Adrenal Hypoplasia

The roles of DAX1 and the undefined autosomal recessive gene in development of the adrenal cortex are not understood.[13] DAX1 appears to be necessary for differentiation of the definitive adult adrenal cortex but not the fetal adrenal cortex because the latter is preserved in patients who have deletions of DAX1. The autosomal recessive gene appears to be important in the development of both the fetal adrenal cortex and the definitive adult adrenal cortex because both are hypoplastic in this form of congenital adrenal hypoplasia.

X-linked congenital adrenal hypoplasia is due to mutation in, or deletion of, the DAX1 (AHCH) gene. The AHCH gene is located on chromosome bands Xp21.3-Xp21.2 and is thought to code for a nuclear receptor; however, the ligand for this particular nuclear receptor is not known, and hence, it is called an orphan nuclear receptor.

The DAX1 gene is also expressed in an alternatively spliced transcript, DAX1a. DAX1 and DAX1a appear to heterodimerize and also dimerize with SF1.[13] DAX1 appears to suppress expression of the SF1- regulated steroidogenic acute regulatory (StAR) protein promoter. How loss of this function results in loss of hypothalamic and adrenal cortical development remains unclear. DAX1 also appears to function as an antitestis gene by acting antagonistically to the sex-determining region (SRY).[14]  In mice, DAX1 or AHCH is essential for the maintenance of spermatogenesis. Lack of the gene product causes progressive degeneration of the testicular germinal epithelium independent of abnormalities in gonadotropin and testosterone production. These changes result in male sterility. Excess expression of DAX1 in the male mouse results in reversal of phenotypic sex.

DAX1 gene mutations result in significant genotypic-phenotypic variability.[15, 16, 17, 13]

• In one family, a DAX1 mutation resulted in congenital adrenal hypoplasia and hypogonadotropic hypogonadism in two brothers. A normal phenotype was found in the affected maternal grandfather, and hypogonadotropic hypogonadism with normal adrenal function was found in a maternal aunt who was homozygous for the mutation.[18]

• The "minipuberty" infancy may be preserved.[19]  Ovaries are intact in affected women.

• Observations in the SF1 knockout mouse and in humans indicate that mutations in SF1 result in congenital adrenal hypoplasia and hypogonadotropic hypogonadism as well. In contrast to DAX1 mutations, however, the phenotype in SF1 defects extends to XY sex reversal (ie, XY karyotype and female external genital appearance), persistence of müllerian structures in XY individuals, and failure of gonadal development (streak gonads).

DAX1 and SF1 messenger ribonucleic acid (mRNA) are expressed in the developing urogenital ridge, gonads, adrenal gland, pituitary gland, and hypothalamus, suggesting a dose-dependent role for both of these genes interacting as transcription factors important in a cascade of developmental gene expression.[20]

Because the gene involved in the autosomal recessive form of the disease is not known, the cause is even less understood.

International statistics

Congenital adrenal hypoplasia is rare. Although the frequency has been estimated in Japan at 1 case per 12,500 births, clinical experience indicates that this disease is not as common as congenital adrenal hyperplasia due to 21-hydroxylase deficiency (incidence is approximately 1 per 10,000-15,000 births worldwide).

Sex- and age-related demographics

Because one form of congenital adrenal hypoplasia is X-linked, the disease occurs more commonly in males.

Patients with congenital adrenal hypoplasia generally present in infancy with signs of adrenal insufficiency. However, the age of onset widely varies, and some cases are not identified until the patient is an adult.[21]  Ouyang et al reported the case of a male patient who did not receive a diagnosis of congenital adrenal hypoplasia until he was 22 years old, when he experienced a slipped capital femoral epiphysis. Addison disease had initially been diagnosed in this patient after he had developed systemic pigmentation at age 2.[22]

Prognosis of untreated congenital adrenal hypoplasia is poor if the disorder is unrecognized or untreated, and death is a common outcome.

With proper treatment and compliance, patients can live a normal life span without limitations.

Hypogonadotropic hypogonadism is nearly certain to develop secondary to DAX1 mutations or deletions. Infertility is common.

