Diamond-Blackfan Anemia 15 with Mandibulofacial Dysostosis

Mendelian MONDO:0011639 Pathograph 20 Show in embeddings browser Diamond-Blackfan Anemia Ribosomopathy Inherited bone marrow failure syndrome

Diamond-Blackfan anemia 15 with mandibulofacial dysostosis (DBA15) is the RPS28-related form of Diamond-Blackfan anemia, in which the erythroid failure of DBA occurs together with a craniofacial phenotype that reads clinically as a mandibulofacial dysostosis - micrognathia, cleft palate, downslanted palpebral fissures, ear anomalies and hearing loss. It was defined in the same six-family series that defined DBA14, and the two entries are siblings: that study set out to explain patients who combined Treacher Collins-like faces with DBA, found the combination was genetically heterogeneous, and named both TSR2 and RPS28 as new disease genes in the process. RPS28 is the more conventional of the two - it encodes eS28, a small ribosomal subunit protein, so the lesion is in a structural component rather than in a chaperone. The striking allelic feature is that every reported variant destroys the RPS28 start codon. Two de novo start-codon variants defined the disease, and the only subsequently reported case carries c.2T>C, p.Met1?. That is a narrower allelic spectrum than most DBA genes show, and the entry records it as an observation rather than as an established requirement - three patients is not a spectrum. Mechanistically it belongs to the ribosomopathies: an RPS28 lesion impedes ribosome biogenesis, and the founding authors attribute both halves of the phenotype - the anemia and the craniofacial malformation - to that single upstream defect acting on cell growth and proliferation.

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1
Mappings
1
Inheritance
4
Pathophys.
17
Phenotypes
2
Gaps
20
Pathograph
1
Genes
5
Medical Actions
3
Differentials
4
References
1
Deep Research
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Mappings

ICD-10-CM
ICD10CM:D61.01 Constitutional (pure) red blood cell aplasia
skos:broadMatch dismech
ICD-10-CM has no code for any individual DBA genotype. D61.01 is the code the whole of Diamond-Blackfan anemia falls under, so it is broader than this entry by the full width of the DBA gene panel; recorded as a broadMatch cross-reference for billing and registry lookup, not as an equivalence. This mirrors the mapping on the sibling DBA14 entry.
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Inheritance

1
Autosomal dominant HP:0000006
Heterozygous, and de novo in every reported case. The founding study described the two probands' variants as de novo, and the third reported patient carries a heterozygous start-codon variant. No transmitted pedigree has been published, so dominance is inferred from heterozygosity and de novo occurrence rather than from observed transmission.
Autosomal dominant inheritance
Show evidence (3 references)
PMID:24942156 SUPPORT Human Clinical
"De novo mutations affecting the RPS28 start codon were found in two unrelated probands, identifying RPS28 as a novel disease gene."
Establishes both the de novo origin and the heterozygous single-gene basis in the two founding probands.
PMID:20301769 SUPPORT INDIRECT Human Clinical
"Each child of an individual with autosomal dominant DBA syndrome has a 50% chance of inheriting the pathogenic variant."
The recurrence risk that genetic counselling has to convey.
PMID:20301769 SUPPORT INDIRECT Human Clinical
"Approximately 40%-45% of individuals diagnosed with autosomal dominant DBA syndrome inherited a DBA syndrome-causing variant from a parent; approximately 55%-60% have a de novo pathogenic variant."
Gives the inherited-versus-de-novo split for autosomal dominant DBA. All three reported RPS28 patients are de novo, which is consistent with the majority case but is far too small a sample to say anything specific about this gene.
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Discussions and Knowledge Gaps

2
Is the RPS28 disease spectrum genuinely restricted to start-codon variants, or does that pattern simply reflect three reported patients?
KNOWLEDGE GAP rps28_start_codon_only
Attached to
genetic#RPS28
All three reported RPS28 alleles destroy the translation initiation codon. If that restriction is real it would be mechanistically interesting - it might mean only a specific consequence of start-codon loss, such as initiation at a downstream methionine producing an N-terminally truncated eS28, causes disease, while a simple null is tolerated or lethal. If it is an artefact of three patients, RPS28 should be read like any other DBA gene. The two readings imply different variant-interpretation practice for a novel RPS28 missense allele, and nothing in the current literature separates them.
Why does a general reduction in ribosome production cause a specifically erythroid failure rather than a uniform proliferative defect?
KNOWLEDGE GAP rps28_erythroid_specificity
Attached to
pathophysiology#Defective Erythropoiesis
This is the central unsolved question of the ribosomopathies and it is named as unknown in the mechanism literature cited here. It is recorded on this entry because the same experimental work shows RPS28 depletion behaves like the other DBA proteins - compromising the rate of ribosome production generally, without a distinctive processing signature - so nothing specific to RPS28 explains the erythroid selectivity either.
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Pathophysiology

4
RPS28 Start-Codon Disruption
The initiating lesion. A heterozygous de novo variant destroys the RPS28 translation initiation codon, so eS28 cannot be translated from that allele. Every reported patient carries a variant of this class.
RPS28 hgnc:10418 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves RPS28 (hgnc:10418). hgnc:10418 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Downstream
Impaired Ribosome Biogenesis Reduced eS28 available for assembly into the small ribosomal subunit compromises subunit production.
Show evidence (2 references)
PMID:24942156 SUPPORT Human Clinical
"De novo mutations affecting the RPS28 start codon were found in two unrelated probands, identifying RPS28 as a novel disease gene."
The lesion itself, in the two founding probands.
PMID:40135709 SUPPORT Human Clinical
"Whole exome sequencing of peripheral blood revealed a heterozygous mutation in the RPS28 gene (c.2T > C, p.Met1?), a novel pathogenic mutation in RPS28."
A third, independently reported allele of the same class, with the p.Met1? annotation naming the loss of the initiator methionine directly.
Impaired Ribosome Biogenesis
Reduced production of the small ribosomal subunit. Experimental depletion of RPS28 in human cells, in a panel alongside the other DBA ribosomal proteins, reduces the corresponding subunit, fully assembled ribosomes and polysomes, and perturbs rRNA processing. The generalisation the same study draws is that what the DBA proteins share is a compromised rate of ribosome production rather than a single common processing step.
ribosome biogenesis GO:0042254 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased ribosome biogenesis (GO:0042254). GO:0042254 is a biological process from the Gene Ontology. ↓ DECREASED rRNA processing GO:0006364 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated rRNA processing (GO:0006364). GO:0006364 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Downstream
Growth delay The founding authors' prediction sentence names reduced growth alongside abnormal embryologic development and defective erythropoiesis, as a third consequence of the same ribosomal lesion rather than as a downstream effect of either. The edge hangs here for that reason, and is typed indirect because the sentence is hedged ("predicted to", "could result in") and no experiment in these sources tests it.
Defective Erythropoiesis Why a general shortage of ribosomes selectively fails red cell production is the central unsolved question of the ribosomopathies, and these sources say so rather than resolving it.
Abnormal Craniofacial Embryonic Development Attributed by the founding authors to altered cell growth and proliferation during embryogenesis, with no intermediate steps established.
Show evidence (3 references)
PMID:18697920 SUPPORT In Vitro
"Depleting r-proteins in one of the subunits caused, with a few exceptions, a decrease in all r-proteins of the same subunit and a decrease in the corresponding subunit, fully assembled ribosomes, and polysomes."
The measured consequence of depleting a small-subunit ribosomal protein in human cells. RPS28 is one of the small-subunit proteins in this depletion panel.
PMID:18697920 SUPPORT In Vitro
"We depleted HeLa cells using siRNA for several individual r-proteins of the small (RPS6, RPS7, RPS15, RPS16, RPS17, RPS19, RPS24, RPS25, RPS28) or large subunit"
Names RPS28 explicitly in the depleted panel, which is what makes the preceding result applicable to this gene rather than to ribosomal proteins in general.
PMID:18697920 SUPPORT INDIRECT In Vitro
"Depletion of r-proteins mutated in DBA always compromised ribosome biogenesis while affecting either subunit and disturbing rRNA processing at different levels"
The study's generalisation across DBA genes. Marked INDIRECT because it is a statement about the DBA gene set as a class, from which the claim about RPS28 follows rather than being made directly.
Defective Erythropoiesis
Mechanism confidence: Hypothetical
Failure of red cell production, giving the macrocytic anemia that defines DBA. The link from a general ribosome shortage to a specifically erythroid failure is explicitly named as unknown in the mechanism literature, which is why this node is graded HYPOTHETICAL despite the anemia itself being beyond doubt: it is the explanation that is provisional, not the finding.
erythroid progenitor cell CL:0000038 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves erythroid progenitor cell (CL:0000038). CL:0000038 is a cell type from the Cell Ontology.
erythrocyte differentiation GO:0030218 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased erythrocyte differentiation (GO:0030218). GO:0030218 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Macrocytic anemia
Show evidence (2 references)
PMID:18697920 SUPPORT Other
"How defects in r-proteins, essential for proliferation in all cells, lead to a human disease with a specific defect in red cell development is unknown."
States the gap directly. It is cited here as the reason for the HYPOTHETICAL grading rather than as support for a mechanism.
PMID:24942156 SUPPORT Human Clinical
"Diamond-Blackfan anemia typically presents in early infancy with macrocytic anemia, elevated erythrocyte adenosine deaminase (eADA) and hemoglobin F, and less commonly associated physical findings such as short stature or thumb anomalies."
Describes the erythroid phenotype this node produces, which is well established even though its mechanism is not.
Abnormal Craniofacial Embryonic Development
Mechanism confidence: Hypothetical
The developmental arm. Impaired ribosome biogenesis is proposed to alter cell growth and proliferation during embryogenesis, producing the mandibulofacial dysostosis phenotype. Graded HYPOTHETICAL because the founding study offers this as a prediction covering all five genotypes in the series and no experiment in these sources tests it for RPS28.
Downstream
Mandibulofacial dysostosis The umbrella craniofacial phenotype that gives the disease its name, and the one the individual features below compose.
Micrognathia
Cleft palate
Downslanted palpebral fissures
Low-set ears
Hypertelorism
Show evidence (1 reference)
PMID:24942156 SUPPORT Human Clinical
"Each of the pathogenic variants identified is predicted to impede ribosome biogenesis, which in turn could result in altered cell growth and proliferation, causing abnormal embryologic development, defective erythropoiesis and reduced growth."
The only statement in these sources linking the ribosomal lesion to the craniofacial phenotype, and it is framed as a prediction.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Diamond-Blackfan Anemia 15 with Mandibulofacial Dysostosis Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

