Short stature and decreased insulin-like growth factor I (IGF-I)/growth hormone (GH)-ratio in an adult GH-deficient patient pointing to additional partial GH insensitivity due to a R179C mutation of the growth hormone receptor.

OBJECTIVE: Genetic factors play an expanding role in understanding growth hormone (GH) disorders, therefore the German KIMS Pharmacogenetics Study was initiated with the aim of genotyping various GH-/IGF-I-axis-related genes of GH-deficient adult patients to investigate genotype:phenotype relationships and response to GH therapy. PATIENTS AND METHODS: 129 consecutively enrolled GH-deficient adult patients were genotyped for variant 1 (V1) of the alternatively spliced noncoding exons in the 5'-untranslated region and for the nine coding exons of the GH receptor (GHR) gene, which obviously play a striking role in the function of the GH-IGF-I-axis. After detection of a heterozygous, non-synonymous mutation R179C in exon 6 in one single patient with acquired GH-deficiency (GHD) in late adulthood, analysis of her clinical data followed, leading to the diagnosis of mild short stature (-1.5SD). For further endocrine evaluation, five pituitary stimulation tests (arginine) of this patient were statistically compared to stimulation tests (arginine) of ten GH-deficient control patients, retrospectively. RESULTS: The formerly in patients with Laron syndrome and idiopathic short stature reported mutation R179C leads to an amino acid change from an arginine residue (codon CGC) to a cysteine residue (codon TGC) in position 179 of the extracellular domain of the GHR. Statistical analysis revealed significant decreased IGF-I/GH(0) ratio (p=0.004) and IGF-I/GH(max) ratio (p=0.001) of the index patient compared to the control patients, implying growth hormone resistance of the index patient at the level of the GHR, according to the detected R179C mutation. CONCLUSIONS: This study reports on the unusual case of a patient with mild short stature, who acquired GHD in late adulthood due to a non-secreting pituitary adenoma and get additionally diagnosed for pre-existing growth hormone insensitivity due to a formerly in two short statured patients described, single, heterozygous, non-synonymous mutation in the GHR. Our findings support the theory that heterozygous mutations in the GHR gene can have mild phenotypical consequences.

[Diagnosis, therapy and screening of multiple endocrine neoplasia type I (MEN I) in four endocrinologic centers]. / Diagnostik, Therapie und Screening bei multipler endokriner Neoplasie Typ I (MEN I) in vier endokrinologischen Zentren.

BACKGROUND: Multiple endocrine neoplasia type I (MEN I) is a hereditary disease characterised by involvement of several endocrine organs (parathyroid, anterior pituitary, pancreatic islet cells and other). In order to build up a German MEN I-register a questionnaire was developed. PATIENTS: In four centres we diagnosed 29 cases of MEN I (average age 53 years, range 27 to 72 years, 21 women, eight men). RESULTS: In 25 patients (86%) we found a primary hyperparathyroidism, in 15 patients (52%) an adenoma of the anterior pituitary (seven patients with growth hormone-secreting adenomas, five patients with prolactinomas, two patients with hormone-inactive and one patient with an ACTH-secreting adenoma), in ten patients (34%) a neoplasm of the pancreatic islet cells (six patients with gastrinomas, four patients with insulinomas and two patients with multihormone tumors) and in ten patients (34%) other endocrine tumors (five carcinoid tumors, three adenomas of the adrenal cortex, one papillary thyroid carcinoma and one thymic tumor). In nine cases nephrolithiasis was the leading symptom of primary hyperparathyroidism. All female patients with prolactinomas developed secondary amenorrhea. In three cases gastrinomas caused duodenal ulcers and three insulinomas were detected by fasting hypoglycemia. A primary hyperparathyroidism was most frequently combined with an adenoma of the anterior pituitary (21%). Detailed screening of 13 families early revealed MEN I in eleven cases. CONCLUSIONS: The manifestation of an endocrine disease in MEN I should initiate further diagnostics. Having established the diagnosis of MEN I, a meticulous work-up of all family members is warranted. The set-up of a register by the successfully tested questionnaire will support these activities and facilitate further research of new genetic markers, follow-up and treatment.

