Hashimoto's thyroiditis in children and adolescents: a retrospective study on clinical, epidemiological and laboratory properties of the disease.

UNLABELLED: Hashimoto's thyroiditis (HT) is the most common cause of goiter and acquired hypothyroidism in children and adolescents in iodine replete areas. To find out the clinical, epidemiological and laboratory characteristics of the disease in childhood, we reviewed files of 162 children and adolescents with HT followed in the Department of Pediatric Endocrinology, Hacettepe University Faculty of Medicine. RESULTS: Female patients constituted 86.4% (n = 140) of all patients with a female:male ratio of 6.4. Mean age at diagnosis was 11.4 +/- 2.97 years (age range 4.4-16.5 years). At the time of diagnosis 43.2% of the patients (n = 70) were euthyroid, 24.1% (n = 39) had subclinical hypothyroidism, 21% (n = 34) had overt hypothyroidism, and 8.6% (n = 14) had overt and 3.1% (n = 5) subclinical hyperthyroidism. CONCLUSIONS: Autoimmune thyroiditis is more frequent in females, and increases in frequency over age during childhood and adolescence. At the time of diagnosis, frequency of overt and subclinical hypothyroidism is similar to that of euthyroid goiter.

A phenocopy of CAII deficiency: a novel genetic explanation for inherited infantile osteopetrosis with distal renal tubular acidosis.

The rare bone thickening disease osteopetrosis occurs in various forms, one of which is accompanied by renal tubular acidosis (RTA), and is known as Guibaud-Vainsel syndrome or marble brain disease. Clinical manifestations of this autosomal recessive syndrome comprise increased bone density, growth failure, intracerebral calcification, facial dysmorphism, mental retardation, and conductive hearing impairment. The most common cause is carbonic anhydrase II (CAII) deficiency. Several different loss of function mutations in CA2, the gene encoding CAII, have been described. To date, there have been no exceptions to the finding of CAII deficiency in patients with coexistent osteopetrosis and RTA. Most often, the RTA is of mixed proximal and distal type, but kindreds are reported in which either distal or proximal RTA predominates. We report the molecular genetic investigation of two consanguineous kindreds where osteopetrosis and distal RTA (dRTA) were both manifest. One kindred harbours a novel homozygous frameshift alteration in CA2. In the other, CAII levels were normal despite a similar clinical picture, and we excluded defects in CA2. In this kindred, two separate recessive disorders are penetrant, each affecting a different, tissue specific subunit of the vacuolar proton pump (H(+)-ATPase), providing a highly unusual, novel genetic explanation for the coexistence of osteopetrosis and dRTA. The osteopetrosis is the result of a homozygous deletion in TCIRG1, which encodes an osteoclast specific isoform of subunit a of the H(+)-ATPase, while the dRTA is associated with a homozygous mutation in ATP6V1B1, encoding the kidney specific B1 subunit of H(+)-ATPase. This kindred is exceptional firstly because the coinheritance of two rare recessive disorders has created a phenocopy of CAII deficiency, and secondly because these disorders affect two different subunits of the H(+)-ATPase that have opposite effects on bone density, but which have only recently been determined to possess tissue specific isoforms.

Nine novel growth hormone receptor gene mutations in patients with Laron syndrome.

The GH receptor (GHR) is a member of the cytokine receptor superfamily; GH binding protein is the solubilized extracellular domain of the GHR. Abnormalities in the GHR produce an autosomal recessive form of GH resistance, the Laron syndrome, characterized by growth failure and the clinical appearance of severe GH deficiency despite elevated circulating GH levels. In 13 unrelated patients with undetectable levels of GH binding protein, we characterized nine novel mutations in the GHR gene. These molecular defects comprise three nonsense mutations (Q65X, W80X, and W157X), one frameshift (36delC), two splice defects (G-->A at 70 + 1, C-->T at 723), and three missense mutations (C38S, S40L, and W50R) located in the extracellular domain of the receptor, and thus would be expected to interfere with GH binding activity. These results further confirm the broad heterogeneity of mutations underlying this rare GH resistance syndrome.

Serum 3 alpha-androstanediol glucuronide measurements in children with congenital adrenal hyperplasia.

