PURPOSE OF THE STUDY.
To identify a potential genetic basis for isolated congenital asplenia.
Thirty-three patients from 23 kindreds with a history of congenital asplenia, including multiplex kindreds that suggested an autosomal dominant inheritance pattern.
Genomic DNA was initially obtained from at least 1 member of each kindred and subjected to whole exome sequencing followed by testing of remaining subjects.
Eighteen (55%) of the 33 subjects from 8 of the 21 kindreds were identified with 7 different heterozygous missense mutations of the gene encoding the ribosomal protein SA (RPSA). The mutations affect highly conserved nucleotides in mammals, vertebrates, and yeast and showed complete penetrance in that all individuals carrying the mutation had isolated congenital asplenia.
Heterozygous mutations in RPSA underlie all isolated congenital asplenia in the multiplex families studied (but not all subjects with isolated congenital asplenia). RPSA is involved in preribosomal processing, but its role in splenic development is unknown at this time. There were no other definable defects observed in these patients. Interestingly, another mutation affecting different ribosomal proteins has been characterized; Diamond-Blackfan anemia is associated with haploinsufficiency in multiple different ribosomal proteins (but not RPSA) and results in bone marrow failure as well as multiple developmental defects. However, in these patients, there is no evidence of splenic abnormalities, and the current study found no evidence of hematologic abnormalities (or developmental abnormalities) in the patients harboring the RPSA mutations.
The importance of this study is that many of these cases developed invasive bacterial infection early in childhood, most often involving Streptococcus pneumoniae (61%) with a high mortality rate (45%) (Mahaoudi N, et al. J Pediatr. 2011;158:142–148, 148.e1). Thus, isolated congenital asplenia has overlapping features with recently defined TLR defects (eg, MyD88, IRAK4 deficiency) in that both are associated with childhood invasive bacterial infections that have a high mortality rate. Consequently, any child with invasive bacterial infection should be evaluated for absence of a spleen (presence of Howell-Jolly bodies, directed imaging studies) as well as studied for other congenital immune defects associated with this clinical presentation. In view of the autosomal dominant transmission of some cases of isolated congenital asplenia, family members of an affected patient should also be evaluated for possible asplenia.
- Copyright © 2013 by the American Academy of Pediatrics