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Definitions

1

Newborn screening by T-cell receptor excision circle quantification

CD45 deficiency produces T lymphopenia from birth, so it falls within the population detectable by universal newborn severe combined immunodeficiency screening, which quantifies T-cell receptor excision circles in dried blood spots. Confirmation is by flow cytometry, where absent surface CD45 on all leukocytes is directly visible and effectively pathognomonic, followed by PTPRC sequencing.

DIAGNOSTIC_CRITERIA

Show evidence (1 reference)

PMID:42079620 SUPPORT Human Clinical

"Severe combined immunodeficiency (SCID) can be detected at birth through T-cell receptor excision circles (TREC) analysis in dried blood spots."

Establishes the screening modality that would detect this disease presymptomatically.

Notes: This describes the screening pathway for severe combined immunodeficiency in general. No published case of immunodeficiency 105 has been reported as detected by newborn screening, so the applicability here is inferred from the T-lymphopenic immunophenotype rather than demonstrated.

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Inheritance

1

Autosomal Recessive HP:0000007

Biallelic loss of function, by homozygous variant, compound heterozygosity, or uniparental isodisomy unmasking a single inherited allele.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:11145714 SUPPORT Human Clinical

"a homozygous 6-bp deletion in the gene encoding CD45 (PTPRC, gene map locus 1q31-32), which results in a loss of glutamic acid 339 and tyrosine 340 in the first fibronectin type III module of the extracellular domain of CD45, is associated with failure of surface expression of CD45 and SCID"

A homozygous variant in a patient with severe combined immunodeficiency, establishing the recessive mode.

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Discussions and Knowledge Gaps

1

Does human CD45 deficiency arrest thymocyte development at the same two checkpoints identified in the Ptprc-null mouse?

KNOWLEDGE GAP human_thymocyte_staging_unobserved

Attached to

pathophysiology#Arrest of Thymocyte Development

The staged block, a halved double-negative to double-positive transition followed by a four to fivefold failure of single-positive maturation, comes entirely from the mouse. The human patients are too few, and were studied by peripheral blood immunophenotyping rather than thymic analysis, for the staging to have been tested in people. The entry states the mechanism at the level the mouse supports and this gap records that the human staging is unobserved rather than confirmed.

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Pathophysiology

4

Loss of CD45 Surface Expression

Biallelic PTPRC loss-of-function variants abolish CD45 at the leukocyte surface. The reported mechanisms differ but converge: a large deletion paired with an intervening-sequence 13 donor splice-site change; a homozygous in-frame six-base-pair deletion removing Glu339 and Tyr340 from the first fibronectin type III module, where modelling places Tyr340 as structurally load-bearing so the protein never reaches the membrane; and uniparental isodisomy of chromosome 1 making a single maternal allele homozygous.

leukocyte CL:0000738

CD45 receptor tyrosine phosphatase activity GO:0005001 ⇓ LOSS OF FUNCTION

Downstream

Failure of Lck Activation CD45 is the phosphatase that removes the inhibitory C-terminal phosphotyrosine from Lck, so its absence leaves Lck autoinhibited.

Show evidence (2 references)

PMID:10700239 SUPPORT Human Clinical

"we identified a male patient with a deficiency in CD45 due to a large deletion at one allele and a point mutation at the other. The point mutation resulted in the alteration of intervening sequence 13 donor splice site."

The first reported human CD45 deficiency and its two-allele mechanism.

PMID:11145714 SUPPORT Human Clinical

"Molecular modeling suggests that tyrosine 340 is crucial for the structural integrity of CD45 protein."

Explains why an in-frame two-residue deletion in the extracellular domain abolishes surface expression rather than merely altering it.

