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Biomedical subjects

I A Hughes

Publications and source records attributed to I A Hughes.

At least 19 recordsLinked to original sources
PubMed1992

Androgen receptor gene mutations identified by SSCP in fourteen subjects with androgen insensitivity syndrome.

The androgen insensitivity syndrome (AIS) is a disorder of male sexual development resulting in a wide range of clinical phenotypes. AIS is classified into two phenotypic forms: complete (CAIS) and partial (PAIS). To determine the molecular basis of the phenotypic diversity in AIS, we have studied 27 subjects (13 CAIS, 14 PAIS), spanning the full range of AIS phenotypes. We report the results of a mutation screen of the androgen receptor gene. The coding regions of the gene were amplified by the polymerase chain reaction and screened for single strand conformation polymorphisms to identify mutations. This was followed by DNA sequencing of putative mutant segments. Androgen receptor gene mutations were identified in nine CAIS and five PAIS subjects. Two of the CAIS mutations in exon A resulted in frameshifts. A third CAIS mutation resulted in the deletion of a single amino acid from the ligand binding domain of the receptor. All other mutations caused single amino acid substitutions in the ligand binding domain. These results suggest that mutations affecting the ligand binding domain of the androgen receptor are the most frequent cause of AIS, although some cases of PAIS may be the result of other, as yet undefined, genetic lesions.

Androgens↗
PubMed1992

Role of the androgen receptor in male sexual differentiation.

The two androgens responsible for all aspects of male sexual differentiation are testosterone and dihydrotestosterone. The action of both these steroids is mediated by a specific intracellular receptor, the androgen receptor, which is a member of the nuclear receptor superfamily. The androgen receptor gene has been cloned and is located on the X chromosome at Xq11-12. Mutations of this gene have been found in subjects with both complete and partial androgen insensitivity. In a study of 27 subjects with the androgen insensitivity syndrome, we have identified mutations in 14, using a rapid mutation screening assay. The same technique has also been used to determine carrier status in an affected family. We have also identified a mutation in two brothers who show perineal hypospadias as the only evidence of undervirilisation. Familial severe hypospadias should therefore be included as part of the phenotypic spectrum of partial androgen insensitivity. The study of naturally occurring mutations of the androgen receptor gene is providing further information on the function of the androgen receptor and its role in normal male sexual differentiation.

Dihydrotestosterone↗
PubMed1992

Male pseudohermaphroditism: clinical management, diagnosis and treatment.

Male pseudohermaphroditism (MPH) is a disorder of sexual differentiation whereby the external genitalia are at variance with a male karyotype and the presence of testes. Abnormalities of Leydig cell function are an important cause of MPH, but postnatal age must be considered when interpreting the testosterone response when HCG stimulation is used as a diagnostic test. Androgen insensitivity is also a common cause of MPH; the specific defect in androgen receptor function is currently the subject of intense study, using a combination of biochemical assays and molecular analysis of the androgen receptor gene. The treatment of MPH is influenced by genital tissue responsiveness to androgens and the technical complexity of reconstructive surgical procedures. There is a need for information on the outcome of MPH treatment regarding pubertal development, sexual performance and fertility.

Androgens↗
PubMed1992

Complete androgen insensitivity due to deletion of exon C of the androgen receptor gene highlights the functional importance of the second zinc finger of the androgen receptor in vivo.

Androgen-dependent gene transcription is mediated by the androgen receptor (AR) through interaction of its central zinc finger region with specific DNA sequences on target genes. Failure of this receptor-mediated gene transcription results in end organ resistance to androgens-the androgen insensitivity syndromes. In a pair of siblings with complete androgen insensitivity who had supranormal levels of androgen binding in genital skin fibroblasts, polymerase chain reaction and Southern blot analysis of the androgen receptor gene confirmed by polymerase chain reaction and sequence analysis of AR cDNA, revealed an in-frame deletion of exon C encoding the second zinc finger of the receptor. The mutant receptor in cultured genital skin fibroblasts had normal androgen binding affinity and was localized in the nucleus but had markedly reduced DNA-binding affinity. When recreated in vitro and tested in a cotransfection assay system the mutant receptor failed to activate transcription of an androgen-responsive reporter gene. This naturally occurring mutation highlights the functional dependence of the AR upon its second zinc finger in vivo and explains the complete insensitivity to androgen manifest by the affected individuals despite increased androgen binding. The elevated AR levels in the subjects' genital skin fibroblasts further suggests a possible role for the second zinc finger in autoregulation of receptor levels in vivo.

