Primary Adrenal Insufficiency
in Boys

Primary adrenal insufficiency, also known as Addison’s disease, is characterized by a deficiency in adrenal hormones due to dysgenesis or destruction of the adrenal cortex or impaired steroidogenesis. Incidence of primary adrenal insufficiency in industrialized countries has been estimated at around 1:10,000 (1-3). In the developing world, the majority of primary adrenal insufficiency is caused by tuberculosis-associated destruction of the adrenal cortex, while in industrialized countries, the etiology of the condition differs with age and gender (4). Autoimmune destruction of the adrenal glands, often occurring as part of autoimmune polyglandular syndrome type 2, is the predominant cause in adults and adolescents, but less common in young children. In young boys, a significant proportion of primary adrenal insufficiency is due to X-linked loss-of-function mutations in the gene ABCD1, giving rise to X-linked adrenoleukodystrophy; X-linked loss-of-function mutations in the gene NR0B1, leading to X-linked adrenal hypoplasia congenita; or autosomal recessive loss-of-function mutations in the gene AIRE, which are associated with autoimmune polyglandular syndrome type 1 and occur with equal frequency in girls (5-8). Identifying mutations in one of these three genes as the underlying cause of primary adrenal insufficiency is important for both prognosis and treatment, since, in each case, primary adrenal insufficiency can be followed by other disease manifestations. In addition, family screening for mutations associated with primary adrenal insufficiency can allow early diagnosis, helping to prevent the occurrence of a life-threatening adrenal crisis.

Genetic testing for mutations in the genes NR0B1, ABCD1, or AIRE associated with primary adrenal insufficiency can allow a diagnosis of X-linked adrenoleukodystrophy, adrenal hypoplasia congenita, or autoimmune polyglandular syndrome type 1, respectively, at any age and detect a predisposition for any of these three syndromes before symptoms develop. Genetic testing can also help identify asymptomatic heterozygous carriers of mutations associated with any of these three syndromes.

Causes of Primary Adrenal Insufficiency in Boys

In older boys (age ten and older), most cases of primary adrenal insufficiency are associated with autoimmune destruction of the adrenal glands, often as part of autoimmune polyglandular syndrome type 2. In younger boys, X-linked adrenoleukodystrophy, adrenal hypoplasia congenita, contiguous gene deletion syndrome, autoimmune polyglandular syndrome type 1, congenital adrenal hyperplasia, or ACTH insensitivity syndrome are the predominant causes of primary adrenal insufficiency (4, 9, 10). The latter three conditions also cause primary adrenal insufficiency in girls.

X-Linked Adrenoleukodystrophy (X-ALD)

Adrenoleukodystrophy occurs in a rare autosomal recessive neonatal form and a much more common X-linked form, which shows a prevalence of 1:42,000 males (11) and presents one of the most common genetic causes of Addison’s disease in boys (9, 12-14).

X-ALD has been associated with loss-of-function mutations in the gene ABCD1, which codes for an ATP-binding peroxisomal membrane protein (5, 15). It is not clear how loss-of-function mutations in the ABCD1 gene product lead to the accumulation of very long chain fatty acids (VLCFA) typical of X-ALD. VLCFA accumulating as cholesteryl esters in the adrenal cortex and as gangliosides in the white matter of the brain are believed to disrupt the structure of cell membranes and increase their microviscosity, impairing normal membrane function (reviewed in 16). In the brain, VLCFA accumulation can also lead to an inflammatory demyelinating reaction similar to that seen in multiple sclerosis. In the adrenals, sequestration of cholesterol in VLCFA cholesteryl esters, which are only inefficiently hydrolyzed, can lead to a shortage of cholesterol for steroid synthesis.

Adrenal Hypoplasia Congenita (X-AHC)

X-AHC has been associated with loss-of-function mutations in the gene NR0B1, which codes for an orphan nuclear receptor (6). NR0B1 is also known as DAX1, or “dosage-sensitive sex reversal adrenal hypoplasia congenita critical region on the X chromosome gene,” reflecting the location of NR0B1 in a region of the X chromosome that, if duplicated, leads to male-to-female sex reversal. NR0B1 is expressed exclusively in tissues directly involved in steroid hormone production and/or reproductive function and all regions of the hypothalamic-pituitary-adrenal-gonadal axis (17). Its gene product is believed to repress transcriptional activation by steroidogenic factor 1 (SF-1), thereby downregulating the expression of several enzymes involved in the hormonal steroidogenic pathways.