Failure of Lck Activation

Lck activity is set by the opposing action of CD45, which removes the inhibitory C-terminal phosphotyrosine, and Csk, which installs it. With CD45 gone, that balance collapses towards the closed, autoinhibited conformation and Lck cannot phosphorylate the T-cell receptor ITAMs that begin proximal signalling.

protein dephosphorylation GO:0006470 ↓ DECREASED

Downstream

Arrest of Thymocyte Development

Show evidence (1 reference)

PMID:32794043 SUPPORT Other

"The balance of phosphorylation at the inhibitory and activating Tyr residues is maintained by a balance between CD45 and Csk and is dependent upon intact intracellular trafficking machinery."

A review establishing that CD45 is one of the two opposing regulators setting Lck's phosphorylation state, which is why its loss is not compensated.

Arrest of Thymocyte Development

Thymocyte maturation depends on T-cell receptor signals at two checkpoints, and both are impaired. In the Ptprc-null mouse the double-negative to double-positive transition is roughly halved and the subsequent maturation of double-positive cells into single-positive thymocytes falls a further four to fivefold, so the deficit compounds. Negative selection is affected too: null thymocytes fail to undergo apoptosis in response to T-cell receptor crosslinking while responding normally to non-receptor signals, which is what localises the lesion to receptor-proximal signalling rather than to the apoptotic machinery.

thymocyte CL:0000893 double-positive thymocyte CL:0000809

T cell differentiation GO:0030217 ↓ DECREASED

thymus UBERON:0002370

Animal models

Ptprc (CD45) null mouse Mouse recapitulates A two-stage developmental block with impaired T-cell-receptor-dependent selection, in the same cell type and at the same checkpoints proposed for the human disease.

Downstream

Decreased total T cell count

Decreased mitogen-induced T-cell proliferation

Severe combined immunodeficiency

Show evidence (2 references)

PMID:8666928 SUPPORT Model Organism

"T cell development is significantly inhibited in CD45-null animals at two distinct stages."

The two-checkpoint block this node describes, demonstrated in the null mouse. No equivalent staged analysis exists in a human patient.

PMID:8666928 SUPPORT Model Organism

"The efficiency of the development of CD4-CD8- thymocytes into CD4+ CD8+ thymocytes is reduced by twofold, subsequently the frequency of successful maturation of the double positive population into mature, single positive thymocytes is reduced by a further four- to fivefold."

Quantifies the deficit at each of the two checkpoints.

B Cell Signalling Failure Despite Normal B Cell Numbers

B cells are generated in normal or increased numbers, so this is not a developmental block in the B lineage. What fails is B-cell receptor signalling: CD45 is required to transmit mitogenic signals through surface IgM and IgD, while CD40-mediated proliferation is preserved. Clinically this is why immunoglobulin concentrations fall progressively with age rather than being absent at presentation, and it is the feature that separates this disorder from the T-negative B-negative severe combined immunodeficiencies.

B cell CL:0000236

B cell receptor signaling pathway GO:0050853 ↓ DECREASED

Animal models

Ptprc (CD45) null mouse Mouse recapitulates B-cell numbers preserved or increased with selective failure of antigen-receptor signalling, matching the human picture of normal B-cell counts and declining immunoglobulins.

Downstream

Decreased circulating immunoglobulin concentration

Show evidence (2 references)

PMID:10700239 SUPPORT Human Clinical

"Despite normal B-lymphocyte numbers, serum immunoglobulin levels decreased with age."

The human observation that grounds this node: numbers preserved, function and output not.

PMID:8666928 SUPPORT Model Organism

"CD45 is absolutely required for the transmission of mitogenic signals via IgM and IgD. By contrast, CD45-null B cells proliferate as well as wild-type cells to CD40-mediated signals."

Localises the B-cell defect to antigen-receptor signalling specifically, sparing the CD40 route.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

4

Blood 3

Decreased total T cell count VERY_FREQUENT HP:0005403

Show evidence (1 reference)

PMID:10700239 SUPPORT Human Clinical

"The population of peripheral blood T lymphocytes was greatly diminished and unresponsive to mitogen stimulation."

