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


Clin Endocrinol. 2021;95(6):818-840. 

In This Article

Which Adolescent Should be Investigated and how Extensively?

The initial assessment in an affected adolescent should not only start the process of diagnosis but should also be used to develop a rapport with the patient and where appropriate, their parents. The delivery of medical, nursing and psychological care needs to be undertaken within a hospital setting that is sensitive for the needs of the young person. The explanation of the diagnosis to the patient and the family is critical and needs to be performed sensitively and carefully over a period of time for reflection and this can be facilitated via expert psychological input. Adolescents usually present to paediatric or adult healthcare teams with a suspected DSD in three ways—a girl with primary amenorrhea (with or without breast development), a girl who virilises at puberty or a boy with pubertal delay (Figure 1). The need for any physical examination or imaging should be discussed with the adolescent and conducted by the most appropriate health professionals within the MDT and with the help of the psychologist or specialist nurse, if necessary. Any examination in clinic should be deferred to subsequent consultations once a rapport has developed with the adolescent. In some cases, this may be best performed under an anaesthetic by a surgeon and/or a gynaecologist. In adolescents with an existing DSD, the period of transition to adult services is an opportunity to review the diagnosis and consider further investigations. The joint DSD clinic serves as the forum where this can be reviewed. This clinic can also function as the forum where new cases in older adults can be discussed within the wider MDT.

Figure 1.

Approach to investigating adolescent girls with primary amenorrhoea

In girls with primary amenorrhoea, investigations should be considered at the age of 13 years if there is no breast development and by 15 years if other aspects of puberty, particularly breast development, have progressed normally. History should include a family history and an assessment of coexisting chronic disease, exercise and weight changes. Physical examination should include measurement of blood pressure, height and weight and assessment of secondary sexual characteristics including clitoral enlargement. Vaginal examination to assess vaginal length is only indicated when considering vaginal dilation as it is not of diagnostic value alone and should be performed by a gynaecologist. The procedure is only required when the individual wishes or when sexual activity is contemplated. An initial investigation screen should combine a transabdominal pelvic ultrasound to identify a uterus with measurements of serum electrolytes, LH, FSH, prolactin, TSH, FT4, SHBG, androstenedione, oestradiol, testosterone, AMH or Inhibin B. Ultrasound scans do not yield information on vaginal anatomy and this is better obtained from magnetic resonance imaging (MRI), which is most useful in cases where there is menstrual obstruction. Raised gonadotrophins or an absent uterus in the presence of normal breast development necessitate chromosome analysis (by karyotype or microarray).

The appearance of clitoromegaly and hirsutism at puberty in the presence of primary amenorrhoea is a classical presentation of 17β-hydroxysteroid dehydrogenase type 3 deficiency and 5α-reductase type 2 deficiency and can also be seen in SF-1 deficiency.[50] It is less typical of partial androgen insensitivity syndrome (PAIS) which is usually associated with atypical genitalia at birth. In all these conditions, Müllerian structures will not be detectable. Also, in partial gonadal dysgenesis and ovotesticular DSD, the mild clitoromegaly that may have been present at birth but overlooked, may become a more prominent feature at adolescence.[50] The differential diagnosis would also include 46, XX CAH and androgen-secreting tumours of the ovary or adrenal gland; in all these cases, Müllerian structures are present. Investigations include serum measurements of LH, FSH, DHEAS, SHBG, androstenedione, testosterone, dihydrotestosterone and 17OHP. A USP can confirm a diagnosis of 5α-reductase type 2 deficiency, disorders of androgen excess or adrenocortical tumour. A pelvic ultrasound will assess the presence of a uterus and determine the need for a chromosome analysis.

Although the commonest cause of delayed puberty is constitutional delay, all boys with delayed puberty who are over the age of 14 years should be assessed carefully.[51] Boys who are overweight or who have penoscrotal webbing need careful examination so that a normal penis is not mistaken for micropenis. Rarely, PAIS, a disorder of testosterone biosynthesis or mild forms of testicular dysgenesis can present in this age group, especially if there is a history of hypospadias repair, orchidopexy or gynaecomastia. First-line investigations include a bone age and serum measurements of LH, FSH and testosterone. For those with raised gonadotrophins, chromosome analysis should be performed to exclude conditions such as Klinefelter's syndrome (47, XXY and mosaic variants) or 45, X/46, XY mosaicism.