Causes of primary adrenal insufficiency in children

INTRODUCTION — Adrenal insufficiency is a potentially life-threatening condition defined by the inability of the adrenal cortex to produce sufficient glucocorticoid and/or mineralocorticoid hormones [1]. Primary adrenal insufficiency results from disease that is intrinsic to the adrenal cortex; the most common cause in childhood is congenital adrenal hyperplasia (CAH). Central adrenal insufficiency is characterized by lack of adrenocorticotropic hormone (ACTH) stimulation of the adrenal cortex, most often as a result of prior high-dose glucocorticoid therapy (which suppresses the hypothalamic-pituitary-adrenal axis). It may also occur in the setting of a central nervous system malformation or disease and/or its treatment, eg, radiation.

The causes of primary adrenal insufficiency will be discussed in this topic review. Other aspects of adrenal insufficiency are discussed in separate topic reviews:

●(See "Clinical manifestations and diagnosis of adrenal insufficiency in children".)

●(See "Causes of central adrenal insufficiency in children".)

●(See "Treatment of adrenal insufficiency in children".)

OVERVIEW OF CLINICAL MANIFESTATIONS — The signs and symptoms of primary adrenal insufficiency vary depending on which hormones are deficient, severity of the defect(s), and duration of the deficiency(ies) (table 1) (see "Clinical manifestations and diagnosis of adrenal insufficiency in children", section on 'Primary adrenal insufficiency'):

●Glucocorticoid deficiency – Deficiency of glucocorticoids (eg, cortisol) causes fatigue, gastrointestinal complaints of nausea and vomiting, hypoglycemia in infancy and early childhood, and skin and mucosal hyperpigmentation.

●Mineralocorticoid deficiency – Deficiency of mineralocorticoids (eg, aldosterone) causes dehydration, electrolyte abnormalities, and, potentially, hypotension.

●Adrenal androgens – Adrenal androgens (eg, dehydroepiandrosterone [DHEA] or DHEAS, its sulfated derivative) are increased in congenital adrenal hyperplasia (CAH), the most common cause of primary adrenal insufficiency. Clinical manifestations may include atypical genital appearance and virilization.

In other types of adrenal insufficiency, adrenal androgens may be deficient, with subtle manifestations that develop after puberty such as decreased sexual hair and libido.

●Adrenal crisis – Adrenal crisis results from acute adrenal insufficiency. The clinical features of adrenal crisis arise from glucocorticoid deficiency (vomiting, fever, and hypoglycemia, occasionally leading to shock) and, if present, mineralocorticoid deficiency (hyponatremia, hyperkalemia, and hypotension). Typically, both hormones are deficient and contribute to the clinical presentation. In severe cases, these deficiencies can lead to hypotension, shock, and even death. A rapid overview of this issue can be found in the accompanying table (table 2).

PATHOGENETIC CATEGORIES OF PRIMARY ADRENAL INSUFFICIENCY — The etiology of primary adrenal insufficiency can be classified based upon pathophysiology (table 3):

●Steroidogenesis disorders – Defects within the biosynthetic pathways of glucocorticoids and/or mineralocorticoids lead to impaired synthesis of cortisol and/or aldosterone. This category includes congenital adrenal hyperplasia (CAH). (See "Genetics and clinical manifestations of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)

●Adrenal damage or dysfunction – Injury from factors extrinsic to the adrenal gland (eg, infection, drugs, autoimmunity, and hemorrhage) may impair adrenal function. Adrenal insufficiency also may develop in the setting of critical illness or mitochondrial disorders such as Kearns-Sayre syndrome.

●Peroxisomal disorders – The adrenal gland can be impaired by accumulation of abnormal very long-chain fatty acids within the peroxisomes (adrenoleukodystrophy [ALD] and other disorders).

●Genetic causes of adrenal hypoplasia – A lack of normal adrenocortical cell differentiation due to pathogenic genetic variants may result in adrenal hypoplasia congenita or several syndromes that include adrenal hypoplasia.

●Inherited adrenal unresponsiveness to adrenocorticotropic hormone (ACTH) – Inherited defects in adrenal responsiveness to ACTH are seen in familial glucocorticoid deficiency (FGD) and triple A syndrome.

●Drugs – Certain drugs can cause adrenal dysfunction, including high-dose ketoconazole.

EPIDEMIOLOGY — The incidence of primary adrenal insufficiency in children is unknown. Congenital adrenal hyperplasia (CAH), which occurs in approximately 1 in 14,200 live births, is the most common cause of primary adrenal insufficiency, accounting for 70 to 85 percent of cases of primary adrenal insufficiency [2-4]. The distribution of specific causes of adrenal insufficiency varies by the populations studied.