17
Blood 2
Macrocytic anemia VERY_FREQUENT HP:0001972 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Macrocytic anemia (HP:0001972). HP:0001972 is a phenotype from the Human Phenotype Ontology.
Sequelae: Hydrops fetalis
Show evidence (1 reference)
PMID:24942156 SUPPORT Human Clinical
"Diamond-Blackfan anemia typically presents in early infancy with macrocytic anemia, elevated erythrocyte adenosine deaminase (eADA) and hemoglobin F"
The macrocytic anemia is what makes these patients DBA rather than an isolated mandibulofacial dysostosis.
Decreased total neutrophil count OCCASIONAL HP:0001875 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased total neutrophil count (HP:0001875). HP:0001875 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40135709 SUPPORT Human Clinical
"In addition, he was found to be granulocytopenic at birth and severely anemic at 2 years and 10 months of age."
Documents the neutropenia and its timing relative to the anemia, which is the detail that makes it notable.
Digestive 1
Feeding difficulties OCCASIONAL HP:0011968 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40135709 SUPPORT Human Clinical
"He was born with micrognathia, cleft palate, and airway obstruction, resulting in neonatal asphyxia and feeding difficulties, which constitute the classic triad of PRS."
Reports the feeding difficulty and attributes it to the airway and palatal anatomy.
Ear 2
Low-set ears OCCASIONAL HP:0000369 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Low-set ears (HP:0000369). HP:0000369 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40135709 SUPPORT Human Clinical
"Low-set ears, downslanted palpebral fissures, bilateral exotropia, a short neck, hypertelorism, a thenar muscle defect, and bilateral severe sensorineural hearing loss were also observed in the boy."
Names low-set ears among the observed features.
Bilateral sensorineural hearing impairment OCCASIONAL HP:0008619 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bilateral sensorineural hearing impairment (HP:0008619), qualified as severity severe. HP:0008619 is a phenotype from the Human Phenotype Ontology.
Severity: SEVERE
Show evidence (1 reference)
PMID:40135709 SUPPORT Human Clinical
"Low-set ears, downslanted palpebral fissures, bilateral exotropia, a short neck, hypertelorism, a thenar muscle defect, and bilateral severe sensorineural hearing loss were also observed in the boy."
The source states the laterality and the severity, both of which are carried into the binding.
Eye 2
Hypertelorism OCCASIONAL HP:0000316 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertelorism (HP:0000316). HP:0000316 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40135709 SUPPORT Human Clinical
"Low-set ears, downslanted palpebral fissures, bilateral exotropia, a short neck, hypertelorism, a thenar muscle defect, and bilateral severe sensorineural hearing loss were also observed in the boy."
Names hypertelorism among the observed features.
Exotropia OCCASIONAL HP:0000577 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Exotropia (HP:0000577). HP:0000577 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40135709 SUPPORT Human Clinical
"Low-set ears, downslanted palpebral fissures, bilateral exotropia, a short neck, hypertelorism, a thenar muscle defect, and bilateral severe sensorineural hearing loss were also observed in the boy."
Names bilateral exotropia among the observed features.
Head and Neck 5
Mandibulofacial dysostosis VERY_FREQUENT HP:0005321 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mandibulofacial dysostosis (HP:0005321). HP:0005321 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24942156 SUPPORT Human Clinical
"Patients with physical findings suggestive of Treacher Collins syndrome (TCS) or mandibulofacial dysostosis (MFD) and macrocytic anemia diagnostic of Diamond-Blackfan anemia (DBA) have been reported."
Defines the combined phenotype that this disease entity was created to explain.
Micrognathia OCCASIONAL HP:0000347 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Micrognathia (HP:0000347). HP:0000347 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40135709 SUPPORT Human Clinical
"He was born with micrognathia, cleft palate, and airway obstruction, resulting in neonatal asphyxia and feeding difficulties, which constitute the classic triad of PRS."
Documents micrognathia and the Pierre Robin sequence it forms part of.
Cleft palate OCCASIONAL HP:0000175 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cleft palate (HP:0000175). HP:0000175 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40135709 SUPPORT Human Clinical
"He was born with micrognathia, cleft palate, and airway obstruction, resulting in neonatal asphyxia and feeding difficulties, which constitute the classic triad of PRS."
Documents the cleft palate as part of the reported triad.
Downslanted palpebral fissures OCCASIONAL HP:0000494 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Downslanted palpebral fissures (HP:0000494). HP:0000494 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40135709 SUPPORT Human Clinical
"Low-set ears, downslanted palpebral fissures, bilateral exotropia, a short neck, hypertelorism, a thenar muscle defect, and bilateral severe sensorineural hearing loss were also observed in the boy."
The source's list of additional dysmorphic features, quoted once and shared by the several phenotypes it names.
Short neck OCCASIONAL HP:0000470 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short neck (HP:0000470). HP:0000470 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40135709 SUPPORT Human Clinical
"Low-set ears, downslanted palpebral fissures, bilateral exotropia, a short neck, hypertelorism, a thenar muscle defect, and bilateral severe sensorineural hearing loss were also observed in the boy."
Names short neck among the observed features.
Metabolism 1
Hydrops fetalis HP:0001789 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is nonimmune hydrops fetalis, annotated with Hydrops fetalis (HP:0001789). HP:0001789 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301769 SUPPORT INDIRECT Human Clinical
"The phenotypic spectrum ranges from a mild form (e.g., mild or no anemia with only subtle erythroid abnormalities and/or physical malformations without anemia) to a severe form of fetal anemia resulting in nonimmune hydrops fetalis."
Gives both ends of the DBA spectrum in one sentence. Quoted here for the severe end; the mild end matters too, because it means an RPS28 relative could carry the variant with minimal anemia.
Nervous System 1
Global developmental delay OCCASIONAL HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40135709 SUPPORT Human Clinical
"His motor and speech development were significantly delayed."
Reports delay across both motor and speech domains, which is what the global term covers.
Respiratory 1
Upper airway obstruction OCCASIONAL HP:0002781 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Upper airway obstruction (HP:0002781). HP:0002781 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40135709 SUPPORT Human Clinical
"He was born with micrognathia, cleft palate, and airway obstruction, resulting in neonatal asphyxia and feeding difficulties, which constitute the classic triad of PRS."
Reports the airway obstruction and, importantly, its immediate consequence - neonatal asphyxia - which is what makes it clinically urgent rather than incidental.
Growth 1
Growth delay FREQUENT HP:0001510 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is growth deficiency, annotated with Growth delay (HP:0001510). HP:0001510 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301769 SUPPORT INDIRECT Human Clinical
"congenital malformations in up to 50% of affected individuals, and growth deficiency in 30% of affected individuals"
The GeneReviews frequency figure. 30% places this in the FREQUENT band and is a real denominator, unlike the single-case observations elsewhere in this entry.
Neoplasm 1
Neoplasm HP:0002664 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is predisposition to AML, myelodysplastic syndrome and solid tumours, annotated with Neoplasm (HP:0002664). HP:0002664 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20301769 SUPPORT INDIRECT Human Clinical
"DBA syndrome is associated with an increased risk for acute myelogenous leukemia, myelodysplastic syndrome, and solid tumors including osteogenic sarcoma."
Names all three malignancy classes. This is the finding that makes lifelong cancer surveillance part of management rather than optional.
PMID:40135709 SUPPORT Human Clinical
"Diamond-Blackfan anemia (DBA) is a congenital erythroid aplasia associated with physical anomalies and a predisposition to cancer."
An independent statement of the cancer predisposition, in the one paper that reports an RPS28 patient specifically.
🧬

Genetic Associations

1
RPS28
Gene: RPS28 hgnc:10418 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is RPS28 (hgnc:10418). hgnc:10418 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:24942156 SUPPORT Human Clinical
"De novo mutations affecting the RPS28 start codon were found in two unrelated probands, identifying RPS28 as a novel disease gene."
Names the gene, the allele class and the de novo origin in one statement.
PMID:40135709 SUPPORT Human Clinical
"A heterozygous mutation in the RPS28 gene (c.2T > C, p.Met1?) is a novel pathogenic mutation associated with DBA."
An independent start-codon allele in a third patient, which is what makes the allelic pattern worth recording.
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Medical Actions

5
Hematopoietic Stem Cell Transplantation
Action: hematopoietic stem cell transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is hematopoietic stem cell transplantation, annotated with Hematopoietic Cell Transplantation (NCIT:C15431). NCIT:C15431 is a clinical intervention from the NCI Thesaurus. Ontology label: Hematopoietic Cell Transplantation NCIT:C15431
Platform: Cell therapy
The definitive treatment for the haematologic component. In the one reported RPS28 patient who received it, from a 9/10 HLA-matched donor, both neutrophil and haemoglobin levels normalised. It does not address the craniofacial malformations or the hearing loss.
Mechanism Target:
Defective Erythropoiesis — Replaces the RPS28-deficient haematopoietic compartment with donor cells, restoring erythropoiesis at its source.
Show evidence (2 references)
PMID:40135709 SUPPORT Human Clinical
"The boy underwent HSCT from 9/10 HLA-matched donor and his neutrophil and hemoglobin levels returned to normal."
The only reported treatment outcome in an RPS28 patient. It is a single case, so it establishes that transplant worked here, not an expected response rate.
PMID:40135709 SUPPORT Human Clinical
"HSCT is an effective treatment for hematological abnormalities in DBA."
The authors' generalisation to DBA as a whole, which is the broader basis for offering transplant in this genotype.
Corticosteroid Therapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: corticosteroid CHEBI:50858 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses corticosteroid (CHEBI:50858). CHEBI:50858 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Standard first-line therapy for the anemia of DBA, started at age 12 months or older. Deliberately deferred through the first year, with chronic transfusion used instead, to avoid steroid-induced growth deficiency. The two sources give different response rates and the entry cites both rather than picking one: the 2014 series says 40%, GeneReviews says 60-80%. They are not directly comparable - the GeneReviews figure describes improvement in red blood cell count on a treatment given at a specified age, while the 2014 figure describes patients categorised as steroid-responsive alongside spontaneous remitters and transfusion-dependent patients. No steroid-response data exist for RPS28 patients specifically, so either way this is offered on the basis of the DBA literature rather than genotype-specific evidence.
Mechanism Target:
Defective Erythropoiesis — Improves red cell output in steroid-responsive DBA. The mechanism of the steroid response in DBA is itself not established.
Show evidence (2 references)
PMID:24942156 SUPPORT INDIRECT Human Clinical
"The anemia remits spontaneously in about 20%, is steroid responsive in 40% and requires long term transfusions in about 40%"
Gives the steroid-response rate for DBA as a whole. Marked INDIRECT because the claim about RPS28 patients follows from their being DBA patients rather than from any RPS28-specific observation.
PMID:20301769 SUPPORT INDIRECT Human Clinical
"Corticosteroid treatment, recommended in children at age 12 months or older, improves the red blood cell count in approximately 60%-80% of affected individuals."
The GeneReviews response rate, higher than the 40% figure above and measured differently. Both are curated so a reader sees the range rather than whichever number the curator happened to meet first; also the source of the age-12-months recommendation.
Iron Chelation Therapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: deferasirox CHEBI:49005 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses deferasirox (CHEBI:49005). CHEBI:49005 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Transfusion-related iron overload is the most common complication in transfusion-dependent patients, and chelation is recommended after ten to twelve transfusions. Deferasirox orally or desferrioxamine subcutaneously are the standard agents. Deferiprone is the agent to avoid. GeneReviews lists it explicitly under agents/circumstances to avoid in DBA because it can cause neutropenia - which is pointed for this genotype specifically, since the one reported RPS28 patient was granulocytopenic from birth.
Mechanism Target:
Macrocytic anemia — Does not treat the anemia. It manages the iron burden that chronic transfusion creates, so it is downstream of the treatment rather than of the disease.
Show evidence (2 references)
PMID:20301769 SUPPORT INDIRECT Human Clinical
"Iron chelation therapy with deferasirox orally or desferrioxamine subcutaneously is recommended after ten to 12 transfusions."
Names both agents and the transfusion count that triggers chelation.
PMID:20301769 SUPPORT INDIRECT Human Clinical
"Agents/circumstances to avoid: Deferiprone for the treatment of iron overload (which can cause neutropenia)"
The drug-safety warning. Curated because this entry also records neutropenia in the only reported RPS28 patient, so the caution is not generic here.
Malignancy Surveillance
Action: cancer surveillanceNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is cancer surveillance, annotated with Cancer Screening (NCIT:C15406). NCIT:C15406 is a clinical intervention from the NCI Thesaurus. Ontology label: Cancer Screening NCIT:C15406
Platform: Other
Lifelong cancer surveillance: history, examination and blood counts every four to six months. A rapid fall in any cell line triggers bone marrow aspirate with biopsy and cytogenetics, looking for acquired abnormalities of chromosomes 5, 7 and 8 that mark myelodysplastic syndrome or leukemia.
Mechanism Target:
Neoplasm — Detects malignant transformation early rather than preventing it. It does not act on the ribosomal defect.
Show evidence (2 references)
PMID:20301769 SUPPORT INDIRECT Human Clinical
"Cancer surveillance includes history, physical examination, and blood counts every four to six months."
The surveillance interval and its components.
PMID:20301769 SUPPORT INDIRECT Human Clinical
"look for acquired abnormalities in chromosomes 5, 7, and 8 that are associated with myelodysplastic syndrome or leukemia"
Names the specific cytogenetic abnormalities the escalation step is looking for, which is what makes this actionable rather than generic vigilance.
Red Cell Transfusion
Action: red blood cell transfusionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is red blood cell transfusion, annotated with Blood Transfusion (NCIT:C15192). NCIT:C15192 is a clinical intervention from the NCI Thesaurus. Ontology label: Blood Transfusion NCIT:C15192
Platform: Other
Long-term transfusion support is required by roughly 40% of DBA patients and is the alternative when the anemia does not respond to steroids.
Mechanism Target:
Macrocytic anemia — Replaces the red cells the marrow does not produce. Purely supportive; it does not act on the ribosomal defect.
Show evidence (1 reference)
PMID:24942156 SUPPORT INDIRECT Human Clinical
"The anemia remits spontaneously in about 20%, is steroid responsive in 40% and requires long term transfusions in about 40%"
Same DBA-wide figure as above, read for the transfusion-dependent fraction. INDIRECT for the same reason.
🔬

