Diagnostic spectrum of congenital hypothyroidism in Turkish children

Background:  Congenital hypothyroidism (CH) is classified as transient or permanent. Transient CH can be treated with short-term thyroxine replacement therapy or followed up without therapy, whereas lifelong thyroxine replacement is needed in permanent CH. Determination of the underlying etiology is essential for determination of follow-up strategy. The purpose of the present study was therefore to assess the role of color Doppler ultrasonography (CDU) in etiologic diagnosis of CH together with radionuclide method and grayscale ultrasonography (GSU).
Methods:  A total of 182 patients (83 female, 99 male) were evaluated. To determine etiologic diagnosis, the patients underwent a free T4 (fT4), thyroid-stimulating hormone (TSH) and urinary iodine level measurement, and thyroid scintigraphy, perchlorate discharge test, CDU, and GSU.
Results:  Fifty-four patients had transient and 97 had permanent CH. Isolated hyperthyrotropinemia was diagnosed in 31 patients. Transient CH was due to iodine deficiency in 22 and excess iodine in 13 patients. In 97 patients with permanent CH, ectopia was present in 32 patients and agenesis of the thyroid gland was found in 22 patients, while 43 were diagnosed with dyshormonogenesis. In the ectopia group, GSU failed to detect ectopic tissues in all cases, whereas CDU was successful in determining the presence of ectopic thyroid in 20 cases. The sensitivity of CDU was 80% in determining ectopic tissue.
Conclusion:  To determine etiologic diagnosis, radionuclide methods and sonographic modalities should be assessed together. The gold standard in the diagnosis of ectopic thyroid tissue is thyroid scintigraphy. CDU may be a major supportive diagnostic tool in the evaluation of ectopic thyroid gland.     

Definitive diagnosis in children with congenital hypothyroidism

OBJECTIVES: To investigate the definitive diagnosis and underlying causes of congenital hypothyroidism (CH) in eligible children through the use of a standardized protocol. STUDY DESIGN: Children > or =3 years of age with CH without an identified permanent cause underwent a diagnostic algorithm. Eligible subjects had an anatomically normal thyroid or had not undergone imaging studies. After thyroxine was discontinued for 4 weeks, thyroid function tests and a thyroid ultrasound were obtained. An abnormal ultrasound was followed by a (99m)Tc thyroid scan. A perchlorate washout test was performed in subjects with a normal ultrasound but abnormal thyroid function tests. Children with normal results were followed for 1 year. RESULTS: Of 33 children, 17 were boys. Nine (27%) had an absent or ectopic thyroid, 12 (36%) had dyshormonogenesis, and 12 (36%) had transient CH. Average thyroxine dose before medication discontinuation was 2.9 +/- 0.83 microg/kg in permanent cases versus 2.0 +/- 0.53 microg/kg in transient (P <.002). No complications from discontinuation of thyroxine occurred. CONCLUSIONS: A significant percentage of children with CH have a transient requirement for thyroid hormone. A standardized protocol with thyroid ultrasonography is a safe and sensitive approach to a trial off of thyroxine in select patients.     

先天性甲状腺功能减退症患儿DUOX2基因突变的研究

目的 研究先天性甲状腺功能减退症(congenital hypothyroidism, CH)患儿DUOX2 基因突变类型和特点,并初步探讨基因型- 表现型的关系,为CH 患儿的基因诊断和基因治疗提供理论依据.方法 从10例CH 伴甲状腺肿大患儿外周血白细胞中提取基因组DNA,采用PCR 扩增和直接测序的方法对DUOX2 全部外显子进行基因突变检测.结果 在1 例患儿中发现DUOX2 基因第28 外显子cDNA 的3632 位点发生了G>A 的突变(c.G3632A),导致第1 211 密码子的精氨酸变为组氨酸(p.R1211H).在3 例患儿中发现DUOX2 基因第17 外显子cDNA 的2 033 位点发生了T>C 的突变(c.T2033C),导致第678 密码子的组氨酸变为精氨酸(p.H678R).此两种突变均为杂合型的错义突变.结论 CH 患儿存在DUOX2 基因杂合突变,该杂合突变可能引起蛋白质功能的改变从而导致CH;基因型与表现型的关系尚不明确,需要进一步的研究.     

