Blood Group, Cromer System

A number sign (#) is used with this entry because the Cromer blood group system is based on homozygous mutation in the CD55 gene (CD55; 125240) on chromosome 1q32.

Description

The Cromer blood group system (CROM) consists of 12 high-prevalence and 3 low-prevalence antigens that reside on decay-accelerating factor (DAF, or CD55; 125240), a regulator of complement activation. Nearly all Cromer antigens result from SNPs in the DAF gene. The red blood cells (RBCs) of people with the Cromer-null phenotype, Inab, lack DAF but do not appear to show increased susceptibility to hemolysis. Antibodies to Cromer antigens are rarely encountered, although evidence suggests that the antibodies may cause accelerated destruction of transfused RBCs. Cromer system antibodies are not associated with hemolytic disease of the newborn, because placenta is a rich source of fetally derived DAF, which is thought to absorb the antibodies (review by Storry et al., 2010).

The Inab phenotype is associated with CHAPLE syndrome (226300) in some individuals.

Clinical Features

Inab Phenotype

Daniels et al. (1982) reported a 27-year-old Japanese man, designated 'Inab,' whose red blood cells failed to react with anti-Cr(a) sera and with 3 Cromer-related sera, designated BP, GT, and KTO. His serum reacted with all red blood cells tested except his own. The patient also had protein-losing enteropathy (see 226300) and an ileocecal tumor; after he underwent hemicolectomy, the protein-losing enteropathy was reported to have resolved. Daniels et al. (1982) suggested that the 'Inab' phenotype represented a null phenotype in the Cromer complex.

Walthers et al. (1983) described a 25-year-old Caucasian man (JF), with a history of Crohn disease (see 266600) and prior transfusions, whose erythrocytes typed Tc(a- b- c-) and Cr(a-) and were also negative for other high-frequency antigens, consistent with the Inab phenotype. The authors noted that this patient and the original Inab proband reported by Daniels et al. (1982) had a history of protein-losing enteropathy.

Lin et al. (1988) reported an 86-year-old Italian American woman and her 70-year-old brother who both exhibited the Inab phenotype but had no history of intestinal disease. The authors noted that the Inab phenotype appeared to be a heritable characteristic in this family.

Dr(a-) Phenotype

Levene et al. (1984) described 2 Israeli sisters (MD and NL), born of Jewish parents from Bukhara, whose red cells had very weak Cr(a) and Tc(a) antigens and reacted only weakly with the antibody of the Cr(a-)Tc(a-) individual, Inab. Both sisters had an antibody, designated anti-Dr(a), to a high-frequency antigen absent from their own cells and Inab cells, but present on Cr(a-)Tc(a+) and Cr(a+)Tc(a-) cells. Levene et al. (1984) stated that this was the third example in which both Cr(a) and Tc(a) antigens were either absent or showed weakened expression on red cells, but the first case in which the unusual phenotype was shown to be inherited.

Levene et al. (1987) studied a 68-year-old Israeli woman, born in Samarkand in the Soviet Union, who had anti-Dr(a) in her serum and whose red cells were Dr(a-), as were those of 3 of her 4 children. All Dr(a-) cells had weakened expression of their Cr(a), Tc(a), Es(a), IFC, and other Cromer-related antigens. Anti-Dr(a) was inhibited by serums from Dr(a+) but not Dr(a-) members of the family. The proband was diagnosed with rectal carcinoma and underwent deep x-ray therapy and surgery. The authors noted that Samarkand is a neighboring city in the same region as Bukhara in the Uzbekskaya SSR in the southern part of the Soviet Union, from which the Dr(a-) family described by Levene et al. (1984) originated, but Levene et al. (1987) stated that there was no evidence to suggest that the 2 families were related.

Reid et al. (1991) reported a 38-year-old Russian woman (KZ), admitted to the hospital for surgery to correct a chronic intestinal disorder of unknown etiology, who they stated was the fourth proband with the Inab phenotype. Lublin et al. (1994) restudied patient KZ and demonstrated that her red cell phenotype was Dr(a-) rather than Inab. Whereas previously immunoblot showed no reaction with KZ red cell membranes, analysis of an immunoblot using murine MoAbs to different epitopes on DAF to increase sensitivity showed that KZ erythrocyte membranes reacted with murine MoAbs at a strength comparable to Dr(a-) membranes, but more weakly than control Dr(a+) membranes. In contrast, Inab phenotype membranes failed to react at all with the DAF MoAbs. Furthermore, flow cytometry studies showed that KZ reacted to the Dr(a+) but not the Dr(a-) variant of DAF, indicating that KZ antibody could distinguish the single amino acid difference between DR(a+) and Dr(a-) (see MOLECULAR GENETICS).

