Mass Screening For Congenital Hypothyroidism Research Articles

A Novel Homozygous Mutation of Thyroid Peroxidase Gene Abolishes a Disulfide Bond Leading to Congenital Hypothyroidism.

Congenital hypothyroidism (CH) is the most prevalent congenital endocrine disorder and causes mental retardation. A male Japanese patient with first cousin marriage parents was diagnosed as CH at 10 months. He was born before introduction of mass screening for CH. With continuous thyroid hormone replacement therapy, normal thyroid hormone status was maintained until adulthood. Genetic screening of next-generation sequencing was performed at the age of 52 years, and we identified a new homozygous thyroid peroxidase (TPO) gene mutation (GRCh38.p13, chromosome 2 at position 1493997, c.1964 G>T, p.Cys655Phe). TPO is an important enzyme to produce thyroid hormone. As demonstrated by a homology analysis of TPO proteins among different species, cysteine 655 residue is highly conserved, suggesting an important role in maintaining TPO function and structure. An in silico study with three-dimensional structure of the novel mutation was performed and suggested that the mutation abolished disulfide bond between cysteines at positions 598 and 655. An in vitro functional analysis using HEK293 cells revealed that TPO activity of the mutant was significantly impaired compared with that of the wild type. Furthermore, study of immunohistochemistry showed that localization of TPO in cells did not differ between the wild type and the mutant. In conclusion, this single disulfide bond loss mutation of a new TPO homozygous mutation, p.Cys655Phe, reduced TPO activity and caused congenital hypothyroidism without affecting subcellular localization of TPO proteins.

Guidelines for Mass Screening of Congenital Hypothyroidism (2014 revision).

Purpose of developing the guidelines: Mass screening for congenital hypothyroidism started in 1979 in Japan, and the prognosis for intelligence has been improved by early diagnosis and treatment. The incidence was about 1/4000 of the birth population, but it has increased due to diagnosis of subclinical congenital hypothyroidism. The disease requires continuous treatment, and specialized medical facilities should make a differential diagnosis and treat subjects who are positive in mass screening to avoid unnecessary treatment. The Guidelines for Mass Screening of Congenital Hypothyroidism (1998 version) were developed by the Mass Screening Committee of the Japanese Society for Pediatric Endocrinology in 1998. Subsequently, new findings on prognosis and problems in the adult phase have emerged. Based on these new findings, the 1998 guidelines were revised in the current document (hereinafter referred to as the Guidelines). Target disease/conditions: Primary congenital hypothyroidism. Users of the Guidelines: Physician specialists in pediatric endocrinology, pediatric specialists, physicians referring patients to pediatric practitioners, general physicians, laboratory technicians in charge of mass screening, and patients.

Thyroid dysfunctions in children detected in mass screening for congenital hypothyroidism

Congenital hypothyroidism (CH) affects approximately 1:3000-1:4000 infants. To determine the prevalence of CH and isolated hyperthyrotropinemia (IHT) in newborns selected in mass screening for CH. Mass screening of 233,120 neonates born in southeastern Poland was carried out and CH-suspected children were identified. Serum thyroid-stimulating hormone and free thyroxine levels were determined during first confirmation and diagnosis re-evaluation in 118 and 34 children, respectively. Additionally, the patients were subjected to thyroid ultrasonography (n=53) and/or scintiscan (n=28). Out of 118 children, first confirmation indicated CH in 58 neonates and IHT in 4 neonates. Out of these, 34 were re-evaluated with regard to diagnosis. A final diagnosis of permanent CH was reported in 34 children with thyroid dysgenesis (n=27) or dyshormonogenesis (n=7), transient CH affected 15 children, and permanent IHT was diagnosed in 6 children. CH prevalence was 1:4570 (permanent 1:6475, transient 1:38,853) and permanent IHT 1:38,853. The prevalence of CH and IHT corresponds to the prevalence of the condition in iodine-sufficient and borderline iodine-deficient areas.

Elevated serum creatinine levels in infants with congenital hypothyroidism: reflection of decreased renal function?

