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An Immune Defect Causing Dominant Chronic Mucocutaneous Candidiasis and Thyroid Disease Maps to Chromosome 2p in a Single Family
Abstract
We describe a large family in which a combination of chronic mucocutaneous candidiasis (fungal infections of the skin, nails, and mucous membranes) and thyroid disease segregate as an autosomal dominant trait with reduced penetrance. The family includes (a) four members with both candidiasis and thyroid disease, (b) five members, including one pair of phenotype-concordant MZ twins, with candidiasis only, and (c) three members with thyroid disease only. A whole-genome scan using DNA samples from 20 members of the family identified a candidate linkage region on chromosome 2p. By sampling additional individuals and genotyping supplementary markers, we established linkage to a region of approximately 15 cM bounded by D2S367 and D2S2240 and including seven adjacent markers consistent with linkage. With a penetrance estimate of.8, which was based on pedigree and affected status, the peak two-point LOD score was 3.70 with marker D2S2328, and the peak three-point LOD score was 3.82. This is the first linkage assignment of a dominant locus for mucocutaneous candidiasis.
... Also reported are the genomewide coverage and estimated genome scan resolution of the genotyped SNPs. As a demonstration of the utility of the genotyping platform in whole-genome scans, we have correctly replicated linkage on chromosome 2p for chronic mucocutaneous candidiasis and/or thyroid disease, previously identified using a panel of microsatellite (STR) markers (Atkinson et al. 2001). Figure 1 is a schematic of the one-primer amplification assay that reduces the complexity of the genome, and enables allele-specific hybridization. ...
... For comparison, panels of ∼400 STRs that are commonly used for genome-wide scans in linkage analysis have average intermarker distances of ∼10 cM (Dubovsky et al. 1995). Atkinson et al. (2001) identified a candidate linkage region on chromosome 2p using a 10-cM STR genome scan in a family with a combination of chronic mucocutaneous candidiasis and thyroid disease. Detailed information on this large nonconsanguineous family is given in that study (Atkinson et al. 2001). ...
... Atkinson et al. (2001) identified a candidate linkage region on chromosome 2p using a 10-cM STR genome scan in a family with a combination of chronic mucocutaneous candidiasis and thyroid disease. Detailed information on this large nonconsanguineous family is given in that study (Atkinson et al. 2001). We attempted to replicate this linkage result using our SNP genotyping method, and generated genotypes from 18 of the individuals in this family. ...
The analysis of single nucleotide polymorphisms (SNPs) is increasingly utilized to investigate the genetic causes of complex human diseases. Here we present a high-throughput genotyping platform that uses a one-primer assay to genotype over 10,000 SNPs per individual on a single oligonucleotide array. This approach uses restriction digestion to fractionate the genome, followed by amplification of a specific fractionated subset of the genome. The resulting reduction in genome complexity enables allele-specific hybridization to the array. The selection of SNPs was primarily determined by computer-predicted lengths of restriction fragments containing the SNPs, and was further driven by strict empirical measurements of accuracy, reproducibility, and average call rate, which we estimate to be >99.5%, >99.9%, and>95%, respectively [corrected]. With average heterozygosity of 0.38 and genome scan resolution of 0.31 cM, the SNP array is a viable alternative to panels of microsatellites (STRs). As a demonstration of the utility of the genotyping platform in whole-genome scans, we have replicated and refined a linkage region on chromosome 2p for chronic mucocutaneous candidiasis and thyroid disease, previously identified using a panel of microsatellite (STR) markers.
... Chronic mucocutaneous candidiasis (CMC) is a syndrome characterized by persistent or recurrent infections caused by Candida species involving the skin, nails and mucous membranes. Most cases of CMC are sporadic [1], secondary to other medical conditions, such as HIV infection, steroid administration, use of dentures or iron deficiency. Primary CMC has been reported to have a genetic basis (familial CMC), either autosomal dominant [2] or recessive [3]. ...
... Primary CMC has been reported to have a genetic basis (familial CMC), either autosomal dominant [2] or recessive [3]. CMC is often accompanied by endocrine or inflammatory disorders [1] with their associated morbidities. The association of CMC with squamous cell carcinoma of the oral cavity or oesophagus have been described in only three reports [4Á6]. ...
... CMC with thyroid disease. In this disorder, a combination of CMC (fungal infections of the skin, nails, and mucous membranes) and thyroid disease segregate as an autosomal dominant trait with reduced penetrance [1]. It is distinguished from APECED by the mode of inheritance and lack of associated multiple endocrinopathy. ...
Chronic mucocutaneous candidiasis (CMC) is often accompanied by endocrine or inflammatory disorders. The association of CMC with squamous cell carcinoma of the oral cavity or oesophagus have been described in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). We describe three cases of CMC and oesophageal cancer without the APECED syndrome. The first case refers to a 41-year-old man with Candida paronychia and oral infection and selective IgA deficiency since childhood, who later developed an oesophageal cancer. The second case is a 30-year-old man who presented CMC features at the age of 2 together with selective IgA deficiency. Later on he was diagnosed with an oesophageal squamous cell carcinoma. His mother, the third case reported, had oral thrush since childhood and at the age of 29 she presented with an oesophageal squamous cell carcinoma. The three patients reported died due to oesophageal cancer. This is the first case report describing the development of oesophageal cancer in patients with CMC without the APECED syndrome. Patients with CMC need close follow-up with good oral hygiene and aggressive treatment of oral and oesophageal candidiasis. Routine endoscopic screening for patients with CMC that develop symptoms of oesophageal candidiasis and for patients with CMC with a family history of oesophageal cancer is suggested. Avoidance of additional risk factors for oral and oesophageal cancer like cigarette smoking and excessive alcohol consumption are also warranted.
... Over the next 40 years, other sporadic and familial cases were reported [15,20- [15,34], dermatophytosis [25,26], bacterial infections of the respiratory tract and staphylococcal diseases of the skin [32,33,61] have been reported in a few patients. In addition, some patients with CMCD display thyroid autoimmunity [2,22,27,35,38,45,54,56 && ,57,58 & ]. Finally, CMCD is generally debilitating, but may also be life-threatening, due to the associated risks of oral or oesophageal squamous cell carcinoma [20,30,50,54,56 && ] and cerebral aneurysm [31,36,37,49,56 && ]. ...
... , recurrent herpes virus disease [59 &] or autoimmune diseases (e.g. thyroid autoimmunity), albeit less severe than that observed in APS-I patients[2,22,27,35,38,45,54,56 && ,57,58 & ]. The clinical boundaries of this entity have still not clearly been described in a large series of patients. ...
Purpose of review:
Chronic mucocutaneous candidiasis (CMC) is characterized by recurrent or persistent symptomatic infection of the nails, skin and mucosae mostly by Candida albicans. CMC is common in patients with profound primary T-cell immunodeficiency, who often display multiple infectious and autoimmune diseases. Patients with syndromic CMC, including autosomal dominant hyper IgE syndrome (AD-HIES) and autosomal recessive autoimmune polyendocrinopathy syndrome type I (APS-I), display fewer other infections. Patients with isolated CMC (CMCD) rarely display any other severe disease. We review here recent progress in the genetic dissection of these three types of inherited CMC.
Recent findings:
Low IL-17 T-cell proportions were reported in patients with AD-HIES bearing heterozygous STAT3 mutations, prone to CMC and staphylococcal diseases, and in a kindred with autosomal recessive CARD9 deficiency, prone to CMC and other fungal infections. High levels of neutralizing autoantibodies against IL-17 cytokines were documented in patients with APS-I presenting with CMC as their only infectious disease. The first three genetic causes of CMCD were then reported: autosomal recessive IL-17RA and autosomal dominant IL-17F deficiencies and autosomal dominant STAT1 gain-of-function, impairing IL-17-producing T-cell development.
Summary:
Inborn errors of human IL-17 immunity underlie CMC. Impaired IL-17 immunity may therefore account for CMC in other settings, including patients with acquired immunodeficiency.
... Most CMC types present an early age of onset and are associated with altered phagocytosis and chemotaxis. 1 To date, only two hereditary forms of CMC have been localised. The classical CMC (autoimmune polyendocrinopathy -candidiasis -ectodermal dystrophy, APECED; MIM *240300) caused by autosomal recessive mutations of the autoimmune regulator gene (AIRE) was mapped to chromosome 21q22.3, ...
... 2,3 while the autosomal dominant CMC, associated with thyroid disease, was assigned to chromosome 2p. 1 We previously reported a five-generation Italian family originating from a small village of Sicily, in which a distinct form of isolated familial chronic nail candidiasis is characterised by early onset infections restricted to the nails of the hands and feet, caused by different species of Candida, and associated with low serum concentration of intercellular adhesion molecule I (ICAM-1). 4 Here we describe the exclusion of linkage to 21q22.3 (APECED), 2p, and 19p13 (ICAM-1) loci. ...
Chronic mucocutaneous candidiases (CMC) are a group of rare disorders where an altered immune response against Candida leads to persistent and/or recurrent infections of the skin, nails, and mucous membranes. We analysed a five-generation Italian family with an isolated form of CMC, affecting nails only, in the presence of low serum concentration of intercellular adhesion molecule I (ICAM-1). We excluded linkage to candidate regions on chromosomes 2p (CMC with thyroid disease), 21q22.3 (APECED), and 19q13 (ICAM-1). We then carried out a genome-wide scan and assigned the CMC locus to a 19 cM pericentromeric region on chromosome 11.
... A whole genome scan, followed by fine-mapping in 34 family members identified a 15-cM region on chromosome 2p with a maximum LOD score of 3.8. 19 In contrast to cutaneous infections, which are heavily dependent on acquired immunity, innate immunity appears to be more important in determining disease outcome during invasive candidiasis. This dichotomy between the two major classes of infections is perhaps best exemplified by the prevalence of oropharyngeal candidiasis in HIV-positive and AIDS patients, who have suppressed T-cell function compared to the relative dearth of invasive infections in the same patients, who have relatively intact phagocytic function. ...
... 65 However, TXB mice developed no resistance to rechallenge. Even at the later stages of infection, when acquired immunity is expected to be operative (days [10][11][12][13][14][15][16][17][18][19][20][21], no demonstrable role was observed for T or B cells. 63 The major role of T cells in protection against systemic candidiasis appears to be in the development of resistance to reinfection after initial inoculation with a vaccine strain of C. albicans. ...
Systemic candidiasis is a significant cause of nosocomial infections and the mechanisms of defense against Candida albicans in humans remain poorly understood. Studies in animal models have demonstrated the importance of innate immunity in controlling the response to infection. Although Th1 cytokines have been shown to direct the overall outcome of infection, the precise role of the Th1/Th2 response and, more generally, the adaptive immune response as a whole, in systemic candidiasis, appears to apply mainly to the development of resistance to reinfection. A genetic approach to the identification of host factors regulating pathogenesis and susceptibility to C. albicans infection has been used in humans and in mouse models of infection. Mouse mutants bearing experimentally induced mutations in specific genes have provided a systematic tool for directly assessing the role of individual proteins in C. albicans susceptibility. Inbred mouse strains have been valuable in showcasing the spectrum of naturally occurring variations in initial susceptibility to infection, and type of disease developed. Crosses between resistant and susceptible strains have led to the detection of additional gene effects affecting innate immunity. Of particular interest is the major effect of a naturally occurring loss-of-function mutation in the C5 complement component that has become fixed in many inbred strains. These and other studies have shown that both a functional complement pathway and robust inflammatory response are critical for resistance to C. albicans.