Incidence of febrile convulsions in children with congenital hypothyroidism

Brain excitability has been inconsistently reported to be increased both in hypo- and hyperthyroidism, but there have been few studies on the effects of thyroid hormones on brain excitability in children. With this in mind, we investigated the incidence of febrile convulsions (FCs) among patients with congenital hypothyroidism, who have been taking L - thyroxine since the age of 1 month. The incidence of FCs among congenital hypothyroid patients was 1.6% (1/63) which was significantly low ( p < 0:05) compared with that of normal control children who visited our hospitals as outpatients (28/341, 8.2%) and that of others (322/3301, 9.8%) investigated 33 years ago in the same area. The incidence of FC among siblings of the 63 patients (7/74, 9.5%) was not statistically different from the controls. At least 8 of the 126 parents (6.4%) had experienced FC, however, only one child was affected in the 8 families. In conclusion, it seems likely that patients with congenital hypothyroidism on regular L -T4 replacement are less prone to experience FC. More studies on the incidence of convulsive disorders in children with thyroid diseases are needed to clarify the effects of thyroid hormones on brain excitability.     

Long-range intelligence development of children with congenital hypothyroidism]

The intellectual development of 105 children with congenital hypothyroidism was assessed. In 70 children the assessment was repeated in several times. Correlations between development of intelligence and influence of biological and/or psychosocial risks were verified.     

Height prognosis in children with late-diagnosed congenital hypothyroidism.

It is a general belief that early and adequate thyroid hormone replacement achieves normalization of growth as well as disappearance of clinical sings and symptoms of hypothyroidism. Due to the lack of comprehensive growth studies, height prognosis has remained controversial in late-diagnosed hypothyroidic children. The limited number of previous studies have suggested permanent height deficit in these children. In this study we present longitudinal growth and final height of 20 children (14 females and 6 males) in whom the duration of hypothyroidism before onset of therapy varied from three to 12.6 years. The etiological distribution of cases revealed ectopic thyroid tissue in nine cases, agenesis in seven, and dyshormonogenesis in four cases. At the time of the diagnosis all hypothyroidic children had severe growth retardation (mean height SDS +/- SD -3.95+/-1.07) due to prolonged hypothyroidism. Although the catch-up spurt corrected an important part of the initial height deficit in all patients, only nine patients reached or exceeded their target height, and the final height of five patients remained below 2 SD of mean. Despite treatment, prolonged hypothyroidism may result in compromised adult height in some patients. The contributing factors to this height deficit may include the duration of hypothyroidism, the height deficit at the time of the diagnosis, etiological differences and the diminished potential for catch-up growth in late-diagnosed hypothyroidism.     

Linear growth in early treated children with congenital hypothyroidism

Length/height was studied from birth to 6 years of age in 103 children with congenital hypothyroidism identified by the Norwegian or Swedish screening programs. We used the "infancy-childhood-puberty (ICP) growth model". This model describes normal linear growth during the first 3 years of life by an infancy component with the addition of a childhood component, the latter acting from the second half of the first year. In comparison with reference children, children with hypothyroidism had reduced growth from 6 to 12 months, and increased growth after 12 months of age. Mean onset of the childhood component of growth was delayed from 8.1 months (SD 1.9) to 10.4 months (SD 2.2) in girls, and from 8.9 months (SD 2.0) to 11.0 months (SD 2.1) in boys. Age at onset of the childhood component was correlated with age at start of treatment ( r = 0.24), and in children with more severe hypothyroidism (pretreatment serum thyroxine <40 nmol/l) inversely correlated with the L-thyroxine dose at start of treatment ( r = -0.40). Change in height standard deviation score from 1 to 3 years of age was correlated with the serum thyroxine concentration at age 1 year ( r = 0.30). The delay in the onset of the childhood component of growth and the association with age at start of treatment and initial L-thyroxine dose indicate that thyroid hormones during the first months of life are essential for normal onset of the childhood component of growth, which otherwise is assumed to be growth hormone-dependent.     

Skeletal maturation during thyroxine treatment in children with congenital hypothyroidism

Heyerdahl S, Kase BF, Stake G. Skeletal maturation during thyroxine treatment in children with congenital hypothyroidism. Acta Prediatr 1994;83:618–22. Stockholm. ISSN 0803–5253
The aim of this investigation was to study if bone age development (assessed by the Greulich & Pyle atlas) was related to L-thyroxine treatment in 47 children with congenital hypothyroidism, treated early and according to general recommendations. In spite of frequent delay in skeletal maturation at diagnosis, the delay in mean bone age at a mean chronological age of 1.5 years was slight (0.5 months), and 30% of the variation in bone age SD score (SDS) at 1.5 years was accounted for by the dose of L-thyroxine and serum thyroxine during the first year. The children with a bone age within ± 1 SDS had a prescribed mean dose of L-thyroxine per kg body weight from 3 to 12 months of age of 5.4 ± 1.7 pg/kg/day, and their mean serum thyroxine concentration during the first year was 175 ± 29 nmol/l. We conclude that bone age at 1.5 years of age was positively correlated with the dose of L-thyroxine and the serum thyroxine concentration during the first year. This supports the general use of bone age assessments as a complement to other treatment variables in the follow-up of children with congenital hypothyroidism.     

