Gonadal and Adrenal Disorders

Adrenocortical failure most commonly is due to a decrease in production of 1 or more adrenal hormones. Clinically relevant deficiencies may involve cortisol or aldosterone or a combination of both. Decreased production of adrenocortical hormones may be a consequence of adrenocortical disease (primary failure) or tropic hormone loss (secondary failure).

Addisonian Crisis Precipitated By Thyroxine Therapy In A Patient With Type 2 Autoimmune Polyglandular Syndrome

Primary hypoadrenalism(Addison’s disease) refers to glucocorticoid deficiency occurring in the setting of adre­nal disease(mostly due to autoimmune adrenalitis), whereas secondary hypoadrenalism arises because of deficiency of ACTH(mostly due to pituitary disease) . A major distinction between these two is that mineralocorticoid deficiency invari­ably accompanies primary hypoadrenalism, but this does not occur in secondary hypoadrenalism because only ACTH is de­ficient; the renin-angiotensin-aldosterone axis is intact and in primary hypoadrenalism skin pigmentation is always present due to increased ACTH secretion(unless of short duration) but it is absent in secondary hypoadrenalism. Addison’s disease or primary adrenocortical failure was first described by English physician Thomas Addison, who found it in six patients with adrenal tuberculosis in 1855(1). Addisonian crisis is a potentially fatal condition associated mainly with an acute defi­ciency of the glucocorticoid cortisol and, to a lesser extent, the mineralocorticoid aldosterone. This is a rare condition with an estimated incidence in the developed world of 0.8 cases per 100,000 and prevalence of 4 to 11 cases/100,000 population. Despite optimised life-saving glucocorticoid replacement and mineralocorticoid-replacement therapy, it is life threatening if overlooked(2-3). Hypothyroidism may mask the addison’s disease so in patients with panhypopituitarism and autoim­mune polyglandular syndrome type 2 thyroxine replacement without adequate steroid replacement may precipitate acute addisonian crisis. Journal of Chitwan Medical College 2013; 3(4); 54-56 DOI: http://dx.doi.org/10.3126/jcmc.v3i4.9557

Evidence of Adrenal Failure in Aging Dax1-Deficient Mice

Dosage-sensitive sex reversal, adrenal hypoplasia congenita (AHC) critical region on the X chromosome, gene 1 (Dax1) is an orphan nuclear receptor essential for development and function of the mammalian adrenal cortex and gonads. DAX1 was cloned as the gene responsible for X-linked AHC, which is characterized by adrenocortical failure necessitating glucocorticoid replacement. Contrary to these human data, young mice with genetic Dax1 knockout (Dax1−/Y) exhibit adrenocortical hyperfunction, consistent with the historic description of Dax1 as a transcriptional repressor that inhibits steroidogenic factor 1-dependent steroidogenesis. This paradox of molecular function and two apparently opposite phenotypes associated with Dax1 deficiency in mice and humans is compounded by the recent observations that under certain circumstances, Dax1 can serve as a transcriptional activator of steroidogenic factor 1. The recently revealed role of Dax1 in embryonic stem cell pluripotency, together with the observation that its expression in the adult adrenal is restricted to the subcapsular cortex, where presumptive undifferentiated progenitor cells reside, has led us to reexamine the phenotype of Dax1−/Y mice in order to reconcile the conflicting mouse and human data. In this report, we demonstrate that although young Dax1−/Y mice have enhanced steroidogenesis and subcapsular adrenocortical proliferation, as these mice age, they exhibit declining adrenal growth, decreasing adrenal steroidogenic capacity, and a reversal of their initial enhanced hormonal sensitivity. Together with a marked adrenal dysplasia in aging mice, these data reveal that both Dax1−/Y mice and patients with X-linked AHC exhibit adrenal failure that is consistent with adrenocortical subcapsular progenitor cell depletion and argue for a significant role of Dax1 in maintenance of these cells.