Records the T lymphopenia that defines the T-negative immunophenotype.

Decreased mitogen-induced T-cell proliferation VERY_FREQUENT HP:0031381

Show evidence (1 reference)

PMID:10700239 SUPPORT Human Clinical

"The population of peripheral blood T lymphocytes was greatly diminished and unresponsive to mitogen stimulation."

The functional assay result. This sentence carries both the count and the proliferation failure; they are recorded as separate phenotypes because a normal count with absent proliferation would still be diagnostic.

Decreased circulating immunoglobulin concentration VERY_FREQUENT HP:0004313

Show evidence (1 reference)

PMID:10700239 SUPPORT Human Clinical

"serum immunoglobulin levels decreased with age"

Establishes the progressive rather than congenital character of the hypogammaglobulinaemia.

Immune 1

Severe combined immunodeficiency VERY_FREQUENT HP:0004430

Show evidence (1 reference)

PMID:10700239 SUPPORT Human Clinical

"The patient presented at 2 months of age with severe combined immunodeficiency disease."

Presentation and age of onset in the index patient.

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Genetic Associations

2

PTPRC (Causative)

Gene: PTPRC hgnc:9666 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:11145714 SUPPORT Human Clinical

"This is the second description of a clinically relevant CD45 mutation, provides direct evidence for the importance of CD45 in immune function in humans, and suggests that abnormalities in CD45 expression are a possible cause of SCID in humans."

The second independent human case, which is what moved CD45 deficiency from a single observation to an established cause.

PMID:22689986 SUPPORT Human Clinical

"Patient SNP array analysis revealed no change in copy number but loss of heterozygosity for the entire length of chromosome 1 (Chr1), indicating that disease was caused by uniparental disomy (UPD) with isodisomy of the entire maternal Chr1 bearing the mutant CD45 allele."

Documents the uniparental isodisomy route to biallelic loss, and with it the diagnostic trap of an apparently homozygous variant present in one parent only.

PTPRC C77G (Susceptibility variant, not a cause of this disease)

Gene: PTPRC hgnc:9666 relationship_type: SUSCEPTIBILITY

Show evidence (1 reference)

PMID:18312479 SUPPORT Human Clinical

"Two polymorphisms (C77G and A138G), which alter CD45 isoform expression, are associated with autoimmune and infectious diseases."

Establishes that these are isoform-altering susceptibility alleles, which is a different claim from causing severe combined immunodeficiency.

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Medical Actions

2

Allogeneic Hematopoietic Stem Cell Transplantation

Action: allogeneic haematopoietic stem cell transplantation Ontology label: Hematopoietic Cell Transplantation NCIT:C15431

Platform: Cell therapy

The only curative treatment for severe combined immunodeficiency, including CD45 deficiency: donor haematopoiesis supplies leukocytes carrying CD45 and reconstitutes antigen-receptor signalling. Outcome depends heavily on whether the diagnosis was made before infection had accumulated.

Mechanism Target:

Loss of CD45 Surface Expression — Donor-derived haematopoietic cells express CD45, so the lesion is corrected at its origin rather than downstream.

Show evidence (2 references)

PMID:40374985 SUPPORT Human Clinical

"The 2-year overall survival (OS) of the late group was 29.2%, in contrast to the 2-year OS of the early diagnosis group of 71.4%"

Quantifies how strongly outcome depends on the timing of diagnosis. This is a general severe combined immunodeficiency cohort, not a CD45-specific one.

PMID:22689986 SUPPORT Human Clinical

"Nonlymphoid blood cells and other mesoderm- and ectoderm-derived tissues retained UPD of the entire maternal Chr1 in this patient, who had undergone successful bone marrow transplantation."

The only genotype-specific transplant datum in the literature: a molecularly confirmed CD45-deficient patient who was successfully transplanted. It is a single patient reported in passing by a paper about something else, so it establishes feasibility rather than outcome.

