6
URRENT PINION
Genetics of adrenocortical disease: an update
Adi Bar-Leva and Justin P. Annesb
Purpose of review
Disease states characterized by abnormal cellular function or proliferation frequently reflect aberrant genetic information. By revealing disease-specific DNA mutations, we gain insight into normal physiology, pathophysiology, potential therapeutic targets and are better equipped to evaluate an individual’s disease risks. This review examines recent advances in our understanding of the genetic basis of adrenal cortical disease.
Recent findings
Important advances made in the past year have included identification of KCNJ5 potassium channel mutations in the pathogenesis of both aldosterone-producing adenomas and familial hyperaldosteronism type III; characterization of phosphodiesterase 11A as a modifier of phenotype in Carney complex caused by protein kinase, cAMP-dependent, regulatory subunit, type-l mutations; the finding of 11@-hydroxysteroid dehydrogenase type I mutations as a novel mechanism for cortisone reductase deficiency; and demonstration of potential mortality benefit in pursuing comprehensive presymptomatic screening for patients with Li-Fraumeni syndrome, including possible reduction in risks associated with adrenocortical carcinoma.
Summary
This research review provides a framework for the endocrinologist to maintain an up-to-date understanding of adrenal cortical disease genetics.
Keywords
adrenal cortex, cAMP-dependent, Carney complex, cortisone reductase deficiency, genetics, hereditary, hyperaldosteronism, Li-Fraumeni, protein kinase, regulatory subunit, type-l
INTRODUCTION
The primary function of the adrenal cortex is to synthesize and secrete corticosteroid and androgen hormones. Pathologic states that disrupt adrenal function are characterized by systemic con- sequences of hormone excess, deficiency or both. Hormonal excess may reflect overproduction that results from an autonomously functioning adenoma, primary hyperplasia, or hyperfunction induced by an increase in stimulating hormones. Apparent hormone excess results from inappropri- ate signaling activity within hormone-responsive tissues independent of hormone secretion. Like- wise, hormonal deficiency may be caused by primary adrenal failure, deficiencies in stimulating hormones, or inadequate hormonal activity as a result of end-organ resistance. Defects within the steroid synthesis pathway may cause features of both hormone excess and deficiency as a result of substrate accumulation and product paucity, respectively. Each disturbance has predictable phenotypic features based on the hormonal axis involved.
Genetic bases for many known adrenocortical conditions have been revealed (Table 1) [1]. This knowledge has greatly impacted our understanding of the physiologic and pathophysiologic functions of the adrenal cortex, and allowed practitioners to provide early diagnosis, anticipatory guidance, and genetic counseling to affected patients and families. For example, management of congenital adrenal hyperplasia following newborn or adult diagnosis can be significantly enhanced by application of known genotype-phenotype correlations [2]. Indeed the goal of genetic research is to yield effec- tive preventive care and rational-targeted therapy. Advances in the field continue to bring us closer to
ªDivision of Endocrinology, Diabetes and Hypertension and ªDivision of Genetics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
Correspondence to Justin Annes MD, PHD, 221 Longwood Avenue-2nd Floor, Boston, MA 02115, USA. Tel: +1 617 525 8111; fax: +1 617 507 2577; e-mail: jannes@partners.org
Curr Opin Endocrinol Diabetes Obes 2012, 19:159-167 DOI:10.1097/MED.0b013e328352f013
KEY POINTS
· The identification of KCNJ5 as a causative gene in both familial hyperaldosteronism type III and sporadic aldosterone-producing adenomas provides diagnostic benefit, insight into disease mechanism, and a potential target for intervention.
· The finding of phosphodiesterase 11A as a modifier of phenotype in Carney complex draws attention to the role of allelic variants in explaining variable expressivity and highlights the potential clinical benefit of personalized risk assessment, presymptomatic screening, and treatment guidelines.
· Mutations in 11ß-hydroxysteroid dehydrogenase type I are a newly identified cause of a clinically mild, dominantly inherited cortisone reductase deficiency (CRD) syndrome. This finding advances our molecular diagnostic capability and expands the CRD clinical phenotype.
