Clinical and metabolic findings in a 6-year-old boy with a Leydig cell tumour.

AIM: To analyse the urinary steroid metabolome in a boy who had true precocious puberty after a Leydig cell tumour. METHOD: Case report and detailed description of clinical and metabolic findings in a 7-year-old-boy with a Leydig cell tumour. RESULTS: Before surgery, the urinary steroid metabolome showed an activation of an alternative route to gonadal androgens independent of dehydroepiandrosterone (DHEA). After surgery, the boy entered true precocious puberty. Under leuprolide acetate treatment, clinical and laboratory findings normalized. CONCLUSION: Central precocious puberty after precocious pseudopuberty may be more common than expected and should be considered in children with persistent or recurrent symptoms after initial treatment of precocious pseudopuberty. Patients with a Leydig cell tumour seem to reactivate the so-called 'back door pathway' of androgen production, which is independent of the classical route via DHEA.

Orbital compression syndrome in sickle cell crisis.

This article is about a 9-year-old boy with known homozygous sickle cell disease who developed unilateral exophthalmia and eyelid swelling during a sickle cell crisis. The symptoms were due to a vaso-occlusive event in the orbital bones,known as orbital compression syndrome, which is a rare complication of sickle cell disease.

Endocrine evaluation after endoscopic third ventriculostomy (ETV) in children.

OBJECTIVE: Endoscopic third ventriculostomy (ETV) is a standard procedure for the treatment of obstructive hydrocephalus in children. Main part of the procedure is the perforation of the third ventricle floor (tuber cinereum). This structure is part of the hypothalamic-pituitary neuronal network of cerebral endocrine regulation. There are no systematic data available about the endocrine status after ETV in children. MATERIALS AND METHODS: We examined 20 children who had undergone ETV. Examination included laboratory tests (adrenocorticotropic hormone, prolactin, insulin-like growth factor 1 [IGF-1], IGF-binding protein 3 [IGFBP-3], fT3, fT4, thyroid-stimulating hormone [TSH], serum osmolarity, electrolytes, glucose, urea, follicle-stimulating hormone [FSH] and luteinizing hormone [LH], and testosterone in selected patients), measurement of weight, height, and head circumference, and physical examination. The study was approved by the Ethics Committee of the Medical Faculty of Kiel University. RESULTS: In seven patients, prolactin was moderately elevated. One patient demonstrated a significantly increased prolactin (56.3 ng/ml). In all eight patients, this was the only laboratory value that was out of the normal range; all other parameters were normal. Three other patients showed one abnormal parameter (decrease in FSH and LH, increase in TSH, decrease in IGF-1 and IGFBP-3). In nine patients, weight or height was not within the 3rd to 97th centiles for age. DISCUSSION AND CONCLUSION: More patients than expected demonstrated endocrine laboratory abnormalities. However, there was no clinical relevance in any of the studied patients. It remains inconclusive whether ETV contributes to the abnormalities of prolactin levels or to other endocrine parameters in pediatric patients. Longitudinal studies are necessary to delineate the effect of ETV on endocrine regulation.

Initially elevated TSH and congenital central hypothyroidism due to a homozygous mutation of the TSH beta subunit gene: case report and review of the literature.

Congenital central hypothyroidism (CCH) is a rare disease which can be caused by mutations in the gene for the thyrotropin (TSH) beta subunit ( TSHB). The diagnosis is usually delayed because the TSH serum levels in these patients are not elevated leading to a negative result in the neonatal TSH screening. Herein, we report a 2-year-old girl with CCH due to a mutation in the TSHB gene, in whom the unusual finding of an initially elevated TSH level complicated the diagnostic workup. The proposita, who had a supposedly normal TSH screening result, is a German girl of non-consanguineous parents. At 5 weeks of age, her thyroid function tests showed peripheral hypothyroidism with a moderately increased TSH (23.8 microIU/ml) so that thyroid hormone substitution was initiated. At the age of 2 years, the administration of TRH failed to increase the TSH serum concentrations, which prompted TSH measurements with two different assay systems. Variable TSH levels ranging from not detectable low to elevated were found so that central hypothyroidism due to a mutation in the TSHB gene was suspected. This was confirmed by molecular analysis of the TSHB gene, which identified a homozygous deletion (delta 313 T) in the coding sequence. This mutation has been found in the German population before and may be a founder mutation. We conclude that depending on the assay system variable TSH serum levels in individuals with mutations in the TSHB gene may complicate the diagnostic workup.

