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Adrenal Hypoplasia
INTRODUCTION

Background: Two identified forms of congenital adrenal hypoplasia exist. The X-linked disorder (OMIM 300200) is caused by a mutation or deletion of the DAX1 gene (dosage-sensitive sex reversal adrenal hypoplasia congenita critical region of the X chromosome, also called the AHCH gene) on the X chromosome. This form usually is associated with hypogonadotropic hypogonadism. It may be part of a contiguous chromosome deletion, which may include congenital adrenal hypoplasia, Duchenne muscular dystrophy (OMIM 310200), and glycerol kinase deficiency (OMIM 307030). The gene involved in the autosomal recessive form (OMIM 240200) is not yet known.

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

Frequency:
 

  • Internationally: Congenital adrenal hypoplasia is rare. Although the frequency has been estimated in Japan at 1 in every 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).

Mortality/Morbidity:

  • Congenital adrenal hypoplasia is a lethal disease unless promptly recognized and appropriately treated. With proper medical treatment, patients do well unless they also are affected with Duchenne muscular dystrophy.
  • Glycerol kinase deficiency, if present, does not result in morbidity but will result in hyperglyceridemia. This is due to a factitiously elevated serum triglyceride concentration.
  • Patients with congenital adrenal hypoplasia due to a mutation or deletion of DAX1 develop hypogonadotropic hypogonadism. Some patients with the X-linked form have been found to have sensorineural deafness (OMIM 300200).

Sex:

History:

  • 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.

Physical:

  • Patients may demonstrate hyperpigmentation from increased serum concentrations of adrenocorticotrophic hormone (ACTH).
  • Signs of dehydration are often present.
  • Hypotension and symptoms of neuroglycopenia may be present.
  • Testes are undescended in many patients; micropenis is rare. Other urologic anomalies have occasionally been reported.
  • Hearing loss may be an associated finding.

Causes:

  • 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 product of DAX1 appears to suppress expression of the steroidogenic factor-1 (SF-1)-regulated steroidogenic acute regulatory (StAR) protein promoter. It is still unclear just how loss of this function results in loss of hypothalamic and adrenal cortical development. DAX1 also appears to function as an antitestis gene by acting antagonistically to sex-determining region (SRY). 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.
  • Several reports of DAX1 gene mutations indicate significant genotypic-phenotypic variability can be seen in these disorders.
    • In 1 reported family, a DAX1 mutation resulted in congenital adrenal hypoplasia and hypogonadotropic hypogonadism in 2 brothers. A normal phenotype was found in the affected maternal grandfather, and hypogonadotropic hypogonadism with normal adrenal function in a maternal aunt who was homozygous for the mutation. Ovaries are intact in affected women.
    • Observations in the SF1 knockout mouse and 1 report 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. Since the gene involved in the autosomal recessive form of the disease is not known, the cause is even less understood.

Other Problems to be Considered:

Addison disease
Adrenoleukodystrophy
Bilateral adrenal hemorrhage
Congenital unresponsiveness to ACTH
Hypoaldosteronism
Renal tubular disorders
46, XY sex reversal due to mutations in genes SRY, SOX9, WT1 (Denys-Drash Syndrome), SF1

Lab Studies:
 

  • The most difficult aspect of adrenal insufficiency is clinical suspicion, because signs and symptoms can be insidious and subtle.
  • When adrenal insufficiency is suspected, promptly obtain the following laboratory studies:
    • Electrolytes

       

    • Blood sugar

       

    • Serum ACTH

       

    • Plasma-renin activity

       

    • Serum cortisol

       

    • Aldosterone

       

    • 17-hydroxyprogesterone
  • When hyponatremia or hyperkalemia are found, either a spot urine test or a 24-hour urine test for sodium, potassium, and creatinine, along with simultaneous serum sodium concentrations and creatinine concentrations, will determine whether inappropriate natriuresis is occurring.
  • 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 60 minutes following cosyntropin is confirmatory.
    • These guidelines do not apply to premature infants and infants with low birth weight who have lower cortisol secretion.
  • A cosyntropin stimulation test will confirm the diagnosis of adrenocortical insufficiency. Controversy exists regarding 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). Since this issue is unresolved, particularly in the pediatric age group, and it is cumbersome to dilute the currently supplied cosyntropin (250 mcg) to 1 mcg, the standard dose is suggested. For infants, the author suggests 50 mcg of cosyntropin (approximately 250 mg/m2).
  • Measure a panel of adrenal cortical hormones either with or without prior cosyntropin stimulation to exclude the various forms of congenital adrenal hyperplasia.
  • 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 in serum.
    • Autoimmune Addison disease is confirmed by the demonstration of antiadrenal antibodies in the serum.

Imaging Studies:
 

  • CT scan 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 scan cannot exclude congenital adrenal hypoplasia due to a DAX1 deletion in an infant, since the fetal adrenal zone is preserved in this condition.
  • Abdominal ultrasound identifies adrenal glands in infants due to the large fetal zone; however, it usually is not helpful in older children.

Other Tests:
 

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

Histologic Findings: 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 often is referred to as the miniature type because of the hypoplastic adrenal cortex.

Medical Care:

  • Patients 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 cc/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 electrolytes, blood sugar, cortisol, 17-hydroxyprogesterone and ACTH concentrations are obtained, treat the patient with glucocorticoids. This therapy is based on suspicion of adrenal insufficiency, since it may be life preserving.
  • A cosyntropin stimulation test will confirm the diagnosis of adrenocortical insufficiency.
  • Dexamethasone may be given prior to the cosyntropin without interfering with the results of the test since acute administration of dexamethasone will not interfere with the cortisol response or with the cortisol assay. Otherwise, hydrocortisone is preferable because of its mineralocorticoid activity.

