Shwachman-Diamond syndrome

Mendelian MONDO:0009833 Pathograph 34 Show in embeddings browser hereditary disease

Shwachman-Diamond syndrome (SDS) is an inherited bone marrow failure syndrome and ribosomopathy defined by the triad of exocrine pancreatic insufficiency, neutropenia with a predisposition to myelodysplastic syndrome and acute myeloid leukemia, and a metaphyseal skeletal dysplasia. Roughly 90% of cases carry biallelic SBDS variants, most of them arising by gene conversion with the adjacent SBDSP1 pseudogene. SBDS partners with the GTPase EFL1 to evict the anti-association factor eIF6 from the pre-60S ribosomal subunit, so its loss uncouples EFL1 GTP hydrolysis from eIF6 release, blocks 80S assembly and produces a global translation deficit that the pancreas, granulopoietic compartment and growth plate tolerate least well. Phenocopies arise from biallelic DNAJC21 (60S maturation) and EFL1 variants and from monoallelic SRP54 variants that impair co-translational protein targeting. The leukemia risk is not a direct consequence of the germline lesion alone: the ribosomal fitness constraint selects somatic hematopoietic clones, of which EIF6-mutant clones are compensatory and TP53-mutant clones are the maladaptive route to myeloid malignancy.

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2
Inheritance
18
Pathophys.
14
Phenotypes
34
Pathograph
6
Genes
6
Medical Actions
3
Subtypes
2
Differentials
2
Models
2
References
🏷

Classifications

ISDS Skeletal Nosology
metaphyseal dysplasias
👪

Inheritance

2
Autosomal recessive inheritance HP:0000007
The SBDS-, DNAJC21- and EFL1-related forms are autosomal recessive, caused by biallelic pathogenic variants.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:20301722 SUPPORT Other
"Autosomal recessive SDS: SDS caused by pathogenic variants in DNAJC21, EFL1, or SBDS is inherited in an autosomal recessive manner."
GeneReviews states the recessive mode for the three recessive SDS genes, including SBDS and DNAJC21 curated here.
PMID:12496757 SUPPORT Human Clinical
"Shwachman-Diamond syndrome (SDS; OMIM 260400) is an autosomal recessive disorder with clinical features that include pancreatic exocrine insufficiency, hematological dysfunction and skeletal abnormalities."
The gene-discovery paper establishes recessive inheritance alongside the defining clinical triad.
Autosomal dominant inheritance HP:0000006
The SRP54-related form is autosomal dominant and usually arises de novo, which is why it is listed separately in the nosology as a Shwachman-Diamond-like syndrome.
Autosomal dominant inheritance
Show evidence (2 references)
PMID:20301722 SUPPORT Other
"Autosomal dominant SDS: SDS caused by pathogenic variants in SRP54 is inherited in an autosomal dominant manner."
GeneReviews separates the dominant SRP54 form from the recessive SDS genes.
PMID:28972538 SUPPORT Human Clinical
"In conclusion, autosomal dominant mutations in SRP54, a key member of the cotranslation protein-targeting pathway, lead to syndromic neutropenia with a Shwachman-Diamond-like phenotype."
The discovery cohort establishes dominant inheritance for the SRP54 form.
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Subtypes

3
⚙

Pathophysiology

18
Biallelic SBDS Loss of Function
Gene conversion between SBDS and its 97%-identical neighbouring pseudogene SBDSP1 imports pseudogene-derived sequence changes that truncate the protein, leaving a hypomorphic residue of SBDS activity.
SBDS hgnc:19440 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SBDS (hgnc:19440). hgnc:19440 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Failure of eIF6 Eviction from the Pre-60S Subunit SBDS is the cofactor that couples EFL1 GTP hydrolysis to eIF6 release, so its loss blocks the eviction step directly.
Show evidence (2 references)
PMID:12496757 SUPPORT Human Clinical
"A pseudogene copy (SBDSP) with 97% nucleotide sequence identity resides in a locally duplicated genomic segment of 305 kb."
Identifies the pseudogene whose conversion generates the recurrent SDS alleles.
PMID:12496757 SUPPORT Human Clinical
"Converted segments consistently included at least one of two pseudogene-like sequence changes that result in protein truncation."
Establishes protein truncation as the functional consequence of the converted alleles.
Biallelic DNAJC21 Loss of Function
DNAJC21 is an rRNA-associated co-chaperone acting at two points of ribosome biogenesis. Biallelic loss corrupts early nuclear rRNA processing as well as the late cytoplasmic maturation of the 60S subunit, and traps the 60S export factor PA2G4 in the cytoplasm.
DNAJC21 hgnc:27030 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves DNAJC21 (hgnc:27030). hgnc:27030 is a gene from the HUGO Gene Nomenclature Committee.
ribosomal large subunit biogenesis GO:0042273 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal ribosomal large subunit biogenesis (GO:0042273). GO:0042273 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Impaired 80S Ribosome Assembly Corrupted 60S maturation reduces the pool of subunits competent to form translating 80S ribosomes.
Show evidence (2 references)
PMID:27346687 SUPPORT In Vitro
"We show that the encoded protein associates with rRNA and plays a highly conserved role in the maturation of the 60S ribosomal subunit."
Establishes the 60S maturation role that biallelic loss disrupts.
PMID:27346687 SUPPORT In Vitro
"DNAJC21 deficiency resulted in cytoplasmic accumulation of the 60S nuclear export factor PA2G4, aberrant ribosome profiles, and increased cell death."
Patient-derived and knockdown cellular data for the proximal molecular defect.
Failure of eIF6 Eviction from the Pre-60S Subunit
Release of the anti-association factor eIF6 is the last step of cytoplasmic 60S maturation and is catalysed by SBDS together with the GTPase EFL1. Disease variants uncouple EFL1 GTP hydrolysis from eIF6 release, so eIF6 remains bound and the subunit cannot join a 40S partner.
ribosomal large subunit assembly GO:0000027 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal ribosomal large subunit assembly (GO:0000027). GO:0000027 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Animal models
Sbds-null mouse ribosome reconstitution Mouse recapitulates Late cytoplasmic 60S subunits isolated from Sbds-deleted mice retain eIF6, the same biochemical lesion described in this node, and support biochemical reconstitution of SBDS/EFL1-catalyzed eIF6 release.
Downstream
Impaired 80S Ribosome Assembly eIF6 retained on the 60S subunit sterically blocks subunit joining, so fewer 80S ribosomes are formed.
Show evidence (1 reference)
PMID:21536732 SUPPORT Model Organism
"Here, by isolating late cytoplasmic 60S ribosomal subunits from Sbds-deleted mice, we show that SBDS and the GTPase elongation factor-like 1 (EFL1) directly catalyze eIF6 removal in mammalian cells by a mechanism that requires GTP binding and hydrolysis by EFL1 but not phosphorylation of eIF6 Ser 235."
Demonstrates in Sbds-null mouse ribosomes that SBDS and EFL1 jointly catalyse the eviction step lost in SDS.
Impaired Co-translational Protein Targeting
In the SRP54-related form the lesion is not ribosome maturation but the signal recognition particle itself. Missense variants in the SRP54 GTPase domain reduce GTPase activity and impair delivery of nascent secretory and membrane polypeptides, a load the granulopoietic and pancreatic acinar compartments are least able to absorb.
SRP54 hgnc:11301 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SRP54 (hgnc:11301). hgnc:11301 is a gene from the HUGO Gene Nomenclature Committee.
Animal models
SRP54-knockdown zebrafish Zebrafish perturbs Morpholino knockdown of srp54 directly manipulates the co-translational targeting defect that monoallelic human SRP54 variants cause, then reports on its downstream consequences.
Downstream
Bone Marrow Failure with Granulopoietic Predominance Zebrafish knockdown of SRP54 reproduces the neutrophil deficit and chemotaxis defect seen in patients.
Exocrine Pancreatic Acinar Failure The same knockdown reduces exocrine pancreas size, matching the pancreatic arm of the human phenotype.
Show evidence (1 reference)
PMID:28972538 SUPPORT In Vitro
"3D protein modeling revealed that the 3 variants affect highly conserved amino acids within the GTPase domain of the protein that are critical for GTP and receptor binding. Indeed, we observed that the GTPase activity of the mutated proteins was impaired."
Establishes impaired SRP54 GTPase activity as the proximal molecular defect of this subtype.
Impaired 80S Ribosome Assembly
The convergent cellular lesion of the SBDS, EFL1 and DNAJC21 forms: mature subunits fail to assemble into translating 80S ribosomes. This is the node at which the otherwise distinct causal genes of nosology group 11 meet.
ribosomal large subunit assembly GO:0000027 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal ribosomal large subunit assembly (GO:0000027). GO:0000027 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Global Translation Deficit Fewer competent 80S ribosomes lowers global protein synthesis. The two steps are close together in time but are separate claims: a cell could in principle compensate for reduced assembly, and the somatic EIF6 arm of this disease is precisely such a compensation.
Show evidence (1 reference)
PMID:30413969 SUPPORT Other
"SBDS, through direct interaction with EFL1, promotes the release of the eukaryotic initiation factor 6 (eIF6) during ribosome maturation, DNAJC21 stabilizes the 80S ribosome, and SRP54 facilitates protein trafficking."
Review statement that the SDS genes converge on ribosome maturation and early protein synthesis.
Global Translation Deficit
Reduced global protein synthesis, the functional consequence that makes SDS a ribosomopathy and the constraint that selects the somatic clones later in the graph.
translation GO:0006412 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased translation (GO:0006412). GO:0006412 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Exocrine Pancreatic Acinar Failure The acinar cell, among the most secretory in the body, is disproportionately sensitive to a global translation deficit.
Bone Marrow Failure with Granulopoietic Predominance Hematopoietic progenitors, and the granulocytic lineage in particular, cannot sustain output under the translation deficit.
Growth Plate Chondrocyte Dysfunction Chondrogenesis is the third tissue named as sensitive to the SDS defect, and is the origin of the metaphyseal dysplasia that places SDS in the metaphyseal group of the skeletal nosology.
Somatic Clonal Hematopoiesis Under Ribosomal Fitness Constraint The translation deficit is itself the selective pressure: it constrains hematopoietic clone fitness and thereby selects somatic mutants.
Show evidence (1 reference)
PMID:30413969 SUPPORT Other
"SBDS, through direct interaction with EFL1, promotes the release of the eukaryotic initiation factor 6 (eIF6) during ribosome maturation, DNAJC21 stabilizes the 80S ribosome, and SRP54 facilitates protein trafficking."
Review statement that the SDS genes converge on ribosome maturation and early protein synthesis.
Exocrine Pancreatic Acinar Failure
Acinar tissue is replaced by fat, producing pancreatic enzyme deficiency, steatorrhoea and malabsorption. Unusually for a structural pancreatic disease, secretory capacity often improves with age, and a substantial minority of patients become pancreatic sufficient in later childhood.
Animal models
SRP54-knockdown zebrafish Zebrafish recapitulates The same knockdown reduces exocrine pancreas size, matching the pancreatic arm of the human phenotype.
Downstream
Malnutrition Fat and fat-soluble vitamin malabsorption drive failure to thrive.
Show evidence (1 reference)
PMID:12120235 SUPPORT Other
"several studies have shown that, with advancing age, about 40-60% of patients become pancreatic sufficient"
Documents the age-dependent partial recovery of exocrine function that distinguishes this node from a fixed structural lesion.
Bone Marrow Failure with Granulopoietic Predominance
Persistent or intermittent neutropenia is the earliest and most constant haematological finding, but the marrow defect is not lineage-restricted and single- or multilineage cytopenias develop over time.
Animal models
SRP54-knockdown zebrafish Zebrafish recapitulates The knockdown reproduces both the neutrophil-count deficit and the chemotaxis defect that mark the granulopoietic arm of the human disease.
Downstream
p53-Dependent Progenitor Apoptosis Ribosomal stress from the maturation defect activates p53 in marrow progenitors, and the resulting apoptosis is the proximate reason the cytopenias develop.
Recurrent Infection Neutropenia, compounded in some patients by hypogammaglobulinaemia, predisposes to recurrent bacterial infection.
Show evidence (1 reference)
PMID:12120235 SUPPORT Other
"Intermittent neutropenia is the most common haematological finding in SDS, but more of the bone marrow cellular elements can be involved."
Supports both the granulocytic predominance and the broader marrow involvement described in this node.
Growth Plate Chondrocyte Dysfunction
The skeletal arm of the disease. Radiographs show delayed appearance of secondary ossification centres, then widening and irregularity of the metaphyses that progresses with age, together with generalised osteopenia. The metaphyseal component worsens while the epiphyseal maturation delay tends to normalise, which is why the nosology classifies SDS as a metaphyseal rather than an epiphyseal dysplasia.
Downstream
Metaphyseal Dysplasia Disordered metaphyseal growth produces the clinical skeletal dysplasia and contributes to short stature independently of malnutrition.
Show evidence (1 reference)
PMID:14984468 SUPPORT Human Clinical
"The typical features were (1) delayed appearance of secondary ossification centers, (2) variable widening and irregularity of the metaphyses in early childhood, followed by progressive thickening and irregularity of the growth plates, and (3) generalized osteopenia."
Radiographic series in molecularly confirmed patients defining the skeletal lesion of this node.
Metaphyseal Dysplasia
The clinically expressed skeletal lesion: metaphyseal dyschondroplasia of the long bones, short ribs with broadened anterior ends, and thoracic narrowing.
Downstream
Short Stature Disordered metaphyseal growth contributes to short stature independently of the nutritional route.
Show evidence (1 reference)
PMID:12120235 SUPPORT Other
"Short ribs with broadened anterior ends and metaphyseal dyschondroplasia of the long bone are the most common findings."
Names the two commonest radiographic findings that constitute this node.
Short Stature
Short stature in SDS has two converging causes, modelled here as two incoming edges: the intrinsic skeletal growth defect, and malnutrition from exocrine pancreatic insufficiency. Studies indicating that patients are genuinely short rather than merely undernourished are why the skeletal route is drawn at all.
Show evidence (1 reference)
PMID:20301722 SUPPORT Other
"In almost all affected children, persistent or intermittent neutropenia is an early finding. Short stature and recurrent infections are common."
Records short stature as a common manifestation.
Malnutrition
Fat and fat-soluble vitamin malabsorption secondary to exocrine pancreatic insufficiency. This is the nutritional route to poor growth, distinct from the skeletal one.
Downstream
Short Stature Malnutrition compounds the intrinsic skeletal growth defect, the second of the two routes into short stature.
Show evidence (1 reference)
PMID:20301722 SUPPORT Other
"exocrine pancreatic dysfunction with malabsorption, malnutrition, and growth failure"
States the pancreatic-to-malnutrition step directly.
p53-Dependent Progenitor Apoptosis
Ribosomal stress activates p53 in haematopoietic progenitors, and the apoptosis that follows is what depletes the marrow. The checkpoint cuts both ways: with p53 intact the cells die, producing the cytopenias, while p53 inactivation lets them survive as aneuploid cells - which is the same checkpoint whose somatic loss defines the pre-malignant clonal arm of this disease.
apoptotic process GO:0006915 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased apoptotic process (GO:0006915). GO:0006915 is a biological process from the Gene Ontology. ↑ INCREASED
Show evidence (2 references)
PMID:37226705 SUPPORT Human Clinical
"Increased apoptosis was observed in SDS-derived BM in combination with p53 overexpression."
Establishes the apoptosis and its association with p53 in patient marrow.
PMID:37226705 SUPPORT In Vitro
"Loss of SBDS was associated with increased apoptosis when checkpoint pathways were intact but resulted in aneuploid cells when p53 was inactivated."
Establishes the two-way dependence on p53 that links the cytopenias to the same checkpoint whose somatic loss drives the maladaptive clonal arm.
Recurrent Infection
Recurrent bacterial infection, particularly respiratory and otologic, is a common presenting problem and the main indication for G-CSF.
Show evidence (1 reference)
PMID:20301722 SUPPORT Other
"In almost all affected children, persistent or intermittent neutropenia is an early finding. Short stature and recurrent infections are common."
GeneReviews records recurrent infection as a common manifestation alongside the early neutropenia.
Somatic Clonal Hematopoiesis Under Ribosomal Fitness Constraint
Multiple independent somatic clones arise in the SDS marrow from early life, selected by the fitness constraint the germline ribosome defect imposes. The clones are not one population: they split into two mechanistically opposed classes with opposite clinical meaning, modelled here as separate downstream nodes so that the graph cannot be read as "clonal hematopoiesis causes leukemia".
Downstream
EIF6-Mutant Compensatory Clonal Expansion The compensatory arm, selected because inactivating EIF6 partially corrects the very defect that constrains clone fitness.
TP53-Mutant Maladaptive Clonal Expansion The pre-malignant arm, selected by removing tumour-suppressor checkpoints rather than by correcting the ribosome defect.
Show evidence (1 reference)
PMID:33637765 SUPPORT Human Clinical
"Here we report that multiple independent somatic hematopoietic clones arise early in life, most commonly harboring heterozygous mutations in EIF6 or TP53."
Establishes the existence and genetic identity of the two somatic clone classes.
EIF6-Mutant Compensatory Clonal Expansion
Somatic EIF6 inactivation ameliorates the underlying ribosome defect and so enhances clone fitness. It carries limited leukemic potential and is deliberately given no edge to malignant transformation: this arm is a compensatory response, not a step toward leukemia, and an edge here would assert the opposite of what the source reports. EIF6 is inactivated by two distinct genetic routes, and both belong here: point mutation, and interstitial deletion of chromosome 20q, which removes the EIF6 locus and is the commoner of the two. This is why del(20q) in an SDS marrow does not carry the ominous meaning it carries in sporadic myelodysplastic syndrome.
Show evidence (2 references)
PMID:33637765 SUPPORT Human Clinical
"EIF6 inactivation mediates a compensatory pathway with limited leukemic potential by ameliorating the underlying SDS ribosome defect and enhancing clone fitness."
Establishes both the compensatory mechanism and the limited leukemic potential that justifies leaving this node without a malignancy edge.
PMID:33637765 SUPPORT Human Clinical
"As expected, we observed frequent interstitial deletions of chromosome 20q (8 of 17, 47%) in patients without MN"
Establishes interstitial del(20q) as frequent, and specifically in patients without myeloid neoplasia, which is what marks it as part of the compensatory rather than the pre-malignant arm.
TP53-Mutant Maladaptive Clonal Expansion
Somatic TP53 mutation improves clone fitness by inactivating tumour-suppressor checkpoints while leaving the ribosome defect uncorrected. This is the arm that carries leukemic potential, and progression to overt leukemia is associated with acquisition of biallelic TP53 alterations.
Downstream
Myeloid Malignant Transformation Progression to overt myeloid malignancy follows acquisition of biallelic TP53 alterations within this clonal lineage.
Show evidence (1 reference)
PMID:33637765 SUPPORT Human Clinical
"TP53 mutations define a maladaptive pathway with enhanced leukemic potential by inactivating tumor suppressor checkpoints without correcting the ribosome defect."
Establishes this arm as the pre-malignant one.
Myeloid Malignant Transformation
Progression to myelodysplastic syndrome or acute myeloid leukemia occurs in a substantial minority of patients, typically at a young age, and is the principal determinant of prognosis. Solid tumours are rare.
Show evidence (2 references)
PMID:37226705 SUPPORT Human Clinical
"In 10-30% of cases, transformation to a myeloid neoplasm occurs."
Quantifies the transformation risk described in this node.
PMID:35322185 SUPPORT Human Clinical
"Increased risk of hematologic malignancies at young ages and the rarity of solid malignancies was observed in both the NCI cohort and published studies."
Cohort evidence for the young age at malignancy and the restriction to haematological cancers.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Shwachman-Diamond syndrome 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

