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Biomedical subjects

M D Donaldson

Publications and source records attributed to M D Donaldson.

At least 37 records · Page 2Linked to original sources
PubMed1996

Male pseudohermaphroditism secondary to panhypopituitarism.

An infant with a 46XY karyotype was born with ambiguous genitalia, including microphallus and perineal hypospadias. A female gender was assigned due to extreme failure of development of the external genitalia. Subsequent investigations demonstrated panhypopituitarism, and it is believed that severe gonadotrophin deficiency was responsible for the intersex state. This case illustrates the need to evaluate the hypothalamic-pituitary axis in selected cases of intersex, and also questions the prevailing assumption that testosterone secretion during embryogenesis is largely pituitary gonadotrophin independent, under the control of human chorionic gonadotrophin.

Disorders of Sex Development↗
PubMed1996

An increased incidence of thyroid antibodies in patients with Turner's syndrome and their first degree relatives.

Previous studies have suggested that there may be a link between Turner's syndrome and autoimmunity. The numbers involved in these studies have tended to be small and few studies have included family members. This study has compared the incidence of thyroid antibodies in the serum of 60 patients with Turner' syndrome and 50 of their mothers with 127 controls. Total T4 and TSH levels were also measured. Of the 60 patients with Turner's syndrome 18 (30%) were positive for either thyroid peroxidase (TPO) and/or thyroglobulin antibodies. The peak incidence of thyroid antibodies occurred at 13 years of age. 11 (22%) of the mothers were also antibody positive. The incidence of thyroid antibodies was significantly higher in both the patients with Turner's Syndrome (30 vs 1.7% p < 0.001) and their mothers (22 vs 6.6% p < 0.05) than in the control groups. The increased incidence of thyroid antibodies found in these patients and their mothers confirms that there is an association between Turner's Syndrome and autoimmunity. However unlike previous studies we found more patients were positive for thyroglobulin than TPO antibodies.

Adolescent↗
PubMed1995

Pelvic ultrasound measurements in normal girls.

Pelvic ultrasound scans were carried out in 153 normal girls aged between 3 days and 14.9 years, in order to obtain reference data for ovarian volume, uterine length and uterine configuration. The right ovary was significantly larger than the left (by about 17%). Ovarian volume increased exponentially with age, over this age range. No relationship with pubertal stage (independent of age) could be demonstrated. Uterine length decreased from birth to 4 years, before steadily increasing. The fundal-cervical ratio (FCR) decreased initially then increased to lie above 1.0 by 15 years of age. A midline endometrial echo was seen in half of the subjects aged less than 6 months, but otherwise it was not seen before 11.8 years of age or at Tanner stage B2. Smoothed reference centile curves for uterine length, right and left ovarian volume were produced, allowing z scores (or SD scores) to be calculated for each measurement.

Adolescent↗
PubMed1995

Pelvic ultrasound findings in different forms of sexual precocity.

Recently produced reference curves for various ultrasound dimensions were used to retrospectively assess 67 pelvic ultrasound scans carried out at the initial presentation in girls with sexual precocity. At presentation the group with precocious puberty had significantly increased uterine lengths and ovarian volumes compared with the normal population, and a significantly increased fundal-cervical ratio. Ovarian volume was also significantly increased in therlarche and thelarche variant. The fundal-cervical ratio was significantly increased in thelarche variant. There was considerable overlap between individuals with sexual precocity and normal subjects. The ultrasound findings that best discriminated early or precocious puberty from other forms of sexual precocity were the presence of a midline endometrial echo, and a uterine length above the 97th centile for age. An entirely normal pelvic ultrasound at presentation did not rule out the possibility of precocious puberty.

Child↗
PubMed1995

Women with steroid 5 alpha-reductase 2 deficiency have normal concentrations of plasma 5 alpha-dihydroprogesterone during the luteal phase.

