OVERVIEW: What every practitioner needs to know
Are you sure your patient has congenital adrenal hyperplasia? What are the typical findings for this disease?
Congenital adrenal hyperplasia (CAH) describes a group of autosomal recessive disorders resulting from a deficiency in one of the enzymes involved in adrenal steroid synthesis. Impaired cortisol synthesis leads to chronic elevations of ACTH and overstimulation of the adrenal cortex resulting in a hyperplastic gland.
The five forms of CAH are summarized in Table I. Impaired enzyme function at each step of adrenal cortisol biosynthesis leads to a unique combination of retained precursors and deficient products. The most common enzyme deficiency, accounting for more than 90% of all CAH, is 21-hydroxylase deficiency (21-OHD). Steroid 21 OHD CAH is the focus of this chapter. Clinical presentation of steroid 21 OHD CAH can vary from mild cases presenting with hyperandrogenic symptoms in adolescence to severe cases presenting with adrenal crisis in the newborn period.
Typical findings of CAH
Females with the salt wasting and simple virilizing forms of classical CAH present with ambiguous genitalia or virilization of a female genitalia in the newborn period. Beginning in utero, prenatal exposure to potent androgens such as testosterone and androstenedione at critical stages of sexual differentiation virilizes the external genitalia of genetic females. The genital ambiguity may be noted on prenatal ultrasound or on physical exam at birth. The degree of genital virilization ranges from mild clitoral enlargement alone to penile urethra with complete labial fusion in rare cases.
Males with salt wasting and simple virilizing forms of classical CAH do not present with ambiguous genitalia. Affected males who are not detected by a newborn screening program are at high risk for a salt-wasting adrenal crisis because their normal male genitalia do not alert medical professionals to their condition. They are often discharged from the hospital after birth without diagnosis. They may present with poor feeding, weight loss, failure to thrive, vomiting, dehydration, or hypotension as a result of inadequate secretion of the salt retaining steroid, aldosterone.
Hyponatremia, hyperkalemia and metabolic acidosis can be seen on laboratory evaluation. This may progress to adrenal crisis with azotemia, vascular collapse and shock if not diagnosed early. Adrenal crisis usually occurs between 1-4 weeks of life. Due to the benefit of early disease detection in preventing morbidities and mortalities, all newborns in the United States are now being routinely screened for this potentially life-threatening disorder. Therefore, most males are diagnosed with CAH prior to the development of symptoms.
In the simple virilizing forms, males will develop premature pubic, axillary hair and acne. Hyperandrogenism during childhood is often associated with rapid linear growth and bone age advancement. This may negatively affect final height.
The nonclassical form of CAH is due a mild deficiency of the 21-hydroxylase enzyme and may present with variable hyperandrogenic symptoms including hirsutism, and acne at any age after birth. These patients can present similar to classical CAH with premature development of pubic, axillary hair, acne and bone age advancement.
Hyperandrogenic symptoms can be more prominent in females and may lead to secondary amenorrhea and infertility. This should be distinguished from Polycystic Ovarian Syndrome.
The clinical manifestations of the different disorders are due to diminished production of cortisol and, depending upon the site of block, decreased or increased production of mineralocorticoids and androgens. 11-beta hydroxylase deficiency may mimic 21 OHD CAH as it leads to virilization, but is associated with increased mineralocorticoid function. 17-alpha-hydroxylase deficiency, 3-beta-hydroxysteroid dehydrogenase deficiency, and lipoid adrenal hyperplasia (STAR deficiency) present with decreased androgen; the latter two are also associated with mineralocorticoid deficiency.
Another rare form of CAH not included in Table I is cytochrome P450 oxidoreductase deficiency, caused by mutations in POR. Urinary steroid excretion indicates an apparent combined partial deficiency of the three steroidogenic enzymes P450C17 (17-hydroxylase), P450C21 (21-hydroxylase) and P450aro (aromatase) because of its necessary role in electron transfer from NADPH to enable enzymatic functions. The phenotypic spectrum of POR deficiency ranges from isolated steroid abnormalities to classic Antley-Bixler syndrome (ABS) in severe cases.
