Fibroblast growth factor receptor 2 mutations in Beare-Stevenson cutis gyrata syndrome.

Beare-Stevenson cutis gyrata syndrome (MIM 123790) is an autosomal dominant condition characterized by the furrowed skin disorder of cutis gyrata, acanthosis nigricans, craniosynostosis, craniofacial dysmorphism, digital anomalies, umbilical and anogenital abnormalities and early death. Many of these features are characteristic of some of the autosomal dominant craniosynostotic syndromes. Mutations in Crouzon, Jackson-Weiss, Pfeiffer and Apert syndromes have been reported in the FGFR2 extracellular domain. In Crouzon syndrome patients with acanthosis nigricans, a recurrent mutation occurs in the transmembrane domain of FGFR3. We now describe the detection of FGFR2 mutations in the Beare-Stevenson cutis gyrata syndrome. In three sporatic cases, a novel missense mutation was found causing an amino acid to be replaced by a cysteine; two had the identical Ty375Cys mutation in the transmembrane domain and one had a Ser372Cys mutation in the carboxyl-terminal end of the linker region between the immunoglobulin III-like (Iglll) and transmembrane domains. In two patients, neither of these mutations were found suggesting further genetic heterogeneity.

HLA-Dw2: a genetic marker for human immune response to short ragweed pollen allergen Ra5. II. Response after ragweed immunotherapy.

After artificial immunization (immunotherapy) with ragweed antigens, specific immunoglobulin G (IgG) antibody (Ab) response to Ra5 was significantly associated with HLA-Dw2 (P less than 0.0001). From a total of 61 treated patients, all 22 Dw2+ subjects made good IgG Ab responses to Ra5 by year 2 of therapy (21 by year 1), even though 8 of them had no detectable IgG Ab and 9 had no detectable IgE Ab before therapy. The prevalence of IgG Ab response among 39 Dw2- subjects was markedly lower; only 11 (28%) responded well after 1-9 yr of therapy. Both by univariate and multivariate statistical analysis, Dw2 was also found to be strongly associated with the quantity of IgG Ab produced. In particular, both the strength and significance of the association between Dw2 and log[IgG Ab] response to Ra5 increased over a 3-yr period of ragweed therapy (P = 10(-9) by year 3). Multiple regression analysis also revealed a weak association with HLA-B13, which became apparent only after year 2 of therapy. Genetic hypotheses for these findings are discussed. In particular, the possibility of a second Ir gene, Ir-Ra5', separate from HLA-Dw2 and possibly located elsewhere in the genome, is considered.

HLA-Dw2: a genetic marker for human immune response to short ragweed pollen allergen Ra5. I. Response resulting primarily from natural antigenic exposure.

Ultra-pure short ragweed pollen allergen Ra5 (5,000 mol wt) was used to investigate the relationship between human leukocyte antigen (HLA) type and IgE and IgG antibody (Ab) responses to Ra5 in two groups of Caucasian subjects, totaling 447 people. Using highly sensitive radioimmunoassay procedures to measure serum IgE and IgG Ab, qualitative responses to Ra5 in both groups were found to be strongly associated with HLA-Dw2 (P less than 0.0001). For example, 95% of 38 people with IgE Ab vs. 22% of 139 ragweed-allergic persons having no detectable IgE Ab to Ra5 were Dw2+. Quantitative log [IgE Ab] and log[IgG Ab] responses to Ra5 were highly correlated with Dw2 (P = 10(-5) to 10(-14)) in four separate multiple regression analyses, examining the relationship between HLA type (and other variables) and Ab levels in the two study groups. Further studies showed that the primary association of Ra5 response was with Dw2 rather than DR2 and that various combinations of A3, B7, and Dw2 were less strongly associated than Dw2 alone.

Association of the HL-A7 cross-reacting group with a specific reaginic antibody response in allergic man.

A relatively small proportion (17 percent) of individuals highly allergic to ragweed were found to develop marked reaginic (immunoglobulin E-mediated) skin sensitivity to a minor ragweed pollen allergen Ra5 (molecular weight 5200). Sensitivity to Ra5 was significantly associated with the possession of a major histocompatibility antigen of the HL-A7 cross-reacting group. This appears to be the first evidence of a strong association between a specific immune response and a specific group of closely related HL-A antigens in man.

