Urinary epidermal and insulin-like growth factor excretion in autistic children.

Growth factors have been implicated in the pathogenesis of autism. We have investigated daily urinary excretion of insulin-like growth factor-1 (IGF-1), epidermal growth factor, and insulin-like growth factor binding protein-3 in autistic children (n=34, age 2-5 years) and age-matched control children (n=29). The mean urinary IGF-1 level was lower in the autism group than the control group (p=0.03). Height was normal. These findings suggest altered IGF-1 metabolism in young autistic children. The cause-effect relationship should be examined by longitudinal studies and insulin-like growth factor provocation tests.

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.

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.

Fludrocortisone treatment in a child with severe cerebral salt wasting.

Hyponatremia is a common complication of intracranial disease or surgery. An evaluation should be undertaken to determine whether cerebral salt wasting (CSW) or inappropriate secretion of antidiuretic hormone is present as a cause. Since the treatment principles are completely different in the two pathological states, differential diagnosis is very important. CSW is defined as the renal loss of sodium leading to hyponatremia and decreased extracellular fluid volume. In the literature, it has been noted that mineralocorticoid administration can be useful in CSW cases. We herein present an 11-year-old boy who developed hyponatremic seizures after intracranial tumor resection. He was diagnosed with CSW on the basis of high urinary sodium excretion and increased urine output, together with signs and symptoms of dehydration. Despite intensive fluid and salt therapy, we were unable to decrease the urinary output. Therefore, fludrocortisone therapy was administered and his urinary output and sodium excretion were decreased and his serum sodium level was normalized. In conclusion, in addition to fluid and salt replacement, mineralocorticoid supplementation also seems to be a safe and effective treatment for CSW.

Clinical and endocrine characteristics in atypical and classical growth hormone insensitivity syndrome.

OBJECTIVE: Classical growth hormone insensitivity syndrome (GHIS) comprises a dysmorphic phenotype, extreme short stature (height SDS < 3), normal GH and low IGF-I and IGFBP-3. Wide clinical variation is recognised with classical and atypical forms. We aimed to delineate features of the milder "atypical" GHIS phenotype, and to determine whether this correlates with milder auxological and biochemical features. METHODS: Fifty-nine patients from a European series of 82 patients with GHIS, with strict diagnostic criteria of GHIS, were studied and assigned to classical or atypical GHIS groups according to facial phenotype, i.e. "classical" required 2 of 3 recognized GHIS features (frontal bossing, mid-facial hypoplasia and depressed nasal bridge), "atypical" required 0 or 1 of these facial features. Classical and atypical GHIS groups were compared in terms of (1) phenotypic features, including high-pitched voice, sparse hair, blue sclera, hypoglycaemia, microphallus, (2) birth length, height SDS, and (3) basal IGF-I, IGF-II, IGFBP-1, IGFBP-3, GHBP and increase in IGF-I on IGF-I generation testing. RESULTS: Fifty patients [24 males, 26 females, aged 8.6 +/- 4.6 years (mean +/- SD)] had "classical GHIS", 9 patients (7 males, 2 females, aged 7.8 +/- 4.1 years) had "atypical GHIS", 7 with normal facies. Atypical GHIS patients had lesser height deficit (Ht SDS -4.0 +/- 1.4) compared to classical GHIS (-6.7 +/- 1.4), less reduction in IGFBP-3 SDS (atypical -5.5 +/- 3.3; classical -8.6 +/- 2.4), and more had normal GHBP (>10% binding). Other variables were also less frequent in atypical GHIS patients: high-pitched voice 11% (70% classical), sparse hair 11% (42% classical), blue sclera 0% (38% classical), hypoglycaemia 11% (42% classical), and microphallus 14% (1 of 7 males), compared to 79% of classical (19 of 24 males). CONCLUSIONS: Atypical GHIS patients, with relatively normal facial appearance, demonstrate less height defect and biochemical abnormalities compared to classical patients. GH insensitivity may be present in children with short stature and an otherwise normal appearance.

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.

Comparison of stimulated growth hormone levels in primed versus unprimed provocative tests. Effect of various testosterone doses on growth hormone levels.