Individuals with POR deficiency have cortisol deficiency, ranging from clinically insignificant to life threatening. Newborn males have ambiguous genitalia, including small penis and undescended testes; newborn females have vaginal atresia, fused labia minora, hypoplastic labia majora, and/or large clitoris. Craniofacial features of ABS can include craniosynostosis, choanal stenosis or atresia, stenotic external auditory canals, and hydrocephalus. Skeletal anomalies involve radiohumeral synostosis, neonatal fractures, congenital bowing of the long bones, camptodactyly, joint contractures, arachnodactyly, and clubfeet.
What other disease/condition shares some of these symptoms?
Ambiguous genitalia or virilization of a female newborn is most commonly caused by 21 OHD CAH. However, exposure to maternal androgens excess in utero must also be considered. This includes exogenous androgens and progestagens, virilizing ovarian or adrenal tumor, and luteoma of pregnancy. Placental aromatase deficiency, a rare disease, is also associated with prenatal virilization. Furthermore, there are chromosomal abnormalities and syndromes of congenital abnormalities that may present with ambiguous genitalia.
Symptoms of the salt wasting form of CAH are nonspecific and include poor feeding, failure to thrive, dehydration, and hypotension. Therefore, the differential diagnosis is wide. Laboratory evaluation is crucial for diagnosis. Hyperkalemia is a major indicator of salt wasting and adrenal crisis. Renal failure, hyperkalemic distal renal tubular acidosis, hypoaldosteronism, and aldosterone resistance should be considered on the differential of hyperkalemia in an infant. The constellation of electrolyte disturbances of hyponatremic hyperkalemic metabolic acidosis with or without hypoglycemia, differentiates 21 OHD CAH from these other etiologies.
What caused this disease to develop at this time?
In the adrenal cortex, there are three pathways that lead to the production of the major adrenal steroid hormones: glucocorticoids (particularly cortisol), mineralocorticoids (particularly aldosterone) and androgens. This occurs through a cascade of reactions by several enzymes, including a series of cytochrome P450 enzymes. The most common form of CAH is 21-hydroxylase deficiency which accounts for more than 90% of cases.
When the function of 21-hydroxylase is inadequate or deficient, the cortisol production pathway is blocked, leading to the accumulation of 17-hydroxyprogesterone (17-OHP). The excess 17-OHP is shunted into the intact androgen pathway where the 17, 20-lyase enzyme converts the17-OHP to androstenedione, which is converted into androgens. This leads to cortisol deficiency and androgen excess. Since the mineralocorticoid pathway requires minimal 21-hydroxylase activity, mineralocorticoid deficiency (salt wasting) is a feature of severe forms of the disease only. Adrenal aldosterone secretion is insufficient for sodium reabsorption by the distal renal tubules, resulting in salt wasting.
The lack of steroid product impairs the negative feedback control of adrenocorticotropin (ACTH) secretion from the pituitary, leading to chronic stimulation of the adrenal cortex by ACTH, resulting in adrenal hyperplasia. Deficiency of cortisol also affects the development and functioning of the adrenal medulla, resulting in lower epinephrine and metanephrine concentrations than those found in unaffected individuals.
Stressful events such as febrile illness, gastroenteritis with dehydration, surgery accompanied by general anesthesia, and major trauma can precipitate adrenal crisis as patients with CAH are unable to increase production of glucocorticoids and mineralocorticoids in response to stress.
What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?
Laboratory studies needed to diagnosis CAH is based on the clinical presentation. In an ill appearing infant or child with suspected salt wasting or adrenal crisis, a basic metabolic panel and blood glucose level should be obtained immediately. Hyponatremic, hyperkalemic metabolic acidosis and hypoglycemia will be evident. To confirm the diagnosis of CAH, in particular 21 OHD CAH, 17-hydroxyprogesterone and adrenal androgens (androstenedione, dehydroepiandrosterone, and testosterone) concentrations along with a plasma renin activity and aldosterone concentration are needed. A very elevated 17-hydroxyprogesterone concentration (>4,000 ng/dl) is diagnostic.