14
Blood 4
Neutropenia Decreased total neutrophil count HP:0001875 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neutropenia, annotated with Decreased total neutrophil count (HP:0001875), qualified as temporality recurrent. HP:0001875 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (1 reference)
PMID:35322185 SUPPORT Human Clinical
"Most patients had the SDS hallmark features of neutropenia (45/45, 100%), pancreatic insufficiency (41/43, 95.3%), and/or bony abnormalities (29/36, 80.6%)."
NCI cohort frequency for neutropenia in molecularly characterised SDS.
Myelodysplasia HP:0002863 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myelodysplasia (HP:0002863). HP:0002863 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30413969 SUPPORT Other
"Almost 15-20% of patients with SDS present myelodysplastic syndrome with a high risk of acute myeloid leukemia (AML) transformation."
Gives the reported frequency of MDS and its onward leukemic risk.
Acute myeloid leukemia HP:0004808 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Acute myeloid leukemia (HP:0004808). HP:0004808 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37226705 SUPPORT Human Clinical
"In 10-30% of cases, transformation to a myeloid neoplasm occurs."
Reports the frequency of transformation to myeloid neoplasia including AML.
Pancytopenia HP:0001876 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pancytopenia (HP:0001876). HP:0001876 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301722 SUPPORT Other
"hematologic abnormalities with single- or multilineage cytopenias and susceptibility to myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML)"
GeneReviews documents multilineage cytopenia as part of the haematological phenotype.
Digestive 1
Exocrine pancreatic insufficiency HP:0001738 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Exocrine pancreatic insufficiency (HP:0001738). HP:0001738 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35322185 SUPPORT Human Clinical
"Most patients had the SDS hallmark features of neutropenia (45/45, 100%), pancreatic insufficiency (41/43, 95.3%), and/or bony abnormalities (29/36, 80.6%)."
Same cohort provides the frequency of pancreatic insufficiency.
Immune 1
Recurrent respiratory infections HP:0002205 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent respiratory infections (HP:0002205). HP:0002205 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35322185 SUPPORT Human Clinical
"Patients with SDS often experience recurrent infections due to neutropenia and in some patients hypogammaglobulinemia."
Supports recurrent infection as a consequence of the immune defect.
Limbs 1
Metaphyseal dysplasia HP:0100255 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Metaphyseal dysplasia (HP:0100255), qualified as course progressive. HP:0100255 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (2 references)
PMID:12120235 SUPPORT Other
"Short ribs with broadened anterior ends and metaphyseal dyschondroplasia of the long bone are the most common findings."
Identifies metaphyseal dyschondroplasia as one of the two commonest skeletal findings.
PMID:14984468 SUPPORT Human Clinical
"There was a tendency towards normalization of the epiphyseal maturation defect and progression of the metaphyseal changes with age."
Supports the progressive clinical course annotated on this phenotype.
Metabolism 1
Elevated hepatic transaminases Elevated circulating hepatic transaminase concentration HP:0002910 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated circulating hepatic transaminase concentration (HP:0002910), qualified as temporality transient. HP:0002910 is a phenotype from the Human Phenotype Ontology.
Temporal: TRANSIENT
Show evidence (1 reference)
PMID:12120235 SUPPORT Other
"Elevated liver enzymes and hepatomegaly are present in the first years of life with subsequent improvement without complications."
Supports both the finding and the transient course annotated here.
Musculoskeletal 2
Osteopenia HP:0000938 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Osteopenia (HP:0000938). HP:0000938 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:14984468 SUPPORT Human Clinical
"The typical features were (1) delayed appearance of secondary ossification centers, (2) variable widening and irregularity of the metaphyses in early childhood, followed by progressive thickening and irregularity of the growth plates, and (3) generalized osteopenia."
Lists generalised osteopenia among the typical radiographic features.
Narrow chest HP:0000774 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Narrow chest (HP:0000774). HP:0000774 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:12120235 SUPPORT Other
"Short ribs with broadened anterior ends and metaphyseal dyschondroplasia of the long bone are the most common findings."
The rib abnormality underlying the narrow thorax is named as one of the commonest findings.
Nervous System 1
Global developmental delay 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:35322185 SUPPORT Human Clinical
"Developmental delay was common (20/34, 58.8%)."
Cohort frequency for developmental delay.
Growth 2
Short stature HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301722 SUPPORT Other
"In almost all affected children, persistent or intermittent neutropenia is an early finding. Short stature and recurrent infections are common."
GeneReviews records short stature as a common manifestation.
Failure to thrive HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29700810 SUPPORT Human Clinical
"All patients present features consistent with IBMFS: bone marrow failure, growth retardation, failure to thrive, developmental delay, recurrent infections, and skin, teeth or hair abnormalities."
Documents failure to thrive in the DNAJC21-related form of the spectrum.
Other 1
Impaired neutrophil chemotaxis HP:0040238 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Impaired neutrophil chemotaxis (HP:0040238). HP:0040238 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:37226705 SUPPORT In Vitro
"Neutrophils isolated from SDS patients exhibit dysregulated chemotaxis due to altered F-actin polymerization capability."
Patient-derived neutrophils establish the chemotaxis defect and its cytoskeletal basis.
PMID:37226705 SUPPORT Model Organism
"Attenuated chemotaxis in neutrophil was shown in a srp54 knockdown zebrafish model."
Model-organism confirmation of the same functional defect in the SRP54 form.
🧬

Genetic Associations

6
SBDS (Causal biallelic variant)
Gene: SBDS hgnc:19440 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SBDS (hgnc:19440). hgnc:19440 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (2 references)
PMID:12496757 SUPPORT Human Clinical
"Here, we report identification of disease-associated mutations in an uncharacterized gene, SBDS, in the interval of 1.9 cM at 7q11 previously shown to be associated with the disease."
The original identification of SBDS as the SDS disease gene.
PMID:37226705 SUPPORT Human Clinical
"Approximately 90% of patients have biallelic pathogenic variants in the SBDS gene located on human chromosome 7q11."
Source for the case fraction recorded here.
DNAJC21 (Causal biallelic variant)
Gene: DNAJC21 hgnc:27030 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is DNAJC21 (hgnc:27030). hgnc:27030 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:27346687 SUPPORT Human Clinical
"Collectively, these findings demonstrate that mutations in DNAJC21 cause a cancer-prone BMF syndrome due to corruption of early nuclear rRNA biogenesis and late cytoplasmic maturation of the 60S subunit."
Establishes causality and the molecular mechanism for this gene.
SRP54 (Causal monoallelic variant)
Gene: SRP54 hgnc:11301 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SRP54 (hgnc:11301). hgnc:11301 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (2 references)
PMID:28972538 SUPPORT Human Clinical
"In conclusion, autosomal dominant mutations in SRP54, a key member of the cotranslation protein-targeting pathway, lead to syndromic neutropenia with a Shwachman-Diamond-like phenotype."
Establishes SRP54 as a dominant cause within the SDS spectrum.
PMID:37226705 SUPPORT Human Clinical
"To date, SBDS, DNAJC21, and SRP54 variants have been associated with myeloid neoplasia."
Records that the SRP54 form shares the myeloid-neoplasia risk.
EFL1 (Causal biallelic variant)
Gene: EFL1 hgnc:25789 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is EFL1 (hgnc:25789). hgnc:25789 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:20301722 SUPPORT Other
"Autosomal recessive SDS: SDS caused by pathogenic variants in DNAJC21, EFL1, or SBDS is inherited in an autosomal recessive manner."
GeneReviews lists EFL1 among the recessive SDS genes.
TP53 (Somatic driver of malignant progression)
Gene: TP53 hgnc:11998 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TP53 (hgnc:11998). hgnc:11998 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:33637765 SUPPORT Human Clinical
"Subsequent development of leukemia was associated with acquisition of biallelic TP53 alterations."
Links somatic biallelic TP53 loss to leukemic progression in SDS.
EIF6 (Somatic compensatory modifier)
Gene: EIF6 hgnc:6159 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is EIF6 (hgnc:6159). hgnc:6159 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:33637765 SUPPORT Human Clinical
"EIF6 inactivation mediates a compensatory pathway with limited leukemic potential by ameliorating the underlying SDS ribosome defect and enhancing clone fitness."
Establishes somatic EIF6 loss as a compensatory rather than pre-malignant event.
💊

