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Review Article
EP14503.RA
GENETIC FORMS OF ADRENAL INSUFFICIENCY Elise M. Brett, MD, FACE, CNSC, ECNU1; Richard J. Auchus, MD, PhD, FACE2 Running title: Genetics of Adrenal Insufficiency
From: 1Division of Endocrinology, Diabetes, and Bone Diseases, Department of Internal Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10128, and 2 Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109.
Correspondence Address: Richard Auchus, MD, PhD, FACE University of Michigan Health System Rm 5560A, MSRBII 1150 W. Medical Center Dr. Ann Arbor, MI 48109 Email: [email protected] or Elise M. Brett, MD, FACE, CNSC, ECNU Icahn School of Medicine at Mount Sinai 1192 Park Avenue New York, NY 10128 Email: [email protected]
DOI:10.4158/EP14503.RA © 2014 AACE.
Disclosure: Nothing to disclose
Keywords: Adrenal insufficiency, polyendocrinopathy, mutation, glucocorticoid, genetics
Abstract: Objective: The AACE Adrenal Scientific Committee has developed a series of articles to update members on the genetics of adrenal diseases. Methods: Case presentation, discussion of literature, table, and bullet points. Results: The genetic mutations associated with several familial causes of adrenal insufficiency have now been identified. The most common ones that will be discussed here include Allgrove syndrome (AAA), adrenoleukodystrophy (ALD), adrenal hypoplasia congenita (AHC), autoimmune polyglandular syndrome type 1 (APS1), congenital adrenal hyperplasia (CAH), lipoid CAH, and familial glucocorticoid deficiency (FGD). Although these diseases most commonly present in childhood, some rarely present in adulthood, and thus all endocrinologists must be familiar with these syndromes. Some patients only DOI:10.4158/EP14503.RA © 2014 AACE.
develop glucocorticoid deficiency, and others have both glucocorticoid and mineralocorticoid deficiency. These diseases may be associated with other conditions, especially neurological disease, hypogonadism, or dermatologic problems. Diagnosis is suspected based on clinical presentation and laboratory findings. Gene testing may be necessary for confirmation of a diagnosis and/or screening of family members. Conclusions: This article briefly reviews the various familial adrenal insufficiency syndromes and the specific associated gene defects.
Abbreviations: AAA = Allgrove syndrome (alachrima-achalasia-adrenal insufficiency); ACTH = adrenocorticotropin; AHC = adrenal hypoplasia congenita; AIRE = autoimmune regulator gene; ALADIN = alacrima-achalasia-adrenal insufficiency neurological disorder; ALD = adrenoleukodystrophy; ALDP = adrenoleukodystrophy protein; AMN = adrenomyeloneuropathy; APECED = autoimmune polyendocrinopathy, candidiasis and ectodermal dystrophy; APS1 = autoimmune polyglandular syndrome type 1; CAH = congenital adrenal hyperplasia; DAX1 = dosage-sensitive sex reversal, adrenal hypoplasia congenita, X-chromosome; FGD = familial glucocorticoid deficiency; LCAH = lipoid CAH; MCM4, mini chromosome maintenance-deficient 4; MC1R and MC2R = melanocortin receptor types 1 and 2; NNT = nicotinamide nucleotide transhydrogenase; SF1 = steroidogenic factor 1; DOI:10.4158/EP14503.RA © 2014 AACE.
StAR = steroidogenic acute regulatory protein; TXNRD2 = thioredoxin reductase type 2; VLCFA = very long-chain fatty acid.
Case. A.I. is a 22-year old male college student who collapsed at an intramural soccer game. He was taken to a local hospital hypotensive and found to have primary adrenal insufficiency. He has no family history of adrenal insufficiency; however, a maternal uncle has some type of neurologic disease. Physical exam demonstrated hyperpigmentation, a normal thyroid, and no vitiligo. Testing for anti-21-hydroxylase antibodies were negative, and thyroid tests were normal. Could he have a genetic disease?
Discussion
During the past 2 decades, the genetic basis for several forms of familial adrenal insufficiency syndromes has been elucidated. The molecular mechanisms for these diseases involve a broad spectrum of cellular and physiologic processes, including metabolism, nuclear protein import, and autoimmunity. The most common types, including those that may present in adulthood, will be discussed below. The early identification of such diseases can have important prognostic and therapeutic implications for patients with regard to surveillance for associated conditions, initiation of early treatment or screening of family members who are at risk.
DOI:10.4158/EP14503.RA © 2014 AACE.
Autoimmune polyendocrinopathy type 1 (APS1) syndrome is a rare disorder with autosomal recessive inheritance in which adrenal insufficiency is associated with autoimmune disorders. It is caused by a mutation in the autoimmune regulator (AIRE) gene on chromosome 21. The AIRE protein is primarily expressed in thymic epithelial cells, and this transcriptional regulator is essential for the removal of autoreactive T-cells and thus the maintenance of self-tolerance. APS1 is also known as the APECED syndrome for autoimmune polyendocrinopathy, candidiasis and ectodermal dystrophy. In the syndrome, adrenal insufficiency is most commonly associated with hypoparathyroidism and chronic mucocutaneous candidiasis, but patients are also at risk for type 1 diabetes, gonadal dysfunction, autoimmune hepatitis, intestinal malabsorption, pernicious anemia, alopecia and vitiligo. The adrenal insufficiency typically presents between 11 and 15 years of age and usually occurs later than the hypoparathyroidism and mucocutaneous candidiasis. Most patients have antibodies against the 21-hydroxylase enzyme characteristic of autoimmune adrenalitis. Males and females are equally affected. The highest incidence has been seen in Finland, Norway, Sardinia and Iranian Jewish populations. Adrenoleukodystrophy (ALD) is a rare X-linked recessive disorder characterized by primary adrenal insufficiency and demyelination within the central or peripheral nervous system. ALD may also be associated with primary testicular failure. The disease results from impaired transport of very-long chainfatty acids (VLCFA) into peroxisomes for beta oxidation. ALD is caused by mutations in the ATP-binding cassette, subfamily D, member 1 (ABCD1) gene DOI:10.4158/EP14503.RA © 2014 AACE.
