What Investigations Should be Performed?
In all infants with atypical genitalia and/or bilateral impalpable gonads, a first tier of investigations should be undertaken to define the sex chromosomes and delineate, by pelvic ultrasound, the internal genitalia and exclude congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency—the commonest cause of a life-threatening condition that is associated with atypical genitalia in the newborn. This first tier should, therefore, also include plasma glucose, serum 17OH-progesterone (17OHP) and serial measurement of electrolytes. Serum 17OHP is usually unreliable before the age of 36 h, and in the salt losing form of CAH, serum electrolytes usually do not become abnormal before day 4 of life. Furthermore, 17OHP concentrations may be falsely elevated in premature or sick neonates and can also be elevated in rarer forms of CAH. The results of PCR or FISH analysis using Y and X-specific markers and the 17OHP results should be available within a maximum of two working days in all specialist centres. In situations where the level of suspicion of CAH is very high and the infant needs immediate steroid hormone replacement therapy, further serum and urine samples should be collected and stored before starting therapy. These should be of a sufficient volume to assess 17OHP, testosterone, androstenedione, renin activity and aldosterone, in that order of priority. Baseline or stimulated serum cortisol concentrations can be difficult to interpret in the newborn especially in the premature infant or following prenatal or postnatal exposure to glucocorticoids. At least one spot or 24-h urine sample (at least 5ml) for a urine steroid profile (USP) should be collected before starting therapy. The results of these initial investigations, and especially the karyotype, shall often dictate the second tier of investigations. It is imperative that a regional protocol that is easily available within the region by all healthcare staff has been developed for these first-tier investigations and this protocol should include details of sample collection and transport as well as contact details of key staff.
In an infant with atypical genitalia, impalpable gonads and a karyotype of 46, XX, and the presence of a uterus, the diagnosis of CAH due to 21-hydroxylase deficiency is very likely. A significantly elevated serum 17OHP as well as a wider range of androgens and a urine steroid profile can confirm this diagnosis and can also identify other rare forms of CAH such as 11β–hydroxylase deficiency. In other infants who are not 46, XX and have had CAH excluded, it is necessary to determine the presence of testes as well as the adequacy of androgen production and at the initial stage this will include the measurement of gonadotrophins, testosterone, serum anti-Müllerian hormone (AMH) and/or serum inhibin B as well as further detailed imaging and laparoscopy. A urine sample should also be collected to assess proteinuria. However, the onset of proteinuria in the glomerulopathy associated with WT1 variants is very variable and if there is a high suspicion then there may be a need for repeated assessments.
Clin Endocrinol. 2021;95(6):818-840. © 2021 Blackwell Publishing