Asplenia, Isolated Congenital

A number sign (#) is used with this entry because of evidence that isolated congenital asplenia (ICAS) is caused by heterozygous mutation in the RPSA gene (150370) on chromosome 3p21.

Description

Isolated congenital asplenia is a rare cause of primary immunodeficiency. Most affected individuals die of severe bacterial infections in early childhood. Isolated asplenia is distinct from asplenia associated with other complex visceral defects, notably heterotaxy syndromes such as Ivemark syndrome (208530) (summary by Mahlaoui et al., 2011).

Clinical Features

Kevy et al. (1968) described a sibship, with consanguineous parents, in which 1 of 2 boys and 2 of 3 girls had splenic hypoplasia. One of the children died at 10 months of overwhelming haemophilus influenzae sepsis. The other 2 had repeated episodes of pneumococcal meningitis and H. influenzae sepsis. Absence of the spleen was demonstrated by radioactive scanning after injection of Au(198) colloid and chromium-tagged, heated red cells, by the presence of Howell-Jolly bodies and Heinz bodies in the peripheral blood, and by failure to synthesize antibody to sheep red blood cells injected intravenously. The situation is comparable to that in infants in whom the spleen is removed in early life.

Among 60 children with asplenia or polysplenia studied in Toronto, Rose et al. (1975) found 2 families in which 2 sibs had isolated asplenia and 1 family in which 2 sibs had polysplenia.

Gates and Black (1986) reported a family ascertained through 2 children, a 5.5-month-old girl and a 3.5-year-old boy, who died from fulminant pneumococcal sepsis. Neither child had Howell-Jolly bodies on peripheral blood smear. Autopsy on each child revealed marked hyposplenia and no other anatomic abnormalities. The mother was demonstrated to have splenic hypoplasia by ultrasound. A male infant delivered at 6 weeks' gestation was found on isotope studies to have no splenic activities although ultrasound showed a splenic mass.

Dyke et al. (1991), Gill and Kara (1991), and Moore (1991) discussed septicemia and adrenal hemorrhage in congenital asplenia.

Gillis et al. (1992) described a boy and a girl, offspring of nonconsanguineous white Australian parents, with fulminant infections early in life. Blood films from both children showed numerous erythrocytes containing Howell-Jolly bodies. Gillis et al. (1992) presented this as an instance of recessively inherited congenital asplenia with normal heart.

Ferlicot et al. (1997) reported a French family in which a previously healthy 22-month-old boy was hospitalized after he sustained a fall followed by vomiting. Examination revealed a conscious child with no neurologic deficits, but he had fever of 40 degrees centigrade. He continued to be febrile and died 7 hours after admission following an episode of cardiorespiratory distress requiring intubation. Postmortem bacteriologic analysis revealed Streptococcus pneumoniae in his cerebrospinal fluid and blood, and autopsy showed a normally situated but very small spleen containing a large fibrous nodule surrounded by abundant iron deposits. There was preservation of the remainder of the splenic architecture, which consisted largely of red pulp; on histology, only 3 Malpighian corpuscles could be distinguished. Ferlicot et al. (1997) concluded that this degree of splenic hypoplasia represented functional congenital asplenia. Ultrasonographic examination of the patient's parents and twin sister revealed no splenic anomalies.

Gilbert et al. (2002) reported an 11-month-old girl with isolated congenital asplenia who developed recurrent pneumococcal meningitis. The first episode was successfully treated, but the second was fatal. Howell-Jolly bodies were found afterwards on blood smears taken during the first episode of pneumococcal meningitis. Her father had developed pneumococcal meningitis, which improved with parenteral antibiotic treatment. Howell-Jolly bodies were present on blood smears from the father but were ascribed to a spleen injury. The father was shown to be asplenic by ultrasound and abdominal CT after the death of the child. Gilbert et al. (2002) reviewed 31 cases in the literature, of which 13 were sporadic and 18 were familial (from 8 families). Of the 8 families, the pattern of only 1 (Kevy et al., 1968) favored autosomal recessive inheritance. Gilbert et al. (2002) emphasized the importance of checking for Howell-Jolly bodies on blood smears and performing an ultrasound examination to rapidly diagnose congenital asplenia to allow life-saving antibiotic prophylaxis and pneumococcal vaccination.