UNLABELLED The effects of hypothyroid status on renal function have been poorly studied in children. We assessed the renal function of hypothyroid infants detected during neonatal mass screening for congenital hypothyroidism (CH). Eighty hypothyroid infants and 20 age-matched normal infants for controls were enrolled. The 80 patients, aged 1 mo, were divided into two groups based on the initial thyroid stimulating hormone (TSH) and free thyroxine (FT4) values: a mild-moderately hypothyroid (MHT) group (n = 64, 31M and 33F) and a severely hypothyroid (SHT) group (n = 16, 3M and 13F). Serum creatinine (SCr), TSH, FT4 and other chemicals were compared before and 2 mo after L-thyroxine (LT4) substitution therapy. The following results were obtained: SCr levels were significantly higher in the SHT group (33.2+/-10.0 micromol/L, p < 0.001) compared with the MHT group (20.6+/-6.4 micromol/L) and normal control group (21.0+/-4.4 micromol/L). Two months after the LT4 replacement therapy, the elevated SCr levels in the SHT group decreased by 41.3% to the level (19.5+/-6.0 micromol/L) very close to that in the MHT group (18.8+/-5.1 micromol/L). No significant differences were noted among BUN levels in the three groups. Although serum creatinine kinase levels were significantly higher in the SHT group (230.3+/-102.3 U/L, p < 0.001) than in the MHT group (121.1+/-60.8 U/L), rhabdomyolysis was not considered to be responsible for the impaired renal function. CONCLUSION From these results we conclude that serum creatinine levels are elevated in congenitally hypothyroid infants. This is a reversible change with thyroid hormone replacement therapy. The possibility of impaired renal functions should be kept in mind when treating hypothyroid infants.

A Japanese Patient of Congenital Hypothyroidism with Cerebellar Atrophy

We encountered a Japanese patient of congenital hypothyroidism with severe cerebellum atrophy. The boy was born after 40 weeks of gestation by normal vaginal delivery from nonconsanguineous parents. There were no abnormal physical findings; however neonatal mass screening for congenital hypothyroidism at 5 days of age demonstrated elevated thyrotropin (TSH) level (15.5 microU/ml, normal range 0.54-10.0 microU/ml). He was suspected to have subclinical or mild congenital hypothyroidism (CH). Thus he was treated with L-thyroxine using a regimen that rendered his serum TSH concentration within normal range from 27 days of age. Despite early and adequate treatment, he showed signs of global developmental delay and became gradually hypotonic and exhibited a staggering gait at 3 years of age. Brain magnetic resonance imaging (MRI) demonstrated marked cerebellar atrophy with an intact brainstem. Thyroidal uptake of radioiodide and thyroid gland size were normal, indicating a functional defect only. The relation between congenital hypothyroidism and severe cerebellar atrophy in our patient is not clear. As only a few cases of the combination of CH and cerebellar anomalies have been described previously, cerebellar symptoms in CH should be examined carefully.

Retrospective analysis of infants designated as positive on mass-screening for congenital hypothyroidism at kagoshima university.

Mass-screening for congenital hypothyroidism has identified cases of mild hypothyroidism, transient hypothyroidism, and transient hyperthyrotropinemia as well as typical hypothyroidism. In this paper, we examine the clinical data of the cases found positive in the screening test at our hospital. From 1989 to 1999 there were 72 patients with positive screening tests who started levothyroxine sodium (l-T4; Thyradin-S) as supplement therapy. At the age of 3 to 4 yr the patients were re-evaluated to determine whether treatment should be continued. Thyroid scintigraphies were done at the same time. We divided these cases into 4 groups. Those in group 1A started l-T4 in early infancy without a TRH test because of obvious clinical evidence of hypothyroidism, and treatment was continued after re-evaluation (n=37). Those in group 1B also started treatment in early infancy without a TRH test, but treatment was discontinued after re-evaluation (n=20). Patients in group 2A started l-T4 after evaluation by a TRH test and treatment was continued after re-evaluation (n=14), while those in group 2B started treatment after a TRH test, but after re-evaluation, treatment was discontinued (n=1). In group 2A, only a low dose of l-T4 was needed, and a slightly elevated TSH and slightly decreased free T4 (FT4) were observed after the drug washout period. However, these patients had an exaggerated response to the TRH test at re-evaluation. These findings indicate that this group, forming not a small part of whole screening-positive subjects, had mild hypothyroidism. Such patients require careful follow-up and repeated evaluation to determine whether treatment should be continued.

