The Rh antigen system is a complex blood group system comprised of Rh proteins, Rh glycoproteins, and other associated proteins, all of which are components of the erythrocyte membrane. The complexity of these proteins has an important role in maintaining the integrity of the erythrocyte membrane. The RhD protein represents the Rh antigen D, and the RhCE protein is responsible for the C, c, E, and e antigenicity. Both proteins are encoded on chromosome 1 and have very similar amino acid sequences and structures, but are antigenically distinct [1]. The RhAG (Rh-associated glycoprotein) has limited (about 40%) similarity to the Rh proteins and is encoded on chromosome 6. The RhD and RhCE proteins form tetrameric complexes with RhAG; the complexes are thought to interact with accessory proteins, such as light-weight (LW) glycoprotein, integrin-associated protein (CD47), glycophorin B, and others [1]. Among these proteins the Rh antigen D is the most immunogenic: therefore, the presence or absence of the Rh D antigen - the Rh positive or negative status - is routinely determined in blood donors or recipients and pregnant women. Nevertheless, for various reasons, Rh immunization may still occur in pregnancy in mothers who lack the D antigen. The reaction may cause hemolytic disease of the newborn [1].

The Rh deficiency syndrome is defined by the absence of all Rh proteins (Rhnull), or by a very substantial reduction in their amounts (Rhmod). Other proteins that are absent or considerably reduced in this condition are RhAG and many of the accessory proteins (for example glycophorin B, LW and Fy5 glycoproteins, U and Duclos antigens) [2]. The Rh deficiency syndrome is either caused by a regulatory element that is located outside the Rh locus (regulatory type deficiency), or by the presence of silent Rh genes at the Rh locus (referred to as amorph type). The genetic defects, which may be due to various mutations or deletions or the combination of both, [3] are recessive in both cases. The symptoms of the disease, i.e. signs of chronic hemolytic anemia, are also the same and are associated with the anomalies in the erythrocyte cell’s membrane structure [4]. The condition is very rare: 1 in about six million is affected [1].

Patients with the Rh deficiency syndrome show signs of compensated hemolytic anemia, the severity of which is variable, with deformities in cell shape [5], i.e. stomatocytosis and spherocytosis. The osmotic fragility of erythrocytes is increased, and their lifespan is decreased. Cation transport and Na+/K+ adenosine triphosphatase activity are increased [6], leading to dehydration of the cell [4]. Another sign of disruption of membrane structure is an abnormal phospholipid distribution [7]. Patients may present with reticulocytosis [5].

• Down Syndrome

  syndromeダウン症候群 Duchenne muscular dystrophy (DMD)デュシェンヌ型筋ジストロフィー[症] ductus arteriosus動脈管 duodenal atresia十二指腸閉鎖[症] dyspnea呼吸困難 e Ehlers-Danlos syndromeエーラース・ダンロス症候群 electroencephalogram (EEG)脳波 emotional abuse情緒的虐待 encephalitis脳炎 encephalopathy脳症 endocardial [tokyo-med.ac.jp]

• Jaundice

  (yellow) R17 ICD-10-CM Diagnosis Code R17 Unspecified jaundice 2016 2017 2018 2019 Billable/Specific Code Type 1 Excludes neonatal jaundice ( P55, P57 - P59 ) newborn P59.9 ICD-10-CM Diagnosis Code P59.9 Neonatal jaundice, unspecified 2016 2017 2018 [icd10data.com]

  Neonatal jaundice due to G6PD deficiency differs from the classic Rhesus (Rh)-related jaundice in its time of onset (peak incidence between day 2 and 3) and severity of jaundice, which outweighs the severity of anemia. [cancertherapyadvisor.com]

  This is the test that is done on the newborn's blood sample, usually in the setting of a newborn with jaundice. [med.stanford.edu]

  Neonatal Jaundice and Disorders of Bilirubin Metabolism. In: Nathan and Oski’s Hematology of Infancy and Childhood, 7th ed. [rarediseases.org]