Androgen-Insensitivity Syndrome↗
PubMed1991

Androgen dependent stimulation of aromatase activity in genital skin fibroblasts from normals and patients with androgen insensitivity.

OBJECTIVE: To measure the effect of androgens or aromatase activity as an index of androgen responsiveness in patients with androgen insensitivity. DESIGN: Genital skin fibroblasts were established in culture using primary skin explants obtained from normal males at the time of circumcision and from androgen insensitive patients who had surgery either for gonadectomy (complete androgen insensitivity syndrome) or for reconstruction of the external genitalia (partial androgen insensitivity syndrome). PATIENTS: Foreskin samples were obtained at the time of circumcision in 27 normal males. Scrotal or labia majora skin was obtained at the time of surgery from 14 patients with the complete and 22 with the partial forms of the androgen insensitivity syndrome. MEASUREMENTS: Basal and stimulated levels of aromatase activity were measured in genital skin fibroblasts following preincubation with natural and synthetic, nonmetabolizable androgens. RESULTS: Following a 48-hour preincubation with testosterone or dihydrotestosterone, there was a five to six-fold stimulation of aromatase activity in normal fibroblasts. Mibolerone, a synthetic androgen, produced similar results. The stimulatory effect was blocked by anti-androgens. Seven patients with partial androgen insensitivity, of whom four were either receptor deficient or showed a qualitative defect in androgen binding, had reduced mibolerone induced stimulation of aromatase activity. All ten patients with receptor negative complete androgen insensitivity had an absent response. There was no aromatase induction in a further three patients with complete androgen insensitivity who were receptor positive. Two siblings in the latter group had an exon deletion encoding for part of the DNA binding domain of the androgen receptor. CONCLUSIONS: Androgens stimulate aromatase activity in genital skin fibroblasts from normals. The response is mediated via the androgen receptor and can be decreased or absent in patients with the androgen insensitivity syndrome. This may be a useful in-vitro marker of androgen responsiveness in such patients.

Androgens↗
PubMed1991

Loss of therapeutic control in congenital adrenal hyperplasia due to interaction between dexamethasone and primidone.

A 14-year-old girl with congenital adrenal hyperplasia showed rapid conversion from undertreatment to overtreatment when primidone, used to treat coexistent epilepsy, was withdrawn while on a constant steroid dose. In addition to signs of hypercortisolism and a decrease in random measurements of plasma testosterone and 170H-progesterone concentrations, the deterioration in control was also illustrated by changes in the pattern of blood spot steroid profiles. Adequate control was achieved only after a 3-fold reduction in steroid dose. The decrease in dose requirement was probably the result of a reversal of liver enzyme induction consequent upon the withdrawal of primidone.

Adolescent↗
PubMed1991

Indwelling cannula for insulin administration in diabetes mellitus.

Experience with an indwelling subcutaneous Teflon cannula for insulin delivery to 10 children with diabetes mellitus is described. There were no significant complications during a one year trial period. The device may particularly benefit children during the early phase after diagnosis and for those with true needle phobia.

Adolescent↗
PubMed1991

Normal postnatal androgen production and action in isolated micropenis and isolated hypospadias.

To try and find out if a defect in androgen biosynthesis or action could be responsible for the incomplete virilisation seen in boys with isolated hypospadias and isolated micropenis, androgen receptor binding was studied in genital skin fibroblasts established from 18 boys with isolated micropenis and 19 boys with isolated hypospadias. The production of gonadotrophins and testosterone was also measured in the boys with micropenis. There was no evidence of gonadotrophin deficiency, or of a defect in testosterone biosynthesis in the boys with micropenis, and there was no evidence of a quantitative or qualitative defect of androgen binding in either group. These isolated abnormalities may be the result of transient defects in androgen synthesis or action, or both, during a critical phase of embryogenesis.

