Evaluation of postoperative fluctuations in plasma sodium concentration and triphasic response after pediatric craniopharyngioma resection: A French cohort study.

INTRODUCTION: Disturbances in plasma sodium levels are a major complication following recent resections of craniopharyngiomas in children. They must be properly managed to avoid neurological sequelae. We aimed to describe the variations and characteristics of postoperative natremia in children who had undergone a first craniopharyngioma resection with a particular focus on the frequency of triphasic syndrome in these patients. METHODS: Paediatric patients with craniopharyngiomas who underwent a first surgical resection in the neurosurgery department of the Hôpital Femme Mère Enfant (Lyon, France) between January 2010 and September 2021 were included in the present study and the medical records were analysed retrospectively. RESULTS: A total of 26 patients were included. Of these, 17 (65.4%) had a postoperative course characterised by the occurrence of both initial diabetes insipidus (DI) and hyponatremia a few days later. Eight patients (30.8%) presented then with isolated and persistent DI. Patients with the triphasic syndrome had a significantly higher grade of Puget classification on MRI (1 and 2), compared to the other patients. CONCLUSION: Dysnatremia is common after craniopharyngioma resections in children. This immediate postoperative complication is particularly difficult to manage and requires rapid diagnosis and prompt initiation of medical treatment to minimize fluctuations in sodium levels and avoid neurological sequelae.

Diagnosis and management of congenital hypopituitarism in children.

Hypopituitarism (or pituitary deficiency) is a rare disease with an estimated prevalence of between 1/16,000 and 1/26,000 individuals, defined by insufficient production of one or several anterior pituitary hormones (growth hormone [GH], thyroid-stimulating hormone [TSH], adrenocorticotropic hormone [ACTH], luteinizing hormone [LH], follicle-stimulating hormone [FSH], prolactin), in association or not with diabetes insipidus (antidiuretic hormone [ADH] deficiency). While in adults hypopituitarism is mostly an acquired disease (tumors, irradiation), in children it is most often a congenital condition, due to abnormal pituitary development. Clinical symptoms vary considerably from isolated to combined deficiencies and between syndromic and non-syndromic forms. Early signs are non-specific but should not be overlooked. Diagnosis is based on a combination of clinical, laboratory (testing of all hormonal axes), imaging (brain magnetic resonance imaging [MRI] with thin slices centered on the hypothalamic-pituitary region), and genetic (next-generation sequencing of genes involved in pituitary development, array-based comparative genomic hybridization, and/or genomic analysis) findings. Early brain MRI is crucial in neonates or in cases of severe hormone deficiency for differential diagnosis and to inform syndrome workup. This article presents recommendations for hormone replacement therapy for each of the respective deficient axes. Lifelong follow-up with an endocrinologist is required, including in adulthood, with multidisciplinary management for patients with syndromic forms or comorbidities. Treatment objectives include alleviating symptoms, preventing comorbidities and acute complications, and optimal social and educational integration.

Urinary gonadotropin assay on 24-h collections as a tool to detect early central puberty onset in girls: determination of predictive thresholds.