[Reduced incidence of side-effects of growth hormone substitution in 404 patients with hypophyseal insufficiency. Results of a multicenter indications study]. / Verminderte Inzidenz von Nebenwirkungen einer Wachstumshormonsubstitution bei 404 Patienten mit Hypophyseninsuffizienz. Ergebnisse einer Multicenteranwendungsbeobachtung. Deutsche KIMS-Studiengruppe.

BACKGROUND: Substitution of pituitary insufficient patients with recombinant human growth hormone (rhGH) in addition to the conventional substitution with glucocorticoids, L-thyroxine and sex hormones has been approved by the regulatory authorities in 1995 with the imposition to conduct surveillance studies to monitor drug safety. RESULTS: 24% of all patients were within their 2nd treatment year, 15% within their 4th year, maximum treatment period was 6 years. There were 2 peaks within the patients age distribution: 30 to 39 years (24%) and 50 to 59 years (24%). The causes for pituitary disease were as follows: pituitary adenomas (47%), idiopathic (16%), craniopharyngeomas (16%) and others (21%). Mean GH dose was 1.5 IU/d s.c. (range 0.4 to 4 IU/d). Serum-IGF-1 increased by 159 and 192% in females and males. Waist circumference decreased by 2% and serum cholesterol was lowered by 5.5% in males. There were 2 cases with new carcinomas, 1 diabetes mellitus II and 1 death. Adverse events (AEs) within KIMS were compared to those of the treatment (GH) and placebo (PI) groups of the previous admission trials (in percent): edema: KIMS 10, GH 37, Pl 3; arthralgia: KIMS 8, GH 19, Pl 2; muscle pain: KIMS 3, GH 16, Pl 3; dizziness: KIMS 2, GH 1, Pl 3; headache: KIMS 2, GH 3, Pl 2; others: KIMS 2, GH 22, Pl 13. The reported incidence of AEs in KIMS was lower than in previous clinical trials. There might be 3 reasons for this: 1. under-reporting, particularly those AEs not likely to be related to GH treatment; 2. doses used in trials were 2-fold higher than in KIMS; 3. dose titration for individual patients. CONCLUSION: Surveillance programs are important for monitoring of drug long-term efficacy and safety.

Spontaneous growth in Turner's syndrome.

The natural course of growth in Turner's syndrome is demonstrated on the basis of growth data from untreated patients. The mean adult height was found to be 145.5 cm (range 136-166 cm), the growth curve was similar to that in comparable studies. A decreased growth potency of skeletal (and other) cell populations seems to be the causal defect, beginning with intrauterine growth retardation. Special other causes like metabolic or endocrine changes could be excluded.

Experience in management of diminished growth in adolescent Turner's syndrome patients.

The aim in the management of patients with Turner's syndrome, besides substitution of sexual steroids, is the attempt to improve their final height. The data allow therapeutic recommendations, which, however, realize only the first intention. The final height, indeed, cannot be improved by traditional methods. Further two alternatives remain to be tested: long time low dose estrogen therapy, and high dosed HGH application.

[Ullrich-Turner syndrome in adolescence and adulthood. Endocrinologic studies]. / Das Ullrich-Turner-Syndrom in Adoleszenz und Erwachsenenalter. Endokrinologische Untersuchungen.

The systematic hormone analyses in patients with Turner's syndrome which up to now were not performed in the size demonstrated do not show beyond the gonadotropic regulating circle any clues to practice relevant disturbances of the hypothalamo-pituitary centres of the classical endocrine regulating circles and in the secretion of steroids. However, an importance is ascribed to the occasional pathological androgen levels, in the individual case therapeutic consequences may be the result (substitution of the deficiency is ascertained, extirpation of the gonads in a tumour with hypersecretion of androgen). The functional investigations of the gonadal regulating circle are of outstanding importance. The diagnostic, therapeutic and prognostic assessment concerning a possible endocrine ovarial residual activity is without doubt possible on the basis of the gonadotropin values.

[Retardation of puberty and growth]. / Retardierung von Pubertät und Wachstum.