Adolescent↗
PubMed1990

5 alpha-reductase deficiency without hypospadias.

A boy aged 4 with penoscrotal hypospadias and his brother aged 12 with micropenis had typical changes of homozygous 5 alpha-reductase deficiency. After three injections of chorionic gonadotrophin there was a trivial rise in plasma dihydrotestosterone with a normal increase in plasma testosterone. Urine steroid chromatography showed abnormally high 5 beta: 5 alpha ratios and 5 alpha-reductase activity was appreciably reduced in genital skin fibroblasts. The results indicate that 5 alpha-reductase deficiency is not invariably associated with genital ambiguity.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1990

Dexamethasone treatment for congenital adrenal hyperplasia.

Ten patients with congenital adrenal hyperplasia (three males, seven females; aged 12-29 years) had their usual glucocorticoid treatment changed to dexamethasone in three crossover dosage regimens. A starting dose of 5 micrograms/kg/day is suggested but as no one dose regimen resulted in adequate control the timing of the dose must be decided for each patient.

Adolescent↗
PubMed1990

Response to treatment of congenital adrenal hyperplasia in infancy.

Nine infants with congenital adrenal hyperplasia were started on replacement doses of hydrocortisone (20.6-32.6 mg/m2/day) without receiving a high dose for an initial period first. Plasma adrenal steroid concentrations fell to acceptable levels by 3 months of age. Adequate biochemical control was maintained and satisfactory growth achieved even though the mean dose of hydrocortisone had been reduced to 15 mg/m2/day by the age of 3 years. Inadvertent overtreatment and growth suppression in infants with congenital adrenal hyperplasia may be avoided by using replacement doses from the start, and by permitting the relative dose of hydrocortisone to fall as the body surface area increases during the first year of life.

17-alpha-Hydroxyprogesterone↗
PubMed1990

Aromatase activity in genital skin fibroblasts from normal and androgen-insensitive individuals.

Human genital skin fibroblasts were used to study aromatase activity by analysing the [3H]H2O released as [1 beta-3H]androstenedione is converted to oestrone. 4-Hydroxyandrostenedione was shown to be a competitive inhibitor of this aromatase activity, the concentration of inhibitor producing 50% inhibition being 1.29 nmol/l. Dexamethasone stimulated the enzyme complex in a dose-dependent manner with half-maximal stimulation at 11.5 nmol/l. A peak of induction occurred after 16 h of preincubation. Measurement of aromatase activity in normal cell strains provided a normal range for the Michaelis-Menten constant (Km) and the maximum velocity (Vmax) of 6.72 +/- 0.54 nmol/l and 215.3 +/- 33.9 fmol/mg protein per h (mean +/- S.E.M., n = 20) respectively. Km values obtained for partial and complete androgen insensitivity syndrome (PAIS and CAIS) patient cell strains were all within the normal range. The mean Vmax +/- S.E.M. in cell strains from patients with PAIS (n = 13) and CAIS (n = 11) were 127.4 +/- 19.2 and 54.8 +/- 19.3 fmol/mg protein per h respectively. Vmax values for patients with CAIS were significantly (P less than 0.001) lower than normal subjects. This suggests that aromatase expression in genital skin fibroblasts is androgen-dependent.

Androgens↗
PubMed1989

Myelodysplastic syndrome with trisomy 8 in an adolescent with Fanconi anaemia and selective IgA deficiency.

