SETD2 and DNMT3A screen in the Sotos-like syndrome French cohort.

BACKGROUND: Heterozygous NSD1 mutations were identified in 60%-90% of patients with Sotos syndrome. Recently, mutations of the SETD2 and DNMT3A genes were identified in patients exhibiting only some Sotos syndrome features. Both NSD1 and SETD2 genes encode epigenetic 'writer' proteins that catalyse methylation of histone 3 lysine 36 (H3K36me). The DNMT3A gene encodes an epigenetic 'reader' protein of the H3K36me chromatin mark. METHODS: We aimed at confirming the implication of DNMT3A and SETD2 mutations in an overgrowth phenotype, through a comprehensive targeted-next generation sequencing (NGS) screening in 210 well-phenotyped index cases with a Sotos-like phenotype and no NSD1 mutation, from a French cohort. RESULTS: Six unreported heterozygous likely pathogenic variants in DNMT3A were identified in seven patients: two nonsense variants and four de novo missense variants. One de novo unreported heterozygous frameshift variant was identified in SETD2 in one patient. All the four DNMT3A missense variants affected DNMT3A functional domains, suggesting a potential deleterious impact. DNMT3A-mutated index cases shared similar clinical features including overgrowth phenotype characterised by postnatal tall stature (≥+2SD), macrocephaly (≥+2SD), overweight or obesity at older age, intellectual deficiency and minor facial features. The phenotype associated with SETD2 mutations remains to be described more precisely. The p.Arg882Cys missense de novo constitutional DNMT3A variant found in two patients is the most frequent DNMT3A somatic mutation in acute leukaemia. CONCLUSIONS: Our results illustrate the power of targeted NGS to identify rare disease-causing variants. These observations provided evidence for a unifying mechanism (disruption of apposition and reading of the epigenetic chromatin mark H3K36me) that causes an overgrowth syndrome phenotype. Further studies are needed in order to assess the role of SETD2 and DNMT3A in intellectual deficiency without overgrowth.

Acute post-streptococcal glomerulonephritis in children of French Polynesia: a 3-year retrospective study.

The aim of this study was to define the current demographic, clinical and prognostic characteristics of acute post-streptococcal glomerulonephritis (APSGN) in French Polynesia and to compare these features with those of other populations. Fifty children, all of whom were <15 years old and had been admitted to the Territorial Hospital of Papeete for APSGN between January 2005 and December 2007, were retrospectively enrolled in the study. Diagnostic criteria were microscopic or macroscopic haematuria, decreased C3 fraction of the complement and evidence of recent streptococcal infection. The annual incidence was 18 cases per 100,000 children <15 years of age in 2007. Most of the children (98%) enrolled in the study were of Polynesian ethnic origin, 27 were male (54%), and the average age at presentation was 6.7 years. Signs of previous respiratory infections were clearly evident in 40% of the children. Most of the patients presented during the rainy season, correlating with the relatively high incidence of skin infections at this time. The majority of patients had proteinuria (98%), with 25% having proteinuria in the nephrotic range (proteinuria/urinary creatinine >3 g/g). The presentation was severe in 22% of the children (congestive cardiac failure, severe hypertension and/or encephalopathy), and renal failure was an initial presenting symptom in 43.7%. The C3 fraction was lower in severe presentations, but the type of haematuria, level of proteinuria and inflammatory syndrome were not correlated with immediate severe forms or with initial renal failure. Haematuria resolved in a mean of 7.7 months and proteinuria in a mean of 3.9 months. None of the children had hypocomplementemia for more than 8 weeks. Acute post-streptococcal glomerulonephritis is endemic among French Polynesians, and they can be considered to be a high-risk population. Despite a high incidence of skin infections, however, the predominance of respiratory infections potentially indicates that French Polynesia is on the way to become a low-incidence area. Systematic detection and treatment of group A Streptococcus should be intensified.

Does rheumatic myocarditis really exists? Systematic study with echocardiography and cardiac troponin I blood levels.

