Poorly Controlled Congenital Hypothyroidism due to an Underlying Allgrove Syndrome.

BACKGROUND: Congenital hypothyroidism of thyroidal origin (CHT) is a common disorder in pediatric endocrinology practices, which can be difficult to manage. Elevated thyrotropin (TSH) concentrations are in the great majority of cases explained by poor compliance to levothyroxine therapy. METHODS: Case description. RESULTS: We present a boy with CHT, with 2 heterozygous mutations in the TSH receptor gene, who showed persistently elevated TSH concentrations and psychomotor retardation, initially misinterpreted as malcompliance. At the age of 4 years, he was diagnosed with adrenal insufficiency, wherefore a broad diagnostic search was initiated. After the start of glucocorticoid replacement therapy, his TSH normalized and the levothyroxine could be lowered. At the age of 6 years, his TSH increased again, this time caused by malabsorption of levothyroxine due to esophageal achalasia. In retrospect, alacrima was also present and the diagnosis of Allgrove syndrome was genetically confirmed. The CHT was considered a separate disease entity. CONCLUSIONS: In case of persistently elevated TSH levels in children with CHT, causes other than noncompliance must be considered. Second, in establishing the cause of adrenal insufficiency, specific symptoms, such as alacrima, are easily overlooked. Third, Allgrove syndrome is a rare disorder, in which diagnostic delay can lead to potentially life-threatening complications.

High-dose GH treatment limited to the prepubertal period in young children with idiopathic short stature does not increase adult height.

OBJECTIVE: To assess the long-term effect of prepubertal high-dose GH treatment on growth in children with idiopathic short stature (ISS). DESIGN AND METHODS: Forty children with no signs of puberty, age at start 4-8 years (girls) or 4-10 years (boys), height SDS <-2.0 SDS, and birth length >-2.0 SDS, were randomly allocated to receive GH at a dose of 2 mg/m(2) per day (equivalent to 75 microg/kg per day at start and 64 microg/kg per day at stop) until the onset of puberty for at least 2 years (preceded by two 3-month periods of treatment with low or intermediate doses of GH separated by two washout periods of 3 months) or no treatment. In 28 cases, adult height (AH) was assessed at a mean (S.D.) age of 20.4 (2.3) years. RESULTS: GH-treated children (mean treatment period on high-dose GH 2.3 years (range 1.2-5.0 years)) showed an increased mean height SDS at discontinuation of the treatment compared with the controls (-1.3 (0.8) SDS versus -2.6 (0.8) SDS respectively). However, bone maturation was significantly accelerated in the GH-treated group compared with the controls (1.6 (0.4) versus 1.0 (0.2) years per year, respectively), and pubertal onset tended to advance. After an untreated interval of 3-12 years, AH was -2.1 (0.7) and -1.9 (0.6) in the GH-treated and control groups respectively. Age was a positive predictor of adult height gain. CONCLUSION: High-dose GH treatment restricted to the prepubertal period in young ISS children augments height gain during treatment, but accelerates bone maturation, resulting in a similar adult height compared with the untreated controls.

Benefit of postponing normal puberty for improving final height.

Experiments of nature and clinical observations have provided indications that postponing puberty may increase final height in short children. In children with central precocious puberty, a GnRH analog (GnRHa) alone is efficacious in increasing final height, but in other conditions a combination of growth hormone (GH) and GnRHa is needed. In GH-deficient children with early onset of puberty and poor height prediction, the combination of GH and GnRHa increases final height by 1.0-1.3 s.d. In children with idiopathic short stature and persistent short stature after intrauterine growth retardation, the combination also appears to be beneficial. Potential side effects include weight gain, a negative effect on bone mineralization, and psychosocial consequences. More data on long-term safety have to be collected before the combination of GH and GnRHa in children with idiopathic short stature should be considered for clinical use outside clinical trials.

Biochemical markers of growth hormone (GH) sensitivity in children with idiopathic short stature: individual capacity of IGF-I generation after high-dose GH treatment determines the growth response to GH.

