Search :     
Articles » Genital anomalies » Ambiguous genitalia
2001-10-05-15 Male pseudohermaphrodism due to 5 a-reductase deficiency © Thomas

Male pseudohermaphrodism due to 5 a-reductase deficiency

Dominique Thomas, MD, C. Heinrichs, MD, L. Watkins- Masters, MD, R. Lejeune, MD, F. Hayez MD

Dept. of Obstetrics and Gynecology, Hôpitaux Iris Sud, site Ixelles, 63 rue J. Paquot, 1050 Brussel, Belgium Ph/Fax: 32.2.641.46.57.

Synonyms: pseudovaginal perineoscrotal hypospadias; PPSH1.

Definition: sex reversal in a normal 46 XY male patient.

Prevalence: unknown

Pathogenesis: 5
a-reductase deficiency resulting in an absence of dihydrotestosterone, which is normally responsible for masculinization of the external genitalia of the fetus2. Gene Map locus: 2p233-4.

Associated abnormalities: none, but can cause significant problems for the subject and his parents when the sex of rearing is inappropriate.

Differential diagnosis: all causes of intersex conditions, especially testicular feminization syndrome (TFS).

Prognosis: The child is best reared as a boy because: first: there is a marked masculinization at puberty, second: the subject could be fertile, and third: there is fetal brain exposure to androgens that could determine ultimate sexual identity5.

Recurrent risk: The heredity is male limited autosomal recessive with a recurrent risk of 1 in 8.

Management: If 5
a-reductase deficiency is known in the family, an antenatal diagnosis could be offered. If abnormal genital morphology is discovered during a routine ultrasound examination, a fetal karyotype should be offered to the parents and the diagnosis of fetal sexual ambiguity must be considered.

Using the sagittal inclination of the embryo’s genital tubercle, fetal gender assignment is now possible as early as 14 weeks6. Normal penile size and its in utero development has been recently described7. Identification of fetal gender is important not only for the parents, but also to detect hypospadias, ambiguous genitalia and cloacal anomalies that could lead to prenatal diagnosis of various genetic syndromes or endocrine disorders.

Case Report:
A 33-year-old Caucasian woman presented for a routine ultrasound evaluation at 12, 20 and 34 weeks of gestation in her second pregnancy. 
Her first baby was born with hypospadias after a normal full term uneventful pregnancy.
She then remarried with her first cousin and suffered an early miscarriage.
There was no history of congenital abnormality in the family.
The current pregnancy was unremarkable.
The following figures are:
embryo of 12 weeks

fetal hand 20 weeks

fetal sex 20 weeks

fetal head 34 weeks

fetal heart 34 weeks 

fetal sex 34 weeks 

fetal sex 34 weeks axial view

fetal lower spine 34 weeks

Two video clips are available of the sex at 20 weeks and the sex at 34 weeks

The ultrasonographer does not describe any abnormality until 34 weeks. The first two ultrasound scans demonstrated normal fetal growth and fetal morphology. The sex was assigned as female. The third ultrasound scan suggested an anomaly of the external genitalia: neither penis nor clitoris was seen but there was significant swelling of the labia majora, and no labia minora were seen. No testes were found in the labial area. The diagnosis of female sex was therefore revised to a diagnosis of sexual ambiguity.
A healthy baby was born at 40 weeks. The phenotype was a normal girl without clitoromegaly but the pediatrician detected two gonads in the inguinal canals, a normal urethral opening and vaginal introitus. Further tests were performed to obtain an adequate diagnosis and to propose appropriate sex rearing to the parents.
The karyotype was 46 normal XY. Because the phenotype was not ambiguous and because circulating testosterone was normal, the diagnosis of complete androgen insensitivity syndrome (CAIS) was proposed to the parents first. After complementary tests including HCG stimulation, which showed an elevated ratio of testosterone to dihydrotestosterone and an ultrasound evaluation, which showed an absent uterus and ovaries, and the presence of a vaginal pouch, the diagnosis was revised to 5
a-reductase deficiencies causing male pseudohermaphrodism. It was definitively confirmed by the identification of the SRD5A2 gene defect in exon 2 responsible for 5 a-reductase deficiency. The baby was homozygous and both parents were heterozygous.
Despite explanation by the medical staff about the virilization of such children after puberty, and the possible imprinting of fetal androgens on fetal brain that give male sexual identification, the parents decided to raise the child as a girl.
They took this decision for several reasons:
1) the desire of the family to have a female child, which predated the pregnancy.
2) because there was no sexual ambiguity at birth
3) even after three years the phallus was inadequately developed (less than 1 cm long).
It was decided to remove the gonads when the child was three and a half years old.