that encodes the peroxisomal membrane protein ALDP, which transports longchain fatty acids into peroxisomes for oxidation. This defect leads to accumulation of VLCFA in plasma and tissues. The brain and adrenal cortex are particularly vulnerable for unknown reasons. The diagnosis is confirmed by finding elevated VLCFA in plasma. Clinical manifestations in ALD are variable. Adrenal failure most commonly presents before age 15 but can also occur at later ages, and adrenal dysfunction typically occurs before the onset of neurological symptoms. A minority of affected patients develop only adrenal insufficiency. Some patients develop the more severe childhood cerebral form that presents as learning deficit or behavioral change and is often rapidly progressive to disability and death. Others develop adrenomyeloneuropathy (AMN), which typically presents in the third decade with stiffness and weakness in legs, loss of sphincter control and sexual dysfunction, and progresses over decades. Heterozygous women can also be affected but have a much milder course and rarely develop cerebral involvement and adrenal insufficiency. While the adrenal insufficiency of ALD is managed with corticosteroid replacement, no reliable treatments exist to curtail the neurologic dysfunction. Dietary supplementation with triglycerides enriched in oleic and erucic acids (Lorenzo’s oil) has been used to limit the elongation of precursors to VLCFA. A two-year trial in the 1990s showed no benefit, but subsequent smaller studies and cases have demonstrated slight benefit. Stem cell transplantation from related donors is also being tested in ALD. DOI:10.4158/EP14503.RA © 2014 AACE.
Adrenal hypoplasia congenita (AHC) is an X-linked recessive disorder characterized by primary adrenal failure and hypogonadotropic hypogonadism with pubertal failure. In AHC, there is a failure of development of the permanent adult adrenal cortex caused by a mutation in the NR0B1 gene, encoding nuclear receptor subfamily 0, group B, number 1 (also known as DAX1 for dosagesensitive sex reversal, adrenal hypoplasia congenita, X-chromosome). Affected individuals may present in infancy with severe salt wasting or have a more insidious onset during childhood. Rarely, AHC can present with adrenal failure later in adulthood. Carrier females may very rarely have symptoms of adrenal insufficiency or hypogonadotropic hypogonadism. DAX1 is a transcription factor, which balances the transcriptional activity of steroidogenic factor 1 (SF1). SF1 is essential for the development of the adrenal cortex and the steroidogenic cells of the gonads, as well as the expression of the steroidogenic enzymes and cofactor proteins necessary for steroidogenesis from cholesterol. Mutations in the NR5A1 gene encoding SF1 are found in about 15% of patients with 46,XY gonadal dysgenesis, and in a minority of these cases, adrenal insufficiency is also present. Thus, patients harboring an SF1 defect can present similar to AHC with both hypogonadism and adrenal insufficiency; however, DAX1 defects cause hypogonadotropic hypogonadism, while SF1 defects cause gonadal dysgenesis with elevated gonadotropins and often undervirilization. Allgrove syndrome, also known as the Triple A syndrome, is a rare autosomal recessive disorder characterized by the triad of adrenocortical failure DOI:10.4158/EP14503.RA © 2014 AACE.
due to ACTH resistance, achalasia and alacrima. Allgrove syndrome is caused by mutations in the AAAS gene on chromosome 12, which encodes for the WDrepeat protein ALADIN. The molecular pathophysiology of this syndrome is poorly understood, but the ALADIN protein is a component of the nuclear pore complex and the nuclear protein import machinery. Defective import of specific nuclear proteins appears to allow oxidative damage in the adrenal glands and other tissues. These patients present typically in childhood with hypoglycemia and adrenal crisis, but the disease has rarely presented as late as the fourth decade. Allgrove syndrome is associated with progressive neurological dysfunction, which may include autonomic, sensory and motor neuropathy. Mild mental retardation may also be present. Mineralocorticoid deficiency develops in a minority of patients. Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders due to the defects of the enzymes involved in adrenal steroidogenesis. CAH is reviewed in detail in another paper in this issue, but we will briefly comment on some forms of CAH as causes of adrenal insufficiency. The enzyme deficiencies result in defects in cortisol biosynthesis with accumulation of precursors, diversion to increased androgen production and variable mineralocorticoid defects. Low cortisol reduces negative feedback and increases ACTH secretion, which results in adrenal hyperplasia. The most common form of CAH, found in 1:16,000 newborns, is 21-hydroxylase deficiency, caused by a deletion or mutation in CYP21A2. There are 3 different phenotypes associated DOI:10.4158/EP14503.RA © 2014 AACE.
with varying degrees of enzyme activity: classic salt wasting, classic simple virilizing and non-classic or late-onset, which does not cause adrenal insufficiency. Mutations in the HSD3B2 gene cause 3β-hydroxysteroid dehydrogenase deficiency, which also causes variable degrees of adrenal insufficiency and androgen excess, but the genital virilization in females is less severe than in 21-hydroxylase deficiency, and the males have androgen deficiency. Patients with 11-hydroxylase deficiency, due to mutations in the CYP11B1 gene, have androgen excess but are protected from adrenal crises due to mineralocorticoid excess. Lipoid congenital adrenal hyperplasia (LCAH), the most severe form of CAH, is most commonly caused by mutations in the STAR gene encoding the steroidogenic acute regulatory protein (StAR). Severe defects in StAR lead to a block in the first step in steroidogenesis, complete deficiency in glucocorticoid, mineralocorticoid and sex steroid hormones, and the pathognomonic massive cholesterol ester accumulation in the adrenal cortex. The disease is most common in Palestinian and Japanese populations. Within the last decade, a milder or nonclassic form of LCAH has been described, in which glucocorticoid deficiency is the primary and usually the only manifestation (see below). Mutations in the CYP11A1 gene encoding the cholesterol side-chain cleavage enzyme cause a similar global loss of steroidogenesis and adrenal insufficiency, but the adrenals are not lipid-laden as in patients with STAR mutations. Familial Glucocorticoid Deficiency (FGD) or hereditary unresponsiveness DOI:10.4158/EP14503.RA © 2014 AACE.