OBJECTIVE AND PATIENTS: To assess multiple dose-response relationships between three GH doses (1.5, 3.0 and 6.0 IU/m2) and nine different biochemical markers of GH sensitivity in a well-defined group of 17 children with idiopathic short stature (ISS). DESIGN AND MEASUREMENTS: Serum levels of IGF-I, IGF-II and IGFBP-3, and peripheral markers leptin, C-terminal propeptide of type I collagen (PICP) and N-terminal propeptide of type III collagen (PIIINP), alkaline phosphatase (AP) and osteocalcin (OC) were measured at the start and after 2 and 12 weeks of periods of no treatment, GH 1.5 IU/m2 and GH 3.0 IU/m2. Twelve-week washout periods were applied between the 12-week GH-treatment periods. High-dose GH treatment was given during the second year of study and all serum markers were measured at start, after 2 and 12 weeks and 1 year of GH 6.0 IU/m2. In 18 non-GH-treated children with ISS the same parameters were measured yearly. The bone resorption marker urinary deoxypyridinoline (DPD) was measured during 12-h day and night periods at start and after 2 weeks GH 1.5, 3.0 and 6.0 IU/m2. RESULTS: All markers were GH dependent, but the timing of maximal response varied among different markers. Height SDS at start, age at start and IGF-II at baseline were inversely related to the first-year growth response (r = -0.73, P = 0.001; r = -0.53, P = 0.03; and r = -0.53, P = 0.03, respectively). Some statistically significant correlations between biochemical responses on low GH doses (1.5 or 3.0 IU/m2) and second-year growth response were found, but these showed no consistent pattern. However, all changes in IGF-I SDS after GH 6.0 IU/m2 measured either after 2 or 12 weeks or 1 year correlated significantly with the second-year growth response (r = 0.55, P = 0.02; r = 0.81, P = 0.001; and r = 0.86, P < 0.001, respectively). Baseline or GH-stimulated levels of peripheral markers did not correlate with the growth response. CONCLUSION: The individual capacity of IGF-I generation after high-dose GH treatment (6.0 IU/m2) determines the growth response on high-dose GH treatment. Peripheral markers do not seem to play a role in growth prediction of children with ISS.

High dose growth hormone treatment induces acceleration of skeletal maturation and an earlier onset of puberty in children with idiopathic short stature.

BACKGROUND: Long term growth hormone (GH) treatment in children with idiopathic short stature (ISS) results in a relatively small mean gain in final height of 3-9 cm, which may not justify the cost of treatment. As it is unknown whether GH treatment during puberty adds to final height gain, we sought to improve the cost-benefit ratio, employing a study design with high dose GH treatment restricted to the prepubertal period. AIMS: To assess the effect of short term, high dose GH treatment before puberty on growth, bone maturation, and pubertal onset. METHODS: Five year results of a randomised controlled study are reported. Twenty six boys and nine girls were randomly assigned to a GH treatment group (n = 17) or a control group (n = 18). Inclusion criteria were: no signs of puberty, height less than -2 SDS, age 4-8 years for girls or 4-10 years for boys, GH concentration >10 micro g/l after provocation, and normal body proportions. To assess GH responsiveness, children assigned to the GH treatment group received GH treatment for two periods of three months (1.5 IU/m2/day and 3.0 IU/m2/day), separated by three month washout periods, during the first year of study. High dose GH treatment (6.0 IU/m2/day) was then started and continued for at least two full years. When puberty occurred, GH treatment was discontinued at the end of a complete year's treatment (for example, three or four years of GH treatment). RESULTS: In response to at least two years on high dose GH treatment, mean (SD) height SDS for chronological age increased significantly in GH treated children from -2.6 (0.5) to -1.3 (0.5) after two years and -1.4 (0.5) SDS after five years of study. No changes in height SDS were observed in controls. A rapid rate of bone maturation of 3.6 years/2 years in treated children compared to 2 years/2 years in controls was observed in response to two years high dose GH treatment. Height SDS for bone age was not significantly different between groups during the study period. GH treated children entered into puberty at a significantly earlier age compared to controls. CONCLUSIONS: High dose GH treatment before puberty accelerates bone age and induces an earlier onset of puberty. This may limit the potential therapeutic benefit of this regimen in ISS.