If the gene for muscle dystrophin is absent as a contiguous gene deletion, Duchenne muscular dystrophy (OMIM 310200) results, and the prognosis is poor.

Morbidity/mortality

Congenital adrenal hypoplasia is a lethal disease unless promptly recognized and appropriately treated. With proper medical treatment, patients do well unless they are also affected with Duchenne muscular dystrophy. Glycerol kinase deficiency, if present, does not result in morbidity but results in hyperglycerolemia. This may be recognized by factitiously elevated serum triglyceride concentrations.

Patients with congenital adrenal hypoplasia due to a mutation or deletion of DAX1 or SF1 (gene name NR5A1) develop hypogonadotropic hypogonadism. Some patients with the X-linked form have been found to have sensorineural deafness (OMIM 300200). Patients with IMAGe association also have intrauterine growth retardation and skeletal and genital abnormalities.

Complications

The main complications of adrenal hypoplasia include hypotension, electrolyte abnormalities, hypoglycemia, and death.

Complications of excessive administration of glucocorticoids are growth failure, obesity, striae, hypertension, hyperglycemia, and cataracts.

Excess mineralocorticoid administration can cause hypertension and hypokalemia.

Patients with X-linked congenital adrenal hypoplasia and defects in SF1 develop hypogonadotropic hypogonadism. Watch for this and treat appropriately if puberty does not occur in a timely fashion. Curiously, the minipuberty that occurs in the newborn period appears to be preserved. Most of these patients also experience testicular atrophy and are infertile.

Perform screening for hearing deficits since some patients with X-linked congenital adrenal hypoplasia have been described to have sensorineural (high-frequency) hearing deficits.

Patients should be advised to wear medical alert bracelets or anklets that alert medical personnel to the diagnosis of adrenal insufficiency and the need for glucocorticoid therapy in times of stress.

Caretakers must be educated about the consequences and the potentiality of death if adequate replacement therapy is not provided.

Teach patients and caretakers how to give supplemental glucocorticoid in times of illness or traumatic stress. Also, teach them how to give injectable glucocorticoid when the patient is vomiting or unable to take the stress doses orally. This information must be periodically reinforced because caretakers are often reluctant to give injectable medication.

Advise family to seek medical help early if the patient becomes ill.

Congenital adrenal hypoplasia most commonly presents in the neonatal period but may not become apparent until later in childhood.

Patients often present in crisis with dehydration, hyponatremia, hyperkalemia, hypotension, or hypoglycemia.

Patients with adrenal hypoplasia secondary to intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies (IMAGe) association have a history of intrauterine growth retardation. Males have genital abnormalities.

Patients may demonstrate hyperpigmentation from increased serum concentrations of adrenocorticotropic hormone (ACTH).

Signs of dehydration are often present.

Hypotension and symptoms of neuroglycopenia may be present.

Testes are undescended in many patients; micropenis may be seen in subjects with hypogonadotropic hypogonadism. Hypospadias or cryptorchidism may be seen in patients with IMAGe association.

Hearing loss may be an associated finding.[21]

A case study by Karsli et al reported two cases of adrenal hypoplasia presenting with chronic respiratory distress.[23]

The most difficult aspect of adrenal hypoplasia is clinical suspicion because signs and symptoms can be insidious and subtle.

• When adrenal insufficiency is suspected, promptly obtain the following laboratory values:

  • Electrolytes

  • Blood sugar

  • Serum adrenocorticotropic hormone (ACTH)

  • Plasma-renin activity

  • Serum cortisol

  • Aldosterone

  • 17-hydroxyprogesterone

  • High-resolution karyotype

• When hyponatremia or hyperkalemia are found, a spot urine test or a 24-hour urine test for sodium, potassium, and creatinine (along with simultaneous serum sodium concentrations and creatinine concentrations) determine whether inappropriate natriuresis is occurring (fractional excretion of sodium >1% in the face of hyponatremia). This occurs with mineralocorticoid deficiency when renal function is otherwise normal. A plasma renin activity (PRA)–to–aldosterone ratio of more than 30 is suggestive of inadequate mineralocorticoid production.

