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46,XY partial gonadal dysgenesis

Synonym(s) 46,XY PGD
46,XY partial testicular dysgenesis
Prevalence Unknown
Inheritance X-linked recessive
or Autosomal dominant
or Autosomal recessive
or Y-linked
Age of onset Infancy
  • Q56.1
MeSH -
MedDRA -


Disease definition

46,XY partial gonadal dysgenesis (46,XY PGD) is a disorder of sex development (DSD) associated with anomalies in gonadal development that results in genital ambiguity of variable degree ranging from almost female phenotype to almost male phenotype in a patient carrying a male 46,XY karyotype.


The prevalence is unknown.

Clinical description

46,XY PGD is characterized by ambiguous external genitalia with or without Müllerian structures. The degree of genital ambiguity varies along a spectrum, ranging from an almost female phenotype with clitoromegaly at one extreme to an almost male phenotype with isolated hypospadias at the other. Many patients present ambiguous genitalia or severe micropenis associated with complete regression of testicular tissue in one or both sides. Embryonic Testicular regression syndrome (ETRS; see this term) is considered as part of the clinical spectrum of PGD. Depending on the mutation, patients can have adrenal insufficiency or renal involvement (i.e. Wilms tumors or nephrotic syndrome). Gonadoblastomas or invasive germ cell tumors occur in around 20-30% of patients.


46,XY PGD is a heterogeneous disorder associated with partial abnormality of both Leydig cell and Sertoli cell function that may result from deletions or point mutations in the SRY gene or dose sensitive sex ( NR0B1) locus duplication on the X chromosome. Most SRY mutations are de novo mutations, however some cases of X-linked inheritance have been observed. More important are mutations in steroidogenic factor 1 (SF1, NR5A1, Ad4BP). SF-1 is a nuclear receptor and regulator of multiple genes involved in adrenal and gonadal development, steroidogenesis, and the reproductive axis. Therefore, affected patients may also have adrenal insufficiency. Syndromic forms of 46,XY PGD have been associated with WT-1 mutations, which lead to variable testicular dysgenesis and an increased risk of renal abnormalities, namely Wilms tumors or nephrotic syndrome.

Diagnostic methods

Diagnosis is made on the basis of clinical findings with cytogenic analysis, endocrine investigations, molecular genetic studies, and sometimes surgical exploration with biopsy.

Differential diagnosis

Differential diagnoses include all forms of syndromic 46,XY gonadal dysgenesis (for example, Frasier syndrome, campomelic dysplasia and 46,XY DSD with adrenal insufficiency; see these terms) and similar phenotypes that can also result from a 45,X/46,XY karyotype, known as 45,X/46,XY mixed gonadal dysgenesis (45,X/46,XY MGD; see this term). The absence of a 45,X lineage is of importance for the management and prognosis.

Antenatal diagnosis

Antenatal diagnosis is possible if a genital malformation is suspected with imaging and if a familial background exists.

Genetic counseling

Genetic counseling is mandatory.

Management and treatment

Management of patients requires a multi-disciplinary team. Psychological evaluation and counseling of parents is necessary. The determination of social sex should consider etiological diagnosis, penis size, ethnic traditions, sexual identity and the acceptance of assigned social sex by the parents. Hormone therapy in patients with female social sex is based on estrogen and progesterone for those patients where uterus is present in order to induce menses and estrogen alone in patients without a uterus. Androgen replacement, including testosterone injections, is given to patients with male social sex. Surgery is required to allow development of adequate external genitalia and removal of internal structures inappropriate for social sex, and should be carried out before 2 years of age. Bilateral gonadectomy should be performed before puberty to avoid degeneration of dysgenetic tissue in patients reared as females due to the relatively high risk of gonadal malignancy.


With early diagnosis, surgery and hormone treatment can result in good outcome, both cosmetically and functionally. Infertility is almost always present.

Expert reviewer(s)

  • Pr Olaf HIORT

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