· The implementation of a comprehensive surveillance protocol in Li-Fraumeni patients, a cancer predisposition syndrome, may improve survival and highlights the importance of TP53 genotyping for patients with adrenocortical carcinoma.
this goal. For example, new research shows potential for future genotype-based treatment of neonatal adrenoleukodystrophy using nonsense suppression technology that allows translational readthrough of stop codons [3”].
Here, we will review significant advances made over the past year in the genetics of adrenal cortical disease. Although numerous publications make notable contributions to this field, we will focus on studies that highlight key genetic principles, most strongly impact our understanding of patho- physiology, and have the potential to affect our treatment approach. (please see [4”-8”,9"",10”-21”, 22"",23”-26”]).
POTASSIUM CHANNEL MUTATIONS IN HYPERALDOSTERONISM
Aldosterone is secreted by cells of the adrenal zona glomerulosa in response to hyperkalemia, and to angiotensin II produced in states of reduced renal perfusion [27]. Both hyperkalemia and angiotensin II-receptor signaling trigger depolarization and activation of voltage-gated Ca2+ channels which, in turn, stimulate the release of aldosterone [28]. When aldosterone release is not responsive to feed- back inhibition the impact is volume expansion, hypertension and hypokalemia. Recent estimates suggest that primary hyperaldosteronism may account for as much as 5-10% of hypertension
[29-32]. Primary hyperaldosteronism is most commonly caused by bilateral hyperplasia (60%), followed by aldosterone-producing adenoma (35%), with familial hyperaldosteronism accounting for only a small percentage of cases [33].
Within the category of familial hyperaldoster- onism, three different types have been identified to date. Familial hyperaldosteronism type I (also known as glucocorticoid remediable aldosteronism) is caused by genetic rearrangement of the CYP11B2 and CYP11B1 genes. This gene fusion causes the expression of CYP11B2 (aldosterone synthase) to be placed under the control of the CYP11B1 (11-ß-hydroxylase) promoter. Because CYP11B1 promoter activity is enhanced by ACTH, treatment with dexamethasone may be used to suppress ACTH production and thereby decrease CYP11B2 pro- duction [34]. In contrast, familial hyperaldosteron- ism types II and III are not glucocorticoid responsive. Familial hyperaldosteronism type II can present with adrenal hyperplasia, adenoma, or both, and is clinically comparable to sporadic hyper- aldosteronism in terms of natural history [35]. It follows an autosomal dominant pattern of inheri- tance, and has been linked to 7p22 [36]. Familial hyperaldosteronism type III was initially described by Geller et al. [37], and noted to present with elevations in 18-oxocortisol and 18-hydroxycortisol leading to severe childhood hypertension and mas- sive adrenal hyperplasia requiring adrenalectomy. The associated gene remained unidentified until now.
