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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.

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.

Background and objectivesIdentifying 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.DesignThis 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.ResultsThe 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.ConclusionThese 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.

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.

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.

ObjectiveIsolated 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 methodsIn 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.ResultsThree PROKR2 mutations previously described in KS and one new PROK2 mutation were found. Investigation of the families showed incomplete penetrance of these mutations.ConclusionsThis 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.