The disturbed puberty is most frequently manifested by a retardation of sexual maturation and growth. For a correct classification of a developmental disturbance the knowledge of the endocrine processes, of the stages of puberty, tables of height and methods of the assessment of the skeletal maturity is necessary, the use of which for the population of the GDR is discussed. The large differential diagnosis of the delayed puberty and of the short stature must be above all concentrated to the causal-therapeutically influencible endocrinopathies, even though the proportion of the constitutional delayed puberty as an extreme variant of the norm with a good spontaneous prognosis prevails. In order to prevent serious psychosocial conflicts, after transgression of a critical age limit of about 16 years in sexual immaturity an adequate hormone treatment should be introduced even then, when the etiopathogenesis of the disturbance could not be completely clarified.

Methimazole and agranulocytosis--clinical study.

The paper deals with agranulocytosis as one of the side effects of methimazole. The analysis of 7 cases allows some conclusions in respect to prevention, early detection and treatment of this rare but serious complication.

[HLA typing in Ullrich-Turner syndrome]. / HLA-Typisierung beim Ullrich-Turner-Syndrom.

33 female patients with established anomaly of gonosomes were examined for the problem of a possible connection of the disease with certain types of HLA. An accumulation of individual specificites of HLA cannot be proved summarizingly; there are no significant differences to the control group. Remarkable and at present not yet to be interpreted is, however, the exclusive occurrence of the HLA-A1 in the 45,X-karyotype and iso-X-chromosomes, which needs further investigations.

[Fertility in the Ullrich-Turner syndrome]. / Fertilität bei Ullrich-Turner-Syndrom.

We report on a 29-year old female patient with Turner's syndrome and sex chromosome mosaic 46,XX/45,X. The female patient shows a few somatic Turner-stigmata, short stature and fertility. The possibility of the development of endocrine active ovaries in women with Turner's syndrome and its consequences has been emphasized.

[Experiences with the intranasal and parenteral use of 1-desamino-8-D-arginine vasopressin (DDAVP)--effect of one time parenteral and intranasal applications]. / Erfahrungen bei der intranasalen und parenteralen Anwendung von 1-Desamino-8-D-Arginin-Vasopressin (DDAVP)--Wirkung einmaliger parenteraler und intranasaler Applikationen.

The balance examinations in 10 patients with a neurohypophyseal diabetes insipidus under various forms of parenteral application (s.c., i.m., i.v.) of the 1-desamino-8-D-arginine-vasopressin show universally the very good antidiuretic effect also under these conditions. Identically with the course of action after intravenous application the maximum of action as obtained after 1 to 2 hours, the duration of action depends on the dosage, in parenteral application of 1 microgram 18 to 24 hours, on an average 20 hours. According to the results demonstrated there are no references to a specific influence of the excretion of sodium, potassium and urea. The particular dynamics of the excretion rates of these substances, of the osmolarity clearance and the osmolarity of the urine is the sequel of the restitution of the renal concentration ability under the application of the antidiuretic hormone.

[Experiences with intranasal and parenteral use of 1-desamino-8-D-arginine vasopressin (DDAVP). Use in the diagnosis of hypophyseal function]. / Erfahrungen bei der intranasalen und parenteralen Anwendung von 1-Desamino-8-D-Arginin-Vasopressin (DDAVP). Anwendung in der Hypophysenfuktionsdiagnostik.

While 1-desamino-8-D-arginine-vasopressin is not suitable for the functional diagnostics of the anterior pituitary gland, it has as in the therapy of the central diabetes insipidus a firm place also in its diagnostics. A hypothalamic neurohypophyseal system was demonstrated. Apart from a secure diagnostic evidence the test shows further advantages in comparison to the hitherto performed methods: an essentially smaller load for patient and personnel, a shorter duration and a simplified performance. First findings in patients with central diabetes insipidus, in a female patient with renal diabetes insipidus and patient without disturbance of the water balance are discussed. A control of our findings in other institutions is desirable.

[Pituitary gland extract insufflation lung]. / Hypophysenextraktschnupferlunge.