The relative frequency of the causes of primary adrenal insufficiency in children are illustrated by two large case series from Canada and Italy [2,4]:

●CAH due to 21-hydroxylase deficiency – 72 to 85 percent

●Other types of CAH – 1 to 2 percent

●Autoimmune polyglandular syndrome (APS) type 1 – 3 to 5 percent

●Autoimmune adrenal insufficiency (either isolated or APS type 2) – 2 to 16 percent

●Adrenoleukodystrophy (ALD) or other peroxisomal defects – 3 to 5 percent

●Adrenal hypoplasia congenita – 1 to 2 percent

●Triple A syndrome – 1 percent

●Undetermined cause – 1 to 6 percent

The rare genetic causes of primary adrenal insufficiency are illustrated by two case series that described children with primary adrenal insufficiency of initially unknown etiology (after excluding most of the most common causes, including classic CAH) [5,6]. After detailed genetic testing using a panel of candidate genes, a genetic diagnosis was reached in most of these children; the most common diagnosis was familial glucocorticoid deficiency (FGD) type 1 due to pathogenic variants in the MC2R gene (20 to 30 percent of the unexplained adrenal insufficiency in this cohort). The remainder had other forms of FGD, triple A syndrome, uncommon forms of CAH, or various forms of adrenal hypoplasia congenita.

DISORDERS OF STEROIDOGENESIS — Pathogenic variants of the genes encoding enzymes in the biosynthetic pathways of the adrenocortical hormones result in the decreased production of glucocorticoids and/or mineralocorticoids. Steroidogenic disorders of cortisol (congenital adrenal hyperplasia [CAH]) are major causes of primary adrenal insufficiency in children [2].

Congenital adrenal hyperplasia — Inherited defects in the enzymatic steps of cortisol biosynthesis (steroidogenesis) result in disease states termed congenital adrenal hyperplasia (CAH) (figure 1). These disorders cause primary adrenal insufficiency because they impair cortisol synthesis (table 4).

The resulting decrease in cortisol levels increases the secretion of adrenocorticotropic hormone (ACTH), thereby stimulating the production of adrenal steroids up to and including the substrate for the defective enzyme. This chronic ACTH stimulation results in hyperplasia of the adrenal cortex. (See "Adrenal steroid biosynthesis".)

The clinical manifestations of these disorders are related to one or more of the following pathologic processes:

●Glucocorticoid deficiency – Impaired synthesis of cortisol.

●Mineralocorticoid deficiency – Impaired synthesis of aldosterone.

●Excessive androgens (or other adrenal hormones) – Lack of negative feedback causes increased pituitary ACTH secretion, which leads, in turn, to excessive synthesis of precursor steroids and oversecretion of steroids whose production does not require the deficient enzyme. These are most commonly androgenic hormones, which cause virilization.

In some types of CAH (eg, 11-beta-hydroxylase deficiency), there is excessive synthesis of mineralocorticoids such as deoxycorticosterone, which can cause hypertension.

The following is a brief summary of the various forms of CAH based upon their enzymatic defects (figure 1), each of which is discussed in detail elsewhere:

●21-hydroxylase deficiency (MIM #201910) – 21-hydroxylase deficiency (due to pathogenic variants in the CYP21A2 gene) accounts for 70 to 85 percent of percent of cases of primary adrenal insufficiency. It is one of the most common (autosomal recessively) inherited diseases. The more severe or "classic" form occurs in approximately 1 in 15,000 live births (figure 1). It usually presents as one of two clinical syndromes in neonates or very young infants:

•A salt-wasting form (hyponatremia, hyperkalemia, and hypotension on account of associated mineralocorticoid deficiency), with atypical genital appearance in affected females (because of adrenal androgen excess)

•A simple virilizing form in affected males and females without salt wasting

(See "Genetics and clinical manifestations of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)

●11-beta-hydroxylase deficiency (MIM #202010) – 11-beta-hydroxylase deficiency (due to pathogenic variants in the CYP11B1 gene) accounts for less than 5 percent of CAH cases (figure 1). Cortisol synthesis is reduced, as in other forms of CAH; however, in this form, there is excessive mineralocorticoid (deoxycorticosterone) accompanying adrenal androgen overproduction. This causes increased sodium retention and hypertension; affected females also have virilization. (See "Uncommon congenital adrenal hyperplasias", section on '11-beta-hydroxylase deficiency'.)

●3-beta-hydroxysteroid dehydrogenase type 2 deficiency (MIM #201810) – 3-beta-hydroxysteroid dehydrogenase type 2 (due to pathogenic variants in the HSD3B2 gene) is a rare form of CAH characterized by impaired synthesis of all steroid hormones, resulting in deficiencies of glucocorticoids, mineralocorticoids, and active androgens (figure 1). Most patients present as neonates or in early infancy. Clinical manifestations result from both cortisol and aldosterone deficiency, including feeding difficulties, vomiting, volume depletion, hyponatremia, and hyperkalemia. Affected females may have mild virilization (an indirect effect of oversecretion of dehydroepiandrosterone [DHEA]), and males have varying degrees of failure of normal genital development, ranging from hypospadias to more severe ambiguity of the external genitalia. (See "Uncommon congenital adrenal hyperplasias", section on '3-beta-hydroxysteroid dehydrogenase type 2 deficiency'.)