Immunoglobulin Replacement Therapy

Action: immunoglobulin replacement therapy Ontology label: Intravenous Immunoglobulin Therapy NCIT:C121331

Platform: Other

Supportive replacement for the progressive hypogammaglobulinaemia, used before and around transplantation.

Target Phenotypes: Decreased circulating immunoglobulin concentration HP:0004313

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Diagnosis

1

Absent surface CD45 on leukocyte immunophenotyping

Because CD45 is carried by every nucleated haematopoietic cell, its absence from the leukocyte surface is directly visible on routine flow cytometry. That makes the confirmatory step for this disease unusually accessible once it is suspected, and it is the one diagnostic finding here that is specific to the genotype rather than shared with severe combined immunodeficiency in general. Molecular confirmation is by PTPRC sequencing.

leukocyte immunophenotyping by flow cytometry NCIT:C113003

Show evidence (2 references)

PMID:11145714 SUPPORT Human Clinical

"We investigated the first SCID patient to be described with minimal cell surface expression of the leukocyte common (CD45) Ag."

Establishes that the diagnosis was made on absent surface CD45, which is what this diagnostic step detects.

PMID:11145714 SUPPORT Human Clinical

"is associated with failure of surface expression of CD45 and SCID"

Links the loss of surface expression to the disease, which is the inference the flow-cytometry result licenses.

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Prevalence

1

Worldwide

Cases In Literature Ultra Rare

Only a handful of unrelated patients have been reported: the index case with a deletion and a splice-site variant, the homozygous six-base-pair deletion case, and the uniparental isodisomy case. No incidence or prevalence estimate exists for this genotype, and none is attempted here. For scale, universal newborn screening in Catalonia gives an incidence of roughly 1 in 46,753 live births for severe combined immunodeficiency of all causes, of which CD45 deficiency is a very small fraction.

Show evidence (1 reference)

PMID:42079620 SUPPORT Human Clinical

"corresponding to an overall incidence of 1:46,753 live births"

Provides the all-cause severe combined immunodeficiency incidence used here only as an upper bound for context, not as an estimate for this disease.

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Animal Models

1

Ptprc (CD45) null mouse

Gene-targeted mouse lacking every CD45 isoform. It reproduces the human immunophenotype in the direction that matters, T cells reduced and B cells preserved or increased, and it is the only source of staged developmental and selection data for this disease, since the human cases are too few for that kind of analysis.

Species

Mouse

Genotype

Ptprc targeted null, all isoforms absent, homozygous

Publication

PMID:8666928

Pathograph links

Arrest of Thymocyte Development recapitulates fidelity: moderate observes: cellular A two-stage developmental block with impaired T-cell-receptor-dependent selection, in the same cell type and at the same checkpoints proposed for the human disease.

Limitations: The mouse is a complete null of every isoform; the human alleles abolish surface expression by different routes and have not been shown to be equivalent nulls. Mouse T lymphopenia is partial, roughly a fivefold reduction in splenic T cells, whereas the human phenotype is described as T-negative severe combined immunodeficiency, so the model is milder than the disease it stands in for.

Readouts

Splenic T cell number

Direction: DECREASED

Interpretation: The peripheral consequence of the thymic block, measured against littermate controls.

Show evidence (1 reference)

PMID:8666928 SUPPORT Model Organism

"The spleens from CD45-null mice contain approximately twice the number of B cells and one fifth the number of T cells found in normal controls."

Quantifies the T-cell reduction, and simultaneously the preserved B-cell compartment.

Thymocyte apoptosis on T-cell receptor crosslinking

Direction: DECREASED

Interpretation: Impaired negative selection. Paired with a preserved response to non-receptor signals, this is what places the lesion in receptor-proximal signalling rather than in the apoptotic machinery itself.

