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1.  Intelligence quotient in children with congenital hypothyroidism: The effect of diagnostic and treatment variables 
Considering the high prevalence of congenital hypothyroidism (CH) in Isfahan, the intelligence quotient (IQ) of children with CH and the effect of diagnostic and treatment variables on it were investigated during the CH screening program.
Materials and Methods:
A total of 120 children in three studied groups were studied in this comparative study the IQ score, in three subsets of verbal IQ, performance IQ and full scale IQ, of children diagnosed with transient congenital hypothyroidism (TCH) and permanent congenital hypothyroidism (PCH) was measured using revised Wechsler pre-school and primary scale of intelligence and compared with the control group. The relation between IQ score with time of treatment initiation and screening thyroid stimulating hormone (TSH) level was evaluated in all studied groups.
Mean of verbal IQ, performance IQ, and full scale IQ score was significantly higher in the control group than CH patients (both permanent and transient) In PCH patients though it was not significant, there was a negative relationship between verbal IQ, performance IQ and full scale IQ and screening TSH and age of treatment initiation. In TCH patients, there was negative and significant relationship between verbal IQ (r = −0.40) and full scale IQ (r = −0.38) and age of treatment initiation (r = −0.46).
Mean IQ score in both PCH and TCH patients were lower than the control group, which correlates negatively with treatment initiation time. Though CH screening and early treatment has improved the prognosis of patients, but early and high dose of treatment in children with CH is recommended.
PMCID: PMC3810573  PMID: 24174944
Congenital hypothyroidism; intelligence quotient; permanent; transient; Wechsler pre-school and primary scale
2.  Prevalence of transient congenital hypothyroidism in central part of Iran 
Congenital hypothyroidism (CH) considered a common endocrine disorder in Iran. We report the epidemiologic findings of CH screening program in Isfahan, seven years after its development, regarding the prevalence of transient CH (TCH) and its screening properties comparing with permanent CH (PCH).
Materials and Methods:
In this cross-sectional study, children with primary diagnosis of CH were studied. Considering screening and follow-up lab data and the decision of pediatric endocrinologists, the final diagnosis of TCH was determined.
A total of 464,648 neonates were screened. The coverage percent of the CH screening and recall rate was 98.9 and 2.1%, respectively. Out of which, 1,990 neonates were diagnosed with primary CH. TCH was diagnosed in 1,580 neonates. The prevalence of TCH was 1 in 294 live births. 79.4% of patients with primary CH had TCH. Mean of screening (54.7 ± 59.0 in PCH vs 21.8 ± 28.9 in TCH), recall (56.5 ± 58.8 in PCH vs 36.6 ± 45.0 in TCH), and thyroid stimulating hormone (TSH) and mean of TSH before (2.0 ± 2.9 in PCH vs 1.6 ± 1.6 in TCH) and after (37.7 ± 29.5 in PCH vs 4.3 ± 1.9 in TCH) discontinuing treatment at 3 years of age was significantly higher in PCH than TCH (P < 0.0000).
The higher rate of CH in Isfahan is mainly due to the transient form of the disease. Further studies for evaluating the role of other environmental, autoimmune and/or genetic factors in the pathophysiology of the disease is warranted.
PMCID: PMC3872610  PMID: 24379847
Congenital hypothyroidism; permanent; transient
3.  Neonatal Thyroid Function in Seveso 25 Years after Maternal Exposure to Dioxin 
PLoS Medicine  2008;5(7):e161.
Neonatal hypothyroidism has been associated in animal models with maternal exposure to several environmental contaminants; however, evidence for such an association in humans is inconsistent. We evaluated whether maternal exposure to 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a persistent and widespread toxic environmental contaminant, is associated with modified neonatal thyroid function in a large, highly exposed population in Seveso, Italy.
Methods and Findings
Between 1994 and 2005, in individuals exposed to TCDD after the 1976 Seveso accident we conducted: (i) a residence-based population study on 1,014 children born to the 1,772 women of reproductive age in the most contaminated zones (A, very high contamination; B, high contamination), and 1,772 age-matched women from the surrounding noncontaminated area (reference); (ii) a biomarker study on 51 mother–child pairs for whom recent maternal plasma dioxin measurements were available. Neonatal blood thyroid-stimulating hormone (b-TSH) was measured on all children. We performed crude and multivariate analyses adjusting for gender, birth weight, birth order, maternal age, hospital, and type of delivery. Mean neonatal b-TSH was 0.98 μU/ml (95% confidence interval [CI] 0.90–1.08) in the reference area (n = 533), 1.35 μU/ml (95% CI 1.22–1.49) in zone B (n = 425), and 1.66 μU/ml (95% CI 1.19–2.31) in zone A (n = 56) (p < 0.001). The proportion of children with b-TSH > 5 μU/ml was 2.8% in the reference area, 4.9% in zone B, and 16.1% in zone A (p < 0.001). Neonatal b-TSH was correlated with current maternal plasma TCDD (n = 51, β = 0.47, p < 0.001) and plasma toxic equivalents of coplanar dioxin-like compounds (n = 51, β = 0.45, p = 0.005).
Our data indicate that environmental contaminants such as dioxins have a long-lasting capability to modify neonatal thyroid function after the initial exposure.
Andrea Baccarelli and colleagues show that maternal exposure to a dioxin following the industrial accident in Seveso, Italy in 1976 is associated with modified neonatal thyroid function even many years later.
Editors' Summary
The thyroid, a butterfly-shaped gland in the neck, controls the speed at which the human body converts food into the energy and chemicals needed for life. In healthy people, the thyroid makes and releases two hormones (chemical messengers that travel around the body and regulate the activity of specific cells) called thyroxine (T4) and triiodothyronine (T3). The release of T4 and T3 is controlled by thyroid secreting hormone (TSH), which is made by the pituitary gland in response to electrical messages from the brain. If the thyroid stops making enough T4 and T3, a condition called hypothyroidism (an underactive thyroid) develops. Adults with hypothyroidism put on weight, feel the cold, and are often tired; children with hypothyroidism may also have poor growth and mental development. Because even a small reduction in thyroid hormone levels increases TSH production by the pituitary, hypothyroidism is often diagnosed by measuring the amount of TSH in the blood; it is treated with daily doses of the synthetic thyroid hormone levothyroxine.
