38 research outputs found
Evolution of thyroid function in preterm infants detected by screening for congenital hypothyroidism
No full textObjective: To determine the evolution of congenital hypothyroidism in preterms and the clinical features of permanent forms. Study design: We retrospectively evaluated 24 preterm children detected by newborn screening for congenital hypothyroidism: first screening with blood-thyroid stimulating hormone cutoff 10 mU/L and second screening with blood-thyroid stimulating hormone cutoff 5 mU/L. After the age of 2 years, patients with eutopic thyroid had diagnostic reevaluations, including thyroid function testing and thyroid ultrasonography after L-thyroxine therapy withdrawal. Results: The first screening identified 21.7% of patients with thyroid stimulating hormone elevation, and the second screening identified 73.9% of patients. One patient (4.4%) was identified with a third screening test; 21 patients had an eutopic thyroid and 3 patients a thyroid dysgenesis. At reevaluation, 5 patients (23.8%) showed permanent hypothyroidism (serum-thyroid stimulating hormone [s-TSH] >10 mU/L) resulting in the need to reintroduce therapy, 5 patients (23.8%) showed persistent hyperthyrotropinemia (s-TSH 5-10 mU/L), and 11 infants (52.4%) transient hypothyroidism (s-TSH <5 mU/L). The main clinical features of patients affected by permanent hypothyroidism were 1 case of assisted reproduction, 2 twins, 2 small for gestational age, 1 maternal thyroiditis, and 2 patients with malformations/syndromes. Conclusions: Premature birth is a significant risk for congenital hypothyroidism with eutopic thyroid. In preterm infants, the evolution of congenital hypothyroidism remains difficult to predict. Our data emphasizes the high incidence of transient hypothyroidism in preterm infants, and the importance of diagnostic reevaluation to determine the definitive diagnosis. © 2014 Elsevier Inc. All rights reserved
Congenital hypothyroidism with gland in situ: diagnostic re-evaluation
No full textIn the past, most congenital hypothyroidism (CH) children with thyroid gland in situ were considered to be affected by hormonogenesis defect. Nowadays, the improved sensitivity of neonatal screening, novel insights into the pathogenic mechanisms and the advances of genetic analyses have reopened the discussion about the etiology of CH with thyroid in situ. We report the etiological re-evaluation of 31 children with thyroid in situ, who had been identified by the CH screening program. The purposes of this re-evaluation were: a) to investigate the definitive diagnosis and pathogenetic mechanism of CH with thyroid in situ in eligible children suspected of dyshormonogenetic defect and b) to verify the adequacy of the treatment schedules. Thirty out of 31 children were affected with permanent hypothyroidism and only one child was euthyroid at re-evaluation (transient CH). Thyroid hormone organisation defects were present in less than half of the CH patients with thyroid in situ (13/30); a higher prevalence of partial defects of iodine organification than severe or complete forms was found. An inactivating TSH-receptor gene mutation was found in only one patient without iodine organification defect. Some questions remain unanswered concerning the adequacy of the schedules of treatment, particularly about the proper treatment of mild and borderline forms of CH
Congenital hypothyroidism with gland in situ: diagnostic revaluation.
No full textIn the past, most Congenital Hypothyroidism (CH) children with thyroid gland in situ were considered to be affected by hormonogenesis defect. Nowadays, the improved sensitivity of neonatal screening, novel insights into the pathogenic mechanisms and the advances of genetic analyses have reopened the discussion about the etiology of CH with thyroid in situ. We report the etiological revaluation of 31 children with thyroid in situ, who had been identified by the CH screening program. The purpose of this revaluation was to investigate the definitive diagnosis and pathogenic mechanism of CH with thyroid in situ in eligible children suspected of dyshormonogenic defect and to verify the adequacy of the treatment schedules.
Thirty out of thirty-one children were affected with permanent hypothyroidism and only one child was euthyroid at revaluation (transient CH). I-123 scintigraphy with perchlorate discharge test showed 13 children with iodine organification defects. In patients without iodine organification defect, analyses of TSH-receptor and PAX8 genes showed an inactivating TSH-receptor gene mutation in one patient.