To determine the genetic basis of sporadic aldosterone-producing adenomas, Choi et al. [38""] performed whole-exome sequencing on aldosterone-producing adenomas and correspond- ing peripheral blood samples. The simultaneous analysis of tumor and peripheral blood DNA is critical for identification of disease-causing somatic mutations (see Table 2). They selected four such paired samples in which tumors were notable for low levels of loss of heterozygosity (LOH); because these tumors did not contain many losses of DNA sequence, Choi et al. hypothesized that discrete somatic mutations were responsible for unregulated tumor growth and aldosterone secretion. Among these four tumor samples, they identified a limited number of putative somatic protein-altering mutations (these mutations were not present in the peripheral blood samples, or in other normal controls). Strikingly, mutation of the potassium channel KCNJ5 appeared twice in this limited sample. The significance of this observation was further ampli- fied when additional low LOH samples were ana- lyzed; eight of 14 such samples contained an identifiable KCNJ5 mutation. Furthermore, among
| Endocrinopathy | Disease | Phenotype | Gene | OMIM | Inheritance |
|---|---|---|---|---|---|
| Glucocorticoid excess | PPNAD | Pigmented adrenocortical nodules, autonomously functioning, leading to Cushing's syndrome. | PRKAR1A | #610489 | AD, part of CNC |
| PPNAD2 | PDE11A | #610475 | AD | ||
| PPNAD3 | PDE8B | #614190 | AD | ||
| McCune Albright | Polyostotic fibrous dysplasia, café au lait pigmentation, and precocious puberty. Can include thyrotoxicosis, pituitary gigantism, and Cushing's syndrome | GNAS 1 | #174800 | Somatic, mosaicism due to early embryonic activating mutations | |
| AIMAH | Macronodular adrenocortical disease, autonomously functioning, leading to Cushing's syndrome | GNAS 1 | #219080 | Somatic, heterozygous mutations, adrenal tissue | |
| Glucocorticoid deficiency | |||||
| Apparent | Glucocorticoid resistance | Elevated cortisol levels with no Cushingoid features, symptoms resembling Addison's disease | NR3C1 | +138040 | AD |
| Primary | APS I | Addison's disease, chronic mucocutaneous candidiasis, hypoparathyroidism | AIRE | #240300 | AR and AD reported |
| APS II | Addison's disease, primary hypothyroidism, DM, pernicious anemia | Associations with HLA-B8, DR3, DR4, and DQ2 | %269200 | AD, AR, and multifactorial described | |
| Adrenoleukodystrophy, X-linked | Primary adrenal insufficiency, degenerative neurological disorder, onset in late childhood | ABCD1 | #300100 | X-Linked | |
| Adrenoleukodystrophy, neonatal | Dolichocephaly, cataracts, esotropia, anteverted nares, skin hyperpigmentation, mental retardation, adrenal insufficiency | PEX1, PEX5, PEX 10, PEX 13, PEX26 | #202370 | AR | |
| Adrenoleukodystrophy, pseudoneonatal | Brachycephaly, hearing loss, hepatic steatosis, seizures, mental retardation, adrenal insufficiency. | ACOX1 | #264470 | AR | |
| Adrenal hypoplasia congenita | Congenital adrenal insufficiency, primary and central hypogonadotrophic hypogonadism | DAX1 NR0B1 | #300200 | X-linked | |
| %240200 | Rare AR, gene not identified | ||||
| ACTH resistance | FGD 1 | Adrenal insufficiency due to ACTH resistance (low cortisol, high ACTH, normal renin and aldosterone) | MC2R | #202200 | AR |
| FGD2 | MRAP | #607398 | AR | ||
| FGD3 | Mapped to 8q11.2-13.2 | %609197 | AR | ||
| Allgrove's syndrome | Triad of adrenal insufficiency, achalasia, and alacrima | ALADIN (AAAS) | #231550 | AR | |
| ACTH deficiency | Isolated ACTH deficiency | Severe neonatal hypoglycemia, and adrenal hypoplasia. | TBX19 | #201400 | AR |
| Propiomelanocortin deficiency | Obesity, adrenal insufficiency, and red hair. | POMC | #609734 | AR | |