Why Was This Study Done?
Although hypothyroidism is most common in ageing women, newborn babies sometimes have hypothyroidism. If untreated, “neonatal” hyperthyroidism can cause severe mental and physical retardation so, in many countries, blood TSH levels are measured soon after birth. That way, levothyroxine treatment can be started before thyroid hormone deficiency permanently damages the baby's developing body and brain. But what causes neonatal hypothyroidism? Animal experiments (and some but not all studies in people) suggest that maternal exposure to toxic chemicals called dioxins may be one cause. Dioxins are byproducts of waste incineration that persist in the environment and that accumulate in people. In this study, the researchers investigate whether exposure to dioxin (this name refers to the most toxic of the dioxins—2,3,7,8-Tetrachlorodibenzo-p-dioxin) affects neonatal thyroid function by studying children born near Seveso, Italy between 1994 and 2005. An accident at a chemical factory in 1976 heavily contaminated the region around this town with dioxin and, even now, the local people have high amounts of dioxin in their bodies.
What Did the Researchers Do and Find?
The researchers identified 1,772 women of child-bearing age who were living very near the Seveso factory (the most highly contaminated area, zone A) or slightly further away where the contamination was less but still high (zone B) at the time of the accident or soon after. As controls, they selected 1,772 women living in the surrounding, noncontaminated (reference) area. Altogether, these women had 1,014 babies between 1994 and 2005. The babies born to the mothers living in the reference area had lower neonatal blood TSH levels on average than the babies born to mothers living in zone A; zone B babies had intermediate TSH levels. Zone A babies were 6.6. times more likely to have a TSH level of more than 5 μU/ml than the reference area babies (the threshold TSH level for further investigations is 10 μU/ml; the average TSH level among the reference area babies was 0.98 μU/ml). The researchers also examined the relationship between neonatal TSH measurements and maternal dioxin measurements at delivery (extrapolated from measurements made between 1992 and 1998) in 51 mother–baby pairs. Neonatal TSH levels were highest in the babies whose mothers had the highest blood dioxin levels.
What Do These Findings Mean?
These findings suggest that maternal dioxin exposure has a long-lasting, deleterious effect on neonatal thyroid function. Because the long-term progress of the children in this study was not examined, it is not known whether the increases in neonatal TSH measurements associated with dioxin exposure caused any developmental problems. However, in regions where there is a mild iodine deficiency (the only environmental exposure consistently associated with reduced human neonatal thyroid function), TSH levels are increased to a similar extent and there is evidence of reduced intellectual and physical development. Future investigations on the progress of this group of children should show whether the long-term legacy of the Seveso accident (and of the high environmental levels of dioxin elsewhere) includes any effects on children's growth and development.
Additional Information.
Please access these Web sites via the online version of this summary at
The MedlinePlus encyclopedia provides information about hypothyroidism and neonatal hypothyroidism; MedlinePlus provides links to additional information on thyroid diseases (in English and Spanish)
The UK National Health Service Direct health encyclopedia provides information on hypothyroidism
The Nemours Foundation's KidsHealth site has information written for children about thyroid disorders
Toxtown, an interactive site from the US National Library of Science, provides information on environmental health concerns including exposure to dioxins (in English and Spanish)
More information about dioxins is provided by the US Environmental Protection Agency and by the US Food and Drug Administration
Wikipedia has a page on the Seveso disaster (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
PMCID: PMC2488197  PMID: 18666825
4.  The effect of glucocorticoids on thyrotropin secretion 
Journal of Clinical Investigation  1969;48(11):2096-2103.
The effect of large doses of glucocorticoids on thyrotropin (TSH) secretion in normal and hypothyroid humans has been studied. Plasma TSH concentrations were measured before, during, and after treatment with dexamethasone given orally for 24-48 hr. In 17 patients with primary hypothyroidism, plasma TSH levels fell significantly during treatment to a mean of 54% of control (range 23-96%). Within 48 hr after the withdrawal of dexamethasone, TSH concentrations transiently increased above pretreatment values. The mean increase was to 156% of control (range 106-294). Similar changes, but of smaller magnitude, were observed in 15 normal subjects. Administration of single oral doses of dexamethasone and oral or intravenous doses of cortisol were followed by reduction of plasma TSH levels to 18-47% of control within 8-12 hr in eight hypothyroid patients. This fall also was followed by significant TSH rises above control values before they returned to the pretreatment levels. Mineralocorticoid administration was not followed by any changes in plasma TSH concentrations in three subjects.
TSH responses to steroid were also studied in rats. In hypothyroid rats given dexamethasone intravenously, plasma TSH fell to 63% of control in 30-90 min and then returned to normal or above in 3-4 hr. Dexamethasone also reduced plasma TSH concentrations in normal rats but no rebound was observed in these animals. Dexamethasone did not block the increase in plasma TSH produced by thyrotropin releasing factor (TRF) administration in vivo. Neither basal nor TRF-mediated TSH release from hemipituitaries in vitro was reduced by dexamethasone or corticosterone. These studies indicate that glucocorticoids reduce TSH secretion and suggest that this effect occurs at a suprahypophyseal level.
PMCID: PMC297463  PMID: 4980930
5.  Audit of screening programme for congenital hypothyroidism in Scotland 1979-93 
Archives of Disease in Childhood  1997;76(5):411-415.
Accepted 30 January 1997

OBJECTIVE—To evaluate the efficiency of the screening programme for congenital hypothyroidism in Scotland and to determine the outcome in the cohort of children with positive testing for thyroid stimulating hormone (TSH).
DESIGN—Establishment of comprehensive database for all Scottish infants with high TSH, detected on Guthrie screening.
SUBJECTS—344 infants born between August 1979 and December 1993 with TSH greater than 40 mU/l on initial Guthrie, or 15-40 mU/l on repeat Guthrie.
MAIN OUTCOME MEASURES—Ages at time of: (a) Guthrie collection, (b) notification of positive result by laboratory, and (c) start of treatment; audit of late diagnosis/missed cases; categorisation of positive cases into definite and probable congenital hypothyroidism, transient TSH elevation, and uncertain status; educational status of children with definite and probable congenital hypothyroidism.