Diagnosis

2
Exome sequencing
The route by which this disease is identified. The founding study reached RPS28 by whole exome analysis of probands whose combined DBA and mandibulofacial dysostosis phenotype had no molecular explanation, and the third patient was diagnosed the same way.
Show evidence (3 references)
PMID:24942156 SUPPORT Human Clinical
"Combining exome analysis and Sanger sequencing, we identified likely pathogenic mutations in 5/6 families."
Describes the diagnostic approach and its yield in the founding series.
PMID:40135709 SUPPORT Human Clinical
"It is crucial to perform a genetic evaluation for syndromic bone marrow failure with congenital anomalies."
The recommendation this diagnostic entry exists to record - genetic evaluation when marrow failure occurs with congenital anomalies.
PMID:20301769 SUPPORT INDIRECT Human Clinical
"The molecular diagnosis of DBA syndrome can be established in a proband by identification of a heterozygous pathogenic variant in a gene associated with autosomal dominant DBA syndrome"
The GeneReviews molecular-diagnostic criterion for the autosomal dominant genotypes, which is the class RPS28 belongs to.
Clinical diagnosis from laboratory and histopathological features
DBA can be diagnosed clinically, before or without a molecular result, from the characteristic picture: profound normochromic and usually macrocytic anemia with normal leukocytes and platelets. Hematologic complications appear in the first year of life in 90% of patients - though the one reported RPS28 patient presented later, at two years ten months.
Show evidence (3 references)
PMID:20301769 SUPPORT INDIRECT Human Clinical
"The clinical diagnosis of DBA syndrome can be established in a proband with characteristic laboratory, histopathology, and clinical features."
Establishes that a clinical diagnosis is possible without molecular confirmation.
PMID:20301769 SUPPORT INDIRECT Human Clinical
"DBA syndrome is characterized by a profound normochromic and usually macrocytic anemia with normal leukocytes and platelets"
The specific haematological pattern the clinical diagnosis turns on - and note that the isolated red-cell involvement it describes is what makes the neutropenia in the reported RPS28 patient atypical.
PMID:20301769 SUPPORT INDIRECT Human Clinical
"The hematologic complications occur in 90% of affected individuals during the first year of life."
Gives the expected age of presentation, against which the reported RPS28 patient's presentation at two years ten months is late.
🌍

Epidemiology

2
Reported case count
Three patients in the literature at the time of this curation: two founding probands and one later case report. RPS28 is correspondingly one of the rarest DBA genotypes.
Show evidence (2 references)
PMID:24942156 SUPPORT Human Clinical
"De novo mutations affecting the RPS28 start codon were found in two unrelated probands, identifying RPS28 as a novel disease gene."
The two founding probands.
PMID:40135709 SUPPORT Human Clinical
"Whole exome sequencing of peripheral blood revealed a heterozygous mutation in the RPS28 gene (c.2T > C, p.Met1?), a novel pathogenic mutation in RPS28."
The third reported patient, and the source describes the allele as novel, which supports the small total count.
Position within the DBA gene panel
Context for how small a slice of DBA this genotype is. RPS19 accounts for about a quarter of DBA; nine further ribosomal genes plus GATA1 account for another quarter to 30%, and a substantial proportion of DBA remains genetically unexplained. RPS28 sits inside that second, thinly populated group.
Show evidence (1 reference)
PMID:24942156 SUPPORT Human Clinical
"In about 25% of DBA patients a RPS19 mutation is present. Mutations in nine additional ribosomal genes and the erythroid transcription factor GATA1 account for another 25-30% of cases, leaving a substantial proportion unaccounted for."
Gives the denominator that places RPS28 among the rare DBA genotypes rather than quantifying RPS28 itself, which no source does.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Diamond-Blackfan Anemia 15 with Mandibulofacial Dysostosis:

Treacher Collins syndrome
Overlapping Features The phenotype these patients are first taken for. TCS is usually caused by a heterozygous TCOF1 variant, with POLR1D and biallelic POLR1C accounting for further cases. It does not carry the DBA erythroid phenotype, and the anemia is what should prompt reconsideration.
Show evidence (1 reference)
PMID:24942156 SUPPORT Human Clinical
"Most TCS patients have a heterozygous TCOF1 mutation, while heterozygous POLR1D and biallelic POLR1C mutations account for additional cases"
Names the genes that have to be excluded, which is what makes this a differential rather than a synonym.
Diamond-Blackfan anemia 14 with mandibulofacial dysostosis (TSR2)
Overlapping Features The X-linked sibling entity, defined in the same six-family series. It is indistinguishable on the craniofacial phenotype alone; the discriminators are the segregation pattern and the gene. Curated separately in this knowledge base.
Show evidence (1 reference)
PMID:24942156 SUPPORT Human Clinical
"In another family a likely pathogenic X-linked mutation affecting a highly conserved residue was found in TSR2, which encodes a direct binding partner of RPS26."
The TSR2 family from the same series, and the note that TSR2 partners RPS26 - which is why these genotypes converge on one phenotype.
Diamond-Blackfan anemia 10 (RPS26)
Overlapping Features Two of the six families in the founding series carried RPS26 variants, one affecting splicing and one truncating. RPS26 is the binding partner of the TSR2 protein, so DBA10, DBA14 and DBA15 all disturb small-subunit assembly by different routes.
Show evidence (1 reference)
PMID:24942156 SUPPORT Human Clinical
"Two mutations in unrelated families were seen in RPS26, the known DBA10 gene. One variant was predicted to affect mRNA splicing, and the other to lead to protein truncation."
The RPS26 families and their allele classes, establishing this as the most common genotype behind the combined phenotype.
{ }

Source YAML

click to show 
name: Diamond-Blackfan Anemia 15 with Mandibulofacial Dysostosis
creation_date: '2026-09-10T19:00:00Z'
category: Mendelian
disease_term:
  preferred_term: Diamond-Blackfan anemia 15 with mandibulofacial dysostosis
  term:
    id: MONDO:0011639
    label: Diamond-Blackfan anemia 15 with mandibulofacial dysostosis
description: >-
  Diamond-Blackfan anemia 15 with mandibulofacial dysostosis (DBA15) is the
  RPS28-related form of Diamond-Blackfan anemia, in which the erythroid failure
  of DBA occurs together with a craniofacial phenotype that reads clinically as
  a mandibulofacial dysostosis - micrognathia, cleft palate, downslanted
  palpebral fissures, ear anomalies and hearing loss.

  It was defined in the same six-family series that defined DBA14, and the two
  entries are siblings: that study set out to explain patients who combined
  Treacher Collins-like faces with DBA, found the combination was genetically
  heterogeneous, and named both TSR2 and RPS28 as new disease genes in the
  process. RPS28 is the more conventional of the two - it encodes eS28, a small
  ribosomal subunit protein, so the lesion is in a structural component rather
  than in a chaperone.

  The striking allelic feature is that every reported variant destroys the RPS28
  start codon. Two de novo start-codon variants defined the disease, and the only
  subsequently reported case carries c.2T>C, p.Met1?. That is a narrower allelic
  spectrum than most DBA genes show, and the entry records it as an observation
  rather than as an established requirement - three patients is not a spectrum.