Sonographic findings of ambiguous genitalia:
The perineal area has to be seen when the legs are spread apart in three planes: coronal, transverse, and sagittal.
The visualization of the labia majora and labia minora leads to the diagnosis of a female fetus.
The distinction between the labia majora and the scrotum could be difficult in the case of a bifid scrotum. In this last case the median raphe is echogenic, and if the testicles are identified within the scrotum, the diagnosis of a male fetus is certain. Descended testes are seen at 25 weeks in 30% of cases and in 97% after 32 weeks8. Nomograms of scrotal circumference during normal prenatal life are available. In cases of ambiguous genitalia the penis could be confused with clitoromegaly. When the karyotype is known from a previous amniocentesis, nomograms of the length of penis may be helpful in early identification of maldevelopment of the genitalia7.
In the present case as in the two previous cases of prenatal diagnosis of ambiguous genitalia9,10 the diagnosis was made on the basis of a third trimester antenatal sonogram. 
The absence of the labia minora in any incidence of the fetal perineum at 34 weeks and the swelling of the labia majora are suggestive of a diagnosis of ambiguous genitalia.

a-reductase is responsible for the conversion of testosterone to a more potent androgen: dihydrotestosterone (DHT) . Virilization during fetal life and male secondary sex characteristic after puberty are consequences of the binding of dihydrotestosterone to its receptor11.
DHT receptors are present in the prostate, urogenital sinus and in the genital tubercle. Fetal masculinization consists of the lengthening of the anogenital distance, fusion of labioscrotal folds and closure of the urethral groove which forms the perineal and penile urethra12. It occurs between 9 weeks and 11 weeks 3 days of human fetal life. The normal development of the gonads, Wolffian ducts, testes, epididymis, vasa deferentia and seminal vesicles is testosterone-dependent and their development is not affected by 5-
a-reductase deficiency. The Sertoli cells will also continue to function normally producing anti Mullerian hormone (AMH)13.
The affected pseudovaginal perineoscrotal hypospadias neonate presents variable degrees of genital ambiguity from the complete absence of virilization as we describe here, usually with blind-ending vagina or urogenital sinus to less severe forms14 presenting with severe hypospadias with the urethra opening into the perineum and an absent prostate. Mullerian structures are also absent. After puberty there is marked virilization: phallic enlargement, testicular descent, scrotal rugation and pigmentation, voice deepening, no breast development nor menstruation. The explanation of this phenomenon has been suggested by the existence of two forms of iso-enzyme for 5-
a-reductase. Thigpen et al2 showed that the type 1 isozyme is not detectable in the fetus, but is permanently expressed in the skin after puberty, nevertheless the type 2 is the predominant isozyme detectable in fetal genital skin, that explains the strong virilization at the time of puberty in type 2 deficient subjects. After puberty, it has been pointed out by many authors that many subjects raised as females change gender role behavior to male15. 
Anderson et al.3 showed the deletion of the gene encoding for 5-
a-reductase type 2 isozyme in classic pseudovaginal perineoscrotal hypospadias and Thipgen et al.4 located the defect to 2p23.
Different mutations can be detected in the SRD5A2 gene that gives variable expression of the enzymatic deficiency14.

When the parents are known to be heterozygous for the mutation of SRD5A2 gene and when the allelic variant is identified by molecular genetics, an antenatal diagnosis can be proposed on material obtained either by amniocentesis or chorionic villus biopsy. When the abnormality is unknown in the family, the antenatal observation of ambiguous genitalia may lead to further investigations. Table I summarizes a clinical approach for disorders of sexual differentiation proposed recently by Warne et al.16 and completed with other information from Morel et al.17, Kupfer et al.13 and Izquierdo et al.14.

