Cases Of Congenital Hypothyroidism Research Articles

An audit to assess the impact of increasing the borderline blood spot TSH cut-off on the detection of cases of congenital hypothyroidism (CHT) identified via newborn screening

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Clinical practice: experience with newborn screening for congenital hypothyroidism in the Republic of Macedonia - a multiethnic country.

To evaluate the thyroid screening program and to estimate the prevalence of congenital hypothyroidism (CH) among newborns in the Republic of Macedonia, we measured thyroid-stimulating hormone (TSH) levels in dried blood spot specimens using the DELFIA fluoroimmunoassay, over a period of 12years. The TSH cutoff level was 10mU/L blood. A total of 215,077 newborns were screened (94.76%). Out of 254 recalled newborns (a recall rate of 0.15%), 83 newborns with CH were detected, yielding a CH prevalence at screening of 1/2,591 (female to male ratio, 1.86:1). Of the CH cases, 47/107,754 (56.6%) neonates were Macedonian, 29/70,330 (34.9%) were Albanian, and 7/15,055 (8.4%) were Roma. The thyroid gland was undetectable on ultrasound in 43 (51.8%) newborns with CH, thyroid hypoplasia was confirmed in 8 (9.6%), while 29 (34.9%) had a normal thyroid gland. In three newborns (3.6%), agenesis of one lobe was confirmed. Therapy with levothyroxin was initiated on average 11.7days after birth. The national thyroid newborn screening program in Macedonia has been successful and effective, providing timely diagnosis and treatment of children with congenital hypothyroidism.

Worldwide Coverage of Newborn Screening for Congenital Hypothyroidism—A Public Health Challenge

Despite the fact that programs began detecting neonates with congenital hypothyroidism (CH) over 40 years ago, at present only 30 % of the world birth population (approximately 127 million) undergoes screening for this disorder. The estimated cost of detection by screening, $15,400 compares with a lifetime expense of $1,296,000 in developed countries. The annual cost of the 30,000 CH cases not identified and treated early is approximately $40 billion dollars. Increasing the coverage of newborn screening worldwide remains a significant public health challenge.

Diseases accompanying congenital hypothyroidism

Extrathyroidal abnormality incidence and especially the incidence of congenital cardiac disease are increased with congenital hypothyroidism. In this present study, it is aimed to evaluate patients who were being followed up for congenital hypothyroidism for accompanying diseases, and to compare impacts of accompanying diseases on prognosis under the light of published articles in the literature. A total of 400 cases which were diagnosed with, treated and followed up for congenital hypothyroidism in our clinic were retrospectively evaluated. Cases with complaining symptoms and without any complaints, but were diagnosed with hypothyroidism as the result of screening tests were enrolled in the study. Of 400 subjects included due to congenital hypothyroidism, 186 (46.5%) were girls and 214 (53.5%) were boys. Accompanying diseases were diagnosed in 113 cases (28.2%). Accompanying diseases according to the frequency order were congenital cardiac disease (n=32, 8.0%), Down syndrome (n=25, 6.3%), inguinal hernia (n=21, 5.30%), undescended testicles (n=8, 2.0%), GH deficiency (n=4, 1.0%), and some other systemic diseases (n=23, 5.8%). In cases accompanied by congenital cardiac diseases, ventricular septal defect (n=10), atrial septal defect (n=9), pulmonary stenosis (n=7), patent ductus arteriosis (n=7), and aortic coarctation (n=3) were detected. In this present study, it was defined that approximately one third of patients with congenital hypothyroidism had an accompanying disease, and cardiac diseases were the most common problem. It is concluded that evaluation of congenital hypothyroidism cases for accompanying diseases, detailed cardiological examination being in the first order, is important for prognosis.