Steroid 5 alpha-reductase 2 deficiency has been identified in two adult women from unrelated families, one a homozygote and the other a compound heterozygote. The homozygote carries the G183S mutation and is the sister of an affected male; the compound heterozygote (R246W/splice junction abnormality) is married to a heterozygote (splice junction abnormality) and is the mother of two compound heterozygotes and two homozygotes. The fact that these two women are the mothers of seven children and appear to be endocrinologically normal confirms the previous deduction that this disorder is not manifest in women. Concentrations of plasma 5 alpha-dihydroprogesterone were normal in these two women during the luteal phase; this finding implies that circulating 5 alpha-dihydroprogesterone in women is derived principally from the steroid 5 alpha-reductase 1 isoenzyme and leaves unresolved the question of whether 5 alpha-dihydroprogesterone plays a physiological role in women.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1994

Hazards of ketoconazole therapy in testotoxicosis.

An eight-year-old boy with Leydig cell hyperplasia (testotoxicosis) was admitted with a three-day history of rash, vomiting and diarrhoea, followed by acute onset of breathlessness and confusion. He was shocked, with liver cell and renal failure, erythematous rash and severe interstitial pneumonitis. He had been treated with ketoconazole for four years prior to admission, receiving 1200mg daily during the preceding year. Cessation of ketoconazole therapy was associated with full clinical recovery but relapse of testotoxicosis. Ketoconazole was reintroduced cautiously at a lower dose, with no ill-effect, and reasonable control of testotoxicosis. We conclude that this boy's illness, including the interstitial pneumonitis, represented a reaction to ketoconazole which was dose-related rather than idiosyncratic.

Child↗
PubMed1994

Presentation, acute illness, and learning difficulties in salt wasting 21-hydroxylase deficiency.

The presentation, pattern of acute illness, and incidence of learning difficulties are described in 63 (33 boys, 30 girls) children with salt wasting 21-hydroxylase deficiency, drawn from a cohort study of congenital adrenal hyperplasia in the South West Region of England between 1968 and 1988. Thirty boys presented with a salt losing crisis from birth whereas the other three boys presented between 2 and 14 months of age with failure to thrive and hyponatraemia. Diagnostic uncertainty led to 13 (43%) of 30 girls developing a salt losing crisis. Five girls were misassigned as boys at birth. There were four deaths in the group, two due to salt losing crisis, one to complications of prematurity possibly compounded by 21-hydroxylase deficiency, and one from heart failure probably related to an excess of steroids. Acute admissions were common, especially during the first year of life, with convulsions in 7% of admissions. The 9% incidence of hypoglycaemia was considered to be an underestimate as blood glucose was measured in only 56 (22%) of 254 admissions. No convulsions occurred in the 38 (15%) admissions where the parents had given intramuscular hydrocortisone before bringing the child to hospital. A high incidence of learning difficulties was found among the 59 surviving children (9/30 (30%) boys and 6/29 (21%) girls), and in only two children could any factor other than 21-hydroxylase deficiency be invoked. Analysis of the subgroup with learning difficulties indicated that they were more ill at presentation with a significantly higher incidence of hypoglycaemia, and that growth in the first year was significantly worse. It is concluded that congenital adrenal hyperplasia remains a formidable disorder with an appreciable mortality and morbidity. The high incidence of learning difficulties seen in salt wasting 21-hydroxylase deficiency needs further attention. A prospective study is indicated to examine the effect of neonatal screening on morbidity from congenital adrenal hyperplasia, particularly the intellectual impairment seen in this study.

Acute Disease↗
PubMed1994

Patterns of obesity in boys and girls after treatment for acute lymphoblastic leukaemia.