Reid et al. (1996) studied 2 cases in which strongly reactive Cromer system antibodies, anti-Cr(a) and anti-Dr(a), became undetectable during the second and third trimesters of pregnancy.

Molecular Genetics

Inab Phenotype

The Inab phenotype, or Cromer null, in which RBCs lack all Cromer system antigens, is very rare. In the 27-year-old Japanese man in whom the Inab phenotype was first detected (Daniels et al., 1982), Lublin et al. (1994) demonstrated homozygosity for a nonsense mutation in exon 2 of the DAF gene (W53X; 125240.0001). The mutation truncated DAF near the N terminus, explaining the complete absence of surface DAF in the red cells of the individual.

In a 28-year-old Japanese woman, Wang et al. (1998) demonstrated that the Cromer Inab phenotype was due to homozygosity for a c.1579C-A transversion at the position 24 bp upstream of the 3-prime end of exon 2 of the CD55 gene (125240.0002). This substitution resulted in an mRNA with a 26-bp deletion, which introduced a frameshift and created a stop codon immediately downstream of the deletion. Translation of the mRNA would be terminated at the first amino acid of the second short consensus repeat (SCR2) domain of DAF. Wang et al. (1998) noted that this proband, like the Italian American woman and her brother with the Inab phenotype reported by Lin et al. (1988), did not have a history of intestinal disease.

In a Japanese woman (Osad family) with the Inab phenotype, who exhibited the characteristic anti-IFC antibody, Daniels et al. (1998) identified homozygosity for the W53X mutation in the DAF gene. She was not known to be related to the Japanese man in whom the phenotype was originally described. Her unaffected parents were heterozygous for the mutation; DNA from her unaffected children was not tested. The proband was also reported to have a capillary angioma of the small intestine.

Dr(a-) Phenotype

In an Israeli woman of Russian ancestry (MD) with the Dr(a-) phenotype, originally described by Levene et al. (1984), Lublin et al. (1991) sequenced the coding region of membrane DAF and identified homozygosity for a missense mutation (S165L; 125240.0003). Sequencing of DNA from the identified region in 2 unrelated Dr(a-) individuals showed that both were homozygous for the same variant in the DAF gene. Lublin et al. (1991) designated the Dr(a-) allele of DAF 'Dr(b).'

In a Russian woman (KZ) with the Dr(a-) phenotype, previously studied by Reid et al. (1991), Lublin et al. (1994) identified homozygosity for the S165L substitution in the DAF gene. Analysis of the proband's cDNA yielded 2 products: a full-length 291-bp sequence with the S165L change, and a more abundant 247-bp product. The authors showed that the single nucleotide transition results in 2 changes: an amino acid substitution that is the basis for the antigenic variation, and an alternative splicing event that underlies the decreased expression of DAF in the Dr(a-) phenotype.

In a Japanese female blood donor (Kim) with the Dr(a-) phenotype, Daniels et al. (1998) identified homozygosity for the S165L substitution in the DAF gene.

Exclusion Studies

Yazer et al. (2006) studied a 1.5-year-old Caucasian boy born with congenital cytomegalovirus disease causing blindness and deafness, who also had severe growth retardation and significant gastroesophageal reflux disease requiring a feeding tube. Routine pretransfusion testing in advance of cochlear implant surgery revealed an Inab phenotype and a potent panagglutinin that did not react with Dr(a-) or IFC erythrocytes. Flow cytometry initially indicated that the patient's red blood cells lacked CD55 (1.6% of that of control); however several months later, CD55-positive cells had increased to 28% of control, and the anti-IFC was virtually undetectable. Analysis of the exons 2 through 6 of the CD55 gene and their flanking intronic sequences revealed no mutations. Yazer et al. (2006) noted that in early reports of the Inab phenotype, the 4 unrelated probands had gastrointestinal abnormalities, but 6 other Inab phenotype individuals, including 2 transient Inab patients, did not show or have a history of gastrointestinal abnormalities.