Congenital hypothyroidism in a child with unsuspected familial dysalbuminemic hyperthyroxinemia caused by a mutation (R218H) in the human albumin gene.

We found familial dysalbuminemic hyperthyroxinemia (FDH) in a 5-month-old boy with congenital hypothyroidism (CH) who had a blood thyrotropin (TSH) level of 479 mU/L but normal total serum thyroxine (T4) and higher than normal total triiodothyronine (T3) levels. Thyroid hormone substitution began at 5 weeks of age when T4 and T3 concentrations were below normal. Until the age of 5 months, treatment with levothyroxine was suboptimal on the basis of high serum TSH levels despite above-normal T4 levels. FDH was confirmed by isoelectric focusing and testing of other family members. DNA analysis of the patient revealed R218H, a mutation in the serum albumin gene associated with FDH, which was also present in the patient's euthyroid father and brother. Thyroid scans, serum thyroglobulin measurements, and free T4 measurements using equilibrium dialysis or 2-step immunoassay methods can identify thyroid hormone-binding protein defects and simplify the diagnosis and treatment of infants with CH.

Simultaneous stimulation of growth hormone, adrenocorticotropin and cortisol with L-dopa/L-carbidopa and propranolol in children of short stature.

In 59 otherwise healthy children of short stature, the simultaneous response of growth hormone, cortisol and plasma adrenocorticotropin (ACTH) to L-dopa/L-carbidopa and propranolol at 45 and 90 min after administration were investigated. A growth hormone response of 10 microg/l or higher was considered positive. The definition of a positive cortisol response included either a hormone increase of at least 193 nmol/l or a peak hormone level of at least 497 nmol/l. The ACTH increase had to be fourfold above 11 pmol/l to be considered positive. In the 59 investigated children, the median basal growth hormone levels increased from 1.35 microg/l to 18.05 microg/l and 10.15 microg/l at 45 and 90 min after stimulation (p < 0.05). The median cortisol levels rose from 242 nmol/l to 439 nmol/l and 612 pmol/l, and the corresponding median ACTH levels from 2.94 pmol/l to 9.63 pmol/l and 11.13 pmol/l at 45 and 90 min after stimulation. Significant positive hormone response rates were 88.1% for growth hormone, 88.1% for cortisol and 69% for ACTH. These results could be attributed to the enhanced stimulating effect of the additional administration of L-carbidopa and propranolol. We conclude that the administration of L-dopa/L-carbidopa and propranolol is useful for the simultaneous evaluation of growth hormone, cortisol and ACTH secretion in children of short stature.

Resistance to thyroid hormone caused by a new mutation (V336M) in the thyroid hormone receptor beta gene.

Resistance to thyroid hormone (RTH), usually caused by an inherited defect of the thyroid hormone receptor, (TRbeta), results in a reduced responsiveness of target tissues to thyroid hormone. Until now, more than 600 cases with RTH have been identified. Although usually linked to the TRbeta gene, located on chromosome 3, RTH may also occur in the absence of mutations in the coding region of this gene. We report a 10-month-old boy who had laboratory findings typical of RTH. He was born prematurely on the 34th week of gestation and his thyrotropin (TSH) during neonatal screening was 121 microU/mL, a value very high for RTH or prematurity. Direct sequencing of the TRbeta gene from the patient's genomic DNA revealed a heterozygous substitution of the normal valine with a mutant methionine in codon 336 (V336M) that has not been previously reported. In vitro expression studies showed that this mutant TRbeta has an impaired triiodothyronine (T3)-dependent transactivation that reduces the activity of the wild-type TRbeta (dominant negative effect). While the functional impairment of V336M is not unusual compared to other TRbeta gene mutations, the very high TSH value in this prematurely born infant suggests that fetuses with RTH have altered maturation of the hypothalamo-pituitary-thyroid axis or actually may suffer from hypothyroidism.

New point mutation (R243W) in the hormone binding domain of the c-erbA beta 1 gene in a family with generalized resistance to thyroid hormone.