We describe a patient with growth failure and multiple congenital anomalies characteristic of Fanconi anaemia, but without the classical feature of progressive bone marrow hypoplasia. Following treatment with growth hormone for a period of 8 years, he presented with myelodysplastic syndrome and a karyotypically abnormal clone in the bone marrow (47,XY,+8). The diagnosis of Fanconi anaemia was supported by the induction of abnormally high levels of characteristic chromosome aberrations in peripheral lymphocytes following exposure in vitro to the bifunctional alkylating agent mitomycin C. Immune function studies also identified a selective IgA deficiency. The relative importance of interacting constitutional and exogenous factors involved in the development of preleukaemia in this patient is discussed.

Adolescent↗
PubMed1989

The pharmacokinetics of low-dose dexamethasone in congenital adrenal hyperplasia.

The pharmacokinetics of dexamethasone, given at low dose, were studied in 13 patients with congenital adrenal hyperplasia (CAH) to ascertain whether kinetics differed in this inherited disorder of cortisol metabolism from those seen in healthy individuals. Changes in plasma dexamethasone concentration after intravenous bolus, measured using a simple novel radioimmunoassay, were well described by a two-compartment open model with first-order kinetics. Values for lambda 2: 0.206 h-1, t1/2: 3.53 h, Vc: 24.41 and f: 0.64 were similar to those previously reported for normal subjects. There were considerable interindividual differences in parameter values and Cmaxp.o. (range 22-67 nmol/l). As suppression of the hypothalamo-pituitary-adrenal axis correlates with plasma dexamethasone levels, this variability may partly explain the differing dose and dose schedule requirements necessary to achieve adequate therapeutic control in the clinical management of CAH.

Administration, Oral↗
PubMed1989

Growth and body proportions in congenital adrenal hyperplasia.

Total height, sitting height, and subischial leg length were measured in 27 patients (19 girls and eight boys aged 4.3-21.1 years) with congenital adrenal hyperplasia to determine the influence of chronic hyperandrogenaemia on body proportions. Proportions were normal in 24 patients with classical congenital adrenal hyperplasia who had received steroid treatment since birth, but one of three patients with non-classical (late onset) congenital adrenal hyperplasia had a disproportionately large trunk. Eleven patients with classical congenital adrenal hyperplasia had completed growth, of whom seven had height standard deviation (SD) scores for chronological age less than zero, and one had extremely short stature (SD score -3.25). In 13 patients who were still growing, nine had height SD scores for chronological age of less than zero despite having mean (SD) advances in bone age over chronological age of 1.64 (1.68) years. Height SD scores for bone age were less than 0 in all 13 patients, indicating a loss of height despite advanced skeletal maturation. Doses of glucocorticoid that permit mild chronic or intermittent hyperandrogenaemia also seem to be associated with mild growth retardation. An adult height below average may be an inevitable consequence for many patients with congenital adrenal hyperplasia receiving conventional glucocorticoid treatment.

Adolescent↗
PubMed1989

Value of selective screening for congenital adrenal hyperplasia in Hungary.

Measurement of the 17-hydroxyprogesterone concentration in blood spots was used to identify cases of congenital adrenal hyperplasia among patients with inappropriate virilisation, or salt wasting, or both. Between 1978 and 1986 61 were identified among 707 patients (278 neonates, 204 infants, and 225 children). The incidence of classic congenital adrenal hyperplasia was calculated for a seven year prospective trial period using the blood spot 17-hydroxyprogesterone method in selective screening. There were 38 salt losers and 14 simple virilisers in 968,303 live births, an incidence of congenital adrenal hyperplasia of 1:18,000 in the Hungarian population. Selective screening led to earlier diagnosis of congenital adrenal hyperplasia and a pronounced decrease in mortality. A central laboratory to measure the blood spot 17-hydroxyprogesterone concentrations is valuable for the investigation of patients at risk for congenital adrenal hyperplasia in countries where blood steroid assays are not readily available.

17-alpha-Hydroxyprogesterone↗
PubMed1989

Congenital hypothyroidism, spiky hair, and cleft palate.

Two brothers are described with athyroidal hypothyroidism, spiky hair, choanal atresia, cleft palate, and bifid epiglottis. Polyhydramnios was present in the third trimester of each pregnancy. These abnormalities appear to represent a new syndrome.

Child, Preschool↗