Monoallelic intragenic POU3F2 variants lead to neurodevelopmental delay and hyperphagic obesity, confirming the gene's candidacy in 6q16.1 deletions.

While common obesity accounts for an increasing global health burden, its monogenic forms have taught us underlying mechanisms via more than 20 single-gene disorders. Among these, the most common mechanism is central nervous system dysregulation of food intake and satiety, often accompanied by neurodevelopmental delay (NDD) and autism spectrum disorder. In a family with syndromic obesity, we identified a monoallelic truncating variant in POU3F2 (alias BRN2) encoding a neural transcription factor, which has previously been suggested as a driver of obesity and NDD in individuals with the 6q16.1 deletion. In an international collaboration, we identified ultra-rare truncating and missense variants in another ten individuals sharing autism spectrum disorder, NDD, and adolescent-onset obesity. Affected individuals presented with low-to-normal birth weight and infantile feeding difficulties but developed insulin resistance and hyperphagia during childhood. Except for a variant leading to early truncation of the protein, identified variants showed adequate nuclear translocation but overall disturbed DNA-binding ability and promotor activation. In a cohort with common non-syndromic obesity, we independently observed a negative correlation of POU3F2 gene expression with BMI, suggesting a role beyond monogenic obesity. In summary, we propose deleterious intragenic variants of POU3F2 to cause transcriptional dysregulation associated with hyperphagic obesity of adolescent onset with variable NDD.

Perinatal, metabolic, and reproductive features in PPARG-related lipodystrophy.

OBJECTIVE: The adipogenic PPARG-encoded PPARγ nuclear receptor also displays essential placental functions. We evaluated the metabolic, reproductive, and perinatal features of patients with PPARG-related lipodystrophy. METHODS: Current and retrospective data were collected in patients referred to a National Rare Diseases Reference Centre. RESULTS: 26 patients from 15 unrelated families were studied (18 women, median age 43 years). They carried monoallelic PPARG variants except a homozygous patient with congenital generalized lipodystrophy. Among heterozygous patients aged 16 or more (n = 24), 92% had diabetes, 96% partial lipodystrophy (median age at diagnosis 24 and 37 years), 78% hypertriglyceridaemia, 71% liver steatosis, and 58% hypertension. The mean BMI was 26 ± 5.0 kg/m2. Women (n = 16) were frequently affected by acute pancreatitis (n = 6) and/or polycystic ovary syndrome (n = 12). Eleven women obtained one or several pregnancies, all complicated by diabetes (n = 8), hypertension (n = 4), and/or hypertriglyceridaemia (n = 10). We analysed perinatal data of patients according to the presence (n = 8) or absence (n = 9) of a maternal dysmetabolic environment. The median gestational age at birth was low in both groups (37 and 36 weeks of amenorrhea, respectively). As expected, the birth weight was higher in patients exposed to a foetal dysmetabolic environment of maternal origin. In contrast, 85.7% of non-exposed patients, in whom the variant is, or is very likely to be, paternally-inherited, were small for gestational age. CONCLUSIONS: Lipodystrophy-related PPARG variants induce early metabolic complications. Our results suggest that placental expression of PPARG pathogenic variants carried by affected foetuses could impair prenatal growth and parturition. This justifies careful pregnancy monitoring in affected families.

Excess of de novo variants in genes involved in chromatin remodelling in patients with marfanoid habitus and intellectual disability.

PURPOSE: Marfanoid habitus (MH) combined with intellectual disability (ID) (MHID) is a clinically and genetically heterogeneous presentation. The combination of array CGH and targeted sequencing of genes responsible for Marfan or Lujan-Fryns syndrome explain no more than 20% of subjects. METHODS: To further decipher the genetic basis of MHID, we performed exome sequencing on a combination of trio-based (33 subjects) or single probands (31 subjects), of which 61 were sporadic. RESULTS: We identified eight genes with de novo variants (DNVs) in at least two unrelated individuals (ARID1B, ATP1A1, DLG4, EHMT1, NFIX, NSD1, NUP205 and ZEB2). Using simulation models, we showed that five genes (DLG4, NFIX, EHMT1, ZEB2 and ATP1A1) met conservative Bonferroni genomewide significance for an excess of the observed de novo point variants. Overall, at least one pathogenic or likely pathogenic variant was identified in 54.7% of subjects (35/64). These variants fell within 27 genes previously associated with Mendelian disorders, including NSD1 and NFIX, which are known to be mutated in overgrowth syndromes. CONCLUSION: We demonstrated that DNVs were enriched in chromatin remodelling (p=2×10-4) and genes regulated by the fragile X mental retardation protein (p=3×10-8), highlighting overlapping genetic mechanisms between MHID and related neurodevelopmental disorders.

Cancer Incidence Among Children in New Caledonia, 1994 to 2012.