Two years after the first mutation on exon 7 in the carboxy-terminal part of the hinge domain (D) was reported (Behr and Loos 1992), we have identified the second mutation on exon 7 in patients with GRTH. Interestingly, our mutation it is not located in the two previously described "hot spot regions", but instead very close to the hinge domain (D) of the receptor protein that is essential for the function of the hormone binding domain (E) (Lin et al., 1991). Confirming the observation that the majority of single base substitutions causing human genetic diseases or DNA polymorphisms follow the hot spot mutation rule of CG to TG and CG to CA transition (Barker et al., 1984), an additional CpG dinucleotide transition has been identified.

Effect of oestrogen/gestagen replacement therapy on liver enzymes in patients with Ullrich-Turner syndrome.

The absence of breast development and the prevention of osteoporosis in Ullrich-Turner syndrome (UTS) require oestrogen/gestagen substitution therapy. In 8 out of 35 (23%) patients with UTS treated with conjugated equine oestrogens and cyclically with norethisterone acetate, the serum liver enzymes increased to conspicuous levels (AST 35; 20-73 U/l, ALT 92; 37-141 U/l, GGT 77; 25-227 U/l, [median; min-max]). These findings were compared with those in 41 tall girls who received a six-fold larger dose of conjugated equine oestrogens for the reduction of final height. None of these 41 girls showed abnormal serum liver enzyme levels. The conspicuous rise in serum liver enzyme levels occurred in the majority of the UTS patients before norethistherone acetate was added to the oestrogen replacement therapy. No essential morphological equivalent was found in liver sonography and biopsy studies. During the follow up the elevated serum liver enzyme levels showed reversibility when medication was temporarily discontinued and either a slow decrease or a steady state after therapy was continued. CONCLUSION. Patients with UTS on oral oestrogen replacement therapy are more susceptible to develop increased serum liver enzyme levels as compared with eukaryotic females treated with the same oestrogen preparation for other disorders. As the underlying pathomechanism is unknown and adverse long-term effects cannot be ruled out, avoiding the portal vein and using the transdermal application of oestrogen may represent a viable solution to the problem.

[Long-term follow-up of a boy with recurrent hypoglycemia and cholestasis in congenital growth hormone deficiency]. / Langzeitbeobachtung eines Knaben mit rezidivierenden Hypoglykämien und Cholestase bei angeborenem Wachstumshormonmangel.

We report on a four-year-old boy with congenital growth hormone deficiency who first presented at age 13 weeks with jaundice and recurrent hypoglycemia. Growth hormone deficiency was diagnosed two years later, after cholestasis and hypoglycemia had almost completely disappeared, but length deficiency became apparent. The reason for the association of cholestasis with growth hormone deficiency remains unexplained. Cholestasis can, especially in combination with hypoglycemia, be a first sign of congenital growth hormone deficiency.

Phenotypic variability in patients with generalised resistance to thyroid hormone.

Genetic linkage of generalised resistance to thyroid hormone (GRTH) to the human thyroid receptor beta 1 gene has been identified. To date 38 different mutations in several kindreds have been documented. We report on a family with GRTH displaying an adenine for guanine substitution at nucleotide 1234 resulting in a threonine for alanine substitution at codon 317 of exon 9. This mutation has been described for different phenotypes, suggesting that the heterogeneity in GRTH may be the result of multiple genetic factors.

[The differentiation between premature thelarche and pubertas praecox on the basis of clinical, hormonal and radiological findings]. / Differenzierung zwischen prämaturer Thelarche und Pubertas praecox anhand klinischer, hormoneller und radiologischer Befunde.

In a retrospective study of 39 girls (aged 10 months to 7 10/12 years) with premature breast development criteria for distinguishing between premature thelarche and precocious puberty were analysed. Serum estradiol levels and bone age were determined and a test with luteinizing hormone-releasing hormone (LHRH) performed (inclusion criteria). On the basis of the LHRH test and bone age, premature thelarche was diagnosed in 29 patients and precocious puberty in ten: while those with premature thelarche had a follicle-stimulating hormone (FSH) pattern of rise, in those with precocious puberty the rise in gonadotropin was of the LH type. The LH/FSH ratio 30 min after stimulation was < 1 (median 0.15 [0.03-0.34] in patients with premature thelarche, but > 1 (median 2.1 [1.34-5.67] in those with precocious puberty. Bone age was accelerated by at least 18 months in those with precocious puberty, but it corresponded to their chronological age or was only slightly accelerated in those with premature thelarche. These data thus indicate that premature thelarche and central precocious puberty can be reliably distinguished by the LHRH test and bone age.

