Sporadic congenital hyperthyroidism due to a spontaneous germline mutation in the thyrotropin receptor gene.

Neonatal hyperthyroidism in the absence of maternal autoimmune thyroid disease and without thyroid-stimulating antibodies in the child is rare. We here describe a boy with severe intrauterine hyperthyroidism and advanced bone age in the absence of thyroid-stimulating autoantibodies. After long term antithyroid treatment and relapse of hyperthyroidism, a near-total thyroid resection was performed. The necessity to progressively decrease postoperative thyroid hormone replacement indicates thyroid tissue regrowth in the small thyroid remnant. Analysis of the genomic DNA of the child's peripheral leukocytes showed a G to A base exchange that led to a heterozygous Ser to Asn conversion at position 505 in the third transmembrane region of the TSH receptor (TSHR). The absence of the Ser505 Asn mutation in all other family members identifies the child's TSHR mutation as a sporadic germline mutation. Transient expression of the mutated TSH receptor in COS-7 cells showed a constitutively activated cAMP cascade. We thus identified a new constitutively activating germline mutation. Neonates with persistent nonautoimmune hyperthyroidism should be investigated for TSHR germline mutations. Because of frequent relapses, patients with sporadic congenital nonautoimmune hyperthyroidism should be treated with early subtotal to near-total thyroid resection. Moreover, post-operative radioiodine treatment should be considered.

Autosomal dominant nonautoimmune hyperthyroidism. Clinical features-diagnosis-therapy.

Autosomal dominant nonautoimmune hyperthyroidism is a hereditary form of hyperthyroidism caused by constitutively activating germline mutations in the TSH-receptor gene. Clinical features comprise familial prevalence of thyroid autonomy in more than 2 generations and conditions of persisting neonatal hyperthyroidism or nonautoimmune hyperthyroidism of childhood onset with frequent relapses of hyperthyroidism under thyrostatic therapy and after thyroid surgery. Once clinically suspected the diagnosis can be confirmed by mutation analysis of genomic DNA extracted from a routinely obtainable EDTA blood sample. In patients with hereditary nonautoimmune hyperthyroidism a near total thyroidectomy is recommended as the first line treatment to avoid relapses from residual thyroid tissue with the activating TSHR mutation. Furthermore, genetic counselling of the affected patients is advised.

Primary systemic carnitine deficiency under successful therapy: clinical, biochemical, ultrahistochemical and renal clearance studies.

Systemic carnitine deficiency is an often fatal, but treatable metabolic disorder which should be considered in any child with repeated episodes of a Reye-like syndrome or a cardiomyopathy. A 4-year-old girl with a typical history and clinical findings was successfully treated with oral carnitine. Despite low liver carnitine, ketogenesis upon fasting was normal. Normal muscle function under therapy was associated with unchanged low muscle carnitine levels. Improvement of mitochondrial structure and function was demonstrated by controlled ultrahistochemical studies. A renal carnitine leak, evident from renal clearance studies, may contribute to the pathogenesis of systemic carnitine deficiency.

[Healthy nutrition in childhood and adolescence]. / Die gesunde Ernährung im Kindes- und Jugendalter.

Nutrient requirements for youngsters are less known exactly than is commonly assumed. Anyway, it is possible to estimate the food consumption by healthy children on the basis of inquiries, so that present trends and problems can be assessed. Lower energy requirements call for a high relative density of nutrients in the food. The intake of these valuable, fibre-rich basic foods from whole grain however, is insufficient, whereas too much saccharose is consumed via beverages and processed milk products. Lower intake of milk leads to lower intake of calcium (the importance of calcium for reducing the incidence of fractures in advanced age is, like many other factors, still controversial). German children do not drink enough, as shown by high urine osmolalities. From all these trends, an optimised mixed food regimen can be recommended. This is described in detail. Nevertheless, intake of zinc, iodine and folic acid remains difficult. More than half of German children have enlarged thyroid glands, as sonography shows. Not so much contaminated food, but our excessive food habits due to abundance are the cause of food-induced diseases. Better toxicological methods and perspectives for a "healthy" environment and, thereby, food, are mandatory.

[Perioperative substitution therapy in congenital adrenogenital syndrome with salt loss]. / Perioperative Substitutionstherapie bei kindlichem adrenogenitalen Syndrom mit Salzverlust.

Patients with an inborn error of adrenal steroid synthesis suffer from primary adrenocortical insufficiency requiring corticosteroid replacement therapy and appropriate stress coverage. The case report of a two year old infant with congenital adrenal hyperplasia of the salt-losing type demonstrates the consequences of an accidental steroid underdosage. The necessity of increased cortisol replacement therapy in case of anesthetic procedures--even of short duration and without surgical measures--is underlined. The details of adequate perioperative steroid and i.v. fluid therapy in pediatric patients with congenital adrenal hyperplasia of the salt-losing type are discussed.