Sustained attention problems in children with early treated congenital hypothyroidism

Sustained attention was studied in 48 children with early treated congenital hypothyroidism and 35 healthy controls, using a computer-paced and a self-paced continuous performance task. The performance of the patients, particularly those in the low T4 group (38 patients with T4 levels < 50 nmol/1 at neonatal screening), declined in the final stage of the computer-paced task, suggesting a problem in remaining attentive over time. The performance of all children declined in the first and improved in the final stage of the self-paced task. This pattern was most pronounced in the low T4 group, reflecting greater variability in their task performance over time, again indicating a problem in sustaining attention. No correlation was found between onset of treatment and sustained attention. The small size of the intermediate T4 group (10 patients with T4 levels ≥ 250 nmol/1 at neonatal screening) made the results more difficult to interpret and may have concealed a problem with sustained attention in this group.     

Growth in children with congenital hypothyroidism detected by neonatal screening

A prospective analysis of physical growth in 56 children with congenital hypothyroidism compared the children's height, weight, and head circumference with population percentiles. Two measures of skeletal maturation and predictions of adult height were also compared with population standards. The mean percentiles for the children's height and head circumference were higher than population means. Although mean bone age scores were slightly higher, predictions of adult height did not differ significantly from midparental height (arithmetic mean of sum of parental heights) and population means. The duration of intrauterine hypothyroidism as measured by gestational bone age and the duration of postnatal hypothyroidism were inversely correlated with heights attained up to 9 years. This association suggests a possible long-term influence of early hypothyroidism on growth. In children with congenital hypothyroidism, maintenance of serum thyroxine levels in the upper half of the normal range results in normal growth patterns.     

Diagnostic dilemmas. Results of screening tests for congenital hypothyroidism

The natural history of congenital hypothyroidism has changed drastically since the institution of newborn screening in North America, Europe, and Japan. Before screening was available, diagnosis of this condition was often delayed. The IQ of 65% of all patients with congenital hypothyroidism was below 85, and 19% were profoundly retarded (IQ less than 15). In two large screening programs in which long-term IQ data are available, no child has tested below the IQ of 74. Furthermore, a comparison of affected children treated within the first month of life with matched controls demonstrated no significant difference in IQ scores between the two groups. Widespread screening has lead to the evaluation of over 7 million infants annually. This represents over 1200 fewer children with subnormal intelligence, and approximately 360 children annually who are saved from the effects of profound mental retardation. There is little doubt that newborn screening is one of the greatest advances in diagnosis and treatment of endocrine disease in the newborn period to occur in the past 20 years. However, even experienced screening programs are not perfect, so the practitioner must remain alert to the possibility of undiagnosed hypothyroidism presenting in infancy.     

Longitudinal assessment of children with congenital hypothyroidism detected by neonatal screening

Clinical and laboratory data from 42 children (31 females and 11 males) with primary congenital hypothyroidism (CH) diagnosed by neonatal screening over a six-year period are reported. The mean age at onset of thyroid hormone therapy was 33 days. The adequacy of replacement therapy was assessed by repeated TT4, FT4, T3 and TSH serum determinations. The high serum TT4 concentrations frequently observed were not accompanied by clinical evidence of hyperthyroidism. rT3 levels determined in 28 CH children with TT4 greater than 15 micrograms/dl were clearly higher than in the controls. The mean weight, length and head circumference remained always between the 50th and 75th centile. The radiological assessment of the knee, mainly the distal femoral surface, has been considered as an important clinical value in the initial diagnosis and in the evaluation of both severity and duration of disease. The psychomotor development was assessed using Brunet-Lezine's test until age 36 months, Stanford-Binet at 4 and 5 and WISC at 6 years of age. The mean global developmental quotients (GDQ) were always between 85 and 97 at 6 to 72 months of age, only eight children were below 85. A significant correlation was found between GDQ at 6 months and the bone age. The neurological examination showed an impairment of posture, coordination and subtle deficits in motor and perceptual abilities in a small percentage of children.     

Psychomotor development of children with congenital hypothyroidism diagnosed by neonatal screening

The psychomotor development in 68 children with congenital hypothyroidism diagnosed during the first two years of a nationwide neonatal screening programme in Sweden was assessed during their first three years of life. Replacement therapy with thyroxine was initiated at the age of 15 +/- 7 days (mean +/- SD). Griffiths tests were performed in 15 patients at the age of 18 months and in 51 patients at 30-47 months. Their developmental quotients did not differ from those of control children, indicating that the psychomotor development in the children with congenital hypothyroidism was normal. In earlier studies of Swedish children with congenital hypothyroidism, diagnosed clinically before the age of three and a half years, the psychomotor development was found to be impaired. In contrast, the patients diagnosed by neonatal screening and given early therapy displayed normal results in Griffiths tests. This indicates that the age at the start of treatment is an important determinant for the prognosis.