Gene interaction at HLA-DQ enhances autoantibody production in primary Sjögren's syndrome.

Primary Sjögren's syndrome is an autoimmune disorder characterized by dryness of the mouth and eyes. The human leukocyte antigen (HLA) locus DQ is related to the primary Sjögren's syndrome autoantibodies that bind the RNA proteins Ro/SSA and La/SSB. Both DQ1 and DQ2 alleles are associated with high concentrations of these autoantibodies. An analysis of all possible combinations at DQ has shown that the entire effect was due to heterozygotes expressing the DQ1 and DQ2 alleles. These data suggest that gene interaction between DQ1 and DQ2 (or alleles at associated loci), possibly from gene complementation of trans-associated surface molecules, influences the autoimmune response in primary Sjögren's syndrome.

Cytotoxic antibody in normal human serums reactive with tumor cells from acute lymphocytic leukemia.

Serums showing complement-dependent cytotoxic reactions to acute lymphocytic leukemia cells were detected in three normal unimmunized subjects. These serums were reactive with tumor cells from 514 (514 tested) acute lymphocytic leukemia patients, and three (12 tested) patients with acute myelocytic leukemia; they did not react with tumor cells from patients with acute monocytic leukemia (two tested), with chronic lymphocytic leukemia (two tested) or with leukolymphosarcoma (two tested); nor did they react with normal lymphocytes from 52 different donors. These reactive serums appear to recognize antigens primarily associated with acute lymphocytic leukemia.

A unique recombination event resulting in a C4A*Q0,C4B*Q0 double null haplotype.

The fourth component of complement (C4) is encoded by two closely linked genes (C4A and C4B) within the MHC. Null alleles at either locus (C4AQ0 or C4BQ0) are relatively common, occurring at the C4A locus in approximately 10% of normal individuals and at the C4B locus in approximately 16% of normal individuals. However, the presence of the double null haplotype (C4A*Q0,B*Q0) on the same chromosome is extremely rare. We recently studied a 7-yr-old patient with recurrent sinopulmonary infections in whom we documented the mechanism by which the C4A*Q0,B*Q0 double null haplotype arose. Evaluation revealed significantly reduced levels of both C4 antigen and C4 hemolytic activity. Analysis of extended haplotypes in the family was performed using MHC typing and genomic DNA analysis. The patient was found to have a C4A*3,B*Q0 haplotype and a C4A*Q0,B*Q0 haplotype. The C4A*3,B*Q0 haplotype was contributed by the father. The mother possessed a C4A*Q0,B*1 haplotype and a C4A*3,B*1 haplotype. The first maternal haplotype was involved in a recombination event within the C4B locus on her other chromosome and resulted in a new C4B*Q0 null allele and the patient's C4A*Q0,B*Q0 haplotype. Segregation analysis mapped the recombination to a region 3' to the unique 6.4-kb TaqI restriction fragment of the maternal C4B locus. This is the first demonstration of a recombination event producing a C4 double null haplotype.

Chronic lymphocytic leukemia and acquired disorders affecting the immune system: a case-control study.

The relationship of a number of subacute or chronic infectious diseases, connective tissue or autoimmune disorders, allergic conditions, and surgical excision of lymphoid tissue with chronic lymphocytic leukemia (CLL) was examined in a case-control study involving 342 cases and 342 matched controls. In both analyses of all matched pairs and those pairs in which both subjects were respondents, no statistically significant association was found between a history of subacute viral infections or subacute and chronic bacterial infections and CLL. Connective tissue or autoimmune disorders also were found not to be associated with CLL. Examination of the association between several allergic conditions and CLL suggested a protective effect as did a "dose-response" analysis, although none of the individual disorders showed a statistically significant relationship; however, a test for linear trend was significant (P = .04). Similarly, examination of the relationship between surgical excision of lymphoid tissue in several anatomic locations and CLL showed a protective effect, statistically significant for tonsillectomy-adenoidectomy (odds ratio = 0.69; 95% confidence interval = 0.48, 0.98). A statistically significant negative dose-response relationship, substantiating the protectiveness of the effect, was found.

A case-control and family study of Waldenstrom's macroglobulinemia.

