Inherited adrenal hypoplasia: not just for kids!

The diagnosis and treatment of inherited forms of adrenal hypoplasia has, in the past, been very much within the realm of the paediatric endocrinologist. However, it is now becoming clear that individuals with this condition have specific needs that must be addressed within the adult clinic, and milder forms of adrenal hypoplasia may only present in later life. In this review, we will provide an overview of the genetics of the inherited forms of adrenal hypoplasia, and highlight issues that might need to be addressed in the transitional and long-term management of patients with these conditions. We will show how knowledge of the underlying genetics can have important implications for counselling, for identifying associated features and for planning long-term care. Given the scope of this article, we will not cover the long-term effects of steroid biosynthetic defects, metabolic disorders (e.g. adrenoleukodystrophy) or other forms of adrenal destruction (e.g. autoimmune endocrinopathy; Vaidya et al., 2000; White & Speiser, 2000), which obviously have important management issues into adulthood too. Adrenal hypoplasia is underdevelopment or atrophy of the adrenal glands, and can occur in secondary or primary forms. Secondary adrenal hypoplasia results from impaired secretion of ACTH from pituitary corticotropes or due to ACTH resistance, and is caused by a lack of tropic stimulation of the adrenal gland. Glucocorticoid synthesis and release are primarily affected in these cases. In contrast, primary adrenal hypoplasia results from abnormal adrenal development and function, usually due to abnormalities in transcription factors expressed within the adrenal gland itself. Primary adrenal hypoplasia often affects the zona glomerulosa, causing mineralocorticoid insufficiency and salt loss, as well as impaired glucocorticoid synthesis and release. Diagnostic clues to the specific cause of adrenal hypoplasia can often be obtained from the patient's biochemical profile at presentation, family history and from any associated clinical features found. Obtaining a reliable measurement of serum ACTH (especially prior to steroid treatment) can be extremely useful in differentiating ACTH insufficiency (inappropriately low ACTH) from ACTH resistance or primary hypoplasia (elevated ACTH). Similarly, evidence of hyponatraemia or hyperkalaemia, low aldosterone, or elevated plasma renin activity would reflect impaired mineralocorticoid secretion. Whilst potentially life-saving steroid treatment should not be delayed, obtaining samples for these tests at the time of presentation can often make the diagnosis easier, and readdressing this once steroid treatment has been started can be challenging. An overview of inherited forms of adrenal hypoplasia and their associated features is shown in Fig. 1 and Table 1. The differential diagnosis of inherited adrenal hypoplasia includes other causes of panhypopituitarism or ACTH deficiency; ACTH resistance of unknown origin [familial glucocorticoid deficiency 2 (FGD2)]; and other causes of Addison's disease or adrenal destruction. Patients with congenital adrenal hyperplasia (e.g. 21-hydroxylase deficiency) or lipoid adrenal hyperplasia [due to defects in steroidogenic acute regulatory protein (StAR), or CYP11A] often have a diagnostic biochemical profile, abnormalities in gonadal steroid production and enlarged adrenals on imaging. However, adrenal imaging is not always reliable, especially early in life, and relatively small adrenals have been reported occasionally in patients with mutations in StAR. Overview of the hypothalamic-pituitary(corticotrope)-adrenal axis. Mutations in the genes listed have been shown to cause adrenal hypoplasia in humans (reprinted with permission from Achermann et al., 2001). ATII, angiotensin II; LCH, Langerhans’ cell histiocytosis; FGD2, familial glucocorticoid deficiency type 2; ALD, adrenoleukodystrophy. ACTH deficiency can occur as part of a combined (multiple) pituitary hormone deficiency, due to isolated ACTH deficiency, or following abnormalities in ACTH post-translational processing. The corticotrope cell lineage is one of the first to differentiate from progenitor cells in the pituitary gland (Fig. 2). Consequently, mutations in factors that affect early pituitary development (e.g. HESX1, LHX4) will result in ACTH deficiency as part of a combined pituitary hormone deficiency (CPHD) in early childhood (Cohen & Radovick, 2002; Scully & Rosenfeld, 2002; Dattani, 2003). Patients with milder forms of these conditions, or mutations in other transcription factors (e.g. PROP1), may develop more limited forms of pituitary hormone deficiency, and ACTH deficiency may only occur with time. Therefore, careful vigilance of patients with pituitary dysfunction may be needed long into adult life. Overview of pituitary development. Mutations in several genes can cause panhypopituitarism (e.g. HESX1, LHX4) or isolated ACTH deficiency (e.g. Tpit, TBX19). Several patients with PROP1 mutations have also developed ACTH deficiency with time. It is unclear whether this is a direct phenomenon or secondary to the transient pituitary enlargement seen in some of these patients (adapted with permission from Achermann & Jameson, 1999). HESX1. HESX1 is a homeodomain transcription factor that is expressed during the early stages of forebrain and pituitary development (Dattani et al., 1998). HESX1 is a functional repressor of putative targets within forebrain and pituitary development, and severe loss-of-function mutations in HESX1 have been described in several patients with variants of septo-optic dysplasia (optic nerve hypoplasia, absent corpus callosum, thin septum pellicidum) and panhypopituitarism (Dattani et al., 1998; Brickman et al., 2001; Tajima et al., 2003; OMIM 601802). Milder loss of function mutations in HESX1 have also been identified. These patients have panhypopituitarism or even isolated GH deficiency in the absence of optic nerve hypoplasia (Thomas et al., 2001; Carvalho et al., 2003). LHX4. Mutations in the Lim-domain factor, LHX4, have been described in a kindred with panhypopituitarism (including ACTH deficiency), but apparently spared gonadotrope function (Machinis et al., 2001; OMIM 602146). These patients have posterior pituitary ectopia and abnormal cerebellar tonsils on MRI scanning. To date, corticotrope function appears to be preserved in families with pituitary dysfunction due to the related Lim-domain factor, LHX3 (Netchine et al., 2000) PROP1. Mutations in PROP1 have been described in over 100 patients with multiple pituitary hormone deficiency (Wu et al., 1998; OMIM 601538). These individuals usually present in childhood with GH and TSH insufficiency. Gonadotropin deficiency may be apparent in early childhood (e.g. micropenis, undescended testes), or may not present until adolescence or even early adulthood (Deladoey et al., 1999). Although most data show that PROP1 is not expressed in the corticotrope cell line, it is emerging that a significant proportion of patients with PROP1 gene mutations actually develop ACTH insufficiency with time (Mendonca et al., 1999; Vallette-Kasic et al., 2001). It remains to be seen whether this is due to a hitherto unknown effect of PROP1 on corticotrope function, or following damage to the corticotrope cell population secondary to the pituitary enlargement seen in some patients (Riepe et al., 2001; Vallette-Kasic et al., 2001). Mutations in several factors involved in ACTH synthesis and processing can cause secondary adrenal hypoplasia due to ACTH insufficiency (Fig. 3). Expression and processing of ACTH. ACTH deficiency can result from abnormalities in Tpit, pro-opiomelanocortin (POMC), or the cleavage enzyme, pro-hormone convertase 1 (PC1). POMC. The mature ACTH peptide is cleaved from pro-opiomelanocortin (POMC), together with other signalling molecules such as the melanocyte-stimulating hormones (α-MSH, β-MSH) and β-endorphin (Fig. 3). As these factors play a central role in appetite regulation and pigmentation, deletions or mutations in the POMC locus have been identified in patients with the syndrome of ACTH-deficient hypocortisolaemia, red hair and obesity (Krude et al., 1998, 2003; OMIM 176830). Tpit (TBX19). POMC transcription is regulated by the corticotrope-specific transcription factor, Tpit (TBX19; Lamolet et al., 2001). Tpit binds to the T-box (TCACACCA) of the POMC promoter and forms a regulatory complex with Pitx1 (Fig. 3). Tpit plays a crucial role in ACTH synthesis by regulating POMC expression as well as in the differentiation of late POMC expressing corticotropes. Mutations in Tpit have now been described in several families with isolated ACTH deficiency (Lamolet et al., 2001; Pulichino et al., 2003a, 2003b; OMIM 604614). Furthermore, recent data suggest that Tpit is a negative regulator