Show evidence (1 reference)

PMID:8666928 SUPPORT Model Organism

"we demonstrate that CD45-null thymocytes are severely impaired in their apoptotic response to cross-linking signals via T cell receptor (TCR) in fetal thymic organ culture. In contrast, apoptosis can be induced normally in CD45-null thymocytes by non-TCR-mediated signals."

The paired positive and negative result that makes this readout interpretable.

Show evidence (1 reference)

PMID:8666928 SUPPORT Model Organism

"We have employed gene targeting to create a strain of transgenic mice that completely lacks expression of all isoforms of CD45."

Establishes the model as a complete null, which is what makes it informative for a loss-of-function disease.

B Cell Signalling Failure Despite Normal B Cell Numbers recapitulates fidelity: moderate observes: cellular B-cell numbers preserved or increased with selective failure of antigen-receptor signalling, matching the human picture of normal B-cell counts and declining immunoglobulins.

Limitations: The mouse readout is proliferation to surface IgM and IgD crosslinking in vitro; the human readout is serum immunoglobulin concentration falling over years. These are different measurements and the correspondence between them is an inference, not an observation.

Show evidence (1 reference)

PMID:8666928 SUPPORT Model Organism

"We conclude that CD45 is not required at any stage during the generation of mature peripheral B cells, however its loss reveals a previously unrecognized role for CD45 in the regulation of certain subpopulations of B cells."

States the model's own conclusion: B-cell generation intact, B-cell regulation not.

{ }

Source YAML

click to show

name: Immunodeficiency 105
creation_date: "2026-09-09T19:45:00Z"
category: Mendelian
synonyms:
- IMD105
- CD45 deficiency
- severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-positive, NK cell-positive
- PTPRC deficiency
description: >-
  Immunodeficiency 105 is a severe combined immunodeficiency caused by biallelic
  loss-of-function variants in PTPRC, which encodes CD45, the leukocyte common
  antigen. CD45 is an abundant receptor-type protein tyrosine phosphatase carried
  by every nucleated haematopoietic cell. Its central job is to dephosphorylate
  the inhibitory C-terminal tyrosine of the Src-family kinases Lck and Fyn, which
  is what licenses them to initiate antigen-receptor signalling. Without CD45,
  Lck stays locked in its autoinhibited conformation, proximal T-cell receptor
  signalling fails, and thymocyte development arrests. The result is a
  T-negative, B-positive severe combined immunodeficiency presenting in the first
  months of life with severe and opportunistic infection.

  Two features distinguish it from most severe combined immunodeficiencies. The
  block is in signalling rather than in receptor assembly or nucleotide
  metabolism, so B cells are produced in normal numbers and are not themselves
  absent; what fails is their function, and serum immunoglobulins therefore fall
  progressively rather than being absent from the outset. And because CD45 is
  carried by all leukocytes, its absence from the cell surface is directly
  visible on routine flow cytometry, which makes the diagnosis unusually
  accessible once it is suspected.

  The disease is defined by a very small number of patients. Curating it is
  therefore an exercise in being explicit about how thin the human evidence is,
  and about which claims come instead from the Ptprc-null mouse.