to ACTH is a group of rare autosomal recessive disorders in which the cells of the zona fasciculata within the adrenal cortex do not produce cortisol in response to ACTH stimulation. Aldosterone production from the zona glomerulosa remains intact. The disease is caused by mutations in the melanocortin type 2 receptor (MC2R) or more commonly in its accessory protein (MRAP), which together yield the functional receptor for ACTH. Loss of cortisol’s negative feedback results in high ACTH, which leads to hyperpigmentation from overstimulation of melanocortin type 1 receptors (MC1R). Patients typically present in infancy with hypoglycemia, hyperpigmentation and failure to thrive, but occasionally patients have not been diagnosed until later in childhood. Hyperkalemia and severe hyponatremia are not seen, due to intact aldosterone production. Patients with FGD are often noted to have tall stature, but the underlying mechanisms are not clear. Because MC2R mutations are found in only a minority of patients with FGD, investigators have searched for other genes in the remaining FGD cohorts. The MRAP mutations were next discovered, and subsequently some FGD kindred were found to harbor STAR mutations and to have the nonclassic form of LCAH. More recently, FGD families have been described with mutations in mini chromosome maintenance-deficient 4 homologue (MCM4) among the Irish traveler population and in nicotinamide nucleotide transhydrogenase (NNT), which encodes an antioxidant protein of the inner mitochondrial membrane. One of these patients presented as late as 8.5 years old. Most recently, one DOI:10.4158/EP14503.RA © 2014 AACE.
consanguineous Kashmiri kindred was shown to have FGD and a nonsense mutation in the TXNRD2, encoding the flavoprotein thioredoxin reductase 2, a selenoprotein that catalyzes the reduction of oxidized thioredoxin. The oldest affected member of this kindred presented at age 10.8. The mechanisms by which these last 3 genetic defects cause FGD are not completely understood. Thus, there are several different causes of adrenal insufficiency in which the specific gene defect is now known, and molecular genetic testing is available for many of these genes. Screening of family members for the disease state or carrier status may also be indicated and can be critical for family planning. When a monogenic cause of adrenal failure is identified, genetic counseling is indicated. In the aforementioned case, the absence of anti-21-hydroxylase antibodies, normal thyroid examination and function and absence of vitiligo suggest that the adrenal insufficiency is not part of an autoimmune polyendocrinopathy syndrome. The history of neurologic disease in the uncle suggests adrenoleukodystrophy or Allgrove syndrome. The X-linked pattern of inheritance makes adrenoleukodystrophy (ALD) most likely, plus there is no mention of alacrima or achalasia to suggest Allgrove. Testing of plasma very long chain fatty acids (VLCFA) is indicated first. The early identification of X-linked ALD is critical as the patient would need to be observed for signs of neurologic dysfunction, as it is essential to start treatment early. Genetic testing is readily available
in
commercial
DOI:10.4158/EP14503.RA © 2014 AACE.
reference
laboratories
(GeneDx,
Athena/Quest
Diagnostics, Mayo Medical Laboratories, Esoterix/Laboratory Corporation of America, ARUP, others) for most of these genes, except for some of the less common FGD syndromes.
Bullet Points •
Many causes of adrenal insufficiency can now be attributed to a single gene defect
•
Some of these conditions previously thought to present only in childhood have also presented in adulthood with variable phenotypes
•
Testing for many of these gene defects is now commercially available
•
Identification of a genetic cause of adrenal insufficiency may alert the clinician to the need for early treatment or surveillance for associated conditions
•
Identification of a genetic cause of adrenal insufficiency can be critical for family planning and screening of family members based on the known pattern of inheritance
References: DOI:10.4158/EP14503.RA © 2014 AACE.
1. Achermann JC, Meeks JJ, Jameson JL. Phenotypic spectrum of mutations in DAX-1 and SF-1. Mol Cell Endocrinol. 2001;185:17-25. 2. Auchus RJ, Arlt W. Approach to the Patient: The Adult with Congenital Adrenal Hyperplasia. J Clin Endocrinol Metab. 2012;98:2645-2655. 3. Bentes C, Santos-Bento M, de Sá J, de Lurdes Sales Luís M, de Carvalho M. Allgrove syndrome in adulthood. Muscle Nerve. 2001;24:292-296. 4. Charmandari E, Nicolaides NC, Chrousos GP. Adrenal Insufficiency. Lancet. 2014;383:2152-2167. 5. Clark AJ, Chan LF, Chung TT, Metherell LA. The genetics of familial glucocorticoid deficiency. Best Pract Res Clin Endocrinol Metab. 2009;23:159165. 6. Engelen M, Kemp S, de Visser M, van Geel BM, Wanders RJ, Aubourg P, Poll-The BT. X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management. Orphanet J Rare Dis. 2012;7:51. 7. Handschug K, Sperling S, Yoon SJ, Hennig S, Clark AJ, Huebner A. Triple A syndrome is caused by mutations in AAAS, a new WD-repeat protein gene. Hum Mol Genet. 2001;10:283-290. 8. Meimaridou E, Hughes CR, Kowalczyk J, Guasti L, Chapple JP, King PJ, Chan LF, Clark AJ, Metherell LA. Familial glucocorticoid deficiency: New genes and mechanisms. Mol Cell Endocrinol. 2013;371:195-200. 9. Metherell LA, Naville D, Halaby G, Begeot M, Huebner A, Nurnberg G, Nurnberg P, Green J, Tomlinson JW, Krone NP, Lin L, Racine M, Berney DOI:10.4158/EP14503.RA © 2014 AACE.
