Genetic Disorders of Adrenocortical Function

Genetic Disorders of Adrenocortical Function Fady Hannah-Shmouni and Constantine A. Stratakis

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Adrenal Gland Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Congenital Adrenal Insufficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Congenital Adrenal Insufficiency due to Primary Adrenal Disorders . . . . . . . . . . . . . . . . . . . . . . . Congenital Adrenal Insufficiency due to Metabolic Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Congenital Adrenal Insufficiency due to Autoimmunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Congenital Adrenal Insufficiency due to Other Genetic Conditions . . . . . . . . . . . . . . . . . . . . . . . . . Adrenocortical Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Classification of Adrenocortical Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Molecular Pathways in Adrenocortical Tumor Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Familial Syndromes Associated with Adrenocortical Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Carney Complex (CNC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Multiple Endocrine Neoplasia Type 1 (MEN1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Congenital Adrenal Hyperplasia (CAH) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Familial Adenomatous Polyposis (FAP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Carney-Stratakis Syndrome (CCS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Carney Triad (CT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Familial Hyperaldosteronism (FH) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Li-Fraumeni Syndrome (LFS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Beckwith-Wiedemann Syndrome (BWS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Neurofibromatosis Type 1 (NF1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Genetic Aberrations in Common Benign Adrenocortical Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Adrenocortical Adenomas (ACAs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Primary Bilateral Macronodular Adrenocortical Hyperplasia (PBMAH) . . . . . . . . . . . . . . . . . . .

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Conflict of Interest Statement: The authors declare that the research was conducted in the absence of any potential conflict of interest. F. Hannah-Shmouni • C.A. Stratakis (*) Section on Endocrinology & Genetics (SEGEN), National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA e-mail: [email protected]; [email protected] # Springer International Publishing AG 2017 A. Belfiore, D. LeRoith (eds.), Principles of Endocrinology and Hormone Action Endocrinology 2, DOI 10.1007/978-3-319-27318-1_29-2

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F. Hannah-Shmouni and C.A. Stratakis

Alterations of Phosphodiesterases (PDEs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . McCune-Albright Syndrome (MAS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Isolated Micronodular Adrenocortical Disease (iMAD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Genetic Counseling of Patients with Disorders of Adrenocortical Function . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Keywords

Adrenal • Cortex • Congenital adrenocortical hypoplasia • Genes • Adrenocortical insufficiency • Molecular genetics • DAX1 • TPIT • SF1 • Glucocorticoid resistance • Mineralocorticoid receptor • Sodium channel defects • Adrenocortical tumors • Adrenal hyperplasia • Cushing syndrome • Genetics • Carney complex • Cyclic AMP • PPNAD • Cancer • Mutations Abbreviations

AC ACTH AIMAH Alleles AMP/ATP BAH BMAH cAMP CNC CS Genes GMP/GDP/GTP GPCRs Heterozygous Homozygous MMAD Mutations PBAD PBMAH PDEs Phenotype PKA PPNAD

Adenyl cyclase Adrenocorticotropic hormone ACTH-independent macronodular adrenal hyperplasia Alternative forms of a gene Adenosine monophosphate/adenosine triphosphate Bilateral adrenocortical hyperplasia Bilateral macronodular adrenal hyperplasia Cyclic adenosine monophosphate Carney complex Cushing syndrome Units of inheritance at specific locations (loci) on a chromosome Guanosine monophosphate/guanosine diphosphate/guanosine triphosphate G protein-coupled receptors A genotype with two different alleles of a gene for a particular trait A genotype with the same allele of a gene for a particular trait Massive macronodular adrenocortical disease Alteration of genetic material producing a new variation Primary bimorphic adrenocortical disease Primary bilateral macronodular adrenocortical hyperplasia Phosphodiesterases Detectable expression of a genotype Protein kinase A Primary pigmented nodular adrenocortical disease

Genetic Disorders of Adrenocortical Function

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Introduction The first detailed description of the human adrenal glands was by Eustachius (1520– 1574); their presence was confirmed by Piccolomini (1562–1605) and Casserius (1552–1616) (Vrezas et al. 2000). Their function, however, was largely unknown until the late nineteenth century. In the last 30 years, our growing understanding of adrenocortical development and function has led to the discovery of numerous genetic disorders that affect the adrenal glands. Developmental pathways have also been linked to the formation of adrenocortical tumors (ACTs), which represent a heterogeneous group of lesions of the adrenal cortex. ACTs have been found to be due to or associated with somatic or germline mutations in key molecular pathways, including the cyclic AMP (cAMP) and Wnt signaling pathways. In this chapter, we review the various genetic causes of adrenocortical disorders and focus on congenital causes of adrenal insufficiency associated with hypoplasia of the adrenal glands, genetic causes of autoimmunity that affect the adrenal glands, and genetic causes of benign and malignant ACT.