Table I: clinical approach of disorders of sexual differentiation

Phenotype 1: the XY female
Etiology Karyotype of affected baby Genetic defect Neonatal emergency Associated anomaly Antenatal diagnosis
Complete XY gonadal dysgenesis (Swyers’s syndrome)  46XY/XO Chromosomal mosaicism
46XY Mutation SRY Skeletal dysplasia

Yp deletion

Mutation genes WT1
  • Denys-Drash syndrome (Wilms tumor)
  • WAGR syndrome
  • Frasier Syndrome
Mutation genes SOX 9 Skeletal dysplasia
Inversion paracentric Y
distal deletion  9p
duplication of the region DSS of chromosome X
Defects in steroid hormone biosynthesis 46XY deficiency in CYP17 (17 a hydroxylase), numerous mutations of  the gene for CYP17
lipoid adrenal hyperplasia salt loss and severe hypoglycemia lips and genitalia deeply pigmented very low maternal estriol
Complete androgen insensitivity syndrome (CAIS) 46XY X- linked disorder: mutations in  androgen encoding gene receptor


Phenotype 2: the XX male
Etiology Karyotype of affected baby Genetic defect Neonatal emergency Associated anomaly Antenatal diagnosis
Small Y-to-X translocation bearing the testis-determining gene 46XX Presence of SRY
unknown 10%


Phenotype 3: infant with ambiguous genitalia
Etiology Karyotype of affected baby Genetic defect Neonatal emergency Associated anomaly Antenatal diagnosis
gonadal dysgenesis and true hermaphrodism 45X/46XY, 46XX puzzling nature risk of gonadal malignancy
defects in steroid hormone biosynthesis:
21-hydroxylase deficiency  46XX mutations gene for 21 hydroxylase (CYP 21) located on chromosome 6 ¾:severe salt- losing form, fatal condition if untreated hyperpigmented genital skin levels of 17OH progesterone in amniotic fluid
17b-hydroxysteroid dehydrogenase deficiency 46XY        
5a-reductase deficiency 46XY SRD5A2 gene defect      
placental aromatase deficiency 46XY mutations in the gene encoding aromatase ( p450 arom)   multicystic ovaries at adolescence high maternal levels of D4-androstene-dione and testosterone and very low levels of oestrogen during pregnancy
11-hydroxylase deficiency 46XX       levels of 11-deoxycortisol (S-compound) in amniotic fluid
7-dehydrocholesterol reductase deficiency 46 XY     Smith-Lemli-Opitz Syndrome levels of 7-dehydrocholesterol in amniotic fluid
3b-hydroxysteroid dehydrogenase deficiency 46 XX   severe water and salt-wasting   high levels of 17-OH pregnenolone in amniotic fluid
20-22-desmolase defect 46XY   water and salt loss    
17-beta hydroxylase defect 46 XY   water and salt retention    
17-20 desmolase deficiency 46XY          
partial androgen insensitivity syndrome (Reifenstein syndrome) 46 XY AR gene mutation
luteinizing hormone receptor gene mutation 46 XY inactivating mutation in the gene encoding LH receptor (probably autosomal recessive inheritance) 
androgens of maternal origin:
ovarian (luteoma of pregnancy, arrhenoblastoma) or adrenal tumour 46 XX 
Cushing’s syndrome 46 XX 
iatrogenic origin (androgens, progestogen: norethindrone, ethisterone, medroxyprogesterone) used to prevent abortion 46 XX 


Phenotype 4: 46 XY male with persistent Müllerian structure
Etiology Karyotype of affected baby Genetic defect Neonatal emergency Associated anomaly Antenatal diagnosis
46XY Mutation in the MIS gene or the MIS receptor gene


Phenotype 5: 46 XX female with Müllerian agenesis: Meyer-Rokitansky-Kuster-Hauser syndrome
Etiology Karyotype of affected baby Genetic defect Neonatal emergency Associated anomaly Antenatal diagnosis
unknown 46XX

First of all, it appears that there are many differential diagnoses for each of the five different phenotypes and we have to keep in mind that some conditions are real neonatal emergencies because they can cause significant metabolic problems such as salt loss. So, the karyotype should be determined as soon as possible and FISH identification of the sex chromosomes should be considered if culture failure is feared with a late amniocentesis. At the time of amniocentesis, especially in the second trimester, certain steroid hormones could be evaluated in the amniotic fluid (table I).
Parents must be informed that there is a problem in determining the sex of their baby and that they will be requested to postpone the registration of the birth and the choice of a name until the end of the period of investigation by the pediatricians.
Postnatal investigations include: physical examination to identify gonads in the scrotum or lower inguinal canal and a pelvic ultrasound to determine if Müllerian structures are present. Laboratory investigations include chromosome analysis performed on T-lymphocytes extended to 50 metaphases, which can identify chromosomal mosaicism. Hormonal testing can specifically identify
pseudovaginal perineoscrotal hypospadias by the presence of an elevated ratio of plasma testosterone to dihydrotestosterone just after the birth or after HCG stimulation18, a normal androstenedione level allows pseudovaginal perineoscrotal hypospadias to be distinguished from 17b-hydroxysteroid dehydrogenase 3 deficiency. Conversely patients with TFS with the same clinical features have elevated serum testosterone and LH19

The authors wish to acknowledge the assistance of Pr Sultan and his staff from Montpellier (France) who performed genetic analysis to identify mutation G115D of the 5
a-reductase 2 gene. 