●17-alpha-hydroxylase deficiency (MIM #202110) – 17-alpha-hydroxylase deficiency (due to pathogenic variants in the CYP17A1 gene) is a rare form of CAH. Patients usually have both 17-alpha-hydroxylase and 17,20-lyase deficiencies (figure 1). Although sufficient cortisol is not produced, large quantities of corticosterone (a steroid with both glucocorticoid and mineralocorticoid activities) are synthesized, reducing the symptoms associated with cortisol deficiency. There is also excess production of deoxycorticosterone, resulting in hypertension. In addition, given that both androgen and estrogen synthesis are impaired, affected male patients have female external genitalia and a blind vagina and affected females have primary amenorrhea and absent secondary sexual characteristics. (See "Uncommon congenital adrenal hyperplasias", section on 'CYP17A1 deficiencies'.)

●Congenital lipoid adrenal hyperplasia (MIM #201710) – Congenital lipoid adrenal hyperplasia is the rarest and usually the most severe form of CAH. Pathogenic variants in the steroidogenic acute regulatory protein (StAR) gene result in an inability to convert cholesterol to pregnenolone, thereby precluding the biosynthesis of all of the major adrenal steroids. The adrenal glands are filled with lipid granules. Patients present as neonates or young infants with symptoms and signs of adrenocortical insufficiency, including poor feeding, vomiting, lethargy, volume depletion, respiratory distress, hyponatremia, hyperkalemia, hypoglycemia, and metabolic acidosis. Affected male infants usually have female external genitalia because of the lack of testicular androgen production, and affected female infants have normally developed genitalia. (See "Uncommon congenital adrenal hyperplasias", section on 'Lipoid congenital adrenal hyperplasia'.)

●P450 side-chain cleavage (P450SCC) deficiency (MIM #613743) – Pathogenic variants in the CYP11A1 gene can lead to a phenotype similar to that of congenital lipoid adrenal hyperplasia, with a more variable age of onset of adrenal insufficiency and a spectrum of external genitalia ranging from complete female to normal male. In addition, CYP11A1 gene pathogenic variants have been identified in milder forms of adrenal insufficiency. (See "Uncommon congenital adrenal hyperplasias", section on 'Cholesterol side-chain cleavage enzyme (CYP11A1) deficiency' and "Causes of differences of sex development", section on 'Other types of congenital adrenal hyperplasia' and 'Familial glucocorticoid deficiency' below.)

●P450 oxidoreductase (POR) deficiency (MIM #613571) – POR deficiency, a rare variant, is caused by a pathogenic variant in the POR gene that encodes cytochrome POR, an enzyme that transfers electrons to CYP21A2 and CYP17A1. This causes a partial deficiency of the enzymes 21-hydroxylase and 17-alpha-hydroxylase, respectively. The condition also known as apparent combined CYP21A2 and CYP17A1 deficiencies, although pathogenic variants in the CYP21A2 and CYP17 genes have not been identified in affected individuals. Affected girls are born with atypical genital appearance, suggesting intrauterine androgen excess; however, in contrast with classic CAH, postnatal serum androgen concentrations are low and virilization does not progress. Boys may have undervirilization. Mothers may have virilization during pregnancy with an affected fetus. Some children also have bone malformations primarily affecting the head and limbs, known as Antley-Bixler syndrome [7]. (See "Uncommon congenital adrenal hyperplasias", section on 'P450 oxidoreductase deficiency (apparent combined CYP17A1 and CYP21A2 deficiency)'.)

Defects in aldosterone production — Pathogenic variants of the CYP11B2 gene are the major genetic causes of impaired mineralocorticoid synthesis (figure 1). As there is no concomitant defect in cortisol biosynthesis, ACTH is not stimulated and, hence, there is no hyperplasia of the adrenal glands as is seen in CAH. Patients usually present in infancy with symptoms of aldosterone deficiency. These include dehydration, salt wasting with hyponatremia and hyperkalemia, and failure to thrive.

The CYP11B2 gene encodes aldosterone synthase, the terminal enzyme in the aldosterone biosynthetic pathway. Pathogenic variants in this gene impair the production of aldosterone either by interfering with the 11-hydroxylation of 11-deoxycorticosterone (usually referred to as DOC) to form corticosterone and 18-hydroxycorticosterone (aldosterone synthase deficiency type 1, MIM #203400) or by interfering with the 18-oxidation of 18-hydroxycorticosterone to form aldosterone (aldosterone synthase deficiency type 2, MIM #610600) [8]. (See "Etiology, diagnosis, and treatment of hypoaldosteronism (type 4 RTA)", section on 'Congenital isolated hypoaldosteronism'.)

Defects in cholesterol biochemistry — Conditions that alter cholesterol availability for steroidogenesis also may present as primary adrenal insufficiency. These include the following:

●Lysosomal acid lipase deficiency – Lysosomal acid lipase deficiency (MIM #278000, or cholesterol ester hydrolase deficiency) occurs because of an autosomal recessive defect in the LIPA gene [9]. Lysosomal acid lipase catalyzes the hydrolysis of cholesterol esters and triglycerides, and its deficiency results in abnormal serum lipid profile in almost all patients [10,11]. Patients develop massive accumulation of lysosomal esterified lipids in target organs.