Medical Actions

6
Pancreatic enzyme replacement and fat-soluble vitamin supplementation
Action: pancreatic enzyme replacement therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is pancreatic enzyme replacement therapy, annotated with Protein Replacement Therapy (NCIT:C16221). NCIT:C16221 is a clinical intervention from the NCI Thesaurus. Ontology label: Protein Replacement Therapy NCIT:C16221
Oral pancreatic enzymes with fat-soluble vitamin supplementation are the standard treatment for the exocrine pancreatic component.
Mechanism Target:
BYPASSES Exocrine Pancreatic Acinar Failure — Replaces the enzymatic output the failing acinar tissue cannot provide; it does not correct the underlying ribosomal defect.
Show evidence (1 reference)
PMID:20301722 SUPPORT Other
"Exocrine pancreatic insufficiency is treated with oral pancreatic enzymes and fat-soluble vitamin supplementation."
GeneReviews names enzyme replacement as the treatment aimed at this mechanism.
Target Phenotypes: Exocrine pancreatic insufficiency HP:0001738 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Exocrine pancreatic insufficiency (HP:0001738). HP:0001738 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301722 SUPPORT Other
"Exocrine pancreatic insufficiency is treated with oral pancreatic enzymes and fat-soluble vitamin supplementation."
Standard-of-care statement for the pancreatic component.
Granulocyte colony-stimulating factor
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: recombinant granulocyte colony-stimulating factor NCIT:C1287 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses recombinant granulocyte colony-stimulating factor (NCIT:C1287). NCIT:C1287 is a therapeutic agent from the NCI Thesaurus.
G-CSF is considered for severe recurrent infection with an absolute neutrophil count persistently at or below 500/mm3, and is particularly useful as cover for dental or orthopaedic procedures. Prolonged use is approached with caution given the underlying leukemia predisposition.
Mechanism Target:
ACTIVATES Bone Marrow Failure with Granulopoietic Predominance — Drives residual granulopoiesis to raise the neutrophil count without addressing the ribosome defect that constrains it.
Show evidence (1 reference)
PMID:20301722 SUPPORT Other
"If recurrent infections are severe and absolute neutrophil counts are persistently ≤500/mm3, treatment with granulocyte-colony stimulation factor (G-CSF) can be considered and may be especially helpful when interventions such as complex dental procedures or orthopedic surgery are being considered."
GeneReviews indication statement for G-CSF in SDS.
Target Phenotypes: Neutropenia HP:0001875 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Neutropenia, annotated with Decreased total neutrophil count (HP:0001875). HP:0001875 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301722 SUPPORT Other
"Prolonged use of cytokine and hematopoietic growth factors (e.g., G-CSF) should be considered with caution."
Records the caution that qualifies this treatment in a leukemia-predisposition syndrome.
Hematopoietic stem cell transplantation
Action: hematopoietic cell transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is hematopoietic cell transplantation (NCIT:C15431). NCIT:C15431 is a clinical intervention from the NCI Thesaurus. Ontology label: Hematopoietic Cell Transplantation NCIT:C15431
HSCT is the only curative option for the haematological disease and is considered for severe marrow failure, MDS or AML. Conditioning is modified because standard agents such as cyclophosphamide and busulfan carry a risk of cardiac toxicity in SDS.
Mechanism Target:
RESTORES Bone Marrow Failure with Granulopoietic Predominance — Replaces the SBDS-deficient haematopoietic compartment with donor cells, correcting the marrow arm of the disease while leaving the pancreatic and skeletal arms untouched.
Show evidence (1 reference)
PMID:20301722 SUPPORT Other
"Hematopoietic stem cell transplantation (HSCT) should be considered for treatment of severe bone marrow failure, MDS, or AML."
Standard-of-care statement for transplantation in SDS marrow disease.
Target Phenotypes: Pancytopenia HP:0001876 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Pancytopenia (HP:0001876). HP:0001876 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301722 SUPPORT Other
"Some drugs used in standard HSCT preparative regimens (e.g., cyclophosphamide and busulfan) may not be suitable because of possible cardiac toxicity."
Documents the SDS-specific conditioning caveat.
Blood and platelet transfusion
Action: blood transfusionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is blood transfusion (NCIT:C15192). NCIT:C15192 is a clinical intervention from the NCI Thesaurus. Ontology label: Blood Transfusion NCIT:C15192
Transfusion support is used for symptomatic anaemia and thrombocytopenia arising from marrow failure.
Target Phenotypes: Pancytopenia HP:0001876 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Pancytopenia (HP:0001876). HP:0001876 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301722 SUPPORT Other
"Blood and/or platelet transfusions may be considered for anemia and thrombocytopenia."
GeneReviews management statement for the cytopenias.
Orthopaedic and pulmonary management of the skeletal dysplasia
Action: orthopedic surgical procedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is orthopedic surgical procedure (NCIT:C16186). NCIT:C16186 is a clinical intervention from the NCI Thesaurus. Ontology label: Orthopedic Surgical Procedure NCIT:C16186
Early orthopaedic and pulmonary referral is required for thoracic dystrophy; skeletal dysplasia, asymmetric growth and joint deformities need ongoing orthopaedic management, with hip and knee radiographs during rapid growth.
Mechanism Target:
MODULATES Metaphyseal Dysplasia — Manages the mechanical consequences of disordered metaphyseal growth rather than the growth-plate lesion itself.
Show evidence (1 reference)
PMID:20301722 SUPPORT Other
"Early pulmonary and orthopedic referral is essential for treatment of thoracic dystrophy; orthopedic management of other skeletal manifestations including skeletal dysplasia, asymmetric growth, and joint deformities."
GeneReviews management statement for the skeletal manifestations.
Target Phenotypes: Metaphyseal dysplasia HP:0100255 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Metaphyseal dysplasia (HP:0100255). HP:0100255 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301722 SUPPORT Other
"Monitor for orthopedic complications with radiographs of the hips and knees during the most rapid growth stages."
Surveillance recommendation supporting ongoing orthopaedic follow-up.
Nutritional and fat-soluble vitamin surveillance
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Nutritional status and fat-soluble vitamin concentrations are followed every six months because malabsorption persists even on enzyme replacement.
Target Phenotypes: Failure to thrive HP:0001508 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301722 SUPPORT Other
"Assessment of nutritional status and measurement of serum concentration of fat-soluble vitamins every six months."
Surveillance recommendation for the nutritional consequences of the disease.
🔬

Diagnosis

5
Clinical recognition of pancreatic plus marrow dysfunction (Exocrine pancreatic dysfunction with bone marrow dysfunction establishes the clinical diagnosis.)
SDS is established clinically by exocrine pancreatic dysfunction together with bone marrow dysfunction, and/or by molecular confirmation in one of the four genes.
diagnostic procedure NCIT:C18020 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:20301722 SUPPORT Other
"The diagnosis of SDS is established in a proband with the classic clinical findings of exocrine pancreatic dysfunction and bone marrow dysfunction and/or biallelic pathogenic variants in DNAJC21, EFL1, or SBDS or a heterozygous pathogenic variant in SRP54 identified by molecular genetic testing."
GeneReviews diagnostic criteria statement.
Molecular genetic testing of the four SDS genes
Sequencing of SBDS, DNAJC21, EFL1 and SRP54. SBDS analysis must account for the 97%-identical SBDSP1 pseudogene, since the common alleles are pseudogene-derived and are easily missed or miscalled by methods that do not discriminate the two loci.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Results: Biallelic SBDS, DNAJC21 or EFL1 variants, or a heterozygous SRP54 variant, confirm the diagnosis.
Show evidence (2 references)
PMID:20301722 SUPPORT Other
"The diagnosis of SDS is established in a proband with the classic clinical findings of exocrine pancreatic dysfunction and bone marrow dysfunction and/or biallelic pathogenic variants in DNAJC21, EFL1, or SBDS or a heterozygous pathogenic variant in SRP54 identified by molecular genetic testing."
Names the four genes whose testing establishes the molecular diagnosis.
PMID:37226705 SUPPORT Human Clinical
"Complicating the sequence analysis is the presence of a pseudogene, SBDSP1 with 97% homology to SBDS."
Source for the pseudogene caveat that governs how SBDS must be sequenced.
Complete blood count with differential
Serial CBC with differential and platelet count detects the neutropenia and tracks evolving multilineage cytopenias.
blood cell count NCIT:C28133 NCI Thesaurus (NCIT)
Results: Persistent or intermittent neutropenia, with or without anaemia and thrombocytopenia.
Show evidence (1 reference)
PMID:20301722 SUPPORT Other
"Complete blood count with white blood cell differential and platelet count at least every three to six months; bone marrow examination every one to three years or more frequently if bone marrow changes are observed."
Supports serial CBC as the core haematological monitoring test.
Bone marrow aspiration and biopsy
Marrow examination at diagnosis and on surveillance detects hypocellularity and, critically, the emergence of dysplasia or a clonal cytogenetic abnormality.
bone marrow aspiration and biopsy NCIT:C92958 NCI Thesaurus (NCIT)
Results: Hypocellular marrow; dysplastic change or clonal cytogenetic abnormalities signal progression.
Show evidence (1 reference)
PMID:20301722 SUPPORT Other
"bone marrow examination every one to three years or more frequently if bone marrow changes are observed"
Surveillance schedule for marrow examination in SDS.
Skeletal radiography
Radiographs of the long bones, hips and knees show the metaphyseal widening and irregularity, delayed secondary ossification centres and osteopenia that define the skeletal phenotype. Abnormalities were present in all patients in a molecularly confirmed series.
X-ray imaging NCIT:C38101 NCI Thesaurus (NCIT)
Results: Metaphyseal widening and irregularity, delayed secondary ossification centres, generalised osteopenia, short ribs with broadened anterior ends.
Show evidence (1 reference)
PMID:14984468 SUPPORT Human Clinical
"Review of their skeletal radiographs showed abnormalities in all patients."
Establishes the sensitivity of skeletal radiography in molecularly confirmed SDS.
📊

Prevalence

1
Worldwide
Birth Prevalence 1.33 per 100,000 1–9 per 100,000
Reported as 1 in 75,000 live births; converted to 1.33 per 100,000.
Show evidence (1 reference)
PMID:37226705 SUPPORT Human Clinical
"Shwachman-Diamond syndrome (SDS) is a rare inherited bone marrow failure syndrome (IBMFS), which occurs in 1/75,000 live births."
Direct source for the birth-prevalence figure converted here.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Shwachman-Diamond syndrome:

Cartilage-hair hypoplasia MONDO:0009595
Overlapping Features The other immuno-osseous metaphyseal dysplasia of nosology group 11. Both present with metaphyseal dysplasia, short stature and haematological abnormality, but CHH is an RNase MRP ribonucleoprotein defect with hypotrichosis and lymphocyte-predominant immunodeficiency, whereas SDS has exocrine pancreatic insufficiency and neutrophil-predominant disease.
Distinguishing Features
  • Hypotrichosis with fine, sparse, light-coloured hair
  • Biallelic RMRP variants rather than a ribosome-maturation gene
  • Exocrine pancreatic insufficiency is absent
Cystic fibrosis MONDO:0009061
Overlapping Features The commonest cause of childhood exocrine pancreatic insufficiency and failure to thrive, and a frequent alternative diagnosis considered before SDS is recognised.
Distinguishing Features
  • Elevated sweat chloride and biallelic CFTR variants
  • Progressive sinopulmonary disease rather than neutropenia
  • No metaphyseal dysplasia
Show evidence (1 reference)
PMID:35322185 SUPPORT Human Clinical
"Patients with SDS are frequently evaluated for cystic fibrosis, celiac disease, Crohn's disease, and other diseases prior to suspicion of SDS because the clinical presentation can vary widely and it is over underrecognized."
Documents cystic fibrosis as a routine alternative diagnosis on the SDS diagnostic pathway.
🐁

Animal Models

2
Sbds-null mouse ribosome reconstitution
Species
Mouse
Genotype
Sbds-deleted
Publication
PMID:21536732
Pathograph links
Failure of eIF6 Eviction from the Pre-60S Subunit recapitulates fidelity: high Late cytoplasmic 60S subunits isolated from Sbds-deleted mice retain eIF6, the same biochemical lesion described in this node, and support biochemical reconstitution of SBDS/EFL1-catalyzed eIF6 release.
Readouts
eIF6 occupancy on isolated 60S subunits
Direction: INCREASED
Show evidence (1 reference)
PMID:21536732 SUPPORT Model Organism
"Here, by isolating late cytoplasmic 60S ribosomal subunits from Sbds-deleted mice, we show that SBDS and the GTPase elongation factor-like 1 (EFL1) directly catalyze eIF6 removal in mammalian cells by a mechanism that requires GTP binding and hydrolysis by EFL1 but not phosphorylation of eIF6 Ser 235."
Establishes that 60S subunits from the null mouse retain eIF6 and that SBDS/EFL1 catalyze its release, the readout this model provides.
Show evidence (1 reference)
PMID:21536732 SUPPORT Model Organism
"Here, by isolating late cytoplasmic 60S ribosomal subunits from Sbds-deleted mice, we show that SBDS and the GTPase elongation factor-like 1 (EFL1) directly catalyze eIF6 removal in mammalian cells by a mechanism that requires GTP binding and hydrolysis by EFL1 but not phosphorylation of eIF6 Ser 235."
The mammalian ribosome-reconstitution result this node's molecular claim is built on came from this null-mouse model.
SRP54-knockdown zebrafish
Species
Zebrafish
Genotype
srp54 morpholino knockdown
Genes
SRP54 hgnc:11301 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns SRP54 (hgnc:11301). hgnc:11301 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:28972538
Pathograph links
Impaired Co-translational Protein Targeting perturbs fidelity: moderate Morpholino knockdown of srp54 directly manipulates the co-translational targeting defect that monoallelic human SRP54 variants cause, then reports on its downstream consequences.
Limitations: A morpholino knockdown in a non-mammalian model, not the patient missense-variant mechanism; it removes SRP54 function outright rather than reproducing the specific hypomorphic GTPase-domain lesion.
Show evidence (1 reference)
PMID:28972538 SUPPORT Model Organism
"Profound reductions in neutrophil counts and chemotaxis as well as a diminished exocrine pancreas size in a SRP54-knockdown zebrafish model faithfully recapitulated the human phenotype."
Establishes the knockdown as informative for the SRP54-related molecular node, since its downstream phenotypes match the human disease.
Bone Marrow Failure with Granulopoietic Predominance recapitulates fidelity: moderate The knockdown reproduces both the neutrophil-count deficit and the chemotaxis defect that mark the granulopoietic arm of the human disease.
Readouts
Neutrophil count
Direction: DECREASED
Show evidence (1 reference)
PMID:28972538 SUPPORT Model Organism
"Profound reductions in neutrophil counts and chemotaxis as well as a diminished exocrine pancreas size in a SRP54-knockdown zebrafish model faithfully recapitulated the human phenotype."
Reports the neutrophil-count reduction measured in the knockdown model.
Neutrophil chemotaxis
Direction: DECREASED
Show evidence (1 reference)
PMID:37226705 SUPPORT Model Organism
"Attenuated chemotaxis in neutrophil was shown in a srp54 knockdown zebrafish model."
Confirms the chemotaxis defect in the srp54 knockdown zebrafish model, independent of the SRP54 discovery paper.
Show evidence (1 reference)
PMID:28972538 SUPPORT Model Organism
"Profound reductions in neutrophil counts and chemotaxis as well as a diminished exocrine pancreas size in a SRP54-knockdown zebrafish model faithfully recapitulated the human phenotype."
Model-organism evidence that the knockdown informs the granulopoietic arm of the human disease.
Exocrine Pancreatic Acinar Failure recapitulates fidelity: moderate The same knockdown reduces exocrine pancreas size, matching the pancreatic arm of the human phenotype.
Readouts
Exocrine pancreas size
Direction: DECREASED
Show evidence (1 reference)
PMID:28972538 SUPPORT Model Organism
"Profound reductions in neutrophil counts and chemotaxis as well as a diminished exocrine pancreas size in a SRP54-knockdown zebrafish model faithfully recapitulated the human phenotype."
Reports the pancreas-size reduction measured in the knockdown model.
Show evidence (1 reference)
PMID:28972538 SUPPORT Model Organism
"Profound reductions in neutrophil counts and chemotaxis as well as a diminished exocrine pancreas size in a SRP54-knockdown zebrafish model faithfully recapitulated the human phenotype."
Model-organism evidence that the knockdown informs the pancreatic arm of the human disease.
{ }