Adrenal Gland Development Following the formation of the adrenal cortex at the fourth week of human embryonic development, a blastema of undifferentiated cells of mesodermal origin forms from either the medial part of the urogenital ridge or mesoderm (Else and Hammer 2005). The adrenogonadal primordium cells undergo proliferation and invasion of the underlying mesenchyme that is dependent on the interplay between the transcriptional factors SF1 and DAX1 (see later) (Else and Hammer 2005; Hanley and Arlt 2006) that ultimately separates from the gonads by day 33 post conception. Further mesodermal cell proliferation, under the control of fetal adrenocorticotropic hormone (ACTH or corticotropin), forms the first evidence for zonation: a definitive zone (DZ) and a fetal zone (FZ) that arise from the celomic epithelium, while the transitional zone (TZ) originates from the mesonephron and arises from the region of Bowman’s capsule (Else and Hammer 2005; Nguyen and Conley 2008). Between the 9th and 12th embryonic week, sinusoidal vascularization of the glands forms the framework for the zonation of the adult cortex (Else and Hammer 2005). Cortisol is produced from the rapidly growing FZ at about the sixth week of development, reaching a peak between the eighth and ninth week (Goto et al. 2006). Gradually, aldosterone and cortisol are made by DZ and TZ cells, whereas the FZ produces primarily dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) that support estrogen production through the fetal-placental unit (Nguyen and Conley 2008). By the ninth week, progenitor populations of the adult adrenal cortex encapsulate the adrenal glands, expressing Nr5a1 and Gli1 (Wood et al. 2013). Migrating neural crest cells forms the adrenal medulla and intermingles with cortical cells of the FZ, attaining a maximum adrenal size by the fourth month. Thereafter, the gradual receding of FZ, and expansion of DZ and TZ, gives rise to the adult zona

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glomerulosa (ZG) and zona fasciculata (ZF), respectively (Else and Hammer 2005; Nguyen and Conley 2008). After birth, FZ involutes and the corticomedullary junction separates between steroid hormone-producing and catecholamine-secreting cells (Else and Hammer 2005). A transition zone of primarily fibrous tissue separates the FZ from the remaining gland. By the end of the second year of life, the first evidence of an anatomically distinct zona reticularis (ZR) appears; however, steroidogenic activity of this zone is not present until the age of 5 years (Wood et al. 2013), concomitant with the onset of adrenarche. The adult adrenal cortex likely reaches maturity as early as 8 years of age to as late as after mid-puberty (Nguyen and Conley 2008; Suzuki et al. 2000; Merke and Stratakis 2006; Sucheston and Cannon 1968). The various developmental stages of the adrenal cortex are portrayed in Fig. 1 (Merke and Stratakis 2006).

Congenital Adrenal Insufficiency Congenital adrenal insufficiency (CAI) represents a heterogeneous group of genetic disorders that affect adrenocortical development and function. The most frequent etiology of CAI is CAH, followed by non-autoimmune and autoimmune etiologies.

Congenital Adrenal Insufficiency due to Primary Adrenal Disorders The proliferation and invasion of adrenogonadal primordium cells are dependent on the interplay between the transcriptional factors SF1 and DAX1 (Else and Hammer 2005; Hanley and Arlt 2006). Mice that are knockouts (KO) for Sf1 have complete absence of the adrenal glands, whereas mice KO for Dax1 have developmental adrenal gland defects without adrenal insufficiency (AI) (Else and Hammer 2005). Regardless of etiology, CAI due to primary adrenal disorders is characterized by hyponatremia, hyperkalemia, acidosis, and an elevated serum concentration of ACTH. In humans, X-linked DAX1 (mutations in NR0B1) defects cause the most common human form of CAI (Muscatelli et al. 1994; Lin et al. 2006). DAX1 is an orphan nuclear receptor that is expressed in the adrenal glands, gonads, ventromedial hypothalamus (VMH), and the pituitary gonadotropes (Ferraz-de-Souza and Achermann 2008). Patients with CAI due to DAX1 are usually 46,XY phenotypic boys and may have hypogonadotropic hypogonadism and a family history of maleonly CAI. DAX1 mutations are also described below under “adrenal hypoplasia congenita”. Humans with heterozygous SF1 (coded by the NR5A1 gene) mutations have AI and gonadal abnormalities (Zanaria et al. 1994). More recently, patients with isolated AI and heterozygous NR5A1 mutations have been described. SF1 gene mutations were also found in patients who also had isolated 46,XY gonadal dysgenesis (Zanaria et al. 1994) and have been rarely identified in patients with CAI without evidence of gonadal defects.