... Wir stuften das Auftreten der Kandidose in beiden Geschwistern daher primär als eine Phänokopie ein. Diese Familie mit AD Vererbungsmuster der CMC wurde bereits 2001 in einem Fachartikel untersucht (Atkinson et al. 2001 ). Alternativ ist auch vorstellbar, dass aufgrund der im Alter zunehmenden Morbidität mildere Kandidose-Episoden der Patientin untergegangen sind oder nicht kritisch hinterfragt wurden. ...
Die Chronische Mukokutane Kandidose (CMC) ist charakterisiert durch chronische Kandida-Infektionen der Schleimhäute und Kutis. Die genetische Ursache bei CMC-Patienten mit autosomal-dominantem (AD) Erbgang ist nicht hinreichend geklärt. Funktionssteigernde bzw. gain-of-function (GOF)-Mutationen im Transkriptionsfaktor STAT1 scheinen hierbei eine große Rolle zu spielen. Im Rahmen dieser Arbeit wurde eine Kohorte, bestehend aus 44 familiären und 18 sporadischen CMC-Patienten, auf STAT1-Mutationen hin untersucht und diese funktionell evaluiert. Außerdem sollte der STAT1-CMC-Phänotyp systematisch erfasst und beschrieben werden.
Die genomische DNA der 62 CMC-Patienten (und von 43 gesunden Angehörigen) wurde exonweise sequenziert. Die funktionellen Auswirkungen von 7 STAT1-Mutationen auf die STAT1-Phosphorylierung wurden mittels FACS und ELISA in T-Zelllinien und Patienten-PBMC evaluiert. Klinische Daten wurden über einen standardisierter Fragebogen erhoben.
Insgesamt identifizierten wir 14 verschiedene, heterozygote STAT1-Mutationen. Etwas mehr als die Hälfte aller CMC-Patienten trug eine STAT1-Mutation (63 %), wobei ca. 80 % der Familien eine Mutation vererbten. Auf funktioneller Ebene fanden sich in den ELISA bei 2 Mutationen Charakteristika einer Hyperphosphorylierung, mittels FACS bei 5 Mutationen. Nach Auswertung von 26 Fragebögen war der STAT1-CMC-Phänotyp heterogener als erwartet. Neben Kandidosen litten viele Patienten auch an bakteriellen und viralen Infektionen in der Vorgeschichte, sowie an Autoimmunerkrankungen, darunter am häufigsten an einer Hypothyreose.
STAT1-GOF-Mutationen sind damit bei über der Hälfte AD-CMC-Fälle ursächlich für die Erkrankung. Weitere Untersuchungen werden benötigt, um den Zusammenhang zwischen der Überaktivität des Transkriptionsfaktors STAT1 und der darauf folgenden Signalachsen-Dysbalance besser zu verstehen. In Anbetracht des heterogenen klinischen Bildes der GOF-STAT1-Mutationen sollte auch dann an diese Mutationsform gedacht werden, wenn eine Kandidose nicht alleinig das Krankheitsbild dominiert.
... U tych pacjentów, w obrębie genu CARD9, dochodzi do mutacji zerowej w obrębie kodonu kodującego aminokwas 295 (Q295X), która skutkuje przedwczesną ciężkie zakażenia bakteryjne, należy zawsze wykonać bardziej szczegółowe badania celem dokładnego określenia typu niedoboru. Badania genetyczne wykazały związek między kandydozą i zapaleniem tarczycy, a chromosomem 2 oraz między kandydozą związaną z niskim poziomem ekspresji ICAM-1 na chromosomie 11, jednak nie zidentyfikowano odpowiedzialnego za to genu [4,69]. Badania genetyczne i funkcjonalne różnych przypadków CMC, wykazały mutację, upośledzającą zdolność układu odpornościowego do kontrolowania Tabela 3. Drobnoustroje powodujące zakażenia u ludzi z niedoborami immunologicznymi różnego rodzaju [27,32,68,75,81,110] Typ niedoboru Drobnoustroje 28]. ...
Primary immunodeficiency diseases (PIDs) are genetic based disorders which lead to the dysfunction of the immune system. There are persistent and recurrent infections within PID patient due to cellular and humoral immunity impairment. The most common infections are caused by Salmonella Enteritidis, Shigella flexneri, Mycobacterium avium complex, Toxoplasma gondii, CMV, Candida albicans, Cryptococcus neoformans or Pneumocystis jiroveci. These infections have a severe course of disease with limited treatment in a conventional way. Full patient recovery after intensive and long-term therapy is often impossible. Viral infections in PID patients are equally frequent. The incidences of Herpesviridae and HCV infections are the same for PID patients and healthy people. However, the infections may have worse course of disease and leave more destruction in the body. Enteroviral infections occur despite the antibodies supplementation; they spread spontaneously throughout the body, also affecting the central nervous system. Skin, nails and mucous membranes infections are equally persistent problems caused by fungi, mainly Candida genus. Infections with these pathogens are often accompanied by hormonal disorders and immunosuppressive therapy. Sepsis and mixed infections are definitely the most dangerous for patients with infections. Infections occur most often in the first years of the child’s life, when the body has not developed yet a fully functioning immunity system. The diagnosis of PNO in infants may be difficult due to the presence of antibodies from mother and the similarity of the symptoms of infectious diseases and common infections.
... type 1(Atkinson et al., 2001). It is unclear whether CMCD, with these or other manifestations(Shama and Kirkpatrick, 1980;Bentur et al., 1991;Germain et al., 1994), is immunologically and genetically related to pure CMCD. ...
My project consists in the molecular and immunological identification and characterization of patients with increased susceptibility to fungal infections with Candida sp. suffering from the Mendelian syndrome of chronic mucocutaneous candidiasis (CMC).CMC is characterized by persistent or recurrent infections of the skin, nails and mucosae by Candida fungi, especially C. albicans. CMC is frequently associated with other opportunistic infections in some acquired or primary immunodeficiencies, or can be associated with autoimmune disorders. Finally, CMC may be present as an isolated form (chronic mucocutaneous candidiasis disease or CMCD) without any other severe infectious or autoimmune clinical manifestation: most reported cases are sporadic, but there are also familial cases with autosomal dominant (AD) or recessive (AR) Mendelian inheritance.Based the literature, which demonstrated a major role of IL-17 cytokines in mucocutaneous immunity with C. albicans, and our recent results, which show an impairment of IL-17 immunity in some primary immunodeficiencies associated with CMC (AD-HIES syndrome, AR APS-1, and CARD9-deficient patients), we hypothesized that among CMCD patients, some might have a genetic defect affecting specifically the IL-17-dependent immunity.At the beginning of my PhD, I participated in the identification of the first two genetic etiologies of CMCD: complete AR IL-17RA and partial AD IL-17F deficiencies. More recently, I identified the third and most common genetic etiology of CMCD by identifying gain of function mutations in the STAT1 gene following an approach exploring the whole genome (sequencing of all exons). These mutations are responsible for a "hyper-response" to type I and II interferons and IL-27, which inhibit the differentiation of IL-17-producing T cells. Impaired IL-17 immunity results in reduced mucocutaneous defenses against C. albicans in humans. In conclusion, we have identified in 2011, the first three genetic etiologies of CMCD with AR IL-17RA and AD IL-17F deficiencies and gain-of-function STAT1 mutations, all associated with an impaired IL-17-dependent immunity. Gain-of-function STAT1 mutations represent the most frequent genetic cause of CMCD with a total of 94 patients reported in the literature since 2011. We have shown that CMCD is a primary immunodeficiency associated with inborn errors of IL-17 immunity. This work has important implications in the field of immunology with the description and characterization of the biological mechanisms involved in protective immunity specific to C. albicans and a better understanding of the pathophysiological mechanisms associated with increased susceptibility to fungal infections in natural conditions of infection, and in the medical field, with the possibility of molecular diagnostics, genetic counseling for a positive diagnosis, and a better follow-up of the patients.
... Patients genetically prone to CMC but normally resistant to most other infections are considered to have CMC disease (CMCD) (Canales et al., 1969;Kirkpatrick et al., 1971;Wells, 1970;Wells et al., 1972). The phenotype is not strictly limited to CMC, because these patients often display other infections, such as staphylococcal cutaneous disease, and even autoimmune manifestations, such as thyroiditis (Atkinson et al., 2001;Liu et al., 2011b). Moreover, this condition is not benign, because the patients can develop mucocutaneous carcinomas and cerebral aneurysms (Leroy et al., 1989;Williamson, 1969). ...
Patients with inborn errors of interleukin-17F (IL-17F) or IL-17RA display chronic mucocutaneous candidiasis (CMC). We report a biallelic missense mutation (T536I) in the adaptor molecule ACT1 in two siblings with CMC. The mutation, located in the SEFIR domain, abolished the homotypic interaction of ACT1 with IL-17 receptors, with no effect on homodimerization. The patients' fibroblasts failed to respond to IL-17A and IL-17F, and their T cells to IL-17E. By contrast, healthy individuals homozygous for the common variant D10N, located in the ACT1 tumor necrosis factor receptor-associated factor-interacting domain and previously associated with psoriasis, had impaired, but not abolished, responses to IL-17 cytokines. SEFIR-independent interactions of ACT1 with other proteins, such as CD40, heat shock protein 70 (HSP70) and HSP90, were not affected by the T536I mutation. Overall, human IL-17A and IL-17F depend on ACT1 to mediate protective mucocutaneous immunity. Moreover, other ACT1-dependent IL-17 cytokines seem to be largely redundant in host defense.
... CMC also develops in about 25% of patients with IL-12p40 and IL-12Rβ1 deficiencies [40]; some of these patients have low proportions of T cells that produce IL-17 and IL-22, so they secrete low amounts of IL-17 and IL-22, likely because of impaired IL-23 responses [91]. Syndromes of CMC with genetic causes not yet defined include autosomal dominant CMC with hypothyroidism and autosomal dominant chronic isolated nail candidiasis [92,93]. An association was described between CMC and the protein tyrosine phosphatase nonreceptor 22, 1858 T, a variant of the lymphoid protein tyrosine phosphatase R620W [94]. ...
Most fungal infections in humans occur in the setting of iatrogenic immunosuppression or HIV infection. In the absence of these factors, fungi cause mild, self-limited infections that typically involve mucocutaneous surfaces. Hence, when persistent or recurrent mucocutaneous infections (chronic mucocutaneous candidiasis [CMC]) or invasive fungal infections (IFIs) develop in a "normal" host, they are indicative of genetic defects causing innate or adaptive immune dysfunction. In this review, recent developments concerning genetic and immunologic factors that affect the risk for IFIs and CMC are critically discussed.