Source YAML

click to show 
name: Shwachman-Diamond syndrome
creation_date: "2026-08-27T00:00:00Z"
category: Mendelian
description: >-
  Shwachman-Diamond syndrome (SDS) is an inherited bone marrow failure syndrome
  and ribosomopathy defined by the triad of exocrine pancreatic insufficiency,
  neutropenia with a predisposition to myelodysplastic syndrome and acute
  myeloid leukemia, and a metaphyseal skeletal dysplasia. Roughly 90% of cases
  carry biallelic SBDS variants, most of them arising by gene conversion with
  the adjacent SBDSP1 pseudogene. SBDS partners with the GTPase EFL1 to evict
  the anti-association factor eIF6 from the pre-60S ribosomal subunit, so its
  loss uncouples EFL1 GTP hydrolysis from eIF6 release, blocks 80S assembly and
  produces a global translation deficit that the pancreas, granulopoietic
  compartment and growth plate tolerate least well. Phenocopies arise from
  biallelic DNAJC21 (60S maturation) and EFL1 variants and from monoallelic
  SRP54 variants that impair co-translational protein targeting. The leukemia
  risk is not a direct consequence of the germline lesion alone: the ribosomal
  fitness constraint selects somatic hematopoietic clones, of which EIF6-mutant
  clones are compensatory and TP53-mutant clones are the maladaptive route to
  myeloid malignancy.
disease_term:
  preferred_term: Shwachman-Diamond syndrome
  term:
    id: MONDO:0009833
    label: Shwachman-Diamond syndrome
parents:
- hereditary disease
synonyms:
- SDS
- Shwachman-Bodian-Diamond syndrome
- Shwachman syndrome
- congenital lipomatosis of pancreas
- metaphyseal dysplasia with pancreatic insufficiency and cyclic neutropenia
classifications:
  isds_skeletal_category:
  - classification_value: metaphyseal_dysplasias
    notes: >-
      ISDS Nosology of Genetic Skeletal Disorders, 2023 revision (Unger,
      Ferreira, Mortier et al., PMID:36779427), Table 1 group 11 "Metaphyseal
      dysplasias". This entry covers three rows of that group, all named under
      the 2023 dyadic scheme after the metaphyseal phenotype rather than the
      eponym: NOS 11-0050 "Metaphyseal dysplasia with pancreatic insufficiency
      and cyclic neutropenia (Shwachman-Bodian-Diamond), SBDS-related"
      (MIM 260400), NOS 11-0070 "Metaphyseal dysplasia with pancreatic
      insufficiency and cyclic neutropenia, DNAJC21-related" (MIM 617052), and
      NOS 11-0080 "Shwachman-Diamond like syndrome, SRP54-related"
      (MIM 618752). The fourth SDS row of the group, NOS 11-0060
      (EFL1-related, MIM 617941), is tagged on the separate
      EFL1-related Shwachman-Diamond syndrome entry.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    The SBDS-, DNAJC21- and EFL1-related forms are autosomal recessive, caused
    by biallelic pathogenic variants.
  evidence:
  - reference: PMID:20301722
    reference_title: Shwachman-Diamond Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Autosomal recessive SDS: SDS caused by pathogenic variants in DNAJC21, EFL1, or SBDS is inherited in an autosomal recessive manner.
    explanation: >-
      GeneReviews states the recessive mode for the three recessive SDS genes,
      including SBDS and DNAJC21 curated here.
  - reference: PMID:12496757
    reference_title: Mutations in SBDS are associated with Shwachman-Diamond syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Shwachman-Diamond syndrome (SDS; OMIM 260400) is an autosomal recessive disorder with clinical features that include pancreatic exocrine insufficiency, hematological dysfunction and skeletal abnormalities.
    explanation: >-
      The gene-discovery paper establishes recessive inheritance alongside the
      defining clinical triad.
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    The SRP54-related form is autosomal dominant and usually arises de novo,
    which is why it is listed separately in the nosology as a
    Shwachman-Diamond-like syndrome.
  evidence:
  - reference: PMID:20301722
    reference_title: Shwachman-Diamond Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Autosomal dominant SDS: SDS caused by pathogenic variants in SRP54 is inherited in an autosomal dominant manner.
    explanation: >-
      GeneReviews separates the dominant SRP54 form from the recessive SDS
      genes.
  - reference: PMID:28972538
    reference_title: >-
      Mutations in signal recognition particle SRP54 cause syndromic neutropenia with Shwachman-Diamond-like features.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In conclusion, autosomal dominant mutations in SRP54, a key member of the cotranslation protein-targeting pathway, lead to syndromic neutropenia with a Shwachman-Diamond-like phenotype.
    explanation: >-
      The discovery cohort establishes dominant inheritance for the SRP54 form.
has_subtypes:
- name: SBDS-related
  display_name: Shwachman-Diamond syndrome 1 (SBDS-related)
  subtype_term:
    preferred_term: Shwachman-Diamond syndrome 1
    term:
      id: MONDO:0044204
      label: Shwachman-Diamond syndrome 1
  description: >-
    Classic SDS, accounting for roughly 90% of cases. Most pathogenic alleles
    are generated by gene conversion with the 97%-identical SBDSP1 pseudogene,
    producing the recurrent c.258+2T>C splice and c.183_184TA>CT truncating
    changes. No individual has been found with two null alleles, implying that
    residual SBDS function is required for life.
  genes:
  - preferred_term: SBDS
    term:
      id: hgnc:19440
      label: SBDS
  evidence:
  - reference: PMID:37226705
    reference_title: >-
      Shwachman-Diamond syndromes: clinical, genetic, and biochemical insights from the rare variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Approximately 90% of patients have biallelic pathogenic variants in the SBDS gene located on human chromosome 7q11.
    explanation: >-
      Quantifies SBDS as the dominant molecular cause of the SDS spectrum.
  - reference: PMID:12496757
    reference_title: Mutations in SBDS are associated with Shwachman-Diamond syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We found recurring mutations resulting from gene conversion in 89% of unrelated individuals with SDS (141 of 158), with 60% (95 of 158) carrying two converted alleles.
    explanation: >-
      Establishes pseudogene conversion as the mutational mechanism of the
      SBDS-related subtype.
- name: DNAJC21-related
  display_name: DNAJC21-related Shwachman-Diamond syndrome
  subtype_term:
    preferred_term: DNAJC21-related Shwachman Diamond syndrome
    term:
      id: MONDO:0700311
      label: DNAJC21-related Shwachman Diamond syndrome
  description: >-
    A recessive phenocopy in which the encoded co-chaperone acts on both early
    nuclear rRNA biogenesis and late cytoplasmic 60S maturation. The reported
    phenotype is a cancer-prone bone marrow failure syndrome that overlaps SDS
    and dyskeratosis congenita, with skin, teeth, hair and retinal findings that
    are unusual in SBDS-related disease.
  genes:
  - preferred_term: DNAJC21
    term:
      id: hgnc:27030
      label: DNAJC21
  evidence:
  - reference: PMID:27346687
    reference_title: >-
      DNAJC21 Mutations Link a Cancer-Prone Bone Marrow Failure Syndrome to Corruption in 60S Ribosome Subunit Maturation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Through exome sequencing, we have now identified a subgroup of these individuals, defined by germline biallelic mutations in DNAJC21 (DNAJ homolog subfamily C member 21).
    explanation: >-
      Establishes biallelic DNAJC21 variants as a distinct cause of inherited
      bone marrow failure in this spectrum.
  - reference: PMID:29700810
    reference_title: Refining the phenotype associated with biallelic DNAJC21 mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additional features present in some individuals include retinal abnormalities, pancreatic insufficiency, liver cirrhosis, skeletal abnormalities, congenital hip dysplasia, joint hypermobility, and cryptorchidism.
    explanation: >-
      Documents the pancreatic and skeletal overlap with SDS that places this
      form in the same nosology group.
- name: SRP54-related
  display_name: SRP54-related Shwachman-Diamond-like syndrome
  description: >-
    A dominant, usually de novo phenocopy caused by missense variants in the
    SRP54 GTPase domain. Congenital neutropenia dominates the presentation and
    the pancreatic and skeletal features are variable, which is why the 2023
    nosology lists it as a Shwachman-Diamond-like syndrome rather than as SDS
    proper.
  genes:
  - preferred_term: SRP54
    term:
      id: hgnc:11301
      label: SRP54
  evidence:
  - reference: PMID:28972538
    reference_title: >-
      Mutations in signal recognition particle SRP54 cause syndromic neutropenia with Shwachman-Diamond-like features.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identified 3 independent patients, each of whom carried a de novo missense variant in srp54 (encoding signal recognition particle 54 kDa). These 3 patients shared congenital neutropenia linked with various other SDS phenotypes.
    explanation: >-
      Defines the SRP54 subtype and its de novo dominant, neutropenia-led
      presentation.
prevalence:
- population: Worldwide
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 1.33
  notes: >-
    Reported as 1 in 75,000 live births; converted to 1.33 per 100,000.
  evidence:
  - reference: PMID:37226705
    reference_title: >-
      Shwachman-Diamond syndromes: clinical, genetic, and biochemical insights from the rare variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Shwachman-Diamond syndrome (SDS) is a rare inherited bone marrow failure syndrome (IBMFS), which occurs in 1/75,000 live births.
    explanation: >-
      Direct source for the birth-prevalence figure converted here.
pathophysiology:
- name: Biallelic SBDS Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Gene conversion between SBDS and its 97%-identical neighbouring pseudogene
    SBDSP1 imports pseudogene-derived sequence changes that truncate the
    protein, leaving a hypomorphic residue of SBDS activity.
  genes:
  - preferred_term: SBDS
    term:
      id: hgnc:19440
      label: SBDS
  evidence:
  - reference: PMID:12496757
    reference_title: Mutations in SBDS are associated with Shwachman-Diamond syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A pseudogene copy (SBDSP) with 97% nucleotide sequence identity resides in a locally duplicated genomic segment of 305 kb.
    explanation: >-
      Identifies the pseudogene whose conversion generates the recurrent SDS
      alleles.
  - reference: PMID:12496757
    reference_title: Mutations in SBDS are associated with Shwachman-Diamond syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Converted segments consistently included at least one of two pseudogene-like sequence changes that result in protein truncation.
    explanation: >-
      Establishes protein truncation as the functional consequence of the
      converted alleles.
  downstream:
  - target: Failure of eIF6 Eviction from the Pre-60S Subunit
    description: >-
      SBDS is the cofactor that couples EFL1 GTP hydrolysis to eIF6 release, so
      its loss blocks the eviction step directly.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:21536732
      reference_title: >-
        Uncoupling of GTP hydrolysis from eIF6 release on the ribosome causes Shwachman-Diamond syndrome.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Functional analysis of disease-associated missense variants reveals that the essential role of SBDS is to tightly couple GTP hydrolysis by EFL1 on the ribosome to eIF6 release.
      explanation: >-
        Directly attributes the eviction failure to loss of SBDS function.
- name: Biallelic DNAJC21 Loss of Function
  biological_scale: MOLECULAR
  description: >-
    DNAJC21 is an rRNA-associated co-chaperone acting at two points of ribosome
    biogenesis. Biallelic loss corrupts early nuclear rRNA processing as well as
    the late cytoplasmic maturation of the 60S subunit, and traps the 60S export
    factor PA2G4 in the cytoplasm.
  genes:
  - preferred_term: DNAJC21
    term:
      id: hgnc:27030
      label: DNAJC21
  biological_processes:
  - preferred_term: ribosomal large subunit biogenesis
    modifier: ABNORMAL
    term:
      id: GO:0042273
      label: ribosomal large subunit biogenesis
  evidence:
  - reference: PMID:27346687
    reference_title: >-
      DNAJC21 Mutations Link a Cancer-Prone Bone Marrow Failure Syndrome to Corruption in 60S Ribosome Subunit Maturation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We show that the encoded protein associates with rRNA and plays a highly conserved role in the maturation of the 60S ribosomal subunit.
    explanation: >-
      Establishes the 60S maturation role that biallelic loss disrupts.
  - reference: PMID:27346687
    reference_title: >-
      DNAJC21 Mutations Link a Cancer-Prone Bone Marrow Failure Syndrome to Corruption in 60S Ribosome Subunit Maturation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      DNAJC21 deficiency resulted in cytoplasmic accumulation of the 60S nuclear export factor PA2G4, aberrant ribosome profiles, and increased cell death.
    explanation: >-
      Patient-derived and knockdown cellular data for the proximal molecular
      defect.
  downstream:
  - target: Impaired 80S Ribosome Assembly
    description: >-
      Corrupted 60S maturation reduces the pool of subunits competent to form
      translating 80S ribosomes.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27346687
      reference_title: >-
        DNAJC21 Mutations Link a Cancer-Prone Bone Marrow Failure Syndrome to Corruption in 60S Ribosome Subunit Maturation.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        DNAJC21 deficiency resulted in cytoplasmic accumulation of the 60S nuclear export factor PA2G4, aberrant ribosome profiles, and increased cell death.
      explanation: >-
        Cellular data showing aberrant ribosome profiles, the direct in-vitro
        support for this edge. The paper's combined causality conclusion is
        cited instead in the genetic section, where its human-genetic character
        is the point.
- name: Failure of eIF6 Eviction from the Pre-60S Subunit
  biological_scale: MOLECULAR
  description: >-
    Release of the anti-association factor eIF6 is the last step of cytoplasmic
    60S maturation and is catalysed by SBDS together with the GTPase EFL1.
    Disease variants uncouple EFL1 GTP hydrolysis from eIF6 release, so eIF6
    remains bound and the subunit cannot join a 40S partner.
  biological_processes:
  - preferred_term: ribosomal large subunit assembly
    modifier: ABNORMAL
    term:
      id: GO:0000027
      label: ribosomal large subunit assembly
  evidence:
  - reference: PMID:21536732
    reference_title: >-
      Uncoupling of GTP hydrolysis from eIF6 release on the ribosome causes Shwachman-Diamond syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Here, by isolating late cytoplasmic 60S ribosomal subunits from Sbds-deleted mice, we show that SBDS and the GTPase elongation factor-like 1 (EFL1) directly catalyze eIF6 removal in mammalian cells by a mechanism that requires GTP binding and hydrolysis by EFL1 but not phosphorylation of eIF6 Ser 235.
    explanation: >-
      Demonstrates in Sbds-null mouse ribosomes that SBDS and EFL1 jointly
      catalyse the eviction step lost in SDS.
  downstream:
  - target: Impaired 80S Ribosome Assembly
    description: >-
      eIF6 retained on the 60S subunit sterically blocks subunit joining, so
      fewer 80S ribosomes are formed.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:21536732
      reference_title: >-
        Uncoupling of GTP hydrolysis from eIF6 release on the ribosome causes Shwachman-Diamond syndrome.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Our findings establish a direct role for SBDS and EFL1 in catalyzing the translational activation of ribosomes in all eukaryotes, and define SDS as a ribosomopathy caused by uncoupling GTP hydrolysis from eIF6 release.
      explanation: >-
        States that the eviction defect is what withholds translational
        activation of the ribosome.
- name: Impaired Co-translational Protein Targeting
  biological_scale: MOLECULAR
  description: >-
    In the SRP54-related form the lesion is not ribosome maturation but the
    signal recognition particle itself. Missense variants in the SRP54 GTPase
    domain reduce GTPase activity and impair delivery of nascent secretory and
    membrane polypeptides, a load the granulopoietic and pancreatic acinar
    compartments are least able to absorb.
  genes:
  - preferred_term: SRP54
    term:
      id: hgnc:11301
      label: SRP54
  evidence:
  - reference: PMID:28972538
    reference_title: >-
