1166 Winrow, Supramaniam

3 Bray RF, Herbst JJ. Pseudotumour cerebri as a sign of 5 Korzets A, Rathaus M, Chen B, Bernheim J. Pseudotumour ,catch-up' growth in cystic fibrosis. Am 7 Dis Child cerebi and nitrofurantoin. Drug Intell Clin Pharmn 1988;22: 1973;126:78-9. 345.

4 Minutello JS, Dimaynga RG, Carter J. Pseudotumour 6 Dekurto E, Manzani C, Zecca G. Convulsions with cerebro- Arch Dis Child: first published as 10.1136/adc.65.10.1166 on 1 October 1990. Downloaded from cerebin; a rare adverse reaction to tetracycline therapy. spinal fluid hypertension during treatment with naladixic J Periodontol 1988;59:848-51. acid. Minerva Pediatr 1986;38:794-5.

5a-Reductase deficiency without

W K Ng, N F Taylor, I A Hughes, J Taylor, P G Ransley, D B Grant

Abstract repair was carried out. A skin biopsy specimen A boy aged 4 with penoscrotal hypospadias for fibroblast culture was taken at that time. and his brother aged 12 with had The older brother was noted to have a small typical changes of homozygous Sa-reductase at birth. He was seen at the age of 12 deficiency. After three injections of chorionic years, at the same time as his brother. His exter- gonadotrophin there was a trivial rise in nal genitalia were normal, apart from the size of plasma dihydrotestosterone with a normal his penis, which had a stretched length of 4 cm. increase in plasma . Urine steroid There was no and the opened at chromatography showed abnormally high 513: the tip of the penis. Both testes were in the scro- Sa ratios and 5a-reductase activity was appre- tum and were 6 ml in volume. ciably reduced in genital skin fibroblasts. The Investigation showed a 46XY karyotype. results indicate that 5a-reductase deficiency After initial investigation a skin biopsy speci- is not invariably associated with genital ambi- men was obtained from the . guity. Plasma testosterone and dihydrotestosterone concentrations were measured by radio- immunoassay before and after three daily injec- 5a-Reductase deficiency is a well recognised but tions of 1000 units of human chorionic gonado- uncommon cause of male pseudohermaphrodit- trophin. Urine steroid concentrations were ism.' Published cases have been characterised measured by gas chromatography as previously by pronounced underdevelopment of the male described,4 and the results expressed in terms of external genitalia with microphallus and incom- SP:a ratios for different steroid metabolites. plete fusion of the labioscrotal folds.2 Many of Fibroblasts were established in ciilture from the reported cases have been initially raised as genital skin to determine 5c-reduct..se activity girls because of the female appearance of the and androgen receptor concentrations. The genitalia at birth but cases with more pro- activity of 5a-reductase was measured after http://adc.bmj.com/ nounced virilisation have been described.3 incubation of fibroblasts with serum free All previously reported males with 5a- medium containing 2 nM of tritiated testoster- reductase deficiency have had some degree of one. The medium was extracted with ethyl genital ambiguity with hypospadias. We acetate and analysed by single step thin layer describe two brothers with the conditic n, one of chromatography. Areas corresponding to di- whom had micropenis without hypospadias hydrotestosterone, 5a-androstanedione, andro- while the other had penoscrotal hypospadias. sterone, epiandrosterone, and the 5a-an- on October 1, 2021 by guest. Protected copyright. Hospital for drostanediols were cut out and counted for Sick Children, tritium. Enzyme activity was expressed in pmol/ Great Ormond Street, Patients and methods mg protein/hour of 5a-reduced products. The London WC1N 3JH concentration of androgen receptors, receptor W K Ng The propositus and his older brother had J Taylor consanguineous parents who come from Pakis- binding affinity, presence or absence of heat P G Ransley tan. At birth, the younger boy was found to labile receptors, and effect of preincubation D B Grant have abnormal external genitalia with a small Department of phallus and hypospadias. When he was 4 years Table I Results of endocrine investigations Clinical Biochemistry, King's College old he was referred for evaluation of his genital Propositus Brother School of Medicine anomaly. At that time he was noted to have a and Dentistry, small penis (stretched length 1-9 cm) with Before human chorionic gonadotrophin: London Testosterone (nmol/l) 0 4 3 1 N F Taylor noticeable chordee and penoscrotal hypospa- Dihydrotestosterone (nmol/1) 01 0-2 The scrotum was normal but the right Testosterone:dihydrotestosterone ratio 4 0 1-5 Department of dias. only testis was palpable. After human chorionic gonadotrophin: Paediatrics, Testosterone (nmol/l) 4-2 21-9 University of Cambridge Initial investigations showed a 46XY Dihydrotestosterone .(nmol/1) 0.1 0 3 School of Clinical karyotype. A sinogram showed a normal Testosterone:dihydrotestosterone ratio 42-0* 73.0* Medicine, Cambridge had a male con- I A Hughes bladder; the proximal urethra Urinary 5,0:5a ratios: figuration with a prominent vermontarum and THF:alloTHFt 24-7 14-3 Correspondence to: 4-7 Dr Grant (no reprints well developed utricle. Aetiocholanolone:androsteronet 0-6 available). After initial evaluation he was given one THB:alloTHB§ 0-8 4-3 Accepted 9 June 1990 *Normal range in prepubertal boys:2-25.' injection of depot testosterone (50 mg) to Mean (SD) results in normal subjects: tl-l (1-7), t0-8 (1-7), (ArchDisChild 1990;65:1166-7) improve the size of his penis and hypospadias S0 7 (1-6). Sa-Reductase deficiency without hypospadias 1167