To determine the value of 3 alpha-androstanediol glucuronide (3-AG) measurements in children with congenital adrenal hyperplasia, we compared serum 3AG, 17-hydroxyprogesterone (17-OHP), androstenedione (A), testosterone (T) and dihydrotestosterone (DHT) levels and 24-h urinary 17-ketosteroid (17-KS) excretion in 42 female children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency, including 27 with the simple virilizing and 15 with the salt-losing form. Their mean age was 74.5 +/- 48.5 months (range, 6-194 months). Twenty-four-hour urinary 17-KS excretion and serum 3-AG, A, T, DHT and 17-OHP levels were measured in the patients. The values were less than the mean + 2 SD of the control group in 63%, 74%, 67%, 69%, 60% and 31% of the patients, respectively. Serum 3-AG levels correlated with 24-h urinary 17-KS excretion (r = 0.66) and plasma A (r = 0.80), 17-OHP (r = 0.56), T (r = 0.79) and DHT (r = 0.62) levels. We conclude that serum 3-AG is a useful metabolic index in the management of children with congenital adrenal hyperplasia.

Review of Turkish patients with growth hormone insensitivity (Laron type).

Clinical spectrum and endocrine details of thirteen Turkish children (age 0.3-14.2 years; eight females and five males; ten prepubertal, three pubertal) with growth hormone insensitivity are presented. All patients display phenotypical features of severe growth hormone deficiency. The diagnosis based on height standard deviation score (SDS), basal growth hormone (GH), basal insulin-like growth factor I (IGF-I, IGF-I response in an IGF generation test and growth hormone binding protein (GHBP) measurements. The median height SDS was -7.4 (range -3.2 to -10), weight for height index was 100 (range 81-152) and bone age/height age ratio was 2 (range 1.6-3.3). Endocrine investigations showed a median basal GH concentration of 61.4 mU/l (range 23.5-120 mU/l). Basal IGF-I level was below 10 ng/ml in all patients except one. None of the patients showed a significant IGF-I response to injections of GH (0.1 U/kg body weight for 4 days). The median IGFBP-3 level was 0.23 mg/l (range 0.1-0.56 mg/l). The GHBP level was undetectable in all of 10 patients. The high number of patients in our center may be due to the high rate of consanguinity among the Turkish population and the referral facility of our center in the area. These patients may benefit from the new therapy with recombinant human IGF-I.

Age-related differences in serum insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 levels in congenital hypothyroidism.

It is well established that thyroid hormones play a fundamental role in normal growth and development. The complex relationship between thyroid hormone and the growth hormone-insulin-like growth factor axis is not completely understood. We investigated age-related differences in serum insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3) levels in 43 patients with primary congenital hypothyroidism. These patients were classified into five age groups (Group I: 0-1 month, Group II: 1 month-1 year, Group III: 1-5 years, Group IV: 5-9 years, Group V: 9-13 years). Patients diagnosed in the first month of life did not display a significant difference in serum IGF-I and IGFBP-3 levels compared to age-matched controls (p > 0.05). However, in groups II to V, IGF-I and IGFBP-3 levels were significantly lower than in controls (p < 0.05). Thyroid hormone replacement therapy increased serum IGF-I and IGFBP-3 levels significantly in 26 hypothyroid children (p < 0.05). Although serum IGF-I and IGFBP-3 levels increase in an age dependent manner in normal children, this increment was not observed in hypothyroid children.

Magnetic resonance imaging in growth hormone deficiency: relationship between endocrine function and morphological findings.

Magnetic resonance imaging (MRI) using gadopentetate dimeglumine (Gd-DTPA) improves the delineation of hypothalamic-pituitary structures and facilitates the detection of anatomical abnormalities which are indicators of permanent growth hormone deficiency (GHD). The aim of this study was to determine the frequency of neuroradiological abnormalities in 85 (52 M, 33 F) patients with hereditary or idiopathic forms of isolated GHD (IGHD) or multiple pituitary hormone deficiency (MPHD) and also to investigate the relationship between anatomical findings and hormonal status. Pituitary hypoplasia with absent or thin infundibulum and ectopic posterior pituitary (EPP) were the most frequent findings in 39 patients with MPHD, whereas in 46 patients with IGHD the most frequent finding was pituitary hypoplasia without neuroradiological abnormalities. All patients whose infundibulum was not visualized after Gd-DTPA injection belonged to the MPHD group; therefore, absence of pituitary stalk can be a good indicator of the severity of hormonal deficiencies. Pituitary hypoplasia was found in all patients with familial IGHD. Among patients with abnormalities of the hypothalamic pituitary area on MRI, normal or breech delivery frequency distributed equally. Therefore it seems that mechanical or hypoxic prenatal events cannot be the primary etiological factor in all patients with neuroradiological abnormalities since half of these patients had normal delivery and birth history. The localization of the bright spot of the posterior pituitary at the level of the median eminence, midstalk position or at the end of the infundibulum may suggest a neuronal migration defect which may occur during early embryogenesis. In conclusion, in children with GHD a careful examination of the hypothalamic pituitary area by MRI after enhancement helps to establish the diagnosis and predicts the prognosis.

