P Heidemann

Molecular and cytogenetic analysis of an interstitial 20p deletion associated with syndromic intrahepatic ductular hypoplasia (Alagille syndrome).

SummaryHigh-resolution chromosome analysis of a 19-year-old female proband with syndromic intrahepatic ductular hypoplasia (Alagille syndrome, AWS) revealed an interstitial deletion of chromosome 20p with breakpoints provisionally located in or close to p11.22 and p12.2. Southern blots from digests of DNA of the proband and her chromosomally normal parents were hybridized with the human DNA probes pR12.21, HuPrPcDNA2, and pDS6-SgI, which have been mapped to the region 20 (p12-pter), and rehybridized with the F IX probe for calibration. Comparing the hybridization signals of the normally sized DNA fragments of the familiy, we found no evidence for loss of any of the three tested distal chromosome 20p loci in our proband. Furthermore, in situ hybridization with HuPrPcDNA2 revealed a specific accumulation of grains at or around the faint distal G band suspected to represent all or most of band p12.3 of the probands deleted 20p and at p12 of the normal chromosome 20. Thus the AWS of our proband is associated with an interstitial deletion that preserved the three tested distal loci on 20p. Since nine further reported cases of 20p deletion are clinically similar, we propose AWS as a further “contiguous gene syndrome” and assign it to an approximately 8-Mb-large chromosome 20p segment (provisionally, p11.23–p12.1).

A familial progressive neurodegenerative disease with 2-oxoglutaric aciduria

A boy and a girl born to a consanguineous Tunisian couple are suffering from a slowly progressive nervous disorder. Initially they both had normal psychomotor development with acquisition of gait and speech. First symptoms in the boy were athetoid movements during the second year of life. He later lost all motor and language skills and developed muscular rigidity and intention tremor. At the age of five years, he was completely bedridden while he appeared mentally much less affected. His younger sister followed a similar course. The major specific abnormality detected was a strikingly elevated excretion of 2-oxoglutaric acid, which was identified by gas liquid chromatography, mass spectrometry, and enzymatic analysis. 2-oxoglutarate dehydrogenase activity in homogenates of cultured skin fibroblasts was reduced to about 25% of control values in both children. Although the pathogenetic mechanisms leading to brain damage remain obscure, the finding strongly suggest an autosomal recessive neurometabolic disease with predominant involvement of the extrapyramidal system.

Incidence of iodine contamination in neonatal transient hyperthyrotropinemia

Transient hyperthyrotropinemia and/or hypothyroidism have been found in many newborn infants during thyroid screening programs. In Europe the most likely causes are iodine deficiency and iodine overload. Because of the high incidence of transient hyperthyrotropinemia in Berlin we measured iodine concentrations in casual urine samples of newborns with TSH elevations. Urine and blood samples were collected on the 5th day of life. In the prospective study 99 out of 9320 newborns (1.06%) displayed TSH concentrations ranging from 20 to 152 μU/ml. All infants had normal TSH levels during a control examination. The urinary iodine concentrations were significantly elevated in 76 out of the 99 newborns. Most of the patients were born in obstetric departments where iodine-containing antiseptic agents were routinely used for disinfection during labor. The use of iodine-containing antiseptic agents not only results in unnecessary control determinations for the thyroid screening program but also causes an undesirable metabolic situtation that may be a potential hazard for the development of the central nervous system.

Effect of different oestrogen doses on final height reduction in girls with constitutional tall stature

The effects of different doses of oestrogens in constitutionally tall girls were evaluated in two centres for paediatric endocrinology. In one centre, 38 girls were treated with a high oestrogen dose of 0.3 to 0.5 mg ethinyloestradiol (EE) daily. In the other, 44 girls received a comparably low dose of 0.1 mg EE per day. Height prediction (HP), chronological age (CA), and height at the onset of treatment were comparable in both groups. Although the duration of treatment was significantly longer in those receiving the low dose, the cumulative oestrogen dose was still significantly lower. The dose of EE had no effect on final height reduction (high dose group: 4.9±2.6 cm, low dose group: 5.1±2.4 cm). Final height was more reduced in both groups when treatment was started at an early bone age (BA) (≤13 years). No serious side effects were observed in either group, however weight gain was more pronounced in girls receiving the higher dose. We conclude that treatment of constitutionally tall girls with low doses of oestrogens is equally effective in reducing the final height as the usually administered high doses. The lowest effective dose has to be determined in a randomized, prospective clinical trial.

