Analysis of Worldwide Carrier Frequency and Predicted Genetic Prevalence of Autosomal Recessive Congenital Hypothyroidism Based on a General Population Database.

To assess how genomic information of the general population reflects probabilities of developing diseases and the differences in those probabilities among ethnic groups, a general population database was analyzed with an example of congenital hypothyroidism. Twelve candidate genes that follow an autosomal recessive inheritance pattern in congenital hypothyroidism (SLC5A5, TPO, TG, IYD, DUOXA2, DUOX2, TSHR, SLC26A7, GLIS3, FOXE1, TSHB, TRHR) in the gnomAD database (v2.1.1) were analyzed. The carrier frequency (CF) and predicted genetic prevalence (pGP) were estimated. The total CF in the overall population was 3.6%. DUOX2 showed the highest CF (1.8%), followed by TG (0.46%), TPO (0.44%), TSHR (0.31%), SLC26A7 (0.144%), DUOXA2 (0.141%), IYD (0.08%), SLC5A5 (0.06%), TRHR (0.059%), GLIS3 (0.059%), TSHB (0.04%), and FOXE1 (0%). The pGP in the overall population was 10.01 individuals per 100,000 births (1:9992). The highest pGP was in the East Asian population at 52.48 per 100,000 births (1:1905), followed by Finnish (35.96), Non-Finnish European (9.56), African/African American (4.0), Latino/Admixed American (3.89), South Asian (3.56), and Ashkenazi Jewish (1.81) groups. Comparing the pGP with the real incidence of congenital hypothyroidism, the pGP in East Asian populations was highly consistent with the real incidence.

The impact of demographic factors on newborn TSH levels and congenital hypothyroidism screening.

CONTEXT: Optimal newborn screening thyroid-stimulating hormone (TSH) cut-offs are contentious. Analysis of demographic factors that impact screen TSH levels may help explain international variance and provide guidance to screening programmes. OBJECTIVE: To determine the influence of demographic factors on newborn screening TSH levels and screening performance parameters. DESIGN AND SETTING: National, retrospective population study using blood spot TSH cards from the New Zealand newborn screening programme in 2010-2015. PATIENTS: 325 685 blood spot cards. MAIN OUTCOME MEASURES: Likelihood of exceeding specific TSH thresholds (TSH ≥5, ≥10 and ≥15 mIU/L) and group-specific screening performance parameters. RESULTS: The likelihood of high TSH levels differed between ethnic groups. Pacific Island infants were more than twice as likely to have high-normal TSH levels (≥5 and ≥10 mIU/L) and nearly twice as likely to have a positive screen (≥15 mIU/L) as New Zealand Europeans. Maori or Chinese ethnicity, male sex, younger gestational age and greater socio-economic deprivation scores were also associated with high-normal TSH levels. At a TSH threshold ≥15 mIU/L, screening sensitivity was lowest (88.89% vs 95.83% overall) and PPV greatest (88.89% vs 62.84%) amongst Asian infants. Early samples were more than three times as likely to reach the screen-positive threshold and more likely to yield a false-positive result (PPV 20.00% vs 68.87%, P = 0.004). CONCLUSIONS: Newborn TSH levels are impacted by a number of demographic variables, particularly ethnicity and age at sample collection. Screening performance may be improved through the use of targeted thresholds.

Newborn Screening for Congenital Hypothyroidism and Congenital Adrenal Hyperplasia.

OBJECTIVE: The Task Force formed by ICMR aimed at studying the prevalence of congenital hypothyroidism and congenital adrenal hyperplasia, the template disorders included in all newborn screening programs, and to evaluate the unidentified challenges in its execution in health care services. It also intended to evaluate the feasibility of newborn screening with regards to different geo-ethnic regions from India. METHODS: Five metropolitan centers identified had further 2 to 11 centers; both the urban and the rural sectors were included and were considered representative of the northern, southern, eastern, western and central parts of the country. A uniform protocol was developed to screen 100,000 neonates (20,000 from each center) beyond 34 wk of gestation for congenital hypothyroidism and congenital adrenal hyperplasia. Samples were collected by heel prick after 24 h of age. The parameters studied were prevalence of these diseases, percentage births covered, the turnaround time, recall rate and follow up of identified neonates as feasibility indicators. All centers participated in the Newborn Screening Quality Assurance Programme (NSQAP), of CDC, Atlanta, USA. RESULTS: In the participating hospitals attached to the centers, 151,765 babies were intramural births. Of these 143,344 (94.5%) babies were eligible for screening. Amongst these births, a sample of 104,094 (73.2%) babies could be covered by the personnel. Overall prevalence of congenital hypothyroidism (CH) was 1 in 722 births; if babies with transient hypothyroidisms were excluded the prevalence was calculated to be 1:1130. The collective prevalence of congenital adrenal hyperplasia was 1 in 5762 with marked regional differences. CONCLUSIONS: This collaborative study has demonstrated the feasibility of establishing a network of committed laboratories and scientists for executing newborn screening. This is expected to have a potential impact on morbidity and mortality and therefore this should be immediately taken up in a national newborn screening program.