      Mutations in signal recognition particle SRP54 cause syndromic neutropenia with Shwachman-Diamond-like features.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      3D protein modeling revealed that the 3 variants affect highly conserved amino acids within the GTPase domain of the protein that are critical for GTP and receptor binding. Indeed, we observed that the GTPase activity of the mutated proteins was impaired.
    explanation: >-
      Establishes impaired SRP54 GTPase activity as the proximal molecular
      defect of this subtype.
  downstream:
  - target: Bone Marrow Failure with Granulopoietic Predominance
    description: >-
      Zebrafish knockdown of SRP54 reproduces the neutrophil deficit and
      chemotaxis defect seen in patients.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Reduced secretory-pathway throughput in maturing myeloid precursors.
    evidence:
    - reference: PMID:28972538
      reference_title: >-
        Mutations in signal recognition particle SRP54 cause syndromic neutropenia with Shwachman-Diamond-like features.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Profound reductions in neutrophil counts and chemotaxis as well as a diminished exocrine pancreas size in a SRP54-knockdown zebrafish model faithfully recapitulated the human phenotype.
      explanation: >-
        Model-organism evidence linking loss of SRP54 function to the
        granulopoietic and pancreatic phenotype.
  - target: Exocrine Pancreatic Acinar Failure
    description: >-
      The same knockdown reduces exocrine pancreas size, matching the pancreatic
      arm of the human phenotype.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:28972538
      reference_title: >-
        Mutations in signal recognition particle SRP54 cause syndromic neutropenia with Shwachman-Diamond-like features.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Profound reductions in neutrophil counts and chemotaxis as well as a diminished exocrine pancreas size in a SRP54-knockdown zebrafish model faithfully recapitulated the human phenotype.
      explanation: >-
        The pancreatic component of the same model-organism result.
- name: Impaired 80S Ribosome Assembly
  biological_scale: CELLULAR
  description: >-
    The convergent cellular lesion of the SBDS, EFL1 and DNAJC21 forms: mature
    subunits fail to assemble into translating 80S ribosomes. This is the node
    at which the otherwise distinct causal genes of nosology group 11 meet.
  biological_processes:
  - preferred_term: ribosomal large subunit assembly
    modifier: ABNORMAL
    term:
      id: GO:0000027
      label: ribosomal large subunit assembly
  evidence:
  - reference: PMID:30413969
    reference_title: >-
      Shwachman-Diamond Syndrome: Molecular Mechanisms and Current Perspectives.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      SBDS, through direct interaction with EFL1, promotes the release of the eukaryotic initiation factor 6 (eIF6) during ribosome maturation, DNAJC21 stabilizes the 80S ribosome, and SRP54 facilitates protein trafficking.
    explanation: >-
      Review statement that the SDS genes converge on ribosome maturation and
      early protein synthesis.
  downstream:
  - target: Global Translation Deficit
    description: >-
      Fewer competent 80S ribosomes lowers global protein synthesis. The two
      steps are close together in time but are separate claims: a cell could in
      principle compensate for reduced assembly, and the somatic EIF6 arm of
      this disease is precisely such a compensation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30413969
      reference_title: >-
        Shwachman-Diamond Syndrome: Molecular Mechanisms and Current Perspectives.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        SBDS, through direct interaction with EFL1, promotes the release of the eukaryotic initiation factor 6 (eIF6) during ribosome maturation, DNAJC21 stabilizes the 80S ribosome, and SRP54 facilitates protein trafficking.
      explanation: >-
        Places the SDS genes at ribosome maturation, upstream of the protein
        synthesis this edge lowers.
- name: Global Translation Deficit
  biological_scale: CELLULAR
  description: >-
    Reduced global protein synthesis, the functional consequence that makes SDS
    a ribosomopathy and the constraint that selects the somatic clones later in
    the graph.
  biological_processes:
  - preferred_term: translation
    modifier: DECREASED
    term:
      id: GO:0006412
      label: translation
  evidence:
  - reference: PMID:30413969
    reference_title: >-
      Shwachman-Diamond Syndrome: Molecular Mechanisms and Current Perspectives.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      SBDS, through direct interaction with EFL1, promotes the release of the eukaryotic initiation factor 6 (eIF6) during ribosome maturation, DNAJC21 stabilizes the 80S ribosome, and SRP54 facilitates protein trafficking.
    explanation: >-
      Review statement that the SDS genes converge on ribosome maturation and
      early protein synthesis.
  downstream:
  - target: Exocrine Pancreatic Acinar Failure
    description: >-
      The acinar cell, among the most secretory in the body, is
      disproportionately sensitive to a global translation deficit.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:12496757
      reference_title: Mutations in SBDS are associated with Shwachman-Diamond syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Archaeal orthologs are located within highly conserved operons that include homologs of RNA-processing genes, suggesting that SDS may be caused by a deficiency in an aspect of RNA metabolism that is essential for development of the exocrine pancreas, hematopoiesis and chrondrogenesis.
      explanation: >-
        A hedged inference in the 2003 discovery paper, from archaeal operon
        synteny rather than functional work, that the RNA/ribosome defect
        selects this tissue. Consistent with the edge but not establishing
        it, hence partial support.
  - target: Bone Marrow Failure with Granulopoietic Predominance
    description: >-
      Hematopoietic progenitors, and the granulocytic lineage in particular,
      cannot sustain output under the translation deficit.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:12496757
      reference_title: Mutations in SBDS are associated with Shwachman-Diamond syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Archaeal orthologs are located within highly conserved operons that include homologs of RNA-processing genes, suggesting that SDS may be caused by a deficiency in an aspect of RNA metabolism that is essential for development of the exocrine pancreas, hematopoiesis and chrondrogenesis.
      explanation: >-
        A hedged inference in the 2003 discovery paper, from archaeal operon
        synteny rather than functional work, that the RNA/ribosome defect
        selects this tissue. Consistent with the edge but not establishing
        it, hence partial support.
  - target: Growth Plate Chondrocyte Dysfunction
    description: >-
      Chondrogenesis is the third tissue named as sensitive to the SDS defect,
      and is the origin of the metaphyseal dysplasia that places SDS in the
      metaphyseal group of the skeletal nosology.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:12496757
      reference_title: Mutations in SBDS are associated with Shwachman-Diamond syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Archaeal orthologs are located within highly conserved operons that include homologs of RNA-processing genes, suggesting that SDS may be caused by a deficiency in an aspect of RNA metabolism that is essential for development of the exocrine pancreas, hematopoiesis and chrondrogenesis.
      explanation: >-
        A hedged inference in the 2003 discovery paper, from archaeal operon
        synteny rather than functional work, that the RNA/ribosome defect
        selects this tissue. Consistent with the edge but not establishing
        it, hence partial support.
  - target: Somatic Clonal Hematopoiesis Under Ribosomal Fitness Constraint
    description: >-
      The translation deficit is itself the selective pressure: it constrains
      hematopoietic clone fitness and thereby selects somatic mutants.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33637765
      reference_title: >-
        Distinct genetic pathways define pre-malignant versus compensatory clonal hematopoiesis in Shwachman-Diamond syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We show that germline SBDS deficiency establishes a fitness constraint that drives selection of somatic clones via two distinct mechanisms with different clinical consequences.
      explanation: >-
        Longitudinal patient sequencing links the germline ribosome defect to
        clonal selection in the marrow.
- name: Exocrine Pancreatic Acinar Failure
  biological_scale: TISSUE
  description: >-
    Acinar tissue is replaced by fat, producing pancreatic enzyme deficiency,
    steatorrhoea and malabsorption. Unusually for a structural pancreatic
    disease, secretory capacity often improves with age, and a substantial
    minority of patients become pancreatic sufficient in later childhood.
  evidence:
  - reference: PMID:12120235
    reference_title: "Shwachman-Diamond syndrome: clinical phenotypes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      several studies have shown that, with advancing age, about 40-60% of patients become pancreatic sufficient
    explanation: >-
      Documents the age-dependent partial recovery of exocrine function that
      distinguishes this node from a fixed structural lesion.
  downstream:
  - target: Malnutrition
    description: >-
      Fat and fat-soluble vitamin malabsorption drive failure to thrive.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301722
      reference_title: Shwachman-Diamond Syndrome.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        exocrine pancreatic dysfunction with malabsorption, malnutrition, and growth failure
      explanation: >-
        GeneReviews states the causal sequence from pancreatic dysfunction to
        growth failure.
- name: Bone Marrow Failure with Granulopoietic Predominance
  biological_scale: TISSUE
  description: >-
    Persistent or intermittent neutropenia is the earliest and most constant
    haematological finding, but the marrow defect is not lineage-restricted and
    single- or multilineage cytopenias develop over time.
  evidence:
  - reference: PMID:12120235
    reference_title: "Shwachman-Diamond syndrome: clinical phenotypes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Intermittent neutropenia is the most common haematological finding in SDS, but more of the bone marrow cellular elements can be involved.
    explanation: >-
      Supports both the granulocytic predominance and the broader marrow
      involvement described in this node.
  downstream:
  - target: p53-Dependent Progenitor Apoptosis
    description: >-
      Ribosomal stress from the maturation defect activates p53 in marrow
      progenitors, and the resulting apoptosis is the proximate reason the
      cytopenias develop.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37226705
      reference_title: >-
        Shwachman-Diamond syndromes: clinical, genetic, and biochemical insights from the rare variants.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Increased apoptosis was observed in SDS-derived BM in combination with p53 overexpression.
      explanation: >-
        Patient marrow shows increased apoptosis together with p53
        overexpression, the observation this edge rests on.
  - target: Recurrent Infection
    description: >-
      Neutropenia, compounded in some patients by hypogammaglobulinaemia,
      predisposes to recurrent bacterial infection.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35322185
      reference_title: >-
        Shwachman Diamond syndrome: narrow genotypic spectrum and variable clinical features.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Patients with SDS often experience recurrent infections due to neutropenia and in some patients hypogammaglobulinemia.
      explanation: >-
        Directly states the causal link from neutropenia to recurrent infection
        in an SDS cohort.
- name: Growth Plate Chondrocyte Dysfunction
  biological_scale: TISSUE
  description: >-
    The skeletal arm of the disease. Radiographs show delayed appearance of
    secondary ossification centres, then widening and irregularity of the
    metaphyses that progresses with age, together with generalised osteopenia.
    The metaphyseal component worsens while the epiphyseal maturation delay
    tends to normalise, which is why the nosology classifies SDS as a
    metaphyseal rather than an epiphyseal dysplasia.
  evidence:
  - reference: PMID:14984468
    reference_title: >-
      Skeletal phenotype in patients with Shwachman-Diamond syndrome and mutations in SBDS.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The typical features were (1) delayed appearance of secondary ossification centers, (2) variable widening and irregularity of the metaphyses in early childhood, followed by progressive thickening and irregularity of the growth plates, and (3) generalized osteopenia.
    explanation: >-
      Radiographic series in molecularly confirmed patients defining the
      skeletal lesion of this node.
  downstream:
  - target: Metaphyseal Dysplasia
    description: >-
      Disordered metaphyseal growth produces the clinical skeletal dysplasia and
      contributes to short stature independently of malnutrition.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:14984468
      reference_title: >-
        Skeletal phenotype in patients with Shwachman-Diamond syndrome and mutations in SBDS.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        There was a tendency towards normalization of the epiphyseal maturation defect and progression of the metaphyseal changes with age.
      explanation: >-
        Establishes the metaphyseal lesion as the progressive component driving
        the clinical dysplasia.
- name: Metaphyseal Dysplasia
  biological_scale: ORGANISM
  description: >-
    The clinically expressed skeletal lesion: metaphyseal dyschondroplasia of
    the long bones, short ribs with broadened anterior ends, and thoracic
    narrowing.
  evidence:
  - reference: PMID:12120235
    reference_title: "Shwachman-Diamond syndrome: clinical phenotypes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Short ribs with broadened anterior ends and metaphyseal dyschondroplasia of the long bone are the most common findings.
    explanation: >-
      Names the two commonest radiographic findings that constitute this node.
  downstream:
  - target: Short Stature
    description: >-
      Disordered metaphyseal growth contributes to short stature independently
      of the nutritional route.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301722
      reference_title: Shwachman-Diamond Syndrome.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        In almost all affected children, persistent or intermittent neutropenia is an early finding. Short stature and recurrent infections are common.
      explanation: >-
        Establishes short stature as a common outcome in a disease whose
        skeletal lesion is described in the preceding node.
- name: Short Stature
  biological_scale: ORGANISM
  description: >-
    Short stature in SDS has two converging causes, modelled here as two
    incoming edges: the intrinsic skeletal growth defect, and malnutrition from
    exocrine pancreatic insufficiency. Studies indicating that patients are
    genuinely short rather than merely undernourished are why the skeletal route
    is drawn at all.
  evidence:
  - reference: PMID:20301722
    reference_title: Shwachman-Diamond Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In almost all affected children, persistent or intermittent neutropenia is an early finding. Short stature and recurrent infections are common.
    explanation: >-
      Records short stature as a common manifestation.
- name: Malnutrition
  biological_scale: ORGANISM
  description: >-
    Fat and fat-soluble vitamin malabsorption secondary to exocrine pancreatic
    insufficiency. This is the nutritional route to poor growth, distinct from
    the skeletal one.
  evidence:
  - reference: PMID:20301722
    reference_title: Shwachman-Diamond Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      exocrine pancreatic dysfunction with malabsorption, malnutrition, and growth failure
    explanation: >-
      States the pancreatic-to-malnutrition step directly.
  downstream:
  - target: Short Stature
    description: >-