This disorder has two forms:

•Wolman disease – This is a fulminant form that presents in infants. It is characterized by calcifications in the adrenal glands and primary adrenal insufficiency. Other features include hepatosplenomegaly, hepatic fibrosis, malabsorption, vomiting, and poor weight gain, all of which contribute to early death by one year of age [12,13].

•Cholesterol ester storage disease – This is a milder phenotype that presents later in life and is characterized by hepatic disease, without adrenal insufficiency (although adrenal calcifications may be present) [11,14]. Key clinical characteristics at presentation include moderate liver enzyme elevations, dyslipidemia (elevated low-density lipoprotein and low high-density lipoprotein), and hepatomegaly with hepatic steatosis and variable degrees of fibrosis [15]. The disorder is often misdiagnosed as nonalcoholic fatty liver disease or a lipid storage disease (eg, Gaucher or Niemann-Pick disease). (See "Metabolic dysfunction-associated steatotic liver disease in children and adolescents", section on 'Tests to exclude other liver diseases' and "Overview of the evaluation of hepatomegaly in adults", section on 'Storage disorders'.)

The disorder can be diagnosed with molecular testing and/or by using an enzyme-based biochemical test, which is commercially available [16]. A list of laboratories that perform this test is available at the Genetic Testing Registry website.

Successful treatment of lysosomal acid lipase deficiency in infants and adults has been reported with sebelipase alfa, a recombinant human lysosomal acid lipase that replaces the deficient enzyme [17-21]. The drug is approved for use in the United States and several other countries [22]. Prior studies reported successful treatment with bone marrow transplantation [23] and stem cells derived from umbilical cord blood [24].

●Smith-Lemli-Opitz syndrome – Smith-Lemli-Opitz syndrome (MIM #270400) is an autosomal recessive disorder of cholesterol biosynthesis caused by pathogenic variants in the DHCR7 gene [25]. The enzyme encoded by this gene is required to convert 7-dehydrocholesterol to cholesterol. The syndrome includes microcephaly, micrognathia, low-set posteriorly rotated ears, and syndactyly of the second and third toes. Affected males have either ambiguous genitalia or nearly normal-appearing female external genitalia (picture 1). Adrenal insufficiency is not universal, but a number of patients have presented with mineralocorticoid deficiency [26].

ADRENAL DAMAGE OR DYSFUNCTION — Bilateral destruction of the adrenal glands by factors extrinsic to the adrenal gland causes adrenal insufficiency in a significant number of children, although this is a less common mechanism of adrenal insufficiency than in adults.

Adrenal hemorrhagic infarction — Causes of adrenal hemorrhagic infarction include:

●Vascular injury – In newborn infants, birth injury to the subcapsular vascular plexus can cause bilateral subcapsular bleeding into the adrenal glands and ischemic damage [27].

●Bacterial infection – Children with serious bacterial infection occasionally develop bilateral adrenal hemorrhage or infarction because of bacterial endotoxin, leading to life-threatening adrenal crisis. This is classically caused by Neisseria meningitidis and is known as Waterhouse-Friderichsen syndrome. It has also been reported with Haemophilus influenzae type B, Pseudomonas aeruginosa, Streptococcus pneumoniae, group B streptococcus, and Staphylococcus aureus. (See "Clinical manifestations of meningococcal infection" and "Clinical manifestations of Staphylococcus aureus infection in adults", section on 'Other manifestations'.)

●Anticoagulant therapy – Anticoagulant therapy and hypercoagulable states are important risk factors for adrenal hemorrhage. (See "Causes of primary adrenal insufficiency (Addison disease)", section on 'Hemorrhagic infarction'.)

Autoimmune disease — Cell-mediated immune mechanisms may cause adrenal damage, resulting in primary adrenal insufficiency, typically called Addison disease. Autoimmune injury causes 15 percent of cases of primary adrenal insufficiency in children [2], although this mechanism is a major cause of primary disease in adults. (See "Causes of primary adrenal insufficiency (Addison disease)", section on 'Autoimmune adrenalitis'.)

Approximately one-half of patients with autoimmune adrenal insufficiency also have autoimmune destruction of other endocrine glands. This combination, known as autoimmune polyglandular syndrome (APS), is observed more frequently in females. Two syndromes, named APS1 and APS2, have specific combinations of autoimmune adrenal insufficiency and involvement of other endocrine organs.

●APS1 (MIM #240300), also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), includes hypoparathyroidism, chronic mucocutaneous candidiasis, and adrenal insufficiency. Other findings include primary hypogonadism and malabsorption. This disease is due to pathogenic variants in the AIRE (autoimmune regulator) gene [28]. (See "Chronic mucocutaneous candidiasis".)

●APS2 (MIM %269200), also known as Schmidt syndrome, is primarily characterized by primary adrenal insufficiency; thyroiditis and type 1 diabetes mellitus are associated findings in some patients. APS2 is more prevalent than APS1. The age of onset ranges from childhood to late adulthood, with most cases presenting between 20 to 40 years of age.

The polyglandular autoimmune syndromes are discussed in greater detail elsewhere. (See "Causes of primary adrenal insufficiency (Addison disease)", section on 'Polyglandular autoimmune syndromes'.)