STUDY QUESTION: Is the 24-h urinary gonadotropin assay an effective diagnostic tool in central precocious puberty (CPP) in girls? SUMMARY ANSWER: This study is the first to provide 24-h urinary gonadotropin assay data, using an electrochemiluminescent immunoassay (CMIA), and to report its usefulness as a tool for the diagnosis of CPP. WHAT IS KNOWN ALREADY: Data about the GnRH test in the diagnosis of CPP are variable and there is no consensus regarding its interpretation. The measurement of FSH and LH in urines was previously reported to be an alternative biological tool. STUDY DESIGN, SIZE, DURATION: This is a retrospective two-cohort study, involving a setting and a validation cohort. A total of 516 girls, included between October 2012 and July 2015, and 632 urinary collections were analyzed in the setting cohort. In the validation cohort, 39 girls were included between January 2021 and May 2023, and 49 urinary collections were analyzed. PARTICIPANTS/MATERIALS, SETTING, METHODS: This study included girls who consulted for an investigation of disturbed growth rate or a clinical suspicion of puberty onset in different medical centres across France (setting cohort). Girls with a suspicion of precocious puberty onset were addressed at the expert centre of paediatric endocrinology of the Groupement Hospitalier Lyon Est (validation cohort). Pelvic ultrasonography was performed and enabled their classification according to clinical and morphologic changes criteria (prepubertal or pubertal groups). The parents collected 24-h urine samples (u24) according to standardized instructions. FSH and LH (urinary or plasmatic) were measured using a current and automated CMIA. MAIN RESULTS AND THE ROLE OF CHANCE: The area under the ROC curves for CPP prediction was 0.709 for u24FSH (P < 0.001), 0.767 for u24LH (P < 0.001), and 0.753 for the u24LH/u24FSH ratio (P < 0.001). We retained all possible combinations of the four thresholds in the validation cohort (u24FSH = 1.1 or 2.0 IU/24 h; u24LH = 0.035 or 0.08 IU/24 h). The combination of u24FSH > 1.1 IU/24 h and u24LH > 0.08 IU/24 h had a positive PV of 85.7% and a negative PV of 94.3%, a sensitivity of 85.7% and a specificity of 94.3%, for classifying prepubertal and pubertal girls in this cohort. LIMITATIONS, REASONS FOR CAUTION: This is a retrospective study, in which a margin of error remains due to the inherent uncertainty regarding the clinical assessment of pubertal onset. It must be considered that the thresholds can only apply to the used reagents; measurements without extractions using other reagents are likely to show important heterogeneity. WIDER IMPLICATIONS OF THE FINDINGS: The assay performed herein is a simple, non-invasive, and analytically robust technique meeting the criteria for an alternative to the GnRH test which could be used to supplement its lack of sensitivity. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was used. All authors declared no conflict of interest. TRIAL REGISTRATION NUMBER: In-house #23-5214 registered study.

Ciliopathy due to POC1A deficiency: clinical and metabolic features, and cellular modeling.

OBJECTIVE: SOFT syndrome (MIM#614813), denoting Short stature, Onychodysplasia, Facial dysmorphism, and hypoTrichosis, is a rare primordial dwarfism syndrome caused by biallelic variants in POC1A, encoding a centriolar protein. SOFT syndrome, characterized by severe growth failure of prenatal onset and dysmorphic features, was recently associated with insulin resistance. This study aims to further explore its endocrinological features and pathophysiological mechanisms. DESIGN/METHODS: We present clinical, biochemical, and genetic features of 2 unrelated patients carrying biallelic pathogenic POC1A variants. Cellular models of the disease were generated using patients' fibroblasts and POC1A-deleted human adipose stem cells. RESULTS: Both patients present with clinical features of SOFT syndrome, along with hyperinsulinemia, diabetes or glucose intolerance, hypertriglyceridemia, liver steatosis, and central fat distribution. They also display resistance to the effects of IGF-1. Cellular studies show that the lack of POC1A protein expression impairs ciliogenesis and adipocyte differentiation, induces cellular senescence, and leads to resistance to insulin and IGF-1. An altered subcellular localization of insulin receptors and, to a lesser extent, IGF1 receptors could also contribute to resistance to insulin and IGF1. CONCLUSIONS: Severe growth retardation, IGF-1 resistance, and centripetal fat repartition associated with insulin resistance-related metabolic abnormalities should be considered as typical features of SOFT syndrome caused by biallelic POC1A null variants. Adipocyte dysfunction and cellular senescence likely contribute to the metabolic consequences of POC1A deficiency. SOFT syndrome should be included within the group of monogenic ciliopathies with metabolic and adipose tissue involvement, which already encompasses Bardet-Biedl and Alström syndromes.

Metabolic disturbances in children with narcolepsy: a retrospective study.