  No pathophysiology node declares conforms_to. kb/modules/ was searched for a
  T-cell-receptor signalling, Src-family kinase regulation, or thymopoiesis
  module and none exists; the closest entries are pathway modules scoped to
  oncogenic signalling, which is a different claim. The proximal-signalling
  chain here is a reasonable candidate for a future module, since it recurs
  across the T-negative combined immunodeficiencies (ZAP70, LCK, CD3 subunits),
  but factoring one out is not this entry's job.
disease_term:
  preferred_term: immunodeficiency 105
  term:
    id: MONDO:0800104
    label: immunodeficiency 105
parents:
- Severe combined immunodeficiency
- Combined immunodeficiency
inheritance:
- name: Autosomal Recessive
  description: >-
    Biallelic loss of function, by homozygous variant, compound heterozygosity,
    or uniparental isodisomy unmasking a single inherited allele.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:11145714
    reference_title: "A deletion in the gene encoding the CD45 antigen in a patient with SCID."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a homozygous 6-bp deletion in the gene encoding CD45 (PTPRC, gene map locus 1q31-32), which results in a loss of glutamic acid 339 and tyrosine 340 in the first fibronectin type III module of the extracellular domain of CD45, is associated with failure of surface expression of CD45 and SCID"
    explanation: >-
      A homozygous variant in a patient with severe combined immunodeficiency,
      establishing the recessive mode.
pathophysiology:
- name: Loss of CD45 Surface Expression
  biological_scale: MOLECULAR
  description: >-
    Biallelic PTPRC loss-of-function variants abolish CD45 at the leukocyte
    surface. The reported mechanisms differ but converge: a large deletion paired
    with an intervening-sequence 13 donor splice-site change; a homozygous
    in-frame six-base-pair deletion removing Glu339 and Tyr340 from the first
    fibronectin type III module, where modelling places Tyr340 as structurally
    load-bearing so the protein never reaches the membrane; and uniparental
    isodisomy of chromosome 1 making a single maternal allele homozygous.
  molecular_functions:
  - preferred_term: CD45 receptor tyrosine phosphatase activity
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0005001
      label: transmembrane receptor protein tyrosine phosphatase activity
  cell_types:
  - preferred_term: leukocyte
    term:
      id: CL:0000738
      label: leukocyte
  evidence:
  - reference: PMID:10700239
    reference_title: "Mutations in the tyrosine phosphatase CD45 gene in a child with severe combined immunodeficiency disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified a male patient with a deficiency in CD45 due to a large deletion at one allele and a point mutation at the other. The point mutation resulted in the alteration of intervening sequence 13 donor splice site."
    explanation: "The first reported human CD45 deficiency and its two-allele mechanism."
  - reference: PMID:11145714
    reference_title: "A deletion in the gene encoding the CD45 antigen in a patient with SCID."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Molecular modeling suggests that tyrosine 340 is crucial for the structural integrity of CD45 protein."
    explanation: >-
      Explains why an in-frame two-residue deletion in the extracellular domain
      abolishes surface expression rather than merely altering it.
  downstream:
  - target: Failure of Lck Activation
    causal_link_type: DIRECT
    description: >-
      CD45 is the phosphatase that removes the inhibitory C-terminal phosphotyrosine
      from Lck, so its absence leaves Lck autoinhibited.
    evidence:
    - reference: PMID:10700239
      reference_title: "Mutations in the tyrosine phosphatase CD45 gene in a child with severe combined immunodeficiency disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The hematopoietic-specific transmembrane protein tyrosine phosphatase CD45 functions to regulate Src kinases required for T- and B-cell antigen receptor signal transduction."
      explanation: "States the regulatory relationship this edge asserts."
- name: Failure of Lck Activation
  biological_scale: MOLECULAR
  description: >-
    Lck activity is set by the opposing action of CD45, which removes the
    inhibitory C-terminal phosphotyrosine, and Csk, which installs it. With CD45
    gone, that balance collapses towards the closed, autoinhibited conformation
    and Lck cannot phosphorylate the T-cell receptor ITAMs that begin proximal
    signalling.
  biological_processes:
  - preferred_term: protein dephosphorylation
    modifier: DECREASED
    term:
      id: GO:0006470
      label: protein dephosphorylation
  evidence:
  - reference: PMID:32794043