Waldenstrom's macroglobulinemia (WM) is a rare disorder of lymphoid and plasma cells characterized by an immunoglobulin M (IgM) monoclonal gammopathy, clinical and immunopathologic similarities with other lymphoproliferative neoplasms, but the etiology of which is unknown. We undertook the first case-control study of this disorder among 65 cases, comprising 87% of all WM patients diagnosed during 1969-1983 in the greater Baltimore, Maryland area. Compared with 213 hospital controls without cancer, cases were slightly better educated, but there were otherwise no differences in sociodemographic factors, history of prior medical conditions, medication use, cigarette smoking, alcohol consumption, specific occupational exposures, employment in any particular industries or occupations, or familial cancer history. Cases were more likely than controls to have first-degree relatives with a history of pneumonia, diphtheria, rheumatic fever, and diabetes mellitus. An exploratory evaluation of immunologic profiles of first-degree relatives of 48% of families of cases revealed that relatives of two cases had asymptomatic IgM (> 750 mg/dl) monoclonal gammopathy and close to 40% of the 109 evaluated had diverse immunologic abnormalities. Larger population-based case-control studies are needed to further evaluate the suggestive evidence of immune dysfunction among families of WM cases.

Ro(SS-A) positive Sjogren's/lupus erythematosus (SC/LE) overlap patients are associated with the HLA-DR3 and/or DRw6 phenotypes.

Ro(SS-A) positive female Sjögren's syndrome (SS) lupus erythematosus (LE) overlap patients are a clinically and serologically homogeneous group generally demonstrating prominent subacute cutaneous lupus erythematosus (SCLE) lesions, cutaneous vasculitis, peripheral and central nervous system disease, pulmonary disease, and a low frequency of glomerulonephritis. They commonly demonstrate rheumatoid factor, hypergammaglobulinemia, antinuclear and Ro(SS-A) La(SS-B) antibody activity. This study indicates that these patients are also immunogenetically similar, sharing a statistically significant increased frequency of HLA-B8, DR3, DRW6, DQ2, and DRw52. Sixty-three percent of these SS/LE patients possess the extended haplotype (P-value 6.0 X 10(-3); RR 9.5) HLA-B8, DR3, DQ2, DRw52. One hundred percent of this SS/LE cohort was DR3 or DRw6 (P-value less than or equal to 5.0 X 10(-3); relative risk 19.1). Fifty percent of these patients were HLA DR3/DRw6 heterozygotes (P-value 1.5 X 10(-6); relative risk 31.2). Thus, HLA-DR3 and DRw6 Ro(SS-A) positive SS/LE patients may possess a similar, if not unique, DR region DNA nucleotide sequence involved in disease susceptibility or immune regulation.

The immunogenetic relationship between anti-Ro(SS-A)/La(SS-B) antibody positive Sjögren's/lupus erythematosus overlap syndrome and the neonatal lupus syndrome.

We have described previously the clinical features of a unique group of anti-Ro(SS-A) antibody positive Sjogren's patients who have cutaneous features of lupus erythematosus, most commonly subacute cutaneous lupus erythematosus, defined as the Sjogren's/lupus erythematosus overlap syndrome. Three of these patients are also mothers of infants with the neonatal lupus erythematosus syndrome, characterized by cutaneous lesions resembling subacute cutaneous lupus erythematosus or congenital heart block. Patients with Sjogren's/lupus erythematosus overlap syndrome, subacute cutaneous lupus erythematosus, and mothers of infants with the neonatal lupus syndrome characteristically have autoantibodies to Ro(SS-A), and in many cases, La(SS-B) antigens. The present study was designed to test the hypothesis that anti-Ro(SS-A)/La(SS-B) positive Sjogren's/lupus overlap patients and mothers of infants with neonatal lupus erythematosus syndrome are immunogenetically homogenous and closely related. We report a strong association with HLA-B8, DR3, DQw2, and DRw52 phenotypes and the HLA-B8, DR3, DQw2, DRw52 extended haplotype in both patient cohorts. Furthermore, we describe disease associations with HLA-DR3/DRw6 heterozygotes in both patient groups. These data demonstrate that anti-Ro(SS-A)/La(SS-B) positive Sjogren's/lupus overlap patients and neonatal lupus syndrome mothers are immunogenetically closely related to each other and appear to be more closely related to both primary Sjogren's syndrome and subacute lupus erythematosus, than to classical systemic lupus erythematosus.