The frequency and pattern of obesity in survivors of acute lymphoblastic leukaemia (ALL) was examined in a retrospective analysis of height and weight at zero, two, and four years from diagnosis in 40 children (19 boys and 21 girls). The children had been treated according to the Medical Research Council protocols UKALL VIII and X, both of which included cranial radiotherapy at a dose of 1800 cGy. Body mass index (BMI), determined as weight/height, was used as a measure of fatness. The BMI Z scores were calculated for each patient from standard tables. The ALL group was compared with a control group of 18 age matched children who had received chemotherapy but no radiotherapy. Changes in BMI between diagnosis and two and four years later were analysed by paired t tests. Mean BMI Z scores at diagnosis were similar between ALL boys, ALL girls, and the control group. Two years after diagnosis the ALL group, particularly the girls, showed a significant increase in BMI. By four years BMI had decreased slightly in the ALL boys, but had increased still further in the ALL girls with 57% having BMI Z scores greater than 2. In the control group BMI increased, but not significantly, at two and four years. It is concluded that the obesity seen in patients treated for ALL is more pronounced in girls than boys, and that cranial irradiation is an important factor.

Body Mass Index↗
PubMed1994

Diagnosis in Prader-Willi syndrome.

Thirty one patients with the putative diagnosis of Prader-Willi syndrome were reassessed clinically and by DNA analysis. Eleven patients were judged not to have Prader-Willi syndrome and 20 to have the condition. This was confirmed by DNA analysis in all but one case. The diagnosis of Prader-Willi syndrome, especially in early infancy, should be made with caution unless confirmed by molecular genetic studies.

Adolescent↗
PubMed1994

Possible role of imprinting in the Turner phenotype.

We have attempted to investigate the role of imprinting in the phenotype of Turner's syndrome. Sixty-three patients were investigated for parental origin of the retained normal X chromosome; 43 were found to retain the maternal X (XM) and 20 the paternal (XP). The relationship between a child's pretreatment height centile and parental height centiles was examined in 36 patients. No significant correlation was found between child and parental height centiles for XP or child and paternal height centiles for XM (p > 0.05) but a strong correlation was found between child's height centile and maternal height centile (p < 0.01) for XM. Using pooled data from this and other studies there was no significant correlation with renal anomalies but a strong correlation between cardiovascular abnormalities and XM (0.01 > p > 0.001) and neck webbing and XM (p < 0.05). We conclude that imprinting may play a part in the Turner's syndrome phenotype, especially with respect to pretreatment height, cardiovascular anomalies, and neck webbing.

Female↗
PubMed1994

Mutation in the human gene for 3 beta-hydroxysteroid dehydrogenase type II leading to male pseudohermaphroditism without salt loss.

A 5-year-old XY pseudohermaphrodite was found to have a defect of steroid biosynthesis consistent with a partial deficiency of the enzyme 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD). Circulating concentrations of delta 5 steroids and delta 5 urinary steroid metabolites were elevated and remained elevated after orchidectomy. There was no evidence of salt loss, plasma renin being within normal limits, and no detectable glucocorticoid abnormality. The coding sequences of the genes for 3 beta-HSD types I and II were amplified by PCR and screened for mutations by denaturing gradient gel electrophoresis (DGGE) and manual and automatic DNA sequencing. A mutation in the gene for 3 beta-HSD type II was observed at codon 173 (CTA-->CGA), leading in the affected patient to a homozygous substitution in which the leucine at residue 173 was altered to an arginine (L173R). The propositus's 2-year-old XX sister was also homozygous for L173R and showed the biochemical characteristics of partial 3 beta-HSD deficiency without clinical symptoms or signs. The mutation segregated as an autosomal recessive. Three related heterozygous adult females showed evidence of a small over-production of delta 5 steroids and steroid metabolites and a variable reduction in ovarian function. Concentrations of delta 5 steroids and steroid metabolites in the heterozygous father of the propositus were within the normal range. These data are discussed in relation to the endocrine causes of pseudohermaphroditism and hirsutism. Evidence for tight linkage between the genes for 3 beta-HSD types I and II was obtained using a microsatellite polymorphism in the third intron of the gene for 3 beta-HSD type II and synonymous and non-synonymous mutations and polymorphisms in the gene for 3 beta-HSD type I. The latter polymorphisms were located 88 bp apart at the 3' end of the type I coding sequence and could be physically resolved as haplotypes using DGGE. The application of DGGE to the analysis of mutations in members of a multigene family is discussed.

3-Hydroxysteroid Dehydrogenases↗