... In our patient also granuloma candidamyceticum was diagnosed during childhood, but then it was not accompanied by internal organ failure. Atkinson et al. [7] described a family with a combination of CMC and thyroid disease, segregating as an autosomal dominant trait with reduced penetrance. In our patient genetic tests were not performed; however, based on the medical history a genetic background may be excluded. ...
Chronic mucocutaneous candidiasis (CMC) is characterized by Candida infection of the mucous membrane, scalp, skin and nails. We present a case of a 42-year-old man who was treated twice in the Dermatological Department. He was admitted the first time as a 7-year-old boy because of skin and mucosal lesions and then the diagnosis of granuloma candidamyceticum was established. Thirty-one years later he was admitted again with a history of facial skin lesions and blepharitis. For a couple of years he had suffered from diabetes and hypothyroidism. The diagnosis of CMC with endocrinopathy was established in our patient.
... type 1 (Atkinson et al., 2001 ...
Chronic mucocutaneous candidiasis disease (CMCD) may be caused by autosomal dominant (AD) IL-17F deficiency or autosomal recessive (AR) IL-17RA deficiency. Here, using whole-exome sequencing, we identified heterozygous germline mutations in STAT1 in 47 patients from 20 kindreds with AD CMCD. Previously described heterozygous STAT1 mutant alleles are loss-of-function and cause AD predisposition to mycobacterial disease caused by impaired STAT1-dependent cellular responses to IFN-γ. Other loss-of-function STAT1 alleles cause AR predisposition to intracellular bacterial and viral diseases, caused by impaired STAT1-dependent responses to IFN-α/β, IFN-γ, IFN-λ, and IL-27. In contrast, the 12 AD CMCD-inducing STAT1 mutant alleles described here are gain-of-function and increase STAT1-dependent cellular responses to these cytokines, and to cytokines that predominantly activate STAT3, such as IL-6 and IL-21. All of these mutations affect the coiled-coil domain and impair the nuclear dephosphorylation of activated STAT1, accounting for their gain-of-function and dominance. Stronger cellular responses to the STAT1-dependent IL-17 inhibitors IFN-α/β, IFN-γ, and IL-27, and stronger STAT1 activation in response to the STAT3-dependent IL-17 inducers IL-6 and IL-21, hinder the development of T cells producing IL-17A, IL-17F, and IL-22. Gain-of-function STAT1 alleles therefore cause AD CMCD by impairing IL-17 immunity.
... Another form of CMC associated with hypothyroidism, apparently with AD inheritance, has been mapped to APECED * This autoantigen has not been unequivocally proven in APECED [57] chromosome 2q (OMIM 606415) [67]. None of the other variants of CMC has been molecularly defined [68,69], and are lumped into the category of chronic and recurrent mucocutaneous infections by Candida species [33]. ...
Background:
Several primary immune deficiency disorders are associated with autoimmunity and malignancy, suggesting a state of immune dysregulation. The concept of immune dysregulation as a direct cause of autoimmunity in primary immune deficiency disorders (PIDDs) has been strengthened by the recent discovery of distinct clinical entities linked to single-gene defects resulting in multiple autoimmune phenomena including immune dysregulation, polyendocrinopathy, enteropathy and X-linked (IPEX) syndrome, and autoimmune polyendocrinopathy, candidiasis and ectodermal dystrophy (APECED) syndrome.
Conclusion:
Reviewing recent advances in our understanding of the small subgroup of PIDD patients with defined causes for autoimmunity may lead to the development of more effective treatment strategies for idiopathic human autoimmune diseases.
... CMC may also strike patients not prone to invasive candidiasis and normally resistant to most other infectious agents, including other fungi. Such patients include those with autoimmune polyendocrine type I syndrome (APS-I, also known as autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy, APECED) [17] and patients with CMC and thyroid diseases [18]. APS-I results from autosomal recessive mutations in the autoimmune regulator gene AIRE [19]. ...
The various clinical manifestations of chronic mucocutaneous candidiasis (CMC) often result from acquired T-cell immunodeficiencies. More rarely, CMC results from inborn errors of immunity, the recent dissection of which has shed light on the molecular mechanisms of mucocutaneous immunity to Candida albicans. CMC may accompany various other infectious diseases in patients with almost any broad and profound T-cell primary immunodeficiency. By contrast, CMC is one of the few key infections in patients with autosomal dominant hyper IgE syndrome (mutations in STAT3), and in rare patients with autosomal recessive predisposition to mucocutaneous and invasive fungal infections (mutation in CARD9). In patients with mutations in STAT3 and CARD9, the development of IL-17-producing T cells is impaired. Moreover, CMC is the principal, if not only, infection in patients with autosomal recessive autoimmune polyendocrinopathy syndrome-I (mutations in AIRE). Patients with this condition have high titers of neutralizing autoantibodies (auto-Abs) against the IL-17 cytokines IL-17A, IL-17F, and IL-22. Collectively, these data suggest that human IL-17A, IL-17F, and IL-22 are essential for mucocutaneous immunity to C. albicans. They also suggest that the distinct syndrome of isolated CMC, without auto-immunity or other infections, may be caused by inborn errors of IL-17 immunity.
... U tome zasigurno imaju svoju ulogu i nasljedni čimbenici. Istraživanja su utvrdila da kod nasljedne kronične mukokutane kandidoze, napose u jednojajčanih blizanaca, postoji i veća sklonost infekciji dermatofitima uz različite endokrine poremećaje 18 . Smatra se da je u sprječavanju nastanka dermatomikoza od najveće važnosti imunološki status medicina 2008, Vol. ...
ABSTRACT. The incidence of cutaneous fungal diseases is constantly increasing. In this review we present the most important factors which influence the manifestation and spreading of fungal infections, based on our previous research and data from current literature. The diversity in clinical presentation and damage of various organs is the consequence of biological characteristics of fungi and humans. We give an overview of the most significant features of fungi as infectious agents, as well as the impact of environmental factors such as clothing and the use of shoes, factors related to the host including other diseases and impaired immunological status in the pathogenesis of fungal infections. We also discuss how the advances in medicine and development of pharmaceutical industry contribute to the incidence of cutaneous fungal diseases and the role of antibiotics, corticosteroids and immunosuppressive agents have in the etiology of fungal infections.
... In this group, mutations in the AIRE gene (autoimmune regulator) have been identified [1]. An autosomal dominant form of CMC is associated with hypothyroidism, and a genetic defect has been suggested for chromosome 2p [2]. Genetic defects for other variants of CMC have not been reported. ...
Chronic mucocutaneous candidiasis (CMC) is a rare disease associated with immunodeficiency and characterized by persistent and refractory infections of the skin, appendages and mucous membranes caused by members of the genus Candida. Several different disorders are classified under this common denominator, including chronic and recurrent mucocutaneous infections due to Candida spp., which are sometimes linked to autoimmune endocrinopathies. These fungal infections are usually confined to the mucocutaneous surface, with little propensity for systemic disease or septicemia. We describe a patient with CMC who had an esophageal candidiasis refractory to treatment for decades and who developed an epidermoid esophageal cancer. No risk factors such as familiar susceptibility, smoking, alcohol drinking, or living in an endemic area were verified. This case report suggests the participation of nitrosamine compounds produced by chronic Candida infections as a risk factor for esophageal cancer in a patient with autosomal-dominant chronic mucocutaneous candidiasis.
... Finally, one the most anciently described immune deficiencies, chronic mucocutaneous candidiasis, represents an unique model of inherited susceptibility to a given microorganism. An associated locus has recently been mapped to chromosome 2 [24]. Identification of the related gene product will attract much attention to studying immunity to fungi infections. ...
... The link between the identified gene defect and the inability to clear Candida remains unknown. Other forms of CMC are also recognized (16); these forms include CMC with thyroid disease and dominant inheritance, for which the immune defect has been mapped to chromosome 2p (2), as well as CMC without endocrinopathy, for which no gene defect has been identified yet. ...
Patients with chronic mucocutaneous candidiasis (CMC) are selectively unable to clear the yeast Candida, which results in persistent debilitating infections affecting the skin, nails, and mucous membranes. The underlying defect
is unknown. Recent animal studies highlighted the importance of type 1 cytokines in protection against Candida, and previous work suggested that CMC patients may exhibit altered cytokine production in response to Candida. Based on these findings, in this study we investigated cytokine production in CMC patients by assessing a range of inflammatory,
anti-inflammatory, type 1, and type 2 cytokines (interleukin-2 [IL-2], IL-4, IL-5, IL-6, IL-10, IL-12, gamma interferon [IFN-γ],
tumor necrosis factor alpha [TNF-α]) in whole-blood cultures in response to five different fractions of Candida albicans (carbohydrate, purified mannan, and protein-rich fractions, etc.), as well as non-Candida antigens. Our results demonstrate that cytokine production is deregulated in a Candida-specific way for some cytokines (IL-2, IL-10), is deregulated more generally for other cytokines (IL-12, IL-6, IFN-γ), and
is not markedly altered for still other cytokines (TNF-α, IL-4, IL-5). The most notable finding in CMC patients was the markedly
impaired production of IL-12 in parallel with dramatically increased levels of IL-6 and IL-10 that occurred selectively in
response to Candida. These results suggest that patients with CMC have impaired production of type 1-inducing cytokines (possibly a macrophage
or dendritic cell defect?), which could result in an inability to mount protective cell-mediated responses and a failure to
clear Candida. Continued tissue damage and inflammation may trigger production of high levels of inhibitory cytokines, such as the IL-10
production seen in our study, which would further reduce production of type 1-inducing cytokines in a positive feedback loop
leading to persistent infection.
... In conclusion, no available data, either experimental or based on sequence conservation, suggest a possible function for the protein. The human homologue of MidA, PRO1853, is located between the polymorphic markers D2S1788 and D2S2328 that have been linked to an autosomal dominant form of chronic mucocutaneous candidiasis associated with thyroid disease (Atkinson et al., 2001). Highly similar proteins to the Dictyostelium MidA can also be recognized in other organisms (Table 2). ...
Genomic sequencing has revealed a large number of evolutionary conserved genes of unknown function. In the absence of characterized functional domains, the discovery of the role of these genes must rely on experimental approaches. We have selected 30 Dictyostelium discoideum genes of unknown function that showed high similarity to uncharacterized human genes and were absent in the complete proteomes from Saccharomyces cerevisiae and S. pombe. No putative functional motifs were found in their predicted encoded proteins. Eighteen genes were successfully knocked-out and three of them showed obvious phenotypes. A detailed analysis of one of them, midA, is presented in this report. Disruption of midA in Dictyostelium leads to pleiotropic defects. Cell size, growth rate, phagocytosis and macropinocytosis were affected in the mutant. During development, midA- cells showed an enhanced tendency to remain at the slug stage, and spore viability was compromised. The expression of MidA fused to GFP in midA- strain rescued the phenotype and the fused protein was located in the mitochondria. Although cellular oxygen consumption, mitochondrial content and mitochondrial membrane potential were similar to wild type, the amount of ATP was significantly reduced in the mutant suggesting a mitochondrial dysfunction. Metabolomic analysis by natural-abundance 13C-nuclear magnetic resonance has shown the lack of glycogen accumulation during growth. During starvation, mutant cells accumulated higher levels of ammonia, which inhibited normal development. We hypothesize that the lack of MidA reduces mitochondrial ATP synthetic capacity and this has an impact in some but not all energy-dependent cellular processes. This work exemplifies the potential of Dictyostelium as a model system for functional genomic studies.
