Pseudovaginal Perineoscrotal Hypospadias

Alternative Names

  • PPSH
  • Male Pseudohermaphroditism due to 5-Alpha-Reductase Deficiency
  • Familial Incomplete Male Pseudohermaphroditism, Type 2
  • 5-Alpha-Reductase 2 Deficiency
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WHO-ICD-10 version:2010

Endocrine, nutritional and metabolic diseases

Disorders of other endocrine glands

OMIM Number

264600

Mode of Inheritance

Autosomal recessive

Gene Map Locus

2p23.1

Description

Pseudovaginal perineoscrotal hypospadias is a rare autosomal recessive disorder of male sexual development. Patients of this disease have a normal 46,XY karyotype, but have incompletely differentiated male genitalia, leading to varying degrees of genital ambiguity; ranging from minimal undervirilization and presentation of normal male anatomy with micropenis or hypospodias, to severe undervirilization and presentation of normal female external genitalia with mild clitoral enlargement. The testes in neonates are usually found either in the inguinal canals bilaterally, or in the labioscrotal folds. Mullerian duct derived structures are not present. By puberty, signs of virilization can be seen, with a prominent Adam's apple, muscularity, body and facial hair being developed, and a deepening of the voice.

The exact frequency of this disorder worldwide is not known. However, some countries like the Dominican Republic, New Guinea, and Turkey have reported higher frequencies. Treatment depends on the gender assignment of the patient. Diagnosis of the disease is usually confirmed by the high testosterone/dihydrotestosterone ratio. Male gender assignment may be supported by dihydrotestosterone administration, although it may be ineffective once puberty has been reached. Female gender identity selection involves orchidectomy prior to puberty and clitoroplasty with estrogen therapy at puberty. Psychosocial support for the patient and the family is very important.

Molecular Genetics

The disease manifests itself due to the inability of the male fetus to convert testosterone into dihydrotestosterone (DHT). This conversion is catalyzed by the enzyme Steroid 5-alpha reductase 2, encoded by the SRD5A2 gene. DHT is essential for the development of normal external male genitalia in the embryo. More than 40 mutations have been so far identified in the SRD5A2 gene, which are believed to lead to the development of this form of male pseudohermaphroditism.

Epidemiology in the Arab World

View Map
Subject IDCountrySexFamily HistoryParental ConsanguinityHPO TermsVariantZygosityMode of InheritanceReferenceRemarks
264600.G.1LebanonMaleYesYes Male pseudohermaphroditism; ... NM_000348.4:c.164T>AHomozygousAutosomal, RecessiveHochberg et al. 1996 Large kindred with P...
264600.G.2LebanonFemaleYesYes Decreased circulating luteinizing hormon... NM_000348.4:c.164T>AHomozygousAutosomal, RecessiveHochberg et al. 1996 Large kindred with P...

Other Reports

Oman

Al-Attia et al. (1987) (Emirates Med J. 1987; 5:236-42) described the case of two Omani children born to consanguineous parents, 18 and 19 years of age, who were unambiguously raised as girls. The younger 'sister' presented to the authors with primary amenorrhea, a marked degree of virilization, moderately deepened voice and absence of gynecomastia. Genital examination revealed a hyperpigmented and rugated scrotum, bilateral and well-developed testicles, a small hypospadic phallus, perineal urethral orifice, rudimentary labia minora, and a short blind-ending vaginal pouch. The patient's self-awareness, orientation, sexual arousal and response were of a male nature. The patient's elder 'sister' had identical physical features. However, self-awareness and orientation was ambivalent. This patient was even married to a man who left 'her'. All the 'female' siblings of the patients appeared to be phenotypically normal. However, at least three other individuals in their kindred were also presumably affected. Biochemical assays of both the patients showed elevated T/DHT levels. In the case of the younger patient, T/DHT levels, both pre- and post-HCG stimulation were raised, as were the 5-beta/5-alpha reduced steroid metabolites levels in the urine. This clearly confirmed the diagnosis of 5-alpha reductase deficiency in these patients. Al-Attia et al. (1987) noted that although both the siblings were raised in the same socio-cultural background and showed the same testosterone levels, their gender identity appeared to be markedly different. The younger patient chose a male gender identity, and underwent surgical correction of hypospadias, whereas the other sibling chose the female identity, and underwent a bilateral orchidectomy.

Al-Attia (1996) studied six Omani Arabs with intersex belonging to interrelated families; all born to consanguineous parents. These families are geographically distributed in various parts of Oman and the United Arab Emirates. The ambiguity of their genitalia was identical, with the testicles at different inguino-scrotal levels. Gynecomastia was absent in adults, and facial and body hair was scanty. Rudimentary prostate was seen in rectal examinations of three of the patients. The karyotype was 46,XY with absence of Barr bodies in all cases. Five of the six cases showed very high T/DT ratios, consistent with the diagnosis of pseudovaginal perineoscrotal hypospadias. However, the development of gender identity and role was not uniform amongst the cases. One of the patients, brought up as a female, was highly self aware of his gender, and demanded a sex reversal. Surgical correction of his hypospadias was performed, and he subsequently got married. The other patients did not have such a smooth transition, with some preferring to continue as females, and one choosing the male role only for sexual activities. Al-Attia (1996) recognized that though androgens had a significant role towards sexual determination, physical morphological features, perceived functional capacities, and societal reactions also played a major role in gender identification.

 

Saudi Arabia

Al-Jurayyan (2011) conducted a retrospective study in the pediatric endocrine clinic at a university hospital Saudi Arabia during the period 1989-2008. Medical records of 81 children with ambiguous genitalia were reviewed. Fifty three (65%) of the patients were genetically females (46XX). Male genetic sex (46XY) was present in only 28 (35%) patients with a diversity of causes including 5-alpha-reductase deficiency in four (14%). Twenty-five (47%) of females were wrongly assigned as males, where only two (7%) males were wrongly assigned as females.

United Arab Emirates

Deeb et al. 2016 studied a large Emirati family where 11 members were born with varying degrees of genital ambiguity. All affected members had a 46XY karyotype, but several of the patients were assigned female at birth. Some of these patients were reassigned as male at later stages of their life. The index patient presented with severe undervirilization with bilaterally palpable gonads. He was raised as male from birth and underwent masculinising surgery. Analysis of the SRD5A2 gene identified a novel homozygous deletion of exon 2. His parents were found to be heterozygous for the mutation.  

[See: Oman > Al-Attia et al., 1987; Al-Attia, 1996].

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