Hearing Impairment in Hypothyroid Dwarf Mice Caused by Mutations of the Thyroid Peroxidase Gene

Thyroid hormone (TH) is essential for proper cochlear development and function, and TH deficiencies cause variable hearing impairment in humans and mice. Thyroid peroxidase (TPO) catalyzes key reactions in TH synthesis, and TPO mutations have been found to underlie many cases of congenital hypothyroidism in human patients. In contrast, only a single mutation of the mouse TPO gene has been reported previously (Tpo(R479C)) but was not evaluated for auditory function. Here, we describe and characterize two new mouse mutations of Tpo with an emphasis on their associated auditory deficits. Mice homozygous for these recessive mutations have dysplastic thyroid glands and lack detectable levels of TH. Because of the small size of mutant mice, the mutations were named teeny (symbol Tpo(tee)) and teeny-2 Jackson (Tpo(tee-2J)). Tpo(tee) is a single base-pair missense mutation that was induced by ENU, and Tpo(tee-2J) is a 64 bp intragenic deletion that arose spontaneously. The Tpo(tee) mutation changes the codon for a highly conserved tyrosine to asparagine (p.Y614N), and the Tpo(tee-2J) mutation deletes a splice donor site, which results in exon skipping and aberrant transcripts. Mutant mice are profoundly hearing impaired with auditory brainstem response (ABR) thresholds about 60 dB above those of non-mutant controls. The maturation of cochlear structures is delayed in mutant mice and tectorial membranes are abnormally thick. To evaluate the effect of genetic background on auditory phenotype, we produced a C3.B6-Tpo(tee-2J) congenic strain and found that ABR thresholds of mutant mice on the C3H/HeJ strain background are 10-12 dB lower than those of mutant mice on the C57BL/6 J background. The Tpo mutant strains described here provide new heritable mouse models of congenital hypothyroidism that will be valuable for future studies of thyroid hormones' role in auditory development and function.

Newborn screening program for congenital hypothyroidism in Montenegro

Objective – The aim of this study was to assess the prevalence of congenital hypothyroidism (CH) over the last 5 years and analyze and summarize the status of newborn screening in Montenegro. Materials and methods – This is a population-based retrospective study. Blood samples were collected from the heels of newborns 48 – 96 hours after birth and thyroid-stimulating hormone (TSH) was determined. The cut off value in our laboratory was 10 mIU/l in whole blood. Dissociation-enhanced lanthanide fluorescent immunoassay (DELFIA) was used for detection. Results – Over the period January 2008 – December 2012, a total of 40,758 newborns were screened and 17 cases were confirmed as CH - both transient and permanent. The program covered all live born infants (100%). Recall rate was 0.97 – 1.36%. Mean age of starting treatment was 21.4±6.4 days. Conclusion – During the period of analysis in our study, 17 cases of CH were detected. The overall prevalence of CH was 1 in 2397 live births. This is the first report on newborn screening for congenital hypothyroidism in Montenegro.

A New PAX8 Mutation Causing Congenital Hypothyroidism in Three Generations of a Family Is Associated with Abnormalities in the Urogenital Tract

Although thyroid dysgenesis is the most common cause of congenital hypothyroidism (CH), its molecular basis remains largely elusive. Indeed, in only a minority of cases with thyroid dysgenesis (2%-3%) was it possible to identify an underlying genetic defect. The objective of this study was to screen the PAX8 gene and the PAX2 gene in a family with six cases of CH spanning three generations and presenting urogenital malformations. Herein, we report a case series and in vitro characterization of the PAX8 gene mutation. Investigations were conducted at a tertiary care referral center. The index case was diagnosed to have congenital hypothyroidism at 7 months of age when he presented with severe impairment of suckling, constipation, and poor development. Treatment with levothyroxine corrected the symptoms and was associated with catch-up growth. His progeny, including two sons, one daughter, and two granddaughters, were affected by CH, and three of them received the diagnosis at neonatal screening. Ultrasound demonstrated normally located thyroid glands with reduced volumes. Five of the six affected family members, including the index case, had urogenital malformations, including incomplete horseshoe kidney, undescended testicles, hydrocele, and ureterocele. Strabismus was found in three out of six affected patients. No other somatic malformations were found. Direct sequencing of the PAX8 gene revealed a new heterozygous mutation (c.74C > G) in all affected individuals. This mutation leads to substitution of proline with arginine at codon 25 (P25R). Fluorescence microscopy showed that P25R is normally located in the nucleus. In transient transfection studies, this mutation causes reduced transcriptional activation ability when using a luciferase reporter construct under the control of a thyroglobulin promoter. This diminished transactivation ability is due to loss of DNA binding capability as shown in electrophoresis mobility shift assay. The sequencing analysis of the PAX2 gene was normal. We conclude that this novel PAX8 mutation is responsible for a severe form of dominantly inherited CH. The mutation seems to be associated with abnormalities of the urogenital tract.

