The Severity of Congenital Hypothyroidism With Gland-In-Situ Predicts Molecular Yield by Targeted Next-Generation Sequencing.

INTRODUCTION: Congenital hypothyroidism with gland-in-situ (CH-GIS) is usually attributed to mutations in the genes involved in thyroid hormone production. The diagnostic yield of targeted next-generation sequencing (NGS) varied widely between studies. We hypothesized that the molecular yield of targeted NGS would depend on the severity of CH. METHODS: Targeted NGS was performed in 103 CH-GIS patients from the French national screening program referred to the Reference Center for Rare Thyroid Diseases of Angers University Hospital. The custom targeted NGS panel contained 48 genes. Cases were classified as solved or probably solved depending on the known inheritance of the gene, the classification of the variants according to the American College of Medical Genetics and Genomics, the familial segregation, and published functional studies. Thyroid-stimulating hormone at CH screening and at diagnosis (TSHsc and TSHdg) and free T4 at diagnosis (FT4dg) were recorded. RESULTS: NGS identified 95 variants in 10 genes in 73 of the 103 patients, resulting in 25 solved cases and 18 probably solved cases. They were mainly due to mutations in the TG (n = 20) and TPO (n = 15) genes. The molecular yield was, respectively, 73% and 25% if TSHsc was ≥ and < 80 mUI/L, 60% and 30% if TSHdg was ≥ and < 100 mUI/L, and 69% and 29% if FT4dg was ≤ and > 5 pmol/L. CONCLUSION: NGS in patients with CH-GIS in France found a molecular explanation in 42% of the cases, increasing to 70% when TSHsc was ≥ 80 mUI/L or FT4dg was ≤ 5 pmol/L.

Earlier diagnosis in anorexia nervosa: better watch growth charts!

BACKGROUND: A better understanding of the healthcare pathway of children and adolescents with anorexia nervosa (AN) may contribute to earlier detection and better disease management. Here we measured and compared the symptomatic time to diagnosis (TTD) (time between the first symptoms, as reported by parents, and the diagnosis) and the auxological TTD (time between the deviation in the weight growth curve and the diagnosis). METHODS: We performed a monocentric retrospective study including all patients age 9 years to 16 years who were hospitalized in Nantes University Hospital for AN between 2013 and 2016. We analysed the two TTDs by medical record review and growth curve investigation. TTDs were described by medians and Kaplan-Meier curves. Two profiles of patients were compared according to the kinetics of growth deviation and the occurrence of symptoms. RESULTS: Among the 137 patients included, the median symptomatic and auxological TTDs was 7.0 months (IQR: 4.0-12.0) and 7.2 months (IQR: 2.0-18.0). TTDs were significantly different but clinically similar. For 48% of the patients, a deviation in the growth curve could have been noted at a median of 9.7 months (IQR: 3.0-18.0) before the first symptoms were reported by parents. Those patients showed significantly slower weight loss than did patients with first symptoms reported before growth deviation (weight loss rate 0.41% vs 1.90% per month, p < 0.0001). CONCLUSIONS: Careful study of growth curves remains an essential step in detecting eating disorders, possibly allowing for earlier detection of the disease in nearly half of these patients.

Increasing knowledge in IGF1R defects: lessons from 35 new patients.

BACKGROUND: The type 1 insulin-like growth factor receptor (IGF1R) is a keystone of fetal growth regulation by mediating the effects of IGF-I and IGF-II. Recently, a cohort of patients carrying an IGF1R defect was described, from which a clinical score was established for diagnosis. We assessed this score in a large cohort of patients with identified IGF1R defects, as no external validation was available. Furthermore, we aimed to develop a functional test to allow the classification of variants of unknown significance (VUS) in vitro. METHODS: DNA was tested for either deletions or single nucleotide variant (SNV) and the phosphorylation of downstream pathways studied after stimulation with IGF-I by western blot analysis of fibroblast of nine patients. RESULTS: We detected 21 IGF1R defects in 35 patients, including 8 deletions and 10 heterozygous, 1 homozygous and 1 compound-heterozygous SNVs. The main clinical characteristics of these patients were being born small for gestational age (90.9%), short stature (88.2%) and microcephaly (74.1%). Feeding difficulties and varying degrees of developmental delay were highly prevalent (54.5%). There were no differences in phenotypes between patients with deletions and SNVs of IGF1R. Functional studies showed that the SNVs tested were associated with decreased AKT phosphorylation. CONCLUSION: We report eight new pathogenic variants of IGF1R and an original case with a homozygous SNV. We found the recently proposed clinical score to be accurate for the diagnosis of IGF1R defects with a sensitivity of 95.2%. We developed an efficient functional test to assess the pathogenicity of SNVs, which is useful, especially for VUS.