| Congenital adrenal hyperplasia (defective cortisol synthesis and hyperandrogenism) | 21-hydroxylase deficiency | Hyperandrogenism +/- salt-wasting (Simple Virilizing versus salt wasting) | CYP21A2 | #201910 | AR |
| 3-B hydroxysteroid dehydrogenase deficiency | Salt wasting, with minimal or no virilization, males may have hypospadias or pseudohermaphroditism | HSD3B2 | #201810 | AR | |
| 17A-hydroxylase deficiency | Ambiguous genitalia, male pseudohermaphroditism, HTN, hypokalemic metabolic alkalosis | CYP 17A1 | #202110 | AR |
| Endocrinopathy | Disease | Phenotype | Gene | OMIM | Inheritance |
|---|---|---|---|---|---|
| 11-ß hydroxlase deficiency | Virilization, ambiguous genitalia, HTN, short stature | CYP11B1 | #202010 | AR | |
| Cytochrome P450 oxidoreductase deficiency | Ambiguous genitalia, bone malformations (POR mutations also result in Antley-Bixler syndrome) | POR | #613571 | AR | |
| POR | #201750 | AR | |||
| Lipoid congenital adrenal hyperplasia | Lipoid adrenal hyperplasia, hypospadias, phenotypic female, salt-wasting | STAR | #201710 | AR | |
| Cortisone reductase deficiency | Relative cortisol deficiency, adrenal hyperplasia, and hyperandrogenism | H6PD | #604931 | AR | |
| HSD11B1 | #604931 | AD | |||
| Mineralocorticoid excess | Bartter syndrome | This group of disorders is marked by impaired chloride reabsorption in the loop of Henle, leading to salt wasting, hypokalemic metabolic acidosis, and hypercalciuria. Because of associated hypertrophy and hyperplasia of juxtaglomerular cells, increased renin-angiotensin activity leads to secondary hyperaldosteronism | |||
| Type I, antenatal | SLC12A1 | #601678 | AR | ||
| Type II, antenatal | KCNJ1 | #241200 | AR | ||
| TypeIII, classic | CLCNKB | #607364 | AR | ||
| Type IVA, with sensorineural hearing loss | BSND | #602522 | AR | ||
| Type IVB | BSND and CLCNKB | #613090 | Digenic, recessive | ||
| Type V, with hypocalcemia | CASR | (+601119) | AD | ||
| Gitelman syndrome | Variant of Bartter syndrome marked by hypokalemia, hypomagnesemia, and hypocalciuria. | SLC12A3 | #263800 | AR | |
| Familial hyperaldosteronism | AD (chimeric fusion of CYP11B1 and CYP11B2) | ||||
| Type I | ACTH-dependent, glucocorticoid remediable | CYP11B1 | #103900 | ||
| Type II | Not responsive to exogenous glucocorticoids | Linkage at 7p22 | %605635 | AD | |
| Type III | Not responsive to exogenous glucocorticoids | KCNJ5 | #613677 | AD | |
| Mineralocorticoid deficiency | Hypoaldosteronism, congenital | Decreased aldosterone due to aldosterone synthase deficiency, salt wasting, hyponatremia, hyperkalemia | CYP11B2 | #203400 | AR |
| Primary | CMO I deficiency | ||||
| CMO II deficiency | CYP11B2 | #610600 | AR | ||
| Apparent | Pseudo-hypoaldosteronism type 1ª | Mineralocorticoid resistance leading to pseudohypoaldosteronism, severe, systemic, persists into adulthood | SCNN1A; SCNN1G; SCNN1B | #264350 | AR |
| Milder form, renal only, resolves early in childhood | NR3C2 | #177735 | AD | ||
| Type II | Hyperkalemia, hyporeninemia, HTN, secondary hyperkalemic periodic paralysis | WNK4, WNK1; PHA IIA | #145260 | AD |
Conditions of hormonal excess or deficiency are listed, with associated phenotypes, genes, and inheritance patterns provided [1]. AD, autosomal dominant; ACTH, adrenocorticotropic hormone; AIMAH, ACTH- independent macronodular hyperplasia; APS, autoimmune polyglandular syndrome; AR, autosomal recessive; CAH, congenital adrenal hypoplasia; CMO, corticosterone methyloxidase; CNC, Carney complex; DM, diabetes mellitus; FGD, familial glucocorticoid deficiency; HTN, hypertension; OMIM, Online Mendelian Inheritance in Man; PPNAD, primary pigmented nodular adrenocortical disease. “Exceptions to clinical descriptions and inheritance patterns are provided in annotated bibliography [20”,21”].