Neurodevelopmental and Body Composition Outcomes in Children With Congenital Hypothyroidism Treated With High-Dose Initial Replacement and Close Monitoring

Despite newborn screening and early levothyroxine replacement, there are continued reports of mild neurocognitive impairment in children with congenital hypothyroidism (CHT). In Auckland, New Zealand, cases are identified by a neonatal screening program with rapid institution of high-dose levothyroxine replacement (10-15 μg/kg·d), producing prompt normalization of thyroid function. Subsequently, frequent monitoring and dose alterations are performed for 2 years. We aimed to assess whether the Auckland treatment strategy prevents impairment of intellectual and motor development. This study encompassed all children with CHT born in 1993-2006 in Auckland and their siblings. Neurocognitive assessments included the following: 1) intelligence quotient via Weschler Preschool and Primary Scale of Intelligence III or Weschler Intelligence Scale for Children IV; 2) Movement Assessment Battery for Children; and 3) Beery Developmental Test of Visual-Motor Integration. Body composition was assessed by dual-energy x-ray absorptiometry. Forty-four CHT cases and 53 sibling controls aged 9.6 ± 3.9 years were studied. Overall intelligence quotient was similar among CHT cases and controls (95.2 vs 98.6; P = .20), and there were also no differences in motor function. Severity of CHT did not influence outcome, but greater time to normalize free T4 was associated with worse motor balance. There were no differences in anthropometry or body composition between groups. These findings suggest that a strategy of rapidly identifying and treating infants with CHT using high-dose levothyroxine replacement is associated with normal intellectual and motor development. The subtle negative impact on motor function associated with time to normalize free T4 levels is consistent with benefit from rapid initial correction.

Permanent and transient congenital hypothyroidism in Fayoum, Egypt: a descriptive retrospective study.

BackgroundCongenital hypothyroidism (CH) is one of the most common preventable causes of mental retardation. One important challenge in understanding the epidemiology of CH is that some newborns will have transient CH, a temporary depression of thyroid hormone concentrations that can last from several days to several months. Studies from other countries have reported that 10 to 15% of children treated for CH ultimately prove not to need treatment past 3 years of age to maintain normal hormone concentrations, and thus have transient hypothyroidism. The purpose of this study was to determine the prevalence of permanent and transient congenital hypothyroidism in Fayoum, Egypt.MethodsCases detected by Fayoum neonatal screening program (NSP) between January 2003 and December 2011, and followed up at health insurance center were included. Permanent or transient CH was determined using results of thyroid function tests.ResultsOf the 248 patients diagnosed primarily with CH by NSP; 204 (82.3%) patients were diagnosed to have permanent CH (prevalence 1/3587 live birth), and 44 (17.7%) patients were diagnosed to have transient CH (prevalence 1/16667 live birth). Initial TSH levels were higher in permanent CH cases than transient cases (p<0.004). Female to male ratio was 0.8 and 0.7 in permanent and transient CH respectively. 161 (65%) patients had thyroid dysgenesis (107 ectopic thyroid gland, 28 athyreosis and 26 thyroid hypoplasia). 87 (35%) patients had intact gland in thyroid scan and were considered to have dyshormonogenesis. Of these 87 patients 44 proved to have transient CH and 43 had permanent CH.ConclusionThe preliminary data from our study revealed that the incidences of CH as well as the permanent form were similar to worldwide reports. Although the high incidence of transient CH in our study could be explained by iodine deficiency further studies are needed to confirm the etiology and plan the treatment strategies.

