ORPHA: 124; DO: 0111894;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 19p13.2 | Diamond Blackfan anemia 15 with mandibulofacial dysostosis | 606164 | Autosomal dominant | 3 | RPS28 | 603685 |
A number sign (#) is used with this entry because of evidence that Diamond-Blackfan anemia-15 with mandibulofacial dysostosis (DBA15) is caused by heterozygous mutation in the RPS28 gene (603685) on chromosome 19p13.
For a discussion of genetic heterogeneity of Diamond-Blackfan anemia, see DBA1 (105650).
Gripp et al. (2014) reported 2 unrelated girls (patients 4 and 5) with Diamond-Blackfan anemia associated with mandibulofacial dysostosis. Both girls were noted at birth to micrognathia, downslanting palpebral fissures, submucosal cleft palate or bifid uvula, and malar hypoplasia. One child (patient 4) had absence of the eyelashes on the medial aspects of the lower lids, resulting in a clinical diagnosis of Treacher Collins syndrome (TCS; 154500), but sequencing of the TCOF1 gene (606847) was negative. This child also had unilateral mixed hearing loss, diaphragmatic hernia, persistent respiratory and feeding problems resulting in poor overall growth, inability to bend the thumbs at the interphalangeal joints, and delayed psychomotor development with mild intellectual disability. Macrocytic anemia due to DBA was diagnosed in the first year of life; she also had intermittent granulocytopenia. Her health was stable at age 22 years. In addition to dysmorphic facial features, the other child had severe sensorineural hearing loss, posteriorly rotated ears, sparse eyebrows, and epicanthal folds; eyelashes were intact. Small external ear canals were noted. She also had bifid uvula and mildly webbed neck. Steroid-responsive DBA was diagnosed in infancy. She had mildly delayed development and was in good heath at age 14 years. Both girls had short stature.
The heterozygous mutations in the RPS28 gene that were identified in patients with DBA15 by Gripp et al. (2014) occurred de novo.
In 2 unrelated girls with DBA and mandibulofacial dysostosis, Gripp et al. (2014) identified the same de novo heterozygous mutation affecting the translation initiation codon of the RPS28 gene (c.1A-G; 603685.0001), predicted to result in haploinsufficiency. The mutation was found by exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant were not performed, but Gripp et al. (2014) noted that RPS28 interacts with other RPS proteins to generate ribosomes, and that the mutation may be comparable to the loss of RPS19 (603474), which is mutated in DBA1. One of the patients had loss of the mutant allele and SNPs on 19p in peripheral blood cells, but not in buccal DNA, whereas the other patient had loss of the mutant allele and SNPs on 19p in buccal DNA only. It was not known whether this tissue-specific allelic imbalance contributed to the clinical presentation.
Hasan and Inoue (1993) described a female born with bilateral microtia, slightly downslanting palpebral fissures, cleft palate, and micrognathia, who presented at the age of 3.5 months with Diamond-Blackfan anemia. The report noted sparse eyelashes on the lower lid. Although the patient had features in common with those of TCS, she did not have the lower lid coloboma characteristic of that disorder. Subsequent analysis of the TCOF1 gene, as reported by Gripp et al. (2001), showed no mutations therein.
Gripp, K. W., Curry, C., Olney, A. H., Sandoval, C., Fisher, J., Chong, J. X.-L., UW Center for Mendelian Genomics, Pilchman, L., Sahraoui, R., Stabley, D. L., Sol-Church, K. Diamond-Blackfan anemia with mandibulofacial dystostosis (sic) is heterogeneous, including the novel DBA genes TSR2 and RPS28. Am. J. Med. Genet. 164A: 2240-2249, 2014. [PubMed: 24942156] [Full Text: https://doi.org/10.1002/ajmg.a.36633]
Gripp, K. W., McDonald-McGinn, D. M., La Rossa, D., McGain, D., Federman, N., Vlachos, A., Glader, B. E., McKenzie, S. E., Lipton, J. M., Zackai, E. H. Bilateral microtia and cleft palate in cousins with Diamond-Blackfan anemia. Am. J. Med. Genet. 101: 268-274, 2001. [PubMed: 11424144] [Full Text: https://doi.org/10.1002/ajmg.1329]
Hasan, R., Inoue, S. Diamond-Blackfan anemia associated with Treacher-Collins syndrome. Pediat. Hemat. Oncol. 10: 261-265, 1993. [PubMed: 8217543] [Full Text: https://doi.org/10.3109/08880019309029494]