In a well appearing child suspected of CAH, an initial evaluation should include a basic metabolic panel along with a 17-OHP concentration. In newborns, this blood sample should be drawn after 48 hours of life. Outside the newborn period, values of 17-OHP on a randomly timed blood samples may not be sufficiently elevated to allow accurate diagnosis. It should also be noted that the normal ranges of 17-OHP concentrations vary for sex and pubertal status and are subject to vary based on the methods utilized by the laboratory.
If the child is hemodynamically stable without metabolic derangements, a corticotropin stimulation test with 250 µg cosyntropin intravenous should be performed to confirm the diagnosis as it is considered the gold standard for diagnosis of nonclassical CAH and enigmatic cases. 17-hydroxyprogesterone, androstenedione, dehydroepiandrosterone, and testosterone concentrations should be obtained at baseline and 60 minutes after administration of cosyntropin. The nomogram relating baseline to ACTH-stimulated serum concentrations of 17-hydroxyprogesterone provides hormonal standards for assignment of 21OHD CAH (See Figure 2).
Hormonal values may be plotted along the regression line and patients are assigned to either the unaffected, carrier or affected categories. Concentrations of the adrenal androgens (androstenedione, dehydroepiandrosterone and testosterone) will be markedly elevated at baseline and further elevated post cosyntropin. Genetic analysis of CYP21A2 gene is suggested when the ACTH stimulation test produces equivalent results or when needed for genetic counseling.
Plasma renin activity (PRA) or direct measurement of renin is helpful in diagnosing salt-wasting forms of CAH. Levels are markedly elevated in individuals with salt-wasting CAH and can be slightly elevated in some with simple virilizing forms of CAH. The serum concentration of aldosterone is inappropriately low compared to the level of renin elevation in salt-wasting CAH.
The newborn screening program is crucial in identifying infants with the classical form of 21 OHD CAH who are at risk for life-threatening salt-wasting crises and females with severe virilization. All US states and 12 other countries include 21-OHD CAH in a mandated universal newborn screening program. The concentration of 17-OHP is measured on a filter paper blood spot sample obtained by the heel-stick technique as used for newborn screening for other disorders. The assay’s sensitivity has been reported as 83%-100%.
Studies reported 40-70% children with CAH were first identified by screening. The current newborn screening program is not designed to detect individuals with the nonclassical form of 21-OHD CAH but may identify some cases. If the 17-hydroxyprogesterone concentration is clearly above the normal range for gestational age, the infant should be evaluated urgently to obtain confirmatory tests including serum 17-OHP, electrolytes and renin.
Confirming the diagnosis
See Figure 1.
If you are able to confirm that the patient has congenital adrenal hyperplasia, what treatment should be initiated?
The main goals of medical therapy for CAH are (1) to replace deficient cortisol with a suitable glucocorticoid, (2) to reduce ACTH oversecretion and thereby prevent excessive androgen secretion, and (3) to replace deficient aldosterone with suitable mineralocorticoid and sodium supplements.
Hydrocortisone (HC) is the preferred treatment for glucocorticoid deficiency in children with CAH. The typical dose of HC in growing CAH patients is 10-15 mg/m2/day divided into 2 or 3 doses per day. Patients with classical 21-OHD CAH require lifelong administration of glucocorticoids. After linear growth is complete, more potent glucocorticoids (such as prednisone and dexamethasone) that tend to suppress growth in childhood can be used.
It is recommended that all patients with classic CAH be treated with fludrocortisone and sodium chloride supplements in the newborn period and early infancy. The typical dose of fludrocortisone is 0.05-0.2 mg daily. Sodium chloride supplementation of 1-2 grams daily divided into 4-6 doses per day is recommended in infancy. The requirement for fludrocortisone and sodium chloride supplementation appears to diminish with age. Patients should be monitored regulary for oversuppression of the renin-angiotensin axis and to prevent complications from hypertension and excessive mineralocorticoid activity.