Thyroid dyshormonogenesis is mainly caused by TPO mutations in consanguineous community

In this study, we aimed to investigate the genetic background of thyroid dyshormonogenesis (TDH). Thyroid dyshormonogenesis comprises 10-15% of all cases of congenital hypothyroidism (CH), which is the most common neonatal endocrine disorder, and might result from disruptions at any stage of thyroid hormone biosynthesis. Currently seven genes (NIS, TPO, PDS, TG, IYD, DUOX2 and DUOXA2) have been implicated in the aetiology of the disease. As TDH is mostly inherited in an autosomal recessive manner, we planned to conduct the study in consanguineous/multi-case families. One hundred and four patients with congenital TDH all coming from consanguineous and/or multi-case families. Initially, we performed potential linkage analysis of cases to all seven causative-TDH loci as well as direct sequencing of the TPO gene in cases we could not exclude linkage to this locus. In addition, in silico analyses of novel missense mutations were carried out. TPO had the highest potential for linkage and we identified 21 TPO mutations in 28 TDH cases showing potential linkage to this locus. Four of 10 distinct TPO mutations detected in this study were novel (A5T, Y55X, E596X, D633N). This study underlines the importance of molecular genetic studies in diagnosis, classification and prognosis of CH and proposes a comprehensive mutation screening by new sequencing technology in all newly diagnosed primary CH cases.

Risk factors for congenital hypothyroidism in Egypt: results of a population case-control study (2003–2010)

BACKGROUND AND OBJECTIVESAlthough the prevention of the neuropsychological consequences of congenital hypothyroidism (CH) through the use of replacement therapy represents an important public health success, knowledge about the modifiable risk factors could reduce the number of infants affected by this disease. This study was carried out to identify risk factors for CH at Fayoum Governorate, Egypt.DESIGN AND SETTINGSThis was a population-based case-control study, which started in 2003 and was carried out for 8 years through Fayoum center of the Egyptian Ministry of Health and Population screening program for CH.METHODSThis study was a population-based case-control study carried out by using national project for CH. One control was enrolled for each new CH infant; 320 cases and 320 controls were enrolled in 8 years. Maternal and neonatal influences were investigated.RESULTSA statistically significant association of CH was observed with birth defects, female gender, gestational age >40 weeks, and gestational diabetes. An increased risk for CH was detected in twins by a multivariate analysis.CONCLUSIONOur results suggest a multifactorial origin of CH in which genetic (high frequency of additional malformations) and environmental factors (especially maternal diabetes) play a role in the development of the disease.

Hipotireoidismo congênito: recomendações do Departamento de Tireoide da Sociedade Brasileira de Endocrinologia e Metabologia

Congenital hypothyroidism (CH) is the most common congenital endocrine disorder, with an incidence of 1:2,000 to 1:4,000 live births and it is a leading preventable mental retardation. Neonatal Screening Programs allow early identification of the disease and the adequate treatment of affected children can avoid the complications related to deprivation of the hormone. Most cases of primary congenital hypothyroidism (85%) are due to thyroid dysgenesis (ectopia, hypoplasia or agenesis) while the remaining result from defects in hormone synthesis. Affected children (> 95%) usually have no symptoms suggesting the disease at birth. The most frequent symptoms and signs are prolonged neonatal jaundice, hoarse cry, lethargy, slow movements, constipation, macroglossia, umbilical hernia, large fontanelle, hypotonia and dry skin. Around the world, various strategies are used for the screening of the CH. In Brazil, screening for CH is mandatory by law and usually done by serum TSH in dried blood collected from the heel. The recommended age for performing this test is after 48 hours of life until the 4th day. Diagnostic confirmation is required dosing TSH and free T4 or total T4 in serum.

Newborn Screening in Slovakia – From 1985 Till Today / Novorodencký skríning na Slovensku – od roku 1985 doposiaľ

Regular newborn screening enables detection of severe disorders in their asymptomatic early phase and thus allows the start of early treatment and prevention of long-term sequelae. This concept is in full accordance with care for so called rare diseases. Recently, the national NBS in Europe are under the supervision of ISNS and EUNENBS to ensure the quality control and unified approach. NBS in Slovak Republic has been provided for the whole population as a governmentally guaranteed activity since 1985. The first screened disorder was congenital hypothyroidism (CH). Patients have been screened for phenylketonuria (PKU) since 1995, for congenital adrenal hyperplasia (CAH) since 2003, and for cystic fibrosis (CF) since 2009. The organizational network of NBS ensures more than 98% coverage of the population of newborns. Between 1985 and 2011, the newborn screening centre (NSC SK) examined 3,239 068 newborn infants and confirmed 413 cases of CH (1: 4 128), 157 cases of PKU (1:5 908), 51 cases of CAH (1:8 677) and 26 CF cases (1:6 315). In 2012, the expanded NBS (ENBS) was introduced. It used tandem mass spectrometry (ms/ms) to detect other nine hereditary metabolic disorders (HMDs), defect of beta-oxidation of fatty acids, carnitine disorders, and organic acidurias. Four month pilot study revealed 12 positive cases in 25 000 screened newborns as well as other HMDs not included in the screening - in “peripheral view” of ms/ms. Since 1. January, ENBS has been performed as a regular NBS in the whole population. In January, fifteen new cases were detected (prevalence even 1:763).