RESULTS—344 positive cases were categorised as having definite (224) and probable (11) congenital hypothyroidism, transient TSH elevation (88), and status uncertain (21). The overall incidence of definite/probable congenital hypothyroidism was 1 in 4400 live births. For the definite/probable groups median age of Guthrie collection was consistently between 6 and 7 days from 1983 onwards but for the whole cohort was later than 10 days in 10.5%. Median age of notification fell from 14days in 1980 to 11 days in 1993. Median age of starting treatment ranged between 11 and 15 days from 1983 onwards. Treatment was delayed in four cases, three due to failed or late Guthrie card submission. Of 149 children with definite/probable congenital hypothyroidism who were of school age, educational status was ascertained in 139 (93%). Only two children (1.4%) were attending special school, one of whom was known to have mild hypothyroidism. Sixteen children (11.5%) were receiving extra help in mainstream education compared with 18% of control children in the Scottish very low birth weight study.
CONCLUSION—The current screening programme is working well, but efficiency could be increased by earlier and more reliable Guthrie collection. A substantial proportion of children picked up on the screening programme have a transient rise in TSH rather than true congenital hypothyroidism. The incidence of special education and learning support in Scottish children with congenital hypothyroidism appears to be no different to that of the general population.

PMCID: PMC1717190  PMID: 9196355
6.  Does Congenital Hypothyroidism Have Different Etiologies in Iran? 
Iranian Journal of Pediatrics  2011;21(2):188-192.
To determine the prevalence of congenital hypothyroidism (CH), permanent and transient CH.
From November 2006 to September 2007, 63031 newborns were screened by measuring serum TSH obtained by heel prick. The neonates who had a TSH≥5mU/L were recalled for measurement of serum T4, thyroid stimulating hormone (TSH) and TSH receptor blocking antibodies (TRBAb) in venous samples. In 43 primarily diagnosed as cases of CH, treatment was discontinued at age 2–3 years for 4 weeks and T4 and TSH were measured again. Permanent or transient CH was determined from the results of these tests and radiologic evaluation.
The incidence of congenital hypothyroidism was found to be 1:1465 with a female to male ratio of 1.19:1. The most common clinical findings were prolonged jaundice (73%), large anterior fontanel (56%) and wide posterior fontanel (55%). In 43 patients with CH, prevalence of permanent and transient form of the disorder was 53.6% and 46.4% respectively. Permanent CH was associated with higher initial TSH level than transient hypothyroidism (P<0.001). The most common etiology of permanent CH was dyshormonogenesis (57%). TRBAb was found in 6.8% of the total 43 cases.
Congenital hypothyroidism in Iran may have different etiologies. Due to higher rate of transient CH than other similar researches, it is reasonable to follow these patients for a longer period to rule out the possibility of permanent hypothyroidism.
PMCID: PMC3446167  PMID: 23056786
Congenital Hypothyroidism; TSH Receptor; Dyshormonogenesis; Thyroid Dysgenesis
7.  The relation between serum and filter paper TSH level in neonates with congenital hypothyroidism 
the aim of this study was to determine the relation between serum and filter paper thyroid-stimulating hormone (TSH) levels in neonates with congenital hypothyroidism (CH). We also tried to determine an appropriate cutoff point of filter TSH for recalling screened neonates.
Materials and Methods:
in this descriptive-analytic study, records of 2283 neonates who had been recalled during CH screening program in Isfahan (Iran) were studied. The relation between serum and filter paper TSH levels in the studied neonates was assessed and the best cutoff point of filter TSH and its sensitivity and specificity for proper diagnosis of CH were determined.
among the studied neonates, 103 (4.5%) were diagnosed with CH. Using receiver operating characteristic (ROC) curve, the best cutoff point for diagnosing CH was 7.5 with a sensitivity of 74.8% and specificity of 71.3%. The rates of false positive and false negative diagnoses at this cutoff point were28.7% and 25.2%, respectively. There was a significant relationship between serum and filter paper TSH levels.
the cutoff point for recall should be changed to 7.5 for appropriate screening outcome. On the other hand, considering the low cost of filter paper and importance of missing any case of CH, changing the cutoff point is not necessary. However, further studies in different parts of Iran are required to obtain more accurate results and consider all related factors.
PMCID: PMC3928837  PMID: 24592370
Congenital hypothyroidism; filter paper; thyroid-stimulating hormone
8.  Serum TSH Level in Healthy Koreans and the Association of TSH with Serum Lipid Concentration and Metabolic Syndrome 
The proper treatment of subclinical hypothyroidism and the normal range of serum thyroid stimulating hormone (TSH) concentration are intensely debated. However, few reports have investigated TSH concentrations in Asian ethnic groups. Therefore, the present study was designed to define the TSH reference range in a Korean population and to investigate the metabolic significance of TSH concentration.
We enrolled patients who underwent medical examination at the CHA Bundang Medical Center. Anthropometric data were evaluated, and serum TSH, free T4, and lipid profiles were assayed.
A total of 7,270 subjects were included. Mean TSH concentration of the study population was 1.82 ± 0.95 mU/L, and we observed a sex-related difference in TSH concentration (male, 1.67 ± 0.87 mU/L; female, 2.02 ± 1.01 mU/L; p < 0.01). When the 2.5 and 97.5 percentiles were calculated, 95% TSH reference limits were 0.52-4.29 mU/L. TSH concentration was higher in elderly subjects, during winter, in postmenopausal women, and in obese males. Moreover, TSH showed significantly positive correlations with serum total cholesterol, triglyceride, and low density lipoprotein cholesterol regardless of sex, age, season, obesity, or menopausal status (all p < 0.01). Finally, TSH concentration was positively related to the prevalence of metabolic syndrome.
We demonstrated the association between TSH concentration within the normal reference range and serum lipid levels. TSH concentration varies according to sex, age, season, and body mass index (only in males). Moreover, high normal TSH levels were significantly associated with an increased prevalence of metabolic syndrome, which may be of importance when evaluating subjects with high normal TSH concentration.
