Primary immunodeficiency diseases in the Middle East.

Reports on primary immunodeficiency diseases (PIDs) have clearly shown wide geographic and ethnic variations. Understanding these variations is expected to play a major role in improving the diagnosis and management of such diseases, and will also affect research on PIDs. In this short review, we explore the unique aspects of primary immunodeficiencies in the Middle East.

The demographics of primary immunodeficiency diseases across the unique ethnic groups in Iran, and approaches to diagnosis and treatment.

Primary immunodeficiency diseases (PIDs) are a heterogeneous group of inherited disorders that cause individuals to be prone to a variety of clinical manifestations, such as infections, autoimmunity, and malignancies. Early diagnosis and adequate treatment of these disorders can reduce morbidity and mortality and provide a relatively high quality of life. In Iran, recent advances in clinical immunology and in the identification of immunodeficiencies have led to reductions in diagnostic delay and severe complications in patients with PIDs. Autosomal recessive and multifactorial types of PID seem to be more common in Iran because of high rates of consanguine marriages and, probably, the genetic background of its ethnic groups. These facts necessitate special diagnostic and treatment approaches, but at the same time reveal an opportunity to observe novel phenotypes and genetic defects.

What caused the epidemic of Pneumocystis pneumonia in European premature infants in the mid-20th century?

An epidemic of interstitial pneumonia principally involving premature infants occurred in Germany and nearby European countries between the 1920s and 1960s. Fatalities were due to Pneumocystis. Because the principal defenses against Pneumocystis are T cells, an acquired T-cell deficiency was postulated. A number of potential causes including malnutrition were considered. All were implausible except for a retrovirus that was benign in adults but virulent in premature infants. Furthermore, we suspect that the virus was imported into Germany from former German African colonies. Premature infants were vulnerable because of the developmental status of their T cells. Given the practices in that part of Europe at that time, the virus was most likely transmitted by contaminated blood transfusions and subsequent contamination of reusable needles and syringes used in injections. Although the epidemic ended 4 decades ago, a search for the postulated retrovirus can be conducted if tissues from affected infants are available.

Identifying undiagnosed primary immunodeficiency diseases in minority subjects by using computer sorting of diagnosis codes.

BACKGROUND: Primary immunodeficiency diseases occur in all populations, but these diagnoses are rarely made in minority subjects in the United States. OBJECTIVE: We sought to develop and validate a method to identify patients without diagnoses but with immunodeficiency in an urban hospital with a substantial minority patient population. METHODS: We developed a scoring algorithm on the basis of International Classification of Disease, Ninth Revision (ICD-9) codes to identify all hospitalized patients age 60 years or less who had been given a diagnosis of 2 or more of 174 ICD-9-coded complications associated with immunodeficiency. Codes were weighted for severity and expressed as a sum for all admissions between October 1, 1995, and December 31, 2002. Patients with, for example, cancer or HIV or those after transplantation or major surgery were excluded. Demographic features of subjects with aggregated ICD-9 codes suggestive of immunodeficiency were compared with those of other inpatients; 59 computer-selected subjects were then tested for immune defects. RESULTS: The computer-identified group contained 533 patients (0.4% of all inpatients), who had been hospitalized 2683 times. The median age was 6.6 years. Sixty-five percent were African American or Hispanic, and 61% were insured by Medicaid, which is significantly more than other inpatients younger than 60 years of age (median age, 32.6 years; 37% minority, 27% insured by Medicaid; P<.0001). Primary immunodeficiency was found in 17 (29%) of the 59 subjects tested. Thirteen other patients had secondary immune defects, and 86% of immunodeficient subjects were Hispanic or African American. CONCLUSIONS: An ICD-9-based scoring algorithm identifies patients demographically different from other hospitalized subjects who have multiple illnesses suggestive of immunodeficiency. This group contains undiagnosed minority patients with immunodeficiency.

Molecular basis of hereditary C1q deficiency.

Complete selective deficiencies of the complement component C1q are rare genetic disorders which are associated with recurrent infections and a high prevalence of lupus erythematosus-like symptoms. The improvements in molecular biology techniques have facilitated the analysis of such genetic defects to a great extend. To date the basis of C1q deficiencies from 13 families have been studied at the genetic level. In each case single base mutations leading to either termination codons, frame shift or amino acid exchanges were thought to be responsible for these defects as no other aberrations were found. In addition to DNA analysis, conventional immunochemical and biochemical methods have contributed substantially to the elucidation of the structural and functional requirements of this complex macromolecule. The present article reviews the different types of C1q defects in regard to structure and function whereas a detailed presentation on the clinical aspects of C1q deficiencies will be given in this issue of the Journal (by WALPORT, DAVIES and BOTTO).