Safety and effectiveness of long-term growth hormone therapy in Japanese patients with adult growth hormone deficiency: a postmarketing, multicenter, observational study.

We aimed to evaluate the long-term safety and effectiveness of growth hormone (GH) therapy in Japanese patients with adult growth hormone deficiency (AGHD). In this observational, multicenter study, Norditropin® (Novo Nordisk A/S, Bagsvaerd, Denmark) was administered as injections of 0.021 mg/kg/week as a starting dose divided into 6-7 doses/week. The dose was increased according to clinical response. Patients' data were obtained from medical records. Measurements (lipids, glucose metabolism, and body composition) taken at baseline; 3, 6, and 12 months; and yearly until the end of the study were collected. Adverse drug reactions (ADRs), serious ADRs, and serious adverse events (SAEs) were evaluated. Of 387 registered patients, 334 were eligible for safety. After GH treatment initiation, a marked decrease in total cholesterol was observed earlier in the child-onset group than in the adult-onset group. LDL-cholesterol also decreased, but no significant differences in changes in LDL-cholesterol between adult-onset and child-onset groups were found. A significant increase in HDL-cholesterol starting 1 year after GH treatment initiation was found in the adult-onset group. There was no effect of GH treatment on glucose metabolism. Because of the small number of dual-energy X-ray absorptiometry data, the overall assessment of changes of body composition was difficult. Fifty-six (16.8%), 12 (3.6%), and 35 (10.5%) patients experienced ADRs, serious ADRs, and SAEs, respectively. This study demonstrated a favorable long-term safety and effectiveness profile of GH therapy in AGHD patients in the real-life Japanese clinical practice setting.

Identification and characterization of novel PAX8 mutations in Congenital Hypothyroidism(CH) in a Chinese population.

OBJECTIVE: Based on mutations in PAX8 is associated with thyroid dysgenesis. We aim to identify and characterize PAX8 mutations in a large cohort of congenital hypothyroidism(CH) from thyroid dysgenesis in Chinese population. METHODS: We screened 453 unrelated Chinese patients with CH from thyroid dysgenesis for PAX8 mutations by sequencing the whole coding regions of PAX8 on genomic DNA isolated from blood. Cell transfection assays using various vector constructs and induced mutagenesis as well as electrophoretic mobility shift assays were used to investigate the effects of selected mutations on the transcribing and binding activities of PAX8 at the promoters of target genes for thyroglobulin (TG) and thyroperoxidase (TPO). RESULTS: Five PAX8 mutations were found, yielding a mutation prevalence of 5/453 (1.1%). We selected two mutations in the critical paired domain of PAX8 and generated mutants D94N and G41V. We demonstrated G41V was unable to bind the specific sequence in the promoters of TG and TPO and activate them. D94N could bind to TG and TPO promoters and normally activate the TG promoter transcription but not the TPO promoter transcription. We also demonstrated a dominant negative role of the PAX8 mutants in impairing the function of the wild-type PAX8. CONCLUSION: We for the first time documented the prevalence and characterized the function of PAX8 mutations in CH in Chinese population. The study specifically demonstrated the role of novel mutations D94N and G41V in impairing the function of PAX8, providing further evidence for genetic PAX8 defects as a disease mechanism in CH.

Defining the Newborn Blood Spot Screening Reference Interval for TSH: Impact of Ethnicity.

