HISTORY OF PRESENT ILLNESS
A 16-day-old male presented to the emergency department with a 24-hour history of decreased level of activity and a choking episode with a feed. The infant has breastfed poorly since birth, worsening during the past several days. Two days prior to presentation, he was started on cow-milk-based formula supplementation; however, he continued to feed poorly. On the day of presentation, when the infant began to take a bottle, he gagged and choked and his eyes appeared to “roll into the back of his head” for approximately 2 seconds. Parents denied tonic-clonic, jerking activity, or color change, although he was less active after this episode. The infant has had decreased urine output, with only one wet diaper in the preceding 24 hours.
This was the fourth child born to a 28-year-old mother at 36 weeks gestation. The pregnancy was complicated by preterm labor and the mother received magnesium tocolysis. At 36 weeks gestation, the magnesium was stopped and labor was allowed to progress. Delivery was uncomplicated. Maternal prenatal labs and cultures were reportedly normal. The child was discharged from the hospital on the second day of life.
T 37.5°C; HR 142 bpm; RR 32/min; BP 95/65 mmHg
Weight and Height 5th percentile
On examination he was observed as being thin appearing and awake, but only cried with stimulation. His anterior fontanel was sunken; his lips and mucous membranes were dry. He had decreased tear production. His lungs were clear. The cardiac examination revealed a normal rate and rhythm without any murmur or abnormal heart sounds. His abdomen was soft without any organomegaly. His extremities were cool with a 2-second capillary refill. Both testicles were descended. His neurologic examination was significant for symmetric hypotonia without any focal abnormalities.
The white blood cell count was 16 300 cells/mm3 (38% segmented neutrophils, 54% lymphocytes, and 6% monocytes). Hemoglobin level was 18.2 g/dL and platelet count was 658 000/mm3. The results of the basic metabolic panel revealed sodium level to be 115 mEq/L; potassium, 7.7 mEq/L; chloride, 81 mEq/L; bicarbonate, 16 mEq/L; blood urea nitrogen, 31 mg/dL; creati-nine, 1.0 mg/dL; glucose, 89 mg/dL; and calcium, 10.7 mg/dL. A serum ammonia level was 39 μg/dL. Lumbar puncture revealed 1 white blood cell/mm3. The cerebrospinal fluid glucose and protein were normal. Cultures of cerebrospinal fluid, blood, and urine were obtained.
COURSE OF ILLNESS
Acutely, the infant received IV normal saline boluses for fluid resuscitation, as well as management to correct his hyperkalemia. He was empirically treated with intravenous hydrocortisone as well as ampicillin and cefotaxime owing to his ill appearance. He was admitted to the neonatal intensive care unit for further evaluation. Careful consideration of the laboratory studies suggested a diagnosis.
DISCUSSION CASE 2-2
Hyponatremia with hyperkalemia in a 2-week-old infant is most concerning for adrenal crisis due to congenital adrenal hyperplasia (CAH). Less common causes for adrenal crisis include adrenal hypoplasia congenita and bilateral adrenal hemorrhage. Other causes of electrolyte abnormalities in a young infant include water intoxication, inappropriate formula preparation, and gastroenteritis. Acute renal failure is uncommon in this age group, but can cause significant electrolyte disturbance. If an ill-appearing infant presents primarily with vomiting, pyloric stenosis and malrotation should be included in the differential diagnosis.
Additional laboratory evaluation revealed markedly elevated levels of 17-hydroxyprogesterone (>120 000 ng/dL; normal 4-200 ng/dL), a precursor for 21-hydroxylase enzyme. Additionally, the ACTH level was markedly elevated at 541 pg/mL (reference range, 9-52 pg/mL). The laboratory pattern was consistent with a salt wasting form of congenital adrenal hyperplasia. The diagnosis is 21-hydroxylase deficiency.
INCIDENCE AND EPIDEMIOLOGY
The adrenal gland is responsible for the production of three categories of steroids; mineralcorticoids, glucocorticoids (cortisol), and androgens (dehydroepiandrosterone, androstenedione, 11-β-hydroxyandrostenedione, and testosterone). Congenital adrenal hyperplasia is a category of autosomal recessive enzyme disorders that result in a deficiency of cortisol synthesis. Cortisol deficiency results in hypersecretion of corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) and subsequent hyperplasia of the adrenal cortex. Depending on the location of the blockade, excesses or deficiencies of the mineralcorticoids and androgens can occur. The biochemical pathways of steroid synthesis are shown in Figure 2-2.
