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Wolcott-Rallison syndrome (WRS) is a rare autosomal recessive disease, characterized by neonatal/early-onset non-autoimmune insulin-requiring diabetes associated with skeletal dysplasia and growth retardation. Fewer than 60 cases have been described in the literature, although WRS is now recognised as the most frequent cause of neonatal/early-onset diabetes in patients with consanguineous parents. Typically, diabetes occurs before six months of age, and skeletal dysplasia is diagnosed within the first year or two of life. Other manifestations vary between patients in their nature and severity and include frequent episodes of acute liver failure, renal dysfunction, exocrine pancreas insufficiency, intellectual deficit, hypothyroidism, neutropenia and recurrent infections. Bone fractures may be frequent. WRS is caused by mutations in the gene encoding eukaryotic translation initiation factor 2α kinase 3 (EIF2AK3), also known as PKR-like endoplasmic reticulum kinase (PERK). PERK is an endoplasmic reticulum (ER) transmembrane protein, which plays a key role in translation control during the unfolded protein response. ER dysfunction is central to the disease processes. The disease variability appears to be independent of the nature of the EIF2AK3 mutations, with the possible exception of an older age at onset; other factors may include other genes, exposure to environmental factors and disease management. WRS should be suspected in any infant who presents with permanent neonatal diabetes associated with skeletal dysplasia and/or episodes of acute liver failure. Molecular genetic testing confirms the diagnosis. Early diagnosis is recommended, in order to ensure rapid intervention for episodes of hepatic failure, which is the most life threatening complication. WRS should be differentiated from other forms of neonatal/early-onset insulin-dependent diabetes based on clinical presentation and genetic testing. Genetic counselling and antenatal diagnosis is recommended for parents of a WRS patient with confirmed EIF2AK3 mutation. Close therapeutic monitoring of diabetes and treatment with an insulin pump are recommended because of the risk of acute episodes of hypoglycaemia and ketoacidosis. Interventions under general anaesthesia increase the risk of acute aggravation, because of the toxicity of anaesthetics, and should be avoided. Prognosis is poor and most patients die at a young age. Intervention strategies targeting ER dysfunction provide hope for future therapy and prevention.

BackgroundThe early gonad is bipotential and can differentiate into either a testis or an ovary. In XY embryos, the SRY gene triggers testicular differentiation and subsequent male development via its action on a single gene, SOX9. The supporting cell lineage of the bipotential gonad will differentiate as testicular Sertoli cells if SOX9 is expressed and conversely will differentiate as ovarian granulosa cells when SOX9 expression is switched off.ResultsThrough copy number variation mapping this study identified duplications upstream of the SOX9 gene in three families with an isolated 46,XX disorder of sex development (DSD) and an overlapping deletion in one family with two probands with an isolated 46,XY DSD. The region of overlap between these genomic alterations, and previously reported deletions and duplications at the SOX9 locus associated with syndromic and isolated cases of 46,XX and 46,XY DSD, reveal a minimal non-coding 78 kb sex determining region located in a gene desert 517–595 kb upstream of the SOX9 promoter.ConclusionsThese data indicate that a non-coding regulatory region critical for gonadal SOX9 expression and subsequent normal sex development is located far upstream of the SOX9 promoter. Its copy number variations are the genetic basis of isolated 46,XX and 46,XY DSDs of variable severity (ranging from mild to complete sex reversal). It is proposed that this region contains a gonad specific SOX9 transcriptional enhancer(s), the gain or loss of which results in genomic imbalance sufficient to activate or inactivate SOX9 gonadal expression in a tissue specific manner, switch sex determination, and result in isolated DSD.