PMCID: PMC3245392  PMID: 22205844
Thyroid function tests; Thyrotropin; Metabolic syndrome
9.  Thyroid screening in pregnancy — A study of 82 women 
To create awareness, lay down a new criterion to pick up probable cases, and draw a proper management protocol for hypothyroidism in pregnancy.
Inclusion criteria — All normal pregnant women and those with thyroid problems were included in the study. Exclusion criteria — All others who had diabetes, collagen disease, heart disease with pregnancy were excluded from the study. Eighty two women were screened for hypothyroidism in pregnancy using T3, T4, TSH and FT4. A new screening criterion was followed [TSH value — 0.5–1.5 mIU/ml i.e biological range]. Women with TSH in pregnancy were followed up. Women with TSH value above 3mIU/ml, were considered hypothyroid and received treatment with L-Thyroxin. The group with a TSH value 2–3 mIU/ml was assessed with FT4. Those with low values or those with increasing TSH value on subsequent follow up received treatment.
Study group consisted of 62 Primigravidae and 20 multigravidae. A. 40[32P + 8M] > 3 TSH value, these women received treatment with L-Thyroxin B. 24[16P + 8M] 2–3 TSH value, C. 18[14P + 4M] <2 TSH value. According to thyroid status, they were categorized into euthyroid — [27 true euthyroid + 4 potential hypothyroid] and overt hypothyroid — [43 adequately treated and 6 inadequately treated], two were untreated. Inadequately treated and potential hypothyroid pregnant women landed with miscarriages or pregnancy inducted hypertension, oligohydramnios and IUGR.
Potential and inadequately treated hypothyroid patients present with problems in pregnancy, while adequately treated hypothyroid and true euthyroid women get normal ongoing pregnancies. So to identify these potential or overt hypothyroid women, thyroid screening with T3, T4, TSH and FT4 must be done during prenatal period, at first booking, and repeated at 8 weeks interval thereafter, in pregnancy. TSH value should be kept below 2mIU/ml to get adequate control.
PMCID: PMC3394518
screening in pregnancy; thyroid and pregnancy; hypothyroidism
10.  Elevated thyroid stimulating hormone is associated with elevated cortisol in healthy young men and women 
Thyroid Research  2012;5:13.
Recent attention has been given to subclinical hypothyroidism, defined as an elevation of TSH (4.5-10 uIU/L) with T4 and T3 levels still within the normal range. Controversy exists about the proper lower limit of TSH that defines patients in the subclinical hypothyroidism range and about if/when subclinical hypothyroidism should be treated. Additional data are needed to examine the relationship between markers of thyroid function in the subclinical hypothyroidism range, biomarkers of health and ultimately health outcomes.
We aimed to assess the relationship between serum TSH levels in the 0.5-10 uIU/L range and serum cortisol in a cohort of healthy young men and women without clinical evidence of hypothyroidism. Based on data in frank hypothyroidism, we hypothesized that serum TSH levels would be positively correlated with serum cortisol levels, suggesting derangement of the cortisol axis even in subclinical hypothyroidism.
We conducted a cross sectional study in 54 healthy, young (mean 20.98 +/− 0.37 yrs) men (19) and women (35). Lab sessions took place at 1300 hrs where blood was drawn via indwelling catheter for later assessment of basal serum TSH, free T3, free T4, and cortisol levels.
All but 1 participant had free T3 levels within the normal reference intervals; free T4 levels for all participants were within the normal reference intervals. Linear regression modeling revealed that TSH levels in the 0.5-10 uIU/L were significantly and positively correlated with cortisol levels. This positive TSH-cortisol relationship was maintained below the accepted 4.5 uIU/L subclinical hypothyroid cutoff. Separate regression analyses conducted by systematically dropping the TSH cutoff by 0.50 uIU/L revealed that the TSH-cortisol relationship was maintained for TSH levels (uIU/L) ≤4.0, ≤3.5, ≤3.0, and ≤2.5 but not ≤2.0. Linear regression modeling did not reveal a relationship between free T3 or free T4 levels and cortisol levels.
Results suggest a positive relationship between TSH and cortisol in apparently healthy young individuals. In as much as this relationship may herald a pathologic disorder, these preliminary results suggest that TSH levels > 2.0 uIU/L may be abnormal. Future research should address this hypothesis further, for instance through an intervention study.
PMCID: PMC3520819  PMID: 23111240
TSH; Free T3; Free T4; Cortisol; Subclinical hypothyroidism
11.  Newborn Screening for Congenital Hypothyroidism 
Newborn screening (NS) for congenital hypothyroidism (CH) is one of the major achievements in preventive medicine. Most neonates born with CH have normal appearance and no detectable physical signs. Hypothyroidism in the newborn period is almost always overlooked, and delayed diagnosis leads to the most severe outcome of CH, mental retardation, emphasizing the importance of NS. Blood spot thyroid stimulating hormone (TSH) or thyroxine (T4) or both can be used for CH screening. The latter is more sensitive but not cost-effective, so screening by TSH or T4 is used in different programs around the world. TSH screening was shown to be more specific in the diagnosis of CH. T4 screening is more sensitive in detecting especially those newborns with rare hypothalamic-pituitary-hypothyroidism, but it is less specific with a high frequency of false positives mainly in low birth weight and premature infants. The time at which the sample is taken may vary. In the majority of the centers, blood is obtained from a heel prick after 24 hours of age to minimize the false positive high TSH due to the physiological neonatal TSH surge that elevates TSH levels and causes dynamic T4 and T3 changes in the first 1 or 2 days after birth. Early discharge of mothers postpartum has increased the ratio of false positive TSH elevations. Although transient hypothyroidism may occur frequently, all these infants should be treated as having CH for the first 3 years of life, taking into account the risk of mental retardation. A reevaluation after 3 years is needed in such patients. The goal of initial therapy in CH is to minimize neonatal central nervous system exposure to hypothyroidism by normalizing thyroid function, as rapidly as possible.
Conflict of interest:None declared.
PMCID: PMC3608007  PMID: 23154158
Neonatal screening; congenital hypothyroidism; iodine deficiency
12.  Hearing Impairment in Congenitally Hypothyroid Patients 
Iranian Journal of Pediatrics  2012;22(1):92-96.
