ABSTRACT
UNLABELLED: Absract Purpose: Mutations in the TPO gene have been reported to cause congenital hypothyroidism (CH), and our aim in this study was to determine the genetic basis of congenital hypothyroidism in two affected children coming from a consanguineous family. METHODS: Since CH is usually inherited in autosomal recessive manner in consanguineous/multi case-families, we adopted a two-stage strategy of genetic linkage studies and targeted sequencing of the candidate genes. First we investigated the potential genetic linkage of the family to any known CH locus using microsatellite markers and then screened for mutations in linked-gene by Sanger sequencing. RESULTS: The family showed potential linkage to the TPO gene and we detected a non-sense mutation (Y55X) in both cases that had total iodode organification defect (TIOD). The mutation segregated with disease status in the family. Y55X is the only truncating mutation in the exon 2 of the TPO gene reported in the literature and results in the earliest stop codon known in the gene to date. CONCLUSIONS: This study confirms the pathogenicity of Y55X mutation and demonstrates that a nonsense mutation in the amino-terminal coding region of the TPO gene could totally abolish the function of the TPO enzyme leading to TIOD. Thus it helps to establish a strong genotype/phenotype correlation associated with this mutation. It also highlights the importance of molecular genetic studies in the definitive diagnosis and accurate classification of CH.
Subject(s)
Autoantigens/genetics , Congenital Hypothyroidism/genetics , Iodide Peroxidase/genetics , Iron-Binding Proteins/genetics , Mutation , Adolescent , Child , Child, Preschool , DNA Mutational Analysis , Female , Humans , Infant , Male , SiblingsABSTRACT
It is known that type 1 diabetes mellitus (type 1 DM) may be associated with other autoimmune diseases. Recently, a patient with an association of type 1 DM and familial Mediterranean fever (FMF) was reported in the medical literature. A 10.5-year-old boy was brought to our clinic with complaints of polydipsia, polyuria and weight loss and was diagnosed as diabetic ketoacidosis due to autoimmune type 1 DM. Insulin therapy was started. Elevated thyroid antibodies associated with diffuse goiter and hypothyroidism led to the diagnosis of autoimmune thyroid disease (ATD), and elevated antiendomysial antibodies and abnormal intestinal biopsy findings led to the diagnosis of celiac disease (CD). L-thyroxine therapy and gluten-free diet were initiated accordingly. At the third-year of follow-up, acute attacks of fever, abdominal pain and chest pain developed. Laboratory investigations, which were normal between the attacks, revealed elevated erythrocyte sedimentation rate, fibrinogen, white blood cell count and pleural effusion on chest X-ray during the attacks. Molecular analysis for FMF revealed compound heterozygous M694I and V726A. The patient responded well to colchicine therapy started at a dose of 1.5 mg/day. We present the second patient with type 1 DM associated with FMF who also had ATD and CD.
Subject(s)
Celiac Disease/complications , Diabetes Mellitus, Type 1/complications , Familial Mediterranean Fever/complications , Thyroiditis, Autoimmune/complications , Thyroxine/therapeutic use , Adolescent , Celiac Disease/diagnosis , Celiac Disease/diet therapy , Child , Colchicine/therapeutic use , Diabetes Mellitus, Type 1/diagnosis , Diabetes Mellitus, Type 1/drug therapy , Diet, Gluten-Free , Familial Mediterranean Fever/diagnosis , Familial Mediterranean Fever/drug therapy , Gout Suppressants/therapeutic use , Humans , Hypoglycemic Agents/therapeutic use , Insulin/therapeutic use , Male , Thyroiditis, Autoimmune/diagnosis , Thyroiditis, Autoimmune/drug therapyABSTRACT
BACKGROUND: Premature born children may show insulin resistance in childhood which may be due to intrauterine or postnatal adverse environmental factors. OBJECTIVE: Aim of this study was to evaluate insulin resistance and body composition in preterm born children born appropriate for gestational age (AGA) or small for gestational age (SGA) and relations with IGF-I, IGFBP-3 axis. METHODS: Ninety-three preterm born children grouped as premature SGA (n = 30) and premature AGA (n = 63) were evaluated at age 4.6 +/- 0.2 years and 4.7 +/- 0.1 years with respect to their glucose, insulin, IGF-I, IGFBP-3, IGFBP-1, leptin levels and body composition by dual-energy X-ray absorptiometry. Their data were compared to that of body mass index (BMI) matched term SGA (n = 42) and term AGA (n = 44) children of age 4.5 +/- 0.2 and 3.8 +/- 0.1 years. All children had height appropriate for their target height. Insulin resistance was evaluated by basal insulin and homeostasis model assessment for insulin resistance (HOMA-IR). RESULTS: Basal insulin level was similar in preterm AGA (4.3 +/- 1.4 pmol/l) and term AGA (7.9 +/- 6.4 pmol/l) children at similar and normal BMI levels. Preterm SGA children had insulin levels (5.0 +/- 3.6 pmol/l) similar to preterm AGA children but significantly lower than that in term SGA children (23.7 +/- 20.8 pmol/l) (P = 0.001). Similar results were obtained for HOMA-IR. Term SGA children had also significantly lower IGFBP-1 levels. Body composition, leptin and IGFBP-3 did not differ between the respective groups. IGF-I was lower in preterm AGA (5.0 +/- 0.6 nmol/l) than in term AGA (8.3 +/- 1.2 nmol/l) (P < 0.001) children. CONCLUSIONS: Premature born AGA and SGA children do not have insulin resistance when compared to term children if they have made a catch-up growth appropriate for their target height and have normal BMI. The similar insulin levels in preterm SGA and preterm AGA children together with increased insulin levels in term SGA children points to the fact that it is the intrauterine restriction in the third trimester that has an adverse effect on future adverse metabolic outcome.