of gonadotrope differentiation through trans-repression of steroidogenic factor-1 (SF-1), highlighting the role that some of these transcription factors can play in switching cell fate in endocrine development (Pulichino et al., 2003b). PC1 (PCSK1). The proprotein convertase family of enzymes plays an important role in pro-hormone processing in several endocrine systems, and pro-hormone convertase 1 (PC1; proprotein convertase, subtilisin/kexin-type, 1; PCSK1) is crucial for the cleavage of mature ACTH from POMC (Fig. 3). Mutations in this enzyme have been reported in two patients with hypocortisolaemia (Jackson et al., 1997; Lindley et al., 2003; OMIM 162150). Additional features of this syndrome include abnormal glucose metabolism, obesity, hypogonadotropic hypogonadism and persistent malabsorptive diarrhoea, reflecting the diverse role PC1 plays in peptide processing in the gut. Whether milder forms of this condition exist in adulthood remains to be elucidated. ACTH has an important tropic effect on adrenal development via the melanocortin-2 receptor (MC2R, ACTH receptor) and subsequent downstream signalling pathways. Abnormalities in these signalling processes result in adrenal hypoplasia due to ACTH resistance. Familial glucocorticoid deficiency (FGD1) results from mutations in the G protein-coupled MC2R (MC2R, ACTH receptor; Clark & Weber, 1998; Elias et al., 1999; Fluck et al., 2002; OMIM 607397). Children with this condition usually present with hypoglycaemia and evidence of glucocorticoid insufficiency. Tall stature has also been reported in children with MC2R mutations, but the diagnostic or biological significance of this is unclear (Elias et al., 2000; Fluck et al., 2002). In general, children with ACTH resistance do not need mineralocorticoid replacement in adolescence or adulthood. Therefore, identifying MC2R mutations in patients with childhood adrenal failure can be useful in predicting the need for long-term mineralocorticoid replacement, when previous biochemical data have been equivocal. Triple A syndrome (Alacrima, Achalasia, Addison's disease) is a well-recognized condition that can present at various ages with isolated adrenal failure, alacrima or upper gastrointestinal abnormalities such as achalasia of the oesophagus (Huebner et al., 2002; OMIM 605378). The penetrance of this condition within families can be highly variable, and neurological (e.g. pupillary and cranial nerve abnormalities, optic atrophy, autonomic dysfunction, distal motor neuropathy, amyotrophy) and dermatological features are increasingly recognized as part of this syndrome (Houlden et al., 2002). Recently, the gene responsible for Triple A has been identified and termed AAAS (Tullio-Pelet et al., 2000; Handschug et al., 2001). The product, ALADIN, is a putative signalling molecule with WD-repeat motifs. To date, mutations in AAAS have been identified in more than 80 families with this condition (Huebner et al., 2002). The structural alterations induced by these amino acid substitutions may affect the ability of the protein to localize to nuclear pore complexes (Cronshaw & Matunis, 2003). Detailed genetic analysis is also revealing the true variability of features within families, with some ‘adrenal only’ forms described (Huebner et al., 2002; Prpic et al., 2003). Therefore, Triple A syndrome should be considered in all patients presenting with adrenal failure, especially when vague neurological features are present or if there is a family history of associated features. Primary adrenal hypoplasia has classically been divided into a X-linked, ‘cytomegalic’ form, where adrenal cells resemble perisitent fetal adrenal tissue, or a recessive form, where the adrenal cortex has a ‘miniature adult’ type structure. The X-linked form of adrenal hypoplasia occurs due to mutations in the orphan nuclear receptor DAX1 [NR0B1, adrenal hypoplasia congenita (AHC); Muscatelli et al., 1994; Zanaria et al., 1994; Phelan & McCabe, 2001; Lalli & Sassone-Corsi, 2003; OMIM 300200]. DAX1 is expressed in the hypothalamus, pituitary gonadotropes, adrenal and gonad, and plays a key role in the development and function of the adrenal and reproductive axes. More than 100 mutations in DAX1 have now been described in individuals or families with X-linked AHC (Fig. 4a; Reutens et al., 1998; Achermann et al., 2001a; Phelan & McCabe, 2001). Most of these mutations affect the structure and function of the DAX1 