Thyroid hormone is necessary for normal development of the auditory system. The aim of this study was to investigate the rate of hearing impairment in congenitally hypothyroid (CH) patients, and its relation with factors such as CH severity and age at starting treatment, during CH screening program in Isfahan.
Hearing acuity was assessed in two groups of children with (94 patients aged 4 months – 3 years) and without CH (450), between 2000-2006. Otoacostic emission (OAE) was performed by a two step method. After two tests without OAE signals bilaterally, they were referred for auditory brainstem response (ABR) test. Subjects with both OAE and ABR abnormal test results were considered to have hearing problem. Obtained data was compared in case and control group and also CH patients with and without hearing impairment.
Three (3.2%) of patients and 1 of control group (0.2%) were diagnosed with sensorineural hearing loss. The rate of hearing loss was not different significantly in two studied groups (P>0.05). There was no difference between age of starting treatment and first T4 and TSH level in CH patients with and without hearing loss (P>0.05). CH neonates with hearing impairment had thyroid dyshormonogenesis according to the follow up results.
The rate of hearing loss was low among our studied CH patients. It may be due to proper management of CH patients. In view of the fact that all CH neonates were dyshormonogentic and considering the relation between certain gene mutations and hearing impairment in CH patients, further studies with larger sample size, with regard to different etiologies of CH should be investigated to indicate the possible gene mutations related to hearing loss in CH.
PMCID: PMC3448222  PMID: 23056865
Hearing impairment; Auditory Brain Stem Response; ABR; Oto Acostic Emission; OAE
13.  Current Loss-of-Function Mutations in the Thyrotropin Receptor Gene: When to Investigate, Clinical Effects, and Treatment 
Thyroid-stimulating hormone receptor (TSHR) loss-of-function (LOF) mutations lead to a wide spectrum of phenotypes, ranging from severe congenital hypothyroidism (CH) to mild euthyroid hyperthyrotropinemia. The degree of TSH resistance depends on the severity of the impairment of the receptor function caused by the mutation and on the number of mutated alleles In this review data about genotype-phenotype correlation and criteria for clinical work-up will be presented and discussed. Complete TSH resistance due to biallelic LOF TSHR mutations must be suspected in all patients with severe not syndromic CH and severe thyroid hypoplasia diagnosed at birth by neonatal screening. Partial forms of TSH resistance show a more heterogeneous hormonal and clinical pattern . In these cases TSH serum levels are above the upper limit of normal range for the age but with a very variable pattern, free thyroxine (T4) concentrations are within the normal range and thyroid size can be normal or hypoplastic at ultrasound scan. An early substitutive treatment with L-T4 must be mandatory in all patients with severe CH due to complete uncompensated TSH resistance diagnosed at birth by neonatal screening. The usefulness of substitutive treatment appears much more controversial in patients with subclinical hypothyroidism due to partial TSH resistance in whom the increased TSH concentration should be able to compensate the mild functional impairment of the mutant receptor. Together with standard criteria we recommend also an accurate clinical work-up to select patients who are candidates for a LOF TSHR mutation.
Conflict of interest:None declared.
PMCID: PMC3608004  PMID: 23154162
Thyrotropin receptor gene mutations; congenital hypothyroidism; Neonatal screening; Subclinical hypothyroidism
14.  Increased plasma thyroid stimulating hormone in treated congenital hypothyroidism: relation to severity of hypothyroidism, plasma thyroid hormone status, and daily dose of thyroxine. 
Archives of Disease in Childhood  1993;69(5):555-558.
Plasma thyroid stimulating hormone (TSH) concentrations obtained during the first four years of treatment in 418 children with congenital hypothyroidism, identified by neonatal screening, were examined in relation to paired measurements of plasma thyroxine (n = 1945), free thyroxine (n = 836), triiodothyronine (n = 480), and free triiodothyronine (n = 231), and estimated daily dose of thyroxine at the time of blood sampling. Overall, plasma TSH was above 7 mU/l in 1280 out of 2960 samples (43%); the percentage was not related to severity of hypothyroidism at diagnosis. Mean values for thyroxine and free thyroxine, and to a lesser extent free triiodothyronine, were consistently lower in samples with TSH concentrations over 7 mU/l and this was the case in patients with either severe or less severe hypothyroidism. Raised TSH concentrations were also associated with lower mean doses of thyroxine (micrograms/kg/day) but here the mean doses of thyroxine in children with severe hypothyroidism were higher than in the children with less severe hypothyroidism. The mean dose of thyroxine associated with low/normal TSH values was highest in the first 6 months and fell progressively. Thyroxine dose was significantly related to thyroxine and free thyroxine concentrations but not to triiodothyronine and free triiodothyronine and the latter appeared to be of limited value as measures of plasma thyroid hormone status during treatment.
PMCID: PMC1029617  PMID: 8257174
15.  Permanent and Transient Congenital Hypothyroidism in Fayoum, Egypt: A Descriptive Retrospective Study 
PLoS ONE  2013;8(6):e68048.
Congenital 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.
Cases 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.
Of 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.
The 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.
PMCID: PMC3695950  PMID: 23840807
16.  Improvement in screening performance and diagnosis of congenital hypothyroidism in Scotland 1979–2003 
Archives of Disease in Childhood  2006;91(8):680-685.
To assess the Scottish newborn screening programme for congenital hypothyroidism from 1994 to 2003 (period 2) for performance and compare with an initial audit covering 1979 to 1993 (period 1).
Performance data—age at blood spot sampling, notification by screening laboratory, start of treatment, and the prevalence of late testing, notification or treatment—were compared, together with the incidence of congenital hypothyroidism.
Comparing data for period 2 with period 1, the mean annual incidence of true congenital hypothyroidism was 1:3655 live births v 1:4363. Median age for Guthrie sampling (all referrals) was 6 v 7 days (p<0.0001). Late sampling (>10 days) had fallen from 10.7% to 7%. For infants requiring repeat sampling before notification, the median (range) interval between initial and final repeat samples was 11 (1 to 52) compared with 14 (3 to 73) days. Median age at notification for true congenital hypothyroidism was 10 v 12 days (p <0.0001). Late notification (>15 days) was justifiable (mild TSH elevation) in 10 of 13 patients in period 2. Median age at start of treatment for true congenital hypothyroidism had improved to 11 days from 13.5 days. For true congenital hypothyroidism, late treatment (>16 days) occurred in 7% of patients compared with 19% (p<0.0001).