Table 2 Sa-Reductase activity and androgen receptor concentrations in genital skinfibroblasts. Values in 22 nornal subjects are also given

Propositus Brother Normal subjects Arch Dis Child: first published as 10.1136/adc.65.10.1166 on 1 October 1990. Downloaded from Sa-Reductase activity (pmoltmg protein/hour) 0 5 0-6 12-8 (range 33-42 3) Androgen receptor concentration (x 10'8M/tLgDNA) 815 939 775 (SD 185) Receptor binding affinity (xo-10M) 0-82 1 09 0-88 (SD 0 35) Thermolabile No No No Augmentation x2-6 x1-8 x1-4

with androgen on receptor concentrations significant rise in plasma dihydrotestosterone (termed 'augmentation') were determined as after human chorionic gonadotrophin stimula- described previously.' 6 tion but very abnormal THF:alloTHF ratios were obtained on urine chromatography. Sa- Reductase activity in fibroblasts grown from Results genital skin was extremely low, findings which The results of endocrine investigations are sum- are typical of homozygous 5a-reductase defi- marised in the tables. ciency. 5a-Reductase deficiency usually produces severe male genital ambiguity with bifid scro- PLASMA ANDROGENS tum, urogenital sinus, and a clitoris like Both boys showed a rise in plasma testosterone phallus,' 2 but three brothers with labioscrotal after stimulation with human chorionic gona- fusion and hypospadias have been described.3 dotrophin, which was appropriate for their The absence of hypospadias in our older patient ages. There was a trivial increase in dihydrotes- is very much in contrast with all previously tosterone and this resulted in extremely high reported cases of 5a-reductase deficiency, and it testosterone:dihydrotestosterone ratios in both is very difficult to account for the absence of boys after human chorionic gonadotrophin hypospadias in the light of current views on (table 1). male external genital development. During early fetal development testosterone is thought to act as a prohormone in the urogenital tissues URINE STEROIDS where it is converted to dihydrotestosterone by Both brothers showed an abnormal pattern of intracellular 5a-reductase, thus effecting virilsa- urinary steroid metabolites, with high ratios for tion of the external genitalia. Penile growth is at 5p:a reduced steroids (table 1). This was most least partly dependent on intracellular Sa- striking in the tetrahydrocortisol:allotetra- reductase as micropenis has been a cardinal hydrocortisol (THF:alloTHF) ratio, which was feature of all reported cases of 5a-reductase 24-7 in the propositus and 14-3 in his older deficiency. brother. In normal adult males the mean (SD) Our findings indicate that there may be con-

ratio is 1-1 (1 7). The ratios for aetiocholana- siderable heterogeneity in the clinical manifesta- http://adc.bmj.com/ lone:androsterone (4-7) and tetrahydrocorti- tions of 5a-reductase deficiency. In the older costerone:allotetrahydrocorticosterone (THB: case, sufficient local dihydrotestosterone must alloTHB) (4-3) were also raised in the proposi- have been produced to allow early virilisation of tus. In his brother the aetiocholanalone:andros- the genitalia with fusion of the labioscrotal folds terone and THB:alloTHB ratios were normal to produce a normal urethra and scrotum. In and this is probably related to the low concen- the younger boy, virilisation was slightly less trations of these metabolites before puberty. complete leading to penoscrotal hypospadias and chordee. Reduced Sa-reductase activity in on October 1, 2021 by guest. Protected copyright. the second half of gestation probably accounts SKIN FIBROBLAST STUDIES for the presence of microphallus at birth. Fibroblast 5a-reductase activity in both brothers was extremely low at 0O5 and 0-6 pmol/ mg protein/hour, as compared with a mean of 1 Peterson RE, Imperato-McGinley J, Gautier T, Sturla E. 12-8 pmol/mg protein/hour (range 3 3-42 3) in Male due to steroid 5a-reductase deficiency. Am J Med 1977;62:170-91. eight normal males (table 2). 2 Johnson L, George FW, Neaves WB, et al. Characterisation Androgen receptor concentration was normal of the testicular abnormality in 5a-reductase deficiency. J Clin Endocninol Metab 1986;63:1091-9. in both brothers at 815 and 939x 10-18 M. 3 Ivarsson S-A, Nielsen MD, Lindberg T. Male pseudoher- There was no evidence of receptor thermolabil- maphroditism due to Sa-reductase deficiency in a Swedish family. EurJ Pediatr 1988;147:532-5. ity, and receptor augmentation after preincuba- 4 Bevan BR, Savvas M, Jenkins JM, Baker K, Pennington tion with androgen was normal. GW, Taylor NF. Abnormal steroid excretion in gestational trophoblastic disease complicated by ovarian theca-lutein cysts. J Clin Pathol 1986;39:627-34. 5 Evans BAJ, Jones TR, Hughes IA. Studies of the androgen receptor: investigation of patients with androgen insensiti- Discussion vity. Clin Endocrinol (Oxf) 1984;20:93-105. The biochemical findings described above indi- 6 Evans BAJ, Hughes IA. Augmentation of androgen receptor binding: in vitro studies in normals and patients with cate that both brothers are homozygous for 5a- androgen insensitivity. Clin Endocrinol (Oxf) 1985;23: reductase deficiency. Not only was there no 567-77.