protein severely, and boys with this condition often present with primary adrenal failure and salt loss in the first weeks of life, or more insidiously with adrenal failure in childhood. As these boys reach adulthood, it is becoming increasingly clear that hypogonadotropic hypogonadism due to impaired gonadotropin synthesis and release is also an integral part of this condition, and testosterone replacement is usually necessary to induce signs of sexual maturation in these individuals. Overview of DAX1 mutations. (a) More than 100 mutations have now been described in DAX1 (NR0B1), some of which are shown here. Most of these are frameshift or nonsense mutations (upper panel) that result in carboxyterminal truncation and significant loss of repressor function. Missense mutations in DAX1 (lower panel) are clustered in the putative ligand-like binding domain (LBD), and may interfere with protein stability and nuclear localization. Several missense mutations (e.g. Y380D, I439S) are associated with a milder loss of function and a delayed onset of adrenal failure in adulthood. Furthermore, patients with extreme amino-terminal nonsense mutations (Q37X, W39X) can also have an adult-onset form of the condition (b). This is likely to be due to ‘phenotypic rescue’ by an alternately translated DAX1 isoform from the methionine at codon 83, which has residual LXXLL domains capable of preserving partial function (reproduced with permission from Achermann et al., 2001b and Ozisik et al., 2003a). Targeted deletion of the gene encoding Dax1 in the mouse produced only a subtle adrenal phenotype. Nevertheless, this model is revealing the importance of Dax1 in testis development and function (Yu et al., 1998). Hemizygous knockout mice are infertile, and testicular histology shows blockage of the rete testis and efferent ductules by aberrantly located Sertoli cells resulting in tubular dilatation; ectopic Leydig cell differentiation within seminiferous tubules; abnormalities in the basement membrane between the myoid and Sertoli cells; and interstitial Leydig cell hyperplasia (Jeffs et al., 2001; Meeks et al., 2003a, 2003b). Furthermore, one-third of animals develop sex-cord-stromal tumours by 1 year of age (Jeffs et al., 2001). Limited data from adult patients with DAX1 mutations has shown a similar pattern of azoospermia, disordered tubular structure and Leydig cell hyperplasia, and a disappointing response to fertility induction with gonadotropin therapy (Fig. 5; Seminara et al., 1999; Tabarin et al., 2000; Mantovani et al., 2002), although apparently normal testicular histology has been reported in infancy in one patient (Brown et al., 2003). The tumour risk in humans or potential benefits of intracytoplasmic sperm injection (ICSI) are not yet known. However, the mouse model is providing important insight into some of the reproductive issues that need to be considered by physicians involved in the long-term care of adults with X-linked AHC, and caution may be needed before embarking on high-dose gonadotropin stimulation. Histological features of the testis from a patient with X-linked AHC. Recently, the importance of Dax1 in testis development and spermatogenesis has been revealed from studies in the mouse. Although data from patients are limited, consistent features include oligo- or azoospermia, disruption of the normal tubular structure, ectasia of the rete testis (not shown), and abnormal proliferation of the interstitial tissue (including Leydig cell hyperplasia, inset) (reproduced with permission from Ozisik et al., 2003a) (magnification: main Fig. 50×, inset 200×). Recently, we have reported several men who first presented in adulthood with mild adrenal insufficiency or partial hypogonadism due to DAX1 mutations. In two of these cases, point mutations in DAX1 (Y380D, I439S) produced only a partial loss of DAX1 repressor function, consistent with the late-onset phenotype in adulthood (Tabarin et al., 2000; Achermann et al., 2001b; Mantovani et al., 2002). In another case, alternate translation from an in-frame methionine (M83) was able to circumvent a nonsense mutation (Q37X) in the amino-terminus of DAX1, thereby producing a truncated protein with partial function (Fig. 4b; Ozisik et al., 2003a). In addition to highlighting some interesting genetic mechanisms of phenotypic expression, these cases clearly show that a diagnosis of X-linked AHC should be considered in all men presenting