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Fig. 1 The development of the fetal and adult adrenal cortex. Between the 9th and 12th embryonic week, sinusoidal vascularization of the adrenal glands forms the framework for the zonation of the adult cortex. Cortisol is produced from the rapidly growing fetal zone (blue) at about the sixth week reaching a peak between the eighth and ninth week of development. Gradually, aldosterone and cortisol are made by definitive zone and transitional zone, whereas the fetal zone produces primarily DHEA and DHEAS that support estrogen production through the fetal-placental unit. Migrating neural crest cells forms the adrenal medulla and intermingles with cortical cells of the fetal zone, attaining a maximum adrenal size by the fourth month. Thereafter, the gradual receding of fetal zone and expansion of the other zones give rise to the adult zona glomerulosa and zona fasciculata. After birth, fetal zone involutes, and the corticomedullary junction separates between steroid hormone-producing and catecholamine-secreting cells. A transition zone of primarily fibrous tissue separates the fetal zone from the remaining gland. By the end of the second year of life, the first evidence for an anatomically distinct zona reticularis appears; however, steroidogenic activity is not present until the age of 5 years, concomitant with the onset of adrenarche. The adult adrenal cortex likely reaches maturity as early as 8 years of age to as late as after mid-puberty (Modified from Merke and Stratakis (2006))

Some genes that have been implicated in hypoplastic adrenals with retention of adrenocortical function may present with mild functional defects in adrenarche and pubertal anomalies but without CAI. Such examples include defects in Wilms’ tumor 1 (WT1), a transcriptional regulator that is mutated in Denys-Drash and Frasier syndromes (Melo et al. 2002), WNT4, and WNT11, which are members of the frizzled receptor family. A missense substitution of the WNT4 gene causes an autosomal recessive syndrome designated as SerKAL (46,XX sex reversal with dysgenesis of kidneys, adrenals, and lungs) (Mandel et al. 2008).

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Congenital Adrenal Insufficiency due to Metabolic Disorders Several rare metabolic disorders may affect adrenocortical function in early life. X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disorder that affects the nervous system white matter and the adrenal cortex due to impaired beta-oxidation of very long chain fatty acids (VLCFAs). This impairment is a result of mutations in a gene encoding a peroxisomal ATP-binding cassette (ABC) transporter (ALD protein) (Feigenbaum et al. 1996). X-ALD is the most common inherited peroxisomal disorder (and metabolic disorder causing CAI) that affects 1/15,000–20,000 males in the Caucasian population (Bezman et al. 2001). Three main phenotypes are seen in affected males: (i) a childhood cerebral form that manifests most commonly between ages 4 and 8 years due to progressive impairment of cognition, behavior, vision, hearing, and motor function leading to total disability within 2 years; (ii) adrenomyeloneuropathy (AMN) that manifests most commonly in the late twenties as progressive paraparesis, sphincter disturbances, sexual dysfunction, and, often, impaired adrenocortical function; and (iii) AI only that presents between age 2 years and adulthood although some degree of neurologic disability may manifest later. Approximately 20% of female carriers develop a milder AMN-like manifestation usually during their late adulthood. Other metabolic causes of CAI include: • Wolman disease (familial xanthomatosis) which is caused by defects in lysosomal acid cholesteryl ester hydrolase that may present with CAI and adrenal calcification (Kahana et al. 1968; Anderson et al. 1994). • Smith-Lemli-Opitz syndrome (SLOS) which is a disorder of cholesterol biosynthesis that is associated with developmental delay, dysmorphic features, and male undervirilization and/or hypogonadism. SLOS may present with CAI, adrenal crisis, or more commonly compensated adrenocortical dysfunction (Chemaitilly et al. 2003; McKeever and Young 1990; Bianconi et al. 2011). • Hereditary cystatin C amyloid angiopathy (HCCAA) which is a genetic amyloid disease that occurs frequently in Iceland and is caused by a mutation in cystatin C that causes amyloid deposition, predominantly in brain arteries and arterioles, but also in tissues outside the brain including the adrenal cortex, resulting in hemorrhage (Palsdottir et al. 2006).