In cases of non-life threatening illness or physiologic stress, the glucocorticosteroid dose should be increased to >3 times the daily maintenance dose (approximately 30-50 mg/m2/day). This increased dose of HC should be divided into 3 or 4 doses per day. If patients are on long-lasting HC equivalents such as dexamethasone, it is recommended that they be converted to hydrocortisone during times of stress because of the long onset of action of hydrocortisone equivalents. Examples of such situations include febrile illness (>38.5°C), gastroenteritis with dehydration, and minor trauma.
Patients and families should be given injection kits of hydrocortisone for emergency use. Hydrocortisone is to be administered intramuscularly. The typical doses are 25 mg for infants, 50 mg for children and 100 mg for adults. Examples of such situations requiring IM hydrocortisone include severe illness, persistent vomiting, unconsciousness and major trauma. Afterwards, patients should be continued on 50-100 mg/m2/day divided into 3-4 doses per day during severe stress.
The Endocrine Society currently recommends increasing the glucocorticosteroid dosage of patient with classical CAH during surgery accompanied by general anesthesia. However, there are no specific guidelines for the dose increase. Our current institutional protocol is to give 25 mg/m2 of hydrocortisone at induction of anesthesia and 50 mg/m2 of hydrocortisone during the operation. Afterwards, patients receive 50 mg/m2 divided every 6 hours during the first 24 hours postoperatively and tapered down to normal preoperative doses over 3-4 days.
Increased glucocorticosteroid doses are not recommended in cases of mental and emotional stress, minor illness, and before physical exercise. We also recommend against the use of stress doses of GC in patients with non-classic CAH unless their adrenal function is suboptimal or iatrogenically suppressed by therapy with glucocorticosteroids.
Those with non-classical 21 OHD CAH are also treated with HC, but the dosage requirements for patients with nonclassical CAH may be less. Most adult males with NC-21 OHD CAH are asymptomatic and often remain undiagnosed; therefore, treatment is generally not necessary. Glucocorticoid treatment may prevent the development of adrenal adenomas.
Routine follow up is recommended every 3 months when children are actively growing. Evaluation may be less often thereafter. Physical exam should focus on linear growth, weight gain, pubertal development, clinical signs of cortisol and androgen excess, and blood pressure. Early morning serum concentrations of 17-OHP, androstenedione, and testosterone should be obtained every 3 months during infancy and every 3-6 months thereafter. Plasma renin activity should be measured regularly in patients with salt wasting CAH. Bone age should be assessed every 6-12 months.
Would imaging studies be helpful? If so, which ones?
Small studies have shown that the adrenals are enlarged on ultrasound in patients with CAH. However, ultrasound cannot be used to reliably diagnose 21 OHD CAH. Imaging studies such as abdominal and pelvic MRI may be helpful if tumors are suspected.
What are the adverse effects associated with each treatment option?
All glucocorticosteroid treated patients should be monitored for iatrogenic Cushing syndrome. Signs and symptoms of Cushing syndrome are centripetal obesity, facial plethora, glucose intolerance, hypertension, hypertension and abdominal striae. Elements of the visit helpful evaluating for excessive glucocorticosteroid dosing are the growth chart for height and weight in children, distribution of bodyfat, presence of pigmented striae, blood pressure measurements, and blood glucose determinations.
Inadequate glucocorticosteroid doses either from underdosing or noncompliance may lead to a state of hyperandrogenism or progression of virilization. Also, due to unregulated ACTH, the adrenal tissue may be overstimulated and lead to hyperplasia and in some cases, testicular adrenal rest tumor in males and myelolipomas in adults.
Long-term glucocorticoid treatment coupled with increased androgens may lead to undesirable metabolic effects in patients with 21 OHD CAH. Increased body mass index and body fat mass have been described in 21 OHD CAH. Higher fasting plasma insulin with reduced insulin sensitivity and elevated serum leptin have also been reported in 21 OHD CAH patients as has a higher frequency of gestational diabetes. Other cardiovascular risk factors, such as increased carotid intima-media thickness and hypertension have been described as well.