Surgical Care:

  • 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.
    • For example, give 50-75 mg/m2 hydrocortisone IM/IV 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 IV q6h 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.
  • 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.

Consultations:

  • Endocrinologist when adrenal insufficiency is suspected
  • Geneticist for genetic counseling

Diet:

  • Patients should not be on a sodium-restricted or fluid-restricted diet.
  • Patients should have ample access to salt since 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) IV as an initial dose and followed by 50-75 mg/m2/d IV in 4 divided doses. Hydrocortisone may be given IM if no IV 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 IV/IM. 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 US. If the patient has good gastrointestinal function, fludrocortisone 0.1-0.2 mg PO may be given to replace aldosterone deficiency.

In hypotensive patients, normal saline (ie, 0.9% NaCl) must be administered by rapid IV infusion over the first hour followed by a continuous infusion. A reasonable amount to restore intravascular volume would be 450 mL/m2, or 20 mL/kg of normal saline IV 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 will correct 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 since 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 PO in 2-3 divided doses. Hydrocortisone is available as tablets of 5, 10, 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 = 40 mg hydrocortisone.

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 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/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 IM/IV or equivalent of methylprednisolone or dexamethasone).

Because hydrocortisone succinate has a short duration of action, the dose must be repeated q6-8h 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 US. All patients with adrenal insufficiency must have injectable glucocorticoid available, and the caretaker must be instructed in its use and importance.
No contraindications to glucocorticoid or mineralocorticoid replacement exist when it is needed, and few adverse drug-to-drug interactions occur.
Patients on physiologic replacement doses of glucocorticoids may receive live virus immunizations.
Drug Category: Glucocorticoids -- 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, since cortisol secretion is an important stress response. In this setting, glucocorticoids are important in maintaining cardiovascular stability.

Drug Name
 		 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, 10, and 20 mg.
Adult Dose Daily dose must be administered in divided doses bid/tid or q6-8h when given IV
Healthy nonstressed individual: Average cortisol secretory rate is 6-10 mg/m2/d
Oral therapy generally must be higher because some metabolism of ingested glucocorticoids occurs as they pass through the liver
Daily replacement: Generally about 10-30 mg/d
Equivalent doses of prednisone 2.5-7.5 mg/d
Adjust dose according to the patient's sense of well-being; recurring abdominal pain, anorexia, nausea, and lack of energy indicate the need for a dose increase
Pediatric Dose Replacement dose: 6-15 mg/m2/d IV divided bid/tid or q6-8h when given IV
Excessive doses result in growth suppression; inadequate doses result in fatigue, gastrointestinal complaints, or asthenia
Contraindications Documented hypersensitivity
Interactions Live virus immunizations may be provided to patients on physiologic replacement doses of glucocorticoids, higher doses may interfere with live virus vaccine response
Pregnancy B - Usually safe but benefits must outweigh the risks.
Precautions Administer with meals to decrease GI upset; early-onset adverse effects include glucose intolerance, hypertension, agitation, and indigestion; late-onset adverse effects include hypertension, urinary calcium loss and osteopenia, gastric irritation and bleeding

Drug Category: Mineralocorticoid -- 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.

Drug Name
 		 Fludrocortisone acetate (Florinef) -- The only available mineralocorticoid. It is only available PO in 0.01 mg tablets. If unable to tolerate oral medication, mineralocorticoid activity can be achieved with high-dose intravenous hydrocortisone.
Adult Dose 0.1-0.2 mg/d PO qd
Pediatric Dose Pediatric doses are similar to adult doses because the aldosterone secretory rate is similar in infants, children, and adults
Usual dose: 0.05-0.2 mg/d PO qd
Infants may require supplementation with NaCl (2-4 g/d PO) because infant formulas are low in sodium
Contraindications Documented hypersensitivity
Interactions Barbiturates, phenytoin, and rifampin can increase hepatic metabolism of fludrocortisone, diminishing its effect; fludrocortisone-induced hypokalemia can enhance digoxin toxicity
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions May elevate blood pressure and must be used with caution and good justification in patients with hypertension; adverse effects include hypertension, edema, congestive heart failure, and hypokalemic alkalosis; carefully titrate dose to level of patient tolerance and effectiveness; monitor for dizziness, severe or continuing headaches, swelling of feet or lower legs, or unusual weight gain; administer with food to minimize gastrointestinal adverse effects

Further Outpatient Care:

  • Patients 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 IM every month and gradually increasing to full adult doses of 200-300 mg IM 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.

Deterrence/Prevention:

  • 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.

Complications:

  • Main complications of adrenal hypoplasia are 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 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.

Prognosis:

  • 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 DAX-1 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.

Patient Education:

  • 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 reinforced periodically, since caretakers are often reluctant to give injectable medication.
  • Advise family to seek medical help early if the patient becomes ill.

Medical/Legal Pitfalls:

  • Congenital adrenal hypoplasia may be overlooked because of the often-insidious nature of the symptoms and the common occurrence of other conditions that mimic this condition (ie, sepsis, hemorrhage, gastroenteritis).

Special Concerns:

  • It is crucial that patients of any etiology are treated with stress doses of glucocorticoids at any time of illness, surgery, or severe stress; otherwise, an adrenal crisis may occur.
 

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