Congenital Adrenal Insufficiency due to Autoimmunity Adrenal gland failure in the context of autoimmune polyglandular syndrome (APS) usually presents after the first 2 years of life. APS is a rare polyendocrinopathy that exists in two major forms: APS-1, or otherwise known as autoimmune polyendocrinopathy-candidiasis-ectodermal dysplasia (APECED) syndrome, is an autosomal recessive disorder that is caused by mutations in the autoimmune regulator (AIRE) gene (Heino et al. 1999) and consists of chronic mucocutaneous candidiasis and/or acquired hypoparathyroidism, Addison’s disease (autoimmune


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adrenalitis), chronic active hepatitis, malabsorption, juvenile onset pernicious anemia, alopecia, primary hypogonadism, and less commonly type 1 diabetes mellitus; autoimmune thyroid disease; ectodermal dystrophy, affecting the dental enamel and nails; vitiligo; or corneal disease (keratopathy). APS-2 is an autosomal dominant disorder with variable expressivity that manifests later in life with type 1 diabetes mellitus and/or autoimmune thyroid disease, among other endocrinopathies, and affects predominately females. A variability of age of onset exists in APS-1, from 6 months to 41 years with a peak around 13 years of age, with AI developing in 60– 100% of patients with APECED and may be preceded by months to years of detectable adrenal cortex autoantibodies. The genetic predisposition of both major types of APS differs. APS-2 involves HLA-B8, HLA-DR3, and HLA-DR4 (chromosome 6), cytotoxic T-lymphocyte antigen-4 (CTLA-4) gene (chromosome 2), and the protein tyrosine phosphatase non-receptor type 22 (PTPN22) genes (chromosome 1) (Kahaly 2012; Dittmar and Kahaly 2003). The gene for APECED is on chromosome 21q22.3 and encodes a 545 amino acid protein, AIRE (autoimmune regulator). AIRE is expressed in tissues that have important role in the maturation of immune system and development of immune tolerance, such as the thymus, lymph nodes, and fetal liver. APS-1 is more common in certain genetically isolate populations, with an incidence of 1:9,000 in Iranian Jews, 1:14,400 in Sardinians, and 1:25,000 in Finnish (Heino et al. 1999). A common Finnish mutation, p.R257X, was shown to be responsible for 82% of Finnish APS-1 cases, while the nonsense mutation, p.R139X, was the major mutation among Sardinians (Heino et al. 1999).

Congenital Adrenal Insufficiency due to Other Genetic Conditions Mutations in a member of the T-box gene family lead to pituitary-dependent CAI without any other defects (isolated ACTH deficiency). All members of the T-box gene family encode an N-terminal DNA-binding domain (the T-box) and are important for the development of several, mostly mesodermal, tissues in the human and mouse embryo. TPIT (or TBX19), one of the members, is a transcription factor that is required for expression of the POMC gene in the differentiating pituitary corticotrophs. Mutations in TPIT are associated with autosomal recessive pituitarydependent CAI (Lamolet et al. 2001), with a typical presentation in the neonate with very low, but not necessarily undetectable, ACTH and cortisol levels, hypoglycemia, seizures, and occasionally death. In one study, 65% of cases of neonatal CAI due to isolated ACTH deficiency were caused by TPIT mutations (Couture et al. 2012). Hereditary resistance to ACTH action (R-ACTH) is an autosomal recessive disorder that is caused by defects of the ACTH receptor (ACTHR) (Tsigos et al. 1993). Disorders of R-ACTH have been described that are biochemically characterized by cortisol, but usually not mineralocorticoid, deficiency: familial glucocorticoid deficiency type 1 (FGD-1) due to inactivating MC2R gene mutations typically present in infancy with severe AI, hypoglycemia, and seizures or later in childhood with a milder form of AI and tall stature (patients end up being taller than their