Congenital Hypothyroidism due to Defects of Thyroid Development and Mild Increase of TSH at Screening: Data From the Italian National Registry of Infants With Congenital Hypothyroidism

Over the years lower TSH cutoffs have been adopted in some screening programs for congenital hypothyroidism (CH) worldwide. This has resulted in a progressive increase in detecting additional mild forms of the disease, essentially with normally located and shaped thyroid. However, the question of whether such additional mild CH cases can benefit from detection by newborn screening and early thyroid hormone treatment is still open. The aim of this study was to estimate the frequency of cases with mild increase of TSH at screening in the Italian population of babies with permanent CH and to characterize these babies in terms of diagnosis classification and neonatal features. Data recorded in the Italian National Registry of infants with CH were analyzed. Between 2000 and 2006, 17 of the 25 Italian screening centers adopted a TSH cutoff at screening of <15.0 μU/mL. It was found that 21.6% of babies with permanent CH had TSH at screening of 15.0 μU/mL or less, whereas this percentage was 54% in infants with transient hypothyroidism. Among the babies with permanent CH and mild increase of TSH at screening (≤15 μU/mL), 19.6% had thyroid dysgenesis with serum TSH levels at confirmation of the diagnosis ranging from 9.9 to 708 μU/mL. These babies would have been missed at screening if the cutoff had been higher. Lowering TSH cutoff in our country has enabled us to detect additional cases of permanent CH, a number of which had defects of thyroid development and severe hypothyroidism at confirmation of the diagnosis.

Congenital Hypothyroidism

Congenital Hypothyroidism

Changes in confirmed plus borderline cases of congenital hypothyroidism in California as a function of environmental fallout from the Fukushima nuclear meltdown

Radiation exposure has been linked to increased risk of congenital hypothyroidism (CH) for decades. CH is a relatively uncommon condition, occurring in about 1 of 2000 US births. Thyroid Stimulating Hormone (TSH) levels for each child born in California permitted an analysis of combined confirmed and borderline CH cases. Borderline/confirmed CH cases are more than seven times greater than just confirmed cases. Airborne levels of gross beta nuclear radiation in the US were elevated in the period starting several days after the Fukushima nuclear meltdown, especially in west coast states like California. The borderline/confirmed CH rate for newborns during the last 9.5 months in 2011 (exposed to Fukushima in utero) vs. births during other periods in 2011 and 2012 (not exposed) was significantly elevated, suggesting that adverse health effects to the newborn thyroid were not restricted to just a small number of confirmed CH cases. The sensitivity of the fetus to radiation exposure, plus the presence of thyroid-seeking radioiodine, suggest further analysis of Fukushima’s potential to cause adverse health effects in newborns is needed.

Epidemiology and Clinical Characteristics of Congenital Hypothyroidism in an Asian Population: A Nationwide Population-Based Study