True hermaphroditism: clinical features, genetic variants and gonadal histology.

True hermaphroditism is a rare cause of intersexuality in which both ovarian and testicular tissue is present in the same individual. We present the clinical findings, karyotype, gonadal histology and management of eight patients with true hermaphroditism. Their ages ranged from 43 days to 12 years at the first evaluation. The presenting symptoms were ambiguous genitalia (6 patients), isolated clitoromegaly (1 patient) and hypospadias (1 patient). The most common karyotype was 46,XX (6 patients). In one patient the karyotype was 46,XY and in another 45,XO/46,XY mosaicism, which is rare in the literature. A vagina was found by genitography in all patients, and at laparotomy the uterus was found normal in five patients, hypoplastic in one patient, as a fibrous band in one, and absent in the remaining patient. Histological investigation of the gonads revealed bilateral ovotestis in two patients, ovotestis plus ovary in two patients, and ovary on one side and testis on the other side in three patients. Five patients were assigned to the female sex, and three to the male sex. One of these patients was changed from male to female after evaluation.

Triple A syndrome mimicking cystic fibrosis.

We report a 2-8/12 year-old male who presented with symptoms resembling cystic fibrosis (failure to thrive, developmental delay and recurrent diarrhea) and had elevated sweat chloride concentration. Mucosal hyperpigmentation led to the diagnosis of adrenal insufficiency which was ultimately shown to be a component of triple A syndrome (achalasia, alacrima, adrenal insufficiency). Elevated sweat chloride concentration normalized after initiation of adrenal replacement therapy. We suggest that non-CF conditions causing elevated sweat chloride concentration should be considered in patients with atypical findings or who do not have objective evidence of pulmonary or exocrine pancreatic disease.

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.

Congenital hypothyroidism in Turkey: a retrospective evaluation of 1000 cases.

In this retrospective investigation, 1000 cases of congenital hypothyroidism followed-up in the Pediatric Endocrinology Unit at Hacettepe University Children's Hospital between 1964-1989 were evaluated with respect to age at diagnosis, main complaints, symptoms and physical findings. The mean age at diagnosis was 49.22 months, with 55.4 percent of patients diagnosed after two years of age and only 3.1 percent during the neonatal period. The main complaints of the patients were growth failure (26.7%), inability to speak (21.4%), and inability to walk (18.1%). The physical signs and symptoms most commonly detected by the physician were hypotonia (72%), constipation (66.8%), cretinoid face (64.6%), and macroglossia (64.6%). These results emphasize the necessity for routine neonatal screening programs to be established in Turkey, with the aim of detecting congenital hypothyroidism.

The epidemiology of juvenile-onset insulin-dependent diabetes mellitus in Turkish children. A retrospective analysis of 477 cases.

The hospital records of 477 patients under 18 years of age with insulin-dependent diabetes mellitus (IDDM) who were followed in the Endocrinology Unit of Hacettepe University Children's Hospital between the years 1969 and 1991 were analyzed for age, sex, residence at time of diagnosis, date of onset of symptoms, date of diagnosis, family history of IDDM, and consanguinity between parents. The distribution of age at diagnosis showed a small peak between 4 and 6 years of age and a main peak between 12 and 14 years. In girls, the main peak appeared between 10 and 12 years, and in boys between 12 and 14. A significant difference was not seen between sexes (239 males and 236 females). The frequency of diagnosis showed seasonal variations the lowest in autumn and the highest in winter. Consanguinity between parents was 23.9 percent, and 10.3 percent of the patients had IDDM in first degree relatives.

The results of long-term growth hormone replacement therapy in Turkish children with growth hormone deficiency.

From a total of 118 patients treated for growth hormone deficiency, 37 (23 boys, 14 girls) have reached their final height. Twenty-five patients had isolated growth hormone deficiency (IGHD) and 12 had multiple pituitary hormone deficiency (MPHD). Growth hormone deficiency was diagnosed and treated late in both boys and girls. The mean height standard deviation score (SDS) for chronological age (CA) increased significantly from -4.43 to -1.94 during the therapy. The target height was not achieved in boys or girls nor in MPHD and IGHD groups, although they have reached the third percentile of the normal Turkish population. The height and chronological age of the patients at the start of the treatment correlated significantly with final height in all patients. Therefore, early diagnosis and treatment is important to complete catch-up growth in growth hormone deficient patients. The height prognosis is improved with administration of a recombinant form of human growth hormone (GH) as daily subcutaneous injections with a dose of 0.1 IU/kg, when compared to the earlier studies with pituitary GH.