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genetically determined final height potential) (Elias et al. 2000), and FGD-2 is caused by non-MC2R mutations in the gene encoding an accessory protein required for ACTH signaling (MC2 receptor accessory protein, MRAP) (Metherell et al. 2005) that lead to severe glucocorticoid deficiency and death if not recognized early. MC2R consists of one coding exon and is located on chromosome 18; FGD-1 due to MC2R mutations is seen in 25–40% of cases (Lin et al. 2007). More recently, additional defects beyond MC2R and MRAP have been described to cause FGD. They are involved in replicative and oxidative stress, including the minichromosome maintenance-deficient 4 homologue (MCM4) (natural killer cell and glucocorticoid deficiency with DNA repair defect – NKGCD) and nicotinamide nucleotide transhydrogenase (NNT) genes (Meimaridou et al. 2013). Finally, genes involved in mitochondrial function such as thioredoxin reductase 2 (TXNRD2), glutathione peroxidase 1 (GPX1), and peroxiredoxin 3 (PRDX3) have also been found to cause FGD. In a recent study of a large cohort of patients with CAI, investigated by whole exome sequencing (WES), mutations in the genes listed here were found in only 17 of 43 patients, indicating that there are additional genetic defects to be discovered that cause this disease (Chan et al. 2015). Allgrove or triple A syndrome (AAAS) is an autosomal recessive multisystem disorder that is characterized by R-ACTH AI, alacrima, achalasia, neurodegeneration, and autonomic dysfunction (Brooks et al. 2004). AI in AAAS may present with neonatal hypoglycemic seizures and adrenal crisis or can be late onset not requiring glucocorticoid replacement therapy until teenage years or later. As in other forms of CAI, rarely patients require mineralocorticoid replacement, as well. The most frequent genetic defect is a splicing mutation (IVS14+1G>A) of the AAAS gene (located on chromosome 12q13) (Brooks et al. 2005), which encodes for a 546 amino acid protein called ALADIN (for alacrima-achalasia-adrenal insufficiency neurologic disorder). Patients with missense mutations in one allele have delayed onset of AI as compared with truncation mutations in both alleles. The frequency of AI is significantly higher in patients with only truncation mutations (Ikeda et al. 2013). Adrenal hypoplasia congenita (AHC) is a disorder that manifests with CAI in infancy. Two major histologic types exist: “cytomegalic” form, due to mutations in the DAX1 gene that is inherited as X-linked recessive and typically presents in males with AI and hypogonadotropic hypogonadism (Achermann and Vilain 1993), and “miniature” form, which is a heterogenous genetic disorder that is autosomal recessive and often associated with other developmental defects including abnormalities of the pituitary gland and the central nervous system. Several rare genetic causes of pituitary-dependent CAI exist in association with other developmental defects: mutations in HESX1, LHX3, LHX4, and SOX3 genes; homozygote or compound heterozygote genetic defects of the ACTH precursor, pro-opiomelanocortin (POMC) gene, its processing enzyme (prohormone convertase 1 or PC1), and the product of the proprotein convertase subtilisin/kexin type 1 (PCSK1) gene (Hanley and Arlt 2006; Ferraz-de-Souza and Achermann 2008; Perry et al. 2005; Krude et al. 2003; Metherell et al. 2006; Jackson et al. 1997; Achermann et al. 1999); and defects that lead to other forms of hypopituitarism (ACTH deficiency in combination with other defects) (Karpac et al. 2007).


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CAI may also be part of a number of developmental conditions caused by genes whose main action is not in the adrenal cortex. These include (i) IMAGe (intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia, genitourinary anomalies) due to mutations in CDKN1C (chromosome 11p15) (Arboleda et al. 2012); (ii) CHARGE syndrome (coloboma of the eye; heart anomaly; atresia, choanal; retardation of mental and somatic development; microphallus; ear abnormalities and/or deafness) due to mutations in the chromodomain helicase DNA-binding protein 7 (CHD7) gene (James et al. 2003; Jongmans et al. 2006); (iii) Meckel syndrome, a severe pleiotropic autosomal recessive developmental disorder caused by mutations in MKS1 (chromosome 17q22) that leads to dysfunction of primary cilia during early embryogenesis (Hsia et al. 1971); or (iv) conditions associated with chromosomal defects, such as duplication in 5p (Chen et al. 1995), tetraploidy, triploidy, trisomy 19, trisomy 21, monosomy 7, and 11q syndrome.