... Such patients typically develop hypoparathyroidism and adrenal failure and thyroid disease is not a major feature. Atkinson et al. 16 have described a large family with an autosomal dominant form of CMC associated with hypothyroidism and with a gene defect localised to chromosome 2p. Interestingly in this family the most consistent immunological feature was a depressed serum IgM concentration, although there were also significant aberrant T-cell responses. ...
Chronic mucocutaneous candidiasis (CMC) refers to a group of disorders which have in common recurrent and persistent infections of the skin, nails and mucous membranes by Candida albicans and occasionally other candida species. A proportion of these patients show an associated endocrinopathy as part of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome. Many cases, however, are not associated with endocrinopathy and demonstrate a variety of T-cell or antigen-presenting cell defects leading to abnormal cell-mediated responses to C. albicans.
... Chronic mucocutaneous candidiasis (CMC) is a rare, complex, and heterogeneous group of syndromes characterized by persistent or recurrent infections of skin, nails, and mucosal tissues with the ubiquitous, opportunistic yeast Candida albicans (Kirkpatrick, 2001). The underlying defect may be a primary immune defect, as it is the case in the recently described subgroup ''Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy'' (APECED) , or in a form of dominant inherited CMC with malfunction of the thyroid gland (Atkinson et al., 2001). However, the link between these mutations and the immune defect(s) remains unclear. ...
Chronic mucocutaneous candidiasis (CMC) constitutes a selective inability to clear infection with the yeast Candida, resulting in persistent debilitating inflammation of skin, nails, and mucous membranes. The underlying defect is unknown. Only recently, IL-17-producing T cells have been reported to be involved in clearing Candida infections. In order to characterize T cellular immune response to Candida, we analyzed T-cell cytokine secretion to Candida antigen and mitogenic stimuli in CMC patients, immunocompetent patients suffering from acute Candida infection, and healthy volunteers. Peripheral blood mononuclear cells (PBMCs) from CMC patients produced significantly lower amounts of IL-17 and IL-22 mRNA and protein when stimulated with Candida albicans or mitogen in vitro compared with that in matched healthy individuals. Additionally, PBMCs from immunocompetent Candida-infected patients secreted more IL-17 and IL-22 than those of both CMC patients and healthy, non-infected controls. Flow cytometry revealed a decreased number of CCR6+ IL-17-producing T cells in CMC patients, whereas the amount of CCR6+/CCR4+ cells was not altered. Levels of differentiating cytokines for human Th17 cells, IL-1beta and IL-6, tended to be higher in CMC patients. The inability to clear C. albicans in CMC patients could be due to a defect in the immune response of IL-17-producing T cells.
Superficial and cutaneous mycosesSubcutaneous mycosesSystemic mycosesGlossary
Chronic mucocutaneous candidiasis is characterized by infections caused by Candida sp, usually Candida albicans, which may be persistent or recurrent on skin, mucous membranes and nails; generally confined on the cutaneous surface and occasionally systemic dissemination. This can be associated to endocrinopathies and autoimmunity. We report a case of chronic mucocutaneous candidiasis with thyroid disease resilient to itraconazole with positive response to voriconazole and immunostimulation.
Chronic mucocutaneous candidiasis (CMCC) is a complex group of disorder characterized by chronic and recurrent Candida infections of the skin, nail and oropharynx. The classification of CMCC varies but is commonly based on the clinical feature, existence of an endocrinopathy, and the pattern of inheritance, which can be either autosomal dominant or recessive. We herein report a rare case of familial CMCC. A family of a 42-year-old woman and her 17- and 12-year-old daughters commonly presented with a recurrent whitish plaque in the oral cavity for several years, and the mother and her 9-year-old son also had presented with dystrophic nails. They had no evidence of concomitant immunodeficiency or endocrinopathy. Candida albicans was commonly isolated from the oral lesion of the mother and two daughters. They were successfully managed with intermittent oral antifungal treatment.
DNA repair mechanisms are critical for immune system maturation. In the absence of genomic stability, not only lymphocyte maturation is imperfect, but other system anomalies and malfunctions would also appear. These include neurodegeneration, growth retardation and cancer predisposition. Di George syndrome is caused by chromosomal deletions on 22q11. The patients do not develop thymus normally and lack parathyroide glands. Cellular immunodeficiency is accompanied by congenital anomalies and hypocalcemia. Wiskott-Aldrich syndrome is an X-linked disorder due to a defective cytoskeleton. The patients are characterized by persistent thrombocytopenia with small platelets, eczema, cellular and humoral immunodeficiency, and autoimmunity. Hyper-IgE syndrome is a human disease of improper cytokine signaling with recurrent skin abscesses, pneumonia and elevated levels of IgE in serum. The syndrome includes other organ defects such as skeletal deformities. Immuno-osseous dysplasias are characterized by association of immunodeficiency and skeletal problems. These patients have variable defects in both humoral and cellular immunity. Chronic mucocutaneous candidiasis is a primary susceptibility to fungal infections and could be inherited in an autosomal dominant or recessive mode. Recurring infections of the skin and mucous membranes with yeasts, mostly Candida albicans, is the common feature. Netherton syndrome is characterized by trichorrhexis invaginata, atopic dermatitis and eczema, high levels of IgE, angioedema, and immunodeficiency. Hoyeraal-Hreidarsson syndrome is characterized by cerebellar hypoplasia, psychomotor retardation, microcephaly, growth failure, and progressive pancytopenia.
Purpose:
Gain-of-function (GOF) mutations in the signal transducer and activator of transcription 1 (STAT1) result in unbalanced STAT signaling and cause immune dysregulation and immunodeficiency. The latter is often characterized by the susceptibility to recurrent Candida infections, resulting in the clinical picture of chronic mucocutaneous candidiasis (CMC). This study aims to assess the frequency of GOF STAT1 mutations in a large international cohort of CMC patients.
Methods:
STAT1 was sequenced in genomic DNA from 57 CMC patients and 35 healthy family members. The functional relevance of nine different STAT1 variants was shown by flow cytometric analysis of STAT1 phosphorylation in patients' peripheral blood cells (PBMC) after stimulation with interferon (IFN)-α, IFN-γ or interleukin-27 respectively. Extended clinical data sets were collected and summarized for 26 patients.
Results:
Heterozygous mutations within STAT1 were identified in 35 of 57 CMC patients (61 %). Out of 39 familial cases from 11 families, 26 patients (67 %) from 9 families and out of 18 sporadic cases, 9 patients (50 %) were shown to have heterozygous mutations within STAT1. Thirteen distinct STAT1 mutations are reported in this paper. Eight of these mutations are known to cause CMC (p.M202V, p.A267V, p.R274W, p.R274Q, p.T385M, p.K388E, p.N397D, and p.F404Y). However, five STAT1 variants (p.F172L, p.Y287D, p.P293S, p.T385K and p.S466R) have not been reported before in CMC patients.
Conclusion:
STAT1 mutations are frequently observed in patients suffering from CMC. Thus, sequence analysis of STAT1 in CMC patients is advised. Measurement of IFN- or IL-induced STAT1 phosphorylation in PBMC provides a fast and reliable diagnostic tool and should be carried out in addition to genetic testing.
Traumatic brain injury can cause endocrine dysfunction, particularly in the pituitary and thyroid. Onychomycosis is a frequent fungal disorder of nails and toes in normal adults and can be associated with hypothyroidism. We present a 35 years old, Chinese male who was affected by onychomycosis, hypothyroidism, and severe traumatic brain injury (TBI). Onychomycosis was present before TBI in one finger only but deteriorated during the acute stage of TBI, and improved significantly only after the introduction of thyroid treatment.
This chapter deals with the yeast Candida,one of the increasingly important human pathogens, and addresses multiple factors that result in either immunity to or infection
with this micro-organism. Factors contributing to the pathogenicity, antigenicity and type of infections caused by the genus
Candidaand its’ species are discussed. An overview of immunity to Candidaincludes previous and recent data on innate and adaptive immune responses, focusing on recognition and sensing of Candidavia pattern recognition receptors (Toll-like receptors, Dectin-1) and their role in directing the ensuing cascade of cytokine
production, that leads to protective or non-protective immunity mediated by cellular and humoral adaptive immune responses.
The disease Chronic Mucocutaneous Candidiasis (CMC), which includes a subgroup of patients with the APECED syndrome (Autoimmune
PolyEndocrinopathy Candidasis Ectodermal Dystrophy), where patients show a selective susceptibility to infections with Candida,is discussed in detail. The role of cell-mediated and humoral immunity in impaired protection against Candidais presented, as well as recent data demonstrating dysregulated cytokine production in response to Candida,which is suggested could be the underlying immune defect in these patients. The importance of CMC as a non-conventional primary
immune deficiency, manifesting as narrow susceptibility to infection with weakly pathogenic microbes is stressed, given that
these unique human “models” have the potential of hugely increasing our understanding of basic immune mechanisms involved
in protection against Candidaand other fungi
Dermatophytes are exogenous pathogens that cause common superficial infections of the skin and keratinized structures arising
from it, such as the hair and nails, known as tinea or dermatophytosis. While there are some fungi such as the lipophilic
yeasts or Malassezia species that are part of the normal flora of the skin, dermatophytes are acquired from an external source. Dermatophytes
are mould fungi which evolved from soil dwelling organisms, the keratinophilic fungi, that adapted to live in an environment
where there was shed hair or skin, e.g. in the vicinity of animal homes or burrows. They adapted to invade keratin on living
hosts and to cause infections on animals or humans. Dermatophytes are therefore known as geophilic, zoophilic, or anthropophilic
depending on whether they originate from soil, animals, or humans, respectively.
Chronic mucocutaneous candidiasis (CMC) is characterized by susceptibility to Candida infection of skin, nails, and mucous membranes. Autoimmune endocrinopathies are common in CMC patients, but there are no
reports of the involvement of systemic autoimmune disorders. We present here the first case of this kind of association in
a patient with an autosomal dominant variant of CMC. The individual had had this disorder since childhood and systemic lupus
erythematosus with secondary antiphospholipid syndrome, as well as renal, articular and hepatic manifestations without thymoma.
To give an overview on the clinical spectrum and the molecular background of host defence against Candida.
For many decades the molecular causes and the pathogenesis for an increased susceptibility to Candida - and fungal infections in general - have been elusive. In 2009 and 2010 interesting reports on the genetic background and the pathomechanisms involved in chronic mucocutaneous candidiasis (CMC) have been published.