A randomized controlled trial of three years growth hormone and gonadotropin-releasing hormone agonist treatment in children with idiopathic short stature and intrauterine growth retardation.

We assessed the effectiveness and safety of 3 yr combined GH and GnRH agonist (GnRHa) treatment in a randomized controlled study in children with idiopathic short stature (ISS) or intrauterine growth retardation (IUGR). Gonadal suppression, GH reserve, and adrenal development were assessed by hormone measurements in both treated children and controls during the study period. Thirty-six short children, 24 girls (16 ISS/8 IUGR) and 12 boys (8 ISS/4 IUGR), with a height SD score of -2 SD or less in early puberty (girls, B2-3; boys, G2-3), were randomly assigned to treatment (n = 18) with GH (genotropin 4 IU/m(2). day) and GnRHa (triptorelin, 3.75 mg/28 days) or no treatment (n = 18). At the start of the study mean (SD) age was 11.4 (0.56) or 12.2 (1.12) yr whereas bone age was 10.7 (0.87) or 10.9 (0.63) yrs in girls and boys, respectively. During 3 yr of study height SD score for chronological age did not change in both treated children and controls, whereas a decreased rate of bone maturation after treatment was observed [mean (SD) 0.55 (0.21) 'yr'/yr vs. 1.15 (0.37) 'yr'/yr in controls, P < 0.001, girls and boys together]. Height SD score for bone age and predicted adult height increased significantly after 3 yr of treatment; compared with controls the predicted adult height gain was 8.0 cm in girls and 10.4 cm in boys. Furthermore, the ratio between sitting height/height SD score decreased significantly in treated children, whereas body mass index was not influenced by treatment. Puberty was effectively arrested in the treated children, as was confirmed by physical examination and prepubertal testosterone and estradiol levels. GH-dependent hormones including serum insulin-like growth factor I and II, carboxy terminal propeptide of type I collagen, amino terminal propeptide of type III collagen, alkaline phosphatase, and osteocalcin were not different between treated children and controls during the study period. Thus, a GH dose of 4 IU/m(2) seems adequate for stabilization of the GH reserve and growth in these GnRHa-treated children. We conclude that 3 yr treatment with GnRHa was effective in suppressing pubertal development and skeletal maturation, whereas the addition of GH preserved growth velocity during treatment. This resulted in a considerable gain in predicted adult height, without demonstrable side effects. Final height results will provide the definite answer on the effectiveness of this combined treatment.

Influence of growth hormone treatment on pubertal timing and pubertal growth in children with idiopathic short stature. Dutch Growth Hormone Working Group.

We studied the influence of recombinant human growth hormone (rhGH) on pubertal timing and pubertal growth in children with idiopathic short stature (ISS), and evaluated whether this was different between children with and without intra-uterine growth retardation (IUGR). Twenty-six (18 M, 6 IUGR; 'treated') subjects were treated with rhGH (6-7 days/week, dosage: 14-28 IU/m2 per week [i.e. 0.2-0.3 mg/kg per week]). Fifty-eight subjects (31 M, 9 IUGR; 'controls') were not treated. All subjects attained final height. Prepubertal height gain was significantly larger in the treated children compared to control children (M: 0.66 SDS, 95% confidence interval [CI] 0.41 to 0.92; F. 0.92 SDS, CI 0.58 to 1.26). Pubertal height gain, peak height velocity and duration of puberty were similar for the treated and control subjects. rhGH advanced the age at peak height velocity by 0.7 years (CI 0.3 to 1.0) in boys, and the age at onset of puberty by 1.1 years (CI 0.3 to 1.9) in girls. The gain in final height was 2-3 cm. Age and height SDS at start were the most important predictors for pubertal height gain, total height gain and final height in a multivariate regression analysis. Total height gain of treated subjects with IUGR was less than that of treated subjects without IUGR. In conclusion, rhGH did not affect pubertal growth in children with ISS, and slightly improved their final height. rhGH treatment should be started early to improve height as much as possible before the onset of puberty.

High-dose growth hormone therapy in idiopathic short stature.