Adrenocortical Tumors The first report of cAMP pathway mutations causing ACTs was in patients with McCune-Albright syndrome (MAS) due to GNAS (encodes the alpha subunit (Gsα) of the stimulatory guanine nucleotide-binding protein) that resulted in adrenocortical hyperplasia and/or benign cortisol-producing adenomas (CPAs) (Weinstein et al. 1991; Stratakis and Boikos 2007). This was rapidly followed by other important discoveries in the genetics of ACT formation, including the regulatory subunit type 1-α (RIα) of protein kinase A (PKA, PRKAR1A gene) and phosphodiesterase 11A and phosphodiesterase 8B (PDE11A and PDE8B genes, respectively) in Carney complex (CNC) and isolated ACTs and/or adrenal hyperplasia, respectively (Stratakis and Boikos 2007). Recently, germline mutations in the tumor suppressor gene ARMC5 (armadillo repeat containing 5) in primary bilateral macronodular adrenocortical hyperplasia (PBMAH) and somatic mutations in KCNJ5 in aldosterone-producing adenomas (APA) further expanded our understanding of tumorigenesis in ACTs (Stratakis and Boikos 2007; Horvath and Stratakis 2008). In this section, we provide a comprehensive review of the genetics of mostly benign ACTs.

Classification of Adrenocortical Tumors A comprehensive classification of ACT was proposed in 2007 (Tables 1, 2, and 3) (Stratakis and Boikos 2007). ACT is divided into adrenocortical adenomas (ACAs), adrenocortical hyperplasia, and adrenocortical cancer (ACC) (Stratakis and Boikos 2007). These lesions can be classified on their radiographic appearance as either unilateral or bilateral or on biochemistry as either functioning or nonfunctioning. ACAs are common incidental findings on imaging (5% of cases); however, adrenocortical hyperplasias are more frequently encountered on imaging (36% of cases) (Saeger et al. 1998) but are often misread as “normal adrenal glands”.

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Table 1 Causes of congenital adrenal insufficiency Congenital adrenal insufficiency Gene (locus) Due to primary adrenal disorders DAX1 NR0B1 (DAX1)

X-linked

SF1 Denys-Drash syndrome Frasier syndrome SerKA

AR AD AD AD

NR5A1 (SF1) WT1 WT1 WNT4

Mode of inheritance

Due to metabolic disorders X-ALD ABCD1

X-linked

Wolman disease

LIPA

AR

Smith-Lemli-Opitz syndrome

DHCR7

AR

Major features DAX1 mutations: 46,XY phenotypic boys, hypogonadotropic hypogonadism, and a family history of maleonly CAI SF1 mutations: AI and gonadal abnormalities Occasionally heterozygous mutations act in AD fashion causing milder phenotypes, such as isolated CAI X-ALD: progressive demyelination of the white matter with or without AI, with less than half of patients presenting with CAI, and some male carriers have no detectable disease until later in life or none at all Wolman disease (familial xanthomatosis): CAI and adrenal calcification Smith-Lemli-Opitz syndrome: developmental delay, dysmorphic features and male undervirilization and/or hypogonadism, CAI, adrenal crisis, or more commonly compensated adrenocortical dysfunction (continued)


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Table 1 (continued) Congenital adrenal insufficiency Hereditary cystatin C amyloid angiopathy

Gene (locus) APP CST3 ITM2B

Due to autoimmune disease APS1 AIRE APS2 HLA-B8, HLA-DR3 and HLA-DR4, CTLA-4, PTPN22; chromosomes 6, 2, and 1

Mode of inheritance AR Sporadic

AR AD

Major features Hereditary cystatin C amyloid angiopathy: most common mutation is in the APP and particularly seen in the Dutch, Italian, Arctic, Iowa, Flemish, and Piedmont populations. Mutations in the CST3 cause the Icelandic type. Familial British and Danish dementia is caused by mutations in ITM2B. Causes adrenal hemorrhage and neurological manifestations APS1: usually manifests in early childhood, consists of chronic mucocutaneous candidiasis and/or acquired hypoparathyroidism, Addison’s disease, chronic active hepatitis, malabsorption, juvenile onset pernicious anemia, alopecia, primary hypogonadism, and infrequently type 1 diabetes mellitus; autoimmune thyroid disease; ectodermal dystrophy, affecting the dental enamel and nails; vitiligo; or corneal disease (keratopathy) APS2: type 1 diabetes mellitus and/or autoimmune thyroid disease has a later but variable age of onset and affects predominately females (continued)