The susceptibility to recurrent Candida infections can be a monogenetic Mendelian trait. The sensing of Candida cell wall components and the consecutive intracellular signalling in myeloid cells via CARD9, but also the role of Th17 cells and their cytokines take centre stage in the human host defence against Candida.
Chronic mucocutaneous candidiasis (CMC) defines a heterogeneous group of orphan and inherited syndromes characterised by chronic and recurrent infections of the skin and mucosa with the yeast Candida. Increasing evidence suggests that this inefficient defence against Candida species is reflected by a DC/T cell defect which results in an impaired Th17 and Th1 immune response and, consecutively, a failed immune instruction of tissue cells. Little is known about the incidence and prognosis of CMC. Clinically, the main complications are debilitating hands (Candida granuloma) and oesophageal stricture with potential mal-digestion/-absorption. Furthermore, the chronic infections are likely a risk factor for the development of squamous cell carcinoma. Since resistance to anti-mycotic drugs evolves rapidly, efficient and flexible therapeutic management is essential for CMC patients.
Chronic mucocutaneous candidiasis may be manifested as a primary immunodeficiency characterized by persistent or recurrent infections of the mucosa or the skin with candida species. Most cases are sporadic, but both autosomal dominant inheritance and autosomal recessive inheritance have been described.
We performed genetic studies in 36 members of a large, consanguineous five-generation family, in which 4 members had recurrent fungal infections and an additional 3 members died during adolescence, 2 after invasive infection of the brain with candida species. All 36 family members were enrolled in the study, and 22 had blood samples taken for DNA analysis. Homozygosity mapping was used to locate the mutated gene. In the 4 affected family members (patients) and the 18 unaffected members we sequenced CARD9, the gene encoding the caspase recruitment domain-containing protein 9, carried out T-cell phenotyping, and performed functional studies, with the use of either leukocytes from the patients or a reconstituted murine model of the genetic defect.
We found linkage (lod score, 3.6) to a genomic interval on chromosome 9q, including CARD9. All four patients had a homozygous point mutation in CARD9, resulting in a premature termination codon (Q295X). Healthy family members had wild-type expression of the CARD9 protein; the four patients lacked wild-type expression, which was associated with low numbers of Th17 cells (helper T cells producing interleukin-17). Functional studies based on genetic reconstitution of myeloid cells from Card9(-/-) mice showed that the Q295X mutation impairs innate signaling from the antifungal pattern-recognition receptor dectin-1.
An autosomal recessive form of susceptibility to chronic mucocutaneous candidiasis is associated with homozygous mutations in CARD9.
We describe three generations of a white family with autosomal dominant chronic mucocutaneous candidiasis (CMCC) and primary hypothyroidism, which was complicated by squamous cell carcinoma (SCC) of the oesophagus in the index case. We report this family to increase awareness of this rare autosomal dominant variant of CMCC endocrinopathy syndrome associated with primary hypothyroidism without evidence of autoimmune endocrinopathy, and to highlight the risk of developing oesophageal SCC at a young age as a fatal complication of CMCC.
Chronic mucocutaneous candidiasis is a primary immune deficiency presenting as an inability to clear fungal infections and consequently as persisting and recurring infections of the skin and mucous membranes with yeasts, mostly Candida albicans. Chronic mucocutaneous candidiasis is a heterogeneous clinical syndrome which usually presents in childhood and can have an autosomal recessive, dominant or sporadic mode of inheritance. Most chronic mucocutaneous candidiasis patients also develop accompanying endocrine and inflammatory disorders that suggest an underlying deregulation of the immune system. It has long been recognized that protection from mucocutaneous candidiasis relies on cell-mediated immunity and studies on animal models have highlighted the essential role of type 1 cytokines in protection against Candida spp. Recent data in patients with chronic mucocutaneous candidiasis have documented altered patterns of cytokine production in response to Candida spp. with decreased production of some but not all type 1 cytokines and increased levels of interleukin-10. The defect underlying altered cytokine production remains unknown but studies are in progress addressing the putative role of dendritic cells and pattern recognition receptors in directing cytokine responses. These novel insights into immune mechanisms responsible for protection against Candida spp. are opening new possibilities of immunomodulation and vaccination that could prove beneficial in the management of chronic mucocutaneous candidiasis.
Over the past two decades the genetic bases for virtually all the well-characterized primary immunodeficiency syndromes have been identified. The investigation of rare, poorly differentiated immunodeficiencies is being hampered by a preoccupation of funding agencies with hypothesis-driven proposals that apply poorly in the case of individual patients. Recent studies at our institution in collaboration with groups at NIH have resulted in the identification of two separate kindreds bearing unique mutations in molecules affecting immune function and a chromosomal linkage in a third family. Thus, a potential solution to the funding problem for studies in primary immunodeficiency could lie in the centralization of investigative expertise and support, perhaps within the walls of the National Institutes of Health, as has been done with great success in Europe.
Unlabelled:
We describe the clinical and immunological features of two families with chronic mucocutaneous candidiasis (CMC) and primary hypothyroidism. Family A includes three siblings with both candidiasis and hypothyroidism and four individuals with hypothyroidism only. Family B includes four members with candidiasis, of whom one (a male child) also had hypothyroidism. All individuals affected with CMC had suffered from oral candidiasis and onychomycosis since infancy. Facial seborrhoic dermatitis, general folliculitis and scaling blepharitis were main manifestations. Hypothyroidism became evident during childhood. No thyroid antibodies were present in the affected siblings in family A, while the male in family B with hypothyroidism had antibodies against thyroid peroxidase at diagnosis. Immunological evaluation revealed intra-individual variations in serum immunoglobulin levels, lymphocyte subsets and proliferative responses, but there were no consistent abnormalities. Vaccine responses were normal. AIRE gene region microsatellite markers did not segregate with disease nor were autoantibodies typical for autoimmune polyendocrine syndrome type 1 detected in the families.
Conclusion:
The link between hypothyroidism and chronic mucocutaneous candidiasis remains to be identified.
The vast majority of known primary immunodeficiencies (PIDs) are autosomal or X-linked recessive Mendelian traits. Only four classical primary immunodeficiencies are thought to be autosomal-dominant, three of which still lack a well-defined genetic etiology: isolated congenital asplenia, isolated chronic mucocutaneous candidiasis, and hyper IgE syndrome. The large deletions on chromosome 22q11.2 associated with Di George syndrome suggest that this disease may be dominant but not Mendelian, possibly involving several genes. The clinical and genetic features of six novel autosomal-dominant primary immunodeficiencies have however been described in recent years. These primary immunodeficiencies are caused by germline mutations in seven genes: ELA2, encoding a neutrophil elastase, and GFI1, encoding a regulator of ELA2 (mutations associated with severe congenital neutropenia); CXCR4, encoding a chemokine receptor (warts, hypogammaglobulinemia, infections and myelokathexis syndrome); LCRR8, encoding a key protein for B-cell development (agammaglobulinemia); IFNGR1, encoding the ligand-binding chain of the interferon-gamma receptor; STAT1, encoding the signal transducer and activator of transcription 1 downstream from interferon-gammaR1 (Mendelian susceptibility to mycobacterial diseases); and IKBA, encoding IkappaBalpha, the inhibitor alpha of NF-kappaB (anhidrotic ectodermal dysplasia with immunodeficiency). These recent data suggest that many more autosomal-dominant PIDs are likely to be identified in the near future.
Chronic mucocutaneous candidiasis is a disorder of the skin, nails or mucous membranes in the absence of another cause of the infection. It is also associated with autoimmune endocrinopathies in 40% of patients. It is thought to be due to a T-cell defect, although no precise mechanism has been elucidated. There have been two previous cases of Pneumocystis carinii pneumonia reported with this condition. We report a fatal case in a 34-year-old male.
Chronic mucocutaneous candidiasis (CMC) is a rare disorder characterized by persistent or recurrent candidal infections of the skin, nails and mucous membranes or by a variable combination of endocrine failure as well as immunodeficiency. Oral clinicopathological features of CMC have seldom been described in detail.
Seven patients with CMC were reported in the study. The clinical and histological findings, etiological Candida species, immunological evaluation, and therapeutic pattern of oral lesions, were analyzed.
Long-standing whitish hyperplastic and nodule-like lesions with exaggerated deep fissure were the typical and characteristic oral manifestations presented by all patients. The tongue was the most common site affected. Histologically, no obvious distinction was found between CMC and other forms of candidal infection. Abnormal proportions of T-lymphocyte subsets and positive titers of autoantibody were observed in three subjects (42.9%) and one patient (14.3%) respectively. Meanwhile, four subjects (57.1%) showed decreased albumin and increased globulin, three cases (42.9%) had high levels of ESR. But no iron deficiency was found. Candida albicans was the microorganism isolated from these patients.
Multiple and widespread candidal infectious lesions can be observed on the oral cavity of CMC patients. Hyperplastic and nodule-like lesion with irremovable whitish patches and deep fissure are the most common oral manifestations of these patients. Dentists, otolaryngologists and pediatricians should be familiar with the clinical appearances of CMC to make an accurate diagnosis. Potential systemic disorders should be concerned to avoid the reoccurrence of oral candidiasis.
Patients suffering from chronic mucocutaneous infections with the yeast Candida albicans (CMC) are discussed to have an underlying primary cellular immunodeficiency. In order to characterise cellular immunity in CMC patients, we analysed chemotaxis and myeloperoxidase (MPO) releases of neutrophils and T cell proliferation and cytokine production to Candida albicans. Patients with chronic mucocutaneous candidiasis (n = 4) and healthy volunteers of same sex and similar age (n = 14) were enrolled into the study. Neutrophil chemotaxis was assessed by transwell migration assay, and MPO release by ELISA. T cell proliferation capacity was investigated by thymidine incorporation and cytokine secretion in supernatants by ELISA. Neither neutrophil migration nor MPO release differed between CMC patients and healthy controls. The relative lymphocyte stimulation index (SI Candida/SI PHA) was heterogenous, but overall it was higher in CMC patients compared to controls. However, Candida-specific IFN-gamma production was significantly reduced in CMC patients. Notably, Candida-specific T cell IL-10 production was markedly higher in CMC patients. The inability to clear the yeast Candida albicans in our CMC patients does not seem to be due to an impaired neutrophil function or reduced antigen specific proliferation of lymphocytes. In fact, our patients tended to proliferate stronger to Candida antigen relative to PHA than healthy controls. However, the impaired Th1 cytokine production with an enhanced IL-10 production could play an important role in the pathogenesis of chronic mucocutaneous Candida infections.
The human genome holds an extraordinary trove of information about human development, physiology, medicine and evolution.
Here we report the results of an international collaboration to produce and make freely available a draft sequence of the human
genome. We also present an initial analysis of the data, describing some of the insights that can be gleaned from the sequence.