Hypergonadotropic hypogonadism, SHBG deficiency and hyperprolactinaemia: a transient phenomenon during induction chemotherapy in leukemic children.

Five pubertal boys (puberty stage Iv–V) and four prepubertal girls with acute lymphoblastic leukemia were treated with a combination of prednisone, vincristine, daunorubicin and l-asparaginase for remission induction. The hypothalamopituitary-gonadal axis was investigated by measuring basal plasma levels of LH, FSH, and PRL in both groups as well as the response to LHRH/TRH stimulation in pubertal boys before, on day 10, 21, and 28 during induction therapy and 23 days after the induction phase (day 51). Furthermore, the binding capacity of sex-hormone-binding globulin (SHBG), plasma levels of testosterone (T) and estradiol (E2) were monitored as well as the testicular volumes of the boys.Within three weeks of induction chemotherapy, plasma T, E2 and the binding capacity of SHBG decreased in both groups, together with a reduction of testicular volumes in the boys. Concommitantly, basal LH, FSH, and PRL values doubled with a normal gonadotrophin response to LHRH. The PRL response to TRH increased at the end of the induction phase, when chemotherapy with vincristine, daunorubicin and l-asparaginase was terminated, but prednisone treatment was continued for 7 another days.During the subsequent prophylactic irradiation of the central nervous system combined with other antileukemic drugs, all hormonal values including testicular volumes in pubertal boys became normal within a period of 3 weeks. Our data clearly demonstrate that an induction chemotherapy regimen such as that employed by the Berlin protocol leads to a transient castrating effect at the gonadal level and to a transient failure of synthesis of SHBG at the hepatic level. Increased prolactin values as well as an increased response to TRH may be related to a decrease in T indicating the existence of a negative feed-back-loop mechanism between T and PRL.

Transient secondary hypothyroidism and thyroxine binding globulin deficiency in leukemic children during polychemotherapy: An effect of L-asparaginase

Recently it has been observed that L-asparaginase causes transient thyroxine binding globulin (TBG) deficiency in adults. In the present study we investigated the influence of L-asparaginase on the pituitary-thyroid axis and on the synthesis of TBG. 14 children with acute lymphoblastic leukemia were treated with a combination of L-asparaginase, vincristine, prednisone and daunomycin for remission induction. Thyroid function was monitored by measuring total T4, free T4, total T3, TSH and TBG with specific radioimmunoassays before, during and after treatment. Within 3 weeks of L-asparaginase therapy total T4 fell significantly from 10.7±1.6 to 2.9±1.8 μg/100 ml, free T4 from 1.77±0.4 to 0.94±0.35 ng/100 ml, total T3 from 0.99±0.23 to 0.35±0.2 ng/ml and TBG from 29.4±3.6 to 8.0±3.8 μg/ml. Basal TSH values tinuation of L-asparaginase, but following further treatment with other antileukemic agents, all values became normal within 2–4 weeks. In 6 patients with hypothyroid free T4 values TRH induced TSH release was totally blocked during L-asparaginase therapy. Our data clearly demonstrated that L-asparaginase caused a transient TBG deficiency. Total T4 and T3 were in the hypothyroid range because of low TBG concentrations. In addition to TBG deficiency transient, secondary hypothyroidism occurred in approximately 40–50% of all patients treated with L-asparaginase. These alterations were most likely caused by drug induced inhibition of protein synthesis. Under certain circumstances thyroid hormone replacement might be life-saving in severely ill patients suffering from transient, drug induced hypothyroidism.

Iodine-induced hypothyroidism and goiter following lipiodolTM lymphography

Hypothyroid goiter is a rare but well recognized complication following long term administration of iodine containing expectorants and disinfectants in children. Only few reports exist on iodine-induced hypothyroidism after a single injection of the iodized radiopaque dye Lipiodol. A 15-year-old boy with previously normal thyroid function is described who developed hypothyroid goiter within six weeks following bipedal lymphography. Urinary iodine excretion was extremely elevated up to 18 mg/day while serum concentrations of total thyroxine were below the euthyroid range and thyrotropin levels were elevated. After oral L-thyroxine treatment the goiter disappeared. Thyroid function remained normal when treatment was discontinued after five months although iodine excretion was still 50 times higher (2.5 mg/day) than in normal age matched children. The observed alterations of the thyroid gland were caused by a long lasting Wolff-Chaikoff effect with a delayed adaptation to high iodide concentrations.