Ascertainment of 21-hydroxylase deficiency in individuals with HLA-B14 haplotype.

21-Hydroxylase activity was measured in North American caucasian individuals with the HLA-B14 antigen to estimate the frequency of heterozygosity for the attenuated congenital adrenal hyperplasia trait. A 30-min iv ACTH stimulation test was administered to 9 normal HLA-B14-positive subjects and to a comparable HLA-B14-negative control group. Changes in plasma progesterone and 17-hydroxyprogesterone over 30 min were summed and expressed as a combined rate of rise. Six of 9 HLA-B14-positive individuals had a rate of rise greater than 2 SD above the mean control value. On this basis, about two thirds of B-14-positive individuals are heterozygote carriers for 21-hydroxylase deficiency. Thus, the frequency of the attenuated form of congenital adrenal hyperplasia linked to the HLA-B14 locus in women is approximately 1 in 6000 if there is only 1 B14, and 1 in 2000 if there are 2 B14s in the HLA type.

The attenuated form of congenital adrenal hyperplasia as an allelic form of 21-hydroxylase deficiency.

A 17-yr-old female presented with marked menstrual irregularities since menarche at age 13 yr and severe hirsutism, particularly facial, since puberty. Her disorder was shown to be related to a mild 21-hydroxylase deficiency and she was diagnosed to have an attenuated (so-called acquired) form of congenital virilizing adrenal hyperplasia. HLA typing and ACTH testing of her parents and siblings provided evidence of a linkage between HLA and 21-hydroxylase deficiency loci. Similar observations have been made previously for the salt-losing and simple virilizing forms of congenital virilizing adrenal hyperplasia, suggesting that these two as well as the attenuated forms are allelic in regard to the 21-hydroxylase deficiency gene.

Coupling of HLA-A3,Cw6,Bw47,DR7 and a normal CA21HB steroid 21-hydroxylase gene in the Old Order Amish.

HLA-Bw47, a rare human histocompatibility antigen, occurs in strong linkage disequilibrium with HLA-A3,Cw6,DR7 and salt-losing congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency and is associated with a contiguous deletion of the active CA21HB gene and the C4B complement gene. We studied the HLA-A3,Cw6,Bw47,DR7 haplotype in 10 subjects of the Old Order Amish of Lancaster County in Pennsylvania and found that this haplotype, which occurs with a similar frequency in this group as in the general caucasoid population, has C4B and Ca21HB genes. These C4B and CA21HB genes are expressed as assessed by C4 typing and iv ACTH testing, respectively. Serological studies indicate that the HLA-D loci of this Amish haplotype are the same as those in patients with HLA-Bw47 and CAH, but different from HLA-D loci coupled to HLA-B13, which some workers have proposed is the progenitor genotype for HLA-Bw47. Our studies demonstrate that 1) HLA-Bw47 is not an invariant marker for salt-losing CAH due to 21-hydroxylase deficiency, and 2) the HLA-Bw47 phenotype coupled to CAH is not derived from the HLA-B13 genotype by a single mutation.

Attenuated forms of congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

A variety of mild forms of congenital adrenal hyperplasia (CAH) due to partial 21-hydroxylase deficiency have recently been described. We report two families in whom members presented with CAH with various degrees of enzyme deficiency. In family A, two children had the classical salt-losing CAH. Their male sibling and mother presented a very mild asymptomatic form of CAH, characterized by elevated basal plasma levels of 17-hydroxyprogesterone (17-OHP) and exaggerated responses of progesterone and 17-OHP to ACTH stimulation. The Hormonal profile and HLA types of these two individuals suggested allelic compounds, having one mutant gene for classical CAH and another for a mild form. In family B, the proband presented an attenuated form of CAH, manifested by amenorrhea and hirsutism, elevated basal levels of plasma 17-OHP and androgens, as well as markedly increased ACTH response. Two of her four siblings had the same ad HLA type, elevated basal plasma 17-OHP levels, and increased ACTH response. Their father, their paternal aunt, and their paternal uncle had the ab HLA type and normal basal plasma 17-OHP but markedly increased ACTH response. The haplotypes a, b, and d were considered to be linked to a mutation resulting in mild 21-hydroxylase deficiency, the homozygotes with ab HLA type having a milder form of CAH than the homozygotes with the ad HLA type. The wide spectrum of clinical and hormonal characteristics among homozygotes for the 21-hydroxylase deficiency trait suggests that their is a continuum of degree of enzyme deficiency. Furthermore, it suggests that most nonclassical subjects are allelic compounds for variable degrees of severity in the mutation at the 21-hydroxylase locus. More specifically, the study of families A and B shows that the so-called cryptic and attenuated forms of CAH have the same pathophysiological basis.