Hashimoto's thyroiditis (HT) and Graves' disease (GD) are auto- immune thyroid diseases (AITD) in which multiple genetic factors are suspected to play an important role. Until now, only a few minor risk factors for these diseases have been identified. Susceptibility seems to be stronger in women, pointing toward a possible role for genes related to sex steroid action or mechanisms related to genes on the X-chromosome. We have studied a total of 45 multiplex families, each containing at least 2 members affected with either GD (55 patients) or HT (72 patients), and used linkage analysis to target as candidate suscep- tibility loci genes involved in estrogen activity, such as the estrogen receptor a and b and the aromatase genes. We then screened the entire X-chromosome using a set of polymorphic microsatellite mark- ers spanning the whole chromosome. We found a region of the X- chromosome (Xq21.33-22) giving positive logarithm of odds (LOD) scores and then reanalyzed this area with dense markers in a mul- tipoint analysis. Our results excluded linkage to the estrogen receptor a and aro- matase genes when either the patients with GD only, those with HT only, or those with any AITD were considered as affected. Linkage to the estrogen receptor b could not be totally ruled out, partly due to incomplete mapping information for the gene itself at this time. The X-chromosome data revealed consistently positive LOD scores (max- imum of 1.88 for marker DXS8020 and GD patients) when either definition of affectedness was considered. Analysis of the family data using a multipoint analysis with eight closely linked markers gen- erated LOD scores suggestive of linkage to GD in a chromosomal area (Xq21.33-22) extending for about 6 cM and encompassing four mark- ers. The maximum LOD score (2.5) occurred at DXS8020. In conclusion, we ruled out a major role for estrogen receptor a and the aromatase genes in the genetic predisposition to AITD. Estrogen receptor b remains a candidate locus. We found a locus on Xq21.33-22 linked to GD that may help to explain the female predisposition to GD. Confirmation of these data in HT may require study of an extended number of families because of possible heterogeneity. (J Clin Endo- crinol Metab 83: 3290 -3295, 1998)
This paper investigates effects on lod scores when one individual in a data set changes diagnostic or recombinant status. First we examine the situation in which a single offspring in a nuclear family changes status. The nuclear-family situation, in addition to being of interest in its own right, also has general theoretical importance, since nuclear families are "transparent"; that is, one can track genetic events more precisely in nuclear families than in complex pedigrees. We demonstrate that in nuclear families log10 [(1-theta)/theta] gives an upper limit on the impact that a single offspring's change in status can have on the lod score at that recombination fraction (theta). These limits hold for a fully penetrant dominant condition and fully informative marker, in either phase-known or phase-unknown matings. Moreover, log10 [(1-theta)/theta] (where theta denotes the value of theta at which Zmax occurs) gives an upper limit on the impact of a single offspring's status change on the maximum lod score (Zmax). In extended pedigrees, in contrast to nuclear families, no comparable limit can be set on the impact of a single individual on the lod score. Complex pedigrees are subject to both stabilizing and destabilizing influences, and these are described. Finally, we describe a "sensitivity analysis," in which, after all linkage analysis is completed, every informative individual in the data set is changed, one at a time, to see the effect which each separate change has on the lod scores. The procedure includes identifying "critical individuals," i.e., those who would have the greatest impact on the lod scores, should their diagnostic status in fact change. To illustrate use of the sensitivity analysis, we apply it to the large bipolar pedigree reported by Egeland et al. and Kelsoe et al. We show that the changes in lod scores observed there, on the order of 1.1-1.2 per person, are not unusual. We recommend that investigators include a sensitivity analysis as a standard part of reporting the results of a linkage analysis.
We describe four improvements we have implemented in a version of the genetic linkage analysis programs in the LINKAGE package: subdivision of recombination classes, better handling of loops, better coordination between the optimization and output routines, and a checkpointing facility. The unifying theme for all the improvements is to store a small amount of data to avoid expensive recomputation of known results. The subdivision of recombination classes improves on a method of Lathrop and Lalouel [Am J Hum Genet 1988;42:498-505]. The new method of handling loops extends a proposal of Lange and Elston [Hum Hered 1975;25:95-105] for loopless pedigrees with multiple nuclear families at the earliest generation. From a practical point of view, the most important improvement may be the checkpointing facility which allows the user to carry out linkage computations that are much longer than the mean-time-to-failure of the underlying computer.
In the past twenty years, a vast amount of work has been done which has broadened our views concerning tetany. Recently, this extensive literature was reviewed and correlated by MacCallum,1 himself one of the foremost contributors. He pointed out that "there may be several types of tetany differing widely in their etiology and in the mechanism of their production although the final changes in the blood which bring about the actual symptoms may be the same." He agreed with Aschenheim that those cases of tetany that are related to the psychoses, infections, intoxications and endocrine disorders can be classified only tentatively, but he demonstrated at least four well studied types: (1) that resulting from extirpation of the parathyroid glands, (2) gastric tetany, (3) tetany from forced respiration and (4) infantile tetany or spasmophilia. He also pointed out the possibility that other types are produced by modification of the diet
Chronic mucocutaneous candidiasis is a complex disorder in which patients have chronic and recurrent Candida albicans infections of the skin, nails, and mucous membranes. There are several subgroups of patients with chronic mucocutaneous candidiasis, and these can be identified by associated disorders such as autoimmune diseases, endocrinopathies, thymoma, and interstitial keratitis, as well as the distribution and severity of the Candida infections. Several other disorders may coexist in patients with chronic mucocutaneous candidiasis. These include other infectious diseases, endocrinopathies, dental enamel dysplasia, vitiligo, and alopecia totalis. Successful treatment programs should include antifungal drugs and manipulations that correct the immunologic abnormalities that predispose the patient to Candida infections.
The molecular background of human autoimmunity is poorly understood. Although many autoimmune diseases have a genetic basis, the actual disease appearance results from a complex interplay between genes and environment and thus these diseases represent typical multifactorial diseases. Even with molecular tools provided by the Human Genome Project, it still remains a challenge to identify the predisposing DNA variants behind such multifactorial traits. Two strategies have been suggested to provide short-cuts to the dissection of the genetic background of complex autoimmune diseases: (i) identification of genes in rare human diseases with a strong autoimmune component or (ii) unravelling loci causing phenotypes resembling autoimmune diseases in inbred mice strains. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a monogenic autosomal disease with a recessive inheritance pattern, characterized by multiple autoimmune endocrinopathies, chronic mucocutaneous candidiasis and ectodermal dystrophies. Since it is the only known human autoimmune disease inherited in a Mendelian fashion, it provides an excellent model to analyse the genetic component of human autoimmunity. The causative gene for APECED was isolated recently by a traditional positional cloning strategy by two independent groups. The cDNA for the APECED gene proved to originate from a novel gene, AIRE, which is expressed prevalently in thymus, pancreas and adrenal cortex. Multiple mutations in AIRE have been identified in APECED patients. The predicted proline-rich AIRE polypeptide harbours two PHD-type zinc finger motifs and contains a putative nuclear targeting signal suggesting its involvement in the regulation of transcription. In the future, functional analysis of the AIRE protein both in vitro and in vivo will provide valuable insight not only into the molecular pathogenesis of APECED but also into the aetiology of autoimmunity in general.
Autoimmune thyroid disease (AITD), including Graves' disease (GD) and Hashimoto's thyroiditis (HT), is caused by multiple genetic and environmental factors. The clinical and immunological features of GD and HT are distinct; however, there are multiplex families with both GD and HT, and cases in which GD evolves into HT. Thus, there may be specific susceptibility loci for GD or HT, and common loci controlling the susceptibility to both GD and HT may exist. A genome-wide analysis of data on 123 Japanese sib-pairs affected with AITD was made in which GD- or HT-affected sib-pairs (ASPs) were studied to detect GD- or HT-specific susceptibility loci, and all AITD-ASPs were used to detect AITD-common susceptibility loci. Our study revealed 19 regions on 14 chromosomes (1, 2, 3, 5, 6, 8, 9, 10, 11, 12, 13, 15, 18 and 22) where the multipoint maximum LOD score (MLS) was >1. Especially, chromosome 5q31-q33 yielded suggestive evidence for linkage to AITD as a whole, with an MLS of 3.14 at D5S436, and chromosome 8q23-q24 yielded suggestive evidence for linkage to HT, with an MLS of 3.77 at D8S272. These observations suggest the presence of an AITD susceptibility locus at 5q31-q33 and a HT susceptibility locus at 8q23-q24.
A family consisting of eight members in three generations (age 10 months to 53 years) affected with chronic mucocutaneous candidiasis was studied along with three Unaffected relatives. Dermatophytosis, loss of teeth and recurrent viral infections were present in some members. Results of tests for endocrinologic, muscle or liver disease, thymoma, iron deficiency, antitissue antibodies and malabsorption were normal in all patients.
Amphotericin B was given orally to four patients with chronic mucocutaneous candidiasis (CMCC) using a total daily dose of 1,000 to 1,800 mg. In one patient continuous treatment over a six-month period resulted in complete clearing of extensive candidal granuloma lesions. In another candidal granuloma patient a slower but continuous excellent response occurred. A hypothyroid patient and a patient with associated thymoma-myositis failed to respond. Higher antibiotic serum levels in the first two patients indicate significant individual variations in absorption may exist and probably account for the different results. The intracellular location of Candida albicans observed with the electron microscope suggests tissue levels were also, and perhaps more directly, involved in the therapeutic response. In view of this experience, and the lack of a nontoxic effective treatment, a more extensive oral trial of amphotericin B in CMCC seems fully justified.
A mother and son had chronic mucocutaneous candidiasis. Vertical inheritance from a mother to son is extremely rare. An attempt was made to identify a defect that would predispose them to their chronic Candida infection. Neutrophil function studies failed to reveal a defect that could be correlated with the pathogenesis of the disease. Both patients failed to demonstrate cutaneous delayed hypersensitivity to Candida albicans antigen but had specific humoral antibodies to the organism. In vitro studies of cellular immunity revealed multiple defects. Endocrine evaluation of the son led to the finding of previously undiagnosed hypothyroidism.
The autoimmune thyroid diseases (AITDs) include two related disorders, Craves disease (CD) and Hashimoto thyroiditis, in which perturbations of immune regulation result in an immune attack on the thyroid gland. The AITDs are multifactorial and develop in genetically susceptible individuals. However, the genes responsible for this susceptibility remain unknown. Recently, we initiated a whole-genome linkage study of patients with AITD, in order to identify their susceptibility genes. We studied a data set of 53 multiplex, multigenerational AITD families (323 individuals), using highly polymorphic and densely spaced microsatellite markers (intermarker distance <10 cM). Linkage analysis was performed by use of two-point and multipoint parametric methods (classic LOD-score analysis). While studying chromosome 20, we found a locus on chromosome 20q11.2 that was strongly linked to GD. A maximum two-point LOD score of 3.2 was obtained at marker D20S195, assuming a recessive mode of inheritance and a penetrance of .3. The maximum nonparametric LOD score was 2.4 (P = .00043); this score also was obtained at marker D20S195. Multipoint linkage analysis yielded a maximum LOD score of 3.5 for a 6-cM interval between markers D20S195 and D20S107. There was no evidence for heterogeneity in our sample. In our view, these results indicate strong evidence for linkage and suggest the presence of a major CD-susceptibility gene on chromosome 20q11.2.