DM, Achermann JC, Arlt W, Clark AJ. Nonclassic lipoid congenital adrenal hyperplasia masquerading as familial glucocorticoid deficiency. J Clin Endocrinol Metab. 2009;94:3865-3871. 10. O'Riordan SM, Lynch SA, Hindmarsh PC, Chan LF, Clark AJ, Costigan C. A novel variant of familial glucocorticoid deficiency prevalent among the Irish Traveler population. J Clin Endocrinol Metab. 2008;93:2896-2899. 11. Prasad R, Chan LF, Hughes CR, Kaski JP, Kowalczyk JC, Savage MO, Peters CJ, Nathwani N, Clark AJ, Storr HL, Metherell LA. Thioredoxin Reductase 2 (TXNRD2) mutation associated with familial glucocorticoid deficiency (FGD). J Clin Endocrinol Metab. 2014;99:E1556-1563. 12. Proust-Lemoine E, Saugier-Veber P, Wémeau JL. Polyglandular autoimmune syndrome type I. Presse Med. 2012;41:e651-e662. 13. Rosatelli MC, Meloni A, Meloni A, Devoto M, Cao A, Scott HS, Peterson P, Heino M, Krohn KJ, Nagamine K, Kudoh J, Shimizu N, Antonarakis SE. A common mutation in Sardinian autoimmune polyendocrinopathy-candidiasisectodermal dystrophy patients. Hum Genet. 1998;103:428-434 14. Vaidya B, Pearce S, Kendall-Taylor P. Recent advances in the molecular genetics of congenital and acquired primary adrenocortical failure. Clin Endocrinol (Oxf). 2000;53:403-418. 15. Wallace IR, Hunter SJ. AAA syndrome--adrenal insufficiency, alacrima and achalasia. QJM. 2012;105:803-804. 16. Zanaria E, Muscatelli F, Bardoni B, Strom TM, Guioli S, Guo W, Lalli E, Moser C, Walker AP, McCabe ERB, Meitinger T, Monaco AP, Sassone-Corsi DOI:10.4158/EP14503.RA © 2014 AACE.
P, Camerino G. An unusual member of the nuclear hormone receptor superfamily responsible for X-linked adrenal hypoplasia congenita. Nature. 1994;372:635-641. 17. Aubourg P, Adamsbaum C, Lavallard-Rousseau MC, Rocchiccioli F, Cartier N, Jambaque I, Jakobezak C, Lemaitre A, Boureau F, Wolf C, et al. A two-year trial of oleic and erucic acids ("Lorenzo's oil") as treatment for adrenomyeloneuropathy. N Engl J Med 1993;329:745-752. 18. Cappa M, Bizzarri C, Petroni A, Carta G, Cordeddu L, Valeriani M, Vollono C, De Pasquale L, Blasevich M, Banni S. A mixture of oleic, erucic and conjugated linoleic acids modulates cerebrospinal fluid inflammatory markers and improve somatosensorial evoked potential in X-linked adrenoleukodystrophy female carriers. Journal of inherited metabolic disease 2012;35:899-907. 19. Achermann JC, Ito M, Hindmarsh PC, Jameson JL. A mutation in the gene encoding steroidogenic factor-1 causes XY sex reversal and adrenal failure in humans [letter]. Nat Genet 1999;22:125-126. 20. Köhler B, Lin L, Ferraz-de-Souza B, Wieacker P, Heidemann P, Schroder V, Biebermann H, Schnabel D, Gruters A, Achermann JC. Five novel mutations in steroidogenic factor 1 (SF1, NR5A1) in 46,XY patients with severe underandrogenization but without adrenal insufficiency. Hum Mutat 2008;29:5964.
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DOI:10.4158/EP14503.RA © 2014 AACE.
Table 1 Disease 1 AAA 2 ALD
Gene AAAS ABCD1
Inheritance pattern Autosomal recessive X-linked recessive
Associated Alacrima, achalasia Neurologic, hypogonadism
3
NR0B1
X-linked recessive
Low gonadotropins and testosterone
Adrenal Insufficiency with Gonadal Dysgenesis 4 APS-1
NR5A1
Autosomal dominant More common 46,XY
Hypogonadotropic hypogonadism Delayed puberty Gonadal dysgenesis Undervirilization
AIRE
Autosomal recessive
5
CAH: 21Hydroxylase
CYP21A2
Autosomal recessive
Positive 21-hydroxylase antibodies Elevated 17OH-progesterone, basal or stimulated
5
HSD3B2
Autosomal recessive
Mucocutaneous candidiasis hypoparathyroidism Variable- salt wasting, simple virilizing, females with ambiguous genitalia Male - undervirilization Female - mild virilization XY sex reversal Glucocorticoid only Hyperpigmentation
All steroids low Elevated ACTH, normal renin and aldosterone
AHC
CAH: 3βHydroxysteroid Dehydrogenase Lipoid 5CAH 6 FGD
Autosomal recessive STAR Autosomal recessive MRAP MC2R NNT MCM4 TXNRD2 1 AAA- Triple A syndrome, Allgrove Syndrome 2 ALD- adrenoleukodystrophy 3 AHC- adrenal hypoplasia congenita 4 APS-1 autoimmune polyglandular syndrome type 1 5 CAH- congenital adrenal hyperplasia 6 FGD- familial glucocorticoid deficiency
Laboratory Men - high VLCFA
High gonadotropins Low testosterone
Elevated 17OH-pregnenolone Elevated DHEA
Review Article
EP14503.RA
GENETIC FORMS OF ADRENAL INSUFFICIENCY Elise M. Brett, MD, FACE, CNSC, ECNU1; Richard J. Auchus, MD, PhD, FACE2 Running title: Genetics of Adrenal Insufficiency
From: 1Division of Endocrinology, Diabetes, and Bone Diseases, Department of Internal Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10128, and 2 Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109.
