Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines

Chronic mucocutaneous candidiasis (CMC) is frequently associated with T cell immunodeficiencies. Specifically, the proinflammatory IL-17A–producing Th17 subset is implicated in protection against fungi at epithelial surfaces. In autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED, or autoimmune polyendocrine syndrome 1), CMC is often the first sign, but the underlying immunodeficiency is a long-standing puzzle. In contrast, the subsequent endocrine features are clearly autoimmune, resulting from defects in thymic self-tolerance induction caused by mutations in the autoimmune regulator (AIRE). We report severely reduced IL-17F and IL-22 responses to both Candida albicans antigens and polyclonal stimulation in APECED patients with CMC. Surprisingly, these reductions are strongly associated with neutralizing autoantibodies to IL-17F and IL-22, whereas responses were normal and autoantibodies infrequent in APECED patients without CMC. Our multicenter survey revealed neutralizing autoantibodies against IL-17A (41%), IL-17F (75%), and/ or IL-22 (91%) in >150 APECED patients, especially those with CMC. We independently found autoantibodies against these Th17-produced cytokines in rare thymoma patients with CMC. The autoantibodies preceded the CMC in all informative cases. We conclude that IL-22 and IL-17F are key natural defenders against CMC and that the immunodeficiency underlying CMC in both patient groups has an autoimmune basis

An Update on Genetics of Adrenal Gland and Associated Disorders

The intricacies of human adrenal development have been under scrutiny for decades. Each year marks the identification of new genes and new interactions between gene products that ultimately will act to produce the fully functioning adult gland. Due to the complexity of this process, genetic missteps may lead to a constellation of pathologies. Recent years have identified several novel genetic causes of adrenal dysgenesis and provided new insights into previously delineated processes. SF1, DAX1 (NR0B1), CDKN1C, SAMD9, GLI3, TPIT, MC2R, MRAP, NNT, TXNRD2, AAAS, and MCM4 are among the genes which have had significant contributions to our understanding of the development and function of both adrenals and gonads. Collection and elucidation of these genetic and clinical insights are valuable tools for clinicians who diagnose and manage cases of adrenal dysfunction

An Update on Genetics of Adrenal Gland and Associated Disorders

The intricacies of human adrenal development have been under scrutiny for decades. Each year marks the identification of new genes and new interactions between gene products that ultimately will act to produce the fully functioning adult gland. Due to the complexity of this process, genetic missteps may lead to a constellation of pathologies. Recent years have identified several novel genetic causes of adrenal dysgenesis and provided new insights into previously delineated processes. SF1, DAX1 (NR0B1), CDKN1C, SAMD9, GLI3, TPIT, MC2R, MRAP, NNT, TXNRD2, AAAS, and MCM4 are among the genes which have had significant contributions to our understanding of the development and function of both adrenals and gonads. Collection and elucidation of these genetic and clinical insights are valuable tools for clinicians who diagnose and manage cases of adrenal dysfunction

Multiple Endocrine Neoplasia in Childhood: An Update on Diagnosis, Screening, Management and Treatment

Multiple endocrine neoplasia (MEN) is a group of heterogenous syndromes characterized by the occurrence of two or more endocrine gland tumors in a patient or related individuals in the same family. They are inherited in an autosomal dominant fashion and are highly penetrant. There are three types of MEN syndromes: MEN type 1 (MEN1), MEN type 2 (MEN2), and MEN type 4 (MEN4). MEN2 is further divided into MEN2A, MEN2B (formerly known MEN3), and familial medullary thyroid carcinoma (FMTC). Although MEN syndromes are rare, it is crucial to identify individuals at risk for potentially life-threatening neoplasias. This review article provides an update on each MEN syndrome, its genetics, diagnosis, and management in children

A Review of Prader–Willi Syndrome

Prader–Willi Syndrome (PWS, OMIM #176270) is a rare complex genetic disorder due to the loss of expression of paternally derived genes in the PWS critical region on chromosome 15q11-q13. It affects multiple neuroendocrine systems and may present failure to thrive in infancy, but then, hyperphagia and morbid obesity starting in early childhood became the hallmark of this condition. Short stature, hypogonadism, sleep abnormalities, intellectual disability, and behavioral disturbances highlight the main features of this syndrome. There have been a significant number of advances in our understanding of the genetic mechanisms underlying the disease, especially discoveries of MAGEL2, NDN, MKRN3, and SNORD116 genes in the pathophysiology of PWS. However, early diagnosis and difficulty in treating some of the disease’s most disabling features remain challenging. As our understanding of PWS continues to grow, so does the availability of new therapies and management strategies available to clinicians and families

