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 Newborn Should be Investigated?

It is generally accepted that investigations are necessary in those cases where the appearance of the genitalia is such that sex assignment is not possible at birth or the appearance is not consistent with any prenatal genetic tests. However, the interpretation of the genital appearance and the ability to assign sex in some cases may depend on the expertise of the observer. Whilst the label of 'ambiguous genitalia' has often been assigned to newborns in whom the most appropriate sex of rearing is not immediately clear to those present at the child's birth, in most cases, the genitalia are not 'ambiguous' but simply 'atypical' and we recommend that the term 'atypical' should be used instead of 'ambiguous'. The birth prevalence of atypical genitalia may be as high as 1 in 300 births[31] but the birth prevalence of infants who require specialist input in the neonatal period is about 1 in 3000 and the birth prevalence of infants in whom sex assignment is delayed beyond birth may be as low as 1 in 11,000 births.[8]

When evaluating infants, the clinical features of the external genitalia that require examination include the presence of gonads in the labioscrotal folds, the fusion of the labioscrotal folds, the size of the phallus and the site of the urinary meatus on the phallus, although the real site of the urinary meatus may, sometimes, only become clear on surgical exploration.[32] These external features can be scored to provide an aggregate score, the external masculinization score (EMS).[33] More recently, the external genitalia score (EGS), has been developed as a gender-neutral alternative to the EMS.[34] The EGS describes the site of urethral meatus and genital tubercle length in greater detail but continues to have a high level of correlation to the original EMS tool.[34] In boys with atypical genitalia, a chromosomal anomaly may be present in approximately 3% of those with isolated cryptorchidism, 7% of those with hypospadias and 13% of those with a combination of cryptorchidism and hypospadias.[35] In boys with XY DSD, comprehensive investigations will reveal an endocrine or genetic abnormality in at least a quarter of cases.[36–39] Routine systematic examination of 423 consecutive, apparently healthy, term newborn boys revealed that 412 (98%) had the maximum EMS of 12, 10 had an EMS of 11 and only 1 out of 423 had an EMS of less than 11.[33] Thus, infants who require further clinical evaluation and need to be considered for investigation for a suspected DSD should include those with isolated perineal hypospadias, isolated micropenis, isolated clitoromegaly, any form of familial hypospadias, isolated bilateral undescended testes and those who have an EMS of less than 11 or an EGS of less than 10.5.[33,34] This will avoid unnecessary detailed investigations of boys with isolated glandular or mid-shaft hypospadias and boys with unilateral inguinal testis. In newborn girls, the length of the clitoris does not seem to be dependent on gestation and a newborn with a length greater than 8mm requires further evaluation.[40] Micropenis is defined as a stretched penile length of less than 2.5SD from the mean and based on contemporary studies from a wide range of countries, a stretched penile length of less than 2cm would represent a reasonable cut off for micropenis in the newborn.[34,41–45] In approximately 25% of affected cases, XY DSD is part of a complex multi-system condition[37,46] and the coexistence of a systemic metabolic disorder, other associated conditions or dysmorphic features would lower the threshold for investigation as would a family history of consanguinity, stillbirths, multiple miscarriages, fertility problems, genital abnormalities, hernias, delayed puberty, genital surgery, unexplained deaths and the need for steroid replacement. Knowledge of birthweight in XY DSD is very helpful given the well-reported association between low birthweight, intra-uterine growth retardation and XY DSD.[31,47]