Rh-Null, Amorph Type

A number sign (#) is used with this entry because of evidence that the amorph type of RH-null phenotype is caused by homozygous mutation in the RHCE gene (111700) on chromosome 1p36.

Description

The RH-null phenotype designates rare individuals whose red blood cells lack all Rh antigens. Two RH-null types, the regulator type (268150) and the amorph type, arising from independent genetic mechanisms have been distinguished. The regulator type is caused by mutation in the RHAG gene (180297). The amorph type arises from mutations at the RH locus itself that silence Rh expression. The RH locus contains the RHD (111680) and RHCE genes tandemly arranged at chromosome 1p36-p34. Four genes must therefore be silenced to produce the RH-null phenotype. The absence of the D antigen, produced by the RHD gene, is common in the human population; the D-negative phenotype may result from deletion or genetic alteration of the RHD gene. The RH-null amorph phenotype thus arises from inactivating mutations in RHCE on a D-negative background (summary by Huang et al., 1998, Huang et al., 2000).

Clinically, Rh-null patients present mild to moderate hemolytic anemia; cells exhibit characteristic morphologic and functional abnormalities including spherocytosis, stomatocytosis, and diminished lifespan. Rh-null patients rarely develop antibodies without stimulation, and most cases occur in response to pregnancy or transfusion (Silvy et al., 2015).

Clinical Features

Seidl et al. (1972) reported 2 German sibs from a consanguineous family in whom Rh determination revealed complete lack of all Rh antigens. In the female sib, hemolytic anemia was detected during hospitalization for bronchopneumonia; a splenectomy was performed because of suspicion of a hereditary spherocytosis. Both she and her male sib reported several periods of jaundice which they attributed to stress situations (e.g., appendectomy, university graduation, business problems). These patients were later analyzed molecularly by Huang et al. (1998) and Cherif-Zahar et al. (1998).

In a survey of 42 examples of the Rh-null phenotype, Nash and Shojania (1987) found that only 5 were of the amorph type.

Perez-Perez et al. (1992) described a Spanish family in which a silent Rh gene was segregating, giving rise to the amorph type of Rh-null in the proposita whose parents were first cousins. She suffered from severe hemolytic anemia. Western blot analysis carried out with glycosylation-independent antibodies directed against the Rh polypeptide and the LW glycoprotein, respectively, confirmed that these protein components were absent from the red cells of the proposita.

Silvy et al. (2015) studied a 32-year-old pregnant woman from Libya with moderate hemolytic anemia and a history of 5 pregnancies with varying degrees of hemolytic disease of the fetus and newborn (HDFN). The fourth pregnancy resulted in stillbirth and the fifth fetus died in utero at 32 weeks' gestation despite a normal ultrasound at 30 weeks. Rh phenotyping revealed that her red blood cells lacked all common Rh antigens.

Molecular Genetics

In 2 German sibs with complete lack of all Rh antigens from a consanguineous family, Huang et al. (1998) and Cherif-Zahar et al. (1998) detected homozygosity for deletion of 2 nonadjacent nucleotides in exon 7 of the RHCE gene (111700.0003). The RHD gene was deleted.

In a Spanish patient previously reported by Perez-Perez et al. (1992), Cherif-Zahar et al. (1998) detected a homozygous splice site mutation at the donor site of intron 4 of the RHCE gene (IVS4+1G-T; 111700.0004). The RHD gene was deleted.

In a 23-year-old Caucasian Brazilian woman and her sister with Rh-null phenotype, Rosa et al. (2005) detected homozygosity for a 1-bp deletion in exon 7 of the RHCE gene (111700.0005). The RHD gene was absent in both sisters.

In a 32-year-old Libyan woman with Rh-null phenotype from a consanguineous family, Silvy et al. (2015) detected homozygosity for a 7-bp duplication (c.1044_1050dup; 111700.0006) in exon 7 of the RHCE gene. The RHD gene was deleted.