Bone mineral density (BMD) is affected by the competing actions of androgen excess (from under treatment) and glucocorticoid excess (from over-treatment) which can both occur simultaneously in a patient. In order to adequately suppress androgen production in patients with 21 OHD CAH, the usual requirement of hydrocortisone is generally higher than the endogenous secretory rate of cortisol. Chronic therapy with glucocorticoids at supraphysiologic levels can result in diminished bone accrual and lead to osteopenia and osteoporosis. Glucocorticoid induced bone loss is a well-known phenomenon and is the most prevalent form of secondary osteoporosis.
Excessive fludrocortisone dosing may lead to a state of mineralocorticoid excess presenting with hypo-reninemic, hypokalemic metabolic alkalosis and hypertension. Inadequate fludrocrotisone dosing cause a patient to be more susceptible to salt wasting and volume depletion. Chronic mineralocorticoid deficiency may prevent normal weight gain.
What are the possible outcomes of congenital adrenal hyperplasia?
If 21 OHD CAH is left untreated or undertreated, the continued exposure to excessive androgens causes progressive penile or clitoral enlargement, the development of premature pubic hair, axillary hair and acne. Hyperandrogenism during childhood often leads to rapid linear growth accompanied by premature epiphyseal maturation and closure, resulting in a final adult height that is typically below that expected from parental heights (on average -1.1 to -1.5 SD below the mid-parental target height).
Precocious puberty may also occur as a result of excessive androgens. Fertility may be affected in females with 21 OHD CAH because of various reasons such as anovulation, secondary polycystic ovarian syndrome, irregular menses, non-suppressible serum progesterone levels, or an inadequate introitus. Those with the salt-wasting form are more often affected.
Children with salt wasting CAH are at risk for significant mortality and morbitiy as this condition can be life-threatening when inadequately treated. Infants with salt wasting CAH may develop poor feeding, weight loss, failure to thrive, vomiting, dehydration, hypotension, hyponatremia, and hyperkalemic metabolic acidosis progressing to adrenal crisis. Adrenal crisis represents a major cause of morbidity and death in childhood. Infant mortality from CAH is estimated between 0%-4%.
What causes this disease and how frequent is it?
Hormonally and clinically defined forms of 21 OHD CAH are associated with distinct genotypes characterized by varying enzyme activity demonstrated through in vitro expression studies. The gene encoding 21 hydroxylase is a microsomal cytochrome P450 termed cytochrome P450, family 21, subfamily A, polypeptide 21 (CYP21A2) located on the short arm of chromosome 6, within the human leukocyte antigen (HLA) complex. More than 150 mutations have been described including point mutations, small deletions, small insertions and complex rearrangements of the gene.
In recessive disorders, the less severe mutation of the two alleles typically dictates phenotype. Classical 21 OHD is most often caused by two alleles with severe mutations. In contrast to the classical form, patients with NC 21 OHD are predicted to have mild mutations on both alleles or one severe and one mild mutation (compound heterozygosity) of CYP21A2.
Approximately 1% of mutations occur de novo. The incidence ranges from 1:10,000 to 1:20,000 births. It is more prevalent in some ethnic groups, particularly in remote geographic regions such as Alaskan Yupiks. Nonclassical forms of CAH are more prevalent; it occurs in approximately 0.1 -0.2% of the general Caucasian population. However, its occurrence is increased to 1-2% in inbred populations such as the Ashkenazi Jewish.
How do these pathogens/genes/exposures cause the disease?
(See what causes this disease)
Other clinical manifestations that might help with diagnosis and management
What complications might you expect from the disease or treatment of the disease?
(See adverse effects and possible outcomes)
Are additional laboratory studies available; even some that are not widely available?
Measurement of other steroids that are expected to be elevated in 21 OHD CAH may be obtained to support the diagnosis. These included 21-deoxycortisol, androstenedione, and testosterone. Plasma renin activity and aldosterone concentrations can be obtained to differentiate the salt wasting form from the simple virilizing form. Molecular genetic testing of the CYP21A2 gene for a panel of nine common mutations and gene deletions detects approximately 80%-98% of disease-causing alleles in affected individuals and carriers.
How can congenital adrenal hyperplasia be prevented?
Congenital adrenal hyperplasia is inherited in an autosomal recessive pattern with most parents being heterozygotes. There is currently no preventative treatment.
