ABSTRACT
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.
Subject(s)
Congenital Hypothyroidism , Humans , Congenital Hypothyroidism/diagnosis , Congenital Hypothyroidism/genetics , Mutation , Genomics , High-Throughput Nucleotide SequencingABSTRACT
STUDY OBJECTIVES: Narcolepsy with cataplexy is associated with obesity in children. We proposed to assess whether metabolic complications were linked to narcolepsy regardless of obesity. The second aim of the study was to compare endocrine comorbidities in obese children with narcolepsy and control patients. METHODS: We performed a case-control study in Pediatric Sleep Unit and Pediatric Endocrinology Unit of Woman Mother Child Hospital (Lyon, France) comparing 22 children with narcolepsy with 22 sex-, pubertal stage-, and BMI-matched non-syndromic obese patients. Clinical examination, biological measurements including an oral glucose tolerance test, and abdominal ultrasound were performed. RESULTS: No difference regarding glucidic, lipid profile, hepatic, respiratory, and cardiovascular parameters were found between narcoleptic and control participants. Insulin sensitivity did not differ between the two groups. Control patients had more first-degree family history of overweight or obesity than children with narcolepsy (83% vs. 50%, p = .05). Prevalence of precocious puberty in children with narcolepsy was not higher than in control participants, but all the cases of advanced puberty involved children with narcolepsy who were diagnosed before 11 years old. All cases of central hypothyroidism belong to the narcoleptic group, who presented lower thyroid-stimulating hormone and fTA values compared to control children (respectively p = .03 and p = .001). CONCLUSIONS: No difference regarding metabolic complications was found between children with narcolepsy and control participants. Thus, metabolic disorders may be related to weight gain rather than a narcolepsy-specific risk. The presence of hypothyroidism and advanced puberty suggests a global involvement of hypothalamic structures in children with narcolepsy.