OBJECTIVE: To show the importance of priming prior to growth hormone (GH) stimulation tests in the diagnosis of GH deficiency, the effect of different doses and schedules of testosterone (T) on GH levels. PATIENTS AND METHODS: Eighty-four prepubertal and early pubertal boys whose heights were 2 SD below the mean and height velocities <4 cm per year and who failed in GH stimulation tests were included in the study. The boys were divided into two groups: the first group consisting of 41 boys was primed with 62.5 mg/m(2) (low dose testosterone - LDT) and the second group consisting of 43 boys with 125 mg/m(2) depot testosterone (conventional dose testosterone - CDT) intramuscularly 1 week before the stimulation test. Twenty-one boys out of 36 who failed in GH stimulation tests after one dose T injection were treated with three doses of 62.5 mg/m(2) T (multiple dose testosterone - MDT) injections monthly and retested. RESULTS: The GH levels increased from 4.80 +/- 2.78 to 11.50 +/- 8.84 ng/ml and from 4.76 +/- 2.46 to 12.98 +/- 8.30 ng/ml by priming with LDT and CDT respectively. The increment of mean GH levels by both LDT and CDT were found to be similar (p = 0.443). The peak GH levels were found to be elevated >10 ng/ml in 22/41 (54%) and 26/43 (60%) who received LDT and CDT respectively (p = 0.528). The mean GH level of 21 boys who received MDT was increased from 5.38 +/- 2.50 ng/ml (by priming with one dose T) to 10.19 +/- 6.13 ng/ml (p = 0.004). Twelve (57%) of 21 boys who received MDT responded to GH stimulation test >10 ng/ml. The T level increased from 0.71 +/- 0.97 to 4.54 +/- 2.80 ng/ml by LDT (p < 0.001) and from 0.65 +/- 0.71 to 7.18 +/- 3.18 ng/ml by CDT (p < 0.001). The increment of T level was higher by CDT than LDT (p = 0.001). There was no correlation between T and peak GH levels after priming. CONCLUSION: LDT is as effective as CDT in priming of GH stimulation tests. The ones who failed in GH stimulation tests after one dose T injection can be primed with MDT. The stimulated GH level after priming was related neither to the plasma level of T nor the dose of T.

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.

Pituitary adenoma associated with gigantism and hyperprolactinemia.

An 11-year-old girl presented with excessive growth, headache, left visual loss and seizures. Her growth hormone (GH) and prolactin (PRL) levels were high and magnetic resonance imaging findings showed an invasive macroadenoma. Gross total tumor removal was performed and then radiotherapy and medical therapy were given. During the follow-up, she developed ACTH deficiency, secondary hypothyroidism and hypogonadism requiring replacement therapy. It is still unclear whether the biological characteristics of GH- and PRL-secreting tumors are different in children from those in adults. More data are needed before a definitive conclusion can be established.

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.

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.

Brown tumour as a complication of secondary hyperparathyroidism in severe long-lasting vitamin D deficiency rickets.

UNLABELLED: Brown tumour is a localised form of fibrous-cystic osteitis associated with primary or secondary hyperparathyroidism. Despite the fact that secondary hyperparathyroidism occurs in vitamin D deficiency rickets, no cases of rickets with brown tumour have so far been described. We present a 2.9-year-old girl who had brown tumour of the mandible due to severe vitamin D deficiency rickets. Treatment with vitamin D3 corrected the hyperparathyroidism rapidly which was followed by gradual regression in tumour size. CONCLUSION: Brown tumour can develop in severe, long-standing vitamin D deficiency rickets and responds to vitamin D treatment.

Iodine deficiency in Turkey.

UNLABELLED: Turkey is an iodine deficiency area. The overall goitre prevalence is thought to be 30%, and most epidemiological studies give figures compatible with mild to moderate iodine deficiency. However, it is suspected that there are regions where iodine deficiency might be more severe than previously known. In this study the goitre prevalence and iodine status in a mountain village in Central Anatolia were investigated and the results compared to those of an urban area with mild iodine deficiency. Parameters of iodine status in the mountainous region showed severe iodine deficiency comparable to that in Central Africa. It seems that there are regions in Turkey where current programmes of salt iodization will be inadequate to correct the problem of iodine deficiency. CONCLUSIONS: Our observations suggest that regional variations in iodine status may impede the success of salt iodization programmes, which alone may not be adequate for correction of the problem country-wide. Alternative sources of iodine should be considered in addition to expanded and more efficient salt iodization programmes.

Urological manifestations of the Wolfram syndrome: observations in 14 patients.

PURPOSE: Since the initial description of the Wolfram syndrome, various anomalies have been associated with this rare entity. Urinary tract dilatation and bladder dysfunction, usually in the form of a large, atonic bladder, are coexisting features of this syndrome that are commonly believed to be secondary to high urine output in diabetes insipidus. The presentation and nature of the urological manifestations of this syndrome remain controversial due to the lack of large series in the literature. We evaluated the urological manifestations of this rare syndrome. To our knowledge we report the largest series of patients (14) with the Wolfram syndrome who underwent a complete urological evaluation. MATERIALS AND METHODS: Eight boys and 6 girls with a mean age of 13.4 years underwent upper tract imaging and a video urodynamic investigation. A multidisciplinary consultation was obtained to investigate all components of the syndrome. RESULTS: Upper tract dilatation was present in 11 patients. Urodynamics revealed a normal bladder in only 1 patient, who also had severe hydronephrosis. Seven patients had a low capacity, high pressure bladder, while 6 had an atonic bladder. The type of bladder dysfunction did not correlate with time since the onset of diabetes mellitus or diabetes insipidus, or the severity of hydronephrosis. Three patients with sphincteric dyssynergia also had a hyperreflexic bladder. CONCLUSIONS: Contrary to some earlier reports, our findings suggest that bladder dysfunction does not always present as a large atonic bladder in the Wolfram syndrome. A low capacity, high pressure bladder with sphincteric dyssynergia is also common. The presence and duration of other syndrome manifestations do not correlate with the type of bladder dysfunction, suggesting that bladder dysfunction may also be a primary rather than secondary component of the syndrome.

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.

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.

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.

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.