with primary adrenal failure, especially in the presence of partial hypogonadism or infertility. The genetic basis of the recessive form of adrenal hypoplasia is not known, although adrenal hypoplasia has been described as part of the IMAGe syndrome (Intrauterine growth retardation, Metaphyseal dysplasia, Adrenal hypoplasia, and Genitourinary malformations; Vilain et al., 1999) and in individuals with certain chromosomal rearrangements (e.g. 5p dup, 11q-). The orphan nuclear receptor steroidogenic factor-1 (SF-1, NR5A1) is a recessive (9p33) factor that plays a crucial regulatory role in the development and function of the adrenal and reproductive axes at many levels (Parker & Schimmer, 1997; Ozisik et al., 2003b). More than 40 different SF-1-responsive target genes have been described (e.g. MC2R, StAR, various steroid hydroxylases and many genes involved in reproductive development and function) and targeted deletion of the gene encoding SF-1 in mice (Ftzf1) results in adrenal agenesis, complete 46,XY sex reversal with persistent Müllerian structures, hypogonadotropic hypogonadism and obesity (Parker & Schimmer, To date, we have described SF-1 mutations in two patients with primary adrenal failure, a phenotype and in the presence of a 46,XY et al., 2002; OMIM In the first a mutation in the primary domain of SF-1 affected binding to most target resulting in a of SF-1 et al., A patient with a similar phenotype was to have a milder loss-of-function mutation in the of SF-1 et al., 2002). This is a secondary and a was necessary for expression of the phenotype in this patient (Fig. Although these mutations are providing useful insight into nuclear and target gene and the crucial role of SF-1 in endocrine development and function. of SF-1 binding to as a In one patient 46,XY adrenal failure and Müllerian a mutation in the primary domain of SF-1 in affected binding to most target resulting in a of SF-1 et al., 1999; et al., patient with a similar phenotype was to have a mutation in the of SF-1 in Achermann et al., 2002). This is a secondary and a was necessary for expression of this phenotype (reproduced with permission from Achermann et al., 2002). Additional mutations in SF-1 have been described in a with primary adrenal failure & 2000), and in a patient who presented in adulthood with primary and impaired development but apparently normal adrenal function et al., 2001). These cases show that the associated with in SF-1 can be Given the diverse role that SF-1 plays in different endocrine systems, it is to that SF-1 mutations be identified in patients as Addison's or in other individuals with adrenal or metabolic features. replacement therapy remains the of treatment for patients with adrenal The are similar to in other forms of Addison's and are than the needed for congenital adrenal In general, and children divided into of such as may be once the effects of these on growth is an replacement is needed when salt loss is but the should be to needs and measurement of plasma renin activity can be useful in In general, mineralocorticoid are in the first of and usually in divided for the first of life. the the patient their should be in and should be to be in and patients should a or and a steroid may include more steroid release or even adrenal The potential benefits of adrenal replacement (e.g. on and sexual function in with Addison's disease is these studies have for adults with genetic forms of adrenal hypoplasia & 2001). the has been in of the mechanisms of adrenal hypoplasia in childhood. As these individuals usually to adulthood with steroid replacement, it is becoming clear that many long-term features which have important management issues for adult too. ACTH deficiency may only be a late of inherited forms of multiple pituitary hormone deficiency; the expression of features in Triple A syndrome can be highly and can include subtle neurological and boys with X-linked adrenal hypoplasia due to mutations in DAX1 have abnormalities in testis development and spermatogenesis with important implications for fertility and long-term Furthermore, it is now clear that subtle or forms of adrenal hypoplasia may first present with adrenal insufficiency in adulthood. These cases highlight the importance of the adult these conditions, and the need for between paediatric and adult as well as and in the management and of patients and families their care. a We are to Jameson, and for useful this