Screening of patients with Turner syndrome for "hidden" Y-mosaicism.

The presence of Y-chromosomal sequences in the cells of patients with Turner-Syndrome (TS) is a risk factor for the development of gonadal tumors. Therefore and since demonstration of Y-material usually results in prophylactic gonadectomy optimal sensitivity and specificity of the diagnosis have to be attempted. We wanted to evaluate the diagnostic potential of cytogenetic investigations as routinely employed in TS. In the most comprehensive study published so far we screened 208 TS patients for the presence of Y-chromosomal sequences by polymerase chain reaction (PCR) specific for eight different loci along the Y-chromosome. Six patients (3%) without cytogenetic evidence of Y-chromosome were found to be Y-positive. Among 12 cases with marker chromosomes two more Y-chromosomal fragments were identified. Thus, PCR-screening for Y-specific sequences was shown to be a valuable tool in the clinical management of Turner patients.

Androgen receptor point mutations as the underlying molecular defect in 2 patients with androgen insensitivity syndrome.

PURPOSE: We have detected androgen receptor (AR) gene mutations as the underlying molecular defect in male pseudohermaphroditism patients. The functional properties of these mutant receptors regarding hormone binding and transactivation were characterized in 2 patients and offered a possible treatment modality for a male pseudohermaphroditism newborn. MATERIALS AND METHODS: Specific binding of dihydrotestosterone, thermostability of the receptor-hormone complex and 5alpha-reductase activity were measured in their genital skin fibroblasts. AR gene mutations were detected by direct sequencing. The ability of the mutant receptors to activate androgen responsive elements in the deoxyribonucleic acid was determined by transactivation experiments. Screening techniques that distinguish between normal and mutant ARs were developed for rapid detection of the mutation in other family members. RESULTS: The 2 patients showed a qualitative and quantitative binding defect. In both patients, point mutations in the ligand binding domain were identified as the underlying cause. Transactivation assays demonstrated that in the newborn increasing androgen concentrations can restore the mutated receptor's function completely, whereas in the patient with complete androgen insensitivity, excessive amounts of synthetic androgens were necessary. Therefore, the newborn received androgen stimulation and underwent surgical correction in the male direction. These experiments revealed that the functional difference between a mutant AR that causes a partial and one that causes a complete androgen insensitivity may be very small. CONCLUSIONS: Identification of the molecular mechanisms that cause the various forms of sex ambiguity will greatly improve both diagnosis and therapy in affected patients. Exact characterization of AR activation and function may offer a possible treatment modality in affected patients.

CYP11B1 mutations causing congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency.

Accurate knowledge of the molecular basis of congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency is a prerequisite for genetic counseling, prenatal diagnosis, and treatment. Analysis of nine patients suffering from severe manifestations of this disorder led to the identification of seven novel mutations in their CYP11B1 genes. A Caucasian patient was homozygous for the missense mutation R448H, previously found only in Jews of Moroccan origin. An Iranian patient was found to be homozygous for a different mutation in the same codon, R448C. Of four unrelated patients, two were homozygous for a nonsense mutation (W247X), whereas two others were compound heterozygotes for W247X in combination with either R448H or E371G. Two other patients were homozygous for either the missense mutation A331V or an in-frame CTG insertion adjacent to codon 464 (InsCTG464). One patient was a compound heterozygote for two mutations in exon 2, a 28-bp deletion (delta 28bpEx2) and the missense mutation V129M. All of the missense mutations and the CTG insertion caused a complete loss of steroid 11 beta-hydroxylating activity when expressed in cultured cells. These data support previous suggestions of mutational hot spots in CYP11B1 and confirm that severe clinical manifestations are associated with complete loss of enzymatic activity.

Characterization of two point mutations in the androgen receptor gene of patients with perineoscrotal hypospadia.