STUDY OBJECTIVES: To determine the prevalence of metabolic syndrome (MS) in children with narcolepsy and to evaluate their clinical and sleep characteristics according to the different components of MS. METHODS: This retrospective study consisted of 58 de novo children with narcolepsy (median age: 12.7 years, 48.3% of boys). The recently published MS criteria in a French population of children were used. Clinical and sleep characteristics were compared between groups with different components of MS. RESULTS: MS was present in 17.2% of children with narcolepsy, among whom 79.3% presented with high homeostasis model assessment for insulin resistance (HOMA-IR), 25.9% with high body mass index, 24.1% with low high-density lipoprotein cholesterol (HDL-C), and 12.1% with high triglycerides. Patients with at least two MS components had more night eating behaviors and tended to have lower percentage of slow-wave sleep and more fragmented sleep. On multiple sleep latency test, they had shorter mean sleep latencies to rapid eye movement (REM), non-REM sleep and tended to have more sleep onset REM periods (SOREMPs) than those with less than two MS components. CONCLUSIONS: Insulin resistance was found to be the core metabolic disturbance in obese as well as in nonobese children with narcolepsy. Children with narcolepsy with at least two MS components presented a more severe daytime sleepiness and a higher prevalence of night-eating behaviors than those with less than two MS components. Such children might benefit from early evaluation and management in order to prevent future complications.

Obesity in children with narcolepsy: metabolic and endocrine comorbidities.

STUDY OBJECTIVES: Narcolepsy with cataplexy is associated with obesity in children. We proposed to assess whether metabolic complications were linked to narcolepsy regardless of obesity. The second aim of the study was to compare endocrine comorbidities in obese children with narcolepsy and control patients. METHODS: We performed a case-control study in Pediatric Sleep Unit and Pediatric Endocrinology Unit of Woman Mother Child Hospital (Lyon, France) comparing 22 children with narcolepsy with 22 sex-, pubertal stage-, and BMI-matched non-syndromic obese patients. Clinical examination, biological measurements including an oral glucose tolerance test, and abdominal ultrasound were performed. RESULTS: No difference regarding glucidic, lipid profile, hepatic, respiratory, and cardiovascular parameters were found between narcoleptic and control participants. Insulin sensitivity did not differ between the two groups. Control patients had more first-degree family history of overweight or obesity than children with narcolepsy (83% vs. 50%, p = .05). Prevalence of precocious puberty in children with narcolepsy was not higher than in control participants, but all the cases of advanced puberty involved children with narcolepsy who were diagnosed before 11 years old. All cases of central hypothyroidism belong to the narcoleptic group, who presented lower thyroid-stimulating hormone and fTA values compared to control children (respectively p = .03 and p = .001). CONCLUSIONS: No difference regarding metabolic complications was found between children with narcolepsy and control participants. Thus, metabolic disorders may be related to weight gain rather than a narcolepsy-specific risk. The presence of hypothyroidism and advanced puberty suggests a global involvement of hypothalamic structures in children with narcolepsy.

Characterization of rapid weight gain phenotype in children with narcolepsy.

OBJECTIVES: To characterize the rapid weight gain (RWG) phenotype associated with the onset of childhood narcolepsy and to determine whether it could constitute a marker of severity of the disease. METHODS: RWG was defined using the BMI z-score slope reported to one year (>0.67 SD) from symptom onset to disease diagnosis. We compared the clinical, metabolic, and sleep characteristics between patients with or without RWG at diagnosis. Pharmacological management, anthropometric, and clinical progression were also evaluated during the follow-up. RESULTS: A total of 84 de novo narcoleptic pediatric patients were included; their median age at diagnosis was 12.0 years; 59.5% boys, 90.5% cataplexy, and 98.7% HLA-DQB1*06:02, 57% had RWG profile. RWG patients were younger at diagnosis than non-RWG patients, despite a shorter diagnostic delay. They had a higher BMI z-score and a higher prevalence of obesity at diagnosis, but not at symptom onset, and higher adapted Epworth Sleepiness Scale and Insomnia Severity Index scores than non-RWG patients. No differences on nocturnal polysomnography and multiple sleep latency tests were found between groups at disease diagnosis. After a median follow-up of 5 years, RWG patients still had a higher BMI z-score and a higher prevalence of obesity despite benefiting from the same therapeutic management and displaying improvement in sleepiness and school difficulties. CONCLUSIONS: Narcoleptic RWG patients were younger, sleepier, and the prevalence of obesity was higher at diagnosis despite a shorter diagnostic delay than that of non-RWG patients. These patients had also a higher risk of developing a long-term obesity, despite a positive progression of their narcoleptic symptoms. RGW could then represent a maker of a more severe phenotype of childhood narcolepsy, which should inspire a prompt and more offensive management to prevent obesity and its complications.

