Dr Margaret Sinnott, Dr Aimée Henry, Dr Shilpa Shah
This case (which has been anonymised) is an interesting one. It started with a midwife’s worry over a baby’s hyperpigmented scrotum found on baby check, and led us through other neonatal concerns including hypoglycaemia and neonatal sepsis until we reached the diagnosis of congenital adrenal hyperplasia.
The story
The baby was Caucasian and the first baby of non-consanguineous parents. On examination his scrotum was hyperpigmented with no other areas of hyperpigmentation identified. The genitalia appeared normal and testes were palpable in the scrotal sac.
The blood sugar was low at 2.6. We treated the baby with glucose as per our hypoglycaemia protocol and ensured good volume feeds – however he continued to have hypoglycaemic episodes and some vomiting, so he was admitted to the Special Care Baby Unit for monitoring (common things being common, we screened for sepsis and gave IV antibiotics). Bloods showed a normal potassium and a low sodium at 132.
Neonatal hypoglycaemia has many causes which are covered here – but in this case, with the hyperpigmented scrotum and the hyponatraemia being big clues, we had a high suspicion of congenital adrenal hyperplasia.
In this article we are going to
- Help you understand the enzyme deficiencies in CAH
- Look at how CAH is diagnosed and treated
- AND we are going to figure out just why on earth this problem with the adrenal gland would give you a hyperpigmented scrotum!
What does the adrenal gland do?
The adrenal gland takes cholesterol and within each zone of the gland, different enzymes convert cholesterol into different end products:
CAH: what’s the problem?
There is a deficiency (or complete absence) of one of the enzymes involved in the cortisol producing pathway. Some of these enzymes are also essential to the aldosterone pathway. The end steroid either can’t be produced, or is only produced in small amounts – which also leads to a buildup of the substrate the deficient enzyme would usually work on.
This substrate will then continue down another pathway, within which all the essential enzymes are working – so generating an excess of other products, for example androgens.
The most common enzyme deficiencies in CAH (and the only ones you really need to know about unless you are an endocrinologist!) are:
– 90-95% of cases
– 5-8% of cases
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What happens if you take 21-hydroxylase out of this pathway?
If 21-hydroxylase is missing or reduced, cortisol and aldosterone synthesis is impaired. This leads to an increase in progesterone and 17a hydroxyprogesterone – which instead take a different route, down the androgen pathway to make testosterone.
CAH is categorised into Classical and Non classical. Classical CAH is sub-categorised into ‘salt wasting’ (complete enzyme deficiency) and ‘simple virilising’ types.
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What is ‘salt wasting’?
Salt wasting means too much sodium is lost in the urine. Due to the deficiency of aldosterone sodium will not be reabsorbed in the distal tubules of the kidneys and potassium will be inappropriately retained. Water will follow the sodium out in the urine, therefore the patient will become dehydrated, hypovolemic and hypotensive. 75% of those with 21 hydroxylase deficient CAH will have salt wasting.
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Hang on… what causes the adrenal hyperplasia bit?
Cortisol levels are regulated by the Hypothalamic – Pituitary – Adrenal (HPA) axis.
Low cortisol makes the hypothalamus release Corticotrophin Releasing Hormone (CRH) and ACTH.
In CAH, the negative feedback loop continues as little or no cortisol is produced.
ACTH continues to be released, overstimulating the adrenal gland. Excess androgens are produced and the adrenal gland becomes enlarged but poorly functioning.
High ACTH levels lead to hyper pigmentation as – this is why a hyperpigmented scrotum can give us the suspicion of CAH!
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Investigations for diagnosis of CAH:
If the 21-hydroxylase enzyme is missing, 17-hydroxyprogesterone (17-OHP) will increase – so a raised 17-OHP level is diagnostic of classical CAH.
There are a few potential issues with this test. 17-OHP can be normal in non-classical CAH, and can be falsely elevated in stressed or prem neonates, and low in neonates exposed to antenatal steroids. For these reasons a corticotropin stimulation test is the gold standard for hormonal diagnosis – but by this point you need a Paediatric Endocrinologist involved (if they aren’t already)!
Other tests – A random urine sample in the first 24 hours of life can be analysed for steroid hormone metabolites and precursors, which can help an endocrinologist differentiate between the different types of CAH. Karyotype (if the baby has ambiguous genitalia) should be used to determine the genetic sex of the baby
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Treatment
Treating CAH means replacing the deficient steroids (cortisol and/or aldosterone) and reducing excess androgens. By replacing cortisol, you stop the HPA negative feedback loop and reduce the amount of androgens produced.
Glucocorticoids: is used as a cortisol replacement. Prednisolone and Dexamethasone aren’t used in childhood because they can suppress growth, but are used in adults with CAH – classical CAH is a condition which needs lifelong treatment. Children with non-classical CAH should have treatment if symptomatic but should be discontinued if symptoms resolve.
****– Dose should be increased in times of stress.
Mineralocorticoid: replaces aldosterone in salt-wasting CAH
Sodium replacement: Given to babies with salt-wasting CAH in the first year of life until adequately weaned onto solid food.
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Long term follow up
All children with CAH are seen regularly in the paediatric endocrine clinic. Their assessment will include
- Monitoring doses of steroid replacement drugs
- Height and weight – excess androgens can initially cause a child to grow rapidly, but lead to a shorter adult height because of premature closure of the epiphyseal plates. Excess glucocorticoid can also hinder growth. Bone age is assessed every 6-12 months.
- Blood Pressure – children with CAH are at risk of hypertension. Monitoring BP also helps to assess how effective aldosterone replacement is.
- Pubertal development – if CAH patients are properly treated, they will usually go through puberty at the expected time. Inadequate treatment or delayed diagnosis can result in central precocious puberty.
- Fertility – Females can have issues with fertility – those with salt wasting CAH being the most affected. Males – In the long term, boys who receive proper treatment can expect to have normal fertility. If not appropriately treated they can have a reduced sperm count. In teenage years and as an adult, regular testicular examinations and ultrasounds are needed to screen for Testicular Adrenal Rest Tumours.
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Summary
- CAH affects the production of cortisol, aldosterone and androgens causing a spectrum of conditions from life threatening to asymptomatic.
- The salt-wasting variant needs to be picked up early to prevent a salt losing adrenal crisis.
- CAH is easier to identify in girls as they often present with ambiguous genitalia.
- Regular, long term follow up is essential to monitor hormone replacement as well as keep track of growth and development.
Authors: Margaret Sinnott (ST3 Paediatrics), Aimée Henry (ST1 Paediatrics) & Shilpa Shah (Paediatric Consultant). Craigavon Area Hospital, Southern Health & Social Care Trust, Northern Ireland