| inherited | when | there as of | expressivity | interferes | these samples only two different mutations of KCNJ5 were observed, both of which affected highly con- | ||||
| are | attention | when loss | disease | that | served amino acids that participate in maintaining | ||||
| mutations | dominantly | to | example, syndromes, that is, | the | the | protein | channel ion selectivity. In fact, the authors went on to demonstrate that the mutations they identified in | ||
| come | lost, | carry | influence | KCNJ5 decreased channel selectivity, allowed Na+ to | |||||
| inappropriately enter cells, and yielded chronic | |||||||||
| germline | as | mutations | For predisposition or | who | that | aberrant | cellular depolarization. The consequences of this | ||
| (such | an | ||||||||
| mutated | Alleles | to | unregulated cellular depolarization are constitutive | ||||||
| inherited | hemizygous. cancer is | individuals | aldosterone production and cellular proliferation. | ||||||
| these | or copy | alleles. | leads | Thus, somatic mutations of KCNJ5 were identified | |||||
| general, | predisposition | disease; | of | whereby | mutation | as a likely and relatively common cause of aldoster- | |||
| normal | one-producing adenomas. | ||||||||
| disease | homozygous principle | unique | |||||||
| In | the | To determine whether mutations in KCNJ5 | |||||||
| next. | to a | hereditary | either underlying If | penetrance, | and | negative | might cause familial hyperaldosteronism type III, | ||
| generation to the | deficiencies) or | result in | to primary malignancy. | incomplete | mutations | dominant | Choi et al. performed targeted sequence analysis on a family with severe hypertension and early-onset of massive bilateral adrenal hyperplasia [37]. A third | ||
| not | a | mutation that was not observed in control samples | |||||||
| do | heterozygous the preventing | from | pathogenic | was identified; this mutation was also shown to | |||||
| from one | enzyme | mutations | from LOH is in | distinguished | between | nonfunctional, pattern | disrupt the selectivity in potassium channel ion permeability and cause inappropriate depolariz- | ||
| locus | ation. Mutations in KCNJ5 were therefore also ident- | ||||||||
| recessive | protective | or | |||||||
| transmitted | Somatic | genetic formation. is | be | interplay | absent inheritance | ified as a cause of familial hyperaldosteronism | |||
| autosomal | cells. | to | type III. | ||||||
| be | a tumor gene | is | complex | either | This work makes several important contri- | ||||
| may | that | This | dominant | butions to the area of adrenal cortical disease, and | |||||
| as | germ | is | |||||||
| and | within conditions | has converted to prevent copy of | phenotypes. | a | more broadly to disorders of endocrine cell hyper- | ||||
| sperm) | (such | of | product autosomal | plasia. First, Choi et al. have identified a molecular | |||||
| disease | sporadic | insufficient | result | gene | basis for both somatic and germline hyperaldoster- | ||||
| or | present | mutation normal | disease | the | onism. Second, this work provides a molecular link | ||||
| is | the an | between cellular growth and hormone secretion. A | |||||||
| (oocytes | not many | other is the | characteristics | which and | similar observation has been made in pancreatic | ||||
| cells | either congenital | and are explain | or copy gene, [39] | differing disease | an individual | in product | islet -cells in which mutations of the potassium channel Kir6.2 causes hyperinsulinemia and ß-cell | ||
| present in germ | lead to risk) | postfertilization disturbances, and | which a deletion remaining abnormal tumor suppressor hypothesis | may produce any | expressed by | function mutations, normal gene genes | hyperplasia [40]. Thus, the connection between repetitive depolarization and cellular growth may be a general principle of endocrine lineage cells. | ||
| and | by a Knudson | allele manifest | the | Third, this work suggests that a medication, similar | |||||
| are | cell malignancy | arise | the for | not | of of | to diazoxide but specific to KCNJ5, might be useful | |||
| mutations | in every in | mutations functional | the process heterozygosity by the | pathogenic may | phenotype | with loss function modifier | in treatment and prevention of aldosterone-produc- ing adenomas. Finally, this work draws attention to | ||
| Germline | present increases | Somatic causing | Refers to heterozygosity, is described | single genotype | disease | contrast with the are termed | mutations in other potassium channel genes as potential targets for future research. Prior work | ||
| principles | A | The | In | has suggested a possible role for such mutations in nonendocrine human malignancies [41-43]. | |||||