Growth Hormone Replacement Therapy Seems to Be Safe in Children with Low-Grade Midline Glioma: A Series of 124 Cases with Review of the Literature.

There is little scientific evidence regarding the safety of GHRT in LGG, where GH deficiency is common. PURPOSE: to compare the recurrence rate in children with midline LGG, depending on whether or not they have received GHRT, in order to assess its impact on the risk of tumor recurrence. METHODS: This bicentric retrospective study included 124 patients under the age of 18 who were diagnosed with a midline low-grade glial tumor between 1998 and 2016. We also reviewed literature on this subject. The main outcome measure was tumor relapse, demonstrated by brain MRI. RESULTS: There were 17 patients in the GH-supplemented group (14%) and 107 patients in the non-supplemented group (86%). Relapse occurred in 65 patients (45.5%); 7 patients died (4.9%); no deaths occurred in patients receiving GHRT. Two patients developed a second tumor (1.4%), none of which had received GHRT. Relapse concerned 36.4% of patients without GHRT and 52.9% of patients with GHRT. The difference was not statistically significant between the two groups (p = 0.3). CONCLUSION: GHRT does not lead to a statistically significant increase in risk of relapse for pediatric midline low-grade pediatric glioma in our cohort. Although these results appear reassuring, future natural history or prospective studies should be done to ascertain these findings. Nevertheless, these reassuring data regarding GHRT are in agreement with the data in the current literature.

Reference values for the external genitalia of full-term and pre-term female neonates.

BACKGROUND AND OBJECTIVES: Identifying virilisation of the genitalia in female newborns early during the neonatal period is important to diagnose pathologies. However, there is no clear threshold for clitoromegaly or for the anogenital ratio. The objective of this study was to define reference values for the external genitalia of full-term and pre-term female neonates. DESIGN: This was a prospective study of all females born in the study centre between May 2014 and July 2016. Clitoral length and anogenital ratio were measured in 619 newborns with a gestational age of 24+2 to 41+3 weeks during their first 3 days of life. Associations between the values at day 3 and gestational age, birth weight and other newborn characteristics were examined by linear regression. RESULTS: The mean clitoral length at day 3 of life was 3.69±1.53 mm (n=551; 95th percentile, 6.5 mm; maximum, 8 mm), and the mean anogenital ratio was 0.42±0.09 (95th percentile, 0.58). There was no significant variation with gestational age or birth weight, and no significant difference between the results at day 0 and day 3. CONCLUSION: These results suggest that clitoromegaly can be defined as a clitoral length >6.5 mm. Values ≥8 mm should prompt further investigations. An anogenital ratio >0.6 should be considered a sign of virilisation. Since clitoral size does not vary with gestational age or birth weight, clitoromegaly should not be attributed to prematurity.

Intrauterine Growth Restriction and Hypertrophic Cardiomyopathy as Prenatal Ultrasound Findings in a Case of Leprechaunism.

Donohue syndrome (leprechaunism; OMIM *246200) is a rare and often lethal autosomal recessive disease caused by mutations in the INSR gene. We report the case of a 29-year-old pregnant woman, primigravida, who was referred at 33 weeks of gestation for severe intrauterine growth restriction (IUGR). Ultrasound examination found severe IUGR associated with an obstructive hypertrophic cardiomyopathy (HCM), confirmed postnatally. The newborn's blood glucose level fluctuated from fasting hypoglycemia to postprandial hyperglycemia. The infant was found to be homozygous for a novel missense pathogenic variant, c.632C>T (p.T211l), in exon 2 of the INSR gene, predicted to result in an abnormal insulin receptor. To our knowledge, this is the first report of leprechaunism being revealed by IUGR and HCM during the prenatal period. Clinicians should keep in mind that the association of these prenatal signs could indicate leprechaunism and specific early neonatal management could be proposed, in particular with recombinant human insulin-like growth factor-I.