Perineoscrotal hypospadia is a major sign of sexual ambiguity due to inadequate androgen action in genetic and gonadal males. In patients showing these symptoms we have detected two androgen receptor gene mutations. In consequence we characterized the properties of the mutant receptors with respect to hormone-binding, transactivation and DNA-binding. An amino acid substitution alanine-596-->threonine in the D-box of the androgen receptor was detected in 3 and 2 brothers, respectively. This mutant receptor, AR-thr596, bound ligand in a normal fashion. It showed a promoter-dependent defect of transactivation and was unable to induce transcription of a promoter containing one androgen responsive element but showed almost wild-type transactivation of a promoter containing two closely spaced androgen-responsive elements. The complex promoter of the human prostate-specific antigen gene was induced with intermediate efficiency. In electrophoretic mobility shift assays AR-thr596 was unable to form a complex with oligonucleotides containing 1 or 2 androgen responsive elements, however its DNA-binding activity was restored by an anti-androgen receptor antibody in the presence of ligand. A point mutation which caused substitution of serine-703 in the hormone-binding domain with glycine was detected in a new-born male with ambiguous genitalia. This mutant receptor, AR-gly703, showed a reduced ligand affinity. The total amount of specific androgen binding sites in genital fibroblasts of the patient was reduced. Transactivation activity of AR-gly703 was dependent on hormone concentration. It was inactive at low levels of androgens but was fully activated in the presence of high androgen concentrations. The nature of the promoter had no effect on transactivation properties of this mutant androgen receptor. Its DNA-binding activity in gel shift experiments was normal.

Hereditary complete deficiency of the fourth component of complement: effects on the kidney.

Hereditary complete C4 deficiency has until now been detected in 18 patients. A disturbed clearance of immune complexes probably predisposes these individuals to systemic lupus erythematosus and other immune complex diseases. Renal involvement of hereditary complete C4 deficiency is described in seven patients from three families. Three patients of one family suffered from SLE and a severe mesangial and endocapillary proliferative glomerulonephritis which required immunosuppressive treatment. In two patients from a second family a mild focal and segmental mesangioproliferative glomerulonephritis was present which, except for an episode of acute renal failure in one patient, did not cause serious clinical problems. One additional child died without renal involvement. The patient from a third family developed Henoch-Schoenlein purpura, mesangioproliferative glomerulonephritis with segmental scarring and terminal renal failure. Immunofluorescence studies showed deposition of immunoglobulins and complement C3 in the glomeruli. Severity of renal disease is probably determined by activation of the alternative pathway of complement in the kidney.

Precocious puberty due to a lipid-cell tumour of the ovary.

A 4-year-old girl with a lipid cell tumour of the ovary showed isosexual precocious pseudopuberty. The endocrine activity of the tumour led to elevated plasma levels of dehydroepiandrosterone sulphate, oestradiol, testosterone and androstenedione. After tumour resection the clinical signs of abnormal hormonal stimulation disappeared within 10 months. The girl developed precocious puberty again 2 years later without any sign of relapse. Therapy with luteinizing hormone releasing hormone agonist was effective although premature activation of the hypothalamic-pituitary-gonadal axis could not clearly be demonstrated by hormonal investigations.

Follow-up of Ullrich's original patient with "Ullrich-Turner" syndrome.

In 1930 Ullrich published the case of the prototype patient with what is now referred to as the Ullrich-Turner syndrome. In 1987 this patient was restudied at the age of 66 years. She permitted a cytogenetic study, a brief clinical evaluation, and reported about her life and adjustments to her condition. This patient had the striking findings of adults with the Ullrich-Turner syndrome and an unequivocal 45,X chromosome constitution in all cells examined, showing that she indeed has the Ullrich-Turner and not the Noonan syndrome. She reached a maximum height of 144.5 cm, had primary amenorrhea, failure of maturation of secondary sexual characteristics, and yet in many personal and professional ways had adjusted admirably to her condition.

[Disorders of thyroid gland function--hypothyroidism in childhood. An ambulatory follow-up study]. / Störungen der Schilddrüsenfunktion--Hypothyreose im Kindesalter. Eine ambulante Kontrolluntersuchung.