Thyroid hormone organification defect were present only in half of the CH patients with thyroid in situ. A higher prevalence of partial defects of iodine organification than severe or complete forms was found. So far, genetic analyses have provided etiological diagnosis in a limited subset of patients. Some questions remain unanswered concerning the proper treatment of mild and borderline forms of CH
NovelNKX2-1frameshift mutations in patients with atypical phenotypes of the brain-lung-thyroid syndrome
No full textbjectives: To verify the involvement of NKX2-1 gene in infants with brain-lung-thyroid (BLT) syndrome and hypothyroid phenotypes variable among congenital hypothyroidism (CH) or idiopathic mild hypothyroidism (IMH) of postnatal onset. Methods: The candidates were selected by a case-finding approach in 130 CH and 53 IMH infants. The NKX2-1 gene was analyzed by direct sequencing and multiplex ligation-dependent probe amplification. The variants were studied in vitro, by expression analyses and luciferase bioassay. Results: Four cases (3 CH and 1 IMH) consistent with BLT syndrome were identified. Two children were affected with respiratory distress and CH, but wild-type NKX2-1 gene. The remaining two presented choreic movements and no pulmonary involvement, but discrepant thyroid phenotypes: one had severe CH with lingual ectopy and the other one IMH with gland in situ. They were carriers of new de novo heterozygous frameshift mutations of NKX2-1 (c.177delG and c.153_166del14). The c.177delG leads to a prematurely truncated protein (p.H60TfsX11) with undetectable activity in vitro. The c.153_166del14 leads to the generation of an elongated aberrant protein (p.A52RfsX351) able to translocate into the nucleus, but completely inactive on a responsive promoter. Conclusions: Two novel heterozygous frameshift mutations of NKX2-1 were identified in 2 cases selected on the basis of a BLT-like phenotype among 183 hypothyroid infants. The atypical hypothyroid phenotypes of these 2 children (CH with lingual ectopy or IMH of postnatal onset) further expand the clinical spectrum that can be associated with NKX2-1 mutations
Total iodide organification defect : clinical and molecular characterization of an Italian family
No full textThyroid peroxidase (TPO) deficiency is frequently involved in total iodide organification defects (TIOD). According to the recessive mode of inheritance, mutations are found in homozygous or in compound heterozygous states. However, a single heterozygous TPO mutation is reported in a high percentage (approximately
20%) of patients with typical TIOD phenotype. In the present study, the genetic and clinical evaluation of a TIOD family is reported. The propositus is an Italian girl with congenital hypothyroidism and positive perchlorate discharge test. Two TPO frameshift mutations were documented: a C deletion at 477 in exon 5, and a GGCC duplication at 1277 in exon 8. Unaffected family members, heterozygous for one of the two TPO mutations, were also studied in order to evaluate in vivo the functional activity of a single TPO allele. They have been found to have normal thyroid morphology and function with normal perchlorate test. In conclusion, the
present study reports the clinical and molecular investigations in an Italian TIOD family. The results show that the TIOD phenotype in the propositus is associated to a compound heterozygous pattern, while a single TPO mutation does not significantly affect in vivo the efficiency of iodide organification. Therefore, extensive analyses of TPO gene and 2p25 locus are needed in the frequent TIOD cases in whom conventional investigations disclosed only one mutant allele
The evolution of neonatal TSH screening strategies modifies the characteristics of congenital hypothyroidism
No full textDifficult treatment of consumptive hypothyroidism in a child with massive parotid hemangioma
No full textConsumptive hypothyroidism is a rare condition related to massive infantile hemangiomas producing an excess of the thyroid-hormone-inactivating enzyme type 3 iodothyronine deiodinase. We report the first case of consumptive hypothyroidism secondary to a large parotid hemangioma, highlighting the difficulties in selecting an adequate therapeutic strategy. The affected child was initially referred to our center for congenital hypothyroidism with a hypoplastic thyroid gland. L-Thyroxine (L-T4) replacement therapy was started at seven days of life. In the following weeks, the hemangioma rapidly increased in volume and the child developed severe hypothyroidism refractory to high doses of L-T4 therapy. The concentration of reverse triiodothyronine was elevated, suggesting that the underlying cause was an excessive conversion of thyroid hormones by high type 3 iodothyronine deiodinase levels in the tumor. Corticosteroid treatment showed only partial benefit. Introduction of propranolol instead led to normalization of thyroid hormones along with a dramatic involution of the hemangiom
Persistent mild hypothyroidism associated with novel sequence variants of the DUOX2 gene in two siblings