AIMS: Revised guidelines for diagnosis of rheumatic fever indicate that rheumatic myocarditis may 'contribute' to the genesis of congestive heart failure. Our objective was to assess non-invasively the presence of non-clinical markers of myocardial involvement in acute rheumatic fever. METHODS: Echocardiography and assessment of cardiac troponin I (cTnI) blood levels were systematically performed in 95 consecutive patients with acute rheumatic fever, who were divided into three groups. Group 1: patients without carditis (n=22); group 2: patients with carditis and without congestive heart failure (n=59); group 3: patients with carditis and congestive heart failure (n=14). RESULTS: Left ventricular ejection fraction was normal in all patients and did not differ between groups (group 1: 0.72+/-0.08, group 2: 0.69+/-0.06, and group 3: 0.66+/-0.07, p=0.09). Left ventricular diameters tend to be larger in group 3, but all patients had severe mitral and/or aortic regurgitation. Mean cTnI was 0.077+/-0.017 ng/ml (normal <0.1 ng/ml), did not differ between groups (p=0.45), and only 13 patients (seven with pericardial effusion) had detectable levels (0.2-0.4 ng/ml). CONCLUSIONS: Our study neither detected cTnI elevations nor echocardiographic abnormalities suggesting significant myocardial involvement during rheumatic fever. Congestive heart failure was always associated to severe valve regurgitation.

Congenital dyserythropoietic anemia, type 1, in a polynesian patient: response to interferon alpha2b.

The authors attempted to assess the utility of interferon alpha2b treatment in a Polynesian girl with a relatively severe form of congenital dyserythropoietic anemia, type 1. The diagnosis was established using routine hematologic and biochemical tests, light and electron microscopy, and electrophoresis of red cell membrane proteins. Response to the treatment was monitored using the blood count and reticulocyte count. The patient was age 14 when interferon treatment was started. Previously, she had been partially dependent on transfusions, and gallstones and iron overload had developed. The dose of interferon alpha2b was initially 3 x 10 units three times a week for 1 year and 3 x 10 units twice a week thereafter. On this treatment, hemoglobin and reticulocytes increased and transfusions became unnecessary. In keeping with a few previous reports, interferon alpha2b proved to be effective in congenital dyserythropoietic anemia, type 1. The patient became transfusion-independent. More cases need to be studied to optimize the dosage of interferon alpha2b and determine how long the treatment can be tolerated.

Childhood malignancies in French Polynesia during the 1985-1995 period.

We report an estimation of the incidence of childhood cancer among natives of French Polynesia (FP) during the 1985-1995 period. Our data were acquired from the Cancer Registry of FP and through an extensive investigation of other potential sources of information. The mean population of children between 1985 and 1995 was estimated to be 63 401 inhabitants, 32 487 of whom were boys and 30 914 girls, born and residing in FP. During the 1985-1995 period, 87 incident cases of childhood cancer were recorded among inhabitants born in FP or of an unknown place of birth (n = 2). Childhood cancer incidence had attained 125 cases/million child years and was very similar among girls (126 x 10(-6)) and boys (123 x 10(-6)), this incidence being slightly lower than among other populations of similar ethnic origin: Standardized Incidence Ratio (SIR) = 0.8 (95% CI: 0.7-1.0) when compared with New Zealand Maoris and SIR = 0.8 (95% CI: 0.6-1.0) when compared with natives from Hawaii. For both sexes considered together, the most frequent cancer type was leukaemia, followed by central nervous system (CNS) malignancies, neuroblastoma, and non-Hodgkin's lymphoma (NHL). Only one case of gonadal and germ cell tumours and one case of carcinoma were reported. Childhood cancer incidence was predominant among children living in the Windward, Leeward and Marquesas Islands and the Tuamotu-Gambier archipelago, but lower in the Austral Islands. The incidence of acute non-lymphocytic leukaemia (ANLL) decreased from 3.3 x 10(-5) between 1985 and 1989, an unexpectedly high incidence, to 0.8 x 10(-5) between 1990 and 1995.