  Mechanistically it belongs to the ribosomopathies: an RPS28 lesion impedes
  ribosome biogenesis, and the founding authors attribute both halves of the
  phenotype - the anemia and the craniofacial malformation - to that single
  upstream defect acting on cell growth and proliferation.
synonyms:
- DBA15
- Diamond-Blackfan anemia caused by mutation in RPS28
- RPS28 Diamond-Blackfan anemia
categories:
- Ribosomopathy
- Inherited Bone Marrow Failure Syndrome
parents:
- Diamond-Blackfan Anemia
- Ribosomopathy
- Inherited bone marrow failure syndrome
mappings:
  icd10cm_mappings:
  - term:
      id: ICD10CM:D61.01
      label: Constitutional (pure) red blood cell aplasia
    mapping_predicate: skos:broadMatch
    mapping_source: dismech
    mapping_justification: >-
      ICD-10-CM has no code for any individual DBA genotype. D61.01 is the code
      the whole of Diamond-Blackfan anemia falls under, so it is broader than
      this entry by the full width of the DBA gene panel; recorded as a
      broadMatch cross-reference for billing and registry lookup, not as an
      equivalence. This mirrors the mapping on the sibling DBA14 entry.
references:
- reference: PMID:20301769
  title: DBA Syndrome.
  tags:
  - GeneReviews
- reference: PMID:24942156
  title: Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the
    novel DBA genes TSR2 and RPS28.
- reference: PMID:40135709
  title: Diagnosis and treatment of Diamond-Blackfan anemia and Pierre-Robin sequence caused by
    a novel mutation of RPS28 gene.
- reference: PMID:18697920
  title: The role of human ribosomal proteins in the maturation of rRNA and ribosome production.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Heterozygous, and de novo in every reported case. The founding study
    described the two probands' variants as de novo, and the third reported
    patient carries a heterozygous start-codon variant. No transmitted pedigree
    has been published, so dominance is inferred from heterozygosity and de novo
    occurrence rather than from observed transmission.
  evidence:
  - reference: PMID:24942156
    reference_title: Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including
      the novel DBA genes TSR2 and RPS28.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'De novo mutations affecting the RPS28 start codon were found in two unrelated probands,
      identifying RPS28 as a novel disease gene.'
    explanation: Establishes both the de novo origin and the heterozygous single-gene basis in the
      two founding probands.
  - reference: PMID:20301769
    reference_title: DBA Syndrome.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Each child of an individual with autosomal dominant DBA syndrome has a 50% chance of
      inheriting the pathogenic variant.'
    explanation: The recurrence risk that genetic counselling has to convey.
  - reference: PMID:20301769
    reference_title: DBA Syndrome.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Approximately 40%-45% of individuals diagnosed with autosomal dominant DBA syndrome
      inherited a DBA syndrome-causing variant from a parent; approximately 55%-60% have a de novo
      pathogenic variant.'
    explanation: Gives the inherited-versus-de-novo split for autosomal dominant DBA. All three
      reported RPS28 patients are de novo, which is consistent with the majority case but is far too
      small a sample to say anything specific about this gene.
epidemiology:
- name: Reported case count
  description: >-
    Three patients in the literature at the time of this curation: two founding
    probands and one later case report. RPS28 is correspondingly one of the
    rarest DBA genotypes.
  evidence:
  - reference: PMID:24942156
    reference_title: Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including
      the novel DBA genes TSR2 and RPS28.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'De novo mutations affecting the RPS28 start codon were found in two unrelated probands,
      identifying RPS28 as a novel disease gene.'
    explanation: The two founding probands.
  - reference: PMID:40135709
    reference_title: Diagnosis and treatment of Diamond-Blackfan anemia and Pierre-Robin sequence caused
      by a novel mutation of RPS28 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Whole exome sequencing of peripheral blood revealed a heterozygous mutation in the RPS28
      gene (c.2T > C, p.Met1?), a novel pathogenic mutation in RPS28.'
    explanation: The third reported patient, and the source describes the allele as novel, which
      supports the small total count.
- name: Position within the DBA gene panel
  description: >-
    Context for how small a slice of DBA this genotype is. RPS19 accounts for
    about a quarter of DBA; nine further ribosomal genes plus GATA1 account for
    another quarter to 30%, and a substantial proportion of DBA remains
    genetically unexplained. RPS28 sits inside that second, thinly populated
    group.
  evidence:
  - reference: PMID:24942156
    reference_title: Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including
      the novel DBA genes TSR2 and RPS28.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'In about 25% of DBA patients a RPS19 mutation is present. Mutations in nine additional
      ribosomal genes and the erythroid transcription factor GATA1 account for another 25-30% of
      cases, leaving a substantial proportion unaccounted for.'
    explanation: Gives the denominator that places RPS28 among the rare DBA genotypes rather than
      quantifying RPS28 itself, which no source does.
genetic:
- name: RPS28
  gene_term:
    preferred_term: RPS28
    term:
      id: hgnc:10418
      label: RPS28
  relationship_type: CAUSATIVE
  notes: >-
    Heterozygous, de novo, and in every reported case affecting the translation
    initiation codon. The founding probands carried start-codon variants; the
    third patient carries c.2T>C, p.Met1?. Whether non-start-codon RPS28 alleles
    can cause disease is unknown - with three patients this is an observation
    about the reported spectrum, not a demonstrated constraint on the gene.
  evidence:
  - reference: PMID:24942156
    reference_title: Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including
      the novel DBA genes TSR2 and RPS28.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'De novo mutations affecting the RPS28 start codon were found in two unrelated probands,
      identifying RPS28 as a novel disease gene.'
    explanation: Names the gene, the allele class and the de novo origin in one statement.
  - reference: PMID:40135709
    reference_title: Diagnosis and treatment of Diamond-Blackfan anemia and Pierre-Robin sequence caused
      by a novel mutation of RPS28 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'A heterozygous mutation in the RPS28 gene (c.2T > C, p.Met1?) is a novel pathogenic
      mutation associated with DBA.'
    explanation: An independent start-codon allele in a third patient, which is what makes the
      allelic pattern worth recording.
pathophysiology:
- name: RPS28 Start-Codon Disruption
  biological_scale: MOLECULAR
  description: >-
    The initiating lesion. A heterozygous de novo variant destroys the RPS28
    translation initiation codon, so eS28 cannot be translated from that allele.
    Every reported patient carries a variant of this class.
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
  genes:
  - preferred_term: RPS28
    term:
      id: hgnc:10418
      label: RPS28
  evidence:
  - reference: PMID:24942156
    reference_title: Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including
      the novel DBA genes TSR2 and RPS28.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'De novo mutations affecting the RPS28 start codon were found in two unrelated probands,
      identifying RPS28 as a novel disease gene.'
    explanation: The lesion itself, in the two founding probands.
  - reference: PMID:40135709
    reference_title: Diagnosis and treatment of Diamond-Blackfan anemia and Pierre-Robin sequence caused
      by a novel mutation of RPS28 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Whole exome sequencing of peripheral blood revealed a heterozygous mutation in the RPS28
      gene (c.2T > C, p.Met1?), a novel pathogenic mutation in RPS28.'
    explanation: A third, independently reported allele of the same class, with the p.Met1?
      annotation naming the loss of the initiator methionine directly.
  downstream:
  - target: Impaired Ribosome Biogenesis
    causal_link_type: DIRECT
    description: >-
      Reduced eS28 available for assembly into the small ribosomal subunit
      compromises subunit production.
    evidence:
    - reference: PMID:24942156
      reference_title: Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including
        the novel DBA genes TSR2 and RPS28.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Each of the pathogenic variants identified is predicted to impede ribosome biogenesis,
        which in turn could result in altered cell growth and proliferation, causing abnormal
        embryologic development, defective erythropoiesis and reduced growth.'
      explanation: The authors' own causal chain, covering this edge and the two downstream branches.
        Note the hedged verbs - predicted, could result - which is why the nodes below are graded as
        they are.
- name: Impaired Ribosome Biogenesis
  biological_scale: CELLULAR
  description: >-
    Reduced production of the small ribosomal subunit. Experimental depletion of
    RPS28 in human cells, in a panel alongside the other DBA ribosomal proteins,
    reduces the corresponding subunit, fully assembled ribosomes and polysomes,
    and perturbs rRNA processing. The generalisation the same study draws is that
    what the DBA proteins share is a compromised rate of ribosome production
    rather than a single common processing step.
  biological_processes:
  - preferred_term: ribosome biogenesis
    modifier: DECREASED
    term:
      id: GO:0042254
      label: ribosome biogenesis
  - preferred_term: rRNA processing
    modifier: DYSREGULATED
    term:
      id: GO:0006364
      label: rRNA processing
  evidence:
  - reference: PMID:18697920
    reference_title: The role of human ribosomal proteins in the maturation of rRNA and ribosome production.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: 'Depleting r-proteins in one of the subunits caused, with a few exceptions, a decrease
      in all r-proteins of the same subunit and a decrease in the corresponding subunit, fully
      assembled ribosomes, and polysomes.'
    explanation: The measured consequence of depleting a small-subunit ribosomal protein in human
      cells. RPS28 is one of the small-subunit proteins in this depletion panel.
  - reference: PMID:18697920
    reference_title: The role of human ribosomal proteins in the maturation of rRNA and ribosome production.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: 'We depleted HeLa cells using siRNA for several individual r-proteins of the small
      (RPS6, RPS7, RPS15, RPS16, RPS17, RPS19, RPS24, RPS25, RPS28) or large subunit'
    explanation: Names RPS28 explicitly in the depleted panel, which is what makes the preceding
      result applicable to this gene rather than to ribosomal proteins in general.
  - reference: PMID:18697920
    reference_title: The role of human ribosomal proteins in the maturation of rRNA and ribosome production.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: 'Depletion of r-proteins mutated in DBA always compromised ribosome biogenesis while
      affecting either subunit and disturbing rRNA processing at different levels'
    explanation: The study's generalisation across DBA genes. Marked INDIRECT because it is a
      statement about the DBA gene set as a class, from which the claim about RPS28 follows rather
      than being made directly.
  downstream:
  - target: Growth delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The founding authors' prediction sentence names reduced growth alongside
      abnormal embryologic development and defective erythropoiesis, as a third
      consequence of the same ribosomal lesion rather than as a downstream effect
      of either. The edge hangs here for that reason, and is typed indirect
      because the sentence is hedged ("predicted to", "could result in") and no
      experiment in these sources tests it.
    evidence:
    - reference: PMID:24942156
      reference_title: Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including
        the novel DBA genes TSR2 and RPS28.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Each of the pathogenic variants identified is predicted to impede ribosome biogenesis,
        which in turn could result in altered cell growth and proliferation, causing abnormal
        embryologic development, defective erythropoiesis and reduced growth.'
      explanation: Names reduced growth as one of the three predicted consequences of the ribosomal
        lesion.
  - target: Defective Erythropoiesis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Why a general shortage of ribosomes selectively fails red cell production
      is the central unsolved question of the ribosomopathies, and these sources
      say so rather than resolving it.
  - target: Abnormal Craniofacial Embryonic Development
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Attributed by the founding authors to altered cell growth and proliferation
      during embryogenesis, with no intermediate steps established.
- name: Defective Erythropoiesis
  biological_scale: TISSUE
  mechanism_confidence: HYPOTHETICAL
  description: >-
    Failure of red cell production, giving the macrocytic anemia that defines
    DBA. The link from a general ribosome shortage to a specifically erythroid
    failure is explicitly named as unknown in the mechanism literature, which is
    why this node is graded HYPOTHETICAL despite the anemia itself being beyond
    doubt: it is the explanation that is provisional, not the finding.
  cell_types:
  - preferred_term: erythroid progenitor cell
    term:
      id: CL:0000038
      label: erythroid progenitor cell
  biological_processes:
  - preferred_term: erythrocyte differentiation
    modifier: DECREASED
    term:
      id: GO:0030218
      label: erythrocyte differentiation
  evidence:
  - reference: PMID:18697920
    reference_title: The role of human ribosomal proteins in the maturation of rRNA and ribosome production.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'How defects in r-proteins, essential for proliferation in all cells, lead to a human
      disease with a specific defect in red cell development is unknown.'
    explanation: States the gap directly. It is cited here as the reason for the HYPOTHETICAL
      grading rather than as support for a mechanism.
  - reference: PMID:24942156
    reference_title: Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including
      the novel DBA genes TSR2 and RPS28.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Diamond-Blackfan anemia typically presents in early infancy with macrocytic anemia,
      elevated erythrocyte adenosine deaminase (eADA) and hemoglobin F, and less commonly associated
      physical findings such as short stature or thumb anomalies.'
    explanation: Describes the erythroid phenotype this node produces, which is well established even
      though its mechanism is not.
  downstream:
  - target: Macrocytic anemia
    causal_link_type: DIRECT
- name: Abnormal Craniofacial Embryonic Development
  biological_scale: TISSUE
  mechanism_confidence: HYPOTHETICAL
  description: >-
    The developmental arm. Impaired ribosome biogenesis is proposed to alter cell
    growth and proliferation during embryogenesis, producing the mandibulofacial
    dysostosis phenotype. Graded HYPOTHETICAL because the founding study offers
    this as a prediction covering all five genotypes in the series and no
    experiment in these sources tests it for RPS28.
  evidence:
  - reference: PMID:24942156
    reference_title: Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including
      the novel DBA genes TSR2 and RPS28.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Each of the pathogenic variants identified is predicted to impede ribosome biogenesis,
      which in turn could result in altered cell growth and proliferation, causing abnormal
      embryologic development, defective erythropoiesis and reduced growth.'
    explanation: The only statement in these sources linking the ribosomal lesion to the craniofacial
      phenotype, and it is framed as a prediction.
  downstream:
  - target: Mandibulofacial dysostosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The umbrella craniofacial phenotype that gives the disease its name, and the one
      the individual features below compose.
  - target: Micrognathia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Cleft palate
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Downslanted palpebral fissures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Low-set ears
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hypertelorism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
phenotypes:
- name: Macrocytic anemia
  category: Hematologic
  description: >-
    The defining haematologic feature of DBA. In the third reported patient it
    was severe and presented at two years ten months, later than the early
    infancy typical of DBA.
  phenotype_term:
    preferred_term: Macrocytic anemia
    term:
      id: HP:0001972
      label: Macrocytic anemia
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:24942156
    reference_title: Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including
      the novel DBA genes TSR2 and RPS28.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Diamond-Blackfan anemia typically presents in early infancy with macrocytic anemia,
      elevated erythrocyte adenosine deaminase (eADA) and hemoglobin F'
    explanation: The macrocytic anemia is what makes these patients DBA rather than an isolated
      mandibulofacial dysostosis.
  sequelae:
  - target: Hydrops fetalis
    causal_link_type: DIRECT
    description: >-
      GeneReviews states the direction: fetal anemia severe enough to cause
      nonimmune hydrops. The edge sits on the anemia rather than on the
      erythropoiesis node because that is the level at which the source makes the
      claim.
    evidence:
    - reference: PMID:20301769
      reference_title: DBA Syndrome.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: 'The phenotypic spectrum ranges from a mild form (e.g., mild or no anemia with only
        subtle erythroid abnormalities and/or physical malformations without anemia) to a severe form
        of fetal anemia resulting in nonimmune hydrops fetalis.'
      explanation: States that the fetal anemia is what results in the hydrops. INDIRECT for the same
        reason as every GeneReviews item here - it is a statement about DBA as a whole reaching RPS28
        by one inference step.
- name: Growth delay
  category: Growth
  description: >-
    Growth deficiency, reported in 30% of individuals with DBA. In this genotype
    it is compounded iatrogenically: chronic transfusion is used through the
    first year specifically to defer steroids and avoid steroid-induced growth
    failure.
  phenotype_term:
    preferred_term: growth deficiency
    term:
      id: HP:0001510
      label: Growth delay
  frequency: FREQUENT
  evidence:
  - reference: PMID:20301769
    reference_title: DBA Syndrome.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: 'congenital malformations in up to 50% of affected individuals, and growth deficiency
      in 30% of affected individuals'
    explanation: The GeneReviews frequency figure. 30% places this in the FREQUENT band and is a
      real denominator, unlike the single-case observations elsewhere in this entry.
- name: Neoplasm
  category: Neoplastic
  description: >-
    Increased risk of acute myelogenous leukemia, myelodysplastic syndrome and
    solid tumours including osteogenic sarcoma. Bound to the general neoplasm
    term because the risk spans three distinct malignancy classes; the specific
    entities are named in the description and in the surveillance treatment
    rather than curated as separate phenotypes, since no source gives a
    per-tumour frequency for this genotype.
  phenotype_term:
    preferred_term: predisposition to AML, myelodysplastic syndrome and solid tumours
    term:
      id: HP:0002664
      label: Neoplasm
  evidence:
  - reference: PMID:20301769
    reference_title: DBA Syndrome.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: 'DBA syndrome is associated with an increased risk for acute myelogenous leukemia,
      myelodysplastic syndrome, and solid tumors including osteogenic sarcoma.'
    explanation: Names all three malignancy classes. This is the finding that makes lifelong cancer
      surveillance part of management rather than optional.
  - reference: PMID:40135709
    reference_title: Diagnosis and treatment of Diamond-Blackfan anemia and Pierre-Robin sequence caused
      by a novel mutation of RPS28 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Diamond-Blackfan anemia (DBA) is a congenital erythroid aplasia associated with
      physical anomalies and a predisposition to cancer.'
    explanation: An independent statement of the cancer predisposition, in the one paper that
      reports an RPS28 patient specifically.
- name: Hydrops fetalis
  category: Prenatal
  description: >-
    The severe end of the phenotypic spectrum: fetal anemia severe enough to
    cause nonimmune hydrops fetalis. Recorded because it defines how wide the
    spectrum is, not because it has been reported in an RPS28 patient.