• Random serum cortisol concentrations must be interpreted within the context in which they were obtained.

  • For example, in a healthy individual, an 8:00 am serum cortisol concentration higher than 10 mcg/dL makes adrenal insufficiency unlikely.

  • A serum cortisol concentration less than 18 mcg/dL in a sick and stressed patient is highly suggestive of adrenal insufficiency.

  • A serum cortisol concentration less than 18 mcg/dL in the presence of an elevated serum ACTH concentration and plasma renin activity confirms adrenal insufficiency. Serum cortisol less than 18 mcg/dL obtained 30-60 minutes following cosyntropin is confirmatory.[24]

  • These guidelines do not apply to premature infants and infants with low birth weight who have lower cortisol secretion and, most likely, decreased cortisol binding to carrier proteins.[25] The diagnosis of adrenal insufficiency in premature infants remains problematic.

• Measure a panel of adrenal cortical hormones either with or without prior cosyntropin stimulation to exclude the various forms of congenital adrenal hyperplasia.

• A cosyntropin stimulation test can confirm the diagnosis of adrenocortical insufficiency.

  • Controversy surrounds whether the best dose of cosyntropin is the standard dose (250 mcg for an adult) or the low dose (1 mcg or 0.5 mcg/m2), which some have advocated as more sensitive for central adrenal insufficiency. A meta-analysis suggested that the low dose cosyntropin stimulation test is superior, but the difference was small.[26] This issue remains unresolved in the pediatric age group.

  • Because dilution of cosyntropin to 1 mcg is cumbersome and prone to error, and because all the above doses are probably supraphysiologic, the author generally uses the standard dose or empirically adjusts the dose for patient size (25 mcg for an infant, 50 mcg for a young child, 100 mcg for an older child, and 250 mcg for an adolescent or adult).

  • When a patient's serum cortisol response to cosyntropin is subnormal but his or her serum ACTH level is not elevated, the possibility of central adrenal insufficiency should be considered. Other indications of pituitary dysfunction such as prior glucocorticoid exposure (suggesting a suppressed hypothalamic-pituitary-adrenal axis) or evidence of other pituitary dysfunction are helpful clues suggesting ACTH deficiency.

  • In central adrenal insufficiency, 3 days of stimulation with ACTH produces a normal cortisol response, indicating intact adrenal glands and implying that the initial low cortisol response to cosyntropin was related to chronic ACTH deficiency. ACTH gel (ACTHar Gel) is administered at 25 U/m2 every 12 hours for 3 days. Plasma cortisol levels should increase to more than 40 mcg/dL in response. This procedure is now seldom performed

• The standard ovine corticotropin-releasing hormone (CRH) stimulation test (1 mcg/kg over 1 min) may be helpful in the differential diagnosis of adrenal insufficiency.

  • A lack of a 2-fold increase in serum ACTH concentration indicates pituitary dysfunction. A 2-fold or greater rise in ACTH levels without a concomitant rise in serum cortisol to more than 18-20 mcg/dL implies primary adrenal insufficiency.[27]

  • Ovine CRH is difficult to obtain, and this test is mainly done for research purposes.

• In the most common form of congenital adrenal hyperplasia caused by 21-hydroxylase deficiency, serum 17-hydroxyprogesterone is markedly elevated.

• Consider adrenoleukodystrophy (OMIM 300100) in older boys with evidence of adrenal insufficiency. Both males and females may be affected with autoimmune Addison disease, another important diagnostic consideration.

  • Adrenal leukodystrophy is also X-linked and can be diagnosed by demonstrating elevated concentrations of very–long-chain fatty acids (>24 carbon) in serum.

  • Autoimmune Addison disease is confirmed by the demonstration of antiadrenal antibodies in the serum.

• Karyotype, fluorescent in situ hybridization (FISH) or microarray analysis may reveal the gene deletion involving DAX1.