There has been an improvement in performance measures for the congenital hypothyroidism screening programme in Scotland. However, late sampling, occurring primarily in inpatients and which is never justified, remains a problem, while the interval between initial and recall sampling is a further source of delay.
PMCID: PMC2083034  PMID: 16595645
congenital hypothyroidism; screening
17.  Plasma TSH and Serum T-4 Levels in Long-term Follow-up of Patients Treated with 131I for Thyrotoxicosis 
British Medical Journal  1974;3(5924):152-153.
In February 1972 58% of patients euthyroid after iodine-131 therapy given for thyrotoxicosis between 1954 and 1966 had a high plasma TSH (>7·4 μU/ml) and 42% a normal plasma TSH level. A group of 69 of the euthyroid patients with high plasma TSH levels (25·0±2·0 μU/ml) in 1972 were re-examined 15 and 24 months later. The mean plasma TSH in the 66 patients remaining euthyroid at 15 months was 22·6±1·8 μU/ml, while three patients had become hypothyroid. At 24 months 64 of the patients were still available for study, of whom 61 remained euthyroid with a mean plasma TSH of 21·6±2·0 μU/ml, and a further three had become hypothyroid.
All of a group of 61 of the euthyroid patients with normal plasma TSH levels (4·0±0·2 μU/ml) in 1972 remained euthyroid at 24 months with a mean plasma TSH of 4·1±0·3 μU/ml, though the plasma TSH level had become slightly raised in three.
The mean serum T-4 level in the euthyroid patients with a high plasma TSH was significantly lower, though still in the normal range, than that in the euthyroid patients with a normal plasma TSH both in 1972 and in 1974.
Since no patient with a normal plasma TSH level after iodine-131 treatment six to 18 years earlier for thyrotoxicosis developed hypothyroidism over a two-year period, the follow-up of such patients need not be so rigorous as that of similarly treated euthyroid patients with raised plasma TSH levels in whom hypothyroidism developed at the rate of 5% per year.
PMCID: PMC1611292  PMID: 4136163
18.  Are patients with primary hypothyroidism in India receiving appropriate thyroxine replacement? An observational study 
A large proportion of patients worldwide under treatment for hypothyroidism with thyroxine show suboptimal Thyroid Stimulating Hormone (TSH) values. There is a paucity of Indian data on ‘out-of-range’ TSH values in patients with primary hypothyroidism receiving levothyroxine treatment.
To assess the percentage of primary hypothyroid patients with abnormal thyroid function despite being prescribed levothyroxine for at least 2 m.
Materials and Methods:
A cross-sectional, single visit, observational study in adult patients with primary hypothyroidism on treatment with levothyroxine for at least 2m was undertaken across 10 cities in India. Compliance to thyroxine therapy was assessed by interviewing the subjects and their quality of life was assessed by administering the SF-36 questionnaire. A random blood sample (5ml) was drawn from the study subjects during the same visit for assessing serum TSH levels. TSH levels were correlated with the current dose of levothyroxine.
A total of 1950 subjects (mean age 41.4 ± 11.17 years; female 81.2%, male 18.8%) with primary hypothyroidism were enrolled in the study. Of the 1925 subjects in whom TSH values were available, 808 (41.97%) were under-treated (TSH > 4 mIU/L) and 243 (12.62%) were over-treated (TSH < 0.4mIU/L). The mean dose of thyroxine in this study was 1.23 μg/kg/day (±0.85). Majority of subjects (90.79%) were compliant/moderately compliant to thyroxine therapy. Age and autoimmune hypothyroidism were the factors that had significant impact on serum TSH. Subjects with abnormal TSH had significantly lower scores for role limitation due to emotional problems (P = 0.0278) and due to physical health (P = 0.0763).
This study concluded that around half (54%) of known hypothyroid subjects had out-of-range serum TSH despite being treated with levothyroxine for at least 2m. The mean daily dose of thyroxine (1.23 μg/kg ± 0.85) was less than the recommended full replacement dose.
PMCID: PMC3968739  PMID: 24701435
Hypothyroidism; India; levothyroxine; primary hypothyroidism; serum TSH; thyroxine
19.  Screening for Congenital Hypothyroidism in Newborns Transferred to Neonatal Intensive Care 
To evaluate the effectiveness of four screening protocols for congenital hypothyroidism (CH) in newborns transferred to the NICU. Determine an evidence base for the Center for Laboratory Standards Institute’s Newborn Screening for Preterm, Low Birth Weight, and Sick Newborns Approved Guideline by evaluating a nearly identical protocol.
Design, Setting & Patients
Michigan newborns transferred to the NICU from 1998–2011 and screened for CH are included in this population-based retrospective cohort study.
Main Outcome Measures
Screening performance metrics are computed and logistic regression is used to test for differences in the likelihood of detection across four periods characterized by different testing protocols.
Primary TSH plus retest at 30 days of life or discharge achieved the greatest detection rate (2.6: 1,000 births screened). The odds of detection was also significantly greater in this period compared to the tandem T4 and TSH testing period and separately compared to TSH testing alone, adjusted for birth weight, sex and race (aOR 1.5; CI 1.0–2.2; p=0.046, and aOR 2.2; CI 1.5–3.4, respectively). Approximately half of the cases detected during primary TSH plus serial testing periods were identified by retest.
Primary TSH testing programs that do not incorporate serial screening may fail to identify approximately half of newborns with congenital thyroid hormone deficiency transferred to the NICU. Tandem T4 and TSH testing programs also likely miss cases who otherwise would receive treatment if serial testing were conducted. Further research is necessary to determine the optimal NBS protocol for CH; strategies combining tandem T4 and TSH with serial testing conditional on birthweight may be useful.
PMCID: PMC4136805  PMID: 23183553
Newborn Screening; Performance Evaluation; Congenital Hypothyroidism; Repeat Testing
20.  Factors involved in the rate of fall of thyroid stimulating hormone in treated hypothyroidism 
Archives of Disease in Childhood  1997;77(6):526-527.