New Caledonia (NC) is a small French territory in the Pacific Ocean with a relatively young (32% under 20) and multiethnic population. It is divided into 3 districts: Loyalty Island, the North, and the South, each with specific population characteristics. The aim of this study was to describe childhood cancer age-standardized incidence rate (ASR) in NC, compare it with the estimated one in France , and to determine whether residence and ethnicity may have an influence on intrapopulation ASR. All incident cancer cases diagnosed between 1994 and 2012 in children (0 to 14 y) resident in NC for more than 6 months were included. With 162 registered cases, the ASR for all cancers combined was 142.2 (range, 104.9 to 193.3) cases per million children per year and was not different from what was estimated in France (156.6). However, incidence varies according to the place of residence, with a higher ASR in the Loyalty Island district for several types of neoplasms, but not according to the ethnicity. The small migratory flux between this district and the rest of the territory may have led to these results, but, because of the small number of cases, no conclusion can be drawn.

Identification of a novel mutation confirms the implication of IFT172 (BBS20) in Bardet-Biedl syndrome.

Bardet-Biedl syndrome (BBS; MIM 209900) is a recessive heterogeneous ciliopathy characterized by retinitis pigmentosa (RP), postaxial polydactyly, obesity, hypogonadism, cognitive impairment and kidney dysfunction. So far, 20 BBS genes have been identified, with the last reported ones being found in one or very few families. Whole-exome sequencing was performed in a consanguineous family in which two affected children presented typical BBS features (retinitis pigmentosa, postaxial polydactyly, obesity, hypogonadism and cognitive impairment) without any mutation identified in known BBS genes at the time of the study. We identified a homozygous splice-site mutation (NM_015662.2: c.4428+3A>G) in both affected siblings in the last reported BBS gene, namely, Intraflagellar Transport 172 Homolog (IFT172). Familial mutation segregation was consistent with autosomal recessive inheritance. IFT172 mutations were initially reported in Jeune and Mainzer-Saldino syndromes. Recently, mutations have also been found in isolated RP and Bardet-Biedl-like ciliopathy. This is the second report of IFT172 mutations in BBS patients validating IFT172 as the twentieth BBS gene (BBS20). Moreover, another IFT gene, IFT27, was already associated with BBS, confirming the implication of IFT genes in the pathogenesis of BBS.

Newly diagnosed rheumatic heart disease among indigenous populations in the Pacific.

OBJECTIVES: Rheumatic heart disease (RHD) remains the leading acquired heart disease in the young worldwide. We aimed at assessing outcomes and influencing factors in the contemporary era. METHODS: Hospital-based cohort in a high-income island nation where RHD remains endemic and the population is captive. All patients admitted with newly diagnosed RHD according to World Heart Federation echocardiographic criteria were enrolled (2005-2013). The incidence of major cardiovascular events (MACEs) including heart failure, peripheral embolism, stroke, heart valve intervention and cardiovascular death was calculated, and their determinants identified. RESULTS: Of the 396 patients, 43.9% were male with median age 18 years (IQR 10-40)). 127 (32.1%) patients presented with mild, 131 (33.1%) with moderate and 138 (34.8%) with severe heart valve disease. 205 (51.8%) had features of acute rheumatic fever. 106 (26.8%) presented with at least one MACE. Among the remaining 290 patients, after a median follow-up period of 4.08 (95% CI 1.84 to 6.84) years, 7 patients (2.4%) died and 62 (21.4%) had a first MACE. The annual incidence of first MACE and of heart failure were 59.05‰ (95% CI 44.35 to 73.75) and 29.06‰ (95% CI 19.29 to 38.82), respectively. The severity of RHD at diagnosis (moderate vs mild HR 3.39 (0.95 to 12.12); severe vs mild RHD HR 10.81 (3.11 to 37.62), p<0.001) and ongoing secondary prophylaxis at follow-up (HR 0.27 (0.12 to 0.63), p=0.01) were the two most influential factors associated with MACE. CONCLUSIONS: Newly diagnosed RHD is associated with poor outcomes, mainly in patients with moderate or severe valve disease and no secondary prophylaxis.

Relationships Between Clinico-Epidemiological Patterns of Invasive Meningococcal Infections and Complement Deficiencies in French South Pacific Islands (New Caledonia).