Loss-of-function mutations in NR0B1 prevent the postnatal development of the adult adrenal cortex, leading to adrenal hypoplasia congenita (X-AHC) and, consequently, deficiency in all adrenocortical hormones. In addition, X-AHC-related loss-of-function mutations in NR0B1 give rise to hypogonadotropic hypogonadism (HHG) by disrupting release of gonadotropin releasing hormone from the hypothalamus and gonadotropin production in the pituitary (18). In males, X-AHC is also associated with reduced spermatogenesis in the testes (19).

Autoimmune Polyglandular Syndrome Type 1 (APS1)

APS1 is characterized by simultaneous presence of chronic mucocutaneous candidiasis, hypoparathyroidism, and/or primary adrenal insufficiency and typically presents in childhood (20). Since several other autoimmune endocrinopathies and ectodermal dystrophies can occur in addition to the three primary component diseases, the syndrome is also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). Incidence of APS1 has been estimated at 1:80,000 in Norway (21), 1: 25,000 in Finland (22) and 1:14,400 in the Sardinian population (23), and may account for up to 15% of all autoimmune adrenalitis (24).

APS1 has been shown to be associated with autosomal recessive loss-of-function mutations in a single gene, subsequently termed autoimmune regulator (AIRE) (7,8). The AIRE gene product, which contains several conserved motifs commonly found in transcription regulators, is preferentially expressed in the thymus, where it is assumed to play a role in the expression of tissue-specific antigens (25). Thymic expression of self-antigens that are otherwise only expressed in peripheral tissues, such as the adrenals, exposes maturing T-cells to these self-antigens, allowing self-reactive T-cells to be eliminated. Presumably, loss-of-function mutations in AIRE prevent thymic expression of tissue-specific antigens, allowing T-cells specific for these self-antigens to persist and to mediate an autoimmune reaction against the tissues expressing these self-antigens (26).

Other Types of Primary Adrenal Insufficiency in Boys

Congenital Adrenal Hyperplasia (CAH)
CAH is due to impaired biosynthesis of adrenal steroids, caused by loss-of-function mutations in any of a number of enzymes. Defects in 21-hydroxylase or 3β-hydroxysteroid dehydrogenase can lead to deficiency in mineralocorticoid synthesis and provoke a salt-wasting crisis in infants (27). Loss-of-function mutations in the steroidogenic acute regulatory (StAR) protein are associated with the most severe form of CAH, lipoid CAH (28).

Contiguous Gene Deletion Syndrome
X-AHC can occur in conjunction with glycerol kinase deficiency and, in some patients, Duchenne muscular dystrophy, due to a contiguous gene deletion spanning NR0B1, the glycerol kinase gene, GK, and, in some cases, the Duchenne muscular dystrophy gene, DMD (4).

Other Types of Autoimmune Adrenalitis
Idiopathic autoimmune adrenalitis is characterized by isolated autoimmunity directed exclusively against the adrenal glands. This form of autoimmune adrenalitis is more common in adults than in children. Similarly, autoimmune polyglandular syndrome type 2, also known as Schmidt’s syndrome, occurs predominantly in adults (20).

ACTH Insensitivity Syndrome
ACTH resistance can occur by itself, causing familial glucocorticoid deficiency, or in conjunction with achalasia of the esophagus and alacrima (Triple A or Allgrove Syndrome). Familial glucocorticoid deficiency has been associated with autosomal recessive inactivating mutations in the ACTH receptor (melanocortin 2 receptor) and with mutations in the melanocortin 2 receptor accessory protein (29, 30). Allgrove Syndrome has been linked to autosomal recessive mutations in the AAAS gene (31).

Clinical Presentation of Primary Adrenal Insufficiency

Chronic primary adrenal insufficiency presents with hyperpigmentation of the skin and mucosal membranes, weakness, fatigue, orthostatic hypotension, anorexia, weight loss, nausea, vomiting, abdominal pain, salt craving, and, in children, hypoglycemia. In infants, most of these symptoms manifest as failure to thrive and vomiting. An acute adrenal, or salt-wasting, crisis is characterized by dehydration and electrolyte imbalances due to mineralocorticoid deficiency; such an acutely life-threatening crisis is often precipitated by stresses such as surgery, trauma, or infection. Primary adrenal insufficiency due to CAH or the contiguous gene deletion syndrome typically presents only in infancy, while X-ALD and autoimmune endocrinopathies generally develop later in childhood; by contrast, X-AHC occurs both in infancy and childhood (4).