In two patients with diabetes insipidus the development of an allergic alveolitis with transition into pulmonary fibrosis could be observed. The alveolitis is evoked by snuffing of posterior pituitary extracts. The pathomechanism of this side effect (disease) is similar to those of other allergic alveolitides (e.g. farmer's lung, bird-fancier's lung, malt-worker's lung etc). This disease can be avoided by changing the therapy of diabetes insipidus to fully synthetic preparations free of protein. When irreversible changes are already present at the stroma of the lung (X-ray picture, function of the lung, histology), then the therapeutic possibilities are restricted and the prognosis is unfavourable.

[Experiences with intranasal and parenteral use of 1-desamino-8-D-arginine vasopressin (DDAVP). Use in a simple test of renal concentrating ability]. / Erfahrungen bei der intranasalen und parenteralen Anwendung von 1-Desamino-8-D-Arginin-Vasopressin (DDAVP). Anwendung in einem einfachen Test des renalen Konzentrationsvermögens.

The possibility of the use of 1-desamino-8-arginine-vasopressin (DDAVP) in a functional test of the renal concentration ability was controlled. In accordance with the data in literature the results allow to propose the DDAVP concentration test as screening method for this renal function. Essential advantages are the short duration and the small laboratory-technical expenditure. A standardized approach including propositions for a critical valuation of the results is represented and its control in patients is described. If the results should be confirmed by a control in other institutions, the test might be recommended for practice.

[Adult myeloneuropathic variant of adrenoleukodystrophy with Addison crisis]. / Myeloneuropathische Erwachsenenvariante der Adrenoleukodystrophie mit Addison-Krise.

In a 32-year-old patient on account of an insufficiency of the adrenal cortex as well as of a leg-related tetraspasticity with a simultaneous subclinical peripheral neuropathy after exclusion of other endocrine and neurological diseases which are to be regarded differential-diagnostically the diagnosis of a myeloneuropathic adult variant of the adrenoleukodystrophy, the adrenomyeloneuropathy, was made. The disease in question is an x-chromosomally inherited disease, the basis of which is a metabolic disease in the destruction of long-chained fatty acids as basal disturbance. The cerebral radiologic exclusion diagnostics was made with CCT and MRT. On the basis of the literature the differential-diagnostic problems of this rare subspecies of the adrenoleukodystrophy which is at present causally not to be treated are discussed and it is referred to the clinical conclusions concerning a timely hormonal substitution therapy and genetic consultation.

[Diagnosis and differential diagnosis of primary empty sella]. / Zur Diagnostik und Differentialdiagnostik der primären Empty Sella.

A report is given on 12 patients (6 men, 6 women) presenting primary Empty Sella who were admitted as inpatients with a provisional diagnosis of a hypophyseal tumour. The most frequent first symptom was uncharacteristic cephalgia. Visual disturbances and an impairment of potency/libido were only mentioned in the second place. 5 of the 12 patients were adipose and overweight, 2 of them additionally showed hypertensive blood pressure values. 2 female patients suffered from galactorrhoea. The typical "Empty Sella Patient" frequently described in the literature - the overweight medium-aged woman was an exception among our patients. Besides the ascertainment of the ophthalmological findings and the performance of a complete endocrinological function diagnosis the respective radiological diagnosis was established: native sellar picture, sella tomography, computer tomography, angiography and pneumocephalography. A high informative value in the differential-diagnostic demarkation from a hypophyseal tumour has until now been attributed to pneumoencephalography with an intracellar accumulation of air being considered to prove the presence of an empty sella. Under modern examination conditions, however, a computer-tomographic clearing will in most cases be possible.

[Paraneoplastic endocrinopathies]. / Paraneoplastische Endokrinopathien.

After the presentation of the definition and of several historical data the present pathophysiological imaginations concerning the problems of the ectopic hormone production are sketched which nowadays not yet have accepted a definitive form. A survey of the at present ascertained paraneoplastic endocrinopathies and several own findings allow a valuation of the significance of these phenomena in practice, taking into consideration the literature.

HLA-DQA1*0301-associated susceptibility for autoimmune polyglandular syndrome type II and III.