Correspondence Address: Richard Auchus, MD, PhD, FACE University of Michigan Health System Rm 5560A, MSRBII 1150 W. Medical Center Dr. Ann Arbor, MI 48109 Email: [email protected] or Elise M. Brett, MD, FACE, CNSC, ECNU Icahn School of Medicine at Mount Sinai 1192 Park Avenue New York, NY 10128 Email: [email protected]
DOI:10.4158/EP14503.RA © 2014 AACE.
Disclosure: Nothing to disclose
Keywords: Adrenal insufficiency, polyendocrinopathy, mutation, glucocorticoid, genetics
Abstract: Objective: The AACE Adrenal Scientific Committee has developed a series of articles to update members on the genetics of adrenal diseases. Methods: Case presentation, discussion of literature, table, and bullet points. Results: The genetic mutations associated with several familial causes of adrenal insufficiency have now been identified. The most common ones that will be discussed here include Allgrove syndrome (AAA), adrenoleukodystrophy (ALD), adrenal hypoplasia congenita (AHC), autoimmune polyglandular syndrome type 1 (APS1), congenital adrenal hyperplasia (CAH), lipoid CAH, and familial glucocorticoid deficiency (FGD). Although these diseases most commonly present in childhood, some rarely present in adulthood, and thus all endocrinologists must be familiar with these syndromes. Some patients only DOI:10.4158/EP14503.RA © 2014 AACE.
develop glucocorticoid deficiency, and others have both glucocorticoid and mineralocorticoid deficiency. These diseases may be associated with other conditions, especially neurological disease, hypogonadism, or dermatologic problems. Diagnosis is suspected based on clinical presentation and laboratory findings. Gene testing may be necessary for confirmation of a diagnosis and/or screening of family members. Conclusions: This article briefly reviews the various familial adrenal insufficiency syndromes and the specific associated gene defects.
Abbreviations: AAA = Allgrove syndrome (alachrima-achalasia-adrenal insufficiency); ACTH = adrenocorticotropin; AHC = adrenal hypoplasia congenita; AIRE = autoimmune regulator gene; ALADIN = alacrima-achalasia-adrenal insufficiency neurological disorder; ALD = adrenoleukodystrophy; ALDP = adrenoleukodystrophy protein; AMN = adrenomyeloneuropathy; APECED = autoimmune polyendocrinopathy, candidiasis and ectodermal dystrophy; APS1 = autoimmune polyglandular syndrome type 1; CAH = congenital adrenal hyperplasia; DAX1 = dosage-sensitive sex reversal, adrenal hypoplasia congenita, X-chromosome; FGD = familial glucocorticoid deficiency; LCAH = lipoid CAH; MCM4, mini chromosome maintenance-deficient 4; MC1R and MC2R = melanocortin receptor types 1 and 2; NNT = nicotinamide nucleotide transhydrogenase; SF1 = steroidogenic factor 1; DOI:10.4158/EP14503.RA © 2014 AACE.
StAR = steroidogenic acute regulatory protein; TXNRD2 = thioredoxin reductase type 2; VLCFA = very long-chain fatty acid.
Case. A.I. is a 22-year old male college student who collapsed at an intramural soccer game. He was taken to a local hospital hypotensive and found to have primary adrenal insufficiency. He has no family history of adrenal insufficiency; however, a maternal uncle has some type of neurologic disease. Physical exam demonstrated hyperpigmentation, a normal thyroid, and no vitiligo. Testing for anti-21-hydroxylase antibodies were negative, and thyroid tests were normal. Could he have a genetic disease?
Discussion
During the past 2 decades, the genetic basis for several forms of familial adrenal insufficiency syndromes has been elucidated. The molecular mechanisms for these diseases involve a broad spectrum of cellular and physiologic processes, including metabolism, nuclear protein import, and autoimmunity. The most common types, including those that may present in adulthood, will be discussed below. The early identification of such diseases can have important prognostic and therapeutic implications for patients with regard to surveillance for associated conditions, initiation of early treatment or screening of family members who are at risk.
DOI:10.4158/EP14503.RA © 2014 AACE.
Autoimmune polyendocrinopathy type 1 (APS1) syndrome is a rare disorder with autosomal recessive inheritance in which adrenal insufficiency is associated with autoimmune disorders. It is caused by a mutation in the autoimmune regulator (AIRE) gene on chromosome 21. The AIRE protein is primarily expressed in thymic epithelial cells, and this transcriptional regulator is essential for the removal of autoreactive T-cells and thus the maintenance of self-tolerance. APS1 is also known as the APECED syndrome for autoimmune polyendocrinopathy, candidiasis and ectodermal dystrophy. In the syndrome, adrenal insufficiency is most commonly associated with hypoparathyroidism and chronic mucocutaneous candidiasis, but patients are also at risk for type 1 diabetes, gonadal dysfunction, autoimmune hepatitis, intestinal malabsorption, pernicious anemia, alopecia and vitiligo. The adrenal insufficiency typically presents between 11 and 15 years of age and usually occurs later than the hypoparathyroidism and mucocutaneous candidiasis. Most patients have antibodies against the 21-hydroxylase enzyme characteristic of autoimmune adrenalitis. Males and females are equally affected. The highest incidence has been seen in Finland, Norway, Sardinia and Iranian Jewish populations. Adrenoleukodystrophy (ALD) is a rare X-linked recessive disorder characterized by primary adrenal insufficiency and demyelination within the central or peripheral nervous system. ALD may also be associated with primary testicular failure. The disease results from impaired transport of very-long chainfatty acids (VLCFA) into peroxisomes for beta oxidation. ALD is caused by mutations in the ATP-binding cassette, subfamily D, member 1 (ABCD1) gene DOI:10.4158/EP14503.RA © 2014 AACE.