Asymptomatic primary empty sella in a 14-year-old girl: comparison of computer tomography and nuclear magnetic resonance imaging.

An enlarged, balloon-shaped sella was detected by chance in a completely asymptomatic 14-year-old girl, who presented with tall stature. While all endocrine functions were found to be normal, metrizamide cisternography with computer tomography revealed a flattened pituitary at the bottom of an empty sella. This could be compared later with nuclear magnetic resonance tomography, thus avoiding intrathecal contrast material and radiation exposure for the patient. The new technique depicts the sellar contents very well.

Immunogenicity of a mammalian cell-derived recombinant human growth hormone preparation during long-term treatment.

The development of anti-human growth hormone (anti-hGH) and anti-host-cell protein antibodies to recombinant hGH (rhGH) of mammalian cell origin was determined in 395 children (304 GH deficiency; 91 Turner syndrome) undergoing long-term treatment (up to 54 months) for growth disorders. In all patients, blood samples were obtained prior to and every 2-3 months during treatment, and analyzed at a central laboratory for anti-hGH antibodies by RIA and antibodies to host-cell antigens by ELISA. During the first 24 months of treatment, 9 (3%) of the 304 patients with GH deficiency developed antibodies to rhGH for longer than 3 months. However, persistent antibodies were seen in only 2 patients, both of whom had proven hGH-N gene defects. In the remaining 7 (2%) anti-rhGH-antibody-positive patients, antibody concentrations showed a tendency to increase for 3-12 months, irrespective of the time of onset of measurable concentrations, and declined thereafter. In these patients, binding capacities were between 0.01 and 0.1 mg/l, and binding affinities were between 7 x 10(8) and 8 x 10(9) l/mol. Height velocity was unaffected in these children. None of the 91 patients with Turner syndrome developed persistent anti-hGH antibodies. Further, no child developed antibodies to host-cell antigens during treatment with rhGH of mammalian cell origin.

Pharmacokinetics and short-term metabolic effects of mammalian cell-derived biosynthetic human growth hormone in man.

The pharmacokinetics and acute effects of an authentic recombinant DNA-derived human growth hormone (rhGH) produced by genetically engineered mammalian cells were determined in 12 healthy volunteers following intravenous (i.v.), intramuscular (i.m.) and subcutaneous (s.c.) administration of 4 IU (1.3 mg) hGH/m2 body surface area. Following i.v. administration, apparent elimination half-life of rhGH was 18 min. Following i.m. administration, a mean peak serum concentration of 36.9 ng/ml (range 13-61 ng/ml) occurred at 3 h, and following s.c. administration, more sustained but lower serum concentrations occurred, with mean peak concentrations of 16.4 and 16.3 ng/ml at 4 and 6 h (ranges 9.0-27.5 ng/ml and 6.5-35.5 ng/ml at 4 and 6 h, respectively). The mean area under the curves was lower after s.c. (134 +/- 48 ng.h.ml-1) than after i.m. (194 +/- 48 ng.h.ml-1) injections (p < 0.03). Comparable results were obtained for the same dose of rhGH given subcutaneously in concentrations of either 4 IU/ml or 10 IU/ml. Both i.m. and s.c. administrations caused similar increases in free fatty acids at 4 h and insulin-like growth factor I at 24 h. Insulin, C-peptide and blood glucose were almost unchanged during the first 4 h after administration, whereas leukocytes increased significantly (p < 0.0001). Local and systemic tolerance were good, and no adverse reactions were observed. In a GH-deficient child, hGH serum levels between 10 and 20 ng/ml were demonstrated for a period of 8 h after s.c. administration of 0.07 IU rhGH/kg body weight.

[Recovery of hypothalamic-pituitary-adrenocortical axis after high-dose dexamethasone treatment (author's transl)]. / Untersuchungen zur Erholung der Hypothalamus-Hypophysen-Nebennierenrindenachse nach hochdosierter Dexamethason- Therapie.

High doses of dexamethasone (Fortecortin) for the prophylaxis of cerebral oedema were administered to 19 children aged 3 to 14 years because of head injury of varying degrees of severity. In order to assess possible suppression of the hypothalamic-pituitary-adrenocortical activity an insulin tolerance test and an intravenous tetracosactid (Synacthen) test was performed 1 to 26 weeks after the last dexamethasone dose. There was no evidence from the insulin tolerance test of inadequate cortisol excretion. After intravenous Synacthen injection satisfactory serum cortisol increase was found. However, from this test there was evidence of a lesser increase of serum cortisol depending on the time elapsed since cessation of dexamethasone. Investigation of circadian cortisol values showed 7 cases with subnormal serum cortisol at 18 o'clock independent of the time elapsed. The hypothalamic-pituitary-adrenocortical axis was functioning again during induced stress 7 days after withdrawal of dexamethasone. Subsequent stress situations do not require treatment with corticoids.