42 children with different kinds of hypothyroidism, who had been treated with thyroid hormones during several years, were thoroughly follow-up examined in 1988. Apart from few exceptions, patients in therapy attained standard data in length. Concerning skeleton maturation, clear differences between boys and girls were found. While male patients, with one exception, showed a retardation of bone-age, in females both, retardation and acceleration of bone-development were found. Serum concentration of FT4 and FT3 were chosen as hormonal parameter, and TSH was taken basal and after stimulation with TRH. Normal FT4 levels were found in 29 patients. In 5 children FT4 was significantly lower, in 8 cases an elevation of this serum-parameter was observed. Measurement of serum FT3 in 27 patients showed normal levels in 18 children. In 4 cases low and in 5 elevated FT4 levels were found. 29 patients had basal TSH concentrations within normal range, in 13 the estimated levels were elevated. TRH-stimulation carried out on 40 children showed normal serum TSH response for 13 of them. In 14 children an exaggerated TSH response to TRH occur, in 13 TSH still remain low after stimulation with TRH. Serum-GOT, -GPT, -Gamma GT and -CK were determined as encymic parameters. In 5 patients a typical hypothyroidism-associated GOT- and CK-elevation was found. 3 children showed an isolated rise of GOT-, 8 an isolated CK-elevation.

[Intersexual genitals]. / Das intersexuelle Genitale.

Genital ambiguity in the newborn baby should be considered to be a medical emergency. Although a considerable number of embryologic, physiologic and hormonal events that effect normal sexual differentiation are well known, our understanding of sexual differentiation is still uncompleted at this point. In the female, XX infant, virilisation may occur in the presence of normals gonads, on the other hand, a female aspect may be present in a XY male infant in the presence of tests. Diagnostic procedures in intersexual states are very complex and may include specific laboratory tests, diagnostic imaging and the biopsy of the gonads. The decisions concerning the management of the child involve emotionally highly-charged value judgments.

[Penoscrotal hypospadias with XXYY chromosome pattern]. / Penoscrotale Hypospadie mit XXYY-Chromosomensatz.

This is the report of a boy, 2 years and 4 months of age who presented with an penoscrotal hypospadia with normal appearing testes. Physical examination and routine laboratory tests revealed--besides a broad base of the nose and clinodactyly--no abnormality. The boy exhibits a normal speech development with retarded global intellectual development. Investigation of the hormon status revealed a disturbance of testosteron secretion and a hypergonadotropic hypogonadism. Chromosomal analysis in lymphocyte cultures revealed a XXYY karyotyp. This chromosomal pattern is seen in 3% of patients with Klinefelter syndrom; the estimated frequency is 1 in 25,000 population. A combination of an XXYY chromosomal pattern with a penoscrotal hypospadia has not been reported in the literature so far.

[Empty sella syndrome in childhood]. / Das Empty-Sella-Syndrom im Kindesalter.

6 cases of the primary empty sella syndrome, 5 boys and 1 girl aged from 1 to 22 years, are being treated. The patients became suspicious due to a deficiency of pituitary hormones, whereby a lack of growth hormone was most common. 5 patients were short of growth; in provocative tests all 6 children showed either a partial or a complete deficiency of growth hormone. 2 patients had secondary hypothyroidism, 2 hypogonadotropic hypogonadism. Sceletal maturation was retarded between 2/12 and 4 4/12 years in all cases. All patients underwent a skull roentgenogram. An enlargement of the sella turcica was found in the case of one boy only. The findings of the other 5 children were inconspicious. For all patients the diagnosis was testified by a cranial computer-tomography.

[Forms of intersexuality in childhood (pathogenesis--clinical aspects--diagnosis--therapy)]. / Intersexformen im Kindesalter (Pathogenese--Klinik--Diagnose--Therapie).

There is a need for early diagnosis and classification of different forms of intersex in children. Biochemical disorders lead to deviations of the normal fetal sex determination. Development anomalies can be generally classified as aberrations of the development of the ovaries (Pseudohermaphroditismus femininus) and abnormalities of the development of the testes (Pseudohermaphroditismus masculinus). Based on a preliminary clinical diagnosis of sexual ambiguity, analytical methods such as chromosome analysis, detection of sex hormones and their metabolites in serum and urine and the determination of hormone-patterns in the skin of the external genitalia are of great importance. Diagnosis of the proper sex may be considered a medical emergency because of the serious psychologic problems for the parents and the child, if sex is errouneously or oncertainly assigned. Diagnosis should be completed within the first few prenatal months of an intersex child in order to schedule a therapy that will determine it's life. Therapy is primarily based on administration of androgenizing or progestional substances and surgical interventions. Additional psychotherapeutic treatment should start in the early formative childhood years to allow a normal cognitive development and maturation of the child according to it's sexual identity.