VERY little exact information is available on the etiology of idiopathic hypoparathyroidism. Since there are normally four parathyroid glands, the question arises as to what phathologic influence could exert itself in all four areas. A priori the loss of some trophic hormone, the presence of some circulating toxin with a specific affinity for parathyroid tissue, or the predilection on the part of the parathyroid glands for some infection (cf. adrenal glands and tuberculosis) might produce atrophy or destruction of all four glands. The authors know of on y two cases of undoubted idiopathic hypoparathyroidism to come to autopsy. As recorded in a previous paper from this clinic (1), the post mortem of a boy who died with idiopathic hypoparathyroidism showed complete aplasia of the epithelial cells of all four parathyroid glands with replacement by fat cells but with retention of the capsules. Cantarow, Stewart and Morgan (2) were unable to find parathyroid tissue in a patient with idiopathic hypoparathyroidism who died.
Three patients with chronic mucocutaneous candidiasis have been studied. In the first patient, who also had an extensive skin infection due to Trichophyton rubrum, aminoaciduria and absence of delayed hypersensitivity to test antigens including oidiomycin were found. The coexistence of aminoaciduria and an immunologie abnormality has not been reported previously in a patient with chronic superficial candidiasis. The second patient had the following abnormalities: candidiasis, primary Addison's disease, enlarged thymus, miniscule spleen devoid of lymphoid tissue and lymphocytic infiltration of the thyroid gland. The third patient represents an example of the rare syndrome of familial juvenile keratoconjunctivitis, primary hypoparathyroidism, primary Addison's disease and superficial candidiasis. The patient who was lymphopenic lacked the addisonian component of the syndrome but had a sister who had the combination of hypoparathyroidism. Addison's disease and ovarian failure without associated candidiasis. Conditions favoring the development and persistence of chronic mucocutaneous candidiasis are discussed, with a review of the pertinent literature.
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is the only described systemic autoimmune disease with established monogenic background, and the first autoimmune disorder localized outside the major histocompatibility complex (MHC) region. The primary biochemical defect in APECED is unknown. We have isolated a novel gene, AIRE, encoding for a putative nuclear protein featuring two PHD-type zinc-finger motifs, suggesting its involvement in transcriptional regulation. Five mutations in AIRE are reported in individuals with this disorder. This is the first report of a single-gene defect causing a systemic human autoimmune disease, providing a tool for exploring the molecular basis of autoimmunity.
Chronic mucocutaneous candidiasis can be defined as a group of syndromes that have as a common feature infections of the skin, nails and mucous membranes withCandida albicans. A variety of disorders including endocrine dysfunctions, alopecia, vitiligo, malabsorption syndromes, neoplasms and other infections may also occur in patients with chronic mucocutaneous candidiasis, but these vary considerably from patient to patient. In most patients with chronic mucocutaneous candidiasis, there are abnormalities of cell-mediated immunity. These may be limited to antigens ofCandida albicans, but in some patients they are more extensive and involve the T-lymphocyte-mediated responses to all antigens. These immunulogic defects are the factors that predispose patients to infections with opportunistic organisms such asCandida spp. Fungal infections in patients with chronic mucocutaneous candidiasis usually respond to treatment with conventional antifungal agents, but often relapse shortly after treatment is stopped unless the defects in the cell-mediated immune system have been corrected.
We describe a second parallel implementation of the ILINK program from the LINKAGE package that improves on our previous implementation. To improve running time we integrated the strategy of parallel estimation of the gradient at a candidate recombination fraction vector with a previously implemented strategy for evaluating in parallel the likelihood at one vector. We also integrated an adaptive loadbalancing strategy in conjunction with our previous static loadbalancing strategy. We implemented a strategy for partitioning input pedigrees, but this slowed down the program; we give some evidence for what the problems are. To best exploit parallelism at all levels of the program and to take advantage of both coarse-grain and fine-grain parallelism it is necessary to combine multiple algorithmic strategies.
Evidence from neurophysiological and psychological studies is coming together to shed light on how we represent and recognize objects. This review describes evidence supporting two major hypotheses: the first is that objects are represented in a mosaic-like form in which objects are encoded by combinations of complex, reusable features, rather than two-dimensional templates, or three-dimensional models. The second hypothesis is that transform-invariant representations of objects are learnt through experience, and that this learning is affected by the temporal sequence in which different views of the objects are seen, as well as by their physical appearance.
Hereditary gingival fibromatosis (HGF, MIM 135300; approved gene symbol GINGF) is an oral disease characterized by enlargement of gingiva. Recently, a locus for autosomal dominant HGF has been mapped to an 11-cM region on chromosome 2p21. In the current investigation, we genotyped four Chinese HGF families using polymorphic microsatellite markers on 2p21. The HOMOG test provided evidence for genetic homogeneity, with evidence for linkage in four families (heterogeneity versus homogeneity test HOMOG, χ2 = 0.00). A cumulative maximum two-point lod score of 5.04 was produced with marker D2S390 at a recombination frequency of θ = 0 in the four linked families. Haplotype analysis localized the hereditary gingival fibromatosis locus within the region defined by D2S352 and D2S2163. This region overlaps by 3.8 cM with the previously reported HGF region. Single-strand conformation polymorphism and sequence analysis of the coding region of cytochrome P450 1B1 (CYP1B1) excluded it as a likely candidate gene.
A family consisting of eight members in three generations (age 10 months to 53 years) affected with chronic mucocutaneous candidiasis was studied along with three unaffected relatives. Dermatophytosis, loss of teeth and recurrent viral infections were present in some members. Results of tests for endocrinologic, muscle or liver disease, thymoma, iron deficiency, antitissue antibodies and malabsorption were normal in all patients. Antibody function and levels, B cell counts, serum complement, leukocyte enzymes, chemotaxis, phagocytosis and adherence were normal in all members. Plasma inhibitors to lymphocyte transformation and leukocyte inhibitory factor were not found. No unique HLA haplotype or antigen segregated in this family. Evaluation of cell-mediated immunity revealed total cutaneous anergy in three of eight whereas four of the other five had negative lymphocyte transformation and skin tests to Candida but responded normally to other antigens. Leukocyte inhibitory factor was not produced to Candida antigen in all four patients tested. T cell counts were within normal limits in all. Extensive evaluation of all limbs of the immune system in this family revealed a defect in cell-mediated immunity to Candida that appeared to be inherited as a dominant characteristic.
A specific inhibitory activity of in vitro proliferative responses of normal human lymphocytes to Candida metabolic antigen was found in the serum of 6 out of 23 children with chronic mucocutaneous candidiasis. In each of the six patients, the presence of an inhibitory activity was associated with Candida-specific cellular defects, characterized by a negative-skin test and a lack of in vitro lymphocyte proliferation. The presence of a circulating inhibitor was detected during relapses of the disease and disappeared under antifungal therapy. This inhibitory effect was not associated with any toxicity on tested lymphocytes. The factor was shown to be nondialysable, thermostable, nonprecipitable with ammonium sulfate and absorbable on anti-Candida antibodies or concanavalin A-coupled agarose columns. Altogether, these results suggest that the inhibitory factor is not an immunoglobulin, but rather a polysaccharidic antigen of Candida albicans. An inhibition of Candida-induced proliferative response of normal human lymphocytes was also obtained by addition of polysacharide antigens or purified mannans from C. albicans to cultures. Candida polysaccharidic antigens appeared, therefore, to be involved in specific depression of cellular functions observed in chronic candidiasis.
A 20-year old women and her infant daughter had recurrent bacterial infections and chronic mucocutaneous candidiasis and were found to have extreme hyperimmunoglobulinemia E, defective neutrophil chemotaxis, and diminished lymphocyte responses to Candida antigen. Studies of members of the mother's family showed mild increases of IgE and mildly depressed chemotactic activity of neutrophils in a brother, the father, and the paternal grandfather. The recurrent bacterial infections in these two patients can be explained by the defective neutrophil chemotaxis. It is not known whether the mucocutaneous candidiasis is related to the neutrophil chemotaxis with the lymphocyte defect being secondary to the Candida infection or, alternatively, the Candida infection being secondary to the lymphocyte defect. Furthermore, the family data suggest a familial pattern of hyperimmunoglobulinemia E and defective neutrophil motility.
We reviewed the clinical course in 43 patients from eight medical centers who were given the diagnosis of chronic mucocutaneous candidiasis, a rare disorder of unknown cause that may occur in childhood. Recurrent or severe infections with organisms other than Candida were seen in 80% of the patients. There were nine cases of septicemia. Seven patients have died; six of these deaths were directly related to non-Candida infectious complications. Endocrine dysfunction, including Addison disease (11 patients) and hypothyroidism (9 patients), was seen in 19 of 43 patients. Immunologic studies failed to reveal a consistent abnormality, although two of five patients with reversed T4/T8 ratios are among those who have died. Ketoconazole was effective in controlling symptoms of candidiasis in most patients. The findings from this study indicate that non-Candida infections cause serious morbidity and may result in death in patients with chronic mucocutaneous candidiasis.
To define the clinical picture and course of the autosomal recessive disease called autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), we report data from our 10-month to 31-year follow-up of 68 patients from 54 families, now 10 months to 53 years of age. The clinical manifestations varied greatly and included from one to eight disease components, 63 percent of the patients having three to five of them. The initial manifestation was oral candidiasis in 41 patients (60 percent), intestinal malabsorption in 6 (9 percent), and keratopathy in 2 (3 percent). All the patients had candidiasis at some time. The earliest endocrine component appeared at 19 months to 35 years of age. Hypoparathyroidism was present in 54 patients (79 percent), adrenocortical failure in 49 (72 percent), and gonadal failure in 15 (60 percent) of the female patients greater than or equal to 13 years of age and 4 (14 percent) of the male patients greater than or equal to 16 years of age. There were multiple endocrine deficiencies in half the patients. From 4 to 29 percent of the patients had periodic malabsorption, gastric parietal-cell atrophy, hepatitis, alopecia, vitiligo, or a combination of these conditions. Dental-enamel hypoplasia and keratopathy were also frequent but were not attributable to hypoparathyroidism. In the patients whose initial manifestation (other than candidiasis) was adrenal failure, the other components developed less often than in the remaining patients. We conclude that the clinical spectrum in patients with APECED is broad. The majority of patients have three to five manifestations, some of which may not appear until the fifth decade. Therefore, all patients need lifelong follow-up for the detection of new components of the disease.
A 22-year-old man with chronic mucocutaneous candidiasis (CMC) and hypothyroidism developed severe bronchiectases following recurrent bronchopneumonia. Immunological investigations revealed IgG2/IgG4 subclass deficiency and absence of antibodies against pneumococcal and Haemophilus polysaccharides. Under regular immunoglobulin substitution every 3 weeks pulmonary symptoms improved markedly.