• Prenatal diagnosis is possible.[28]

CT is the best imaging study for the adrenal gland. It excludes the possibility of bilateral adrenal hemorrhage, which can present with an identical clinical picture. However, CT cannot exclude congenital adrenal hypoplasia due to a DAX1 deletion in an infant because the fetal adrenal zone is preserved in this condition.

Abdominal ultrasonography identifies adrenal glands in infants due to the large fetal zone; however, it usually is not helpful in older children.

Gene studies of the DAX1 gene on the X chromosome or fluorescent in situ hybridization (FISH), using an appropriate complimentary DNA (cDNA) probe to the region containing DAX1, confirms the existence of a deletion in the DAX1 region of the X chromosome.

The 2 described forms of congenital adrenal hypoplasia differ in anatomic findings.

The X-linked form is associated with hypoplasia of the definitive adult zone of the adrenal cortex with preservation of the fetal zone. Histologically, the adrenal cortex is disorganized and the cells are cytomegalic.

The autosomal recessive form is associated with absence of the fetal zone and severe hypoplasia of the definitive adult adrenal zone. This is often referred to as the miniature type because of the hypoplastic adrenal cortex.

Congenital adrenal hypoplasia due to SF1 defect is associated with gonadal dysgenesis (streak gonad, gonad replaced by fibrous material).

Patients with adrenal hypoplasia are generally hypovolemic and may be hypoglycemic; therefore, initial therapy should consist of intravenous normal saline and dextrose.

If hypotensive, a bolus dose of 20 mL/kg of isotonic intravenous fluid over the first hour may be necessary to restore blood pressure. This can be repeated if the blood pressure remains low.

Once samples for serum electrolytes, blood sugar, cortisol, 17-hydroxyprogesterone, and adrenocorticotropic hormone (ACTH) concentrations are obtained, treat the patient with glucocorticoids. This therapy is based on suspicion of adrenal insufficiency because it may be life preserving.

A cosyntropin stimulation test confirms the diagnosis of adrenocortical insufficiency.

Dexamethasone may be given prior to the cosyntropin without interfering with the results of the test because acute administration of dexamethasone does not interfere with the cortisol response or with the cortisol assay. Otherwise, hydrocortisone is preferable because of its mineralocorticoid activity.

Surgery is not necessary in the management of congenital adrenal hypoplasia; however, a patient requiring surgery must be covered with stress doses of glucocorticoids during the perioperative period.

The following recommendations are empiric rather than evidence-based:

• Administer 50-75 mg/m2 hydrocortisone intramuscularly or intravenously on call prior to surgery.

• During the procedure, treat the patient with additional hydrocortisone. This may be accomplished with either a hydrocortisone drip of 2-4 mg/m2/h, or as an additional bolus of 10-25 mg/m2 intravenously every 6 hours throughout the procedure.

• Continue hydrocortisone in the immediate postoperative period.

• On the second and third postoperative day, the dose of hydrocortisone can be decreased by 50% each day, to a minimum of the patient's usual daily requirement, provided no complications exist and the patient is recovering well.

• By the fourth postoperative day, the usual daily dose of steroids may be resumed if the patient is recovering well. If complications occur, stress doses of glucocorticoids must be continued.

• Fludrocortisone may be held on the day of surgery and while the patient is receiving stress doses of hydrocortisone because this high dose should provide ample mineralocorticoid effect.

• If the patient is unable to take fludrocortisone by mouth in the postoperative period, stress doses of hydrocortisone may be continued for a longer period to provide adequate mineralocorticoid activity.

The following consultations may be obtained:

• Endocrinologist when adrenal insufficiency is suspected

• Geneticist for genetic diagnosis and counseling

Diet

Patients should not be on a sodium-restricted or fluid-restricted diet.

Patients should have ample access to salt, because patients are deficient in aldosterone secretion and, therefore, are generally salt wasters.

Monitor and restrict caloric intake if excess weight gain occurs on therapy because glucocorticoids stimulate appetite and weight gain.

Activity

After appropriate glucocorticoid and mineralocorticoid therapy is instituted, no restrictions on activity are necessary.