    No frequency is recorded. An earlier revision banded this VERY_RARE, but the
    quoted sentence describes where hydrops sits on the severity spectrum and
    gives no rate - so the band was a number this curator supplied, sitting next
    to a verified quote that appeared to license it and did not. Absent is the
    honest state.
  phenotype_term:
    preferred_term: nonimmune hydrops fetalis
    term:
      id: HP:0001789
      label: Hydrops fetalis
  evidence:
  - reference: PMID:20301769
    reference_title: DBA Syndrome.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: 'The phenotypic spectrum ranges from a mild form (e.g., mild or no anemia with only
      subtle erythroid abnormalities and/or physical malformations without anemia) to a severe form
      of fetal anemia resulting in nonimmune hydrops fetalis.'
    explanation: Gives both ends of the DBA spectrum in one sentence. Quoted here for the severe
      end; the mild end matters too, because it means an RPS28 relative could carry the variant
      with minimal anemia.
- name: Mandibulofacial dysostosis
  category: Craniofacial
  description: >-
    The craniofacial phenotype that brought these patients to attention -
    clinically suggestive of Treacher Collins syndrome, but occurring with DBA and
    without a TCOF1 variant.
  phenotype_term:
    preferred_term: Mandibulofacial dysostosis
    term:
      id: HP:0005321
      label: Mandibulofacial dysostosis
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:24942156
    reference_title: Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including
      the novel DBA genes TSR2 and RPS28.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Patients with physical findings suggestive of Treacher Collins syndrome (TCS) or
      mandibulofacial dysostosis (MFD) and macrocytic anemia diagnostic of Diamond-Blackfan anemia
      (DBA) have been reported.'
    explanation: Defines the combined phenotype that this disease entity was created to explain.
- name: Micrognathia
  category: Craniofacial
  description: Small mandible, part of the Pierre Robin triad in the third reported patient.
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:40135709
    reference_title: Diagnosis and treatment of Diamond-Blackfan anemia and Pierre-Robin sequence caused
      by a novel mutation of RPS28 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'He was born with micrognathia, cleft palate, and airway obstruction, resulting in
      neonatal asphyxia and feeding difficulties, which constitute the classic triad of PRS.'
    explanation: Documents micrognathia and the Pierre Robin sequence it forms part of.
- name: Cleft palate
  category: Craniofacial
  description: Palatal clefting, present with micrognathia and glossoptosis as a Pierre Robin
    sequence.
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:40135709
    reference_title: Diagnosis and treatment of Diamond-Blackfan anemia and Pierre-Robin sequence caused
      by a novel mutation of RPS28 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'He was born with micrognathia, cleft palate, and airway obstruction, resulting in
      neonatal asphyxia and feeding difficulties, which constitute the classic triad of PRS.'
    explanation: Documents the cleft palate as part of the reported triad.
- name: Upper airway obstruction
  category: Respiratory
  description: >-
    Neonatal airway obstruction from the Pierre Robin sequence, severe enough to
    cause asphyxia at birth in the third reported patient.
  phenotype_term:
    preferred_term: Upper airway obstruction
    term:
      id: HP:0002781
      label: Upper airway obstruction
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:40135709
    reference_title: Diagnosis and treatment of Diamond-Blackfan anemia and Pierre-Robin sequence caused
      by a novel mutation of RPS28 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'He was born with micrognathia, cleft palate, and airway obstruction, resulting in
      neonatal asphyxia and feeding difficulties, which constitute the classic triad of PRS.'
    explanation: Reports the airway obstruction and, importantly, its immediate consequence -
      neonatal asphyxia - which is what makes it clinically urgent rather than incidental.
- name: Downslanted palpebral fissures
  category: Craniofacial
  description: Downward-slanting palpebral fissures, a Treacher Collins-like feature.
  phenotype_term:
    preferred_term: Downslanted palpebral fissures
    term:
      id: HP:0000494
      label: Downslanted palpebral fissures
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:40135709
    reference_title: Diagnosis and treatment of Diamond-Blackfan anemia and Pierre-Robin sequence caused
      by a novel mutation of RPS28 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Low-set ears, downslanted palpebral fissures, bilateral exotropia, a short neck,
      hypertelorism, a thenar muscle defect, and bilateral severe sensorineural hearing loss were
      also observed in the boy.'
    explanation: The source's list of additional dysmorphic features, quoted once and shared by the
      several phenotypes it names.
- name: Low-set ears
  category: Craniofacial
  description: Low-set ears, part of the dysmorphic picture.
  phenotype_term:
    preferred_term: Low-set ears
    term:
      id: HP:0000369
      label: Low-set ears
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:40135709
    reference_title: Diagnosis and treatment of Diamond-Blackfan anemia and Pierre-Robin sequence caused
      by a novel mutation of RPS28 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Low-set ears, downslanted palpebral fissures, bilateral exotropia, a short neck,
      hypertelorism, a thenar muscle defect, and bilateral severe sensorineural hearing loss were
      also observed in the boy.'
    explanation: Names low-set ears among the observed features.
- name: Hypertelorism
  category: Craniofacial
  description: Increased interocular distance.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:40135709
    reference_title: Diagnosis and treatment of Diamond-Blackfan anemia and Pierre-Robin sequence caused
      by a novel mutation of RPS28 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Low-set ears, downslanted palpebral fissures, bilateral exotropia, a short neck,
      hypertelorism, a thenar muscle defect, and bilateral severe sensorineural hearing loss were
      also observed in the boy.'
    explanation: Names hypertelorism among the observed features.
- name: Bilateral sensorineural hearing impairment
  category: Otologic
  description: >-
    Bilateral severe sensorineural hearing loss. Hearing loss is a recurring
    feature of the mandibulofacial dysostosis phenotypes, and its severity here
    drives management.
  phenotype_term:
    preferred_term: Bilateral sensorineural hearing impairment
    term:
      id: HP:0008619
      label: Bilateral sensorineural hearing impairment
    severity: SEVERE
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:40135709
    reference_title: Diagnosis and treatment of Diamond-Blackfan anemia and Pierre-Robin sequence caused
      by a novel mutation of RPS28 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Low-set ears, downslanted palpebral fissures, bilateral exotropia, a short neck,
      hypertelorism, a thenar muscle defect, and bilateral severe sensorineural hearing loss were
      also observed in the boy.'
    explanation: The source states the laterality and the severity, both of which are carried into
      the binding.
- name: Exotropia
  category: Ophthalmologic
  description: Bilateral divergent strabismus.
  phenotype_term:
    preferred_term: Exotropia
    term:
      id: HP:0000577
      label: Exotropia
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:40135709
    reference_title: Diagnosis and treatment of Diamond-Blackfan anemia and Pierre-Robin sequence caused
      by a novel mutation of RPS28 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Low-set ears, downslanted palpebral fissures, bilateral exotropia, a short neck,
      hypertelorism, a thenar muscle defect, and bilateral severe sensorineural hearing loss were
      also observed in the boy.'
    explanation: Names bilateral exotropia among the observed features.
- name: Short neck
  category: Skeletal
  description: Shortened neck.
  phenotype_term:
    preferred_term: Short neck
    term:
      id: HP:0000470
      label: Short neck
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:40135709
    reference_title: Diagnosis and treatment of Diamond-Blackfan anemia and Pierre-Robin sequence caused
      by a novel mutation of RPS28 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Low-set ears, downslanted palpebral fissures, bilateral exotropia, a short neck,
      hypertelorism, a thenar muscle defect, and bilateral severe sensorineural hearing loss were
      also observed in the boy.'
    explanation: Names short neck among the observed features.
- name: Global developmental delay
  category: Neurodevelopmental
  description: >-
    Significant delay in motor and speech development in the third reported
    patient. Worth noting that severe bilateral hearing loss was present in the
    same child, so the speech component is confounded.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:40135709
    reference_title: Diagnosis and treatment of Diamond-Blackfan anemia and Pierre-Robin sequence caused
      by a novel mutation of RPS28 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'His motor and speech development were significantly delayed.'
    explanation: Reports delay across both motor and speech domains, which is what the global term
      covers.
- name: Decreased total neutrophil count
  category: Hematologic
  description: >-
    Granulocytopenia from birth in the third reported patient, preceding the
    anemia by more than two years. Cytopenias outside the red cell line are not
    typical of DBA, and this is a single observation.
  phenotype_term:
    preferred_term: Decreased total neutrophil count
    term:
      id: HP:0001875
      label: Decreased total neutrophil count
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:40135709
    reference_title: Diagnosis and treatment of Diamond-Blackfan anemia and Pierre-Robin sequence caused
      by a novel mutation of RPS28 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'In addition, he was found to be granulocytopenic at birth and severely anemic at 2
      years and 10 months of age.'
    explanation: Documents the neutropenia and its timing relative to the anemia, which is the detail
      that makes it notable.
- name: Feeding difficulties
  category: Gastrointestinal
  description: Neonatal feeding difficulty arising from the Pierre Robin sequence.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:40135709
    reference_title: Diagnosis and treatment of Diamond-Blackfan anemia and Pierre-Robin sequence caused
      by a novel mutation of RPS28 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'He was born with micrognathia, cleft palate, and airway obstruction, resulting in
      neonatal asphyxia and feeding difficulties, which constitute the classic triad of PRS.'
    explanation: Reports the feeding difficulty and attributes it to the airway and palatal anatomy.
treatments:
- name: Hematopoietic Stem Cell Transplantation
  description: >-
    The definitive treatment for the haematologic component. In the one reported
    RPS28 patient who received it, from a 9/10 HLA-matched donor, both neutrophil
    and haemoglobin levels normalised. It does not address the craniofacial
    malformations or the hearing loss.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: hematopoietic stem cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_mechanisms:
  - target: Defective Erythropoiesis
    description: Replaces the RPS28-deficient haematopoietic compartment with donor cells, restoring
      erythropoiesis at its source.
  evidence:
  - reference: PMID:40135709
    reference_title: Diagnosis and treatment of Diamond-Blackfan anemia and Pierre-Robin sequence caused
      by a novel mutation of RPS28 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'The boy underwent HSCT from 9/10 HLA-matched donor and his neutrophil and hemoglobin
      levels returned to normal.'
    explanation: The only reported treatment outcome in an RPS28 patient. It is a single case, so it
      establishes that transplant worked here, not an expected response rate.
  - reference: PMID:40135709
    reference_title: Diagnosis and treatment of Diamond-Blackfan anemia and Pierre-Robin sequence caused
      by a novel mutation of RPS28 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'HSCT is an effective treatment for hematological abnormalities in DBA.'
    explanation: The authors' generalisation to DBA as a whole, which is the broader basis for
      offering transplant in this genotype.
- name: Corticosteroid Therapy
  description: >-
    Standard first-line therapy for the anemia of DBA, started at age 12 months
    or older. Deliberately deferred through the first year, with chronic
    transfusion used instead, to avoid steroid-induced growth deficiency.

