonatal deterioration with severe lactic acidosis and liver failure. Initial evaluation revealed massive polyuria and renal failure with 3-methylglutaconic aciduria. Symptoms and biological findings progressively improved with symptomatic treatment but lactic acidosis and high lactate to pyruvate ratio along with 3-methylglutaconic aciduria persisted. At 8 months of age, a subacute neurological degradation occurred with severe hypotonia, dystonia with extrapyramidal movements and failure to thrive. Brain MRI revealed basal ganglia lesions suggestive of Leigh syndrome. At 3 years of age, sensorineural deafness was documented. MEGDEL syndrome was further confirmed by the identification of an already reported homozygous mutation in SERAC1.ConclusionTransient neonatal polyuria and renal failure have not been reported to date in SERAC1 defective patients. Such neonatal kidney findings expand the clinical spectrum of MEGDEL syndrome.