Abstract

It is also described as pseudohermaphrodism with normal virilisation at puberty. 5 Alfa reductase deficiency presents with ambiguous genetalia with small hypospadiac phallus, blind vaginal pouch with normal testis and woolfian duct and absent mullerian ducts. It has a 46 XY karyotype and autosomal recessive disorder. The child is usually raised as female and at puberty she shows signs of virilisation and changed gender identity of incomplete masculine male due to 5 Alfa reductase deficiencies.

Case Report

A 14 year old girl with above average academic performance was brought with complaints of hoarseness of voice, sudden height spurt, and inability of non attainment of menarche. There was absence of gynaecomastia, reduced facial and body hair and selective signs of masculisation like deepening of voice, increase in muscle mass and phallus enlargement since 1 year. Patient was a case of full term normal delivery with no associated disease in family.

On examination

Pt was well built 172 cms in height, 64 kg in weight, with arm span of 168 cms with evidence of masculine shoulders, hoarse voice, and unilateral nasal defect. There was reduced facial and body hair, no temporal hair recession, nonpalpable prostate and no breast developments.

Local genitalia examinations revealed pubic, male hair pattern, hypertrophied clitoris with phallus measuring 2.5 cm with prepuce over glans and perennial hypospadius. Labia were in form of bilateral labioscrotal fold and flat mons. Mobile firm testes were palpable in the labioscrotal fold, just below the urethral opening. A blind vaginal pouch about 7 cm was present with absent uterus. Other systemic examinations like RS/CVS/CNS/abdomen were normal.

Investigations

Routine biochemical investigation was within normal limits. Hormonal investigations were as follows: T3-3.80 mg\dl, T4 - 10.9 mg\dl, TSH - 2.2 mu\ml.LH-5.1 mg\ml, FSH-48.089 miu\ml, Testosterone 389.75 ng\ml.

Reduced levels of 5 alfa\5 beta C21 and C19 steroids in urine.

Increased in plasma LDH ratio before and after hCG stimulation.

Increase in plasma LDH and reduced conversion of Testosterone into dihydrotestosterone in vivo.
Karyotype was 46 XY.

Fig. 1 : Palpable testes in 5a - reductase deficiency.		Fig. 2 : Post operative (orchidectomy).

Discussion

5 Alfa reductase deficiency was described by Nowakowski and Lenz in 1961 in Dominic republic and later in Papua New Guinea and Urke. It is transmitted as autosomal recessive trait having X-karyotype with normal differentiated testes, male internal ducts and ambiguous external genitalia. At puberty selective signs of masculisation appear like virilisation at puberty without gynaecomastia, reduced facial and body hair, no temporal hair recession, increased muscle mass, hoarse voice, increase in the phallus enlargement upto 4-8 cms in length. The bifid scrotum become ruggaed and pigmented and testes enlarge and descend in labioscrotal folds. Semen analysis in one patient revealed 40 million sperms per ml in testicular biopsy genesis. Most of the patients were raised as females.

The hormonal profile in these patient is consistent with defective conversion of 5 Alfa reductase ion of testosterone to dihydrotestosterone in androgen tissues. After the onset of puberty the plasma testosterone levels are normal to elevated and dihydrotestosterone levels significantly reduced in affected males. Prepubertally the testosterone \ dihydrotestosterone ratio may be normal in unaffected males under basal condition, however after hCG stimulation of testosterone secretion, an abnormal ratio can be demonstrated. Postpubertal plasma LH concentration are usually elevated and plasma FSH levels tend to be higher than in age matched controls. Also there is diminished ratio of urinary 5 Alfa reductions of 5 beta reduced C19 and C21 steroids and deficiency or abnormal 5 Alfa reductase activities in cultured fibroblast from genital skin.
Clinically the syndrome can be diagnosed prepubertally and postpubertally by administration of hCG 1000-2000 unit’s IM every 72 hours for 3 days. Affected patients have high LDH ratio after hCG.

Genetic heterogeneity of the defect is seen as

1. Severe 5 Alfa reductase deficiency-defective binding of Testosterone
2. Unstable 5 Alfa reductase - intermediate activity with decreased affinity of enzyme for cofactor NADPH.
3. Unstable 5 Alfa reductase with decreased affinity for substrate. Testosterone and cofactor.

The early diagnosis is very important for future assignment of sex of the infant. The child should be reared as male and undergo appropriate plastic surgery on their external genitalia. Testosterone and dihydr-otestosterone therapy can be given to augment phallic size and to facilitate surgical repair.

Pt diagnosed after puberty and raised as females should undergo prophylactic orchidectomy prior to puberty, and supplemented with oestrogen therapy at puberty. Standard treatment for babies is gonadectomy to avoid neoplasia and virilisation at puberty and feminizing genital surgery.

References

1. Andersson S, Berman DM, Jenkins EP, Russell DW. Deletion of steroid 5 alpha-reductase 2 gene in male pseudohermaphroditism. Nature 1991; 354 (6349) : 159-61.
2. Anwar R, Gilbey SG, New JP, Markham AF. Male pseudohermaphroditism resulting from a novel mutation in the human steroid 5 alpha-reductase type 2 gene (SRD5A2). Mol Pathol 1997; 50 (1) : 51-2.
3. Boudon C, Lobaccaro JM, Lumbroso S, et al. A new deletion of the 5 alpha-reductase type 2 gene in a Turkish family with 5 alpha-reductase deficiency. Clin Endocrinol (Oxf) 1995; 43 (2) : 183-8.
4. Cai LQ, Zhu YS, Katz MD, et al. 5 alpha-reductase-2 gene mutations in the Dominican Republic. J Clin Endocrinol Metab 1996; 81 (5) : 1730-5.
5. Can S, Zhu YS, Cai LQ, et al. The identification of 5 alpha-reductase-2 and 17 beta-hydroxysteroid dehydrogenase-3 gene defects in male pseudohermaphrodites from a Turkish kindred. J Clin Endocrinol Metab 1998; 83 (2) : 560-9.
6. Ferraz LF, Mathias Baptista MT, Maciel-Guerra AT, et al. New frameshift mutation in the 5 alpha-reductase type 2 gene in a Brazilian patient with 5 alpha-reductase deficiency. Am J Med Genet 1999; 87 (3) : 221-5.
7. Forti G, Falchetti A, Santoro S, et al. Steroid 5 alpha-reductase 2 deficiency : virilization in early infancy may be due to partial function of mutant enzyme. Clin Endocrinol (Oxf) 1996; 44 (4) :
   477-82.
8. Gad YZ, Nasr H, Mazen I, et al. 5 alpha-reductase deficiency in patients with micropenis. J Inherit Metab Dis 1997; 20 (1) : 95-101.
9. Greene SA, Symes E, Brook CG. 5-alpha-Reductase deficiency causing male pseudohermaphroditism. Arch Dis Child 1978; 53 (9) : 751-3.
10. Hines M. Abnormal sexual development and psychosexual issues. Baillieres Clin Endocrinol Metab 1998; 12 (1) : 173-89.
    

*Associate Professor, **Resident, Department of Ophthalmology, T.N.M.C and B.Y.L. Nair Hospital, Mumbai - 400 008.