Absence of exercise-induced leptin suppression associated with insufficient epinephrine reserve in patients with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

OBJECTIVE: Patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency suffer from glucocorticoid and mineralocorticoid deficiency. They have insufficient epinephrine reserves and increased basal leptin levels and are often insulin resistant. In healthy subjects, an inhibitory effect of acute catecholamine elevation on the leptin plasma concentrations has been reported. However, it is not yet known how leptin levels respond to exercise in CAH patients. METHODS: We performed a cycle ergometer test in six CAH patients to measure the response of plasma leptin, glucose and the catecholamines, epinephrine (E) and norepinephrine (N), as well as their respective metabolites, metanephrine (M) and normetanephrine (NM), to intense exercise. RESULTS: Baseline leptin concentrations in CAH patients were not different from those of controls. Leptin levels decreased significantly with exercise in healthy controls, whereas they remained unchanged in CAH patients. In contrast to controls, CAH patients showed no rise of plasma glucose. Basal and stimulated E and M levels were significantly lower in CAH patients compared to controls. Baseline and stimulated N and NM levels were comparable, showing a significant rise after exercise. Peak systolic blood pressure and peak heart rate in both groups were comparable. CONCLUSION: CAH patients do not manifest exercise-induced leptin suppression. The most probable reason for this is their severely impaired epinephrine stress response. In addition, epinephrine deficiency is leading to secondary changes in various catecholamine dependent metabolic pathways, e. g., energy balance. Although obvious clinical sequelae are so far unknown, the catecholamine-deficient state and the resulting hyperleptinemia might contribute to the severity of the disease in CAH.

Three novel point mutations of the CYP21 gene detected in classical forms of congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

Congenital adrenal hyperplasia (CAH) [OMIM 201 910] is a group of autosomal recessive disorders most commonly due to 21-hydroxylase deficiency and presenting with a wide range of clinical manifestations. A limited number of inactivating pseudogene-derived mutations account for the majority of 21-hydroxylase gene ( CYP21) mutations, additional rare mutations can be found in single families and small populations. We found three novel CYP21 mutations in CAH patients suffering from the classical form of the disease, of which one is a frameshift mutation (1353-1354insA) leading to a premature termination codon (K277K, Q228A...E294X), one results in a premature stop codon (2551C>T, R444X), and one is a missense mutation (2609T>C; P463L). The frameshift and premature stop mutations can be predicted to result in a CYP21 protein without any residual enzyme activity. To determine the functional consequences of the P463L mutation, the IN VITRO enzyme activity was studied in COS-7 cells and revealed a reduced 21-hydroxylase activity of 2.6+/-0.8 (SD)% for the conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol and of 3.0+/-0.5 % for the conversion of progesterone to 11-deoxycorticosterone (DOC). We conclude that functional analyses of unknown mutations provide information on the disease severity and should be always performed when novel CYP21 mutations are detected. Knowledge of the residual 21-hydroxylase function improves both genetic counselling and individual clinical management in CAH patients.

[Calcinosis cutis in Albright hereditary osteodystrophy: pseudohypoparathyroidism type Ia]. / Calcinosis cutis bei hereditärer Albright-osteodystrophie: pseudohypoparathyreoidismus typ Ia.

Albright hereditary osteodystrophy (AHO) is characterized by a symptom complex including short stature, brachymetacarpia, obesity, round facies, cutaneous osteomas, and mental retardation. AHO is caused by mutations in the GNAS-gene localized on chromosome 20 encoding for Gsalpha protein, a signal transducer of endocrine pathways. Therefore, AHO is often associated with endocrinopathy such as pseudohypoparathyroidism or hypothyroidism. A nine-month-old boy presented with typical features of this syndrome. The diagnosis was confirmed by biochemical and molecular analyses. An unusual feature was calcinosis cutis at such an early age, which led to extensive differential diagnostic procedures.

Sigmoid diverticulitis in patients with Williams-Beuren syndrome: relatively high prevalence and high complication rate in young adults with the syndrome.

In a retrospective survey of 128 adults with Williams-Beuren syndrome (age range 18-62 years) sigmoid diverticulitis was reported in 10 patients (2 f, 8 m). The diagnosis of diverticulitis had been made between the ages of 17.1 and 39.6 years. An additional four patients (age range 23.5-32.2 years) had presented with sigmoid diverticulosis. In eight patients the course of the disease was complicated, some of them having to undergo multiple surgery. Conservative therapy was successful in only one female and one male patient with diverticulitis. Thus, we conclude that there is an increased prevalence of sigmoid diverticulitis in adult patients with Williams-Beuren syndrome (8% vs. 2% in the normal population in the age group below 40 years).