Association of maternal nutrition with transient neonatal hyperinsulinism.

OBJECTIVE: The objective was to determine whether maternal nutritional factors are associated with transient neonatal hyperinsulinism (HI). DESIGN AND SETTING: Case control study in 4 French tertiary Obstetrics and Neonatology Departments between 2008 and 2015. METHODS: Sixty-seven mothers of neonates diagnosed with transient hyperinsulinism and 113 mothers of controls were included. The screening for hyperinsulinemic hypoglycemia in neonates was performed because of clinical symptoms suggestive of hypoglycemia or in the presence of conventional risk factors (small-for-gestational-age, prematurity, anoxo-ischemia, hypothermia, macrosomia, gestational diabetes). Hyperinsulinemic hypoglycemia was confirmed in the HI neonates and ruled out in the controls. This allowed for comparing maternal nutrition in cases and controls in a context of similar risk factors. One to 2 mothers of control neonates were included per case, and a food frequency questionnaire was addressed to the mothers between day 5 and day 10 after the birth of their newborn. RESULTS: Crude odds ratio showed that maternal weight gain, abnormal fetal rate, C-section, gender, consumption of fresh cooked vegetables, fresh fruits and fruit juices, low fat diary products, light fat products, and daily bread were significantly associated with hyperinsulinism. Maternal body mass index, hypertension, gestational diabetes, birth weight percentile, gestational age and 5-minute Apgar score were not related to HI. In a multiple backward logistic regression model, consumption of fresh cooked vegetable ≥1/day (OR = 0.33 [0.14-0.77]) and light-fat products ≥1/week (OR = 0.24 [0.08-0.71]) was protective against hyperinsulinism, whereas gestational weight gain >20 kg (OR = 9.5 [2.0-45.5]) and between 15-20 kg (OR = 4.0 [1.2-14.0]), abnormal fetal heart rate (OR = 4.4 [1.6-12.0]), and C-section (OR = 3.4 [1.3-8.9]) were risk factors. CONCLUSIONS: A diet rich in fresh cooked vegetable and reduced in fat, together with the avoidance of a high gestational weight gain may be protective against transient neonatal hyperinsulinism.

[Clinic of somatoform disorders in abused adolescents]. / Clinique des troubles somatoformes chez les adolescents maltraités.

UNLABELLED: Child abuse represents a contributing factor to develop various psychopathological disorders, such as somatoform disorders. OBJECTIVES: Improving the detection of child abuse, based on the analysis of somatoform disorders and the comparison between non-abused and abused patients, in a population of hospitalized teens in a general pediatric ward. METHODS: A retrospective study at the University Hospital of Nantes, involving every adolescents from 11 to 16 y.o. hospitalized in pediatric ward and cured by the child psychiatrist medical team, whatever the reason, over the year 2012 (n=231). RESULTS: Thirty-three percent of hospitalized adolescents had history of abuse. Physical abuses were dominant (54% vs. 24% sexual vs. 22% psychological). Our study highlight a statistically significant difference on the frequency of somatoform disorders between abused adolescents and not abused witness population (70% vs. 40%; P=0.0001). Gastrointestinal complaints (25% vs. 14.2%; P=0.0434) and musculoskeletal pains (13.2% vs. 4.5%; P=0.0291) appeared more significantly in abused adolescents population rather than non-abused adolescents. Somatoform disorders were not related to the frequency or type of abuse, except for gastrointestinal complaints, being more frequent in patients who were psychologically abused (51.7% vs. 26.7% sexual vs. 11.8% physical; P=0.005). CONCLUSION: Somatoform disorders are an interesting way to spot adolescents suffering from abuse, justifying a systematic investigation for child abuse. It remains, however, a warning not directing to any specific type of abuse.

