Since CAH is an autosomal recessive disease, most children with CAH are born to parents unaware of the risk and with no family history. Each child will have a 25% chance of being born with the disease. Classification The condition can be classified into "salt-wasting", "simple virilizing", and "nonclassical" forms. Type Sex steroid effects Other effects Severe<unk> -hydroxylase deficiency causes salt-wasting CAH The most common cause of ambiguous genitalia due to prenatal virilization of genetically female (XX) infants. Life-threatening vomiting and dehydration occurring within the first few weeks of life. Aldosterone and cortisol levels are both reduced. Moderate<unk> -hydroxylase deficiency is referred to as simple virilizing CAH Typically is recognized as causing virilization of prepubertal children. Cortisol is reduced, but aldosterone is not. Still milder forms of<unk> -hydroxylase deficiency are referred to as nonclassical CAH Can cause androgen effects and infertility in adolescent and adult women. Neither aldosterone nor cortisol are reduced. The salt-wasting and simple virilizing types are sometimes grouped together as "classical". Newborn screening Conditions justifying newborn screening for any disorder include (1) a simple test with an acceptable sensitivity and specificity, (2) a dire consequence if not diagnosed early, (3) an effective treatment if diagnosed, and (4) a frequency in the population high enough to justify the expense. In the last decade more states and countries are adopting newborn screening for salt-wasting CAH due to<unk> -hydroxylase deficiency, which leads to death in the first month of life if not recognized. The salt-wasting form of CAH has an incidence of 1 in 15,000 births and is potentially fatal within a month if untreated. Steroid replacement is a simple, effective treatment. However, the screening test itself is less than perfect. While the 17α-hydroxyprogesterone level is easy to measure and sensitive (rarely missing real cases), the test has a poorer specificity. Screening programs in the United States have reported that 99% of positive screens turn out to be false positives upon investigation of the infant. This is a higher rate of false positives than the screening tests for many other congenital metabolic diseases. Measurement of 17α-hydroxyprogesterone (17α-OHP) by LC-MS/MS reduces false positive rate in newborn screening in comparison to measurement by immunoassays. 17α-OHP steroid precursors and their sulphated conjugates which are present in the first two days after birth in healthy infants and longer in pre-term neonates, cross-react in immunoassays with 17α-OHP, giving falsely high 17α-OHP levels. When a positive result is detected, the infant must be referred to a pediatric endocrinologist to confirm or disprove the diagnosis. Since most infants with salt-wasting CAH become critically ill by 2 weeks of age, the evaluation must be done rapidly despite the high false positive rate. Levels of 17α-hydroxyprogesterone, androstenedione, and cortisol may play a role in screening. Additional markers While 17α-hydroxyprogesterone with or without ACTH stimulation is the main marker for<unk> -hydroxylase deficiency, other markers have been proposed, with various degrees of acceptance: *<unk> -Deoxycortisol is elevated in<unk> -hydroxylase deficiency. However, it is not elevated in preterm infants or in other forms of congenital adrenal<unk> . Unlike 17α-hydroxyprogesterone,<unk> -deoxycortisol is not produced in the gonads and is uniquely adrenal-derived. Consequently,<unk> -deoxycortisol it is a more specific marker of the<unk> -hydroxylase deficiency than 17α-hydroxyprogesterone. Even so,<unk> -deoxycortisol measurement has not been commonly performed by laboratories until 2019, thus, as of 2020, experience is limited. *<unk> -Deoxycorticosterone, also known as 11β-hydroxyprogesterone (11β-OHP), have been proposed as a marker in 1987. A study in 2017 has shown that in subjects with<unk> -hydroxylase deficiency, serum 11β-OHP concentrations range from 0.012 to 3.37 ng/mL, while in control group it was below detection limit of 0.012 ng/mL. This marker did not gain acceptance as of 2020 due to the fact that the test for the levels of this steroid is not routinely offered by diagnostic laboratories. * Progesterone levels are higher in CAH subjects. A study has revealed that serum progesterone concentrations in boys (10 days to 18 years old) with<unk> -hydroxylase deficiency reached levels up to 10.14 ng/mL, i.e. similar to female luteal values, while in the control group of boys average level was 0.07 ng/mL (0.22 nmol/L), with values ranging from 0.05 to 0.40 ng/mL. The authors of the study propose to use progesterone as an additional marker for<unk> -hydroxylase deficiency. The study shows that the progesterone levels in CAH and non-CAH females are the same as in CAH and non-CAH males respectively – it is the condition that affects progesterone levels, not the sex, but for women between menarch and menopause, progesterone should be measured in days 3-5 of the cycle to have diagnostic value – the same condition also applies for 17α-hydroxyprogesterone. The specificity of progesterone as a marker of<unk> -hydroxylase deficiency, as opposed to deficiency of other enzymes involved in steroid pathways, was not well studied as of 2020. * Cortisol is one of the two main final products of<unk> -hydroxylase, and the deficiency of this enzyme may lead to a certain degree of cortisol deficiency. Cortisol levels are lower in CAH subjects, on average, however, in milder cases cortisol levels can be normal, but as of 2020, this has not been yet well studied. Cortisol measurement using immunoassays is prone to cross-reactivity with various substances including<unk> -deoxycortisol that raises due to<unk> -hydroxylase deficiency, leading to falsely high cortisol levels when the true cortisol is actually low. The selectivity offered by liquid chromatography-tandem mass spectrometry (LC-MS/MS) has largely overcome these limitations. As a result, the use of LC-MS/MS instead of immunoassays in cortisol measurement aims to provide greater specificity. * 11-Deoxycortisol is a direct product of 17α-hydroxyprogesterone, with<unk> -hydroxylase catalyzing the reaction, and an intermediate product towards cortisol pathway. Reduced<unk> -hydroxylase activity leads to decreased levels of 11-deoxycortisol, but not all laboratories specify minimum reference value it, since it is mostly used as a biomarker for 11β-hydroxylase deficiency, where 11-deoxycortisol levels increase dramatically, so the laboratories may only specify the maximum reference value.
Congenital adrenal hyperplasia due to 21-hydroxylase deficiency
Congenital adrenal hyperplasia due to 17α-hydroxylase deficiency
Congenital adrenal hyperplasia due to 11β-hydroxylase deficiency
Congenital adrenal hyperplasia due to 3β-hydroxysteroid dehydrogenase deficiency
Primary pigmented nodular adrenocortical disease
Lipoid congenital adrenal hyperplasia
Cortisone reductase deficiency
Pituitary ACTH hypersecretion