We have studied T- and B-cell responses to antigens of Candida albicans in 18 patients suffering from chronic mucocutaneous candidiasis. We have shown that in vitro production of antibody to one of these antigens, mannan, was absent during the active phase of the disease and that this absence was consequent to the activation of specific CD8(+) and CD8(-) suppressor T lymphocytes. Such activation was also observed when control T lymphocytes were incubated in the presence of monocytes and a high concentration of mannan. This suppressive effect was specific to antigens of Candida albicans, was radiosensitive, and was not consequent to the secretion of prostaglandin E2. It appeared as well that the induction of these suppressor T cells was HLA-DQ restricted. The suppressor T-cell activity induced by antigens of Candida albicans in vitro is thus comparable to the suppressor T-cell activity observed in vivo in patients affected with chronic mucocutaneous candidiasis. Defective handling of mannan by monocytes could result in the accumulation of mannan, resulting in the activation of specific T suppressor cells and in the consequent cellular immunodeficiency specific to Candida albicans. Successful treatment of the candidiasis resulted in complete correction of the immune abnormalities.
Thirty-one patients with autoimmune polyglandular disease type I who initially had no adrenocortical and/or ovarian failure were followed for 1.2-12.1 yr (mean, 8.3) by determinations of adrenal (AA) and steroidal cell antibodies (SCA) and functional tests. Adrenocortical failure developed in 13 and ovarian failure in 11 patients. SCA or AA preceded adrenocortical failure in 12 of the 13 patients and were found in 2 of 9 patients (so far) who still have normal adrenal function (P = 0.001). SCA preceded ovarian failure in all 11 patients and were found in 6 of 11 patients who still have normal ovarian function (P = 0.02). The sensitivities/specificities/predictive values were 0.77/0.78/0.90 in all patients for SCA predicting adrenocortical failure, and 0.92/0.89/0.92 for adrenal-binding antibody (which includes all AA and most SCA) in predicting adrenocortical failure. The sensitivities/specificities/predictive values in females who initially had normal adrenocortical and ovarian function were 1.0/0.56/0.50 for SCA in predicting ovarian failure, 0.86/0.83/0.86 for SCA in predicting adrenocortical failure, and 1.0/1.0/1.0 for adrenal-binding antibody in predicting adrenocortical failure. Thus, the appearance of AA or SCA in a male patient without adrenocortical failure or a female patient without adrenocortical or ovarian failure signals a high risk of their development.
A genetic analysis was made of 58 patients and their 42 families with APECED (autoimmune polyendocrinopathy--candidosis--ectodermal dystrophy). APECED is characterized by hypoparathyroidism, primary adrenocortical failure and chronic mucocutaneous candidosis, but none of its components is constant. Other endocrine deficiencies can occur as well and also dystrophy of dental enamel and nails. The proportion of affected siblings was 0.147 +/- 0.034 (S.D.) when corrected for truncate single ascertainment, 0.246 +/- 0.019 when corrected for a priori truncate complete ascertainment and 0.240 +/- 0.047 when corrected for a posteriori truncate complete ascertainment. The male/female ratio was 1.04. The results are compatible with autosomal recessive transmission. No heterozygous manifestations of the gene were found. The gene is enriched in isolated subpopulations in central and eastern Finland. APECED is part of the "Finnish heritage of disease".
Immunological studies in an 11-year-old patient with chronic mucocutaneous candidiasis are presented. Defective cellular immunity, both in vivo and in vitro, were identified. There was complete anergy, with negative intradermal tests for delayed hypersensitivity with eight antigens and a lack of response to dinitrochlorobenzene after contact sensitisation. A skin graft has not been rejected after more than a year. The patient's lymphocytes responded by proliferation in vitro to stimulation with phytohæmagglutinin, but not with mumps or monilia antigens. His cells neither responded nor stimulated in a one-way mixed lymphocyte culture. His serum inhibited the proliferative response of normal control lymphocytes stimulated with candida and mumps antigens, and allogeneic cells. These abnormal responses seem to be the result of the serum factor inhibiting the proliferative response of the small lymphocytes. The defect appears to be genetic, as there are other affected members in the family.
A mother and son had chronic mucocutaneous candidiasis. Vertical inheritance from a mother to son is extremely rare. An attempt was made to identify a defect that would predispose them to their chronic Candida infection. Neutrophil function studies failed to reveal a defect that could be correlated with the pathogenesis of the disease. Both patients failed to demonstrate cutaneous delayed hypersensitivity to Candida albicans antigen but had specific humoral antibodies to the organism. In vitro studies of cellular immunity revealed multiple defects. Endocrine evaluation of the son led to the finding of previously undiagnosed hypothyroidism.
Chronic mucocutaneous candidiasis is a complex disorder in which patients have chronic and recurrent Candida albicans infections of the skin, nails, and mucous membranes. There are several subgroups of patients with chronic mucocutaneous candidiasis, and these can be identified by associated disorders such as autoimmune diseases, endocrinopathies, thymoma, and interstitial keratitis, as well as the distribution and severity of the Candida infections. Several other disorders may coexist in patients with chronic mucocutaneous candidiasis. These include other infectious diseases, endocrinopathies, dental enamel dysplasia, vitiligo, and alopecia totalis. Successful treatment programs should include antifungal drugs and manipulations that correct the immunologic abnormalities that predispose the patient to Candida infections.
Immune globulins in sera of normal persons of various ages were quantitated by a radial diffusion technique; the levels changed considerably with age, especially during early infancy. Adult levels (γG 1158 ± 305, γM 99 ± 27, and γA 200 ± 61 mg/100 ml) generally were attained by 16 years of age. In all specimens of umbilical cord serum the level of γG was similar to that of adult serum and a trace quantity of γM (mean 10 mg/100 ml) was present; in one-third there was a trace amount of γA-globulin. The level of γM increased rapidly after birth but synthesis of γG and, especially, γA was delayed. Because of these normal alterations, it is recommended that specimens of serum be compared with those of age-matched control subjects for optimal evaluation.
There was significant elevation of levels of γG-, γA-, and total γ-globulins, and diminution of that of γM in the serum of mongols over 10 years of age. The diminution of γM may be implicated in the poor response of mongols to immunizing antigens and the increased susceptibility of such patients to infections. Mongols may have a genetic instability of immune globulin synthesis analogous to their abnormality of leukopoiesis.
Patients with sex chromosome abnormalities or trisomy 18 syndrome had normal levels of immune globulins, whereas those with neutropenia had elevated levels of all immune globulins. Abnormal levels determined in 12 cases of antibody deficiency diseases are presented.
Three patients with chronic mucocutaneous candidiasis have been studied. In the first patient, who also had an extensive skin infection due to Trichophyton rubrum, aminoaciduria and absence of delayed hypersensitivity to test antigens including oidiomycin were found. The coexistence of aminoaciduria and an immunologie abnormality has not been reported previously in a patient with chronic superficial candidiasis. The second patient had the following abnormalities: candidiasis, primary Addison's disease, enlarged thymus, miniscule spleen devoid of lymphoid tissue and lymphocytic infiltration of the thyroid gland. The third patient represents an example of the rare syndrome of familial juvenile keratoconjunctivitis, primary hypoparathyroidism, primary Addison's disease and superficial candidiasis. The patient who was lymphopenic lacked the addisonian component of the syndrome but had a sister who had the combination of hypoparathyroidism. Addison's disease and ovarian failure without associated candidiasis. Conditions favoring the development and persistence of chronic mucocutaneous candidiasis are discussed, with a review of the pertinent literature.
Carbohydrate antigens from Candida albicans, essentially mannan, have previously been shown to persist in the serum of some patients with chronic mucocutaneous candidiasis, and to be able to inhibit specifically the candida antigen-induced proliferation of control lymphocytes. Lymphocytes from three out of six patients were shown to be hypersensitive to mannan inhibition. These data were explained by the demonstration of an apparently selective impairment of radiolabelled mannan handling by two patients' monocytes following a normal uptake. This defect was observed both in active and remission phases of the infection suggesting an intrinsic defect of patients' monocytes. In experiments performed with control lymphocytes, it was shown that mannan exerted its suppressive effect by interfering with candida antigen presentation by adherent cells to autologous T lymphocytes. Furthermore, mannan neither was cytotoxic nor induced suppressor T cells. Altogether, these data suggest that the in vivo persistance of mannan, in some patients, is secondary to a primary macrophage dysfunction leading to impairment of specific cellular immune responsiveness.
A computer program that calculates lod scores and genetic risks for a wide variety of both qualitative and quantitative genetic traits is discussed. An illustration is given of the joint use of a genetic marker, affection status, and quantitative information in counseling situations regarding Duchenne muscular dystrophy.
Four adult patients with chronic mucocutaneous candidiasis were studied to establish a possible role for cimetidine as an immunomodulator. These patients had negative baseline in-vivo and in-vitro cell-mediated immune response to candida antigen as measured by intradermal skin tests, lymphocyte transformation, and leukocyte migration inhibitory factor production to cimetidine, 300 mg by mouth, four times daily. Subsequently four of four patients developed strong (greater than 15 mm) intradermal skin test reactions, and two of four patients produced leukocyte migration inhibitory factor to candida antigen. Skin tests and leukocyte migration inhibitory factor production reverted to baseline negative values when repeated 4 weeks after discontinuation of therapy. After 4 additional weeks on cimetidine, four of four patients showed strong positive skin tests and leukocyte migration inhibitory factor production to candida antigen. Lymphocyte transformation was not affected by therapy.
Cystinuria is a classic heritable aminoaciduria that involves the defective transepithelial transport of cystine and dibasic amino acids in the kidney and intestine. Six missense mutations in the human rBAT gene, which is involved in high-affinity transport of cystine and dibasic amino acids in kidney and intestine, segregate with cystinuria. These mutations account for 30% of the cystinuria chromosomes studied. Homozygosity for the most common mutation (M467T) was detected in three cystinuric siblings. Mutation M467T nearly abolished the amino acid transport activity induced by rBAT in Xenopus oocytes. These results establish rBAT as a cystinuria gene.
Riedel's thyroiditis is a rare condition with an unknown aetiology. The condition was discovered by Riedel in 1883. In 1904, Hashimoto described another condition of invasive fibrous thyroiditis. Since then it has been discussed whether Hashimoto's thyroiditis and Riedel's thyroiditis are one disease in different states or whether they are two different diseases. Hashimoto's thyroiditis is known to have an autoimmune aetiology and can be seen in conjunction with other autoimmune diseases such as pernicious anaemia. The co-existence of Riedel's thyroiditis and pernicious anaemia is reported for the first time in this case story. Our patient was initially treated with a high dose of steroids and today is well on low-dose steroids and without relapse. The co-existence mentioned, the good effect of steroid treatment, the frequent presence of thyroid autoantibodies and lymphoid infiltration of the thyroid gland resembling that of Hashimoto's thyroiditis might indicate an autoimmune aetiology. It may be that the action on fibroblasts of cytokines known to be released by infiltrating lymphocytes constitutes a possible fibrogenic mechanism, but the primary lesion is still unknown.