      Malnutrition compounds the intrinsic skeletal growth defect, the second
      of the two routes into short stature.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:12120235
      reference_title: "Shwachman-Diamond syndrome: clinical phenotypes."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Growth retardation is a typical manifestation.
      explanation: >-
        Confirms growth failure as a typical manifestation of the disease.
- name: p53-Dependent Progenitor Apoptosis
  biological_scale: CELLULAR
  description: >-
    Ribosomal stress activates p53 in haematopoietic progenitors, and the
    apoptosis that follows is what depletes the marrow. The checkpoint cuts both
    ways: with p53 intact the cells die, producing the cytopenias, while p53
    inactivation lets them survive as aneuploid cells - which is the same
    checkpoint whose somatic loss defines the pre-malignant clonal arm of this
    disease.
  biological_processes:
  - preferred_term: apoptotic process
    modifier: INCREASED
    term:
      id: GO:0006915
      label: apoptotic process
  evidence:
  - reference: PMID:37226705
    reference_title: >-
      Shwachman-Diamond syndromes: clinical, genetic, and biochemical insights from the rare variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Increased apoptosis was observed in SDS-derived BM in combination with p53 overexpression.
    explanation: >-
      Establishes the apoptosis and its association with p53 in patient marrow.
  - reference: PMID:37226705
    reference_title: >-
      Shwachman-Diamond syndromes: clinical, genetic, and biochemical insights from the rare variants.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Loss of SBDS was associated with increased apoptosis when checkpoint pathways were intact but resulted in aneuploid cells when p53 was inactivated.
    explanation: >-
      Establishes the two-way dependence on p53 that links the cytopenias to the
      same checkpoint whose somatic loss drives the maladaptive clonal arm.
- name: Recurrent Infection
  biological_scale: ORGANISM
  description: >-
    Recurrent bacterial infection, particularly respiratory and otologic, is a
    common presenting problem and the main indication for G-CSF.
  evidence:
  - reference: PMID:20301722
    reference_title: Shwachman-Diamond Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In almost all affected children, persistent or intermittent neutropenia is an early finding. Short stature and recurrent infections are common.
    explanation: >-
      GeneReviews records recurrent infection as a common manifestation
      alongside the early neutropenia.
- name: Somatic Clonal Hematopoiesis Under Ribosomal Fitness Constraint
  biological_scale: CELLULAR
  description: >-
    Multiple independent somatic clones arise in the SDS marrow from early life,
    selected by the fitness constraint the germline ribosome defect imposes. The
    clones are not one population: they split into two mechanistically opposed
    classes with opposite clinical meaning, modelled here as separate downstream
    nodes so that the graph cannot be read as "clonal hematopoiesis causes
    leukemia".
  evidence:
  - reference: PMID:33637765
    reference_title: >-
      Distinct genetic pathways define pre-malignant versus compensatory clonal hematopoiesis in Shwachman-Diamond syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report that multiple independent somatic hematopoietic clones arise early in life, most commonly harboring heterozygous mutations in EIF6 or TP53.
    explanation: >-
      Establishes the existence and genetic identity of the two somatic clone
      classes.
  downstream:
  - target: EIF6-Mutant Compensatory Clonal Expansion
    description: >-
      The compensatory arm, selected because inactivating EIF6 partially
      corrects the very defect that constrains clone fitness.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33637765
      reference_title: >-
        Distinct genetic pathways define pre-malignant versus compensatory clonal hematopoiesis in Shwachman-Diamond syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        EIF6 inactivation mediates a compensatory pathway with limited leukemic potential by ameliorating the underlying SDS ribosome defect and enhancing clone fitness.
      explanation: >-
        Identifies the compensatory clonal pathway and its limited leukemic
        potential.
  - target: TP53-Mutant Maladaptive Clonal Expansion
    description: >-
      The pre-malignant arm, selected by removing tumour-suppressor checkpoints
      rather than by correcting the ribosome defect.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33637765
      reference_title: >-
        Distinct genetic pathways define pre-malignant versus compensatory clonal hematopoiesis in Shwachman-Diamond syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        TP53 mutations define a maladaptive pathway with enhanced leukemic potential by inactivating tumor suppressor checkpoints without correcting the ribosome defect.
      explanation: >-
        Identifies the maladaptive clonal pathway and its enhanced leukemic
        potential.
- name: EIF6-Mutant Compensatory Clonal Expansion
  biological_scale: CELLULAR
  description: >-
    Somatic EIF6 inactivation ameliorates the underlying ribosome defect and so
    enhances clone fitness. It carries limited leukemic potential and is
    deliberately given no edge to malignant transformation: this arm is a
    compensatory response, not a step toward leukemia, and an edge here would
    assert the opposite of what the source reports. EIF6 is inactivated by two
    distinct genetic routes, and both belong here: point mutation, and
    interstitial deletion of chromosome 20q, which removes the EIF6 locus and is
    the commoner of the two. This is why del(20q) in an SDS marrow does not
    carry the ominous meaning it carries in sporadic myelodysplastic syndrome.
  evidence:
  - reference: PMID:33637765
    reference_title: >-
      Distinct genetic pathways define pre-malignant versus compensatory clonal hematopoiesis in Shwachman-Diamond syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      EIF6 inactivation mediates a compensatory pathway with limited leukemic potential by ameliorating the underlying SDS ribosome defect and enhancing clone fitness.
    explanation: >-
      Establishes both the compensatory mechanism and the limited leukemic
      potential that justifies leaving this node without a malignancy edge.
  - reference: PMID:33637765
    reference_title: >-
      Distinct genetic pathways define pre-malignant versus compensatory clonal hematopoiesis in Shwachman-Diamond syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      As expected, we observed frequent interstitial deletions of chromosome 20q (8 of 17, 47%) in patients without MN
    explanation: >-
      Establishes interstitial del(20q) as frequent, and specifically in
      patients without myeloid neoplasia, which is what marks it as part of the
      compensatory rather than the pre-malignant arm.
- name: TP53-Mutant Maladaptive Clonal Expansion
  biological_scale: CELLULAR
  description: >-
    Somatic TP53 mutation improves clone fitness by inactivating
    tumour-suppressor checkpoints while leaving the ribosome defect uncorrected.
    This is the arm that carries leukemic potential, and progression to overt
    leukemia is associated with acquisition of biallelic TP53 alterations.
  evidence:
  - reference: PMID:33637765
    reference_title: >-
      Distinct genetic pathways define pre-malignant versus compensatory clonal hematopoiesis in Shwachman-Diamond syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      TP53 mutations define a maladaptive pathway with enhanced leukemic potential by inactivating tumor suppressor checkpoints without correcting the ribosome defect.
    explanation: >-
      Establishes this arm as the pre-malignant one.
  downstream:
  - target: Myeloid Malignant Transformation
    description: >-
      Progression to overt myeloid malignancy follows acquisition of biallelic
      TP53 alterations within this clonal lineage.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Acquisition of a second TP53 hit, producing biallelic TP53 inactivation in the expanded clone.
    evidence:
    - reference: PMID:33637765
      reference_title: >-
        Distinct genetic pathways define pre-malignant versus compensatory clonal hematopoiesis in Shwachman-Diamond syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Subsequent development of leukemia was associated with acquisition of biallelic TP53 alterations.
      explanation: >-
        Ties the transition to overt leukemia to biallelic TP53 inactivation
        rather than to clonal hematopoiesis as such.
- name: Myeloid Malignant Transformation
  biological_scale: ORGANISM
  description: >-
    Progression to myelodysplastic syndrome or acute myeloid leukemia occurs in
    a substantial minority of patients, typically at a young age, and is the
    principal determinant of prognosis. Solid tumours are rare.
  evidence:
  - reference: PMID:37226705
    reference_title: >-
      Shwachman-Diamond syndromes: clinical, genetic, and biochemical insights from the rare variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 10-30% of cases, transformation to a myeloid neoplasm occurs.
    explanation: >-
      Quantifies the transformation risk described in this node.
  - reference: PMID:35322185
    reference_title: >-
      Shwachman Diamond syndrome: narrow genotypic spectrum and variable clinical features.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Increased risk of hematologic malignancies at young ages and the rarity of solid malignancies was observed in both the NCI cohort and published studies.
    explanation: >-
      Cohort evidence for the young age at malignancy and the restriction to
      haematological cancers.
phenotypes:
- name: Neutropenia
  category: Hematologic
  diagnostic: true
  description: >-
    Persistent or intermittent neutropenia, present in essentially all affected
    children and usually the earliest abnormality.
  phenotype_term:
    preferred_term: Neutropenia
    term:
      id: HP:0001875
      label: Decreased total neutrophil count
    temporality: RECURRENT
  evidence:
  - reference: PMID:35322185
    reference_title: >-
      Shwachman Diamond syndrome: narrow genotypic spectrum and variable clinical features.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most patients had the SDS hallmark features of neutropenia (45/45, 100%), pancreatic insufficiency (41/43, 95.3%), and/or bony abnormalities (29/36, 80.6%).
    explanation: >-
      NCI cohort frequency for neutropenia in molecularly characterised SDS.
- name: Impaired neutrophil chemotaxis
  category: Immunologic
  description: >-
    A functional neutrophil defect distinct from, and additional to, the low
    neutrophil count: SDS neutrophils show dysregulated chemotaxis traced to
    altered F-actin polymerization. It matters clinically because it means
    infection risk is not fully predicted by the absolute neutrophil count, and
    it is reproduced in the srp54 zebrafish model.
  phenotype_term:
    preferred_term: Impaired neutrophil chemotaxis
    term:
      id: HP:0040238
      label: Impaired neutrophil chemotaxis
  evidence:
  - reference: PMID:37226705
    reference_title: >-
      Shwachman-Diamond syndromes: clinical, genetic, and biochemical insights from the rare variants.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Neutrophils isolated from SDS patients exhibit dysregulated chemotaxis due to altered F-actin polymerization capability.
    explanation: >-
      Patient-derived neutrophils establish the chemotaxis defect and its
      cytoskeletal basis.
  - reference: PMID:37226705
    reference_title: >-
      Shwachman-Diamond syndromes: clinical, genetic, and biochemical insights from the rare variants.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Attenuated chemotaxis in neutrophil was shown in a srp54 knockdown zebrafish model.
    explanation: >-
      Model-organism confirmation of the same functional defect in the SRP54
      form.
- name: Exocrine pancreatic insufficiency
  category: Gastrointestinal
  diagnostic: true
  description: >-
    Fatty replacement of the pancreas with enzyme deficiency, steatorrhoea and
    malabsorption; present in over 95% of cohort patients, though secretory
    capacity may improve with age.
  phenotype_term:
    preferred_term: Exocrine pancreatic insufficiency
    term:
      id: HP:0001738
      label: Exocrine pancreatic insufficiency
  evidence:
  - reference: PMID:35322185
    reference_title: >-
      Shwachman Diamond syndrome: narrow genotypic spectrum and variable clinical features.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most patients had the SDS hallmark features of neutropenia (45/45, 100%), pancreatic insufficiency (41/43, 95.3%), and/or bony abnormalities (29/36, 80.6%).
    explanation: >-
      Same cohort provides the frequency of pancreatic insufficiency.
- name: Metaphyseal dysplasia
  category: Skeletal
  diagnostic: true
  description: >-
    Metaphyseal dyschondroplasia of the long bones with widening and
    irregularity that progresses through childhood; the feature that places SDS
    in the metaphyseal group of the ISDS skeletal nosology.
  phenotype_term:
    preferred_term: Metaphyseal dysplasia
    term:
      id: HP:0100255
      label: Metaphyseal dysplasia
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:12120235
    reference_title: "Shwachman-Diamond syndrome: clinical phenotypes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Short ribs with broadened anterior ends and metaphyseal dyschondroplasia of the long bone are the most common findings.
    explanation: >-
      Identifies metaphyseal dyschondroplasia as one of the two commonest
      skeletal findings.
  - reference: PMID:14984468
    reference_title: >-
      Skeletal phenotype in patients with Shwachman-Diamond syndrome and mutations in SBDS.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There was a tendency towards normalization of the epiphyseal maturation defect and progression of the metaphyseal changes with age.
    explanation: >-
      Supports the progressive clinical course annotated on this phenotype.
- name: Osteopenia
  category: Skeletal
  description: >-
    Generalised osteopenia is a consistent radiographic finding across the SDS
    skeletal series.
  phenotype_term:
    preferred_term: Osteopenia
    term:
      id: HP:0000938
      label: Osteopenia
  evidence:
  - reference: PMID:14984468
    reference_title: >-
      Skeletal phenotype in patients with Shwachman-Diamond syndrome and mutations in SBDS.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The typical features were (1) delayed appearance of secondary ossification centers, (2) variable widening and irregularity of the metaphyses in early childhood, followed by progressive thickening and irregularity of the growth plates, and (3) generalized osteopenia.
    explanation: >-
      Lists generalised osteopenia among the typical radiographic features.
- name: Narrow chest
  category: Skeletal
  description: >-
    Short ribs with broadened anterior ends narrow the thorax; severe thoracic
    dystrophy is the reason GeneReviews recommends early pulmonary and
    orthopaedic referral.
  phenotype_term:
    preferred_term: Narrow chest
    term:
      id: HP:0000774
      label: Narrow chest
  evidence:
  - reference: PMID:12120235
    reference_title: "Shwachman-Diamond syndrome: clinical phenotypes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Short ribs with broadened anterior ends and metaphyseal dyschondroplasia of the long bone are the most common findings.
    explanation: >-
      The rib abnormality underlying the narrow thorax is named as one of the
      commonest findings.
- name: Short stature
  category: Growth
  description: >-
    Short stature reflects an intrinsic growth defect as well as malabsorption;
    weight and length are deficient from birth and remain below normal.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:20301722
    reference_title: Shwachman-Diamond Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In almost all affected children, persistent or intermittent neutropenia is an early finding. Short stature and recurrent infections are common.
    explanation: >-
      GeneReviews records short stature as a common manifestation.
- name: Failure to thrive
  category: Growth
  description: >-
    Malabsorption from exocrine pancreatic insufficiency causes failure to
    thrive, often the presenting complaint in infancy.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:29700810