  CHD)先天性心疾患 congenital hiatus hernia先天性食道裂孔ヘルニア congenital hypoparathyroidism先天性副甲状腺機能低下症 congenital hypothyroidism先天性甲状腺機能低下症 congenital malformation先天奇形 congenital myopathy先天性ミオパチ（シ）－ congenital omphalocele先天性臍帯ヘルニア constipation便秘[症] constitutional jaundice [tokyo-med.ac.jp]

• Hypotension

  Allergic or hypersensitivity reactions may occur with Rhophylac; early signs of hypersensitivity include generalized urticaria, chest tightness, wheezing, hypotension, and anaphylaxis. Rhophylac is derived from human plasma. [rhophylac.com]

  Untreated B 12 deficiency causes balance problems, paresthesias, weakness, dizziness, postural hypotension, and visual disturbances. [pharmacytimes.com]

• Short Arm

  1974, Mapping human autosomes: Evidence supporting assignment of Rhesus to the short arm of chromosome no. 1, Science 184 : 966–968. CrossRef Google Scholar Merlie, J. [link.springer.com]

Patients with the Rh deficiency syndrome may be identified through routine testing, or because of signs of anemia. Family history may reveal consanguineous parentage [8].

Hematologic tests will show signs of mild hemolytic anemia, with somewhat low total hemoglobin, hematocrit, and mean corpuscular hemoglobin values [8]. The reticulocyte count may be higher than normal [5] [8]. The peripheral smear shows some cells with abnormal shapes i.e. stomatocytes and spherocytes. The osmotic fragility of red cells is examined by exposing them to various NaCl concentrations and following the degree of hemolysis: patients with the Rh deficiency syndrome have characteristically higher osmotic fragility than healthy individuals [5] [8]. The serum bilirubin concentration may be slightly increased because of the chronic hemolysis [5]. Monoclonal antibodies can be used to determine individual antigens within the Rh family of proteins and associated proteins. The tests will show that the Rh D, C, c, E, and e antigens, together with those for some other membrane glycoproteins are missing in cases with the Rh deficiency syndrome [8].

In patients with the Rhnull syndrome, antibodies to erythrocytes encountered through transfusion or during pregnancy may have specificities to one antigen (for example anti-C), a mixture of antigens, or all Rh antigens. These antibodies can be detected by the indirect antiglobulin test. The anti-total Rh antibody is called anti Rh29 [1] [2].

• Human Papillomavirus

  Furthermore, in contrast to AD-HIES, in autosomal recessive form of the syndrome, a predisposition to severe fungal and viral cutaneous infections occurs with herpes simplex and herpes zoster, molluscum contagiosum and human papillomavirus [ 80 ]. [ojrd.biomedcentral.com]

1. Avent ND, Reid ME. The Rh blood group system: a review. Blood. 2000 Jan 15;95(2):375-387.
2. Chérif-Zahar B, Raynal V, Le Van Kim C, et al. Structure and expression of the RH locus in the Rh-deficiency syndrome. Blood. 1993 Jul 15;82(2):656-562.
3. Huang CH, Chen Y, Reid ME, Seidl C. Rhnull disease: the amorph type results from a novel double mutation in RhCe gene on D-negative background. Blood. 1998 Jul 15;92(2):664-671.
4. Cartron JP. Rh-deficiency syndrome. Lancet. 2001 Dec;358 Suppl:S57.
5. Sturgeon P. Hematological observations on the anemia associated with blood type Rhnull. Blood. 1970 Sep;36(3):310-320.
6. Lauf PK, Joiner CH. Increased potassium transport and ouabain binding in human Rhnull red blood cells. Blood. 1976 Sep;48(3):457-468.
7. Kuypers F, van Linde-Sibenius-Trip M, Roelofsen B, Tanner MJ, Anstee DJ, Op den Kamp JA. Rhnull human erythrocytes have an abnormal membrane phospholipid organization. Biochem J. 1984 Aug 1;221(3):931-934.
8. Qureshi A, Salman M, Moiz B. Rhnull: a rare blood group phenotype. J Pak Med Assoc. 2010 Nov;60(11):960-961.