Ambiguous genitalia Pathology Case Study No.14

Ambiguous genitalia Pathology Case Study No.14 is being discussed here. A short is given of the patient and you should try to find the reason and cause of Ambiguous genitalia and at the end the answer is given for the ease. Now let’s move to the scenario

History of Ambiguous genitalia:

A 25-year-old refugee takes her 10-day-old son to the hospital after finding the least child response than normal, does not eat properly, and vomits several times in the past Few days. The baby was born vaginally at term by the child’s aunt and the mother received no prenatal or postnatal care.

Examination:

Examination reveals an ill-looking neonate with evidence of dehydration (HR 180, BP 65/30, CRT 3s, sunken fontanelles). There are no rashes. On unclothing the child and examining the external genitalia, a phallic-appearing structure is noted and there is fusion of the skin folds surrounding it. No testes are palpated and the physician is uncertain about the sex of the neonate.

Investigation:

  • Haemoglobin: 17
  • Hematocrit: 55%
  • White cells: 14
  • Sodium: 135
  • Potassium: 6.2
  • Urea: 19.5
  • Creatinine: 65ABG (on air): pH 7.28

Requirement:

  1. What are the possible causes of ambiguous genitalia? What are the basic principles of evaluating this condition?
  2. What is the likely diagnosis in this case and why?
  3. What treatment does this baby now require?

 

Solution:

About 1 in 4500 newborns has what can be considered “ambiguous genitalia.” Broadly speaking, there are two causal categories of ambiguous genitalia:

1. Virilized XX woman. This can be the result of androgens of fetal origin (eg, congenital adrenal hyperplasia [CAH]) or maternal (eg, drugs such as progesterone and danazol, androgen-secreting maternal tumors of the ovary or adrenal gland). The other main causes are dysmorphic disorders such as Beckwith-Wiedemann and Seckel syndromes.

2. Undervirilized XY male. This may be due to a biosynthetic defect leading to reduced fetal androgen production (eg, Leydig cell defects, 5-α-reductase deficiency, anti-Müllerian hormone deficiency), unresponsiveness of end organs to androgens (androgen insensitivity syndrome), dysmorphic syndromes (eg, Smith-Lemli-Opitz), and testicular dysgenesis or dysfunction.

Evaluation of ambiguous genitalia should begin with the history to look for the use of any drugs that may cause female virilization, any evidence of maternal virilization that may suggest an androgen-secreting maternal tumor, and any family history of a genetic disorder.

A complete examination of the child is required to assess the child’s general condition, identify dysmorphic features, and evaluate the external genitalia (number of gonads, degree of virilization, length of the phallus, and any hyperpigmentation suggesting excessive adrenocorticotropic hormone [ACTH] production) . The most important initial tests are to determine the karyotype and evaluate the internal anatomy using pelvic ultrasound. The other priority is avoiding a salt loss crisis (seen in CAH); therefore, blood tests are required for levels of electrolytes, LH, FSH, and androgens (testosterone, DHEA, androstenedione, and 17-OH-progestrone). In this newborn, the physical examination is consistent with clitoromegaly and labial fusion, suggesting a virilized XX female, although a formal karyotypic analysis is required for confirmation. Blood tests are informative of the diagnosis as they reveal mild hyponatremia, hyperkalemia, evidence of hypovolemia, and acidosis. These are consistent with the salt-wasting form of 21-hydroxylase deficiency, the enzyme defect that accounts for more than 90% of CAH cases.

CAH is an autosomal recessive condition caused by deficiencies in one of the five enzymes necessary for the synthesis of adrenal steroids (see Figure 20.1). 21-hydroxylase is required for the synthesis of aldosterone and cortisol, but not that of adrenal androgens. Cortisol deficiency leads to positive feedback regulation of ACTH, which overstimulates the adrenal cortex and leads to adrenal hyperplasia. Since there is a blockage in the production of adrenal mineralocorticoids and glucocorticoids, steroid precursors are diverted into the androgen pathway, leading to their overproduction and subsequent virilization. Aldosterone and cortisol deficiency leads to a state of adrenal insufficiency, causing hyponatremia, hyperkalemia, acidosis, and circulatory collapse (typically between days 5 and 15).

This case illustrates the severest form of 21-hydroxylase deficiency, the so-called ‘salt-wasting’ subtype, where there is total lack of the enzyme. Partial enzyme deficiency produces a less severe phenotype (‘simple virilizing’) with adequate aldosterone production, and hence no fluid or electrolyte losses, but with still a strong virilizing effect. Non-classic 21-hydroxylase deficiency is commoner than classic forms of the disease and produces late-onset and mild clinical symptoms (e.g. premature puberty, tall stature, hirsuitism, oligomenorrhoea), usually without gross virilization at birth image
Figure 20.1 Adrenal steroid biosynthetic pathway

This case illustrates the severest form of 21-hydroxylase deficiency, the so-called ‘salt-wasting’ subtype, where there is total lack of the enzyme. Partial enzyme deficiency produces a less severe phenotype (‘simple virilizing’) with adequate aldosterone production, and hence no fluid or electrolyte losses, but with still a strong virilizing effect. Non-classic 21-hydroxylase deficiency is commoner than classic forms of the disease and produces late-onset and mild clinical symptoms (e.g. premature puberty, tall stature, hirsuitism, oligomenorrhoea), usually without gross virilization at birth.

The diagnosis of 21-hydroxylase deficiency can be made by the finding of randomly elevated levels of 17-hydroxyprogesterone in the blood. Measurement of this metabolite after ACTH stimulation can help determine the clinical subtype, with the highest levels being seen with the salt-wasting forms and the lowest levels with nonclassical deficiency. Management of this infant involves urgent fluid resuscitation with subsequent glucocorticoid and mineralocorticoid replacement. The other problem is that of virilized genitalia, which can be surgically corrected in the first year of life.

Key Points

  • Ambiguous genitalia in a newborn may represent either an over-virilized XX female
    or an under-virilized XY male.
  • Congenital adrenal hyperplasia is usually due to a deficiency of 21-hydroxylase,
    and is a common cause of ambiguous genitalia.
  • When 21-hydroxylase is completely deficient, newborns may present with a ‘salt-wasting’ crisis as a result of their lack of mineralocorticoids.

Reference Book: 100 Cases in Clinical Pathology

 

Recommended:

 

Check more articles here

 

Medical Tools here

 

More Case studies here

One comment

Leave a Reply

Your email address will not be published.