Differences in infantile growth patterns in Turner syndrome girls with and without spontaneous puberty.

OBJECTIVE: The role of prepubertal estrogen in child growth was modeled using Turner's syndrome, comparing growth patterns of girls who later did or did not enter puberty spontaneously. The hypothesis was that TS patients with normal prepubertal estrogen levels would have a different growth pattern from those with subnormal estrogen levels. STUDY DESIGN: Growth data from 78 full-term patients with Turner's syndrome were collected retrospectively. 24/78 later developed spontaneous puberty, (+Pub), and their growth data were compared to TS patients without spontaneous puberty (-Pub). A nonlinear mixed model was fitted using the bi-exponential model. RESULTS: The growth velocity difference between the -Pub and +Pub groups suggests an early infantile growth advantage in the -Pub group, which disappears before the end of the first year of life; growth velocity remains similar (+/- 1 cm/y) for the next 6 years and declines at age 7-8 years in the +Pub group faster than it does in the -Pub group. Bi-exponential analysis showed that both the 1st (restrictive) and 2nd exponent (forward) were different (p = 0.0003). CONCLUSIONS: Comparison of girls with or without spontaneous puberty suggests a role for estrogen in child growth. Estrogens restrict infantile growth, as well as growth during the mid-childhood spurt.

Congenital adrenal hyperplasia - how to improve the transition from adolescence to adult life.

Congenital adrenal hyperplasia (CAH) is caused by a defect in the biosynthesis of cortisol that results in maximal activity of the hypothalamic-pituitary adrenal axis with hyperplasia of the adrenals and hyperandrogenism due to the accumulation of androgen precursors. In the salt-wasting subtype of the disorder, which accounts for appr. 75 % of patients with classical CAH, patients are unable to synthesise sufficient amounts of aldosterone and are prone to life-threatening salt-losing crises, whereas the simple virilising form is predominantly characterized by clitoris hypertrophy and posterior labial fusion. In addition, a non-classical variant can be discerned which in most cases is diagnosed at the time of puberty or early adolescence when hirsutism and menstrual irregularities may occur. The vast majority of CAH patients have 21-hydroxylase deficiency (90 - 95 %). Less common forms, such as 11beta-hydroxylase deficiency, will not be discussed in this review. Unfortunately, a considerable number of CAH patients is lost to regular and competent follow-up once they move out of paediatric care. This is most probably the result of insufficient co-operation between paediatric and adult endocrinologists at the time of transition from adolescence to adulthood. Furthermore, there is a lack of clinical guidance regarding psychosexual development in these patients. In this overview we will focus on special aspects of CAH treatment in adolescence and adulthood, and report on our 10-year experience with a transfer system for endocrine patients from paediatric to internal medical care, known as the "Kieler Modell". For practical purposes, we here provide charts for follow-up of CAH patients that can be adapted for use in any endocrine outpatient clinic.

Association of morphological characteristics with precocious puberty and/or gelastic seizures in hypothalamic hamartoma.

The pathogenesis of central precocious puberty (PP) and/or gelastic seizures due to a hypothalamic hamartoma (HH) is still under debate. We evaluated the association of clinical symptoms with morphology and localization of the HH in 34 patients. The majority (86.4%) of HHs in patients with isolated PP (n = 22; 68.2% females) revealed a parahypothalamic position without affecting the third ventricle (91%). Half of them were pedunculated, and 40.9% showed a diameter less than 10 mm. In contrast, 11 of 12 patients with seizures, eight of whom were male, presented with a sessile intrahypothalamic hamartoma, 10 of which distorted the third ventricle. Logistic regression analysis revealed an increased relative risk (RR) for epilepsy in males (RR, 4.3; 95% confidence interval, 0.96-19). However, combination of the risk factor gender with intrahypothalamic position (RR, 19; 1.3-285) and distortion of the third ventricle (RR, 10; 0.6-164) reduced the risk associated with male gender to 1.1. The position of a HH and involvement of the third ventricle are likely to be more predictive for clinical characteristics than size and shape. Male gender was associated with an intrahypothalamic HH and epilepsy, suggesting a sexually dimorphic developmental pattern of this heterotopic mass.

Are needle-free injections a useful alternative for growth hormone therapy in children? Safety and pharmacokinetics of growth hormone delivered by a new needle-free injection device compared to a fine gauge needle.