that encodes the peroxisomal membrane protein ALDP, which transports longchain fatty acids into peroxisomes for oxidation. This defect leads to accumulation of VLCFA in plasma and tissues. The brain and adrenal cortex are particularly vulnerable for unknown reasons. The diagnosis is confirmed by finding elevated VLCFA in plasma. Clinical manifestations in ALD are variable. Adrenal failure most commonly presents before age 15 but can also occur at later ages, and adrenal dysfunction typically occurs before the onset of neurological symptoms. A minority of affected patients develop only adrenal insufficiency. Some patients develop the more severe childhood cerebral form that presents as learning deficit or behavioral change and is often rapidly progressive to disability and death. Others develop adrenomyeloneuropathy (AMN), which typically presents in the third decade with stiffness and weakness in legs, loss of sphincter control and sexual dysfunction, and progresses over decades. Heterozygous women can also be affected but have a much milder course and rarely develop cerebral involvement and adrenal insufficiency. While the adrenal insufficiency of ALD is managed with corticosteroid replacement, no reliable treatments exist to curtail the neurologic dysfunction. Dietary supplementation with triglycerides enriched in oleic and erucic acids (Lorenzo’s oil) has been used to limit the elongation of precursors to VLCFA. A two-year trial in the 1990s showed no benefit, but subsequent smaller studies and cases have demonstrated slight benefit. Stem cell transplantation from related donors is also being tested in ALD. DOI:10.4158/EP14503.RA © 2014 AACE.
Adrenal hypoplasia congenita (AHC) is an X-linked recessive disorder characterized by primary adrenal failure and hypogonadotropic hypogonadism with pubertal failure. In AHC, there is a failure of development of the permanent adult adrenal cortex caused by a mutation in the NR0B1 gene, encoding nuclear receptor subfamily 0, group B, number 1 (also known as DAX1 for dosagesensitive sex reversal, adrenal hypoplasia congenita, X-chromosome). Affected individuals may present in infancy with severe salt wasting or have a more insidious onset during childhood. Rarely, AHC can present with adrenal failure later in adulthood. Carrier females may very rarely have symptoms of adrenal insufficiency or hypogonadotropic hypogonadism. DAX1 is a transcription factor, which balances the transcriptional activity of steroidogenic factor 1 (SF1). SF1 is essential for the development of the adrenal cortex and the steroidogenic cells of the gonads, as well as the expression of the steroidogenic enzymes and cofactor proteins necessary for steroidogenesis from cholesterol. Mutations in the NR5A1 gene encoding SF1 are found in about 15% of patients with 46,XY gonadal dysgenesis, and in a minority of these cases, adrenal insufficiency is also present. Thus, patients harboring an SF1 defect can present similar to AHC with both hypogonadism and adrenal insufficiency; however, DAX1 defects cause hypogonadotropic hypogonadism, while SF1 defects cause gonadal dysgenesis with elevated gonadotropins and often undervirilization. Allgrove syndrome, also known as the Triple A syndrome, is a rare autosomal recessive disorder characterized by the triad of adrenocortical failure DOI:10.4158/EP14503.RA © 2014 AACE.
due to ACTH resistance, achalasia and alacrima. Allgrove syndrome is caused by mutations in the AAAS gene on chromosome 12, which encodes for the WDrepeat protein ALADIN. The molecular pathophysiology of this syndrome is poorly understood, but the ALADIN protein is a component of the nuclear pore complex and the nuclear protein import machinery. Defective import of specific nuclear proteins appears to allow oxidative damage in the adrenal glands and other tissues. These patients present typically in childhood with hypoglycemia and adrenal crisis, but the disease has rarely presented as late as the fourth decade. Allgrove syndrome is associated with progressive neurological dysfunction, which may include autonomic, sensory and motor neuropathy. Mild mental retardation may also be present. Mineralocorticoid deficiency develops in a minority of patients. Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders due to the defects of the enzymes involved in adrenal steroidogenesis. CAH is reviewed in detail in another paper in this issue, but we will briefly comment on some forms of CAH as causes of adrenal insufficiency. The enzyme deficiencies result in defects in cortisol biosynthesis with accumulation of precursors, diversion to increased androgen production and variable mineralocorticoid defects. Low cortisol reduces negative feedback and increases ACTH secretion, which results in adrenal hyperplasia. The most common form of CAH, found in 1:16,000 newborns, is 21-hydroxylase deficiency, caused by a deletion or mutation in CYP21A2. There are 3 different phenotypes associated DOI:10.4158/EP14503.RA © 2014 AACE.
with varying degrees of enzyme activity: classic salt wasting, classic simple virilizing and non-classic or late-onset, which does not cause adrenal insufficiency. Mutations in the HSD3B2 gene cause 3β-hydroxysteroid dehydrogenase deficiency, which also causes variable degrees of adrenal insufficiency and androgen excess, but the genital virilization in females is less severe than in 21-hydroxylase deficiency, and the males have androgen deficiency. Patients with 11-hydroxylase deficiency, due to mutations in the CYP11B1 gene, have androgen excess but are protected from adrenal crises due to mineralocorticoid excess. Lipoid congenital adrenal hyperplasia (LCAH), the most severe form of CAH, is most commonly caused by mutations in the STAR gene encoding the steroidogenic acute regulatory protein (StAR). Severe defects in StAR lead to a block in the first step in steroidogenesis, complete deficiency in glucocorticoid, mineralocorticoid and sex steroid hormones, and the pathognomonic massive cholesterol ester accumulation in the adrenal cortex. The disease is most common in Palestinian and Japanese populations. Within the last decade, a milder or nonclassic form of LCAH has been described, in which glucocorticoid deficiency is the primary and usually the only manifestation (see below). Mutations in the CYP11A1 gene encoding the cholesterol side-chain cleavage enzyme cause a similar global loss of steroidogenesis and adrenal insufficiency, but the adrenals are not lipid-laden as in patients with STAR mutations. Familial Glucocorticoid Deficiency (FGD) or hereditary unresponsiveness DOI:10.4158/EP14503.RA © 2014 AACE.