CONTEXT: There is variability in the congenital hypothyroidism (CH) newborn screening TSH cutoff across the United Kingdom. OBJECTIVE: To determine the influences of year, gender, and ethnicity on screening variability and examine whether there is an optimal operational TSH cutoff. DESIGN AND SETTING: Single center, retrospective population study using blood spot TSH cards received by the Great Ormond Street Hospital Screening Laboratory between 2006 and 2012. PATIENTS: A total of 824 588 newborn screening blood spot TSH cards. INTERVENTION: Blood spot TSH results were recorded with demographic data including the Ethnic Category Code. MAIN OUTCOME MEASURES: The proportions of samples exceeding different TSH cutoffs, ranked by ethnicity. RESULTS: The proportion of samples exceeding the TSH cutoff increased over time, with the cutoff at 4 mU/L, but not at 6 mU/L. There was a consistent trend with ethnicity, irrespective of cutoff, with the odds ratio of exceeding the TSH cutoff lowest (∼1.0) in White babies, higher in Pakistani and Bangladeshi (>2.0), and highest in Chinese (>3.5). CONCLUSIONS: The blood spot TSH screening data demonstrate a clear ranking according to ethnicity for differences in mean TSH. This suggests that there may be ethnic differences in thyroid physiology. Ethnic diversity within populations needs to be considered when establishing and interpreting screening TSH cutoffs.

High prevalence of DUOX2 mutations in Japanese patients with permanent congenital hypothyroidism or transient hypothyroidism.

BACKGROUND: Dual oxidase 2 (DUOX2) mutations are a cause of dyshormonogenesis (DH) and have been identified in patients with permanent congenital hypothyroidism (PH) and with transient hypothyroidism (TH). We aimed to elucidate the prevalence and phenotypical variations of DUOX2 mutations. METHODS: Forty-eight Japanese DH patients were enroled and analysed for sequence variants of DUOX2, DUOXA2, and TPO using polymerase chain reaction-amplified direct sequencing. RESULTS: Fourteen sequence variants of DUOX2, including 10 novel variants, were identified in 11 patients. DUOX2 variants were more prevalent (11/48, 22.9%) than TPO (3/48, 6.3%) (p=0.020). The prevalence of DUOX2 variants in TH was slightly, but not significantly, higher than in PH. Furthermore, one patient had digenic heterozygous sequence variants of both DUOX2 and TPO. CONCLUSIONS: Our results suggest that DUOX2 mutations might be the most common cause of both PH and TH, and that phenotypes of these mutations might be milder than those of other causes.

Biochemical, radiological, and genetic characterization of congenital hypothyroidism in Abu Dhabi, United Arab Emirates.

BACKGROUND: Congenital hypothyroidism (CH) is caused by thyroid gland (TG) dysgenesis or inadequate thyroid hormone biosynthesis in a structurally normal gland. Different etiologies are known to be associated with various clinical, biochemical and imaging markers and a subset of cases have an underlying genetic basis. Despite the presence of neonatal screening programs in the UAE, there is a lack of data on the disease etiology in the area. We aim to study the etiology of CH in our center and examine its relationship with the clinical, biochemical, genetic and radiological features. METHODS: Patients with CH who were followed in our center between 2011 and 2014 are enrolled in the study. Data collected included gender, gestational age, history of CH in a first-degree relative, initial thyroid stimulating hormone (TSH) and thyroxine (T4) levels, imaging findings, associated disease/malformation and treatment details. Selected patients with associated systemic disease or familial CH underwent genetic testing. RESULTS: Sixty-five patients were enrolled. Ten patients underwent genetic study: seven patients with associated congenital disease/malformation, one with a sibling and two with cousins with CH. Forty-nine subjects had technetium99 and/or ultrasound scans. Dyshormonogenesis was diagnosed in two-thirds of the patients. Three patients of 10 tested had likely causative genetic mutations; two homozygous thyroid peroxidase (TPO) and one heterozygous thyroid stimulating hormone receptor (TSHR) missense mutations. CONCLUSIONS: Dyshormonogenesis is the commonest etiology in CH in the studied group. It is expected that genetic mutations are more prevalent in our region due to the nature of the CH etiology and the rate of high consanguinity rate.

Single newborn screen or routine second screening for primary congenital hypothyroidism.