Acute therapy

For a patient with suspected but unproved adrenal insufficiency, dexamethasone is best used to correct the glucocorticoid deficiency. This allows immediate procession to a cosyntropin stimulation test for confirming diagnosis. If a cosyntropin stimulation test is not planned, give stress doses of hydrocortisone (50-75 mg/m2 or 1-2 mg/kg) intravenously as an initial dose and followed by 50-75 mg/m2/d intravenously in 4 divided doses. Hydrocortisone may be given intramuscularly if no intravenous access is available but works less quickly. Comparable stress doses of methylprednisolone are 10-15 mg/m2 and of dexamethasone 1-1.5 mg/m2 intravenously or intramuscularly.

Methylprednisolone and dexamethasone have negligible mineralocorticoid effects. Therefore, if the patient is hypovolemic, hyponatremic, or hyperkalemic, large doses of hydrocortisone (even double or triple the stress doses mentioned above) are preferred. At the present time, no parenteral form of mineralocorticoid is available in the United States. If the patient has good GI function, fludrocortisone (0.1-0.2 mg orally) may be given to replace aldosterone deficiency.

In hypotensive patients, normal saline (ie, 0.9% NaCl) must be administered by rapid intravenous infusion over the first hour followed by a continuous infusion. A reasonable amount to restore intravascular volume is 450 mL/m2 or 20 mL/kg of normal saline intravenously over the first hour, followed by 3200 mL/m2/d or 200 mL/kg/100 kcal of estimated resting energy expenditure as normal saline or 0.45% NaCl in subsequent hours. Dextrose must also be provided. If the patient is hypoglycemic, 2-4 mL/kg of D10W corrects it. D5W must be provided to prevent further hypoglycemia or to prevent hypoglycemia from occurring if the patient is not hypoglycemic. Potassium is generally not needed in the acute situation, especially because patients with adrenal hypoplasia are often hyperkalemic.

Chronic medical therapy

In growing children with adrenal insufficiency, chronic glucocorticoid replacement must be balanced to prevent symptoms of adrenal insufficiency, while still allowing the child to grow at a normal rate and prevent symptoms of glucocorticoid excess. The dose must be tailored to each patient but generally runs in the range of 7-20 mg/m2/d of hydrocortisone orally in 2-3 divided doses. Hydrocortisone is available as tablets of 5 mg, 10 mg, and 20 mg. Hydrocortisone is recommended in the pediatric population because of its lower potency, which permits easier titration of appropriate doses. In large patients, prednisone or even dexamethasone may be substituted. The estimated equivalency is 1 mg prednisone = 4 mg hydrocortisone and 1 mg dexamethasone = 50 mg hydrocortisone, but this varies from patient to patient.

Patients with congenital adrenal hypoplasia also have mineralocorticoid deficiency and, therefore, must be provided with fludrocortisone (0.1-0.2 mg/d). Provide infants with NaCl (2-5 g/d PO) to counteract salt wasting. The dose of glucocorticoid is adjusted clinically (absence of symptoms of glucocorticoid deficiency or excess and normal growth).

In the author's experience, plasma adrenocorticotropic hormone (ACTH) concentrations are of little help in adjusting doses of glucocorticoid in patients with primary adrenal insufficiency. Symptoms of salt craving, blood pressure, plasma renin activity, and electrolytes are helpful in adjusting the dose of fludrocortisone. Salt craving and an elevated plasma renin activity suggest the need for a larger dose of fludrocortisone, whereas elevated blood pressure or suppressed plasma renin activity suggests the need for a lower dose of fludrocortisone.

Stress and illness

One of the important physiological responses to stress is an increase in cortisol production mediated by ACTH. Patients with adrenal insufficiency, of whatever etiology, are unable to mount this response and must be provided with stress doses of glucocorticoids. In patients with minor illness (fever < 38°C) administer at least double the dose of hydrocortisone. In patients with more severe illness (fever >38°C), administer triple the dose of glucocorticoids. If the patient is vomiting or listless, give parenteral glucocorticoids (hydrocortisone 50-75 mg/m2 intramuscularly or intravenously or equivalent of methylprednisolone or dexamethasone).