This article reviews the available data on the effect of growth hormone (GH) administration on the growth of children with idiopathic short stature. The 1st year growth response appears clearly dose dependent, if the mean values from various clinical trials are combined. Dose dependency has also been shown in prospective trials. The dose dependency of the long-term growth response was less convincing in a large prospective study. The effect on final height cannot be proven with certainty in uncontrolled studies. If all available results from clinical trials are combined, a positive correlation between response and dose appears likely.

Spontaneous growth and response to growth hormone treatment in children with growth hormone deficiency and idiopathic short stature.

Isolated idiopathic growth hormone deficiency (GHD) and idiopathic short stature (ISS) can be difficult to distinguish, but the therapeutical consequences are different. In this report the data on final height of untreated and treated children with GHD and ISS are reviewed. Untreated GH-deficient individuals who underwent spontaneous puberty (22 male, 14 female patients) reached a mean final height of 4.7 SD (range 3.9 to 6.0) below the population's mean. If puberty was induced (19 male patients), mean final height SD score (SDS) was -3.1. Traditional regimens of GH administration (2-4 injections/wk) in 236 children (184 boys, 52 girls) with GHD and spontaneous puberty resulted in a final height SDS of -2.8 (range -1.5 to -4.7). In 190 children in whom puberty was induced (139 boys, 51 girls) mean final height was -1.6 (range - -1.1 to -2.4). The mean gain in final height SDS is therefore estimated at 1.5-2.0 in average cases, and 3.5 in extreme cases. Preliminary data suggest that on present regimens mean final height may approach target height. In untreated boys with ISS the mean final height was 2-5 cm lower than that predicted before puberty, whereas in girls it was almost equal to the prediction. After GH treatment the mean final height was 0.4-3.0 cm higher than the predicted adult height, which results in an average net gain in final height SDS of approximately 0.5-0.8 (3-5 cm).

Slow baseline growth and a good response to growth hormone (GH) therapy are related to elevated spontaneous GH pulse frequency in girls with Turner's syndrome.

Spontaneous growth and growth responses to GH therapy vary considerably among girls with Turner's syndrome. In an attempt to clarify this variability, we assessed growth parameters, 24-h GH profiles, arginine-stimulated serum GH levels, and plasma insulin-like growth factor-I (IGF-I) concentrations in a group of 41 girls with Turner's syndrome with a mean (+/- SD) age of 13 +/- 3 yr (range, 6.7-18.9). We subsequently treated all girls with biosynthetic GH (24 IU/m2 x week) and documented the growth response after 1 yr of therapy. GH profiles were analyzed according to Pulsar and Cluster, and GH secretion rates were calculated by waveform-independent deconvolution (Pulse). Factor analysis selected the mean 24-h GH secretion rate and number of GH peaks according to Cluster and Pulse as the principal GH profile variables to be used for further analysis. The mean (+/- SD) daily pituitary GH secretion rate was 127 +/- 47 micrograms/L.24 h (range, 37-232). The GH secretion rate correlated inversely with body mass index (r = -0.45; P < 0.01; n = 41). There was no relationship between the GH secretion rate and the growth parameters before or after GH therapy. However, the number of GH peaks (Pulse) correlated negatively with baseline height velocity (r = -0.53; P = 0.03) and was a positive predictor for height velocity increment during the first year of GH therapy (r = 0.71, P = 0.001). The mean (+/- SD) IGF-I level was 217 +/- 91 ng/mL (range, 87-413). There was no relationship between GH secretion rate or growth parameters and IGF-I. However, the number of GH peaks correlated negatively with IGF-I (r = -0.49; P = 0.04; n = 17). We conclude that an elevated spontaneous GH pulse frequency pattern is associated with relatively low IGF-I levels and slow baseline growth in girls with Turner's syndrome and that girls with such a pulse pattern may benefit most from exogenous GH therapy.

Multiple hormone deficiencies in children with hemochromatosis.