Narcolepsy with cataplexy: Does age at diagnosis change the clinical picture?

OBJECTIVE: To compare symptoms and sleep characteristics in patients diagnosed with narcolepsy-cataplexy (NC) before and after the age of 18 years. METHODS: De novo patients with NC diagnosis completed a standardized questionnaire and interview, followed by a sleep study. The clinical and sleep measures were compared between patients diagnosed before (46 children, median age: 12 year old) and after (46 adults, median age: 28.5 year old) 18 years of age. RESULTS: The frequency of obesity (54% vs 17%), night eating (29% vs 7%), parasomnia (89% vs 43%), sleep talking (80% vs 34%), and sleep drunkenness (69% vs 24%) were higher in children than in adults, the frequency of sleep paralysis was lower (20% vs 55%) but the frequency of cataplexy and the severity of sleepiness were not different. Children scored higher than adults at the attention-deficit/hyperactivity disorder (ADHD) scale. Depressive feelings affected not differently children (24%) and adults (32%). However, adults had lower quality of life than children. There was no difference between groups for insomnia and fatigue scores. Quality of life was essentially impacted by depressive feelings in both children and adults. Obstructive apnea-hypopnea index (OAHI) was lower in children with higher mean and minimal oxygen saturation than in adults. No between-group differences were found at the multiple sleep latency test. The body mass index (z-score) was correlated with OAHI (r = .32). CONCLUSION: At time of NC diagnosis, children have more frequent obesity, night eating, parasomnia, sleep talking, drunkenness, and ADHD symptoms than adults, even if sleepiness and cataplexy do not differ. These differences should be considered to ensure a prompt diagnosis.

Hypopituitarism in Patients with Blepharophimosis and FOXL2 Mutations.

BACKGROUND: FOXL2 is the gene involved in blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES). There have been few single case reports of growth hormone deficiency (GHD) with this syndrome, and Foxl2 is known to be involved in pituitary development in mice. Our aim was to analyze the prevalence of FOXL2 gene alteration in a series of patients with congenital hypopituitarism and eyelid anomalies. METHODS: FOXL2 was analyzed in 10 patients with hypopituitarism (ranging from isolated GHD to complete pituitary hormone deficiency) and eyelid anomalies (typical BPES in 4 patients and milder anomalies in 6 patients). In patients with an FOXL2 mutation, we ruled out other possible molecular explanations by analyzing a panel of 20 genes known to be associated with hypopituitarism, and a candidate gene approach was used for patients without an FOXL2mutation. RESULTS: Three patients had an FOXL2mutation. All 3 had typical BPES. Their pituitary phenotype varied from GHD to complete pituitary hormone deficiency and their pituitary morphology ranged from normal to an interrupted pituitary stalk. No mutations were found in genes previously associated with hypopituitarism. CONCLUSION: Our study shows that some patients with BPES have hypopituitarism with no molecular explanation other than FOXL2 mutation. This points toward an involvement of FOXL2 in human pituitary development.

Impaired histaminergic neurotransmission in children with narcolepsy type 1.

OBJECTIVE: Narcolepsy is a sleep disorder characterized in humans by excessive daytime sleepiness and cataplexy. Greater than fifty percent of narcoleptic patients have an onset of symptoms prior to the age of 18. Current general agreement considers the loss of hypothalamic hypocretin (orexin) neurons as the direct cause of narcolepsy notably cataplexy. To assess whether brain histamine (HA) is also involved, we quantified the cerebrospinal fluid (CSF) levels of HA and tele-methylhistamine (t-MeHA), the direct metabolite of HA between children with orexin-deficient narcolepsy type 1 (NT1) and controls. METHODS: We included 24 children with NT1 (12.3 ± 3.6 years, 11 boys, 83% cataplexy, 100% HLA DQB1*06:02) and 21 control children (11.2 ± 4.2 years, 10 boys). CSF HA and t-MeHA were measured in all subjects using a highly sensitive liquid chromatographic-electrospray/tandem mass spectrometric assay. CSF hypocretin-1 values were determined in the narcoleptic patients. RESULTS: Compared with the controls, NT1 children had higher CSF HA levels (771 vs 234 pmol/L, P < 0.001), lower t-MeHA levels (879 vs 1924 pmol/L, P < 0.001), and lower t-MeHA/HA ratios (1.1 vs 8.2, P < 0.001). NT1 patients had higher BMI z-scores (2.7 ± 1.6 vs 1.0 ± 2.3, P = 0.006) and were more often obese (58% vs 29%, P = 0.05) than the controls. Multivariable analyses including age, gender, and BMI z-score showed a significant decrease in CSF HA levels when the BMI z-score increased in patients (P = 0.007) but not in the controls. No association was found between CSF HA, t-MeHA, disease duration, age at disease onset, the presence of cataplexy, lumbar puncture timing, and CSF hypocretin levels. CONCLUSIONS: Narcolepsy type 1 children had a higher CSF HA level together with a lower t-MeHA level leading to a significant decrease in the t-MeHA/HA ratios. These results suggest a decreased HA turnover and an impairment of histaminergic neurotransmission in narcoleptic children and support the use of a histaminergic therapy in the treatment against narcolepsy.