Identifying the Deleterious Effect of Rare LHX4 Allelic Variants, a Challenging Issue.

LHX4 is a LIM homeodomain transcription factor involved in the early steps of pituitary ontogenesis. To date, 8 heterozygous LHX4 mutations have been reported as responsible of combined pituitary hormone deficiency (CPHD) in Humans. We identified 4 new LHX4 heterozygous allelic variants in patients with congenital hypopituitarism: W204X, delK242, N271S and Q346R. Our objective was to determine the role of LHX4 variants in patients' phenotypes. Heterologous HEK293T cells were transfected with plasmids encoding for wild-type or mutant LHX4. Protein expression was analysed by Western Blot, and DNA binding by electro-mobility shift assay experiments. Target promoters of LHX4 were cotransfected with wild type or mutant LHX4 to test the transactivating abilities of each variant. Our results show that the W204X mutation was associated with early GH and TSH deficiencies and later onset ACTH deficiency. It led to a truncated protein unable to bind to alpha-Gsu promoter binding consensus sequence. W204X was not able to activate target promoters in vitro. Cotransfection experiments did not favour a dominant negative effect. In contrast, all other mutants were able to bind the promoters and led to an activation similar as that observed with wild type LHX4, suggesting that they were likely polymorphisms. To conclude, our study underlines the need for functional in vitro studies to ascertain the role of rare allelic variants of LHX4 in disease phenotypes. It supports the causative role of the W204X mutation in CPHD and adds up childhood onset ACTH deficiency to the clinical spectrum of the various phenotypes related to LHX4 mutations.

A new mutation in the C-SH2 domain of PTPN11 causes Noonan syndrome with multiple giant cell lesions.

Noonan syndrome (NS), an autosomal dominant multisystem disorder, is caused by the dysregulation of the RAS-MAPK pathway and is characterized by short stature, heart defects, pectus excavatum, webbed neck, learning problems, cryptorchidism and facial dysmorphism. We here present the clinical and molecular characterization of a family with NS and multiple giant cell lesions (MGCLs). The proband is a 12-year-old girl with NS and MGCL. Her mother shows typical NS without MGCL. Whole-exome sequencing of the girl, her mother and her healthy maternal grand parents revealed a previously unobserved mutation in exon 5 of the PTPN11 gene (c.598 A>T; p.N200Y), transmitted from the mother to the proband. As no other modification in the RAS-MAPK pathway genes as related to Rasopathies was detected in the proband, this report demonstrates for the first time that a unique mutation affecting this, otherwise unaffected signaling route, can cause both NS and NS/MGCL in the same family. This observation further confirms that NS/MGCL is not a distinct entity but rather that MGCL represents a rare complication of NS. Moreover, the localization of the p.N200Y mutation suggests an alternative molecular mechanism for the excessive phosphatase activity of the PTPN11-encoded protein.

Exudative retinopathy, cerebral calcifications, duodenal atresia, preaxial polydactyly, micropenis, microcephaly and short stature: a new syndrome?

The association of Coats disease with intrauterine growth retardation, intracranial calcification, leukodystrophy, brain cysts, osteopenia, and gastrointestinal bleeding defines Coats plus syndrome caused by mutations in the CTC1 gene, encoding conserved telomere maintenance component 1. Here, we report on a child with exudative retinopathy, cerebral calcifications, duodenal atresia, preaxial polydactyly, micropenis, microcephaly, and short stature, in whom no mutations in CTC1 were found. Our patient shares some features seen in other diseases associated with telomere shortening including Hoyeraal-Hreidarsson and Revesz syndromes. We therefore measured telomere length by Flow-Fish which was normal. The association of duodenal atresia and microcephaly also suggested a diagnosis of Feingold syndrome. However, direct sequencing of MYCN was normal, and we did not detect any hemizygous deletion of the miR-17∼92 polycistronic miRNA cluster. To our knowledge, the phenotype we report on has not been described previously, leading us to speculate that this condition may represent a new syndrome.