Routine second screening of most newborns at 8-14 days of life for a panel of newborn conditions occurs in 12 U.S. states, while newborns in the other states typically undergo only a single routine newborn screen. The study objective was to evaluate screening consequences for primary congenital hypothyroidism (CH) in one- and two-screen states according to laboratory practices and medical or biochemical characteristics of screen-positive cases. Individual-level medical and biochemical data were retrospectively collected and analyzed for 2251 primary CH cases in one-screen (CA, WI) and two-screen (AL, DE, MD, OR, TX) states. Aggregate data were collected and analyzed for medical and biochemical characteristics of all screened newborns in the states. Among the states evaluated in this study, the detection rate of primary CH was higher in the one-screen states. In the two-screen states, 11.5% of cases were detected on the second screen. In multivariate analyses, only race/ethnicity was a significant predictor of cases identified on the first versus second screen, which likely reflects a physiologic difference in primary CH presentation. Newborn screening programs must heed the potential for newborns with CH not being detected by a single screen, particularly newborns of certain races/ethnicities. If the two-screen states converted to a single screen using their current algorithms, newborns currently identified on the routine second screen would presumably not be detected, resulting in probable delayed diagnosis and treatment. However, based on the one-screen state experiences, with appropriate modifications in screening method and algorithm, the two-screen states might convert to single screen operation for CH without loss in performance.

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

UNLABELLED: 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 12 years. The TSH cutoff level was 10 mU/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 11.7 days after birth. CONCLUSION: The national thyroid newborn screening program in Macedonia has been successful and effective, providing timely diagnosis and treatment of children with congenital hypothyroidism.

Epidemiology and clinical characteristics of congenital hypothyroidism in an Asian population: a nationwide population-based study.

BACKGROUND: The 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. METHODS: In 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. RESULTS: A 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. CONCLUSIONS: CH incidence was higher in Taiwan than in Western countries. Early diagnosis may decrease the risk of mental and physiological delay.

Birth prevalence of disorders detectable through newborn screening by race/ethnicity.

PURPOSE: The purpose of this study was to describe the birth prevalence of genetic disorders among different racial/ethnic groups through population-based newborn screening data. METHODS: Between 7 July 2005 and 6 July 2010 newborns in California were screened for selected metabolic, endocrine, hemoglobin, and cystic fibrosis disorders using a blood sample collected via heel stick. The race and ethnicity of each newborn was self-reported by the mother at the time of specimen collection. RESULTS: Of 2,282,138 newborns screened, the overall disorder detection rate was 1 in 500 births. The disorder with the highest prevalence among all groups was primary congenital hypothyroidism (1 in 1,706 births). Birth prevalence for specific disorders varied widely among different racial/ethnic groups. CONCLUSION: The California newborn screening data offer a unique opportunity to explore the birth prevalence of many genetic disorders across a wide spectrum of racial/ethnicity classifications. The data demonstrate that racial/ethnic subgroups of the California newborn population have very different patterns of heritable disease expression. Determining the birth prevalence of these disorders in California is a first step to understanding the short- and long-term medical and treatment needs faced by affected communities, especially those groups that are impacted by more severe disorders.

Nonclassic TSH resistance: TSHR mutation carriers with discrepantly high thyroidal iodine uptake.

CONTEXT: Inactivating mutations in the TSH receptor gene (TSHR) cause TSH resistance. Most patients with TSH resistance have low to normal thyroidal radioiodine uptake (RAIU), which is consistent with the physiological knowledge that TSH stimulates iodine uptake. To date, only one TSHR mutation-carrying family with discrepantly high RAIU has been reported. OBJECTIVE: We aimed to test whether TSHR mutation carriers with high RAIU are observed in a cohort of Japanese patients with congenital hypothyroidism (CH). SUBJECTS AND METHODS: Twenty-four Japanese CH patients with high RAIU were screened for TSHR mutations. The capacities of mutant TSHR to activate Gs- and Gq-coupled signaling pathways were evaluated in vitro. RESULTS: Two patients were found to have biallelic TSHR mutations: p.[T145I]+[R450H] in one and p.[R450H]+[I661fs] in the other. The two subjects had permanent CH with slightly high RAIU (41.8 and 43.0%, reference 8-40) but did not have goiter. One had a slightly high perchlorate discharge rate (10%, reference <10). Expression experiments revealed that T145I-TSHR retained partial ability to transduce both Gs- and Gq-coupled pathways, whereas I661fs-TSHR could transduce neither of them. R450H-TSHR had partial ability to transduce Gs-coupled signaling but had abrogated ability to transduce Gq-coupled signaling, indicating that coupling to Gq was dominantly affected. CONCLUSIONS: We show that 8% of Japanese CH patients with high RAIU (two in 24) has inactivating TSHR mutations. Expression of this apparently discrepant phenotype, which we term nonclassic TSH resistance, is presumably associated with the characteristic signaling property of the mutant TSHR, namely the Gq-dominant coupling defect.