Congenital hypogonadotropic hypogonadism with split hand/foot malformation: a clinical entity with a high frequency of FGFR1 mutations.

PURPOSE: Congenital hypogonadotropic hypogonadism (CHH) and split hand/foot malformation (SHFM) are two rare genetic conditions. Here we report a clinical entity comprising the two. METHODS: We identified patients with CHH and SHFM through international collaboration. Probands and available family members underwent phenotyping and screening for FGFR1 mutations. The impact of identified mutations was assessed by sequence- and structure-based predictions and/or functional assays. RESULTS: We identified eight probands with CHH with (n = 3; Kallmann syndrome) or without anosmia (n = 5) and SHFM, seven of whom (88%) harbor FGFR1 mutations. Of these seven, one individual is homozygous for p.V429E and six individuals are heterozygous for p.G348R, p.G485R, p.Q594*, p.E670A, p.V688L, or p.L712P. All mutations were predicted by in silico analysis to cause loss of function. Probands with FGFR1 mutations have severe gonadotropin-releasing hormone deficiency (absent puberty and/or cryptorchidism and/or micropenis). SHFM in both hands and feet was observed only in the patient with the homozygous p.V429E mutation; V429 maps to the fibroblast growth factor receptor substrate 2α binding domain of FGFR1, and functional studies of the p.V429E mutation demonstrated that it decreased recruitment and phosphorylation of fibroblast growth factor receptor substrate 2α to FGFR1, thereby resulting in reduced mitogen-activated protein kinase signaling. CONCLUSION: FGFR1 should be prioritized for genetic testing in patients with CHH and SHFM because the likelihood of a mutation increases from 10% in the general CHH population to 88% in these patients.

Pathology or normal variant: what constitutes a delay in puberty?

Puberty is a complex maturation process that begins during fetal life and persists until the acquisition of reproduction function. The fundamental event that activates puberty occurs in the hypothalamus. A complex neuron network stimulates GnRH secretion, which stimulates pituitary gonadotropin secretion and then gonadal steroid secretion. Pubertal delay is defined as the presentation of clinical signs of puberty 2-2.5 SD later than in the normal population. Three major groups of etiopathogeneses are described: (1) hypogonadotropic hypogonadism, (2) hypergonadotropic hypogonadism, and (3) constitutional delay of puberty (CDP) - the most common cause of delayed puberty in boys. The differential diagnosis between CDP and isolated hypogonadotropic hypogonadism remains difficult. Mechanisms of pubertal timing are now better understood and genetic or epigenetic causes can explain some pubertal delays. However, there are still unexplained mechanisms. Treatment of delayed puberty is necessary to ensure full pubertal development for the adolescent and in case of hypogonadism, to restore fertility. Finally, precocious diagnosis of hypogonadism is primordial but can be difficult during childhood and in cases of partial hypogonadism. The study of genetic pubertal diseases or of different animal models could help to discover new diagnostic or therapeutic tools.

PROKR2 and PROK2 mutations cause isolated congenital anosmia without gonadotropic deficiency.