Plasma Free Fatty Acids in Neonates with Congenital Hypothyroidism

Since the introduction of neonatal mass screening for congenital hypothyroidism (CH), numerous cases have been detected. It is of interest that even severely hypothyroid neonates rarely exhibit bradycardia, hypothermia, or inactivity, which have been recognized as typical signs of CH. Regarding neonates and young infants, few reported data are available on the effects of thyroid hormones on energy expenditure. Plasma free fatty acids (FFAs), markers for lipolysis, play essential roles in maintaining physiologic homeostasis. To study fuel utilization in CH neonates, we measured heart rates, plasma FFA, and thyroid hormones before and after levothryoxine (LT4) replacement therapy. Fifty-five screen-detected CH neonates and 29 age-matched normal neonates for controls were enrolled. The CH neonates were divided into two groups according to serum thyroid hormone levels: a mildly hypothyroid group (n = 37), serum thyrotropin (TSH) less than 100 microIU/mL and free thyroxine (FT4) 0.6 ng/dL or more; and a severely hypothyroid group (n = 18), TSH 100 microIU/mL or more and FT4 less than 0.6 ng/dL. Twenty-four of the 55 patients had their heart rates measured by electrocardiography. Fasting blood samples were taken from the subjects during physical movements. Serum levels of TSH, FT4, FFA, and other blood chemicals, measured on an autoanalyzer system in our hospital, were compared before and after LT4 substitution therapy. The following results were obtained. The mean plasma FFA values before LT4 replacement were 208.5 +/- 89.4 microEq/L in the mildly hypothyroid group, 228.5 +/- 114.7 microEq/L in the severely hypothyroid group, and 213.9 +/- 97.7 microEq/L in controls. No statistical differences were noted among the three values. Two months after LT4 replacement therapy, at the age of 3 months, plasma FFA concentrations significantly increased in both groups compared with those before the therapy. Control infants also showed a significant increase in plasma FFA concentrations from 1 to 3 months of age. There were no significant differences in plasma FFA concentrations among the three groups at the age of 3 months. No significant correlations were found between plasma FFA and serum thyroid hormones. From these results it is suggested that in neonates and young infants, thyroid hormones do not play major roles in mobilization of fats through the adrenergic regulation of lipolysis for energy supply. This may be one of the reasons for the unexpectedly mild signs and symptoms in the screen-detected hypothyroid neonates.

Elevated serum creatinine levels in infants with congenital hypothyroidism: reflection of decreased renal function?

The effects of hypothyroid status on renal function have been poorly studied in children. We assessed the renal function of hypothyroid infants detected during neonatal mass screening for congenital hypothyroidism (CH). Eighty hypothyroid infants and 20 age-matched normal infants for controls were enrolled. The 80 patients, aged 1 mo, were divided into two groups based on the initial thyroid stimulating hormone (TSH) and free thyroxine (FT4) values: a mild-moderately hypothyroid (MHT) group (n = 64, 31M and 33F) and a severely hypothyroid (SHT) group (n = 16, 3M and 13F). Serum creatinine (SCr), TSH, FT4 and other chemicals were compared before and 2 mo after L-thyroxine (LT4) substitution therapy. The following results were obtained: SCr levels were significantly higher in the SHT group (33.2+/-10.0 micromol/L, p < 0.001) compared with the MHT group (20.6+/-6.4 micromol/L) and normal control group (21.0+/-4.4 micromol/L). Two months after the LT4 replacement therapy, the elevated SCr levels in the SHT group decreased by 41.3% to the level (19.5+/-6.0 micromol/L) very close to that in the MHT group (18.8+/-5.1 micromol/L). No significant differences were noted among BUN levels in the three groups. Although serum creatinine kinase levels were significantly higher in the SHT group (230.3+/-102.3 U/L, p < 0.001) than in the MHT group (121.1+/-60.8 U/L), rhabdomyolysis was not considered to be responsible for the impaired renal function. From these results we conclude that serum creatinine levels are elevated in congenitally hypothyroid infants. This is a reversible change with thyroid hormone replacement therapy. The possibility of impaired renal functions should be kept in mind when treating hypothyroid infants.

Enzyme Immunoassay of Thyroid-Stimulating Hormone Using Dried Blood Samples a Simple Technique of Screening for Congenital Hypothyroidism

Abstract A method for enzyme imnunoassay of thyroid-stimulating hormone (TSH) in dried blood spotted onto filter paper has been developed. TSH was conjugated to horse-radish peroxidase according to Nakane's method. Separation of the bound and free fractions was obtained by a double antibody solid phase method using polyacetal beads which were coated with the purified IgG fraction from goat anti-rabbit IgG serum. p-Hydroxyphenyl propionic acid was used as substrate for the fluorophotometric assay of peroxidase activity. The assay sensitivity is 0.07, μU TSH/assay tube, which is equivalent to μU/ml when five 3 mm discs of dried blood spot are assayed. TSH values in dried blood samples obtained by this method correlate well with those of serum samples obtained by radioimmunoassay (r=0.89). The coefficients of variation were 6.8 to 13.4% (within assay) and 5 to 40% (between assay). The enzyme immunoassay of TSH presented here is applicable to the mass-screening for congenital hypothyroidism of neonate.