Neonatal age and point of careTSH testing in the monitoring of iodine deficiency disorders: findings from western Uganda.

BACKGROUND: Iodine deficiency is a major public health problem throughout Africa. Although salt for human consumption is said to contain adequate amounts of iodine in Uganda, iodine intake may not be optimal. We undertook a field study to assess the adequacy of iodine nutrition in western Uganda using on-site measurement methods of neonatal thyroid stimulating hormone (TSH) levels as recommended by the World Health Organization (WHO) for monitoring the degree of iodine deficiency during pregnancy. METHODS: The study design consisted of a prevalence study using the percentage of newborns between the ages of 3 and 7 days with TSH >5 mIU/L, measured with a point-of-care immunochromatographic TSH assay, as a surrogate marker of iodine deficiency. Five districts in western Uganda were selected for study on the basis of a past history of iodine deficiency. One thousand seventy-eight newborns from the five districts were sequentially enrolled in each separate district and tested between July 2007 and January 2008. RESULTS: The prevalence of TSH levels >5 mlU/L ranged from 20% to 32%. Neonates tested on or before the age of 3 days were more likely to have a TSH level >5 mlU/L than those tested beyond the age of three days (28.2% vs. 18.7%, p < 0.001). CONCLUSIONS: Assessing neonatal TSH levels in developing countries with a TSH assay method suitable for field use can be successfully used to screen for congenital hypothyroidism and to indirectly assess a population's iodine status. Based on the percentage of neonates with TSH values >5 mIU/L, presumptive iodine deficiency persists in western Uganda. This finding suggests that continued monitoring of iodine nutrition in the area surrounding the Rwenzori Mountains in Uganda and Congo is needed. Due to the progressive fall in the percent of TSH values >5 mIU/L from day three to day five of life, we conclude that TSH measurement earlier than day five of life in newborns at risk for iodine deficiency may be misleading. Guidelines for the use of neonatal TSH to monitor iodine nutrition should specify that TSH measurement take place no earlier than day five of life.

Variation by ethnicity in the prevalence of congenital hypothyroidism due to thyroid dysgenesis.

BACKGROUND: The scant data on ethnic differences in the prevalence of congenital hypothyroidism (CH) have generally not taken etiology of CH into account. Our hypothesis is that the prevalence of CH due to thyroid dysgenesis (TD) varies by ethnicity. METHODS: This case-control study included all patients with CH due to TD (a condition of unknown origin) or to dyshormonogenesis (DH, of known autosomal recessive transmission) between 1987 and 2009. Etiology was established by (99m)Tc scintigraphy. The parents self-assessed their ethnicity, which we grouped in Caucasian, Hispanic, black, Asian, and Maghreb/Middle East. We compared ethnicity between the 190 patients with TD (147 ectopies, 40 athyreoses, and 3 orthotopic hypoplasias) and the 44 patients with DH. Ethnicity was also compared to the reference population of the city of Montreal. Prevalence odds ratios (POR) were calculated and compared by the bilateral Fisher's exact test. RESULTS: The ethnic composition of the DH group was similar to that of the reference population. In blacks, TD prevalence of 1 in 190 (0.5%) was low compared to that of DH (4 in 44; 9.1%; POR 0.06; 95% confidence interval: 0.001-0.56; p = 0.005). In contrast, Caucasians showed an increased TD prevalence of 166 in 190 (87.3%) compared to that of DH (30 in 44; 68.2%; POR 3.21; 95% confidence interval: 1.37-7.34; p = 0.0052). No statistically significant differences were observed between other ethnic groups. CONCLUSION: TD is less prevalent in blacks and more prevalent in Caucasians. Blacks being more genetically diverse, this is an argument for an oligogenic inheritance of susceptibility to TD.