The rate of fall of serum thyroid stimulating hormone (TSH) concentrations in 32 hypothyroid infants (11 boys, 21 girls) was studied after starting treatment with thyroxine to determine whether it was influenced by initial TSH concentration or the cause of the hypothyroidism. Of 27 patients who had isotope scans before treatment was started, 11 (40%) were athyrotic, 10 (38%) had an ectopic gland, and six (22%) probably had dyshormonogenesis. Treatment was started with thyroxine at 100 µg/m2/24 hours at a mean age of 26 days (range 14-45). Serum TSH concentrations remained increased in 26 (81%) at 3 months, 20 (62.5%) at 6 months, and nine (28%) at 1 year and beyond. The mean age for serum TSH to reach the normal range was 0.79 years (range 0.15-2.1 years). Diagnosis (in 27 patients) and initial results (in 32) made no difference to the rate of fall. 

PMCID: PMC1717416  PMID: 9496191
21.  Patterns of Interferon-Alpha–Induced Thyroid Dysfunction Vary with Ethnicity, Sex, Smoking Status, and Pretreatment Thyrotropin in an International Cohort of Patients Treated for Hepatitis C 
Thyroid  2013;23(9):1151-1158.
Interferon-alpha (IFNα)–induced thyroid dysfunction occurs in up to 20% of patients undergoing therapy for hepatitis C. The diversity of thyroid disease presentations suggests that several different pathological mechanisms are involved, such as autoimmunity and direct toxicity. Elucidating the relationships between risk factors and disease phenotype provides insight into the mechanisms of disease pathophysiology.
We studied 869 euthyroid patients from the ACHIEVE 2/3 trial, a randomized international clinical trial comparing pegylated-IFNα2a weekly or albumin-IFNα2b every 2 weeks for up to 24 weeks in patients with hepatitis C, genotype 2 or 3, from 136 centers. The study population was 60% male and 55% white. Serum thyrotropin (TSH) and free thyroxine were measured before therapy, monthly during treatment from week 8, and at 4- and 12-week follow-up visits.
Overall, 181 (20.8%) participants had at least one abnormal TSH during the study. Low TSH occurred in 71 (8.2%), of whom 30 (3.5%) had a suppressed TSH below 0.1 mU/L. Hypothyroidism occurred in 53 patients (6.1%), with peak TSH above 10 mU/L in 12 patients (1.4%). Fifty-seven patients had a biphasic thyroiditis (6.6%), with extreme values for the nadir and/or peak TSH in all but one. Medical therapy was given to one thyrotoxic patient, four hypothyroid patients, and 26 biphasic thyroiditis patients. Multivariate logistic regression analysis demonstrated that biphasic thyroiditis is associated with being female and higher pretreatment serum TSH, whereas being Asian or a current smoker decreased the risk of thyroiditis. Hypo- and hyperthyroidism are most strongly predicted by the pretreatment TSH.
Biphasic thyroiditis accounted for the majority (58%) of clinically relevant IFNα-induced thyroid dysfunction. We confirmed our recent findings in a related cohort that female sex is a risk factor for thyroiditis but not hypothyroidism. Further, in this large multiethnic study, the risk of thyroiditis is dramatically increased, specifically for white women. Smoking was found to be protective of thyroiditis. These results support closer monitoring of women and those with a serum TSH at the extremes of the normal range during therapy so that prompt intervention can mitigate the consequences of thyroid dysfunction associated with IFNα treatment.
PMCID: PMC3770239  PMID: 23517287
22.  In Thyroidectomized Patients with Thyroid Cancer, a Serum Thyrotropin of 30 μU/mL After Thyroxine Withdrawal Is Not Always Adequate for Detecting an Elevated Stimulated Serum Thyroglobulin 
Thyroid  2013;23(2):185-193.
The thyrotropin (TSH) level or duration of thyroid hormone withdrawal (THW) required to detect stimulated thyroglobulin (Tg) in differentiated thyroid cancer (DTC) monitoring is unknown. The objective of this study was to evaluate the TSH cutoff of >30 μU/mL as a means to detect stimulated Tg ≥2 ng/mL after THW (THW-Tg≥2), and sensitivity of the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) questionnaire for detecting hypothyroid symptoms.
This was a prospective longitudinal cohort study done at a tertiary academic medical center. Forty-seven patients with DTC undergoing their first Tg stimulation or after previously abnormal Tg stimulation had weekly measurements of TSH and Tg during the 4 weeks THW, and repeated questionnaire assessments.
TSH did not reach a plateau in any patient, and in those whose Tg did not remain undetectable, Tg continued to rise. Seventy-five percent of patients had an undetectable Tg <0.2 ng/mL at baseline (95% were <0.5 mg/mL) with 16% remaining undetectable throughout THW. The majority of patients (72.7% and 97.8%) achieved TSH >30 μU/mL by 3 and 4 weeks THW, respectively. Of the 15 patients with maximum stimulated THW-Tg≥2, 38% were detected before the minimal TSH >30 μU/mL cutoff. At 2 weeks THW, 3 had a TSH>30 μU/mL, and none of them had Tg ≥2 ng/mL. At 3 weeks THW, 11 had a TSH >30 μU/mL, and 64% of them had Tg ≥2 ng/mL. Only 60% were detected at 3-week THW regardless of their TSH level. Eighty-six percent were detected by TSH 60–<80 μU/mL. Conversely, all patients whose serum Tg was <0.2 ng/mL when their serum TSH was >20 μU/mL did not achieve a THW-Tg≥2.
The minimal TSH cutoff of >30 μU/mL was inadequate to detect many patients with final stimulated THW-Tg≥2 during complete THW. TSH >80–100 μU/mL was a better cutoff, achieved in only 53% after 4-week THW. Conversely, we propose a preliminary THW-stopping rule for ending THW early in selected patients. In patients with a Tg <0.2 ng/mL when TSH >20 μU/mL, all had a final stimulated Tg ≤2 ng/mL, potentially saving qualifying patients 40% of THW duration compared to 4-week THW. FACIT-F correlated with TSH, but was not sensitive to detect mild hypothyroidism.