FIGURE 2-2. Adrenal steroid biosynthesis pathway.
The incidence of CAH ranges from 1 in 5000 to 1 in 15 000. Severity of illness depends on the severity of the genetic mutation. Although several enzyme deficiencies can result in CAH, 90%-95% are due to lack of 21-hydroxylase and 4% are due to 11β-hydroxylase deficiency. Other rare enzyme defects that have been described include 3β-hydroxysteroid dehydrogenase deficiency, 17a-hydroxylase deficiency, and cholesterol side chain cleavage enzyme deficiency, or lipoid CAH.
Clinical presentation of CAH depends on the gender of the patient as well as the enzyme deficiency. The key feature of classic 21-hydroxylase deficiency is androgen excess. Patients have inadequate production of glucocorticoids and miner-alocorticoids and subsequent ACTH stimulation. Excess precursors are shunted to the androgen pathway, leading to androgen excess and virilization. In the female, there is usually some degree of clitoromegaly and labial fusion. CAH is the most common cause of ambiguous genitalia in genetic females. The female internal genital organs are normal. Androgen excess in male infants is often limited to subtle penile enlargement.
While 25% of patients with 21-hydroxylase deficiency present with virilization alone, approximately 75% of patients will also present with salt wasting. Mineralocorticoid deficiency results in an inability to exchange potassium for sodium in the distal tubule of the nephron and hence there is sodium loss in the urine and an inability to secrete potassium. This electrolyte abnormality is referred to as salt wasting. Patients with the salt wasting type of CAH become symptomatic shortly after birth. They have progressive weight loss, dehydration, and vomiting. If the condition is not recognized, adrenal crisis and death occur.
Virilized females are often diagnosed at birth due to the ambiguous genitalia, whereas male patients may be diagnosed at one to two weeks of birth with a salt wasting CAH or in early childhood when they present with premature development of secondary sexual characteristics. Newborn screening for 21-hydroxylase deficiency is performed in most states in the United States of America.
The deficiency of 11β-hydroxylase results in both androgen and mineralocorticoid excess and therefore presents with virilization alone without salt wasting. Patients may have hypertension because of salt retention.
Other forms of CAH are extremely rare and may cause ambiguous genitalia in males. The 3β-hydroxysteroid dehydrogenase defect presents with salt wasting and virilization or ambiguous genitalia. The deficiency of 17a-hydroxylase may also cause hypertension and ambiguous genitalia. Lipoid CAH, while very rare, is often the most severe form, patients present with salt wasting and female phenotype.
There are several tests to assess for CAH.
Serum electrolytes. Hyponatremia, hyperkalemia, and hypoglycemia, while not adiagnostic, are often the laboratory abnormalities that prompt further investigation.
Other studies. In classic 21-hydroxylase deficiency, serum levels of 17-hydroxyprogesterone are markedly elevated. Interpretation of 17-hydroxyprogesterone levels in neonates is difficult because this level may be elevated in sick or premature infants and in healthy infants during the first two days of life. Cortisol levels are typically low in patients with salt wasting variety and normal in patients with virilization.
In 11-hydroxylase deficiency, the levels of 11-deoxycorticosterone and 11-deoxycortisol are elevated. The 3β-hydroxysteroid dehydrogenase defect will cause levels of 17-hydroxypregneno-lone to be elevated as well as 17-hydroxyprogesterone and hence may be confused with 21-hydroxylase deficiency.
Acutely, identification and management of adrenal crisis is critical. Aggressive fluid resuscitation and management of abnormal serum electrolytes as well as administration of stress dose IV hydro-cortisone are paramount.
Long-term management of CAH includes administration of glucocorticoids to inhibit excessive production of androgens. The most frequently recommended glucocorticoid is hydrocortisone administered orally. Dosages should be individualized based on growth and hormone levels. The administration of exogenous glucocorticoids continues indefinitely. Children with CAH require higher doses of glucocorticoids during periods of stress, such as illness, infection, and surgery. In the long term, patients with 21-hydroxylase deficiency reach an adult height below their predicted height based on mid-parental target height; treatment with growth hormone alone or in combination with a luteinizing hormone releasing hormone analog.
If the patient also has salt wasting, then mineralocorticoid replacement and sodium supplementation are also required. Fludrocortisone (florinef) is the currently recommended mineralocorticoid.
In the neonate with ambiguous genitalia, determining the sex is important. Consultation with a pediatric urologist can assist in achieving a more normal appearance. Because CAH is autosomal recessive, it is important to test siblings of affected patients.
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