Most Likely Causes of Primary Adrenal Insufficiency in Children

Clinical Presentation of X-ALD

In males, X-ALD is generally associated with impaired adrenocortical function (16). In some patients, primary adrenal insufficiency remains the only symptom; most patients, however, also develop neurological problems. The most severe form of X-ALD is the childhood cerebral form, which affects about 35% of patients (32) and typically manifests between the ages of 4 and 8 years. It is characterized by inflammatory myelopathy and is associated with rapidly progressive impairment of cognition, behavior, vision, hearing, and motor function, often resulting in total disability within two years.

Adrenomyeloneuropathy (AMN) is the most common form of X-ALD, accounting for about 45% of all cases (32). In AMN, neurological problems manifest later in life and, at least initially, are due to non-inflammatory axonopathy without inflammatory brain involvement (33). Symptoms such as spastic paraparesis, sphincter disturbances, distal sensory loss, stiffness or weakness of legs, and sexual dysfunction become apparent in the late twenties and show slow progression, sometimes over decades. About half of all patients with AMN eventually also develop some brain involvement, which becomes severely progressive in about 10-20% of patients with AMN (34). The phenotype of X-ALD cannot be predicted from the genotype and is highly variable even within families (16, 35). In most cases of X-ALD in males, primary adrenal insufficiency precedes the onset of neurological problems.

Female carriers of an X-ALD-associated mutations in ABCD1 typically do not show impairment of adrenal function, but many develop symptoms of myeloneuropathy during adulthood (36). Symptoms include spastic paraparesis and bladder or bowel dysfunction, and are usually mild to moderate.

Clinical Presentation of X-AHC

X-AHC affects almost exclusively males. The presenting feature is typically primary adrenal insufficiency, with onset in infancy in about 60% and in childhood in about 40% of all cases (19). Virtually all X-AHC is associated with HHG and, in males, sterility. While newborn males with an X-AHC-associated mutation in NR0B1 may show normal serum gonadotropin and testosterone levels, most later fail to enter puberty or undergo only partial puberty without treatment. Occasionally, chronic excessive ACTH levels from adrenal insufficiency may stimulate Leydig cells and lead to gonadotropin-independent precocious puberty (37, 38). In 10% of cases, male infants with X-AHC have bilaterally undescended testes (18, 19).

Clinical Presentation of APS1

APS1 is characterized by the combined occurrence of chronic mucocutaneous candidiasis, autoimmune hypoparathyroidism, and/or autoimmune primary adrenal insufficiency. At least one of the three component diseases typically manifests before age ten, and two or three are usually apparent by age twenty. Additional autoimmune phenotypes such as acute hepatitis, celiac disease, pernicious anemia, primary hypogonadism, hypothyroidism, insulin-dependent diabetes mellitus, vitiligo, and alopecia can continue to develop until at least the fifth decade of life (20). Ectodermal dystrophies such as dental enamel hypoplasia and keratopathy are also common. The exact phenotypic spectrum of APS1 can vary widely, even between siblings sharing the same causative loss-of-function mutations in AIRE (39). More autoimmune phenotypes have been observed simultaneously in one patient for APS1 than for any other autoimmune polyglandular syndrome.

Diagnosis of Primary Adrenal Insufficiency

Diagnosis of primary adrenal insufficiency is based on detection of high serum ACTH in the presence of low or normal serum cortisol or the lack of an increase in serum cortisol levels in response to cosyntropin administration.

Diagnosis of X-ALD

Diagnosis of X-ALD in males can be achieved by measuring plasma concentrations of VLCFA, which are elevated in more than 99% of males at risk for or affected with X-ALD (16). However, only 85% of female carriers show elevated plasma VLCFA. Genetic testing for X-ALD can allow a diagnosis of X-ALD or detect a predisposition for X-ALD in males and identify female carriers of X-ALD-associated mutations in ABCD1.

Diagnosis of X-AHC

Diagnosis of X-AHC is suggested by primary adrenal insufficiency in conjunction with bilaterally undescended testes in infants or delayed puberty later in childhood. Imaging studies such as an abdominal CT scan or an MRI can confirm adrenal hypoplasia, but may be difficult to interpret. Genetic testing for X-AHC-associated mutations in NR0B1 can allow a differential diagnosis of X-AHC or detect a predisposition for X-AHC at any age and identify female carriers of X-AHC-associated mutations in NR0B1.

