Society for Endocrinology UK Guidance on the Initial Evaluation of a Suspected Difference or Disorder of Sex Development (Revised 2021)

S. Faisal Ahmed; John Achermann; Julie Alderson; Naomi S. Crouch; Sue Elford; Ieuan A. Hughes; Nils Krone; Ruth McGowan; Talat Mushtaq; Stuart O'Toole; Leslie Perry; Martina E. Rodie; Mars Skae; Helen E. Turner

Disclosures

Clin Endocrinol. 2021;95(6):818-840. 

In This Article

XY DSD With low Testosterone and low Precursors

The differential diagnosis of 46, XY DSD associated with low testosterone and low precursors includes high defects in steroid synthesis (steroidogenic acute regulatory (StAR) protein, P450 side-chain cleavage (P450scc) enzyme/CYP11A1, sometimes Smith-Lemli-Opitz/DHCR7); LH receptor defects (LHCGR); and partial and complete forms of gonadal dysgenesis (Table 3).

Of note, complete or partial combined 17α-hydroxylase/17,20-lyase deficiency (CYP17A1) may also present with 'low testosterone and low precursors' if DHEAS and androstenedione are the only intermediates measured. The actual diagnosis can be reached by assessment of adrenal function by measuring ACTH, ACTH-stimulated cortisol, plasma renin activity (PRA), 11-deoxycorticosterone (DOC), corticosterone, aldosterone, measurement of Δ5 (pregnenolone, 17OHPreg) and Δ4 (progesterone, 17OHP) precursors or urine steroid analysis. Isolated 17,20-lyase deficiency, cytochrome b5 deficiency and PORD might also be diagnosed by this approach. Proximal blocks (StAR, P450scc) in the pathway affect steroidogenesis in the adrenal gland as well as the developing gonad.

LH receptor defects ('Leydig cell hypoplasia') typically result in elevated basal LH, hyper-responsive LH to GnRH stimulation, low precursors and testosterone, and impaired androgen response to hCG stimulation. No Müllerian structures will be present and adrenal function is normal. A spectrum of phenotypes has been reported including atypical genitalia and micropenis. In some cases, basal LH may not be elevated at times when the HPG axis is quiescent (6 months to late childhood).

In complete gonadal dysgenesis ('Swyer syndrome'), affected people will usually have a female phenotype with intra-abdominal dysgenetic streak gonads and a risk of tumour development. In some situations, ovotestes or even undifferentiated gonadal tissue may be found.[94] Müllerian structures are usually present due to impaired AMH secretion in early foetal life. Androgens and their precursors will be low, LH elevated, depending on age and a poor or absent testosterone response to hCG stimulation is seen. AMH concentrations will be low or undetectable, and adrenal function is usually normal unless the underlying defect is in steroidogenic factor-1 (NR5A1) or related adrenal or gonadal factors.

Partial gonadal (testicular) dysgenesis can present with a spectrum of phenotypes ranging from clitoromegaly, to atypical genitalia or severe hypospadias. Müllerian structures may or may not be present and testes of variable size and architecture are present along the path of descent. The biochemical profile is similar to complete gonadal dysgenesis, but generally less severe. If mild degrees of clitoromegaly in infancy are overlooked, a 46, XY child with partial gonadal dysgenesis may first present at puberty with progressive androgenization. Genetic analysis and associated features may be useful in defining the molecular aetiology of gonadal dysgenesis (Table 4). This group of conditions are also associated with a risk of tumour development which may be related to the extent of androgenization of the external genitalia in the XY child.[95]

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