The clinical safety, use and pharmacokinetics of a new needle-free device for delivery of growth hormone (GH) were compared with those of conventional needle injection devices. In an open-label, randomized, 4-period crossover study, 18 healthy adults received single subcutaneous injections of Genotropin administered by the Genotropin ZipTip needle-free device and by conventional injection. Bioequivalence was established between the devices. In a separate open-label, randomized, multicenter, 2-period crossover study, pediatric patients underwent 2-weeks Genotropin treatment administered by the Genotropin ZipTip and by a fine-gauge needle device (>95% used the Genotropin Pen). In total, 128/133 patients who were treated completed the study. Genotropin ZipTip was well tolerated and >50% of patients found no difference between the devices for all parameters assessed. After study completion, >20% patients preferred to continue using Genotropin ZipTip. Although statistical analyses demonstrated superiority of the Genotropin Pen versus Genotropin ZipTip for bleeding, pain, soreness, and bruising, Genotropin ZipTip was considered to provide a safe and bioequivalent alternative to needle injection.

Chromatographic system for the simultaneous measurement of plasma 18-hydroxy-11-deoxycorticosterone and 18-hydroxycorticosterone by radioimmunoassay: reference data for neonates and infants and its application in aldosterone-synthase deficiency.

A new chromatographic system for the steroid precursor separation and a sensitive radioimmunoassay system for the subsequent measurement of 18-hydroxy-11-deoxycorticosterone and 18-hydroxycorticosterone has been developed. 18-Hydroxy-11-deoxycorticosterone and 18-hydroxycorticosterone were extracted with methylene chloride and separated from cross-reacting steroids by Sephadex LH-20 column chromatography. Anti-18-hydroxy-11-deoxycorticosterone and anti-18-hydroxycorticosterone antibodies raised in rabbits were used. The lower detection limit of the assay is 0.03 nmol/l and 0.128 nmol/l for 18-hydroxy-11-deoxycorticosterone and 18-hydroxycorticosterone, respectively. Normal values for this assay in 128 healthy neonates and infants aged 0-5 months were established as a basis for the early hormonal diagnosis of aldosterone synthase deficiency types I and II. Its application for the diagnosis of aldosterone synthase deficiency is demonstrated in two patients with homozygous mutation/deletion in the encoding CYP11B2 gene.

Adult height after GH therapy in 188 Ullrich-Turner syndrome patients: results of the German IGLU Follow-up Study 2001.

OBJECTIVES: We aimed to evaluate the factors influencing true adult height (HT) after long-term (from 1987 to 2000) GH treatment in Ullrich-Turner syndrome (UTS) based on modalities conceived in the 1980s. DESIGN: Out of 347 near-adult (>16 Years) patients from 96 German centres, whose longitudinal growth was documented within KIGS (Pharmacia International Growth Database), 188 (45, X=59%; bone age >15 Years) were available for further anthropometric measurements. RESULTS: At a median GH dose of 0.88 (10th/90th percentiles: 0.47/1.06) IU/kg per week, a gain of 6.0 (-1.3/+13) cm above the projected adult height was recorded. Variables were recorded at GH start, after 1 Year GH, puberty onset, and last visit on GH therapy. At these visits, the median ages were 11.7, 12.7, 14.2, 16.6 and 18.7 Years; and median heights, 0.4, 1.1, 1.7, 1.7 and 1.3 SDS (UTS) respectively. Height gain (DeltaHT) after GH discontinuation was 1.5 cm. Total DeltaHT correlated (P<0.001) negatively with bone age and HT SDS at GH start, but positively with DeltaHT after the first Year, DeltaHT at puberty onset, and GH duration. Final HT correlated (P<0.001) positively with HT at GH start, first-Year DeltaHT, and HT at puberty onset. Body mass index increased slightly (P<0.05), with values at start and adult follow-up correlating highly (R=0.70, P<0.001). No major side effects of GH occurred. CONCLUSIONS: GH dosages conceived in the 1980s are safe but too low for most UTS patients. HT gain and height are determined by age and HT at GH start. Height gain during the first Year on GH is indicative of overall height gain. After spontaneous or induced puberty, little gain in height occurs.

Repyloromyotomy for recurrent infantile hypertrophic pyloric stenosis after successful first pyloromyotomy.

The authors report on a male infant aged 4(1/2) weeks who underwent a pyloromyotomy for hypertrophic pyloric stenosis. After an uncomplicated postoperative course with normal feeding and weight gain, projectile vomiting reoccurred. The boy underwent a repyloromyotomy for recurrent hypertrophic pyloric stenosis. The underlying cause of a recurrent hypertrophic pyloric stenosis after a successful pyloromyotomy may be explained by the natural history of the disease.