    reference_title: Refining the phenotype associated with biallelic DNAJC21 mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients present features consistent with IBMFS: bone marrow failure, growth retardation, failure to thrive, developmental delay, recurrent infections, and skin, teeth or hair abnormalities.
    explanation: >-
      Documents failure to thrive in the DNAJC21-related form of the spectrum.
- name: Recurrent respiratory infections
  category: Immunologic
  description: >-
    Neutropenia, sometimes with hypogammaglobulinaemia, causes recurrent
    bacterial infection.
  phenotype_term:
    preferred_term: Recurrent respiratory infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
  evidence:
  - reference: PMID:35322185
    reference_title: >-
      Shwachman Diamond syndrome: narrow genotypic spectrum and variable clinical features.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with SDS often experience recurrent infections due to neutropenia and in some patients hypogammaglobulinemia.
    explanation: >-
      Supports recurrent infection as a consequence of the immune defect.
- name: Myelodysplasia
  category: Hematologic
  description: >-
    Myelodysplastic syndrome develops in a substantial minority and marks the
    transition from marrow failure to clonal disease.
  phenotype_term:
    preferred_term: Myelodysplasia
    term:
      id: HP:0002863
      label: Myelodysplasia
  evidence:
  - reference: PMID:30413969
    reference_title: >-
      Shwachman-Diamond Syndrome: Molecular Mechanisms and Current Perspectives.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Almost 15-20% of patients with SDS present myelodysplastic syndrome with a high risk of acute myeloid leukemia (AML) transformation.
    explanation: >-
      Gives the reported frequency of MDS and its onward leukemic risk.
- name: Acute myeloid leukemia
  category: Neoplastic
  description: >-
    AML is the principal malignant outcome, arises at young ages, and is
    associated with acquisition of biallelic TP53 alterations in the marrow.
  phenotype_term:
    preferred_term: Acute myeloid leukemia
    term:
      id: HP:0004808
      label: Acute myeloid leukemia
  evidence:
  - reference: PMID:37226705
    reference_title: >-
      Shwachman-Diamond syndromes: clinical, genetic, and biochemical insights from the rare variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 10-30% of cases, transformation to a myeloid neoplasm occurs.
    explanation: >-
      Reports the frequency of transformation to myeloid neoplasia including
      AML.
- name: Pancytopenia
  category: Hematologic
  description: >-
    Marrow involvement is not confined to the granulocytic lineage; single- or
    multilineage cytopenias develop and may progress to severe marrow failure.
  phenotype_term:
    preferred_term: Pancytopenia
    term:
      id: HP:0001876
      label: Pancytopenia
  evidence:
  - reference: PMID:20301722
    reference_title: Shwachman-Diamond Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      hematologic abnormalities with single- or multilineage cytopenias and susceptibility to myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML)
    explanation: >-
      GeneReviews documents multilineage cytopenia as part of the haematological
      phenotype.
- name: Global developmental delay
  category: Neurologic
  description: >-
    Developmental delay and attention or learning problems are common and
    increasingly recognised as part of the phenotype rather than a consequence
    of chronic illness.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:35322185
    reference_title: >-
      Shwachman Diamond syndrome: narrow genotypic spectrum and variable clinical features.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Developmental delay was common (20/34, 58.8%).
    explanation: >-
      Cohort frequency for developmental delay.
- name: Elevated hepatic transaminases
  category: Hepatic
  description: >-
    Transient hepatomegaly with elevated liver enzymes is typical in the first
    years of life and usually improves without sequelae.
  phenotype_term:
    preferred_term: Elevated circulating hepatic transaminase concentration
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
    temporality: TRANSIENT
  evidence:
  - reference: PMID:12120235
    reference_title: "Shwachman-Diamond syndrome: clinical phenotypes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Elevated liver enzymes and hepatomegaly are present in the first years of life with subsequent improvement without complications.
    explanation: >-
      Supports both the finding and the transient course annotated here.
biochemical: []
genetic:
- name: SBDS
  association: Causal biallelic variant
  gene_term:
    preferred_term: SBDS
    term:
      id: hgnc:19440
      label: SBDS
  frequency: approximately 90% of patients
  notes: >-
    Most alleles arise by gene conversion with the SBDSP1 pseudogene, producing
    the recurrent c.258+2T>C and c.183_184TA>CT changes. Biallelic null
    genotypes are not observed, implying residual function is required for life.
  evidence:
  - reference: PMID:12496757
    reference_title: Mutations in SBDS are associated with Shwachman-Diamond syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report identification of disease-associated mutations in an uncharacterized gene, SBDS, in the interval of 1.9 cM at 7q11 previously shown to be associated with the disease.
    explanation: >-
      The original identification of SBDS as the SDS disease gene.
  - reference: PMID:37226705
    reference_title: >-
      Shwachman-Diamond syndromes: clinical, genetic, and biochemical insights from the rare variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Approximately 90% of patients have biallelic pathogenic variants in the SBDS gene located on human chromosome 7q11.
    explanation: >-
      Source for the case fraction recorded here.
  case_fractions:
  - population: National Cancer Institute IBMFS cohort
    case_fraction_percent: 68.1
    cohort_size: 47
    notes: >-
      Lower than the ~90% usually quoted because the NCI cohort deliberately
      enrols SDS-like as well as molecularly confirmed SDS participants.
    evidence:
    - reference: PMID:35322185
      reference_title: >-
        Shwachman Diamond syndrome: narrow genotypic spectrum and variable clinical features.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        PVs in SBDS were present in 32/47 (68.1%) participants.
      explanation: >-
        Direct cohort figure for the SBDS share of participants.
- name: DNAJC21
  association: Causal biallelic variant
  gene_term:
    preferred_term: DNAJC21
    term:
      id: hgnc:27030
      label: DNAJC21
  notes: >-
    Biallelic variants cause a cancer-prone bone marrow failure syndrome through
    corruption of nuclear rRNA biogenesis and late cytoplasmic 60S maturation.
  evidence:
  - reference: PMID:27346687
    reference_title: >-
      DNAJC21 Mutations Link a Cancer-Prone Bone Marrow Failure Syndrome to Corruption in 60S Ribosome Subunit Maturation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Collectively, these findings demonstrate that mutations in DNAJC21 cause a cancer-prone BMF syndrome due to corruption of early nuclear rRNA biogenesis and late cytoplasmic maturation of the 60S subunit.
    explanation: >-
      Establishes causality and the molecular mechanism for this gene.
- name: SRP54
  association: Causal monoallelic variant
  gene_term:
    preferred_term: SRP54
    term:
      id: hgnc:11301
      label: SRP54
  notes: >-
    Heterozygous, usually de novo, missense variants in the GTPase domain.
    Reported alongside SBDS and DNAJC21 as an SDS gene associated with myeloid
    neoplasia.
  evidence:
  - reference: PMID:28972538
    reference_title: >-
      Mutations in signal recognition particle SRP54 cause syndromic neutropenia with Shwachman-Diamond-like features.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In conclusion, autosomal dominant mutations in SRP54, a key member of the cotranslation protein-targeting pathway, lead to syndromic neutropenia with a Shwachman-Diamond-like phenotype.
    explanation: >-
      Establishes SRP54 as a dominant cause within the SDS spectrum.
  - reference: PMID:37226705
    reference_title: >-
      Shwachman-Diamond syndromes: clinical, genetic, and biochemical insights from the rare variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To date, SBDS, DNAJC21, and SRP54 variants have been associated with myeloid neoplasia.
    explanation: >-
      Records that the SRP54 form shares the myeloid-neoplasia risk.
- name: EFL1
  association: Causal biallelic variant
  gene_term:
    preferred_term: EFL1
    term:
      id: hgnc:25789
      label: EFL1
  notes: >-
    The fourth SDS gene, curated in full in the separate
    EFL1-related Shwachman-Diamond syndrome entry; listed here so the genetic
    spectrum of the disease is complete.
  evidence:
  - reference: PMID:20301722
    reference_title: Shwachman-Diamond Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Autosomal recessive SDS: SDS caused by pathogenic variants in DNAJC21, EFL1, or SBDS is inherited in an autosomal recessive manner.
    explanation: >-
      GeneReviews lists EFL1 among the recessive SDS genes.
- name: TP53
  association: Somatic driver of malignant progression
  gene_term:
    preferred_term: TP53
    term:
      id: hgnc:11998
      label: TP53
  notes: >-
    Not a germline cause. Somatic TP53 mutation is the maladaptive clonal
    pathway in the SDS marrow, and biallelic TP53 loss accompanies progression
    to leukemia.
  evidence:
  - reference: PMID:33637765
    reference_title: >-
      Distinct genetic pathways define pre-malignant versus compensatory clonal hematopoiesis in Shwachman-Diamond syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Subsequent development of leukemia was associated with acquisition of biallelic TP53 alterations.
    explanation: >-
      Links somatic biallelic TP53 loss to leukemic progression in SDS.
- name: EIF6
  association: Somatic compensatory modifier
  gene_term:
    preferred_term: EIF6
    term:
      id: hgnc:6159
      label: EIF6
  notes: >-
    Somatic EIF6 inactivation partially corrects the germline ribosome defect
    and expands clones with limited leukemic potential; the mechanistic mirror
    image of the TP53 pathway and a candidate therapeutic target.
  evidence:
  - reference: PMID:33637765
    reference_title: >-
      Distinct genetic pathways define pre-malignant versus compensatory clonal hematopoiesis in Shwachman-Diamond syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      EIF6 inactivation mediates a compensatory pathway with limited leukemic potential by ameliorating the underlying SDS ribosome defect and enhancing clone fitness.
    explanation: >-
      Establishes somatic EIF6 loss as a compensatory rather than pre-malignant
      event.
environmental: []
treatments:
- name: Pancreatic enzyme replacement and fat-soluble vitamin supplementation
  description: >-
    Oral pancreatic enzymes with fat-soluble vitamin supplementation are the
    standard treatment for the exocrine pancreatic component.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: pancreatic enzyme replacement therapy
    term:
      id: NCIT:C16221
      label: Protein Replacement Therapy
  target_phenotypes:
  - preferred_term: Exocrine pancreatic insufficiency
    term:
      id: HP:0001738
      label: Exocrine pancreatic insufficiency
  target_mechanisms:
  - target: Exocrine Pancreatic Acinar Failure
    treatment_effect: BYPASSES
    description: >-
      Replaces the enzymatic output the failing acinar tissue cannot provide;
      it does not correct the underlying ribosomal defect.
    evidence:
    - reference: PMID:20301722
      reference_title: Shwachman-Diamond Syndrome.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Exocrine pancreatic insufficiency is treated with oral pancreatic enzymes and fat-soluble vitamin supplementation.
      explanation: >-
        GeneReviews names enzyme replacement as the treatment aimed at this
        mechanism.
  evidence:
  - reference: PMID:20301722
    reference_title: Shwachman-Diamond Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Exocrine pancreatic insufficiency is treated with oral pancreatic enzymes and fat-soluble vitamin supplementation.
    explanation: >-
      Standard-of-care statement for the pancreatic component.
- name: Granulocyte colony-stimulating factor
  description: >-
    G-CSF is considered for severe recurrent infection with an absolute
    neutrophil count persistently at or below 500/mm3, and is particularly
    useful as cover for dental or orthopaedic procedures. Prolonged use is
    approached with caution given the underlying leukemia predisposition.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: recombinant granulocyte colony-stimulating factor
      term:
        id: NCIT:C1287
        label: Recombinant Granulocyte Colony-Stimulating Factor
  target_phenotypes:
  - preferred_term: Neutropenia
    term:
      id: HP:0001875
      label: Decreased total neutrophil count
  target_mechanisms:
  - target: Bone Marrow Failure with Granulopoietic Predominance
    treatment_effect: ACTIVATES
    description: >-
      Drives residual granulopoiesis to raise the neutrophil count without
      addressing the ribosome defect that constrains it.
    evidence:
    - reference: PMID:20301722
      reference_title: Shwachman-Diamond Syndrome.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        If recurrent infections are severe and absolute neutrophil counts are persistently ≤500/mm3, treatment with granulocyte-colony stimulation factor (G-CSF) can be considered and may be especially helpful when interventions such as complex dental procedures or orthopedic surgery are being considered.
      explanation: >-
        GeneReviews indication statement for G-CSF in SDS.
  evidence:
  - reference: PMID:20301722
    reference_title: Shwachman-Diamond Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Prolonged use of cytokine and hematopoietic growth factors (e.g., G-CSF) should be considered with caution.
    explanation: >-
      Records the caution that qualifies this treatment in a
      leukemia-predisposition syndrome.
- name: Hematopoietic stem cell transplantation
  description: >-
    HSCT is the only curative option for the haematological disease and is
    considered for severe marrow failure, MDS or AML. Conditioning is modified
    because standard agents such as cyclophosphamide and busulfan carry a risk
    of cardiac toxicity in SDS.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: hematopoietic cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_phenotypes:
  - preferred_term: Pancytopenia
    term:
      id: HP:0001876
      label: Pancytopenia
  target_mechanisms:
  - target: Bone Marrow Failure with Granulopoietic Predominance
    treatment_effect: RESTORES
    description: >-
      Replaces the SBDS-deficient haematopoietic compartment with donor cells,
      correcting the marrow arm of the disease while leaving the pancreatic and
      skeletal arms untouched.
    evidence:
    - reference: PMID:20301722
      reference_title: Shwachman-Diamond Syndrome.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Hematopoietic stem cell transplantation (HSCT) should be considered for treatment of severe bone marrow failure, MDS, or AML.
      explanation: >-
        Standard-of-care statement for transplantation in SDS marrow disease.
  evidence:
  - reference: PMID:20301722
    reference_title: Shwachman-Diamond Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Some drugs used in standard HSCT preparative regimens (e.g., cyclophosphamide and busulfan) may not be suitable because of possible cardiac toxicity.
    explanation: >-
      Documents the SDS-specific conditioning caveat.
- name: Blood and platelet transfusion
  description: >-
    Transfusion support is used for symptomatic anaemia and thrombocytopenia
    arising from marrow failure.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: blood transfusion
    term:
      id: NCIT:C15192
      label: Blood Transfusion
  target_phenotypes:
  - preferred_term: Pancytopenia
    term:
      id: HP:0001876
      label: Pancytopenia
  evidence:
  - reference: PMID:20301722
    reference_title: Shwachman-Diamond Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Blood and/or platelet transfusions may be considered for anemia and thrombocytopenia.
    explanation: >-
      GeneReviews management statement for the cytopenias.
- name: Orthopaedic and pulmonary management of the skeletal dysplasia
  description: >-
    Early orthopaedic and pulmonary referral is required for thoracic dystrophy;