OBJECTIVE: Isolated congenital anosmia (ICA) is a rare phenotype defined as absent recall of any olfactory sensations since birth and the absence of any disease known to cause anosmia. Although most cases of ICA are sporadic, reports of familial cases suggest a genetic cause. ICA due to olfactory bulb agenesis and associated to hypogonadotropic hypogonadism defines Kallmann syndrome (KS), in which several gene defects have been described. In KS families, the phenotype may be restricted to ICA. We therefore hypothesized that mutations in KS genes cause ICA in patients, even in the absence of family history of reproduction disorders. DESIGN AND METHODS: In 25 patients with ICA and olfactory bulb agenesis, a detailed phenotype analysis was conducted and the coding sequences of KAL1, FGFR1, FGF8, PROKR2, and PROK2 were sequenced. RESULTS: Three PROKR2 mutations previously described in KS and one new PROK2 mutation were found. Investigation of the families showed incomplete penetrance of these mutations. CONCLUSIONS: This study is the first to report genetic causes of ICA and indicates that KS genes must be screened in patients with ICA. It also confirms the considerable complexity of GNRH neuron development in humans.

DLK1 is a somato-dendritic protein expressed in hypothalamic arginine-vasopressin and oxytocin neurons.

Delta-Like 1 Homolog, Dlk1, is a paternally imprinted gene encoding a transmembrane protein involved in the differentiation of several cell types. After birth, Dlk1 expression decreases substantially in all tissues except endocrine glands. Dlk1 deletion in mice results in pre-natal and post-natal growth deficiency, mild obesity, facial abnormalities, and abnormal skeletal development, suggesting involvement of Dlk1 in perinatal survival, normal growth and homeostasis of fat deposition. A neuroendocrine function has also been suggested for DLK1 but never characterised. To evaluate the neuroendocrine function of DLK1, we first characterised Dlk1 expression in mouse hypothalamus and then studied post-natal variations of the hypothalamic expression. Western Blot analysis of adult mouse hypothalamus protein extracts showed that Dlk1 was expressed almost exclusively as a soluble protein produced by cleavage of the extracellular domain. Immunohistochemistry showed neuronal DLK1 expression in the suprachiasmatic (SCN), supraoptic (SON), paraventricular (PVN), arcuate (ARC), dorsomedial (DMN) and lateral hypothalamic (LH) nuclei. DLK1 was expressed in the dendrites and perikarya of arginine-vasopressin neurons in PVN, SCN and SON and in oxytocin neurons in PVN and SON. These findings suggest a role for DLK1 in the post-natal development of hypothalamic functions, most notably those regulated by the arginine-vasopressin and oxytocin systems.

[The genetic control of puberty onset]. / Le contrôle génétique de l'initiation de la puberté.

Puberty is triggered by a complex neuroendocrine mechanism that leads to an increase in GnRH release at the end of the childhood and, hence, to reactivation of the gonadotropic axis. Recent human genetic studies have led to major breakthroughs in our understanding of puberty onset. A network of hypothalamic neurons controlling GnRH release has just been characterized. It appears that the timing of puberty onset is under the control of the heterochronic gene Lin28, which encodes a protein regulating microRNA maturation. Characterization of additional gene defects associated with abnormal puberty onset is needed to further characterize this neuroendocrine network and to identify new therapeutic targets for reproductive disorders.

[Biological mechanisms and genes involved in puberty]. / Mécanismes biologiques et gènes impliqués dans le développement de la puberté.

Puberty is an important step in human development. Onset of puberty, including neurobiological mechanisms important for the increase of hypothalamic GnRH pulses remains a mystery. After birth, GnRH secretion remains elevated and then decreases during childhood regardless of any steroid gonadal feedback. This period of quiescence of the gonadotropic axis during childhood is linked to a central inhibition of GnRH secretion which is replaced by an activator tone at puberty. The study of the pathology of the pubertal timing, including delayed puberty led to the discovery of new genes involved in the migration of GnRH neurons and genes involved in the neuroendocrine regulation of the gonadotropic axis. Recently, the emphasis on the importance of the kiss/GPR54 system in modulating control of the gonadotropic axis at puberty has recently emerged from Human genetics studies.