Automated chromatographic system for the simultaneous measurement of plasma pregnenolone and 17-hydroxypregnenolone by radioimmunoassay.

A new, simple, rapid and highly practicable automated chromatographic system for the separation, and a sensitive radioimmunoassay system for the subsequent measurement of pregnenolone and 17-hydroxypregnenolone has been developed. Pregnenolone and 17-hydroxypregnenolone were extracted with methylene chloride and separated from cross-reacting steroids by mechanised Sephadex-LH20 multi-column chromatography. Anti-pregnenolone and anti-17-hydroxypregnenolone were obtained by immunising rabbits with pregnenolone-20-oxime-BSA and 17-hydroxypregnenolone-20-oxime-BSA. The lower detection limit of the assay is 0.15 and 0.28 nmol/l for pregnenolone and 17-hydroxypregnenolone, respectively. Normal values for this assay in young male adults, in adult females, and in prepubertal boys and girls were established as a basis for the functional diagnosis of androgen excess syndromes/steroidogenesis defects.

Longitudinal imaging reveals pituitary enlargement preceding hypoplasia in two brothers with combined pituitary hormone deficiency attributable to PROP1 mutation.

Mutations of the PROP-1 gene cause combined pituitary hormone deficiency. Progressive ACTH/cortisol insufficiency is found in a few patients. Congenital hypoplasia of the anterior pituitary gland is the most common magnetic resonance imaging finding in patients with PROP-1 mutations. We present two brothers with compound heterozygosity for the two mutations 150delA and 301-302delAG of the PROP-1 gene. Both showed combined pituitary hormone deficiency of GH, TSH, PRL, and gonadotropins, as is typical for PROP-1 deficiency. We observed a developing insufficiency of ACTH and cortisol secretory capacity in both patients. Computed tomography revealed an enlarged pituitary in the older brother at 3.5 yr of age. Repeated magnetic resonance imaging after 12 yr showed a constant hypoplasia of the anterior pituitary lobe. Similarly, magnetic resonance imaging of the younger brother showed a constant enlargement of the anterior pituitary gland until 10 yr. At the age of 11 yr, the anterior pituitary was hypoplastic. The reason for pituitary enlargement in early childhood with subsequent decrease in pituitary size is not known. We speculate that altered expression of early transcription factors could be involved. Because both patients have the same PROP-1 mutations and an identical pattern of combined pituitary hormone deficiency, we suggest that early pituitary enlargement may be the typical course in such patients in whom pituitary surgery is not indicated.

Pathogenesis and epidemiology of precocious puberty. Effects of exogenous oestrogens.

Precocious puberty is generally defined as the appearance of secondary sex characteristics before age 8 years in girls (or menarche before age 9 years) and before 9 years in boys. The overall incidence of sexual precocity is estimated to be 1:5,000 to 1:10,000 children. The female-to-male ratio is approximately 10:1. In addition to the psychosocial disturbances associated with precocious puberty, the premature pubertal growth spurt (with less time for prepubertal growth) and the accelerated bone maturation result in reduced adult height. Precocious puberty may be gonadotrophin-dependent [i.e. of central origin with premature activation of the gonadotrophin-releasing hormone (GnRH) pulse generator] or gonadotrophin-independent (i.e. peripheral where the GnRH pulse generator is suppressed). This can be determined by GnRH testing. The pathophysiology is the basis for different diagnostic and therapeutic strategies, i.e. in the first case a stimulated LH/FSH ratio >1 and suppressive treatment with GnRH agonists (e.g. in hypothalamic hamartoma), and in the second decreased gonadotrophins and removal or suppression of the endogenous or exogenous sex steroid source (e.g. congenital adrenal hyperplasia). While several cases of gonadotrophin-independent precocious puberty due to oestrogen exposure via the transdermal, oral, or inhalative route have been reported, no case is known with the development of subsequent secondary central precocious puberty. Food contamination with oestrogens is theoretically possible, but would most probably be sporadic and, thus, would not lead to precocious puberty. As steroid hormones in meat production are banned in the European Union, no data on the impact of environmental oestrogenic substances on human maturation are currently available. In conclusion, the risk for children to develop precocious puberty through exposure to oestrogens (or androgens) in the environment or in food is very low. Nevertheless, studies of the effects of defined environmental oestrogenic substances on the human reproductive system and on pubertal development are warranted.