to ACTH is a group of rare autosomal recessive disorders in which the cells of the zona fasciculata within the adrenal cortex do not produce cortisol in response to ACTH stimulation. Aldosterone production from the zona glomerulosa remains intact. The disease is caused by mutations in the melanocortin type 2 receptor (MC2R) or more commonly in its accessory protein (MRAP), which together yield the functional receptor for ACTH. Loss of cortisol’s negative feedback results in high ACTH, which leads to hyperpigmentation from overstimulation of melanocortin type 1 receptors (MC1R). Patients typically present in infancy with hypoglycemia, hyperpigmentation and failure to thrive, but occasionally patients have not been diagnosed until later in childhood. Hyperkalemia and severe hyponatremia are not seen, due to intact aldosterone production. Patients with FGD are often noted to have tall stature, but the underlying mechanisms are not clear. Because MC2R mutations are found in only a minority of patients with FGD, investigators have searched for other genes in the remaining FGD cohorts. The MRAP mutations were next discovered, and subsequently some FGD kindred were found to harbor STAR mutations and to have the nonclassic form of LCAH. More recently, FGD families have been described with mutations in mini chromosome maintenance-deficient 4 homologue (MCM4) among the Irish traveler population and in nicotinamide nucleotide transhydrogenase (NNT), which encodes an antioxidant protein of the inner mitochondrial membrane. One of these patients presented as late as 8.5 years old. Most recently, one DOI:10.4158/EP14503.RA © 2014 AACE.
consanguineous Kashmiri kindred was shown to have FGD and a nonsense mutation in the TXNRD2, encoding the flavoprotein thioredoxin reductase 2, a selenoprotein that catalyzes the reduction of oxidized thioredoxin. The oldest affected member of this kindred presented at age 10.8. The mechanisms by which these last 3 genetic defects cause FGD are not completely understood. Thus, there are several different causes of adrenal insufficiency in which the specific gene defect is now known, and molecular genetic testing is available for many of these genes. Screening of family members for the disease state or carrier status may also be indicated and can be critical for family planning. When a monogenic cause of adrenal failure is identified, genetic counseling is indicated. In the aforementioned case, the absence of anti-21-hydroxylase antibodies, normal thyroid examination and function and absence of vitiligo suggest that the adrenal insufficiency is not part of an autoimmune polyendocrinopathy syndrome. The history of neurologic disease in the uncle suggests adrenoleukodystrophy or Allgrove syndrome. The X-linked pattern of inheritance makes adrenoleukodystrophy (ALD) most likely, plus there is no mention of alacrima or achalasia to suggest Allgrove. Testing of plasma very long chain fatty acids (VLCFA) is indicated first. The early identification of X-linked ALD is critical as the patient would need to be observed for signs of neurologic dysfunction, as it is essential to start treatment early. Genetic testing is readily available
in
commercial
DOI:10.4158/EP14503.RA © 2014 AACE.
reference
laboratories
(GeneDx,
Athena/Quest
Diagnostics, Mayo Medical Laboratories, Esoterix/Laboratory Corporation of America, ARUP, others) for most of these genes, except for some of the less common FGD syndromes.
Bullet Points •
Many causes of adrenal insufficiency can now be attributed to a single gene defect
•
Some of these conditions previously thought to present only in childhood have also presented in adulthood with variable phenotypes
•
Testing for many of these gene defects is now commercially available
•
Identification of a genetic cause of adrenal insufficiency may alert the clinician to the need for early treatment or surveillance for associated conditions
•
Identification of a genetic cause of adrenal insufficiency can be critical for family planning and screening of family members based on the known pattern of inheritance
References: DOI:10.4158/EP14503.RA © 2014 AACE.
1. Achermann JC, Meeks JJ, Jameson JL. Phenotypic spectrum of mutations in DAX-1 and SF-1. Mol Cell Endocrinol. 2001;185:17-25. 2. Auchus RJ, Arlt W. Approach to the Patient: The Adult with Congenital Adrenal Hyperplasia. J Clin Endocrinol Metab. 2012;98:2645-2655. 3. Bentes C, Santos-Bento M, de Sá J, de Lurdes Sales Luís M, de Carvalho M. Allgrove syndrome in adulthood. Muscle Nerve. 2001;24:292-296. 4. Charmandari E, Nicolaides NC, Chrousos GP. Adrenal Insufficiency. Lancet. 2014;383:2152-2167. 5. Clark AJ, Chan LF, Chung TT, Metherell LA. The genetics of familial glucocorticoid deficiency. Best Pract Res Clin Endocrinol Metab. 2009;23:159165. 6. Engelen M, Kemp S, de Visser M, van Geel BM, Wanders RJ, Aubourg P, Poll-The BT. X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management. Orphanet J Rare Dis. 2012;7:51. 7. Handschug K, Sperling S, Yoon SJ, Hennig S, Clark AJ, Huebner A. Triple A syndrome is caused by mutations in AAAS, a new WD-repeat protein gene. Hum Mol Genet. 2001;10:283-290. 8. Meimaridou E, Hughes CR, Kowalczyk J, Guasti L, Chapple JP, King PJ, Chan LF, Clark AJ, Metherell LA. Familial glucocorticoid deficiency: New genes and mechanisms. Mol Cell Endocrinol. 2013;371:195-200. 9. Metherell LA, Naville D, Halaby G, Begeot M, Huebner A, Nurnberg G, Nurnberg P, Green J, Tomlinson JW, Krone NP, Lin L, Racine M, Berney DOI:10.4158/EP14503.RA © 2014 AACE.