Infection — Infection of the adrenal gland with the following organisms can lead to adrenal insufficiency in children:

●Tuberculosis – In miliary tuberculosis, Mycobacterium tuberculosis can infiltrate and destroy the adrenal glands. Adrenal calcifications are sometimes seen on abdominal radiographs. (See "Clinical manifestations, diagnosis, and treatment of miliary tuberculosis".)

●Fungal infections – Adrenal insufficiency may develop in disseminated histoplasmosis and, less often, in coccidioidomycosis and blastomycosis. (See "Pathogenesis and clinical manifestations of disseminated histoplasmosis", section on 'Adrenal involvement' and "Causes of primary adrenal insufficiency (Addison disease)", section on 'Disseminated fungal infections'.)

●HIV infection – HIV disease is associated with a variety of abnormalities in pituitary and adrenal function, but overt adrenal insufficiency is rare. In addition, adrenocortical function can be altered by medications used in the treatment of HIV infection, including ketoconazole, rifampin, and megestrol acetate. (See "Pituitary and adrenal gland dysfunction in patients with HIV".)

Infectious adrenalitis is discussed in greater detail elsewhere. (See "Causes of primary adrenal insufficiency (Addison disease)", section on 'Infectious adrenalitis'.)

Mitochondrial disorders — Case reports describe adrenal insufficiency developing in some individuals with mitochondrial disorders related to pathogenic variants in mitochondrial DNA. The disorders include Kearns-Sayre syndrome (MIM #530000), a mitochondrial DNA deletion syndrome (chronic progressive external ophthalmoplegia with onset during childhood, heart block, and retinal pigmentary changes) [29,30], and Pearson syndrome (MIM #557000; sideroblastic anemia and pancreatic dysfunction) [31]. MELAS syndrome (MIM #540000; mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) has also been associated with adrenal insufficiency. An autosomal dominant mitochondrial disorder due to POLG1 (polymerase, DNA, gamma-1) gene pathogenic variants can cause adrenal insufficiency as well [31]. (See "Myopathies affecting the extraocular muscles in children", section on 'Kearns-Sayre syndrome' and "Causes and pathophysiology of the sideroblastic anemias", section on 'Pearson syndrome (large deletion of mitochondrial DNA)'.)

Critical illness-related corticosteroid insufficiency — Critical illness-related corticosteroid insufficiency (CIRCI) is defined as dysfunction of the hypothalamic-pituitary-adrenal axis that occurs during critical illness [32]. The most common clinical manifestation is pressor-resistant hypotension. This was first described in adults with sepsis and has subsequently been reported in children [33,34]. It is thought to be caused by adrenal insufficiency together with tissue corticosteroid resistance. It is characterized by an exaggerated and protracted proinflammatory response, especially in the settings of septic shock and in early severe acute respiratory distress syndrome. (See "Glucocorticoid therapy in septic shock in adults".)

Affected patients have decreased basal cortisol production and synthesis, presumed to be due to adrenal damage causing loss of adrenal reserve or substrates for steroidogenesis. They also have an inadequate cortisol response to stress and/or to an intravenous cosyntropin (ACTH) stimulation test. Of note, a low total cortisol concentration in a critically ill patient may be caused by hypoproteinemia (more specifically, low corticosteroid-binding globulin, also known as transcortin and serpin A6), even when adrenal function and free cortisol are normal [35]. (See "Diagnosis of adrenal insufficiency in adults", section on 'Critical illness'.)

Transient adrenal insufficiency in premature infants — Premature infants have multiple risk factors for relative adrenal insufficiency. The adrenal cortex has not yet undergone the normal physiologic switch from the fetal adrenal cortex, which is focused on the production of sex steroid precursors, to the mature function of the adult adrenal cortex, which is focused on the production of cortisol and aldosterone, as well as androgen precursors. In addition, critical illness adds stress that may further impair cortisol production [36]. The immaturity of the adrenocortical response to stress is reflected in a high ratio of cortisol precursors to cortisol in these infants [37]. As in older patients, refractory hypotension is a clinical manifestation that responds to hydrocortisone treatment. There are conflicting data in the literature regarding the clinical significance of transient adrenal insufficiency in prematurity, and standards regarding its diagnosis are lacking.

PEROXISOMAL DISORDERS — Peroxisomes are subcellular organelles that are present in all cells except mature erythrocytes. These structures catalyze numerous catabolic functions (eg, beta-oxidation of very long-chain fatty acids) and anabolic functions (eg, bile acid synthesis). (See "Peroxisomal disorders".)

Peroxisomal disorders are a heterogeneous group of inborn errors of metabolism. They may either result from a defect in a single peroxisomal enzyme or from abnormal peroxisomal biogenesis affecting multiple peroxisomal functions.

The clinical manifestations of peroxisomal disorders vary. Neurologic impairment is observed in most peroxisomal disorders. The adrenal gland is involved in adrenoleukodystrophy (ALD), as well as in the disorders resulting from abnormal peroxisome biogenesis (such as neonatal ALD, Refsum disease, and Zellweger syndrome).