1) Walsh PC, Malden JD, Harrod MJ, Goldstein JL, Donald PC, Wilson JD. Familial incomplete pseudohermaphrodism, type2. Decreased dihydrotestosterone formation in pseudovaginal perineoscrotal hypospadias. N Engl J Med 1974;291:944-949
2) Thigpen AE, Silver RI, Guileyardo JM, Casey ML, Mc Conell JD, Russel DW: Tissue distribution and ontogeny of 5-
a-reductase isoenzyme expression. J Clin Invest 1993; 92:903-910
3) Andersson S, Berman DM, Jenkins EP, Russel DW. Deletion of steroïd 5-
a-reductase 2 gene in male pseudohermaphroditsm.. Nature 1991; 354: 159-161
4) Thigpen AE, Davis DL, Milatovich A, Mendonca BB, Imperato-Mc Ginley J, Griffin JE, Francke U, Wilson JD, Russel DW. The molecular genetics of steroid 5-
a-reductase 2 deficiency. J Clin Invest 1992; 90:799-809
5) Lerman SE, McAleer IM, Kaplan GW. Sex assignement in case of ambiguous genitalia and its outcome. Urology 2000; 55: 8-12
6) Emerson DS, Felker RE, Brower D. The sagittal sign: an early second trimester indicator of fetal gender. J. Ultrasound Med 1997; 8: 293-297
7) Zalel Y, Pinhas- Hamiel O, Lipitz S, Mashiach S, Achiron R. The development of fetal penis. An utero sonographic evaluation. Ultrasound Obstet Gynecol 2001; 17: 129-131
8) Achiron R, Pinhas-Hamiel O, Zalel Y, Rotstein Z, Lipitz S. Development of male gender: prenatal sonographic measurement of the scrotum and evaluation of testicular descent. Ultrasound Obstet Gynecol 1998; 11: 242-245
9) Cooper C, Mahony B, Bowie J, Pope I. Prenatal ultrasound diagnosis of ambiguous genitalia. J Ultrasound Med 1985; 4: 433-436
10) Sivan E, Koch S, Reea A. Sonographic prenatal diagnosis of ambiguous genitalia. Fetal Diagn Ther 1995; 10:311-314
11) Wilson JD, Griffin JE, George FW. The role of gonadal steroïd in sexual differentiation. Rec Progr Horm Res 1981; 37: 1-39
12) Josso N. Hormonal regulation of sexual differenciation. Sem Perinat 1992; 16:279-288
13) Kupfer SR, Quigley CA, French FS. Male pseudohermaphrodism. Sem perinat 1992; 19: 319-331
14) Izquierdo G, Glassberg K, Gender assignement and gender identity in patients with ambiguous genitalia. Urology 1993; 42:232-242
15) Imperato- Mc Ginley J, Peterson RE, Gautier T, Sturla E. Androgens and the evolution of male gender identity among male pseudohermaphroditis with 5-a- reductase deficiency. New Eng J Med 1979; 300:1233-1237
16) Warne GL, Zajac JD,. Disorders of sexual differentiation. Endo Met Clinics North Am 1998; 27: 945-967
17) Morel Y, Tardy V, Calemard-Michel L, Guibaub L, Till M, Forest M. Conduite à tenir devant la découverte d’un état intersexué lors d’une grossesse. Séminaire Pédiatrique Endocrinologie et développement de l’enfant 22-23/01/2001 Lyon
18) Peterson RE, Imperato-Mc Ginley J, Gautier T, Sturla E. Male pseudohermaphrodism due to steroïd 5-a- reductase deficiency. Am J Med 1977; 62: 170-191
19) Pagon R.Diagnostic approch to newborn with ambiguous genitalia. Pediatr Clin North Am. 1987; 34: 1019-1031

Help Support :