| genetic | mutations | PHOSPHODIESTERASE 11A AS A MODIFIER OF PHENOTYPE | |||||||
| 2. Key | mutations | mutations | expressivity | genes | negative | of heterozygosity. | Carney complex (CNC) is a rare autosomal domi- nant multiple neoplasia syndrome with pan-ethnic distribution [44]. Patients with CNC are character- | ||
| loss | ized by a combination of myxomas, spotty skin | ||||||||
| Table | Germline | Somatic | LOH | Variable | Modifier | Dominant | LOH, | pigmentation, and endocrine tissue overactivity [45]. The most common endocrine manifestation |
1752-296X @ 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
of this syndrome is primary pigmented nodular adrenocortical disease (PPNAD), which may present as an isolated finding in some individuals [46]. Loss-of-function mutations in the cAMP-dependent protein kinase type-I regulatory subunit (PRKAR1A) gene can be found in approximately 75% of patients who meet clinical criteria for the diagnosis of CNC. However, the variable expressivity (see Table 2) of this disorder continues to pose challenges for diag- nosing CNC, establishing screening guidelines, and providing anticipatory guidance to affected individ- uals and families [44]. Although some genotype- phenotype correlations have been proposed, these remain controversial and do not account for the significant intrafamilial variability observed [44,47]. Prior work by Libe et al. [48] has shown that common allelic variants of phosphodiesterase 11A (PDE11A) are overrepresented in patients with adre- nocortical tumors]. This finding suggests a patho- genic role for PDE11A variants, a conclusion supported by the observed LOH of the wild-type PDE11A locus in adrenocortical tumor DNA [49].
In their current work, Libe et al. [50""] tested the hypothesis that PDE11A variants influence the expressivity of CNC by analyzing the PDE11A locus in 150 patients with an identifiable PRKAR1A mutation. The authors found that the prevalence of PDE11A variants was overrepresented in patients with PPNAD: 30.8 versus 13% for those with and without PPNAD, respectively (P=0.025). In addition, for men with large-cell calcifying Sertoli cell tumors (LCCSCT) versus without, the pre- valence of PDE11A variants was 50 versus 10%, respectively (P=0.0056). These results support the role of PDE11A variants as modifiers of the CNC phenotype: when PDE11A variants are present in conjunction with PRKAR1A mutations, the risks of PPNAD and LCCSCT are increased.
We have chosen to highlight this work for two reasons. First, it bears potential clinical implications for patients with CNC. In the future, PDE11A sequencing in addition to PRKAR1A analysis may be utilized to establish genotype-specific risk pre- dictions and screening approaches. Second, this work highlights the important principle of modify- ing genes. As shown in Fig. 1, PDE11A and PRKAR1A both act to repress the activity of protein kinase A (PKA), a strong growth promoting signaling enzyme [51]. Indeed, common PDE11A variants might increase tumor formation by increasing cAMP levels in CNC patients who already have enhanced PKA activity caused by the loss of PRKAR1A. Thus, PDE11A variants, not pathogenic mutations in the traditional sense, act cooperatively with pathogenic PRKAR1A mutations to promote cellular growth, and thereby impact disease expressivity.
Ligand binding
AC
GPCR
ATP
CAMP
PDE11A
PRKAR1A
PKA
Adrenal cortical proliferation
NOVEL MECHANISM FOR CORTISONE- REDUCTASE DEFICIENCY
Steroid biosynthetic disorders leading to androgen excess are well known, with 1 in 10000 to 1 in 15 000 live births affected by congenital adrenal hyperplasia (CAH). Although the majority of CAH (90-95%) is caused by 21-hydroxylase deficiency, pathogenic mutations in several additional loci also cause CAH (Table 1). Cortisone-reductase deficiency (CRD) is a rare cause of CAH with a distinct pheno- type. CRD is characterized by a relative cortisol deficiency resulting from inadequate regeneration of cortisol from cortisone. This inadequate
regeneration triggers a compensatory increase in ACTH production that drives adrenal gland hyper- plasia and hyperandrogenism. CRD typically presents as precocious pseudopuberty in males during childhood, and as hirsuitism and oligome- norrhea in females during adolescence and adult- hood. The regeneration of cortisol from cortisone is carried out by the homodimeric enzyme 11ß- hydroxysteroid dehydrogenase type 1 (HSD11B1) and is dependent upon the presence of a high NADPH/NADP+ ratio, which is maintained by enzy- matic activity of hexose-6-phosphate dehydrogen- ase (H6PD) (Fig. 2) [52,53]. Previously, mutations in H6PD have been shown to cause CRD [54].