What is the evidence?
Nimkarn, S, Lin-Su, K. “Steroid 21 hydroxylase deficiency congenital adrenal hyperplasia”. Endocrinol Metab Clin NorthAm. vol. 38. pp. 699-718.
Nimkarn, S. “New MI (Updated Aug 24, 2010) 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia”.
Speiser, PW, Azziz, R, Baskin, LS. “Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline”. J Clin Endocrinol Metab. vol. 95. pp. 4133-4160.
Pang, S, Shook, MK. “Current Status of Neonatal Screening for Congenital Adrenal Hyperplasia”. Current Opinion in Pediatrics. vol. 9. pp. 419-423.
Muthusamy, K, Elamin, MB, Smushkin, G. “Clinical review: Adult height in patients with congenital adrenal hyperplasia: a systematic review and metaanalysis”. J Clin Endocrinol Metab. vol. 95. pp. 4161-4172.
Wilson, RC, Nimkarn, S, Dumic, M. “(2007) Ethnic-specific distribution of mutations in 716 patients with congenital adrenalhyperplasia owing to 21-hydroxylase deficiency”. Mol Genet Metab. vol. 90. pp. 414-421.
Ongoing controversies regarding etiology, diagnosis, treatment
Genital ambiguity in female fetuses may be reduced or eliminated by suppressing fetal androgen production through administration of dexamethasone to the mother beginning early in gestation and continuing until delivery. Howeevr, prenatal treatment is considered experimental and should only be used within the context of a formal IRB-approved clinical trial.
Conventional surgical repair in females with ambiguous genitalia caused by CAH generally included removing redundant erectile clitoral tissue while preserving the sexually sensitive glans clitoris and vaginoplasty to provide a normal vaginal orifice that functions adequately for menstruation, intromission and delivery. Feminizing surgery with clitoroplasty is cosmetic and possibly harmful to future sexual functioning and therefore is controversial and even considered unethical by many until the young woman can consent with a full understanding of the risks and benefits.
Vaginoplasty is less controversial and many urologists recommend it be done earlier rather than later given some evidence of increased risk of urinary tract infections as a result of pooling of urine in the urogenital sinus. A discussion of the controversy and all possible therapeutic options for the child, including early versus delayed surgery, should occur with the parents. A multidisciplinary approach with pediatric endocrinolgy, urology, genetics and psychology is important when considering surgical repair. Emphasis should be on functional outcome rather than a strictly cosmetic appearance.
The standard treatment of CAH is glucocorticoids in all forms of CAH and mineralocorticoticoids in the salt wasting form. Growth and development are major focuses of attention when treating patients with CAH. Short stature may result from hypercortisolism associated with excessive doses of glucocorticoids and hyperandrogenism associated with poorly controlled CAH. Treatments such as growth hormone therapy, GnRH agonists, and aromatase inhibitors have been used to improve final adult height, but are considered experimental.
Bilateral adrenalectomy may be considered only in selected cases that have failed medical therapy, especially in rare cares of adult females with salt wasting CAH and infertility. Furthermore, risk for non compliance leading to potential fatal adrenal crisis must be considered before surgery.
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- OVERVIEW: What every practitioner needs to know
- Are you sure your patient has congenital adrenal hyperplasia? What are the typical findings for this disease?
- What other disease/condition shares some of these symptoms?
- What caused this disease to develop at this time?
- What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?
- Confirming the diagnosis
- If you are able to confirm that the patient has congenital adrenal hyperplasia, what treatment should be initiated?
- Would imaging studies be helpful? If so, which ones?
- What are the adverse effects associated with each treatment option?
- What are the possible outcomes of congenital adrenal hyperplasia?
- What causes this disease and how frequent is it?
- How do these pathogens/genes/exposures cause the disease?
- Other clinical manifestations that might help with diagnosis and management
- What complications might you expect from the disease or treatment of the disease?
- Are additional laboratory studies available; even some that are not widely available?
- How can congenital adrenal hyperplasia be prevented?
- What is the evidence?
- Ongoing controversies regarding etiology, diagnosis, treatment