[Septo-optic dysplasia with congenital hypopituitarism (author's transl)]. / Septo-optische Dysplasie mit kongenitalem Hypopituitarismus.

The syndrome of septo-optic dysplasia with congenital hypopituitarism consists of optic nerve hypoplasia, midline malformations of the prosencephalon and hypothalamic hypopituitarism. There is great variability of these features and clinical manifestation is age-dependent: Newborns present with hypoglycemic seizures, apnea, cyanosis, hypotonia, prolonged jaundice (and micropenis in boys) because of growth hormone and/or ACTH-deficiencies. Wandering eye movements and more or less visual disturbance become evident during infancy and growth retardation even later in some cases. Early recognition is facilitated by the pathognomonic fundoscopic findings, together with normal electroretinogram, absent visually evoked potentials and computer tomography. Early hormone substitution is essential to prevent hypoglycemic damage.

Familial Cushing's syndrome due to pigmented multinodular adrenocortical dysplasia.

Cushing's syndrome was diagnosed in a 14 year old girl and, 5 years later, in her nephew (sister's son) also when he was 14 years of age. Administration of tetracosactid (Synacthen) did not stimulate adrenocortical function in either patient, nor did dexamethasone suppress the elevated urinary steroids in the girl, and only partially suppressed them in the boy. Both patients were adrenalectomized and made an uneventful recovery. The surgical specimens were identical both on gross inspection and histologically, showing the typ ical morphological features of pigmented multinodular adrenocortical dysplasia. We believe that this lesion represents an inherited adrenocortical maldevelopment (rather than true neoplasia) leading to an autonomous adrenocortical hyperfunction which typically manifests itself clinically during adrenarche (i.e. functional adrenocortical maturation) at the beginning of puberty. Family Cushing's syndrome, caused by pigmented multinodular adrenocortical dysplasia, represents a disease entity.

[Height and weight of 70 prenatally dystrophic children of ages 5 to 11]. / Grösse und Gewicht 70 pränatal dystropher Kinder im Alter von 5-11 Jahren.

Growth-retarded, markedly slim children with poor appetite are often seen by a pediatric endocrine service without any previous information to their parents about known correlations between their condition and poor intrauterine growth. There are follow-up studies covering the first years of life, but only a few concerning growth prognosis in later years. Therefore, full-term, nonasphyxiated small-for-date children were traced by a questionnaire at ages between 5 to 11 years, and growth data were evaluated using standard deviation scores (x-means/s): for the whole group the height deficit was -0.724 +/- 0.965 SD, whereas normal persons show a deviation from normality of 0.000 +/- 1.000 SD (p less than 0.001); it was -0.823 +/- 0.949 SD and -0.495 +/- 0.927 SD for children with birth weights below and above the 3rd percentile for birth weight resp., and -1.285 +/- 1.031 and -1.261 +/- 1.069 SD for children whose length or length and weight were below the 3rd percentile at birth. The weight deficit (0.048 +/- 0.999 SD) of the whole group was statistically but not medically significant. There was no correlation to the parents or the mothers heights. These data correspond well with those from a review of the literature. Together with an accurate bone age determination our data could help to improve the counselling of involved families about growth prognosis of their originally small for date children.

Urinary free T4 and T3 in healthy infants and during noise exposure.

There is concern about noise exposure in the hospital environment and its effects on infants. Stress reactions, however, are difficult to measure, especially in this age group. Urinary T4 and T3 have proved to be equivalent to catecholamine determinations in helicopter pilots and in motion sickness. They represent the free fraction of thyroid hormones in serum. Timed collections of urine were made in 78 healthy infants and in 43 infants exposed to standardized noise. T4 and T3 were determined by RIA on Sephadex columns. Medians and ranges are given for day and night and before, during and after noise exposure.

Aldosterone deficiency II (CMO II deficiency) is not the result of a mutation of an MspI restriction site within the CYP11B gene.

We report our investigations of a German family with aldosterone deficiency (CMO II deficiency). Restriction fragment length polymorphism analysis using a P450c11 probe demonstrates that a MspI restriction site mutation within the CYP11B gene cannot be the underlying cause for this defect, as has been suggested previously.

[Asymptomatic, excessive hypercalcemia n a 12-year-old boy]. / Asymptomatische, exzessive Hypercalcämie bei einem 12jährigen.