Renal Failure Associated with APECED and Terminal 4q Deletion: Evidence of Autoimmune Nephropathy

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive disorder caused by mutations in the autoimmune regulator gene (AIRE). Terminal 4q deletion is also a rare cytogenetic abnormality that causes a variable syndrome of dysmorphic features, mental retardation, growth retardation, and heart and limb defects. We report a 12-year-old Saudi boy with mucocutaneous candidiasis, hypoparathyroidism, and adrenocortical failure consistent with APECED. In addition, he has dysmorphic facial features, growth retardation, and severe global developmental delay. Patient had late development of chronic renal failure. The blastogenesis revealed depressed lymphocytes' response toCandida albicansat 38% when compared to control. Chromosome analysis of the patient revealed 46,XY,del(4)(q33). FISH using a 4p/4q subtelomere DNA probe assay confirmed the deletion of qter subtelomere on chromosome 4. Parental chromosomes were normal. The deleted array was further defined using array CGH.AIREfull gene sequencing revealed a homozygous mutation namely 845_846insC. Renal biopsy revealed chronic interstitial nephritis with advanced fibrosis. In addition, there was mesangial deposition of C3, C1q, and IgM. This is, to the best of our knowledge, the first paper showing evidence of autoimmune nephropathy by renal immunofluorescence in a patient with APECED and terminal 4q deletion.

Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy

Context: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy is known as a rare hereditary disease with classic triad of mucocutaneous candidiasis, hypoparathyroidism, and adrenocortical failure, two of which, diagnostic dyad, are required for the diagnosis. Evidently many patients suffer unrecognized because the condition is more variable and complex. Objective: The objective of the study was to describe the variability of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy for promoting recognition and adequate follow-up of patients. Setting: The Finnish series of patients is the largest internationally. Patients: The study population was all 91 known Finnish patients. Results: Besides the classical triad, a dozen autoimmune endocrine and other components occurred variably, several of them dangerous. The initial manifestation appeared within the age range of 0.2–18 yr, mucocutaneous candidiasis being part of it in 60% of the patients, hypoparathyroidism in 32%, and adrenocortical failure in 5%. But 23% of the patients had one to six other components before the diagnostic dyad: hepatitis, keratoconjunctivitis, chronic diarrhea, periodic rash with fever. The dyad appeared 0.2–20 yr later. Prevalence of most components increased with age, diabetes mellitus, hypothyroidism, and testicular failure becoming common toward middle age. Tubulointerstitial nephritis occurred in 9% of the patients, apparent mineralocorticoid excess in 9%, asplenia in 19% of adults, and oral or esophageal squamous cell carcinoma in 10% of patients older than 25 yr. Conclusions: Any child or young adult with one of the many disease components should be examined for others and consideration of AIRE mutation assay.

Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy Syndrome with Renal Failure: Impact of Posttransplant Immunosuppression on Disease Activity

Context: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive disorder caused by mutations in the gene AIRE (autoimmune regulator). APECED affects mainly endocrine organs resulting in hypoparathyroidism, adrenocortical failure, diabetes mellitus, hypogonadism, and hypothyroidism. Nonendocrine organ manifestations are autoimmune hepatitis, vitiligo, pernicious anemia, exocrine pancreatic insufficiency, and alopecia. APECED’s first manifestation generally is mucocutaneous candidiasis presumably related to T cell dysfunction. Patient: A 5-yr-old Iranian girl presented first with pernicious anemia, exocrine pancreatic insufficiency, and nail candidiasis. She had renal dysfunction due to chronic interstitial nephritis (CIN), which progressed to end-stage renal failure. She was transplanted 1 yr later. Common causes of CIN were excluded. APECED was suspected first because she developed progressively hypoparathyroidism, adrenocortical failure, glucose intolerance, and hypothyroidism. Results: Genetic analysis revealed a large homozygous deletion (g.424_2157del1734), spanning exons 2–4, in the AIRE gene. The predicted protein, if it is produced, has only 44 amino acids (exon 1) in common with the wild-type protein. Immunosuppression after the first renal transplant included prednisone, azathioprine, and cyclosporine A. Multiple acute rejection episodes occurred. Chronic rejection resulted in lost graft and she was retransplanted 2 yr later. Surprisingly, all APECED-related symptoms including candidiasis and autoantibody levels decreased, presumably due to the reinforced immunosuppression (tacrolimus, mycophenolate mofetil, prednisone). Conclusions: This is the first report of an APECED patient with CIN resulting in end-stage renal failure. Clinical and biological improvement was observed under posttransplant multidrug immunosuppression including tacrolimus and mycophenolate mofetil.