Objective Prader-Willi syndrome (PWS) is a genetic neurodevelopmental disorder with a characteristic trajectory. Infants display hypotonia, poor social and feeding skills, and high risk of choking, which have been shown to improve after oxytocin (OT) treatment. Our aim is to demonstrate the efficacy of intranasal OT treatment administered in the postnatal critical period on infant feeding skills and document its long-term effects. Methods We enrolled 52 infants with PWS (median age 2.2 months) in a European double-blind randomized placebo-controlled study. Infants were randomly assigned in a 1:1 ratio to either 4 IU/day of OT or placebo for a 4-week evaluation of efficacy. A second randomization in each group was performed. Infants in the placebo group were randomized into 4 weeks of OT followed by 4 weeks of placebo or 8 consecutive weeks of OT. Those in the OT group were randomized into additional 4 weeks of OT followed by 4 weeks of placebo or 8 consecutive weeks of placebo. Infants were followed-up to 26 weeks from baseline. Feeding skills were evaluated using Neonatal Oral-Motor Scale (NOMAS) as primary endpoint and videofluoroscopy of swallowing study (VFSS) as key secondary endpoint. Subsequently, 40 infants included in France (OT-exposed cohort) participated in a new study to document long term safety of OT treatment and to compare them with an unexposed cohort ( n  = 24) at about 3 years of age. Prevalence and severity of comorbidities of the disorder were compared between the two cohorts. Results OT was well tolerated. At 4 weeks, NOMAS normalization rates were similar between OT and placebo, but OT yielded a higher VFSS responder rate (53.3% vs 16.7%, p  = 0.05) and a greater reduction in VFSS total score (LS mean difference −1.55; 95% CI −2.9 to −0.2; p  = 0.03). At 3 years, the OT-exposed cohort demonstrated consistently better motor, adaptive and behavioral outcomes than unexposed controls. Conclusions The primary endpoint did not show significant difference between OT and placebo groups. However, using VFSS we showed for the first time a positive effect of 4 weeks intranasal OT treatment on swallowing. We also document long-term effect on disease trajectory, with less severe comorbidities.

MODY (Maturity-Onset Diabetes of the Young) is characterized by autosomal dominant mode of inheritance, early onset of diabetes in the absence of autoimmunity directed to pancreatic β-cells, impaired insulin secretory capacity, however, maintained over time, and extra-pancreatic manifestations in some patients. Its prevalence has been estimated 0.6% to 6.5% of all diabetes in Europe and the USA. Pathogenic variants in the genes encoding glucokinase or transcription factors HNF1A or HNF4A are responsible for the majority of cases of monogenic forms of diabetes referred to as MODY. The objective of the French National Diagnosis and Care Protocol (PNDS, Protocole National de Diagnostic et de Soins) dedicated to GCK -MODY (formerly MODY2), HNF1A -MODY (MODY3), and HNF4A -MODY (MODY1) is to provide to health professionals a guide for optimal management and care of patients, based on a critical literature review and multidisciplinary expert consensus. The PNDS, written by members of the French National Reference Center for Rare Diseases of Insulin Secretion and Insulin Sensitivity (PRISIS), is available on the French Health Authority website (in French). Thorough analysis of personal and family history, clinical examination and biochemical testing are key to raise the diagnosis, which has to be confirmed by molecular analysis. The attending physician, in conjunction with the national care network, will ensure that the patient receives optimal care through regular follow-up and screening. Overall, the management of patients with MODY requires the collaboration of several health care providers.

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.

Background: Achondroplasia is the most common short-limbed skeletal dysplasia resulting from gain-of-function pathogenic variants in fibroblast growth factor receptor 3 (FGFR3) gene, a negative regulator of endochondral bone formation. Most treatment options are symptomatic, targeting medical complications. Infigratinib is an orally bioavailable, FGFR1–3 selective tyrosine kinase inhibitor being investigated as a direct therapeutic strategy to counteract FGFR3 overactivity in achondroplasia. Objectives: The main objective of PROPEL is to collect baseline data of children with achondroplasia being considered for future enrollment in interventional studies sponsored by QED Therapeutics. The objectives of PROPEL 2 are to obtain preliminary evidence of safety and efficacy of oral infigratinib in children with achondroplasia, to identify the infigratinib dose to be explored in future studies, and to characterize the pharmacokinetic (PK) profile of infigratinib and major metabolites. Design: PROPEL (NCT04035811) is a prospective, noninterventional clinical study designed to characterize the natural history and collect baseline data of children with achondroplasia over 6−24 months. PROPEL 2 (NCT04265651), a prospective, phase II, open-label study of infigratinib in children with achondroplasia, consists of a dose-escalation, dose-finding, and dose-expansion phase to confirm the selected dose, and a PK substudy. Methods and analysis: Children aged 3−11 years with achondroplasia who completed ⩾6 months in PROPEL are eligible for PROPEL 2. Primary endpoints include treatment-emergent adverse events and change from baseline in annualized height velocity. Four cohorts at ascending dose levels are planned for dose escalation. The selected dose will be confirmed in the dose-expansion phase. Ethics: PROPEL and PROPEL 2 are being conducted in accordance with the International Conference on Harmonization Good Clinical Practice guidelines, principles of the Declaration of Helsinki, and relevant human clinical research and data privacy regulations. Protocols have been approved by local health authorities, ethics committees, and institutions as applicable. Parents/legally authorized representatives are required to provide signed informed consent; signed informed assent by the child is also required, where applicable. Discussion: PROPEL and PROPEL 2 will provide preliminary evidence of the safety and efficacy of infigratinib as precision treatment of children with achondroplasia and will inform the design of future studies of FGFR-targeted agents in achondroplasia. Registration: ClinicalTrials.gov: NCT04035811; NCT04265651.