Recent work by Lawson et al. [55""] demonstrates that mutations in the HSD11B1 gene also cause CRD. The authors performed germline DNA sequence analysis of the HSD11B1 locus in two males with normal H6PD gene sequencing and CRD phenotypes of mild hyperandrogenism and premature pseudopuberty, elevated urinary cortisol degradation products (cortols). Each of these patients was found to be heterozygous for an HSD11B1 missense mutation. Both of the identified mutations alter highly conserved amino acids that participate in enzyme homodimerization. Sub- sequent molecular studies demonstrated that the coexpression of mutant HSD11B1, harboring either of the identified mutations, with wild-type HSD11B1 results in dramatically reduced enzyme
G6P
NADP
Cortisol
H6PD
HSD11B1
6PG
NADPH
Cortisone
stability and enzymatic activity. Thus, a single germ- line mutation in HSD11B1 that disrupts enzyme complex formation is sufficient to cause the CRD phenotype observed in these two patients.
Three important contributions are made by this study. First, a new hereditary basis for CRD has been identified. Second, the CRD phenotype has been expanded to include more mild disease. Third, this work highlights how enzyme deficiencies, which are characteristically inherited in an autosomal reces- sive pattern, may be inherited in an autosomal dominant pattern as a result of protein multimeri- zation and a consequent dominant-negative effect (See Table 2).
SURVEILLANCE PROTOCOL FOR LI- FRAUMENI
Patients with adrenocortical carcinoma (ACC), even in the absence of family history, are at high risk of harboring germline TP53 mutations [56]. In a series of patients with ACC diagnosed between the ages of 18 and 40, the risk of germline TP53 mutation was 13% [57]. This risk is substantially higher with ACC diagnosed before age 18; germline TP53 mutations are found in 50-80% of apparently sporadic child- hood ACCs [58]. Germline mutations in TP53 are identified in 70% of patients who meet criteria for Li-Fraumeni syndrome, an autosomal dominant cancer predisposition syndrome that includes sig- nificantly elevated risks for early onset sarcoma, breast cancer, brain tumors, and leukemia, among other malignancies [59-60]. Although these risks are well established, the variable expression of this syndrome and minimal genotype-phenotype cor- relations have rendered providers with limited guidelines for surveillance and risk management [61]. In the setting of extremely high lifetime cancer risks (50% by age 30, and 90% by age 60), the need for an effective surveillance protocol is evident [62].
In a prospective observational study of eight families with Li-Fraumeni, Villani et al. [63""] imple- mented a comprehensive cancer screening protocol to determine if patient survival could be improved. The surveillance protocol included ACC screening with an ultrasound of the abdomen and pelvis, urinalysis, and serum measurement of beta-hCG, AFP, 17-OH-progesterone, testosterone, and dehy- droepiandosterone sulfate every 3-4 months. Of 18 patients undergoing surveillance, seven were found to have asymptomatic tumors during the study period; all seven survived through a median follow-up period of 2 years. Among the 16 patients in the nonsurveillance group, 10 were found to have cancers, all of which were identified symptomati- cally. Only two of these 10 patients were living at the
end of the follow-up period (6 years). This corre- sponds to a 3-year overall survival of 100% for patients in the surveillance group, versus 21% for patients in the nonsurveillance group (P=0.0155).