    The two sources give different response rates and the entry cites both rather
    than picking one: the 2014 series says 40%, GeneReviews says 60-80%. They are
    not directly comparable - the GeneReviews figure describes improvement in red
    blood cell count on a treatment given at a specified age, while the 2014
    figure describes patients categorised as steroid-responsive alongside
    spontaneous remitters and transfusion-dependent patients. No steroid-response
    data exist for RPS28 patients specifically, so either way this is offered on
    the basis of the DBA literature rather than genotype-specific evidence.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: corticosteroid
      term:
        id: CHEBI:50858
        label: corticosteroid
  target_mechanisms:
  - target: Defective Erythropoiesis
    description: Improves red cell output in steroid-responsive DBA. The mechanism of the steroid
      response in DBA is itself not established.
  evidence:
  - reference: PMID:24942156
    reference_title: Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including
      the novel DBA genes TSR2 and RPS28.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: 'The anemia remits spontaneously in about 20%, is steroid responsive in 40% and requires
      long term transfusions in about 40%'
    explanation: Gives the steroid-response rate for DBA as a whole. Marked INDIRECT because the
      claim about RPS28 patients follows from their being DBA patients rather than from any
      RPS28-specific observation.
  - reference: PMID:20301769
    reference_title: DBA Syndrome.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Corticosteroid treatment, recommended in children at age 12 months or older, improves
      the red blood cell count in approximately 60%-80% of affected individuals.'
    explanation: The GeneReviews response rate, higher than the 40% figure above and measured
      differently. Both are curated so a reader sees the range rather than whichever number the
      curator happened to meet first; also the source of the age-12-months recommendation.
- name: Iron Chelation Therapy
  description: >-
    Transfusion-related iron overload is the most common complication in
    transfusion-dependent patients, and chelation is recommended after ten to
    twelve transfusions. Deferasirox orally or desferrioxamine subcutaneously are
    the standard agents.