Adrenoleukodystrophy — ALD consists of a spectrum of phenotypes that vary in age and severity of clinical presentation. It is an X-linked disorder and thus causes clinical disease primarily in males, which affects adrenal function, testicular function, and central and peripheral nervous systems. Female heterozygotes occasionally develop symptoms in adulthood. In boys with a new presentation of primary adrenal insufficiency, prompt evaluation for ALD is important because early diagnosis of ALD is likely to improve outcomes. (See "Clinical features, evaluation, and diagnosis of X-linked adrenoleukodystrophy".)

Several clinical phenotypes have been described in boys and men with X-linked ALD, including childhood cerebral ALD, adolescent cerebral ALD, adult cerebral ALD, adrenomyeloneuropathy, and adrenal insufficiency alone (table 5). The form with adrenal insufficiency alone usually presents between two and eight years of age. Different phenotypes also can be seen in a single pedigree. Adrenal failure may predate, occur simultaneously with, or follow the onset of the neurologic deterioration. Adrenal insufficiency is the initial manifestation in 38 percent of patients with ALD and eventually develops in more than 80 percent of patients over their lifetime [38,39].

Newborn screening for ALD has been implemented in most of the United States. Information on implementation by individual states and other countries around the world (eg, Taiwan, Japan, the Netherlands) is available on the ALD database website. Newborn screening allows for early identification of the condition prior to the development of adrenal insufficiency, as well as the timely identification of boys with cerebral ALD to permit appropriate monitoring and treatment with hematopoietic cell transplantation [38]. Individuals who are diagnosed with ALD with newborn screening require surveillance to monitor for disease manifestations including adrenal insufficiency [40]. The early identification of impairment in adrenal reserve and timely initiation of glucocorticoid replacement treatment could prevent morbidity associated with adrenal insufficiency in these patients [41]. (See "Clinical features, evaluation, and diagnosis of X-linked adrenoleukodystrophy", section on 'Evaluation and diagnosis' and "Management and prognosis of X-linked adrenoleukodystrophy", section on 'Surveillance'.)

ALD is caused by pathogenic variants in the ABCD1 gene, which prevent normal transport of very long-chain fatty acids into peroxisomes, thereby preventing beta-oxidation and breakdown of very long-chain fatty acids. Accumulation of abnormal very long-chain fatty acids in affected organs (central nervous system, Leydig cells of the testes, and adrenal cortex) is presumed to be the underlying pathologic process of these disorders [42]. In the adrenal gland, abnormal very long-chain fatty acids may directly alter cellular function by inhibiting the effects of adrenocorticotropic hormone (ACTH) on the adrenocortical cells or indirectly by initiating an autoimmune response. In almost all cases, adrenocortical failure occurs, along with irreversible degenerative neurologic defects. (See "Clinical features, evaluation, and diagnosis of X-linked adrenoleukodystrophy".)

Other causes — In Zellweger syndrome (MIM #214100) and its variants, the neurologic and adrenocortical abnormalities present in the neonatal period [43,44]. With these autosomal recessive disorders, pathogenic variants have been identified in the genes encoding for peroxins (primarily PEX1 and PEX6), which are required for peroxisomal biogenesis. (See "Peroxisomal disorders", section on 'Zellweger spectrum disorders'.)

All of these pathogenic variants result in cellular accumulation of abnormal very long-chain fatty acids, as seen in ALD. However, unlike in ALD, the peroxisomes in these diseases are fewer in number and smaller than normal in size. In Zellweger syndrome, peroxisomes are totally absent and affected infants generally do not survive their first year of life.

GENETIC CAUSES OF ADRENAL HYPOPLASIA

Adrenal hypoplasia congenita — Adrenal hypoplasia congenita is usually an X-linked disorder caused by pathogenic variants in the NR0B1 (DAX1) gene (MIM #300200). NR0B1 is expressed in the adrenal cortex, gonads, hypothalamus, and pituitary gland. Male fetuses with pathogenic variants have abnormal development of the adrenal cortex during the first trimester of gestation, resulting in impaired cortisol and aldosterone secretion. In a series of 155 pediatric patients with unexplained primary adrenal insufficiency (after excluding congenital adrenal hyperplasia [CAH] and other common causes), 8 percent had pathogenic variants in NR0B1/DAX1 [5].

Pathogenic variants in the NR5A1 (SF1) gene can also cause adrenal hypoplasia (MIM #612964), as well as a spectrum of differences in sex development [5,45]. The NR5A1 gene regulates tissue-specific expression of cytochrome P450 steroid hydroxylases and is expressed in the gonads, adrenal glands, anterior pituitary gland, and hypothalamus. It interacts with NR0B1/DAX1 and is important in both male sexual differentiation and adrenal gland development. (See "Evaluation of the infant with atypical genital appearance (difference of sex development)".)

Although most patients with adrenal hypoplasia congenita present as neonates (one to four weeks of age), the age and severity of the disease can vary. Some individuals, for example, present later in childhood. Clinical manifestations include:

●Neonatal presentation – Affected neonates most often present with signs and symptoms of a salt-losing crisis similar to that of classic CAH, including hyponatremia, hyperkalemia, hypovolemia, and hypotension. Patients have low serum cortisol and aldosterone levels and elevated plasma adrenocorticotropic hormone (ACTH) levels, as well as hyperpigmentation. (See "Clinical manifestations and diagnosis of adrenal insufficiency in children", section on 'Adrenal crisis'.)