Serial measurements of transient evoked otoacoustic emissions (TEOAEs) in healthy newborns and in newborns with perinatal infection.

Detection of hearing impairment in early childhood is difficult. We serially recorded transient evoked otoacoustic emissions (TEOAEs) to search for signs of ototoxicity in term, healthy newborns and compared the results to a second group of term babies treated for perinatally acquired bacterial infection with ampicillin plus either cefotaxime or plus aminoglycoside. At initial evaluation, in the group of 45 healthy children born at term, well reproducible emissions were observed in all but two children. In each of these two, initially well reproducible TEOAEs were detected in one ear only. At the time of the second recording (mean at day 8.5) excellent emissions were seen in all ears of all children. Similarly, in the second group receiving ampicillin plus either cefotaxime or plus aminoglycoside, the height of emissions as well as TEOAE-reproducibility was equal or even increased at the time of the second evaluation in all 17 patients. In the following group of 59 patients, all receiving ampicillin plus aminoglycoside, again TEOAEs were equal or improved at the time of follow-up examinations. In all patients, a reduced general condition tended to be associated with less reproducible TEOAEs. We conclude that at conventional doses in low-risk infants, aminoglycosides are unlikely to cause ototoxicity and that in early childhood serial TEOAE-recording may be useful for evaluation of inner ear function.

Familial insulin resistant diabetes associated with acanthosis nigricans, polycystic ovaries, hypogonadism, pigmentary retinopathy, labyrinthine deafness, and mental retardation.

Two sibs, whose parents are first cousins, had diabetes mellitus with hyperinsulinism, insensitive insulin receptors, and acanthosis nigricans. Both patients had pigmentary retinopathy, secondary cataracts, labyrinthine deafness, mental retardation, and cerebral atrophy. They were disproportionately short with relatively broad hands and feet and slightly coarse face. The young woman had secondary amenorrhea and polycystic ovaries and the boy gynecomastia and hypergonadotrophic hypogonadism. This appears to be the second family with a new autosomal recessive disorder differing from Alström syndrome by the presence of mental retardation and absence of renal insufficiency. Impaired insulin receptor binding and polycystic ovaries are described as part of this syndrome.

[Mediastinal teratocarcinoma and hypophyseal stalk germinoma in a patient with Klinefelter syndrome]. / Mediastinales Terato-Carzinom und Hypophysenstielgerminom bei einem Patienten mit Klinefelter Syndrom.

A 8 1/2 year old boy is reported, who was admitted because of rapid growth and premature development of pubic hair. Pseudopubertas praecox was diagnosed, caused by a beta-HCG producing mediastinal teratocarcinoma. The patient also had a pituitary germinoma. His karyotype was 47, XXY. While the association of Klinefelter's syndrome and breast cancer is well known, only recently an increased incidence of mediastinal germ cell tumors in this syndrome has been established, which again is demonstrated in this case report.

[Treatment of marked gynecomastia in puberty with tamoxifen]. / Behandlung der ausgeprägten Pubertätsgynäkomastie mit Tamoxifen.

Based on the good results of another author 10 boys with marked pubertal gynecomastia were treated with the antioestrogen Tamoxifen (Nolvadex) at a dose of 20-40 mg/d orally for 2-12 months. In most cases the gynecomastia decreased totally, only two patients experienced palpable subareolar glandular tissue at the end of therapy. Side effects were not noted. During therapy levels of estradiol and testosteron increased, with a more pronounced elevation of estradiol. Basal values of LH and FSH remained nearly unchanged, but LH showed an increased response to LH-RH, which could be explained by the antioestrogenic effect of Tamoxifen at the hypothalamic level. The reduction of breast size in spite of increased estradiol levels on the other hand, suggests that the mean therapeutic effect of tamoxifen is through estrogen receptor blockade of breast tissue.