Magnetic resonance imaging (MRI) findings in isolated growth hormone deficiency.

In this study the presence of pituitary-hypothalamic abnormalities was searched by magnetic resonance (MR) imaging in 30 children (18 males and 12 females, aged 7.4 to 23 years) with isolated growth hormone deficiency (IGHD). Small anterior pituitary was demonstrated in 18 patients and ectopic posterior pituitary (EPP) in four of them. Pituitary stalk was found to be thin in two patients with anterior pituitary hypophasia and EPP and was visible only in post-gadolinium images. In one patient, a hypothalamic mass was found and the bright spot of the posterior pituitary was found without diabetes insipidus, possibly due to a variation in the intensity of the bright signal. Eight patients had normal pituitary imaging suggesting functional damage. In all five patients with familial growth hormone deficiency the anterior pituitary was hypoplastic. We conclude that a high percentage of patients with IGHD had anomalies of the hypothalamo-pituitary region, which could be demonstrated by MR imaging. Furthermore, the low frequency of perinatal abnormalities in these patients suggested developmental defect as the cause of the morphostructural abnormalities. The presence of the familial cases with the same defect pointed to the genetic origin in some instances.

Diabetes mellitus, diabetes insipidus, optic atrophy and deafness (DIDMOAD syndrome).

Two patients with diabetes mellitus (DM), diabetes insipidus (DI), optic atrophy (OA), deafness (D) and dilatation of the urinary tract-the so-called DIDMOAD syndrome are presented. In one of the patients, the presenting components were DI and OA. In the second case, DM was the first manifestation to be diagnosed, and in this patient the course of the syndrome was complicated by associated epileptical activity disorders, and later septicemia. The admission of these patients led us to review the literature describing this syndrome.

Leprechaunism in two Turkish patients.

We report two cases of Leprechaunism with the classical features. The first case had hyperglycemia and severe hyperinsulinemia. The postmortem examination of the second child revealed enlargement of both ovaries, islet cell hyperplasia in the pancreas, and cholestasis and paucity of bile ducts in the liver. Cystic changes were noted in the ovaries, and the kidneys contained a few small cortical cysts. Both patients died at early ages.

Neonatal thyroid screening: methods-efficiency-failures.

Newborn screening for congenital hypothyroidism (CH) is one of the major achievements of preventive medicine, as the condition occurs frequently (1/4000 newborns) and results in brain damage if not detected and treated in the first few days of life. Measurement of T4 and/or TSH in dried blood spots collected on the second through fifth days of life are the most widely used methods in screening programs for CH currently. Some children with the disease may be missd in any screening program, however, owing to factors related to the disease itself and the methods employed in its detection, as well as factors ascribed to the element of human error, ie screening errors. The methods employed in newborn screening programs for CH, their efficiency in disease detecetion, and biological factors as well as screening errors leading to missed cases are discussed.

Growth response to growth hormone-releasing hormone(1-29)-NH2 compared with growth hormone.

To assess the growth-promoting effect of different doses of growth hormone-releasing hormone(1-29)-NH2 (GHRH(1-29)-NH2) in GH deficiency (GHD) of hypothalamic origin, 43 prepubertal children aged between 4.3 and 18.9 years (mean 10.4 +/- 2.9 years) were randomly assigned to three treatment regimens: low-dose GHRH(1-29)-NH2 (LD group; n = 15), high-dose GHRH(1-29)-NH2 (HD group; n = 12) and GH (GH group; n = 16). The LD group received GHRH(1-29)-NH2 at 30 micrograms/kg/day s.c. in three daily doses, the HD group received 60 micrograms/kg/day s.c. in three daily doses and the GH group received GH, 0.1 IU/kg/day s.c. once daily. All children were treated for a period of 6 months. Evaluation included anthropometry, bone age, intravenous and subcutaneous GHRH(1-29)-NH2 tests and determination of insulin-like growth factor I (IGF-I) levels. An increase in height velocity of 2 cm/year or more was observed in all except two children. Height velocity during treatment was lowest in the LD group, but comparable in the HD and GH groups. An increase in height SDS for bone age occurred only in the GH-treated group. GH responses to intravenous GHRH(1-29)-NH2 showed a priming effect of the LD GHRH(1-29)-NH2 treatment, while a decrease in response occurred in the GH-treated group. Following a subcutaneous test dose of one-third of the daily dose of GHRH(1-29)-NH2, GH levels remained unchanged in both the LD and HD groups. There was accumulation of GHRH immunoreactivity over time in the HD group, but there was no correlation between measured GHRH and GH levels.(ABSTRACT TRUNCATED AT 250 WORDS)