●Hypogonadotropic hypogonadism – In surviving affected males treated with replacement steroids, prepubertal gonadal development is normal, but pubertal development is impaired, resulting in hypogonadism. The site of the defect appears to be within the hypothalamic-pituitary-gonadal axis.

●Atypical genital appearance – Infants with NR5A1 gene pathogenic variants may present with 46,XY sex reversal, with atypical genital appearance noted at birth in affected males (MIM #612965), with or without adrenal insufficiency [45,46].

Syndromes with adrenal hypoplasia — Case studies of patients with adrenal hypoplasia who do not have a NR0B1/DAX1 gene pathogenic variants have been reported. The underlying defects in these patients include:

●MIRAGE syndrome – MIRAGE syndrome (MIM #617053) is characterized by myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy. It is caused by heterozygous pathogenic variants of the SAMD9 gene.

●IMAGe syndrome – IMAGe syndrome (MIM #614732) is characterized by intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies. The defective gene (CDKN1C) in several unrelated pedigrees encodes cyclin-dependent kinase inhibitor 1C [47,48].

●Xp21 contiguous gene complex – The NR0B1/DAX1 gene is contiguous with the dystrophin (Duchenne muscular dystrophy) and glycerol kinase (juvenile glycerol kinase deficiency) genes on the short arm of the X chromosome [49]. There are case reports of patients with deletions of this complex who present with adrenal insufficiency, muscular dystrophy, and intellectual disability. Other features include short stature, testicular abnormalities (eg, cryptorchidism and/or hypogonadism), and peculiar facies (drooping mouth and wide-set eyes) [50,51].

●RENI syndrome – RENI syndrome (MIM #617575; renal, endocrine, neurologic, and immune syndrome) is caused by pathogenic variants in the SGPL1 gene that result in accumulation of lysosomal sphingolipid species. The clinical phenotype includes early primary adrenal insufficiency, steroid-resistant nephrotic syndrome, cryptorchidism, primary hypothyroidism, and neurologic symptoms [52,53]. (See "Congenital nephrotic syndrome", section on 'Other genetic causes'.)

INHERITED ADRENAL UNRESPONSIVENESS TO ADRENOCORTICOTROPIC HORMONE — Familial glucocorticoid deficiency (FGD) and triple A syndrome are characterized by unresponsiveness of the adrenal gland to adrenocorticotropic hormone (ACTH). These are types of primary adrenal insufficiency because they are caused by genetic defects within the adrenal gland. However, mineralocorticoid secretion is typically normal so that their clinical presentation may be similar to disorders of central adrenal insufficiency. (See "Causes of central adrenal insufficiency in children".)

Familial glucocorticoid deficiency — FGD type 1 (MIM #202200) is caused by pathogenic variants of the MC2R gene (also known as the ACTH receptor gene), which result in unresponsiveness to ACTH stimulation. The lack of ACTH stimulation of cells in the zona fasciculata and reticularis leads to decreased or no production of cortisol. In contrast, the zona glomerulosa is unaffected and continues to normally secrete aldosterone. FGD type 1 is an autosomal recessive disorder. In a series of pediatric patients with primary adrenal insufficiency that remained unexplained after excluding the most common causes, a detailed genetic analysis revealed MC2R pathogenic variants in 20 percent [5].

Other forms of FGD are caused by pathogenic variants in the MRAP gene (FGD type 2; MIM #607398), which encodes a membrane protein that interacts with MC2R [54]; NNT gene (FGD type 4; MIM #614736), TXNRD2 gene (FGD type 5; MIM #617825), or MCM4 gene [5].

Patients with FGD present early in childhood with feeding difficulties (eg, vomiting), failure to thrive, muscle weakness, hyperpigmentation, and hypoglycemia that may result in seizures. Laboratory evaluation reveals low fasting serum glucose and normal potassium, with or without dilutional hyponatremia. Cortisol secretion is low but not absent, causing subnormal but detectable plasma cortisol concentrations. Plasma ACTH levels are elevated. Aldosterone secretion is normal and also increases appropriately with sodium restriction.

A phenotype similar to FGD may be caused by variants in the CYP11A1 gene. This was shown in a genetic analysis of an international cohort of 19 individuals with primary adrenal insufficiency of unknown etiology with pathogenic variants in CYP11A1. Many of these subjects were initially thought to have typical FGD based on their clinical features. These individuals were compound heterozygotes for pathogenic variants in CYP11A1 that were predicted to be non-deleterious if present alone, based on modeling and in vitro studies [55]. Other pathogenic variants in CYP11A1 cause a more severe phenotype. (See 'Congenital adrenal hyperplasia' above.)