[Diagnosis of growth hormone deficiency with the growth hormone releasing factor GRF 1-40. The potentials and limits]. / Diagnostik des Wachstumshormonmangels mit dem Wachstumshormon-Releasing-Faktor GRF 1-40. Möglichkeiten und Grenzen.

Eleven patients with constitutionally delayed development, seven patients with idiopathic growth hormone deficiency and ten patients with craniopharyngeoma received growth hormone releasing factor GRF 1-40 in a dose of 1 micrograms/kg body weight as a bolus injection. In the patients with constitutionally delayed development, a mean maximum HGH value of 86.7 microU/ml was measured 30 minutes after GRF injection. Considerably higher HGH stimulation values were thus obtained after GRF than with conventional stimulation methods. In the patients with idiopathic growth hormone deficiency or craniopharyngeoma, there was mostly only a slight rise of the growth hormone level with a delayed onset. Merely two patients with craniopharyngeoma could be adequately stimulated in accordance with conventional criteria (HGH greater than 12 microU/ml), although their values also remained markedly below those of the patients with constitutionally delayed development. Both patients had somatomedin C values which were below that normal for their age; together with the delayed rise in HGH after GRF, this allowed diagnosis of growth hormone deficiency.

Radioimmunological determination of somatomedin B in healthy children and in children with growth disturbances.

Serum somatomedin B levels were determined by radioimmunoassay in 209 healthy boys and girls from one month to 16 years of age. Low values were found up to the second year life. In the first year the mean level was 13.8 mg/l in girls and 11.5 mg/l in boys. In older children the values increased to levels between 13 and 22 mg/l in boys and between 13 and 18.5 mg/l in girls. They were independent of the stage of pubertal development. Somatomedin B levels were normal in 71 children with constitutional growth delay, primordial dwarfism, familial dwarfism and other forms of growth disturbance. The mean levels were between 12.1 and 14.4 mg/l. Values below 6 mg/l were present only in children with hGH deficiency. In these patients we could find an increase of the mean level from 4.3 mg/l without therapy to 9.4 mg/l under treatment. Thus the determination of somatomedin B seems to be useful for the diagnosis of hGH deficiency.

[Improvement in the longitudinal growth in Ullrich-Turner syndrome with oxandrolone. Function of urinary excretion of steroid hormones]. / Verbesserung des Längenwachstums bei Ullrich-Turner-Syndrom durch Oxandrolon. Abhängigkeit von der Steroidhormonausscheidung im Urin.

Urinary excretion of steroid hormone metabolites pregnandiol, pregnantriol, aetiocholanolone, dehydroepiandrosterone and androsterone of 20 patients with Turner's syndrome was measured by gas chromatography. In some of the patients urinary excretion did not reach the minimal value obtained in a control group. Sixteen of these patients were given an average daily dose of 0.1 mg oxandrolone/kg body-weight. Mean value for bone age, after an average treatment duration of 17.3 months (s = 9.7), increased by 12.6 months (s = 12.7). Growth rate was 5.9 cm (s = 1.9) per year. Androsterone and dehydroepiandrosterone excretion in patients in whom the chronological age/bone age ratio had worsened, was more than double that in patients in whom it had improved. Measurement of the urinary excretion of dehydroepiandrosterone and androsterone thus seems to be of prognostic value in the treatment of Turner's syndrome with androgens.

[Diagnosis of pancreatic insufficiency with fluorescein dilaurate in patients with cystic fibrosis (author's transl)]. / Diagnose der exokrinen Pankreasinsuffizienz mit Fluorescein-Dilaurat bei Patienten mit cystischer Fibrose.

The tubeless pancreas-function test with fluorescein dilaurate, which is based on the saponification of the test substance by pancreas-specific arylesterases, and which has proved itself in adults, was given to children for the first time. After reduction of the size of the test dose and the amount of liquid to be drunk, there were no difficulties in carrying out the test. Elimination of the fluorescein released from the flourescein dilaurate and excreted via the kidneys was clearly less in patients with cystic fibrosis than in normal subjects. Thus, the test in its modified form for children can provide adequate differentiation between normal and pathological pancreas function.