    skeletal dysplasia, asymmetric growth and joint deformities need ongoing
    orthopaedic management, with hip and knee radiographs during rapid growth.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: orthopedic surgical procedure
    term:
      id: NCIT:C16186
      label: Orthopedic Surgical Procedure
  target_phenotypes:
  - preferred_term: Metaphyseal dysplasia
    term:
      id: HP:0100255
      label: Metaphyseal dysplasia
  target_mechanisms:
  - target: Metaphyseal Dysplasia
    treatment_effect: MODULATES
    description: >-
      Manages the mechanical consequences of disordered metaphyseal growth
      rather than the growth-plate lesion itself.
    evidence:
    - reference: PMID:20301722
      reference_title: Shwachman-Diamond Syndrome.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Early pulmonary and orthopedic referral is essential for treatment of thoracic dystrophy; orthopedic management of other skeletal manifestations including skeletal dysplasia, asymmetric growth, and joint deformities.
      explanation: >-
        GeneReviews management statement for the skeletal manifestations.
  evidence:
  - reference: PMID:20301722
    reference_title: Shwachman-Diamond Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Monitor for orthopedic complications with radiographs of the hips and knees during the most rapid growth stages.
    explanation: >-
      Surveillance recommendation supporting ongoing orthopaedic follow-up.
- name: Nutritional and fat-soluble vitamin surveillance
  description: >-
    Nutritional status and fat-soluble vitamin concentrations are followed
    every six months because malabsorption persists even on enzyme replacement.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:20301722
    reference_title: Shwachman-Diamond Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Assessment of nutritional status and measurement of serum concentration of fat-soluble vitamins every six months.
    explanation: >-
      Surveillance recommendation for the nutritional consequences of the
      disease.
diagnosis:
- name: Clinical recognition of pancreatic plus marrow dysfunction
  description: >-
    SDS is established clinically by exocrine pancreatic dysfunction together
    with bone marrow dysfunction, and/or by molecular confirmation in one of the
    four genes.
  presence: >-
    Exocrine pancreatic dysfunction with bone marrow dysfunction establishes the
    clinical diagnosis.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  evidence:
  - reference: PMID:20301722
    reference_title: Shwachman-Diamond Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The diagnosis of SDS is established in a proband with the classic clinical findings of exocrine pancreatic dysfunction and bone marrow dysfunction and/or biallelic pathogenic variants in DNAJC21, EFL1, or SBDS or a heterozygous pathogenic variant in SRP54 identified by molecular genetic testing.
    explanation: >-
      GeneReviews diagnostic criteria statement.
- name: Molecular genetic testing of the four SDS genes
  description: >-
    Sequencing of SBDS, DNAJC21, EFL1 and SRP54. SBDS analysis must account for
    the 97%-identical SBDSP1 pseudogene, since the common alleles are
    pseudogene-derived and are easily missed or miscalled by methods that do not
    discriminate the two loci.
  results: >-
    Biallelic SBDS, DNAJC21 or EFL1 variants, or a heterozygous SRP54 variant,
    confirm the diagnosis.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:20301722
    reference_title: Shwachman-Diamond Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The diagnosis of SDS is established in a proband with the classic clinical findings of exocrine pancreatic dysfunction and bone marrow dysfunction and/or biallelic pathogenic variants in DNAJC21, EFL1, or SBDS or a heterozygous pathogenic variant in SRP54 identified by molecular genetic testing.
    explanation: >-
      Names the four genes whose testing establishes the molecular diagnosis.
  - reference: PMID:37226705
    reference_title: >-
      Shwachman-Diamond syndromes: clinical, genetic, and biochemical insights from the rare variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Complicating the sequence analysis is the presence of a pseudogene, SBDSP1 with 97% homology to SBDS.
    explanation: >-
      Source for the pseudogene caveat that governs how SBDS must be sequenced.
- name: Complete blood count with differential
  description: >-
    Serial CBC with differential and platelet count detects the neutropenia and
    tracks evolving multilineage cytopenias.
  results: >-
    Persistent or intermittent neutropenia, with or without anaemia and
    thrombocytopenia.
  diagnosis_term:
    preferred_term: blood cell count
    term:
      id: NCIT:C28133
      label: Blood Cell Count
  evidence:
  - reference: PMID:20301722
    reference_title: Shwachman-Diamond Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Complete blood count with white blood cell differential and platelet count at least every three to six months; bone marrow examination every one to three years or more frequently if bone marrow changes are observed.
    explanation: >-
      Supports serial CBC as the core haematological monitoring test.
- name: Bone marrow aspiration and biopsy
  description: >-
    Marrow examination at diagnosis and on surveillance detects hypocellularity
    and, critically, the emergence of dysplasia or a clonal cytogenetic
    abnormality.
  results: >-
    Hypocellular marrow; dysplastic change or clonal cytogenetic abnormalities
    signal progression.
  diagnosis_term:
    preferred_term: bone marrow aspiration and biopsy
    term:
      id: NCIT:C92958
      label: Bone Marrow Aspiration and Biopsy
  evidence:
  - reference: PMID:20301722
    reference_title: Shwachman-Diamond Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      bone marrow examination every one to three years or more frequently if bone marrow changes are observed
    explanation: >-
      Surveillance schedule for marrow examination in SDS.
- name: Skeletal radiography
  description: >-
    Radiographs of the long bones, hips and knees show the metaphyseal widening
    and irregularity, delayed secondary ossification centres and osteopenia that
    define the skeletal phenotype. Abnormalities were present in all patients in
    a molecularly confirmed series.
  results: >-
    Metaphyseal widening and irregularity, delayed secondary ossification
    centres, generalised osteopenia, short ribs with broadened anterior ends.
  diagnosis_term:
    preferred_term: X-ray imaging
    term:
      id: NCIT:C38101
      label: X-Ray Imaging
  evidence:
  - reference: PMID:14984468
    reference_title: >-
      Skeletal phenotype in patients with Shwachman-Diamond syndrome and mutations in SBDS.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Review of their skeletal radiographs showed abnormalities in all patients.
    explanation: >-
      Establishes the sensitivity of skeletal radiography in molecularly
      confirmed SDS.
differential_diagnoses:
- name: Cartilage-hair hypoplasia
  description: >-
    The other immuno-osseous metaphyseal dysplasia of nosology group 11. Both
    present with metaphyseal dysplasia, short stature and haematological
    abnormality, but CHH is an RNase MRP ribonucleoprotein defect with
    hypotrichosis and lymphocyte-predominant immunodeficiency, whereas SDS has
    exocrine pancreatic insufficiency and neutrophil-predominant disease.
  disease_term:
    preferred_term: cartilage-hair hypoplasia
    term:
      id: MONDO:0009595
      label: cartilage-hair hypoplasia
  distinguishing_features:
  - Hypotrichosis with fine, sparse, light-coloured hair
  - Biallelic RMRP variants rather than a ribosome-maturation gene
  - Exocrine pancreatic insufficiency is absent
- name: Cystic fibrosis
  description: >-
    The commonest cause of childhood exocrine pancreatic insufficiency and
    failure to thrive, and a frequent alternative diagnosis considered before
    SDS is recognised.
  disease_term:
    preferred_term: cystic fibrosis
    term:
      id: MONDO:0009061
      label: cystic fibrosis
  distinguishing_features:
  - Elevated sweat chloride and biallelic CFTR variants
  - Progressive sinopulmonary disease rather than neutropenia
  - No metaphyseal dysplasia
  evidence:
  - reference: PMID:35322185
    reference_title: >-
      Shwachman Diamond syndrome: narrow genotypic spectrum and variable clinical features.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with SDS are frequently evaluated for cystic fibrosis, celiac disease, Crohn's disease, and other diseases prior to suspicion of SDS because the clinical presentation can vary widely and it is over underrecognized.
    explanation: >-
      Documents cystic fibrosis as a routine alternative diagnosis on the SDS
      diagnostic pathway.
animal_models:
- name: Sbds-null mouse ribosome reconstitution
  species: Mouse
  genotype: Sbds-deleted
  publication: PMID:21536732
  modeled_mechanisms:
  - target: Failure of eIF6 Eviction from the Pre-60S Subunit
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Late cytoplasmic 60S subunits isolated from Sbds-deleted mice retain
      eIF6, the same biochemical lesion described in this node, and support
      biochemical reconstitution of SBDS/EFL1-catalyzed eIF6 release.
    readouts:
    - name: eIF6 occupancy on isolated 60S subunits
      target: Failure of eIF6 Eviction from the Pre-60S Subunit
      direction: INCREASED
      evidence:
      - reference: PMID:21536732
        reference_title: >-
          Uncoupling of GTP hydrolysis from eIF6 release on the ribosome causes Shwachman-Diamond syndrome.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Here, by isolating late cytoplasmic 60S ribosomal subunits from Sbds-deleted mice, we show that SBDS and the GTPase elongation factor-like 1 (EFL1) directly catalyze eIF6 removal in mammalian cells by a mechanism that requires GTP binding and hydrolysis by EFL1 but not phosphorylation of eIF6 Ser 235.
        explanation: >-
          Establishes that 60S subunits from the null mouse retain eIF6 and
          that SBDS/EFL1 catalyze its release, the readout this model
          provides.
    evidence:
    - reference: PMID:21536732
      reference_title: >-
        Uncoupling of GTP hydrolysis from eIF6 release on the ribosome causes Shwachman-Diamond syndrome.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Here, by isolating late cytoplasmic 60S ribosomal subunits from Sbds-deleted mice, we show that SBDS and the GTPase elongation factor-like 1 (EFL1) directly catalyze eIF6 removal in mammalian cells by a mechanism that requires GTP binding and hydrolysis by EFL1 but not phosphorylation of eIF6 Ser 235.
      explanation: >-
        The mammalian ribosome-reconstitution result this node's molecular
        claim is built on came from this null-mouse model.
- name: SRP54-knockdown zebrafish
  species: Zebrafish
  genotype: srp54 morpholino knockdown
  genes:
  - preferred_term: SRP54
    term:
      id: hgnc:11301
      label: SRP54
  publication: PMID:28972538
  modeled_mechanisms:
  - target: Impaired Co-translational Protein Targeting
    relationship: PERTURBS
    fidelity: MODERATE
    description: >-
      Morpholino knockdown of srp54 directly manipulates the co-translational
      targeting defect that monoallelic human SRP54 variants cause, then
      reports on its downstream consequences.
    limitations: >-
      A morpholino knockdown in a non-mammalian model, not the patient
      missense-variant mechanism; it removes SRP54 function outright rather
      than reproducing the specific hypomorphic GTPase-domain lesion.
    evidence:
    - reference: PMID:28972538
      reference_title: >-
        Mutations in signal recognition particle SRP54 cause syndromic neutropenia with Shwachman-Diamond-like features.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Profound reductions in neutrophil counts and chemotaxis as well as a diminished exocrine pancreas size in a SRP54-knockdown zebrafish model faithfully recapitulated the human phenotype.
      explanation: >-
        Establishes the knockdown as informative for the SRP54-related
        molecular node, since its downstream phenotypes match the human
        disease.
  - target: Bone Marrow Failure with Granulopoietic Predominance
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The knockdown reproduces both the neutrophil-count deficit and the
      chemotaxis defect that mark the granulopoietic arm of the human disease.
    readouts:
    - name: Neutrophil count
      target: Bone Marrow Failure with Granulopoietic Predominance
      direction: DECREASED
      evidence:
      - reference: PMID:28972538
        reference_title: >-
          Mutations in signal recognition particle SRP54 cause syndromic neutropenia with Shwachman-Diamond-like features.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Profound reductions in neutrophil counts and chemotaxis as well as a diminished exocrine pancreas size in a SRP54-knockdown zebrafish model faithfully recapitulated the human phenotype.
        explanation: >-
          Reports the neutrophil-count reduction measured in the knockdown
          model.
    - name: Neutrophil chemotaxis
      target: Bone Marrow Failure with Granulopoietic Predominance
      direction: DECREASED
      evidence:
      - reference: PMID:37226705
        reference_title: >-
          Shwachman-Diamond syndromes: clinical, genetic, and biochemical insights from the rare variants.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Attenuated chemotaxis in neutrophil was shown in a srp54 knockdown zebrafish model.
        explanation: >-
          Confirms the chemotaxis defect in the srp54 knockdown zebrafish
          model, independent of the SRP54 discovery paper.
    evidence:
    - reference: PMID:28972538
      reference_title: >-
        Mutations in signal recognition particle SRP54 cause syndromic neutropenia with Shwachman-Diamond-like features.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Profound reductions in neutrophil counts and chemotaxis as well as a diminished exocrine pancreas size in a SRP54-knockdown zebrafish model faithfully recapitulated the human phenotype.
      explanation: >-
        Model-organism evidence that the knockdown informs the granulopoietic
        arm of the human disease.
  - target: Exocrine Pancreatic Acinar Failure
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The same knockdown reduces exocrine pancreas size, matching the
      pancreatic arm of the human phenotype.
    readouts:
    - name: Exocrine pancreas size
      target: Exocrine Pancreatic Acinar Failure
      direction: DECREASED
      evidence:
      - reference: PMID:28972538
        reference_title: >-
          Mutations in signal recognition particle SRP54 cause syndromic neutropenia with Shwachman-Diamond-like features.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Profound reductions in neutrophil counts and chemotaxis as well as a diminished exocrine pancreas size in a SRP54-knockdown zebrafish model faithfully recapitulated the human phenotype.
        explanation: >-
          Reports the pancreas-size reduction measured in the knockdown
          model.
    evidence:
    - reference: PMID:28972538
      reference_title: >-
        Mutations in signal recognition particle SRP54 cause syndromic neutropenia with Shwachman-Diamond-like features.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Profound reductions in neutrophil counts and chemotaxis as well as a diminished exocrine pancreas size in a SRP54-knockdown zebrafish model faithfully recapitulated the human phenotype.
      explanation: >-
        Model-organism evidence that the knockdown informs the pancreatic arm
        of the human disease.
clinical_trials: []
datasets: []
notes: >-
  Curated to complete ISDS Nosology group 11 (Metaphyseal dysplasias). The entry
  is keyed on MONDO:0009833, the parent Shwachman-Diamond syndrome class, and
  covers the SBDS-, DNAJC21- and SRP54-related rows of that group; the
  EFL1-related row has its own dismech entry (MONDO:0044205) and is
  cross-referenced here in the genetic section rather than duplicated.
references:
- reference: PMID:20301722
  title: "Shwachman-Diamond Syndrome."
  tags:
  - GeneReviews
  findings: []
- reference: PMID:36779427
  title: "Nosology of genetic skeletal disorders: 2023 revision."
  findings: []
📚

References & Deep Research

References

2
PMID:20301722
Shwachman-Diamond Syndrome.
No top-level findings curated for this source.
PMID:36779427
Nosology of genetic skeletal disorders: 2023 revision.
No top-level findings curated for this source.