Some of the limitations of this study are inherent in its observational design. In the absence of randomization, patients electing to pursue versus decline surveillance may differ in important health and behavioral measures. Moreover, the short duration of the study makes it unclear if the mortality benefit observed in the surveillance group is truly the result of early malignancy detection. Despite its limitations, this work is notable for two reasons. First, the presence of ACC should raise concern for a hereditary condition and promote consideration of Li-Fraumeni syndrome. Second, this study makes a tentative but important step toward validating a gene-specific surveillance pro- tocol that may confer a mortality benefit - repre- senting the very goal of personalized medicine.
CONCLUSION
Advances in adrenocortical genetics achieved this year were important not only in understanding the particular disorders studied, but also in expanding the applications of key genetic concepts highlighted above. The presented research in adrenocortical genetics makes significant contributions to our knowledge base, focuses the direction of future research, and provides avenues for genetics-based disease risk stratification and intervention.
Acknowledgements
We wish to thank Dr Florencia Halperin for her thought- ful reading of our manuscript.
Conflicts of interest
Support provided by NIH Grant DK084206 (JPA). The authors have no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
of special interest
of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 235-236).
1. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine. Online Mendelian Inheritance in Man. http:// www.ncbi.nlm.nih.gov/omim. [Accessed 1 February 2012]
2. Balsamo A, Baldazzi L, Menabo S, Cicognani A. Impact of molecular genetics on congenital adrenal hyperplasia management. Sex Dev 2010; 4:233-248.
3. Dranchak PK, Di Pietro E, Snowden A, et al. Nonsense suppressor therapies
rescue peroxisome lipid metabolism and assembly in cells from patients with specific PEX gene mutations. J Cell Biochem 2011; 112:1250-1258.
Nonsense suppressor therapies allowing translational readthrough of stop codons are being examined across various genetic diseases. This study of two such aminoglycoside therapies demonstrates potential benefit of G418 in increasing very long chain fatty acid catabolismand plasmalogen biosynthesis in the setting of PEX mutations.
4. Almeida MQ, Harran M, Bimpaki El, et al. Integrated genomic analysis of nodular tissue in macronodular adrenocortical hyperplasia: progression of tumorigenesis in a disorder associated with multiple benign lesions. J Endocrinol Metab 2011; 96:E728-E738.
Smaller nodules in ACTH-independent macronodular hyperplasia (AIMAH) were shown to exhibit metabolic derangements, whereas larger AIMAH nodules were more likely to overexpress genes in oncogenic pathways.
5. Brønstad I, Wolff AS, Løvås K, et al. Genome-wide copy number variation (CNV) in patients with autoimmune Addison’s disease. BMC Med Genet 2011; 12:111.
High copy number variation (CNV) of ADAM3A and low CNV of UGT2B28 are associated with Addison’s disease. Aberrant T-cell maturation and steroid inacti- vation may participate in the development of this autoimmune disease.
6. Wang Y, Busin R, Reeves C, et al. X-linked adrenoleukodystrophy: ABCD1
de novo mutations and mosaicism. Mol Genet Metab 2011; 104:160- 166.
This analysis of families with X-linked adrenoleukodystrophy identifies cases of gonadal mosaicism, a rare cause of an increased recurrence risk in the setting of an apparently de-novo mutation.
7. Parajes S, Kamrath C, Rose IT, et al. A novel entity of clinically isolated adrenal insufficiency caused by a partially inactivating mutation of the gene encoding for P450 side chain cleavage enzyme (CYP11A1). J Clin Endocrinol Metab 2011; 96:E1798-E1806.
A new genotype-phenotype correlation: partial CYP11A1 deficiency may cause adrenal insufficiency with normal male genital development.
8. Mendiratta MS, Yang Y, Balazs AE, et al. Early onset obesity and adrenal
insufficiency associated with a homozygous POMC mutation. Int J Pediatr Endocrinol 2011; 2011:5.
Novel presentation: a POMC mutation was shown to present with weight gain and adrenal insufficiency in the absence of red hair.
9. Ghizzoni L, Cappa M, Vottero A, et al. Relationship of CYP21A2 genotype
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