Etiologic factors in renovascular fibromuscular dysplasia. A case-control study.

The role of several factors that have been suggested as being of etiologic importance in renovascular fibromuscular dysplasia was examined in a case-control study of 33 patients with angiographically demonstrated fibromuscular dysplasia and 61 renal transplant donor control subjects with normal renal arteries. The factors studied included use of oral contraceptive agents or markers of sex hormone dysfunction, mechanical stress to the renal artery wall, human lymphocytic antigen (HLA) type, cigarette smoking, history of hypertension for more than 5 years, and family history of cardiovascular disease. The risk of fibromuscular dysplasia was significantly (p = 0.003) increased (odds ratio = 4.1, 95% confidence interval = 1.5-10.9) among cigarette smokers. A significant (p less than 0.001) dose-response relation was noted between cigarette use and the risk of fibromuscular dysplasia developing (odds ratio = 8.6 for those who had smoked more than 10 pack-years). Personal history of hypertension more than 5 years was also associated (odds ratio = 5.0, 95% confidence interval = 1.1-22.8) with a significantly (p = 0.036) increased risk for the development of fibromuscular dysplasia. HLA-DRw6 antigen was more common in the 33 fibromuscular dysplasia patients than in the 61 renal transplant donor control subjects (odds ratio = 3.00, p = 0.067) or a second group of 934 ambulatory control subjects (odds ratio = 2.51, p = 0.031). Adjustment for cigarette smoking increased the odds ratio to 5.0 (95% confidence interval = 1.3-19.6). There was a positive though not statistically significant (odds ratio = 1.7, p = 0.175) association noted between family history of cardiovascular disease and fibromuscular dysplasia.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypomorphic C4B* 15 variant of the fourth component of complement.

We report a rare 'hypomorphic' C4 allotype detected during routine screening in controls for the Rogers:1 epitope. C4B* 15 was distinguished by having only faint staining when using polyclonal anti-C4 antibody on agarose immunoelectrophoresis (e.g. hypomorphic), having relatively weak hemolytic activity but being strongly reactive with monoclonal antibody to Rodgers 1. TaqI restriction fragment length polymorphism (RFLP) demonstrated that C4B* 15 segregated with 7 kb and 5.4 kb C4 gene fragments and with the haplotype HLA-A2,C-, B50,BW6,DR7,DQ2,DR52,SO7C2(1,15). The 5.4-kb fragment was more intense than the 7.0-kb fragment, suggesting duplication of the 5.4-kb fragment. This hypomorphic C4 allotype (genotype frequency = 0.0088) has diminished expression of C4 epitopes commonly recognized by polyclonal anti-C4 and may be missed by standard phenotyping methods.

Neonatal lupus erythematosus syndrome: analysis of C4 allotypes and C4 genes in 18 families.