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Table 1 (continued) Congenital adrenal insufficiency Gene (locus) Due to rare genetic syndromes T-box gene family TPIT

Hereditary resistance to ACTH action A – FGD type 1

B – FGD type 2

Mode of inheritance AR

Major features TPIT mutation: neonatal onset CAI, hypoglycemia, seizures, and occasionally death

AR MC2R, MCM4, NNT

MRAP

Allgrove (triple A) syndrome

AAAS

AR

Adrenal hypoplasia congenital: A – Cytomegalic form B – Miniature form Intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies (IMAGe) Coloboma, heart defect, choanal atresia, retarded growth and development, genital abnormality, and ear abnormality (CHARGE syndrome)

NR0B1 (DAX1)

X-linked recessive

CDKN1C (11p15)

AD with paternal imprinting

CHD7 Duplication in 5p

AD Sporadic

FGD-1: infancy with severe AI (most require only glucocorticoid replacement), hypoglycemia, and seizures or later in childhood with a milder form of AI and are taller than their expected (by genetic target) height FGD-2: severe glucocorticoid deficiency and death AAAS: AI, alacrima, achalasia, neurodegeneration, and autonomic dysfunction Adrenal hypoplasia congenital: cytomegalic form: males with adrenal insufficiency and hypogonadotropic hypogonadism. Miniature” form: CAI, developmental defects including abnormalities of the pituitary gland and the central nervous system

AAAS: AI alacrima, achalasia, neurodegeneration, and autonomic dysfunction, AI adrenal insufficiency, AD autosomal dominant, APS autoimmune, polyglandular syndrome, AR autosomal recessive, CAI congenital adrenal insufficiency, IMAGe intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies, CHARGE coloboma, heart defect, choanal atresia, retarded growth and development, genital abnormality, and ear abnormality, SerKA female-to-male sex reversal and kidney, adrenal, and lung dysgenesis, FGD familial glucocorticoid deficiency.


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Table 2 Classification and characteristics of adrenocortical tumors Adrenocortical Genes lesions (locus) ACA CTNNB1 (3p22.1)

APA

Histolopathology ACA are small (G/p.L206R) cortical atrophy. Heterogeneity with an estimated incidence of with lipid-depleted cells approximately 42% in CPA admixed may be present Somatic mutations in GNAS were identified in 5–17% of CPA The somatic allelic losses of PRKAR1A were found in 23% of CPA that were smaller tumors and exhibited a paradoxical increase in urinary cortisol levels after dexamethasone suppression, due to increased glucocorticoid receptor expression in ACT CTNNB1 (S45P, S45F) in approximately 23.1% of CPA (continued)

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Table 2 (continued) Adrenocortical Genes lesions (locus) PBMAH ARMC5 (16p11.2) MEN1 (11q13)

Histolopathology Distinct adenomas (usually two or three), >1 cm, with internodular atrophy, or hyperplasia without atrophy

FH (1q42.343) APC (5q22.2)

PBAD

i-PPNAD

c-PPNAD

PRKAR1A (17q22-24) PDE11A (2q31.2) GNAS (20q13) GNAS Distinct adenomas (>1 cm), with (20q13) occasional microadenomas and internodular atrophy PRKAR1A Microadenomatous (T mutation (continued)


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Table 2 (continued) Adrenocortical Genes lesions (locus)

iMAD

Histolopathology

Characteristics

appears to confer a more severe CNC phenotype, while the splice variant c.709(-7-2)del6 and the initiation alternating substitution c.1A>G/p.M1Vp have been associated with incomplete penetrance of CNC, as seen in i-PPNAD CNC1: The hotspot c.491492delTG mutation is most closely associated with lentigines, cardiac myxoma, and thyroid tumors when opposed to all other PRKAR1A mutations Expressed RIα mutant protein present with more severe and aggressive CNC phenotype CNC2: Sporadic disease later in life with a lower frequency of myxomas, schwannomas, thyroid, and LCCSCT PDE11A Microadenomatous (G/p.M1V, in approximately 50% of cases.


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Multiple Endocrine Neoplasia Type 1 (MEN1) Multiple endocrine neoplasia type 1 (MEN1) is also an AD syndrome due to a heterozygous inactivating germline mutation of the tumor suppressor gene MEN1 (11q13) (Chandrasekharappa et al. 1997) that is found in approximately 90% of affected individuals. The clinical features of MEN1 include primary hyperparathyroidism due to parathyroid hyperplasia, pituitary adenomas, neuroendocrine tumors, and facial angiofibromas, among others (Thakker et al. 2012). Nonfunctional ACTs are seen in approximately 20% of patients with MEN1 (Gatta-Cherifi et al. 2012), while functional ACTs are rare (primarily primary aldosteronism) (Gatta-Cherifi et al. 2012; Simonds et al. 2012).