    Deferiprone is the agent to avoid. GeneReviews lists it explicitly under
    agents/circumstances to avoid in DBA because it can cause neutropenia - which
    is pointed for this genotype specifically, since the one reported RPS28
    patient was granulocytopenic from birth.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: deferasirox
      term:
        id: CHEBI:49005
        label: deferasirox
  target_mechanisms:
  - target: Macrocytic anemia
    description: Does not treat the anemia. It manages the iron burden that chronic transfusion
      creates, so it is downstream of the treatment rather than of the disease.
  evidence:
  - reference: PMID:20301769
    reference_title: DBA Syndrome.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Iron chelation therapy with deferasirox orally or desferrioxamine subcutaneously is
      recommended after ten to 12 transfusions.'
    explanation: Names both agents and the transfusion count that triggers chelation.
  - reference: PMID:20301769
    reference_title: DBA Syndrome.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Agents/circumstances to avoid: Deferiprone for the treatment of iron overload (which
      can cause neutropenia)'
    explanation: The drug-safety warning. Curated because this entry also records neutropenia in the
      only reported RPS28 patient, so the caution is not generic here.
- name: Malignancy Surveillance
  description: >-
    Lifelong cancer surveillance: history, examination and blood counts every four
    to six months. A rapid fall in any cell line triggers bone marrow aspirate
    with biopsy and cytogenetics, looking for acquired abnormalities of
    chromosomes 5, 7 and 8 that mark myelodysplastic syndrome or leukemia.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: cancer surveillance
    term:
      id: NCIT:C15406
      label: Cancer Screening
  target_mechanisms:
  - target: Neoplasm
    description: Detects malignant transformation early rather than preventing it. It does not act
      on the ribosomal defect.
  evidence:
  - reference: PMID:20301769
    reference_title: DBA Syndrome.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Cancer surveillance includes history, physical examination, and blood counts every
      four to six months.'
    explanation: The surveillance interval and its components.
  - reference: PMID:20301769
    reference_title: DBA Syndrome.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: 'look for acquired abnormalities in chromosomes 5, 7, and 8 that are associated with
      myelodysplastic syndrome or leukemia'
    explanation: Names the specific cytogenetic abnormalities the escalation step is looking for,
      which is what makes this actionable rather than generic vigilance.
- name: Red Cell Transfusion
  description: >-
    Long-term transfusion support is required by roughly 40% of DBA patients and
    is the alternative when the anemia does not respond to steroids.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: red blood cell transfusion
    term:
      id: NCIT:C15192
      label: Blood Transfusion
  target_mechanisms:
  - target: Macrocytic anemia
    description: Replaces the red cells the marrow does not produce. Purely supportive; it does not
      act on the ribosomal defect.
  evidence:
  - reference: PMID:24942156
    reference_title: Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including
      the novel DBA genes TSR2 and RPS28.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: 'The anemia remits spontaneously in about 20%, is steroid responsive in 40% and requires
      long term transfusions in about 40%'
    explanation: Same DBA-wide figure as above, read for the transfusion-dependent fraction. INDIRECT
      for the same reason.
diagnosis:
- name: Exome sequencing
  description: >-
    The route by which this disease is identified. The founding study reached
    RPS28 by whole exome analysis of probands whose combined DBA and
    mandibulofacial dysostosis phenotype had no molecular explanation, and the
    third patient was diagnosed the same way.
  evidence:
  - reference: PMID:24942156
    reference_title: Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including
      the novel DBA genes TSR2 and RPS28.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Combining exome analysis and Sanger sequencing, we identified likely pathogenic
      mutations in 5/6 families.'
    explanation: Describes the diagnostic approach and its yield in the founding series.
  - reference: PMID:40135709
    reference_title: Diagnosis and treatment of Diamond-Blackfan anemia and Pierre-Robin sequence caused
      by a novel mutation of RPS28 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'It is crucial to perform a genetic evaluation for syndromic bone marrow failure with
      congenital anomalies.'
    explanation: The recommendation this diagnostic entry exists to record - genetic evaluation when
      marrow failure occurs with congenital anomalies.
  - reference: PMID:20301769
    reference_title: DBA Syndrome.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: 'The molecular diagnosis of DBA syndrome can be established in a proband by
      identification of a heterozygous pathogenic variant in a gene associated with autosomal
      dominant DBA syndrome'
    explanation: The GeneReviews molecular-diagnostic criterion for the autosomal dominant genotypes,
      which is the class RPS28 belongs to.
- name: Clinical diagnosis from laboratory and histopathological features
  description: >-
    DBA can be diagnosed clinically, before or without a molecular result, from
    the characteristic picture: profound normochromic and usually macrocytic
    anemia with normal leukocytes and platelets. Hematologic complications appear
    in the first year of life in 90% of patients - though the one reported RPS28
    patient presented later, at two years ten months.
  evidence:
  - reference: PMID:20301769
    reference_title: DBA Syndrome.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: 'The clinical diagnosis of DBA syndrome can be established in a proband with
      characteristic laboratory, histopathology, and clinical features.'
    explanation: Establishes that a clinical diagnosis is possible without molecular confirmation.
  - reference: PMID:20301769
    reference_title: DBA Syndrome.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: 'DBA syndrome is characterized by a profound normochromic and usually macrocytic anemia
      with normal leukocytes and platelets'
    explanation: The specific haematological pattern the clinical diagnosis turns on - and note that
      the isolated red-cell involvement it describes is what makes the neutropenia in the reported
      RPS28 patient atypical.
  - reference: PMID:20301769
    reference_title: DBA Syndrome.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: 'The hematologic complications occur in 90% of affected individuals during the first
      year of life.'
    explanation: Gives the expected age of presentation, against which the reported RPS28 patient's
      presentation at two years ten months is late.
differential_diagnoses:
- name: Treacher Collins syndrome
  description: >-
    The phenotype these patients are first taken for. TCS is usually caused by a
    heterozygous TCOF1 variant, with POLR1D and biallelic POLR1C accounting for
    further cases. It does not carry the DBA erythroid phenotype, and the anemia
    is what should prompt reconsideration.
  evidence:
  - reference: PMID:24942156
    reference_title: Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including
      the novel DBA genes TSR2 and RPS28.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Most TCS patients have a heterozygous TCOF1 mutation, while heterozygous POLR1D and
      biallelic POLR1C mutations account for additional cases'
    explanation: Names the genes that have to be excluded, which is what makes this a differential
      rather than a synonym.
- name: Diamond-Blackfan anemia 14 with mandibulofacial dysostosis (TSR2)
  description: >-
    The X-linked sibling entity, defined in the same six-family series. It is
    indistinguishable on the craniofacial phenotype alone; the discriminators are
    the segregation pattern and the gene. Curated separately in this knowledge
    base.
  evidence:
  - reference: PMID:24942156
    reference_title: Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including
      the novel DBA genes TSR2 and RPS28.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'In another family a likely pathogenic X-linked mutation affecting a highly conserved
      residue was found in TSR2, which encodes a direct binding partner of RPS26.'
    explanation: The TSR2 family from the same series, and the note that TSR2 partners RPS26 - which
      is why these genotypes converge on one phenotype.
- name: Diamond-Blackfan anemia 10 (RPS26)
  description: >-
    Two of the six families in the founding series carried RPS26 variants, one
    affecting splicing and one truncating. RPS26 is the binding partner of the
    TSR2 protein, so DBA10, DBA14 and DBA15 all disturb small-subunit assembly by
    different routes.
  evidence:
  - reference: PMID:24942156
    reference_title: Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including
      the novel DBA genes TSR2 and RPS28.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Two mutations in unrelated families were seen in RPS26, the known DBA10 gene. One
      variant was predicted to affect mRNA splicing, and the other to lead to protein truncation.'
    explanation: The RPS26 families and their allele classes, establishing this as the most common
      genotype behind the combined phenotype.
discussions:
- discussion_id: rps28_start_codon_only
  kind: KNOWLEDGE_GAP
  attaches_to:
  - genetic#RPS28
  prompt: >-
    Is the RPS28 disease spectrum genuinely restricted to start-codon variants,
    or does that pattern simply reflect three reported patients?
  rationale: >-
    All three reported RPS28 alleles destroy the translation initiation codon. If
    that restriction is real it would be mechanistically interesting - it might
    mean only a specific consequence of start-codon loss, such as initiation at a
    downstream methionine producing an N-terminally truncated eS28, causes
    disease, while a simple null is tolerated or lethal. If it is an artefact of
    three patients, RPS28 should be read like any other DBA gene. The two readings
    imply different variant-interpretation practice for a novel RPS28 missense
    allele, and nothing in the current literature separates them.
- discussion_id: rps28_erythroid_specificity
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Defective Erythropoiesis
  prompt: >-
    Why does a general reduction in ribosome production cause a specifically
    erythroid failure rather than a uniform proliferative defect?
  rationale: >-
    This is the central unsolved question of the ribosomopathies and it is named
    as unknown in the mechanism literature cited here. It is recorded on this
    entry because the same experimental work shows RPS28 depletion behaves like
    the other DBA proteins - compromising the rate of ribosome production
    generally, without a distinctive processing signature - so nothing specific to
    RPS28 explains the erythroid selectivity either.
notes: >-
  Curated de novo as the sibling of the existing DBA14 entry, which was created
  from the same founding paper (PMID:24942156) and which already carried a
  differential-diagnosis entry anticipating this genotype. Structure, the ICD10CM
  broadMatch mapping and the parents list deliberately mirror DBA14 so the two
  read as a pair.

  Evidence rests on three papers: the founding six-family series (PMID:24942156),
  the single subsequent case report (PMID:40135709), and the human ribosomal
  protein depletion study (PMID:18697920), which is the only source here that
  measures anything about RPS28 rather than predicting it.

  Two gradings a reviewer may want to check. Both Defective Erythropoiesis and
  Abnormal Craniofacial Embryonic Development are mechanism_confidence
  HYPOTHETICAL. In the first case it is the explanation and not the finding that
  is provisional - the anemia is beyond doubt, but why a general ribosome shortage
  selectively fails erythropoiesis is stated as unknown in the cited literature.
  In the second, the founding authors' link from the ribosomal lesion to the
  craniofacial phenotype is explicitly a prediction ("is predicted to impede",
  "could result in"), covering all five genotypes in their series collectively,
  and no experiment in these sources tests it for RPS28.

  Frequency bands come from two different kinds of source and are banded
  accordingly. The GeneReviews figures are real denominators over the whole of
  DBA - growth deficiency 30%, congenital malformations up to 50%, haematologic
  onset in the first year in 90% - and are banded from those numbers. Everything
  drawn from the single RPS28 case report is banded OCCASIONAL uniformly,
  including the craniofacial features that an earlier revision of this entry
  banded FREQUENT. That split was inconsistent: four of those features come from
  one sentence of one n=1 abstract, and one n=1 observation cannot support two
  different tiers. They are now level.

  CORRECTION. An earlier revision of this entry stated that the DBA GeneReviews
  chapter (PMID:20301769) is "a bibliographic stub with no abstract text, so
  there is nothing cached to quote". That was wrong, and it was wrong because the
  read was truncated: the cached record is 122 lines and opens with about 30
  lines of bibliographic header, so a look at the first dozen lines shows only
  the header. The chapter carries the full four-section GeneReviews abstract -
  CLINICAL CHARACTERISTICS, DIAGNOSIS/TESTING, MANAGEMENT, GENETIC COUNSELING -
  and it is now tagged in `references:` and mined across phenotypes, diagnosis,
  treatments and inheritance, as the sibling DBA14 entry does.

  Directness. Every evidence item citing the GeneReviews chapter (PMID:20301769)
  is marked directness: INDIRECT, without exception. Each of them is a statement
  about DBA as a whole - a recurrence risk, a malformation rate, a management
  recommendation, a diagnostic criterion - and reaches an RPS28 patient by one
  inference step from the class to this member of it. An earlier revision marked
  exactly one of the fourteen, which asserted a distinction between them that
  does not exist. This is an assessment, not a completeness exercise: the items
  drawn from the RPS28 case report and from the founding series carry no
  directness value, because nobody has judged those.

  The corticosteroid response rate differs between sources and both are cited
  rather than one being chosen silently: 40% in the 2014 series, 60-80% in
  GeneReviews. They measure different things - improvement in red cell count on
  treatment given at a specified age, versus a category in a three-way split that
  also counts spontaneous remitters and transfusion-dependent patients - and the
  treatment description says so.
📚

References & Deep Research

References

4
PMID:20301769
DBA Syndrome.
No top-level findings curated for this source.
PMID:24942156
Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28.
No top-level findings curated for this source.
PMID:40135709
Diagnosis and treatment of Diamond-Blackfan anemia and Pierre-Robin sequence caused by a novel mutation of RPS28 gene.
No top-level findings curated for this source.
PMID:18697920
The role of human ribosomal proteins in the maturation of rRNA and ribosome production.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Post-approval follow-up: remove an unsourced frequency band, level directness across GeneReviews items, connect two orphan phenotypes · 2026-09-10T20:18:19Z · View source

Follow-up push after the approving re-review on PR #11639, taking the four non-blocking suggestions the reviewer explicitly said to take "only if something else brings you back". Nothing else brought me back; one of the four is a false statement rather than a nit, and that was worth the approval this push drops. CORRECTION TO THE FIRST RECORD IN THIS DIRECTORY. That record's final sentence still reads: "The DBA GeneReviews chapter PMID:20301769 was retrieved but its PubMed record is a bibliographic stub with no abstract text, so nothing is quoted from it." That is false, for the reason the second record in this directory sets out - the cached record is 122 lines opening with about 30 lines of bibliographic header, and only the header was read. The chapter carries the full four-section abstract and is now tagged and mined across all four sections. The first record is left as written and this one supersedes that sentence. Noting a process error alongside it. That same record was earlier corrected IN PLACE for a different false claim (about the deep-research report's validation blocks), which is not how append-only provenance is supposed to work; the reviewer on a sibling PR in this batch, #11642, made the point explicitly - amend via a new record once a PR has been through a round. Correcting it in place a second time would compound that, so this record exists instead. SUGGESTION 1, and the reason this push happened at all. Hydrops fetalis was banded VERY_RARE. The quoted GeneReviews sentence describes where hydrops sits on the severity spectrum - "to a severe form of fetal anemia resulting in nonimmune hydrops fetalis" - and gives no rate whatsoever. The band was a number this curator supplied, sitting immediately beneath a verified exact quote that appeared to license it and did not. That is the same defect class as an unsourced CURIE: a fabricated value made to look sourced by proximity to a real one, and it is worse here than in prose because a frequency band is machine-readable and will be believed. The band is removed rather than softened, and the phenotype description now says what happened and that absent is the honest state. It sat in the same entry whose notes paragraph this round rewrote to explain banding discipline, which is the part worth remembering. SUGGESTION 2. Every one of the fourteen evidence items citing PMID:20301769 now carries directness: INDIRECT. Exactly one of the fourteen carried it before, which asserted a distinction between them that does not exist: each is a statement about DBA as a whole - a recurrence risk, a malformation rate, a management recommendation, a diagnostic criterion - reaching an RPS28 patient by one inference step from the class to this member. This is an assessment and not a completeness exercise; CLAUDE.md is explicit that directness should be left absent where nobody has judged it, so the items from the RPS28 case report and the founding series still carry no value. The notes record the rule. The mechanical edit for this went wrong first, and the gate caught it. A line-oriented insertion pass put a second directness key into treatments[1].evidence[1], next to the one already there. PyYAML keeps the last silently, so just validate passed; just check-duplicate-keys reported it at line 821. That is precisely the case CLAUDE.md describes when it says a duplicate key is invisible to every renderer and test in the repo while being fatal to reference validation. Removed, re-checked clean. SUGGESTION 3. The two remaining orphan phenotypes are connected. Growth delay hangs off Impaired Ribosome Biogenesis rather than off the craniofacial node, because the founding authors' prediction sentence names reduced growth alongside abnormal embryologic development and defective erythropoiesis as a third consequence of the same lesion, not as a downstream effect of either; the edge is typed INDIRECT_UNKNOWN_INTERMEDIATES to match the sentence's hedged verbs. Hydrops fetalis is a sequela of Macrocytic anemia typed DIRECT, because GeneReviews states that direction outright - fetal anemia resulting in hydrops - and the edge sits at the level at which the source makes the claim rather than one node upstream. SUGGESTION 4 is this record. VALIDATION. just validate passes with 55/55 snippets verified, up from 53/53. just validate-terms, check-entity-refs, check-causal-targets, check-duplicate-keys, check-qualifier-terms, check-enum-values, check-snippet-length, check-snippet-grading and check-title-snippets all pass.