Clinical and endocrinologic study of precocious puberty in girls.

We describe 30 girls with precocious puberty whom we have seen during the last ten years. Modern procedures such as cerebral computer tomography and abdominal sonography increase diagnostic accuracy so that the incidence of idiopathic precocious puberty is likely to diminish. Abdominal sonography is of value in detecting and monitoring the growth of ovarian cysts and thus exploratory laparotomy can be avoided in those cases in which cysts regress rapidly. A modified classification of precocious is proposed.

Endocrinological problems in malformation of the male genitalia.

There are two groups of congenital defects of the male genitalia: defects of organogenesis (e. g., aplasia of the external genitalia) and malformations due to defective hormonal influences on these organs. The pathophysiological mechanisms of the functional malformations can be a defect of androgen biosynthesis in the gonads, defects of conversion of precursor hormones into the biologically active compound, and defects at the receptor site with a faulty hormonal utilisation. All these defects in the production of a biologically active substance can be present and operating very early in life, i. e., in the embryonal or foetal period. Problems can arise from the mother and particularly the placenta, or from the child (pituitary). The production of an antimüllerian hormone in Sertoli cells has been recently reported as an additional important mechanism. These hormonal defects influence the development of the male genitourinary tract system. Testosterone biosynthesis has several enzymatic steps: The synthesis of androgens starts early in the embryonal period, with the final transformation of the indifferent organ into the differentiated external male genitalia occurring under the influence of the foetal testosterone. Targets for these hormonal malfunctions are, besides the urogenital system, an enzyme (5-alpha-hydroxylase) and cytoplasmic and nuclear receptor sites on the skin of the external genital region. One of the clinical manifestations of such a hormonal malfunction is a defective virilisation of the external male genitals, with several types of hypospadias. Complete and partial defects of testosterone biosynthesis are known. Extensive laboratory investigations disclose the specific defect. Besides hypospadias, similar malformations occur in the form of ambiguous external genitalia if testosterone cannot metabolize into dihydrotestosterone in the target cell. In earlier descriptions this congenital genitourinary defect was called pseudovaginal perineoscrotal hypospadias. Today, the specific defect is identified as a 5-alpha-reductase deficiency. The diagnosis is established by a skin biopsy of the genital area. Ambiguous genitalia of variable expression are present if the receptor sites at the target cells are defective. The clinical presentation is known as testicular feminization or hereditary male pseudohermaphroditism. Incomplete partial expression of this disorder is known. The diagnosis is made clinically, and diagnosis is proven by investigation of hormone receptor sites in the target cells in the skin of the genital region.(ABSTRACT TRUNCATED AT 400 WORDS)

Studies on a family with the factor VII defect.

Investigations in a family with an isolated factor VII deficiency are reported. In one of the propositi VII Ag was reduced, in all other family members VII Ag was in the low normal range. Other investigators have observed various activation patterns of factor VII in four deficient families which were tested with thromboplastins from different sources. In contrast to most of these earlier studies the degree of activation with different thromboplastins was very similar regardless which thromboplastin was tested. These results confirm the heterogeneity of the factor VII defect. Platelet aggregation which was tested in one of the propositi with ADP, adrenaline, and collagen was found to be normal. No cold activation of factor VII was observed.

[Aarskog syndrome (author's transl)]. / Aarskog-Syndrom -- röntgenologische und endokrinologische Untersuchungsergebnisse.

Report of radiologic and hormonal results of a patient with typical stigmata of the Aarskog-syndrome. X-Ray findings are not been found to give diagnostic clues, whereas the hormonal findings are considered specific-typical: FSH and LH levels prior to orchidopexy are in a range are as seen with hypergonadotropic hypogonadism. One year after the orchidopexy LH values were found to be normal, the FSH again showed increased titer. The growth hormones concentrations are normal but Somatomedin-activity is decreased.