Triple A syndrome — The combination of ACTH-resistant cortisol deficiency, achalasia, and absent lacrimation is known as the triple A syndrome (MIM #231550), also known as Allgrove syndrome. Many of these patients also have neurologic disorders including peripheral, autonomic, and central nervous system impairments [56,57]. This is an autosomal recessive disorder resulting from a defect in the AAAS gene, located on chromosome 12q13, that encodes the ALADIN protein (an acronym for alacrimia-achlasia-adrenal insufficiency and neurologic disorder). Some also have a mild defect in mineralocorticoid (aldosterone) secretion, particularly when salt restricted. In the above case series of patients with unexplained primary adrenal insufficiency, 7 percent had pathogenic variants in AAAS [5]. (See "Achalasia: Pathogenesis, clinical manifestations, and diagnosis".)

DRUGS — Drugs that inhibit cortisol synthesis include aminoglutethimide, high-dose ketoconazole, metyrapone, mitotane, and etomidate.

END-ORGAN UNRESPONSIVENESS — In disorders due to end-organ unresponsiveness, clinical manifestations are similar to those seen in the primary deficiency of the specific hormone (eg, cortisol or aldosterone). Examples include the following:

●Cortisol resistance – Familial or sporadic glucocorticoid resistance (MIM #615962; also known as Chrousos syndrome) is a rare hereditary disorder resulting from pathogenic variants in the glucocorticoid receptor gene, leading to diminished cortisol action and secondary stimulation of adrenocorticotropic hormone (ACTH) release. Although there are high circulating levels of cortisol and ACTH, the patient is not Cushingoid. The glucocorticoid receptor defect results in clinical manifestations similar to those of glucocorticoid deficiency, combined with symptoms of mineralocorticoid and androgen excess.

●Aldosterone resistance – Pseudohypoaldosteronism type 1 is a rare hereditary disorder characterized by generalized resistance to the actions of aldosterone. The autosomal recessive form (MIM #264350) is lifelong and more severe (also associated with lower respiratory tract disease) and is due to loss-of-function pathogenic variants in the gene encoding the epithelial sodium channel. Patients with this form typically present in infancy with clinical manifestations similar to those of mineralocorticoid deficiency (salt wasting, with hypovolemia and hyperkalemia), except for increased levels of plasma and urinary aldosterone. The autosomal dominant form (MIM #177735) is usually due to inactivating pathogenic variants in the mineralocorticoid receptor gene. These disorders are discussed elsewhere. (See "Genetic disorders of the collecting tubule sodium channel: Liddle syndrome and pseudohypoaldosteronism type 1", section on 'Pseudohypoaldosteronism type 1'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Adrenal insufficiency".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Congenital adrenal hyperplasia (The Basics)")

SUMMARY

●Definitions – Primary adrenal insufficiency is defined as the impaired synthesis and/or release of adrenocortical hormones on account of disease intrinsic to the adrenal cortex. Central adrenal insufficiency is characterized by lack of adrenocorticotropic hormone (ACTH) stimulation of cortisol production. (See 'Pathogenetic categories of primary adrenal insufficiency' above.)

●Clinical manifestations – The clinical manifestations of adrenal insufficiency depend on the type of hormonal class affected and severity of the defect(s) (table 1). The adrenal hormones are glucocorticoids (eg, cortisol), mineralocorticoids (eg, aldosterone), and androgens (eg, dehydroepiandrosterone [DHEA]). Adrenal crisis results from acute adrenal insufficiency, which requires prompt recognition and treatment, as summarized in the accompanying table (table 2). (See "Clinical manifestations and diagnosis of adrenal insufficiency in children".)

●Causes – Primary adrenal insufficiency is caused by either genetic defects or acquired disease that affect adrenal function by the following processes (table 3):

•Steroidogenic disorders – Including congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, which is the most common cause of primary adrenal insufficiency in children. (See 'Disorders of steroidogenesis' above.)

•Adrenal damage – Including autoimmune injury (Addison disease) and critical illness-related corticosteroid insufficiency (CIRCI). (See 'Adrenal damage or dysfunction' above.)

•Peroxisomal disorders – Including adrenoleukodystrophy (ALD), which is seen in boys. It can present with neurologic dysfunction, adrenal insufficiency, or both (table 5). (See 'Peroxisomal disorders' above.)

•Genetic causes of adrenal hypoplasia – Including adrenal hypoplasia congenita, which typically presents in neonates with signs and symptoms of a salt-losing crisis similar to that seen in classic CAH. In addition, several syndromes are associated with adrenal hypoplasia (MIRAGE syndrome, IMAGe syndrome, and a form of steroid-resistant nephrotic syndrome). (See 'Genetic causes of adrenal hypoplasia' above.)

•Inherited adrenal unresponsiveness to ACTH – Including familial glucocorticoid deficiency (FGD) and triple A syndrome. (See 'Inherited adrenal unresponsiveness to adrenocorticotropic hormone' above.)

•Drugs – Including ketoconazole. (See 'Drugs' above.)

●Evaluation – A clinical approach to the diagnosis of adrenal insufficiency and determining its cause is presented separately. (See "Clinical manifestations and diagnosis of adrenal insufficiency in children".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Patricia A Donohoue, MD, who contributed to earlier versions of this topic review.