PMCID: PMC3919477  PMID: 22978687
23.  Prevalence of Subclinical Hypothyroidism in Pregnant Women in Tehran-Iran 
Maternal subclinical hypothyroidism during pregnancy is associated with various adverse outcomes. Recent consensus guidelines advocate universal thyroid function screening during pregnancy. There are no data from Iran about the prevalence of thyroid hypofunction in pregnancy. This study aims to find the prevalence of thyroid dysfunction.
Materials and Methods
In this descriptive cross sectional study, thyrotropin (TSH) was measured in 3158 pregnant women irrespective of gestational age from October 2008-March 2012. If TSH was more than 2.5 mIU/L in the first trimester or more than 3 mIU/L in the second or third trimester, free T4 was measured to diagnose subclinical/ overt hypothyroidism. If serum free T4 was in the normal range (0.7-1.8 ng/dl) the diagnosis was subclinical hypothyroidism and if below the normal range, overt hypothyroidism was diagnosed.
A total of 3158 pregnant women were evaluated. One hundred forty seven of them were diagnosed as hypothyroidism. Subclinical hypothyroidism and overt hypothyroidism were present in 131 (89.1%) and 16 (10.9%) women respectively. Prevalence of subclinical hypothyroidism was 4.15%. Most of the subclinical and overt hypothyroidism cases were diagnosed in the first trimester.
It appears logical to check TSH during pregnancy due to the observed prevalence of subclinical hypothyroidism.
PMCID: PMC4107690  PMID: 25083181
Hypothyroidism; Pregnancy; Prevalence; Thyrotropin
24.  Longitudinal study on thyroid function in patients with thalassemia major: High incidence of central hypothyroidism by 18 years 
Primary hypothyroidism is one of the most frequent complications observed in-patients suffering from thalassemia. We investigated and reviewed the thyroid function in all thalassemic patients attending the Pediatric Endocrine Clinic of Hamad Medical Center, Doha, Qatar during the last 10 years of follow-up.
Patients and Methods:
A total of 48 patients with ί-thalassemia major between 5 years and 18 years of age. Thyroid dysfunction was defined as follows: Overt hypothyroidism (low Free thyroxine [FT4] and increased thyroid-stimulating hormone [TSH] levels >5 μIU/ml); subclinical hypothyroidism (normal FT4, TSH between 5 μIU/ml and 10 μIU/ml) and central (secondary) hypothyroidism (low FT4 and normal or decreased TSH).
A total of 48 patients (22 males and 26 females) completed a 12 year-period of follow-up. During this period, hypothyroidism was diagnosed in 17/48 (35%) of patients. There was no significant difference in the prevalence in males 7/22 (32%) versus females 10/26 (38%). Sixteen of the patients had hypothyroidism after the age of 10 years (94%). The prevalence of overt hypothyroidism had risen from 0% at the age of 7 years to 35% at the age of 18 years. None of the patients had high anti-thyroperoxidase antibody titers. Out of 17 patients, 13 patients with hypothyroidism had normal or low TSH level (not appropriately elevated) indicative of defective hypothalamic pituitary response to low FT4 (central hypothyroidism). Three patients (6.3%) had subclinical hypothyroidism (TSH between 5 uIU/ml and 10 uIU/ml and normal FT4). The general trend of FT4 level showed progressive decrease over the 12 years, whereas, TSH levels did not show a corresponding increase. These data suggested defective hypothalamic pituitary thyroid axis involving both TSH and FT4 sretion in patients with thalassemia major over time. There was a significant negative correlation between serum ferritin and FT4 (r = −0.39, P = 0.007), but no correlation was found between ferritin and TSH.
Worsening of thyroid function was observed in 35% of the studied thalassemic patients by the age of 18 years. The lack of proper increase of TSH in response to the low circulating levels of FT4 in 13/17 (76%) of these patients indicates a relatively high incidence of defective pituitary thyrotrophic function in these patients.
PMCID: PMC3872691  PMID: 24381890
Ferritin; free thyroxine; growth; hypothyroidism; prevalence; thalassemia; thyroid stimulating hormone
25.  Vertical Transmission of Hypopituitarism: Critical Importance of Appropriate Interpretation of Thyroid Function Tests and Levothyroxine Therapy During Pregnancy 
Thyroid  2013;23(7):892-897.
Typically, newborns with congenital hypothyroidism are asymptomatic at birth, having been exposed to euthyroid mothers. However, hypopituitarism may be associated with central hypothyroidism, preserved fertility, and autosomal dominant inheritance, requiring increased attention to thyroid management during pregnancy.
Patient Findings
A woman with a history of growth hormone deficiency and central hypothyroidism gave birth to a term male neonate appropriate for gestational age. Due to low thyrotropin (TSH) in the second trimester, the levothyroxine dose was decreased by the obstetrician, and free T4 was low throughout the latter half of pregnancy. The neonatal laboratory evaluation showed central hypothyroidism with a low T4 of 2.1 μg/dL (4.5–11.5) and an inappropriately normal TSH of 0.98 uIU/mL (0.5–4.5); undetectable growth hormone, IGF-I, and IGFBP3; a normal cortisol level; and a normal gonadotropin surge. After initiation of levothyroxine in the first week, both tone and feeding tolerance improved. However, the patient was found to have hearing loss, gross motor delay, and speech delay.
In this report, we review a case of vertical transmission of a dominant negative POU1F1 mutation in which fetal abnormalities due to the hypothyroxinemic state during gestation may have been exacerbated by a decrease in the mother's levothyroxine dose based on a low TSH in early gestation. Both mother and fetus were unable to synthesize sufficient thyroid hormone, which may be responsible for the patient's clinical presentation.
This case underscores several important points in the management of women with hypopituitarism. First, it is important that patients and clinicians are both aware of the differences in etiology, as well as appropriate screening and treatment, of primary versus central hypothyroidism. Second, it is necessary to monitor the thyroid hormone status closely during pregnancy to prevent fetal sequelae of maternal hypothyroidism. Third, genetic screening of patients with combined pituitary hormone deficiency is necessary, so that prenatal genetic counseling may be an option for expecting parents.
PMCID: PMC3704046  PMID: 23397938

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