Increased incidence of extrathyroidal congenital malformations in Japanese patients with congenital hypothyroidism and their relationship with Down syndrome and other factors.

BACKGROUND: Much remains unknown regarding extrathyroidal congenital malformations (ECMs) in patients with primary congenital hypothyroidism (PCH) and Down syndrome (DS). Here, we investigated the frequency of ECMs in patients with PCH, particularly among patients with or without DS. METHODS: In a retrospective review of questionnaires based on medical records, ECMs were identified in 1520 patients with PCH and were compared with congenital malformations among nationwide live births or liveborn infants with DS. The ECMs in PCH patients with or without DS were then analyzed. The statistical analysis was based on the Poisson distribution. Ethnicity, sex, and familial and seasonal factors were also observed in relation to the ECMs. RESULTS: The incidences of ECMs (222/1520, 14.6%) and DS (86/1520, 5.7%) were significantly higher among the PCH patients than among the general population. Among the 127 PCH patients without chromosomal abnormalities, 101 had a single ECM and 26 had multiple ECMs. Unlike previously reported American and Egyptian patients with PCH, a significantly higher incidence of cardiovascular malformations was observed in the Japanese PCH patients, and a female predominance was also observed, except in patients with multiple ECMs. Regarding the PCH patients with DS, a significantly higher, male-predominant incidence of duodenal atresia was observed, compared with data for liveborn infants with DS, whereas a male-predominant, significantly higher incidence of gastrointestinal malformations and a female-predominant, significantly higher incidence of cardiovascular malformations were found compared with data among PCH patients without DS. Moreover, urogenital and orofacial ECMs were absent among the PCH patients with DS. Regarding PCH patients without DS, a male-predominant, significantly higher incidence of urogenital malformations and a female-predominant, significantly higher incidence of cardiovascular and nervous malformations were found, compared with data for nationwide live births. In PCH patients with DS and in PCH patients with a single ECM, both familial and seasonal factors existed, while in PCH patients with multiple ECMs, only familial factors were observed. CONCLUSION: The incidence of ECMs in PCH patients was significantly higher than in the normal population, and ethnic-, sex-, and DS-related differences were observed. Genetic and environmental factors were also identified in PCH patients with ECMs.

Thyrotropin receptor and thyroid transcription factor-1 genes variant in Chinese children with congenital hypothyroidism.

The aim of the present study was to investigate the mutation/variant of thyrotropin receptor (TSHR) and thyroid transcription factor-1 (TTF-1) genes in Chinese children with congenital hypothyroidism (CH). Seventy-nine and forty-nine Chinese children with CH were enrolled for molecular analysis of the TSHR gene and TTF-1 gene, respectively. One hundred normal children were evaluated as control. The coding regions of TSHR and TTF-1 genes were amplified by polymerase chain reaction and sequenced. Sequencing of the TSHR gene revealed a compound heterozygous variants (Pro52Thr/Val689Gly) and a heterozygous variant (Gly245Ser) in 2 of 79 patients. In 30 patients and 33 controls the normal cytosine at position 2181 in exon 10 of TSHR gene was replaced by a guanineCresulting in the replacement of Asp (727) by Glu. In 47 patients and 50 controls, the normal thymidine at position 561 in exon 7 of TSHR gene was replaced by a cytosine. This substitution did not change the amino acid in position 187. Sequencing of the TTF-1 gene revealed no mutation or polymorphism in 49 patients and 100 controls. In conclusion, three heterozygous variants (Pro52Thr, Gly245Ser, Val689Gly) of TSHR gene were firstly detected in Chinese children with CH. There were polymorphisms in exon 10 at nucleotide 2181 (C/G) and in exon 7 at nucleotide 561 (T/C) in TSHR gene. No mutation or polymorphism was detected in the coding region of TTF-1 gene. The mutation/variant of TSHR and TTF-1 genes is relatively rare in Chinese children with CH.

Clinical and genetic characteristics of congenital hypothyroidism due to mutations in the thyroid peroxidase (TPO) gene in Israelis.