Perplexity ▸
Diamond-Blackfan Anemia 15 with Mandibulofacial Dysostosis: A Comprehensive Disease Characteristics Report
sonar-deep-research 20 citations 2026-09-10T18:20:28.818844

Diamond-Blackfan Anemia 15 with Mandibulofacial Dysostosis: A Comprehensive Disease Characteristics Report

Diamond-Blackfan anemia 15 with mandibulofacial dysostosis (DBA15) is an ultra-rare ribosomopathy defined by the coexistence of classic Diamond-Blackfan anemia (DBA)—a congenital, typically macrocytic pure red cell aplasia—and a characteristic pattern of craniofacial malformation within the mandibulofacial dysostosis (MFD) spectrum, caused by heterozygous germline mutation of the ribosomal protein gene RPS28 on chromosome 19p13.2.[1][4][8] It represents a genetically and clinically distinct subtype within the broader DBA syndrome, which encompasses multiple ribosomal protein and related genes, yet it shares the core pathophysiological mechanism of impaired ribosome biogenesis leading to nucleolar stress, p53 activation, and selective apoptosis of erythroid progenitors and craniofacial neural crest derivatives.[2][11][13][20] De novo loss-of-function variants that specifically disrupt the canonical translation initiation codon of RPS28 have been identified in at least two unrelated probands with DBA and Treacher Collins–like MFD features, firmly establishing RPS28 haploinsufficiency as the molecular basis of DBA15.[1][2][5][14] The phenotype combines severe early-onset anemia, often manifesting in infancy, with micrognathia, downslanting palpebral fissures, submucous cleft palate or bifid uvula, and malar hypoplasia, alongside variable growth restriction and other congenital anomalies typical of DBA.[2][4][8][11] This report synthesizes current knowledge on DBA15 across epidemiology, genetics, pathophysiology, clinical presentation, diagnostics, prognosis, treatment, prevention, and model systems, integrating evidence from human clinical studies, model organisms, and in vitro functional work to support ontological and mechanistic annotations for a structured disease knowledge base.

1. Disease Information

1.1 Definition and Clinical Overview

Diamond-Blackfan anemia 15 with mandibulofacial dysostosis (DBA15) is formally defined as a subtype of Diamond-Blackfan anemia characterized by the coexistence of DBA and craniofacial anomalies in the MFD spectrum, with a material basis in heterozygous mutation of the RPS28 gene on chromosome 19p13.2.[1][4][8][10] MedGen and Disease Ontology entries describe DBA15 as “Diamond-Blackfan anemia and mandibulofacial dysostosis (micrognathia, downslanting palpebral fissures, submucosal cleft palate or bifid uvula, and malar hypoplasia) that has material basis in heterozygous mutation in the RPS28 gene on chromosome 19p13.2.”[4][8][10] Clinically, the hematological component corresponds to classic DBA syndrome, which is characterized by profound normochromic, usually macrocytic anemia, reticulocytopenia, and severe reduction or absence of erythroid precursors in an otherwise cellular bone marrow, typically presenting in the first year of life.[11][12][13] The craniofacial component overlaps with Treacher Collins syndrome (TCS) and other mandibulofacial dysostoses, with micrognathia, malar hypoplasia, downslanting palpebral fissures, and cleft palate or submucous cleft often noted in affected individuals.[2][5][9][14]

GeneReviews and Orphanet both emphasize that DBA as a syndrome encompasses a spectrum ranging from severe fetal anemia with nonimmune hydrops fetalis to mild or even subclinical erythroid abnormalities with isolated congenital malformations.[4][11][15] DBA15 lies within this spectrum but is distinguished by its specific molecular cause and the consistent presence of MFD features, placing it at the intersection of ribosomopathies that primarily affect hematopoiesis and those that primarily affect craniofacial development.[2][5][13][20] The condition is rare enough that current knowledge is derived almost entirely from aggregated disease-level resources (e.g., OMIM, GeneReviews, MedGen, Orphanet) and a small number of case reports and exome studies rather than large clinical series or registry-based analyses.[1][2][4][5][14]

1.2 Key Identifiers and Ontology Mapping

DBA15 is indexed in several major biomedical databases and ontologies. OMIM lists it under entry #606164 – Diamond-Blackfan anemia 15 with mandibulofacial dysostosis, specifying the causal gene RPS28 (MIM 603685).[1] MedGen assigns Concept ID C4225411 for DBA15, and links it to OMIM 606164 and to the Monarch Initiative disease ontology concept MONDO:0011639.[4] Disease Ontology, via the Zebrafish Model Organism Database (ZFIN) and DOID registry, records DBA15 under DOID:0111894, explicitly defining it as a Diamond-Blackfan anemia with mandibulofacial dysostosis due to heterozygous RPS28 mutation.[8][10] Orphanet includes DBA15 in its broader Diamond-Blackfan anemia entry, which lists multiple OMIM-linked genetic subtypes, including 606164 for RPS28-associated disease.[15]

Standard coding systems for anemia and bone marrow failure syndromes, such as ICD-10 and ICD-11, do not yet distinguish DBA15 from other DBA subtypes but classify DBA under congenital pure red cell aplasia or congenital aregenerative anemia (ICD-10 D61.0, ICD-11 3A60.1).[12][15] MeSH includes “Diamond-Blackfan Anemia” (D029503) but does not yet provide a separate descriptor for DBA15.[15] In the Human Phenotype Ontology (HPO), relevant disease-level mappings include “Diamond-Blackfan anemia” (HP:0001931) and “Mandibulofacial dysostosis” (HP:0001999), which together capture many of the key phenotypic hallmarks of DBA15.[2][5][11] For disease ontology annotation, the primary term is MONDO:0011639 – Diamond-Blackfan anemia 15 with mandibulofacial dysostosis, linked to RPS28 and OMIM 606164.[4][8]

1.3 Synonyms and Alternative Names

Several synonymous labels appear across databases and the clinical literature. MedGen and NORD list the following synonyms: “DBA15,” “Diamond Blackfan anemia 15 with mandibulofacial dysostosis,” “Diamond Blackfan anaemia 15 with mandibulofacial dysostosis,” “Diamond-Blackfan anemia caused by mutation in RPS28,” and “RPS28 Diamond-Blackfan anemia.”[4][6] OMIM uses “Diamond-Blackfan anemia 15 with mandibulofacial dysostosis; DBA15” to emphasize both the ordinal numbering (15) within the DBA locus series and the distinctive craniofacial phenotype.[1] In research articles, the phenotype is frequently described as “Diamond-Blackfan anemia with mandibulofacial dystostosis” or as a “Treacher Collins–like phenotype with DBA,” reflecting the observed overlap with TCS.[2][5][14]

These synonyms reflect the evolution of nomenclature from purely phenotypic descriptions (DBA with MFD, DBA-TCS overlap) to more precise genotype-driven labels specifying the causal gene (RPS28), consistent with modern practice in monogenic disease classification.[2][5][11][14] For ontology alignment, “DBA15” functions as a short-form label, whereas “Diamond-Blackfan anemia 15 with mandibulofacial dysostosis” remains the preferred full name in MONDO and Disease Ontology.[4][8][10]

1.4 Source of Information: Patient-Level vs Aggregated Data

Given the extreme rarity of DBA15, nearly all available information is derived from aggregated disease-level resources based on small numbers of individual patients rather than from large population-based or electronic health record (EHR) datasets.[1][2][4][5][11][14] The foundational evidence for DBA15 comes from the exome sequencing study by Gripp et al. (2014, American Journal of Medical Genetics A), which identified de novo RPS28 start codon mutations in two unrelated probands with DBA and MFD, and from the subsequent OMIM and GeneReviews entries that synthesized these findings into a recognized clinical entity.[1][2][5][11][14] As that study notes, “De novo mutations affecting the RPS28 start codon were found in two unrelated probands, identifying RPS28 as a novel disease gene,” and “We conclude that the phenotype combining features of TCS with DBA is genetically heterogeneous.”[2][5][14]

Broader epidemiologic, diagnostic, and therapeutic data come from large DBA cohorts such as the North American Diamond Blackfan Anemia Registry (DBAR) and other registry-based series, which typically do not distinguish RPS28-associated cases but provide a framework for extrapolating expected hematologic and long-term outcomes.[11][13][18][20] Thus, this report integrates high-resolution genotype–phenotype information from a handful of documented DBA15 cases with generalizable data from DBA registries and reviews, acknowledging that some inferences about incidence, prognosis, and treatment course are extrapolated from the larger DBA population rather than directly demonstrated for DBA15.[11][13][18][20]

2. Etiology

2.1 Primary Disease Causal Factors: Genetic Basis

DBA15 is a monogenic,

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 8
Resolved 8
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 8
On topic 7
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 4
Resolved 4
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 0
Terms whose name was checked 3
Terms named correctly 0
Terms named as a different term 1
Terms whose name is worth a second look 2

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • HP:0001931 (1 mention) - the report calls it "Diamond-Blackfan anemia"; HP calls it Hypochromic anemia

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • MONDO:0011639 (2 mentions) - the report calls it "Diamond-Blackfan anemia 15 with mandibulofacial dysostosis, linked to RPS28 and OMIM 606164"; MONDO calls it Diamond-Blackfan anemia 15 with mandibulofacial dysostosis**
  • HP:0001999 (1 mention) - the report calls it "Mandibulofacial dysostosis"; HP calls it Abnormal facial shape, and lists "Facial dysmorphism" among its other names