A cervical lymph node enlarged since 3 weeks was to be removed in a 12-year-old boy, whose only complaint was slight fatigue. Routine screening revealed hypercalcemia of 7.3-8.1 mval/l. This rose to 9.2 mval/l despite furosemide-induced high fluid turnover and prednisone while diagnostic evaluation proceeded. Serum phosphate was low consistently. Malignancy, vitamin D-intoxication, immobilisation and familial conditions could be ruled out as causes. Highly elevated serum-parathormone levels inspite of hypercalcemia, and ultrasonography of the neck were the most helpful evidence of a parathyroid adenoma. Calcitonin was effective in lowering serum-calcium to 6-7 mval/l preoperatively.

[Iodine excretion and dietary iodine supply in newborn infants in iodine-deficient regions of West Germany]. / Jodausscheidung und alimentäre Jodversorgung bei Neugeborenen in Jodmangelgebieten der Bundesrepublik.

Urinary iodine excretion was measured on the fifth day of life in 461 neonates from nine different towns in the Federal Republic of Germany. There was a progressive fall in levels from north to south, with highest values in Hamburg (2.9 micrograms/dl) and lowest in Freiburg (1.2 micrograms/dl). All levels were lower than those of neonates in other countries in which iodine is added to salt: Stockholm (61 neonates) 9.6 micrograms/dl, Zurich (63) 4.75 micrograms/dl. Iodine analysis of mothers in G ottingen on the fifth day post-partum indicated that iodine excretion in urine of mothers with goitre (51 cases) was significantly lower than in a control group without goitre (38): 17.6 compared with 30.0 micrograms/g creatinine, and the iodine content of breast milk in the goitre group was significantly lower than that of the control group (1.75 compared with 2.5 micrograms/dl). Iodine content in artificial infant milk preparations was of a similar range. These results indicate that iodine supply during the neonatal period in the Federal Republic of Germany is very low; they support the demand for general iodine-salt prophylaxis.

Adult height in boys and girls with untreated short stature and constitutional delay of growth and puberty: accuracy of five different methods of height prediction.

To determine how accurately several methods of height prediction estimate adult height, we compared height predictions calculated by the Bayley-Pinneau, Roche-Wainer-Thissen (RWT), target height, and Tanner-Whitehouse Mark I (TW-MI), and Mark II (TW-MII) methods with final adult height in 37 boys and 32 girls with short stature and constitutional delay of growth and puberty. They were first seen at a chronologic age (mean +/- SD) of 14.80 +/- 1.70 years (boys) and 12.87 +/- 2.56 years (girls). Adult height at 23.14 +/- 1.95 years and 21.05 +/- 2.02 years was 170.4 +/- 5.4 cm (boys) and 157.8 +/- 4.2 cm (girls), respectively, and thus within the lower range of normal. Height predictions were calculated for the total group and for patients with parents of normal (group 1) as well as short stature (group 2). For boys, the RWT method gave very accurate results, underestimating adult height by -0.6 cm for the total group. The prediction errors for the other methods were -7.3 cm (TW-MI), -4.2 cm (TW-MII), and +3.1 cm (Bayley-Pinneau method) or +1.7 cm (target height). For girls, no method was superior in estimating adult height. The mean prediction error was -0.8 cm, -2.1 cm, and -1.8 cm with the Bayley-Pinneau, TW-MI, and TW-MII methods, respectively. In contrast, adult height was overpredicted by +2.3 cm and +1.2 cm with the RWT and target height methods. We conclude that patients with short stature and constitutional delay of growth and puberty reach an adult height in the lower range of normal. Height prediction methods differ with respect to their accuracy and their tendency to overestimate or underestimate adult height.

Adrenal insufficiency, myopathic hypotonia, severe psychomotor retardation, failure to thrive, constipation and bladder ectasia in 2 brothers: adrenomyodystrophy.

Two brothers are described who manifested primary adrenal insufficiency, dystrophic myopathy, severe psychomotor retardation, failure to thrive, fatty degeneration of the liver, megalocornea, chronic constipation, and terminal bladder ectasia until their death at 3 8/12 and 1 7/12 years, respectively. The differential diagnosis to similar syndromes is discussed. This combination of problems apparently has not yet been described. The term adrenomyodystrophy is suggested.

Neurological and adrenal dysfunction in the adrenal insufficiency/alacrima/achalasia (3A) syndrome.

Review of 20 patients with glucocorticoid deficiency (three cases also with salt loss) associated with absent tear secretion (19 cases) and achalasia of the cardia (15 cases) revealed neurological abnormalities in 17 including hyper-reflexia, muscle weakness, dysarthria, and ataxia together with impaired intelligence and abnormal autonomic function, particularly postural hypotension. These findings indicate that significant neurological problems are common in this multisystem disorder.