DM, Achermann JC, Arlt W, Clark AJ. Nonclassic lipoid congenital adrenal hyperplasia masquerading as familial glucocorticoid deficiency. J Clin Endocrinol Metab. 2009;94:3865-3871. 10. O'Riordan SM, Lynch SA, Hindmarsh PC, Chan LF, Clark AJ, Costigan C. A novel variant of familial glucocorticoid deficiency prevalent among the Irish Traveler population. J Clin Endocrinol Metab. 2008;93:2896-2899. 11. Prasad R, Chan LF, Hughes CR, Kaski JP, Kowalczyk JC, Savage MO, Peters CJ, Nathwani N, Clark AJ, Storr HL, Metherell LA. Thioredoxin Reductase 2 (TXNRD2) mutation associated with familial glucocorticoid deficiency (FGD). J Clin Endocrinol Metab. 2014;99:E1556-1563. 12. Proust-Lemoine E, Saugier-Veber P, Wémeau JL. Polyglandular autoimmune syndrome type I. Presse Med. 2012;41:e651-e662. 13. Rosatelli MC, Meloni A, Meloni A, Devoto M, Cao A, Scott HS, Peterson P, Heino M, Krohn KJ, Nagamine K, Kudoh J, Shimizu N, Antonarakis SE. A common mutation in Sardinian autoimmune polyendocrinopathy-candidiasisectodermal dystrophy patients. Hum Genet. 1998;103:428-434 14. Vaidya B, Pearce S, Kendall-Taylor P. Recent advances in the molecular genetics of congenital and acquired primary adrenocortical failure. Clin Endocrinol (Oxf). 2000;53:403-418. 15. Wallace IR, Hunter SJ. AAA syndrome--adrenal insufficiency, alacrima and achalasia. QJM. 2012;105:803-804. 16. Zanaria E, Muscatelli F, Bardoni B, Strom TM, Guioli S, Guo W, Lalli E, Moser C, Walker AP, McCabe ERB, Meitinger T, Monaco AP, Sassone-Corsi DOI:10.4158/EP14503.RA © 2014 AACE.
P, Camerino G. An unusual member of the nuclear hormone receptor superfamily responsible for X-linked adrenal hypoplasia congenita. Nature. 1994;372:635-641. 17. Aubourg P, Adamsbaum C, Lavallard-Rousseau MC, Rocchiccioli F, Cartier N, Jambaque I, Jakobezak C, Lemaitre A, Boureau F, Wolf C, et al. A two-year trial of oleic and erucic acids ("Lorenzo's oil") as treatment for adrenomyeloneuropathy. N Engl J Med 1993;329:745-752. 18. Cappa M, Bizzarri C, Petroni A, Carta G, Cordeddu L, Valeriani M, Vollono C, De Pasquale L, Blasevich M, Banni S. A mixture of oleic, erucic and conjugated linoleic acids modulates cerebrospinal fluid inflammatory markers and improve somatosensorial evoked potential in X-linked adrenoleukodystrophy female carriers. Journal of inherited metabolic disease 2012;35:899-907. 19. Achermann JC, Ito M, Hindmarsh PC, Jameson JL. A mutation in the gene encoding steroidogenic factor-1 causes XY sex reversal and adrenal failure in humans [letter]. Nat Genet 1999;22:125-126. 20. Köhler B, Lin L, Ferraz-de-Souza B, Wieacker P, Heidemann P, Schroder V, Biebermann H, Schnabel D, Gruters A, Achermann JC. Five novel mutations in steroidogenic factor 1 (SF1, NR5A1) in 46,XY patients with severe underandrogenization but without adrenal insufficiency. Hum Mutat 2008;29:5964.
DOI:10.4158/EP14503.RA © 2014 AACE.
DOI:10.4158/EP14503.RA © 2014 AACE.
Table 1 Disease 1 AAA 2 ALD
Gene AAAS ABCD1
Inheritance pattern Autosomal recessive X-linked recessive
Associated Alacrima, achalasia Neurologic, hypogonadism
3
NR0B1
X-linked recessive
Low gonadotropins and testosterone
Adrenal Insufficiency with Gonadal Dysgenesis 4 APS-1
NR5A1
Autosomal dominant More common 46,XY
Hypogonadotropic hypogonadism Delayed puberty Gonadal dysgenesis Undervirilization
AIRE
Autosomal recessive
5
CAH: 21Hydroxylase
CYP21A2
Autosomal recessive
Positive 21-hydroxylase antibodies Elevated 17OH-progesterone, basal or stimulated
5
HSD3B2
Autosomal recessive
Mucocutaneous candidiasis hypoparathyroidism Variable- salt wasting, simple virilizing, females with ambiguous genitalia Male - undervirilization Female - mild virilization XY sex reversal Glucocorticoid only Hyperpigmentation
All steroids low Elevated ACTH, normal renin and aldosterone
AHC
CAH: 3βHydroxysteroid Dehydrogenase Lipoid 5CAH 6 FGD
Autosomal recessive STAR Autosomal recessive MRAP MC2R NNT MCM4 TXNRD2 1 AAA- Triple A syndrome, Allgrove Syndrome 2 ALD- adrenoleukodystrophy 3 AHC- adrenal hypoplasia congenita 4 APS-1 autoimmune polyglandular syndrome type 1 5 CAH- congenital adrenal hyperplasia 6 FGD- familial glucocorticoid deficiency
Laboratory Men - high VLCFA
High gonadotropins Low testosterone
Elevated 17OH-pregnenolone Elevated DHEA