We examined 18 families with infants who had neonatal lupus erythematosus (NLE) syndrome to determine whether abnormalities in C4 phenotypes and genotypes were an additional risk factor for this syndrome. Fifteen of 18 mothers of infants with NLE (83%) had C4 null allotypes compared with 36% of population controls (p = less than .001). This increased frequency was due mainly to the presence of C4A null allotypes (11/18, 61%). C4 gene abnormalities, i.e., deletion or probable duplication, were present in 100% (16/16) of mothers of infants with NLE. The most common molecular genetic abnormality in mothers of infants with NLE in this study was deletion of C4A genes. Duplication of C4A and C4B loci was also commonly seen. Duplication of C4A genes was detected only in mothers of infants with complete congenital heart block (CCHB), and duplication of C4B was detected only in mothers of infants with dermatitis. No significant increase in C4A or C4B null allotypes or protein deficiencies was noted in mothers of infants with neonatal lupus when compared with anti-Ro(SS-A)-positive mothers delivered of clinically normal infants. Fathers of infants with NLE showed a trend toward increase in C4B null allotypes when compared with population controls (75%, 3/4, p = .06). The two infants with CCHB examined were C4B protein-deficient, in contrast to infants with lupus dermatitis, who had frequent C4B null allotypes but no C4B protein deficiency. C4B null allotypes were not seen in unaffected siblings of infants with NLE and in only 1 of 7 anti-Ro(SS-A)-positive mothers who delivered clinically normal infants. We conclude that inheritance of C4A null allotypes is not predictive of increased risk of neonatal lupus when present in anti-Ro(SS-A)-positive women. Examination of paternal and maternal C4 genes of additional infants with NLE, in particular those with CCHB, and of normal infants born to anti-Ro(SS-A)-positive mothers--and of the normal infants' parents--is required to determine if abnormal C4B genes are a critical factor rendering susceptibility to the NLE syndrome.

Neonatal lupus erythematosus. A clinical, serological and immunogenetic study with review of the literature.

Neonatal lupus erythematosus (NLE) is an inflammatory disorder of neonates characterized by transient cutaneous lesions and/or congenital heart block. The cutaneous lesions usually heal with minimal scarring, but healing may be delayed for many months in occasional cases. Photosensitivity is recognized as a component of this syndrome. A large proportion of this maternal population is asymptomatic, although the mothers' potential risk for developing CTD in the future remains to be determined. Moreover, this maternal group may exhibit a tendency to fetal wastage. La(SSB) and/or Ro(SSA) antibody is almost universally present in the sera of the neonatal lupus mothers and their infants. Since these antibodies may have a pathogenetic role in NLE, screening of infants with isolated CHB and/or cutaneous lesions suggestive of LE, and their mothers, for the presence of Ro(SSA) and La(SSB) antibodies is strongly recommended. HLA studies reveal that infants of Ro-positive mothers bearing the HLA, A1, B8, DR3, MB2 and MT2 phenotypes are at increased risk of developing neonatal lupus, in sharp contrast to infants of Ro-positive mothers bearing the DR2 and/or MB1/MT1 phenotypes. Recognition of the protean manifestations of this complex disorder by obstetricians, pediatricians, cardiologists, and dermatologists will undoubtedly lead to increased detection of NLE and afford further opportunity to elucidate more fully the etiology of this syndrome.

Familial systemic lupus erythematosus: immunogenetic studies in eight families.

Familial SLE provides a unique opportunity to study the relationships of previously associated genetic factors (HLA and complement component deficiencies) to the occurrence of SLE, other immune disorders, and autoantibodies in families. Thus, eight families containing two or more affected members with SLE (n = 22) and their relatives (n = 40) were examined for HLA genotypes, complement components and autoantibodies. Among the 40 non-SLE relatives, 7 (18%) had other immune diseases, including thyroid disease in 2, rheumatoid arthritis in 2, ITP in 2, and Henoch-Schönlein purpura in one. This compared to 4 of the 22 SLE patients (also 18%) of whom 3 had thyroid disease and one PSS. Eleven non-SLE relatives (28%) had ANA, which was in high-titer in 5 (13%). Eleven (28%) had antibodies to ssDNA, and one had a BFP. Only the SLE patients had antidsDNA, Ro(SSA), Sm or nRNP. A heterozygous C2 deficiency (C2D) was found in only one of the seven kindreds studied, and followed an A25, B18 DR7 haplotype. Heterozygous C2D, however, was inherited by only one of three family members with SLE. HLA-DR2 occurred in 36% and DR3 in 36% of SLE patients, which was not significantly different from either non-SLE family members or unrelated local controls. Sib pair analysis of seven sets presented here and seven from two published reports, demonstrated only random distribution with SLE. Similarly, other immune disorders and autoantibodies followed no consistent HLA haplotypes or DR specificities. Interestingly, DR2 and/or DR3 were found in five of the six patients (83%) having anti-ro(SSA) antibodies (p = NS). These data strongly suggest that genetic factors (other than HLA and complement component deficiencies) and/or environmental factors are necessary for the expression of SLE and other immune abnormalities in lupus families.