OBJECTIVES: Iodide organification defect (IOD) is characterized by a reduced ability of the thyroid gland to retain iodide and results in hypothyroidism. Mutations in the thyroid peroxidase (TPO) gene are a frequent cause of IOD. While TPO mutations have been identified in various populations, none have been reported in Israeli patients with IOD. The objectives of this study were to characterize the molecular basis of IOD in an Israeli Arab-Muslim population and to analyse the clinical, neurological and imaging data of patients with TPO mutations followed for up to 29 years. PATIENTS: Twenty-two patients from six core families with congenital hypothyroidism (CH) and IOD living in the same region. DESIGN AND MEASUREMENTS: All subjects underwent clinical, hormonal and imaging evaluation. The TPO gene was directly sequenced and the presence of specific mutations among family members was determined by restriction fragment length polymorphism (RFLP). RESULTS: All patients had congenital and persistent primary hypothyroidism. The thyroid gland was demonstrated in all subjects by technetium (99mTc) scans. A positive perchlorate discharge test (mean 87%) was indicative of IOD. Enlargement of the thyroid gland was shown in 64% of our patients, mostly with multinodular appearance, and in some with retrosternal invasion. Neurological complications were observed in 13 patients (59%). Four subjects, who carry two different TPO mutations, had sensorineural deafness. Two previously described TPO gene mutations [G1567A (G493S) and C1708T (R540X)] and one novel TPO gene mutation [C965T (S292F)] were identified. The two previously described mutations were present in 90% of the subjects. Haplotyping suggested a distant common ancestry for each of these two mutations. CONCLUSIONS: Three different TPO gene mutations were found to be responsible for IOD in a consanguineous Israeli population. The high rate of development of multinodular glands (MNGs) in our cohort of patients indicates the need for long-term follow-up of patients with TPO gene mutations.

Influence of timing and dose of thyroid hormone replacement on mental, psychomotor, and behavioral development in children with congenital hypothyroidism.

OBJECTIVES: To evaluate the influence of initial and postinitial treatment factors on cognitive, psychomotor, and psychological outcome in schoolchildren with congenital hypothyroidism (CH). STUDY DESIGN: We studied 45 patients (19 with severe CH and 26 with mild CH) and 37 control children by correlating initial and postinitial treatment factors (free thyroxine and thyroid-stimulating hormone [TSH] concentrations, and the percentage of overtreatment and undertreatment periods) with the results of neuropsychological tests and behavior (as reported on the Teacher Report Form [TRF]). RESULTS: The global IQ of the children with CH was comparable to that of the controls; visuomotor and verbal scores were lower, and total TRF scores were higher. Ethnic group, previous development, and overtreatment predicted IQ and verbal scores, with higher scores seen for the overtreated patients than for the control children and those patients who had not been overtreated. As initial treatment was less satisfactory, total TRF scores were higher. CONCLUSIONS: Our study suggests that initial and postinitial suboptimal treatment of CH leads to abnormalities in IQ and specific fields. Overtreatment may advance cognitive development in 5-1/2- to 7-year-olds. Suboptimal initial treatment may lead to behavioral problems. We recommend that TSH concentrations be maintained within the normal range in patients with CH.

Neurodevelopmental outcomes in congenital hypothyroidism: comparison of initial T4 dose and time to reach target T4 and TSH.

OBJECTIVES: To compare neurodevelopmental outcomes in severe and moderate congenital hypothyroidism (CH) among 3 different initial L-thyroxine doses and to examine the effect of the time to thyroid function normalization on neurodevelopmental outcomes. STUDY DESIGN: Neurodevelopmental assessments of 31 subjects included the Mullen Scales of Early Learning, Wechsler Preschool and Primary Scale of Intelligence-Revised, Wechsler Intelligence Scale for Children, Wide-Range Achievement Test, and Child Behavioral Checklist. RESULTS: Subjects started on higher initial L-thyroxine doses (50 mug) had full-scale IQ scores 11 points higher than those started on lower (37.5 mug) initial doses. However, verbal IQ, performance IQ, and achievement scores did not differ among the 3 treatment cohorts. Subjects with moderate CH had higher full-scale IQ scores than subjects with severe CH, regardless of the initial treatment dose. Subjects who took longer than 2 weeks to normalize thyroid function had significantly lower cognitive, attention, and achievement scores than those who achieved normal thyroid function at 1 or 2 weeks of therapy. CONCLUSIONS: Initial L-thyroxine dose and faster time to normalization of thyroid function are important to optimal neurodevelopmental outcome. In severe CH, it is important to choose an initial dose at the higher end of the recommended range to achieve these goals.