Because hydrocortisone succinate has a short duration of action, the dose must be repeated every 6-8 hours until the patient is well. Cortisone acetate and hydrocortisone acetate both have a longer duration of action (up to 24 h) but are often difficult to obtain in the United States. All patients with adrenal insufficiency must have injectable glucocorticoid available, and the caretaker must be instructed in its use and importance.

Hydrocortisone suppositories may be tried in patients or families who cannot administer injectable glucocorticoids. However, absorption is less predictable.

No contraindications to glucocorticoid or mineralocorticoid replacement are recognized when it is needed, and few adverse drug-to-drug interactions occur.

Patients on physiologic replacement doses of glucocorticoids may receive live virus immunizations.

Class Summary

This agent is responsible for the replacement of aldosterone deficiency. It is essential in maintaining electrolyte equilibrium and intravascular volume. Mineralocorticoid deficiency results in hyponatremia, hyperkalemia, and hypotension.

Fludrocortisone acetate (Florinef)

The only available mineralocorticoid. It is only available PO in 0.1 mg tablets. If unable to tolerate PO medication, mineralocorticoid activity can be achieved with high-dose intravenous hydrocortisone.

Class Summary

These agents are used to replace insufficient cortisol production resulting from adrenal hypoplasia. This is necessary in unstressed children to maintain appetite and weight. It is especially important in individuals who are stressed or ill because cortisol secretion is an important stress response. In this setting, glucocorticoids are important in maintaining cardiovascular stability.

Hydrocortisone (A-Hydrocort, Cortef, Solu-Cortef)

This is preferable to other glucocorticoids (ie, prednisone, dexamethasone) for long-term glucocorticoid replacement in children because its lower potency and shorter half-life make growth inhibition less likely as a complication, provided the dose is correct. Hydrocortisone is available in tablets of 5 mg, 10 mg, and 20 mg.

Patients with adrenal hypoplasia on chronic glucocorticoid therapy must be monitored for adequacy of dosing.

• Too little therapy results in symptoms of adrenal insufficiency (anorexia, nausea, vomiting, abdominal pain, asthenia).

• Too much therapy results in excess weight gain, cushingoid features, hypertension, hyperglycemia, cataracts, osteopenia, and growth failure.

• Growth failure is one of the more sensitive indicators of excess exposure in children.

• Blood pressure and plasma renin activity provides a guide for adequacy of mineralocorticoid therapy.

If no signs of puberty are seen by age 14-15 years, suspect hypogonadotropic hypogonadism.

• This is associated with low serum concentrations of gonadotropins (eg, leuteinizing hormone [LH] and follicle-stimulating hormone [FSH]) and low serum concentration of testosterone in the male.

• Patients with hypogonadotropic hypogonadism may be unresponsive to gonadotropin-releasing hormone (GnRH) analogues suggesting insufficiency of pituitary secretion of gonadotropins, as well as a deficiency of GnRH.

• The simplest treatment for hypogonadotropic hypogonadism in the male is testosterone enanthate or cypionate in oil initially at 75-100 mg intramuscularly every month and gradually increasing to full adult doses of 200-300 mg intramuscularly every 2 weeks.

• Testosterone also can be administered by cutaneous patch or gel; however, this makes adjustment of dose more difficult, and accurate dosing for adolescents has yet to be resolved.

• Oral preparations of androgen (oxandrolone, Halotestin) are more likely to cause hepatic dysfunction than injectable preparations or transdermal preparations. Transcutaneous preparations provide more stable serum concentrations.

With proper identification of the genetic cause, prenatal diagnosis should be possible once an index case is identified in a family.

Prenatal diagnosis is also possible by taking serial measurements of dehydroepiandrosterone sulfate (DHEAS) and estriol in maternal plasma during pregnancy, because these hormones are derived from the fetal adrenal cortex. These hormones are unusually low in cases of fetal adrenal hypoplasia; however, this test is nonspecific. Low levels of these hormones also are observed in panhypopituitarism, in steroid sulfatase deficiency, and in women treated with glucocorticoids during pregnancy.