A Review of Prader–Willi Syndrome

Prader–Willi Syndrome (PWS, OMIM #176270) is a rare complex genetic disorder due to the loss of expression of paternally derived genes in the PWS critical region on chromosome 15q11-q13. It affects multiple neuroendocrine systems and may present failure to thrive in infancy, but then, hyperphagia and morbid obesity starting in early childhood became the hallmark of this condition. Short stature, hypogonadism, sleep abnormalities, intellectual disability, and behavioral disturbances highlight the main features of this syndrome. There have been a significant number of advances in our understanding of the genetic mechanisms underlying the disease, especially discoveries of MAGEL2, NDN, MKRN3, and SNORD116 genes in the pathophysiology of PWS. However, early diagnosis and difficulty in treating some of the disease’s most disabling features remain challenging. As our understanding of PWS continues to grow, so does the availability of new therapies and management strategies available to clinicians and families

CYP11B1 gene mutations in patients congenital adrenal hyperplasia in Turkey

Background: Congenital adrenal hyperplasia (CAH) due to11b-hydroxylase deficiency (11OHD), a rare autosomal recessivedisorder, is the second most common form of CAH, resulting inglucocorticoid deficiency, hyperandrogenism and hypertension.Objective and hypotheses: To investigate the specific CAHmutations in CYP11B1 gene and to examine for genotypephenotypecorrelations. Method: 21 patients (nZ9, 46, XX;nZ12, 46, XY) with the classical 11OHD from 20 unrelatedTurkish families were included in this study. Diagnosis of 11OHDwas based on both clinical and hormonal criteria. Mutationscreening of CYP11B1 gene was performed using direct Sangersequencing analysis. Known mutations were confirmed bydatabase and literature search. Novel mutations were analyzedby in silico prediction tools (PolyPhen-2, SIFT and MutationTaster). Results: The age of diagnosis at onset ranged from 6 daysto 12.5 years. The rate of consanguinity was very high (75%). Fourout of nine 46, XX patients received a late diagnosis (age 2–8.7years) and were raised as males due to severe masculinization(Prader genital stages IV and V). Mutation analyses in 20 indexpatients revealed 12 different mutations in CYP11B1 gene. Thesemutations were homozygous (HM) p.L299P (30%, 6/20), HMp.R141X (10%, 2/20), HM c.954GOA (silence, cryptic splicing;10%, 2/20), HM IVS8C2TOC (novel splice-donor mutation, 5%,1/20), compound heterozygous (CHT)((p.L299P)C(IVS8C2TOC); 5%, 1/20), HM p.W116C (5%, 1/20), HM p.R384Q (5%, 1/20),HM p.R448C (5%, 1/20), HM c.1449_1451delGGT (5%, 1/20),CHT ((G393CAG)C(p.L299P)); 5%, 1/20), HMc.1179_1180dupGA (novel; 5%, 1/20) and HM p.R143P (novelmissense; 5%, 1/20). One patient had mutation in only one allele(p.T318M). There was no definitive correlation between genotypeand phenotype. Conclusion: In this study, three different novelmutations were detected and the p.L299P was found to be the mostcommon mutation. The results of the study might contribute tothe establishment of molecular screening strategies. Identificationof the disease causing mutations provides reliable information forgenetic counseling for the families

Interferon autoantibodies associated with AIRE deficiency decrease the expression of IFN-stimulated genes

Neutralizing autoantibodies to type I, but not type II, interferons (IFNs) are found at high titers in almost every patient with autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), a disease caused by AIRE gene mutations that lead to defects in thymic T-cell selection. Combining genome-wide expression array with real time RT-PCR assays, we here demonstrate that antibodies against IFN-α cause highly significant down-regulation of interferon-stimulated gene expression in cells from APECED patients' blood by blocking their highly dilute endogenous IFNs. This down-regulation was lost progressively as these APECED cells matured in cultures without neutralizing autoantibodies. Most interestingly, a rare APECED patient with autoantibodies to IFN-ω but not IFN-α showed a marked increase in expression of the same interferon-stimulated genes. We also report unexpected increases in serum CXCL10 levels in APECED. Our results argue that the breakdown of tolerance to IFNs in AIRE deficiency is associated with impaired responses to them in thymus, and highlight APECED as another autoimmune disease with associated dysregulation of IFN activity