No significant differences were reported for the frequency of DR3-DQ2 and DR4-DQ8 haplotypes in a recent study of one of the largest cohorts worldwide of patients with isolated Addison's disease compared to patients with APS II. However, previous studies had suggested that the HLA-DQ genes, especially DQA1*0102, may be a genetic marker for resistance to autoimmune thyroid disease, which is the most frequent disease in APS II or III. Until now, HLA-DQA1 alleles have not been systematically investigated in APS. We determined the HLA-DR and HLA-DQA1 association in 112 unrelated patients with APS II (n = 29), APS III (n = 83) and 184 unrelated patients with single-component diseases without further manifestations of APS: Graves' disease (n = 70), Hashimoto's thyroiditis (n = 53), autoimmune Addison's disease (n = 15), vitiligo (n = 16) and alopecia (n = 30), and 72 healthy controls - German Caucasians - to identify possible predisposing and protective HLA class II alleles in APS. In agreement with previous studies, we detected a significantly higher frequency of DR 3 and/or DR 4 in patients with APS II and III compared to controls. In patients with APS II, we detected a significantly higher frequency of DQA1*0301 and *0501 compared to controls confirming the increased frequency of an extended HLA DRB1-*04-DQA1-*03-DQB-*03 haplotype as previously described. In contrast, only DQA1*0301 was increased in our patients with APS III compared to controls. Moreover, we detected an increased frequency of DQA1*0301 in patients with APS, whereas DQA1*0301 was only significantly elevated in alopecia in patients with single-component diseases without APS. Therefore, our results indicate an association between DQA1*0301 and APS II or III since this allele was otherwise not significantly associated with any of its component diseases except alopecia. Moreover, our data imply that the allele DQA1*0301 is a marker of increased risk for further APS manifestations in patients who suffer from an organ-specific autoimmune disease.

[Long-term study in congenital refractory anemia and secondary siderosis]. / Langzeitbeobachtung bei kongenitaler therapierefraktärer Anämie mit sekundärer Siderose.

It is reported on the course of the disease in a female patient with congenital therapy-refractory anaemia, in whom a transfusion siderosis of high degree with functional disturbances of the myocardium and the liver, with endocrine disturbances (primary hypothyroidism and normogonadotropic hypogonadism) and with small growth became clinically manifest. A reduction of the iron overload by a continuous desferrioxamine therapy in form of long-term subcutaneous infusions over two years could be proved. Possibilities and problems of treatment and conclusions relevant to practice are described.

[45,X/46,X,del(Yq) sex chromosome mosaicism--analysis of the phenotypic expression]. / Das 45,X/46,X,del(Yq)-Geschlechtschromosomenmosaik--analyse der phänotypischen Ausprägung.

Three female patients with Turner-syndrome (sexual infantilism, short stature and somatic Turner-stigmata) have been analysed cytogenetically by means of different banding techniques. A deletion of the distal heterochromatic band Yq12 of the Y chromosome was observed in a mosaic with a 45,X-cell line, i.e. the karyotype is 45,X/46,X,del(Y)(q12). In order to get information about the phenotypic expression of the 45,X/46,X,del(Yq) mosaicism all previously published cases have been reviewed. Comparing the phenotypes of all 45,X/46,X,del(Yq) mosaic cases three different phenotype categories of sexual development can be distinguished: female individuals with sexual infantilism and Turner-stigmata, individuals with ambiguous genitals, ranging from clitoris hypertrophy of female genitals to hypospadia of males, male individuals, who are infertile (azoospermic). A comparison of the appearance of external genitals with the status of gonads of all patients revealed an unequivocal relationship between the gonad status and the resulting phenotype category. Furthermore, the role of Y-chromosomal loci determining testicular differentiation (biological function of H-Y antigen) for male development has been emphasized. The effect of the 45,X-cell line on the expression of short stature and somatic Turner-stigmata is independent of sexual development. Considering the great phenotypic variability of the 45,X/46,X,del(Yq) mosaicism it seems impossible to deduce a definitive phenotype. This problem is acute in prenatal diagnosis especially.