Maturity-Onset Diabetes of the Youth (MODY) diabetes remains commonly misdiagnosed. A monogenic form should be suspected in individuals presenting hyperinsulinemic hypoglycemia (HH) associated with, either later development of MODY (hypoglycemia-remission-diabetes sequence), or with first/second-degree family history of diabetes. Herein, we aimed to describe this individual or family monogenic association between HH and diabetes, and identify potential genotype–phenotype correlations. We conducted a systematic review of 26 studies, including a total of 67 patients with this association resulting from variants in GCK (n = 5 cases), ABCC8 (n = 29), HNF1A (n = 5), or HNF4A (n = 28). A family history of hypoglycemia and/or diabetes was present in 91% of cases (61/67). Median age at first hypoglycemia was 24 h after birth. Diazoxide was initiated in 46 children (46/67–69%); responsiveness was found in 91% (42/46). Median HH duration was three years (1 day-25 years). Twenty-three patients (23/67–34%) later developed diabetes (median age: 13 years; range: 8–48); more frequently in those untreated with diazoxide. This association was most commonly inherited in an autosomal dominant manner (43/48–90%). Some genes were associated with less severe initial hypoglycemia (HNF1A), shorter duration of HH (HNF4A), and more maternal (ABCC8) or paternal (HNF4A) transmission. This study illustrates that the same genotype can give a biphasic phenotype in the same person or a reverse phenotype in the same family. Wider awareness of this association is necessary in pediatrics to establish annual monitoring of patients who have presented HH, and during maternity to screen diabetes and optimize genetic counseling and management of pregnancy, childbirth, and the newborn.PROSPERO registration: CRD42020178265.

Background. The use of miRNAs as biomarkers for Type 1 Diabetes (T1D) risk is attractive as T1D is usually diagnosed in front of acute symptoms. As miR-375 is highly expressed in the endocrine pancreas, we postulated that its circulating level might reflect beta cell alterations and might be altered in the blood of T1D patients recently diagnosed. Methods. Sera were obtained from 22 T1D children at onset of the disease, before subcutaneous insulin treatment, and from 10 nondiabetic pediatric controls. MiR-375 seric level was quantified by stem-loop RT-PCR-based assay. MiRNAs regulations in isolated human islets in response to high glucose concentrations were determined by TaqMan Low-Density Array. Results. The abundance of miR-375, among the 410 miRNAs detected in human islets, mirrored its well-established role in rodent islet biology. Upregulated miRNAs targeted genes involved in islet homeostasis and regulation of beta cell mass. Downregulated miRNAs, including miR-375, were involved in pancreas secretion and protein turnover. Seric level of miR-375 was lower in T1D children versus age-matched controls, without any correlations with HbA1c, glycaemia, and number of autoantibodies. Conclusion. Altered circulating level of miR-375 at onset of T1D might be a general biomarker of metabolic alterations and inflammation associated with the disease.