Congenital Adrenal Hyperplasia (CAH) Congenital adrenal hyperplasia (CAH) refers to a group of autosomal recessive disorders due to single gene defects in the various steps of cortisol biosynthesis. CAH represents a continuous phenotypic spectrum with over 95% of all cases caused by 21-hydroxylase deficiency that is classified into classic salt wasting, classic simple virilizing, and nonclassic (Speiser et al. 2010). Patients with CAH are predisposed to benign ACT, including adrenocortical adenomas, myelolipomas, and bilateral hyperplasia, due to a compensatory increase in ACTH secretion from pituitary corticotrophs that promotes proliferation of ACT.

Familial Adenomatous Polyposis (FAP) Familial adenomatous polyposis (FAP) is an AD disorder due to genetic defects in the tumor suppressor gene APC (5q22.2) that predisposes to large precancerous colorectal polyps in the second and third decades of life. Bi-allelic inactivation of APC (copresence of germline and somatic mutations) leads to tumorigenesis through activation of the Wnt/β-catenin pathway. Extra-colonic manifestations are common and include ACT and adrenocortical hyperplasias, PBMAH (Hsiao et al. 2009), ACC, papillary thyroid carcinomas, lipomas, and pancreatic carcinomas (Gaujoux et al. 2010; Berthon et al. 2012).

Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an AD disorder caused by inactivating mutations of the tumor suppressor gene fumarate hydratase (FH, 1q42.3-43) that predispose to hereditary leiomyomatosis, renal cancer, and ACT (approximately 8%). Bi-allelic inactivation of FH leads to increased tumorigenesis through the activation of the hypoxia-induced factor 1 (HIF1) pathway that results in alterations in glycolytic activity, neovascularization, and downregulation of apoptotic mechanisms in tumor tissue. PBMAH or isolated adrenal nodularity has been

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reported in HLRCC (Matyakhina et al. 2005), where loss of heterozygosity for FH was confirmed in tumor tissue (Matyakhina et al. 2005).

Carney-Stratakis Syndrome (CCS) Carney-Stratakis syndrome (CSS) is an AD disorder that predisposes to the formation of gastrointestinal tumors (GIST), paragangliomas (PGL), and ACT (Carney and Stratakis 2002). Germline mutations in SDHB (1p36), SDHC (1q21), and SDHD (11q23) that were known to be involved in inherited PGL and pheochromocytoma but were not previously involved in familial GIST or in ACTs have been linked to CSS. ACTs including PBMAH and nonfunctional tumors are rare in CSS.

Carney Triad (CT) Carney triad (CT) is a sporadic condition that predisposes to hamartomatous lesions in various organs (pulmonary chondromas and pigmented and other skin lesions), GIST, sarcomas, PGL, esophageal leiomyoma, and ACA. CT is the only known adrenal disease that has among its clinical manifestations adrenocortical and medullary involvement, such as coexisting PBMAH or ACA, often nonfunctional, and pheochromocytomas or PGL (Carney et al. 1977). The genetics of CT is complex; a subset of patients may carry germline variants in the SDHA, SDHB, or SDHC, including loss of regions on the short arm (1p) and the long arm (1q) of chromosome 1 (Boikos et al. 2016), or recurrent aberrant dense DNA methylation at the gene locus of SDHC that leads to a reduced mRNA expression of SDHC and concurrent loss of the SDHC subunit on the protein level (Haller et al. 2014). Various ACT including subclinical Cushing syndrome due to ACT were proposed as the fourth component of the Carney triad (Carney et al. 2013).

Familial Hyperaldosteronism (FH) Familial hyperaldosteronism (FH) is a group of AD disorders consists of three types. Type I (also known as glucocorticoid-remediable aldosteronism, GRA) is characterized by a chimeric fusion of CYP11B2 and CYP11B1 (8q24.3), rendering the aldosterone synthase hybrid gene to be under the regulation of ACTH rather than the renin-angiotensin system (Lifton et al. 1992), and should be considered in patients with early-onset hypertension (