PURPOSE: Invasive Meningococcal Disease (IMD) is three fold more common in New Caledonia (NC) than in metropolitan France and many IMD cases (35.7%) are due to Y and W135 serogroups. The purpose of our study was to identify IMD risk factors in NC. METHODS: A retrospective study of all IMD cases that occurred in NC between 2005 and 2011 was conducted. Socio-environmental, clinical and biological data were collected. A search for immune deficiency was proposed to all cases. IMD presentation and outcome were compared according to meningoccal serogroups and the complement deficiency status (C-deficiency). RESULTS: Sixty-six sporadic IMD cases (29 B serogroup, 20 Y or W135, 6 C, 1 A, 10 unknown) occurred in 64 patients often <24 years-old and of Melanesian origin. Five patients died (7.8%). No socio-environmental risk factors were identified. No asplenia, HIV infection or immunoglobulin deficiencies were found. Two patients had diabetes and 28 of 53 (52.8%) patients had C-deficiency including 20 (71.4%) cases of late complement component deficiency. Patients with C-deficiency were mainly Melanesian (92.8%) originating from the Loyalty Islands (62.1%). They were mostly infected with Y/W135 (42.9%) or B serogroups (32.1%). They often developed later and more severe disease than patients without C-deficiency (need for intensive cares in 60% versus 28.0% of cases, p = 0.01). CONCLUSIONS: A high prevalence of C-deficiency in the Melanesian population may explain epidemiological and clinical features of IMD in NC. Our results imply an adaptation of meningococcal vaccine strategies in NC.

Association between age and severity to leptospirosis in children.

BACKGROUND: In endemic areas, leptospirosis is more common and more severe in adults compared with children. Reasons to explain this discrepancy remain unclear and limited data focusing on adolescents are available. The objective of the study was to describe disease spectrum and outcome differences in children and adolescents admitted for leptospirosis in a large at-risk population. METHODS: Clinical and laboratory data were obtained on hospitalized cases in New Caledonia from 2006 to 2012. RESULTS: Data of 60 patients <18 years of age (25 children under 14 and 35 adolescents aged 14 to 17) with confirmed leptospirosis were analyzed. Compared with children, adolescents presented more often with classic features of Weil disease (p = 0.02), combining hepatic and renal involvement with or without pulmonary participation. Jarisch-Herxheimer reactions were observed more often among adolescents (p<0.01). The overall case fatality rate was low (1 adolescent versus 0 children). CONCLUSION: Severe leptospirosis in adolescents may be more likely to show adults' characteristics compared with children. Further studies are required to explore age-dependant host factors, including puberty-related physiological changes.

Lower respiratory infections among hospitalized children in New Caledonia: a pilot study for the Pneumonia Etiology Research for Child Health project.

We conducted a prospective pilot study over a 1-year period in New Caledonia in preparation for the Pneumonia Research for Child Health (PERCH) project. The pathogens associated with hospitalized lower respiratory infections in children were identified through the use of culture of induced sputum and blood, urinary antigen detection, polymerase chain reaction (PCR) on respiratory specimens, and serology on paired sera. Respiratory viruses were detected on respiratory specimens by immunofluorescence and PCR, and by serology on paired sera. Pathogens were detected in 87.9% of the 108 hospitalized cases. Viruses represented 81.6% of the 152 pathogens detected. Respiratory syncytial virus and rhinovirus were the most frequent, accounting for 32.2% and 24.3% of the pathogens identified, respectively. Only 26.3% of 99 induced sputum specimens collected were determined to be of good quality, which may be a consequence of the collection method used.

Nanophthalmos in a Melanesian population.

PURPOSE: To characterize the ophthalmic features and causes of visual loss in a cohort of Melanesians living in New Caledonia with nanophthalmos. METHODS: In this observational study, axial length, visual acuity (VA), cycloplegic autorefraction were assessed and dilated fundus examination was performed. Visual impairment was defined as VA<6/12 in the better eye, hypermetropia as >+1.0 dioptre (D), astigmatism as >or=1.0 D and anisometropia as >or=1.0 D difference between both eyes. Unilateral amblyopia was defined as at least a two-line difference in VA between both eyes and bilateral amblyopia as VA<6/12 in both eyes which was not adequately explained by refractive error and macular folds. RESULTS: Seventeen community-dwelling participants (aged 1.1-45.3 years) with short axial length (range from 16.1 to 21.6 mm) were identified. Of the 17 subjects, 14 were found to have crowded optic discs, three with papillomacular folds, three with a papillomacular band and three with macular radial folds. Further, all subjects demonstrated bilateral hypermetropia (range from +1.3 D to +15.1 D). A high proportion of subjects had astigmatism (12) and anisometropia (nine) in at least one eye. Visual impairment was found in nine subjects: five bilateral and four unilateral. Causes of visual impairment included amblyopia (seven), ametropia (seven) and macular folds (two). Amblyopia was attributed to several factors, including hypermetropia, anisometropia, astigmatism and esotropia. CONCLUSIONS: In this sample of Melanesians with nanophthalmos, a spectrum of ophthalmic features that was consistent with intraocular crowding was found. Over half of the subjects were visually impaired, mostly due to amblyopia and ametropia. Further characterization of the underlying genetic cause of nanophthalmos in this cohort will be the focus of future studies.