Oxandrolone treatment for growth promotion in Turner's syndrome

Progressive growth failure in patients with the pure form or mosaicism of Turners syndrome causes short stature. Oxandrolone (Ox) has been reported as being effective in producing acceleration in height in these patients. 25 patients 10 to 17 years old were treated orally with Ox in a dosage of 0.1 mg/kg/day for 1 to 3.5 years. Growth velocity per year (mean ± SD) for all patients was 2.8 ± 1.0 cm before treatment and 5.3 ± 2.1, 3.9 ± 1.9 and 2.8 ± 1.8 cm after 1,2 and 3 years of therapy, respectively. Patients younger than 14 years exhibited the best response. Bone age remained retarded during treatment. Using the method of Bayley and Pinneau for height prediction we found that the estimated height increased from 143.2 ± 5.4 to 145.8 ± 5.9 cm for all patients after 1 year of treatment. A 3 year follow-up of 8 patients showed an increase of predicted height from 140.6 ± 5.1 cm to 146.1 ± 4.6 cm. Our data indicate that Ox has a beneficial effect (p < 0.001) on growth velocity for the first year of therapy and may cause a moderate gain in final adult height.

REDUCTION OF FINAL HEIGHT IN TALL GIRLS FOLLOWING ESTROGEN ADMINISTRATION IS NOT DOSE DEPENDANT

Effects of Ethinylestradiol (EE) in girls with tall stature were assessed in a collaborative study of two centers comparing 38 girls (I), receiving 0.3 - 0.5 mg EE daily, with 44 girls on 0.1 mg EE daily (II). To minimize errors of height prediction (HP) bone ages (BA) were determined according to GREULICH and PYLE by using the mean of four determinations of both centers. Final height (FH) was predict according to the tables of BAYLEY and PINNEAU and was measured at a chronological age (CA) of 19.8 ± 1.2 years (y). Prior to EE administration the following findings did not differ (I vs II): CA (12.5 vs 12.4 y), BA (12.4 vs 12.4 y), length (+3,2 vs + 3.2 SDS) and HP (+3.8 vs +3.8 SDS). Evaluation of the differences between SDS of HP and SDS of FH showed no difference with respect to dose, however, an increased BA at the onset was correlated with a smaller reduction (Table I).Cumulative dose (218±86 vs 64±20 mg), BA at the end (15±0.5 vs 15.9±0.5y) and growth after discontinuation of EE (2.7±1.8 vs 1.8±1.2 cm) did differ.Conclusion: 0.1 mg EE is as effective as 0.3 mg EE daily.

197 GROWTH HORMONE SECRETION IN CONSTITUTIONAL DELAY OF 197 GROWTH AND DEVELOPMENT (CD)

Recently growth hormone (GH) treatment of patients with CD has been advocated because of insufficient GH secretion during sleep. We intended to prove these findings by comparing GH secretion during spontaneous sleep between 8 p.m. and 2 a.m. every 30 min and EEG controlled sleep during the first slow wave sleep (SWS) at night every 10 min.Patients: Sleep studies were performed in 13 boys with CD aged 11 to 16.8 years and heights below 2 SD for age. Bone age retardation was 1.5 to 5 years, pubertal development Tanner 1 to 2. Five healthy controlls with comparable age and pubertal development served as controlls. Informed consent was obtained from all parents.Results: 13 patients with CD secreted 2025 ng × min × ml−1 GH (696 - 4175) during spontaneous sleep and 9 pts 550 ng × min × ml−1 GH (351 - 2215) during SWS. Four controlls showed 1715 (618 - 2480) during spontaneous sleep and 5 controlls 693 (435 - 868) during SWS respectively. All values are given as median and range in brackets. Median of GH peak was 20.5 and 20.9 during SWS and 28.1 and 20.5 ng/ml during spontaneous sleep in patients and controlls respectively.Conclusion: Since there was no evidence of insufficient GH secretion during sleep in patients with CD, GH treatment of these patients cannot be based on insufficient GH secretion during sleep in these children.