BackgroundThe incidence of congenital hypothyroidism (CH) has been increasing in Western countries, and some populations, including Asians, have a higher incidence. Delayed diagnosis and early treatment influence the outcome of CH. We investigated the incidence and clinical characteristics of CH in Taiwan.MethodsIn this retrospective database study we identified cases of CH diagnosed during 1997–2008 in the Taiwan National Health Insurance Research Database (NHIRD). Patients who had a Serious Accidents and Diseases certificate were included in the incidence calculation. We focused on CH patients who were born during 1997–2003 and determined their age at diagnosis and CH-related clinical features. Mental retardation and physiological delays were evaluated with respect to age at diagnosis.ResultsA total of 1482 cases were identified. Incidence during the 12-year period was 5.02 per 10 000 births. Among 1115 patients, the most common clinical features of CH were developmental delay (9.6%), constipation (11.6%), and delayed physiological development (9.1%). Congenital anomalies of the heart (7.7%), epilepsy (2.7%), and infantile cerebral palsy (3.2%) were also noted. Survival analysis showed that the risks of mental retardation (hazard ratio [HR], 3.180) and delayed physiological development (HR, 1.908) were greater when age at diagnosis was greater than 1 year.ConclusionsCH incidence was higher in Taiwan than in Western countries. Early diagnosis may decrease the risk of mental and physiological delay.

Neglected case of congenital hypothyroidism in a 17-year-old female

Introduction: congenital hypothyroidism is one of the most common endocrinal disorders in newborns. the slow development of obvious clinical symptoms, coupled with the importance of early treatment led to the implementation of widespread newborn screening for this condition. case report: this paper presents a case of congenital hypothyroidism that was born at home and was not screened for hypothyroidism. A 17-year-old female patient complained of short stature, mental retardation, delayed puberty and chronic constipation as a result of neglected hypothyroidism. conclusion: this case discusses the importance of neonatal screening programs for early detection of congenital hypothyroidism cases that are unfortunately still being neglected in some areas of developing countries. It also shows the value of early and adequate replacement therapy for the detected cases as this could protect them against irreversible growth retardation and mental retardation. this is because any diagnostic delay, inadequate treatment or even poor compliance to treatment is always associated with irreversible damage as those manifested in this case.

After-newborn follow-up of newborn screening

As frequently reported in The Journal, the past decades have witnessed an exponential growth in the number of disorders included in newborn screening panels. Although the protocols for identifying the referring these children are well-established, the mechanisms for following these children years later are not as clear. In this issue of The Journal, Korzeniewski et al use data from Michigan's screening program to examine the fate of children detected by hypothyroidism screening after 3 years of age. As expected, a number of these children were found to have transient hypothyroidism and were able to discontinue replacement therapy. The worrisome finding in the study, however, was the number of children who were lost to follow-up, including some who discontinued therapy without firm proof that their condition was transient. The authors of this very provocative study call for better long-term follow-up of children with congenital hypothyroidism, including more structured systems. The same could be said for a number of other disorders detected during the newborn period. Article page 177▶ Transient Hypothyroidism at 3-Year Follow-Up among Cases of Congenital Hypothyroidism Detected by Newborn ScreeningThe Journal of PediatricsVol. 162Issue 1PreviewTo investigate the rate of transient thyroid deficiency and treatment compliance among cases with congenital hypothyroidism diagnosed and followed-up after age 3 years by newborn screening (NBS). Full-Text PDF

Early Adiposity Rebound and Obesity in Children with Congenital Hypothyroidism

Earlier adiposity rebound (AR) is correlated with obesity. Our goal is to examine rates of obesity and AR in congenital hypothyroidism (CHT) and analyze the risk factors of obesity. We retrospectively reviewed the cases with abnormal newborn screens of thyroid-stimulating hormone (TSH) from 1990 to 2005 and enrolled permanent CHT patients who continued to receive treatment after the 3(rd) year of life. We determined subgroups of obesity/being overweight and normal body mass index (BMI) by the latest BMI at 6-7 years of age. BMI at each age and the age of AR were compared with the general population in Taiwan. The statistical correlation of obesity with the age and BMI at both AR and first peak, and thyroid function was calculated. A total of 90 cases of CHT were enrolled. The prevalence of obesity/being overweight was 32.2%. The age of AR was 4.94 ± 1.81 and 4.58 ± 1.86 years old in boys and girls, respectively. The age of AR in the girls with CHT was earlier than in girls in general, but no statistical significance was found in boys with CHT compared to the general population. Obesity was correlated with earlier age of AR, higher BMI at first peak and AR, and lower T4 after treatment, but not with the age of first peak of BMI, T4/TSH at diagnosis and AR, and TSH after treatment. Children with CHT have a higher risk of obesity due to earlier age of AR. We recommend that supervision and intervention on weight control should be provided to prevent the occurrence of obesity later.