Mahlaoui et al. (2011) reported the retrospective identification of 20 patients from 10 unrelated French families with isolated congenital asplenia or hyposplenia, 2 of which had been previously described (family B, Ferlicot et al., 1997; family C, Gilbert et al., 2002). None of the families was consanguineous. The median age at diagnosis was 11 months, and most symptomatic patients presented by 12 months of age with an invasive bacterial infection, most commonly Streptococcus pneumoniae. All 13 patients tested had Howell-Jolly bodies on peripheral blood smear, and 4 patients had thrombocytosis. Other immunologic studies were normal, and patients developed antibody responses. Nine (45%) of 20 patients died of overwhelming sepsis at a median age of 12 months. There appeared to be a decreasing incidence of severe infections with age.

Koss et al. (2012) reported detailed features of a family of African descent with congenital asplenia (family E in Mahlaoui et al., 2011). In this family, 3 children died of fulminant infection within the first year of life; they were not further studied. A fourth child died of sepsis at age 23 months. Postmortem examination of this child showed asplenia with normal heart and visceral placement. The fifth child and the father were found to have ICAS; the child was placed on prophylaxis, whereas the father did not have a history of infections, suggesting incomplete penetrance.

Inheritance

The possibility of autosomal dominant inheritance of congenital hyposplenia was raised by Gates and Black (1986).

An autosomal dominant mode of inheritance was plausible in 4 of the 10 families studied by Mahlaoui et al. (2011).

Lindor et al. (1995) reported 2 father-son pairs with isolated nonsyndromal asplenia and suggested that this may represent an autosomal trait due to mutation in a gene involved in spleen development and determination of laterality.

Bolze et al. (2013) found heterozygous mutations with complete penetrance in 8 kindreds, confirming autosomal dominant inheritance.

Molecular Genetics

Bolze et al. (2013) studied 33 patients with isolated congenital asplenia from 23 kindreds, including 5 kindreds previously reported by Mahlaoui et al. (2011) and the family described by Ferlicot et al. (1997). They identified 7 different heterozygous mutations in the RPSA gene (150370.0001-150370.0007) in 18 patients from 8 kindreds corresponding to more than half the patients and over one-third of the kindreds studied. The clinical penetrance in these kindreds was complete. Expression studies indicated that mutations carried by the patients (a nonsense mutation, a frameshift duplication, and 5 different missense mutations) caused autosomal dominant ICAS by haploinsufficiency. Index patients were recruited to the study on the basis of 3 criteria: no spleen or very small spleen detected by ultrasound; presence of Howell-Jolly bodies in blood smears; and absence of congenital heart defects.

Population Genetics

Mahlaoui et al. (2011) estimated the incidence of congenital asplenia to be 0.51 per 1 million births in France, based on birth records between 1957 and 2006.

Animal Model

Roberts et al. (1994) found isolated asplenia in mice with homozygous deficiency for the Hox11 gene (186770).

History

In 3 members of a family of African descent with isolated congenital asplenia, Koss et al. (2012) identified a heterozygous mutation in the NKX2-5 gene (P236H; 600584.0024). The family had previously been reported as family E by Mahlaoui et al. (2011). Bolze et al. (2013) found that affected members of this family (kindred B) carried a heterozygous mutation in the RPSA gene (R186C; 150370.0005). In total, Bolze et al. (2013) identified heterozygous coding mutations underlying isolated congenital asplenia in all 8 multiplex families displaying an autosomal dominant pattern of inheritance investigated. Collectively, their results suggested that heterozygous coding mutations in RPSA underlie most cases of isolated congenital asplenia, with apparently complete penetrance.