Patients with thalassemia major require multiple blood transfusions leading to hemochromatosis. These patients often have pubertal delay and growth failure, the etiology of which has not been fully elucidated. We performed an extensive endocrine evaluation which included measurements of spontaneous and stimulated levels of gonadotropins, GH, thyroid hormone, and adrenal hormones in 17 patients between the ages of 12 and 18 yr with hemochromatosis receiving desferoxamine therapy. All of the 17 patients had at least one endocrine abnormality, and 12 had more than one abnormality. Abnormalities of the hypothalamic-pituitary-gonadal axis were the most common. Six patients had clinical evidence of delayed puberty with spontaneous and stimulated gonadotropin and sex steroid levels appropriate for their delayed pubertal stage. All 14 children in puberty LH pulsatility index below the mean for pubertal stage compared to normal children. Six of the 14 had LH pulsatility index more than 2 SD below the mean for pubertal stage. This may be an indicator of abnormal pituitary function. Six patients failed either the provocative GH tests (peak GH < 7 micrograms/L) or had a mean spontaneous GH less than 1 microgram/L. The 4 patients who failed provocative tests had growth velocities more than 2 SD below the mean for bone age. Three patients had evidence of primary hypothyroidism. We conclude that all patients with hemochromatosis need periodic careful endocrine evaluations because the incidence of endocrine dysfunction is substantial and they may benefit from hormonal therapy.

Growth hormone secretion in patients with Turner's syndrome as determined by time series analysis.

Twenty-four-hour growth hormone (GH) profiles in 26 girls with Turner's syndrome were compared with those of 26 normally growing short children and 24 slowly growing short children. All children were prepubertal and below 12 years of age. A subgroup of 13 girls was treated with ethinyl estradiol and a 24-h GH profile was reassessed. In an additional group of 45 girls with Turner's syndrome (aged 6.7-18.9 years) the effect of age, spontaneous breast development and ethinyl estradiol treatment was studied. The profiles were assessed by Fourier analysis. The oscillatory activity and the mean 24-h GH concentration were similar in children with Turner's syndrome and the normally growing short children, in contrast to lower levels in the slowly growing short children. The periodicity of GH secretion was similar in all groups. In the longitudinal study, ethinyl estradiol treatment resulted in a significant increase in pulse amplitude, but not in periodicity. In the cross-sectional study there was no significant difference between the subgroups of girls with either presence or absence of breast development or ethinyl estradiol treatment. GH secretion was not significantly related to age, height in standard deviation score or height velocity. These data imply that there is no abnormality in GH secretion in girls with Turner's syndrome.

Comparison of four computerized models to estimate 24-hour growth hormone secretion in girls with Turner's syndrome.

Daily pituitary growth hormone (GH) secretion can be estimated from a 24-hour GH profile by various methods. We have used four methods to assess GH secretion in 36 girls with Turner's syndrome: the method described by Thompson et al., the Pulsar algorithm combined with the method of Hellman et al. and two deconvolution techniques. The number of detected peaks varied considerably among the methods. The mean (+/- SD) total daily secretion per square meter body surface was 0.53 (0.19) U/m2.day by deconvolution, in contrast to 0.31 (0.17) with the Hellman method and 1.06 (0.37) according to Thompson. The differences are explained by different assumptions about the metabolic clearance rate and various methodological aspects. Assuming a degradation rate of 50%, the growth hormone substitution dosage would be 1-2 IU/m2.day in GH-deficient children. The usual dosage in girls with Turner's syndrome is expected to lead to serum GH levels approximately 4 times higher than in the untreated state.

Spontaneous growth hormone secretion increases during puberty in normal girls and boys.