No full textOne of the steps in thyroid hormone biosynthesis is the generation of hydrogen peroxide by dual oxidases (DUOX). Only one study reported mutations in DUOX2 gene in congenital hypothyroidism (CH) associated with total iodide organification defect (TIOD) in homozygosity or with partial iodide organification defect (PIOD) in heterozygous patients. We report genetic and phenotypic characterization of a family affected with isolated CH. The proband was positive at neonatal TSH screening. High serum TSH with low FT4 confirmed the diagnosis. At 4 years, TSH was high after L-T(4) withdrawal and (123)I scintigraphy with perchlorate discharge test revealed a PIOD. His brother was negative at TSH screening, but perinatal iodine overload was documented by urinary test. Serum TSH was elevated at postnatal day 11 and progressively increased together with a decline in urinary iodine. Reevaluation at 4 years confirmed a persistent hyperthyrotropinemia associated with PIOD. Both siblings resulted compound heterozygotes for two novel DUOX2 variants, a nonsense mutation (c.2524C>T, p.Arg842X) and a missense substitution (c.1126C>T, p.Arg376Trp), undetected in 140 control alleles. The parents had normal thyroid function and were heterozygous carriers of mutant alleles. In conclusion, we report two novel sequence variants in DUOX2 gene that are associated with persistent mild hypothyroidism and PIOD in two siblings. Different neonatal iodine supply apparently acted as disease modifier, justifying the discrepant results at TSH screening in the two siblings with same DUOX2 genotype and suggesting that mild dyshormonogenic defects may remain undisclosed in areas characterized by elevated iodine intake
Congenital hypothyroidism with eutopic thyroid gland : analysis of clinical and biochemical features at diagnosis and after re-evaluation
No full textContext: In recent years changes in screening strategies for congenital hypothyroidism (CH) led to an increased detection of mild forms of CH, associated with eutopic thyroid gland. Objectives: We aimed to determine the clinical evolution of CH with eutopic thyroid gland and to find out prognostic factors at diagnosis and follow-up. Patients and Methods: We retrospectively analyzed agroup of84 children withCH andeutopic thyroid gland treated at our institution. They all underwent clinical re-evaluation after the age of 3, based on thyroid function testing after L-thyroxine therapy withdrawal, thyroid ultrasonography, and 123I scintigraphy with perchlorate discharge test. Genetic analysis was performed in selected cases. Results: At re-evaluation, 34.5% of patients showed permanent hypothyroidism and needed L-thyroxine reintroduction, 27.4% had persistent hyperthyrotropinemia (TSH5-10mU/L), and 38.1% had transient hypothyroidism. Major risk factors for permanent CH were prematurity, first-degree familial history of goiter/nodules, thyroid hypoplasia at diagnosis, and high L-thyroxine requirements at follow-up. Iodine organification defects were found in 29.7% of patients, 30% of whom harbored DUOX2 mutations. TSH receptor gene mutations were found in 8.7% of patients with persistent thyroid dysfunction and negative perchlorate discharge test. Conclusions: Only one-third of patients with CH and eutopic thyroid gland needed to continue L-thyroxine therapy after re-evaluation. A frequent finding was the persistence of mild hyperthy-rotropinemia. The evolution of CH remains difficult to predict, although different clinical features might suggest different outcomes. Mutations in the genes commonly linked to mild forms of CH were documented in a minority of cases. Copyrigh
A 7-year experience with low blood TSH cutoff levels for neonatal screening reveals an unsuspected frequency of congenital hypothyroidism (CH)
No full textContext The guidelines of the National Academy of Clinical Biochemistry advocated the use of low bloodspot TSH (b-TSH) threshold for newborn screening of congenital hypothyroidism (CH). The impact generated by the application of this indication is largely unknown. Objective To determine the impact on CH epidemiology and classification generated by the introduction of low b-TSH cutoff. Design Retrospective study of 629,042 newborns screened with b-TSH cutoffs of 12 (years 1999-2002) or 10 mU/l (2003-2005). Measurements Congenital hypothyroidism incidence and classification. Results were compared with those virtually obtained with the previous cutoff (20 mU/l). Clinical re-evaluation after L-T4 withdrawal of a representative group of 140 CH children at 3-5 years. Results Low b-TSH cutoffs allowed the detection of 435 newborns with confirmed CH (incidence 1:1446). Forty-five percent of CH infants, including 12/141 dysgenesis, would have been missed using the 20 mU/l cutoff. In contrast to current classification, 32% CH newborns had thyroid dysgenesis and 68% had a gland in situ (GIS). Premature birth was present in 20% of cases being associated with a 3-5 fold increased risk of GIS CH. Re-evaluation at 3-5 years showed a permanent thyroid dysfunction in 78% of 59 CH toddlers with GIS. Conclusions The use of low b-TSH cutoff allowed the detection of an unsuspected number of children with neonatal hypothyroidism, evolving in mild permanent thyroid dysfunction later in life. The incidence of CH in this Italian population appears to be double than previously thought with a clear-cut prevalence of functional defects over dysgenetic ones