Large Genomic Rearrangements in the Hepatocyte Nuclear Factor-1β ( TCF2 ) Gene Are the Most Frequent Cause of Maturity-Onset Diabetes of the Young Type 5 Christine Bellanné-Chantelot 1 , Séverine Clauin 1 , Dominique Chauveau 2 , Philippe Collin 3 , Michèle Daumont 4 , Claire Douillard 5 , Danièle Dubois-Laforgue 6 , Laurent Dusselier 7 , Jean-François Gautier 8 , Michel Jadoul 9 , Marie Laloi-Michelin 10 , Laetitia Jacquesson 11 , Etienne Larger 12 , Jacques Louis 7 , Marc Nicolino 13 , Jean-François Subra 14 , Jean-Marie Wilhem 15 , Jacques Young 16 , Gilberto Velho 17 and José Timsit 6 1 Department of Cytogenetics and Molecular Biology, Hôpital Saint-Antoine, Assistance Publique-Hôpitaux de Paris, Paris, France 2 Department of Nephrology, Hôpital de Rangueil, Toulouse, France 3 Department of Internal Medicine, Centre Hospitalier de Niort, Niort, France 4 Department of Endocrinology, Centre Hospitalier de Vienne, Vienne, France 5 Department of Endocrinology, Centre Hospitalier de Béthune, Béthune, France 6 Department of Immunology and Diabetology, Paris Descartes University, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Paris, France 7 Department of Endocrinology, Hôpital Sainte-Blandine, Metz, France 8 Department of Endocrinology, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Paris, France 9 Cliniques Saint-Luc, Université Catholique de Louvain, Bruxelles, Belgium 10 Department of Internal Medicine, Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris, Paris, France 11 Department of Endocrinology, Hôpital Saint-Antoine, Assistance Publique-Hôpitaux de Paris, Paris, France 12 Department of Endocrinology, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, Paris, France 13 Department of Endocrinology, Hôpital Debrousse, Lyon, France 14 Department of Nephrology, Centre Hospitalier Universitaire d’Angers, Angers, France 15 Department of Internal Medicine, Centre Hospitalier Saint-Morand, Altkirch, France 16 Department of Endocrinology, Hôpital de Kremlin-Bicêtre, Assistance Publique-Hôpitaux de Paris, Le Kremlin-Bicêtre, France 17 Inserm U695, Faculté de Médecine Xavier Bichat, Paris, France Address correspondence and reprint requests to Christine Bellanne-Chantelot, Hopital Saint Antoine, Service de Cytogenetique, 184 Rue du Faubourg Saint-Antoine, 75012 Paris, France. E-mail: christine.bellanne{at}sat.ap-hop-paris.fr Abstract Maturity-onset diabetes of the young (MODY) 5 is caused by mutations in the TCF2 gene encoding the transcription factor hepatocyte nuclear factor-1β. However, in 60% of the patients with a phenotype suggesting MODY5, no point mutation is detected in TCF2 . We have hypothesized that large genomic rearrangements of TCF2 that are missed by conventional screening methods may account for this observation. In 40 unrelated patients presenting with MODY5 phenotype, TCF2 was screened for mutations by sequencing. Patients without mutations were then screened for TCF2 rearrangements by the quantitative multiplex PCR of short fluorescent fragments (QMPSF). Among the 40 patients, the overall detection rate was 70%: 18 had point mutations, 9 had whole-gene deletions, and 1 had a deletion of a single exon. Similar phenotypes were observed in patients with mutations and in subjects with large deletions. These results suggest that MODY5 is more prevalent than previously reported, with one-third of the cases resulting from large deletions of TCF2 . Because QMPSF is more rapid and cost effective than sequencing, we propose that patients whose phenotype is consistent with MODY5 should be screened first with the QMPSF assay. In addition, other MODY genes should be screened for large genomic rearrangements. HNF, hepatocyte nuclear factor MODY, maturity-onset diabetes of the young QMPSF, quantitative multiplex PCR of short fluorescent fragments STS, sequence-tagged site Footnotes Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org . Accepted July 25, 2005. Received April 27, 2005. DIABETES

In type I blepharophimosis/ptosis/epicanthus inversus syndrome (BPES), eyelid abnormalities are associated with ovarian failure. Type II BPES shows only the eyelid defects, but both types map to chromosome 3q23. We have positionally cloned a novel, putative winged helix/forkhead transcription factor gene, FOXL2 , that is mutated to produce truncated proteins in type I families and larger proteins in type II. Consistent with an involvement in those tissues, FOXL2 is selectively expressed in the mesenchyme of developing mouse eyelids and in adult ovarian follicles; in adult humans, it appears predominantly in the ovary. FOXL2 represents a candidate gene for the polled/intersex syndrome XX sex-reversal goat.