To test the hypothesis that GH secretion increases during puberty, we measured GH levels in samples obtained every 20 min for 24 h from 132 normal children and adolescents. In both girls and boys, GH levels increased during puberty. The increase in mean levels was earlier in girls than boys, was most evident at night, and was due to increased pulse amplitude rather than a change in pulse frequency. The mean nighttime GH level in girls with bone ages (BA) greater than 12 to 14 yr were significantly greater than the mean level in girls with BA less than 8 yr (7.3 +/- 3.0 vs. 3.4 +/- 1.7 micrograms/L; P less than 0.01) and were greatest at breast stage 3 (7.9 +/- 2.5 micrograms/L). GH pulse amplitude increased significantly before pubertal onset in girls and was significantly greater at BA greater than 12 to 14 yr than at BA of 8 yr or less (13.9 +/- 6.0 vs. 7.9 +/- 4.8 micrograms/L; P less than 0.01) and greatest at breast stage 3 (15.0 +/- 6.3 micrograms/L). The pubertal increase in GH secretion was delayed in boys compared to girls, with the lowest mean 24-h GH and mean nighttime GH values in boys with BA greater than 8 to 11 yr. The mean nighttime GH level at BA greater than 11 to 13 yr in boys was significantly greater than that in the boys with BA greater than 8 to 11 yr (5.8 +/- 2.9 vs. 3.5 +/- 2.1 micrograms/L; P less than 0.05) and was greatest at a testicular volume of more than 10 to 15 mL (6.5 +/- 2.0 micrograms/L). The mean nighttime GH pulse amplitude in boys was significantly greater at BA greater than 11 to 13 yr than at BA greater than 8 to 11 yr (13.9 +/- 5.7vs. 7.3 + 2.6 micrograms/L, P less than 0.05) and was greatest at a testicular volume greater than 20 mL (15.8 +/- 12.0 micrograms/L). The mean nighttime GH levels correlated inversely with body mass index in both sexes, although the correlation achieved statistical significance only for the girls, being stronger in breast stage 3 to 5 girls (r = -0.57 P = 0.0007; n = 32) than in stage 1 and 2 girls (r = -0.38; P = 0.03; n = 32). These observations in normal adolescents emphasize the importance of interpreting spontaneous GH levels in short children in relation to normative data appropriate for sex, body mass, and bone age or pubertal stage.

Low growth hormone levels are related to increased body mass index and do not reflect impaired growth in luteinizing hormone-releasing hormone agonist-treated children with precocious puberty.

To test the hypothesis that GH deficiency might explain the low growth velocity of some LHRH agonist (LHRHa)-treated children with central precocious puberty, we measured stimulated (n = 81) and spontaneous (n = 32) GH levels during or after LHRHa treatment. GH stimulation tests in the children who were receiving LHRHa treatment were performed after 2 days of ethinyl estradiol administration. Thirty-one of 81 children (38%) who underwent GH stimulation tests had subnormal responses (less than or equal to 7 micrograms/L) to all tests administered (at least 2 stimuli), including 22 of 67 (33%) who had precocious puberty that was idiopathic or associated with hypothalamic hamartoma. Eleven of 32 children (34%) who underwent measurement of the mean nighttime spontaneous GH level had levels below the normal range for prepubertal children (less than 1.2 microgram/L). Despite the high incidence of subnormal GH levels, there appeared to be no relationship between the GH levels of these children and their growth characteristics. The height, growth velocity, bone maturation rate, predicted height, and insulin-like growth factor-I levels were not different between the children with low GH levels and the children with normal GH levels. Conversely, the GH levels were not different between the children with subnormal growth rates and the children with normal growth rates. Thus, variation in the growth rates of these LHRHa-treated children with central precocious puberty could not be explained by variation in the stimulated or spontaneous secretion of GH. In attempting to understand the high incidence of low GH levels in children with precocious puberty, we examined the relationship between GH level and body mass index (BMI). Both the stimulated (r = -0.33; P less than 0.002) and the spontaneous (r = -0.61; P less than 0.0002) GH levels were inversely related to BMI. Moreover, the children with precocious puberty as a group had significantly elevated BMI [1.2 +/- 0.1 (+/- SE) SD units] compared to normal children of the same age (P less than 0.0001). Thus, increased body mass may explain the high incidence of subnormal GH levels in these patients, and normative GH levels adjusted for body mass are needed before it can be concluded that the apparently subnormal GH levels in LHRHa-treated children with precocious puberty are in fact low.

[Is circumoral cyanosis a sign of peripheral or of central cyanosis?]. / Is 'het maskertje' teken van perifere of van centrale cyanose?

Two hundred Dutch paediatricians were invited to give their description and interpretation of the concept of 'circumoral cyanosis'. Analysis of the results shows great inter-doctor variability: 63% considered the circumoral cyanosis as a pathologic sign and 70% as an expression of central cyanosis, although in textbooks and publications this sign is defined as an expression of peripheral cyanosis and is not considered to be pathological.