Uniparental disomy in cartilage-hair hypoplasia.

Cartilage-hair hypoplasia (CHH) is an autosomal recessive disorder that presents with pleiotropic manifestations including impaired skeletal growth and cellular immunity. It is most prevalent among two founder populations, the Old Order Amish in the USA and the Finns. The gene has been localized to 9p13 by linkage analysis and linkage disequilibrium mapping. A statistically significant deficiency of affected members resulting in a lower than expected segregation ratio has been reported in the Amish, but was not found in a previous study in Finnish CHH families. Reduced penetrance was the mechanism suggested in the Amish, but could not be verified by haplotype analyses performed after the assignment of the CHH gene. Here we have carried out segregation analysis of 101 Finnish CHH families, but again, evidence of a significant deficiency of affected members was not found. Nevertheless, among 54 uniplex families, 2 patients with CHH and uniparental disomy (UPD) for chromosome 9 were discovered. UPD might contribute to low segregation ratios by increasing the number of families with only 1 affected individual. These observations show that UPD may occur in an unexpectedly high number of the patients and should be taken into account in the genetic counselling and prenatal diagnostics of CHH families.

Inherited human complement C5 deficiency. Nonsense mutations in exons 1 (Gln1 to Stop) and 36 (Arg1458 to Stop) and compound heterozygosity in three African-American families.

Hereditary C5 deficiency has been reported in several families of different ethnic backgrounds and from different geographic regions, but the molecular genetic defect causing C5 deficiency has not been delineated in any of them. To examine the molecular basis of C5 deficiency in the African-American population, the exons and intron/exon boundaries of the C5 structural genes from three C5-deficient (C5D) African-American families were sequenced, revealing two nonsense mutations. The nonsense mutations are located in exon 1 (C84AG to TAG) in two of the C5D families (Rhode Island and North Carolina) and in exon 36 (C4521GA to TGA) in the third C5D family (New York). The exon 1 and 36 mutations are contained in codons that encode the first amino acid of the C5 beta-chain (Gln1 to Stop) and residue 1458 in the alpha-chain (Arg1458 to Stop), respectively. Allele-specific PCR and sequence analyses demonstrated that the exon 1 mutation is present in only one of the C5 null genes in both the Rhode Island and North Carolina families, and the exon 36 mutation is contained in only one C5 null gene in the New York family. Neither of the nonsense mutations was found in the European or Caucasian-American C5D individuals examined. Collectively, these data indicate that: 1) C5 deficiency is caused by several different molecular genetic defects, 2) C5 deficiency in the African-American population can be explained in part by two distinct nonsense mutations in exons 1 and 36, and 3) compound heterozygosity exists in all of the reported African-American C5D families.

Case report: familial chronic mucocutaneous candidiasis complicated by deep candida infection.

Chronic mucocutaneous candidiasis (CMC) is usually characterized by onset in childhood and is almost never complicated by deep fungal infection. The authors report two cases of fatal candida meningitis in patients who suffered from mild, adult-onset CMC. The pedigrees suggest an autosomal recessive disorder. In the index cases and in a symptomatic sibling, the immunologic work-up showed a specific cellular deficit as opposed to Candida albicans, as is typical of other forms of CMC. Both families were of French Canadian descent and originated from eastern Quebec. Three other cases of primary candida meningitis in patients of the same ethnic origin are also reported and reviewed. It is suggested that these cases may represent a variant of familial adult-onset CMC, in which there is a striking predisposition to deep infection.

IgA deficiency.

IgA deficiency, the most common primary immunodeficiency, is a very heterogeneous clinical disorder which may be associated with a variety of infections, allergies, autoimmune disorders, gastrointestinal diseases, and genetic disorders. The central phenotypic feature of this immunodeficiency is a B cell differentiation arrest, the extent of which may determine the clinical variability. Integrity of the immunoglobulin genes and their expression by immature B cells in affected individuals suggests an immunoregulatory basis for the B cell arrest. Genetic studies imply that a susceptibility gene in or near the major histocompatibility locus may predispose homozygous individuals to a spectrum of antibody deficiencies which may range from isolated IgA deficiency to panhypogammaglobulinemia. Essential cofactors in the pathogenesis of IgA deficiency include environmental factors, such as certain drugs and viral infections.