Diagnosis of APS1

Diagnosis of APS1 is based on the presence of at least two of its three primary component diseases. Typically, chronic mucocutaneous candidiasis develops first, followed by hypoparathyroidism and/or primary adrenal insufficiency. Diagnosis of APS1 is supported by detection of characteristic autoantibodies (40). Genetic testing for APS1-associated sequence variants in AIRE can allow a diagnosis of APS1 after only one of the characteristic component diseases has developed or detect a predisposition for APS1 before any symptoms appear.

Treatment of Primary Adrenal Insufficiency

Primary adrenal insufficiency is treated with glucocorticoid and mineralocorticoid replacement and, in young children, dietary sodium supplements.

Treatment of X-ALD

The AMN form of X-ALD can be treated symptomatically with muscle relaxants and pain medication. Bone marrow or hematopoietic stem cell transplantation may slow down progression of the childhood cerebral form if performed early in the disease course (41). Once brain involvement has progressed too far, however, bone marrow transplantation is no longer effective. At the same time, this high risk procedure should not be performed before neurological problems become apparent, since occurrence of the childhood cerebral phenotype cannot be predicted. Dietary treatment with Lorenzo’s oil, a 1:4 mixture of erucic acid and oleic acid, lowers plasma levels of VLCFA, but has no effect on accumulation of VLCFA in the brain of symptomatic patients. However, treatment with Lorenzo’s oil may reduce the risk of neurological abnormalities if initiated in neurological asymptomatic boys under the age of six (42).

Treatment of X-AHC

In patients with X-AHC, puberty can be initiated by administration of testosterone. Fertility, however, can generally not be restored.

Treatment of APS1

Management of APS1 is based on treatment of the component diseases. Immunosuppressive therapy may be indicated in severe cases of APS1 (43).

Genetics of X-ALD, X-AHC, and APS1

X-ALD shows X-linked recessive inheritance. The childhood cerebral form of X-ALD affects exclusively males, who harbor only one X chromosome (hemizygotes). Many females heterozygous for an X-ALD associated mutation in ABCD1 will eventually show mild to moderate symptoms typical of AMN, but without adrenal involvement (36). Regardless of whether a female heterozygote shows any symptoms, her sons are at a 50% risk of being affected with X-ALD. Genetic analysis of how the different X-ALD phenotypes segregate within families suggests the presence of an autosomal modifier gene (16).

X-AHC shows X-linked recessive inheritance and affects predominantly males. Females heterozygous for an X-AHC associated mutation in NR0B1 show an extreme delay in the onset of puberty (44), and their sons are at a 50% risk of being affected with X-AHC. Homozygosity for an X-AHC associated mutation in NR0B1 has been reported to lead to HHG without adrenal involvement (45). Homozygosity in females is likely to be extremely rare, as most males with X-AHC are sterile.

APS1 shows autosomal recessive inheritance and affects both males and females (7,8).

Genetic Testing for Primary Adrenal Insufficiency in Boys

The Primary Adrenal Insufficiency Evaluation detects mutations in the genes ABCD1, NR0B1, and AIRE and can diagnose X-ALD, X-AHC, or APS1, respectively, at any age and before characteristic symptoms become apparent. The Primary Adrenal Insufficiency Evaluation is indicated by primary adrenal insufficiency in boys or by a family history of X-AHC, X-ALD, or APS1. Early diagnosis is crucial for all three conditions to prevent occurrence of an adrenal crisis. In addition, early detection of X-ALD can allow potentially preventative dietary treatment with Lorenzo’s oil and help to increase vigilance for manifestation of neurological problems, so that the “window of opportunity” for bone marrow transplantation will not be missed.

Early detection of X-AHC allows timely initiation of treatment with testosterone. Early detection of APS1 alerts both the patient and the physician to a patient’s high risk for developing a range of autoimmune phenotypes, prompting increased vigilance that can help to permit early intervention and prevent potentially fatal complications from untreated endocrinopathies. In addition, the Primary Adrenal Insufficiency Evaluation enables carrier testing to identify X-ALD or X-AHC-associated mutations in asymptomatic heterozygous females, who may transmit the condition to their sons.

How Is Genetic Testing for X-ALD, X-AHC, or APS1 Performed?

DNA for sequencing is obtained from leukocytes present in a small blood sample. The coding sequences of ABCD1, NR0B1, and AIRE are amplified in a highly specific manner through a polymerase chain reaction (PCR), and all PCR products are fully sequenced. Sequencing results are interpreted, and a detailed result report is sent to the patient’s physician.

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