    reference_title: "The role of competing mechanisms on Lck regulation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The balance of phosphorylation at the inhibitory and activating Tyr residues is maintained by a balance between CD45 and Csk and is dependent upon intact intracellular trafficking machinery."
    explanation: >-
      A review establishing that CD45 is one of the two opposing regulators setting
      Lck's phosphorylation state, which is why its loss is not compensated.
  downstream:
  - target: Arrest of Thymocyte Development
    causal_link_type: DIRECT
- name: Arrest of Thymocyte Development
  biological_scale: CELLULAR
  description: >-
    Thymocyte maturation depends on T-cell receptor signals at two checkpoints,
    and both are impaired. In the Ptprc-null mouse the double-negative to
    double-positive transition is roughly halved and the subsequent maturation of
    double-positive cells into single-positive thymocytes falls a further four to
    fivefold, so the deficit compounds. Negative selection is affected too:
    null thymocytes fail to undergo apoptosis in response to T-cell receptor
    crosslinking while responding normally to non-receptor signals, which is what
    localises the lesion to receptor-proximal signalling rather than to the
    apoptotic machinery.
  cell_types:
  - preferred_term: thymocyte
    term:
      id: CL:0000893
      label: thymocyte
  - preferred_term: double-positive thymocyte
    term:
      id: CL:0000809
      label: double-positive, alpha-beta thymocyte
  biological_processes:
  - preferred_term: T cell differentiation
    modifier: DECREASED
    term:
      id: GO:0030217
      label: T cell differentiation
  locations:
  - preferred_term: thymus
    term:
      id: UBERON:0002370
      label: thymus
  evidence:
  - reference: PMID:8666928
    reference_title: "CD45-null transgenic mice reveal a positive regulatory role for CD45 in early thymocyte development, in the selection of CD4+CD8+ thymocytes, and B cell maturation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "T cell development is significantly inhibited in CD45-null animals at two distinct stages."
    explanation: >-
      The two-checkpoint block this node describes, demonstrated in the null mouse.
      No equivalent staged analysis exists in a human patient.
  - reference: PMID:8666928
    reference_title: "CD45-null transgenic mice reveal a positive regulatory role for CD45 in early thymocyte development, in the selection of CD4+CD8+ thymocytes, and B cell maturation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The efficiency of the development of CD4-CD8- thymocytes into CD4+ CD8+ thymocytes is reduced by twofold, subsequently the frequency of successful maturation of the double positive population into mature, single positive thymocytes is reduced by a further four- to fivefold."
    explanation: "Quantifies the deficit at each of the two checkpoints."
  downstream:
  - target: Decreased total T cell count
    causal_link_type: DIRECT
  - target: Decreased mitogen-induced T-cell proliferation
    causal_link_type: DIRECT
  - target: Severe combined immunodeficiency
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: B Cell Signalling Failure Despite Normal B Cell Numbers
  biological_scale: CELLULAR
  description: >-
    B cells are generated in normal or increased numbers, so this is not a
    developmental block in the B lineage. What fails is B-cell receptor
    signalling: CD45 is required to transmit mitogenic signals through surface
    IgM and IgD, while CD40-mediated proliferation is preserved. Clinically this
    is why immunoglobulin concentrations fall progressively with age rather than
    being absent at presentation, and it is the feature that separates this
    disorder from the T-negative B-negative severe combined immunodeficiencies.
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  biological_processes:
  - preferred_term: B cell receptor signaling pathway
    modifier: DECREASED
    term:
      id: GO:0050853
      label: B cell receptor signaling pathway
  evidence:
  - reference: PMID:10700239
    reference_title: "Mutations in the tyrosine phosphatase CD45 gene in a child with severe combined immunodeficiency disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite normal B-lymphocyte numbers, serum immunoglobulin levels decreased with age."
    explanation: >-
      The human observation that grounds this node: numbers preserved, function
      and output not.
  - reference: PMID:8666928
    reference_title: "CD45-null transgenic mice reveal a positive regulatory role for CD45 in early thymocyte development, in the selection of CD4+CD8+ thymocytes, and B cell maturation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "CD45 is absolutely required for the transmission of mitogenic signals via IgM and IgD. By contrast, CD45-null B cells proliferate as well as wild-type cells to CD40-mediated signals."
    explanation: >-
      Localises the B-cell defect to antigen-receptor signalling specifically,
      sparing the CD40 route.
  downstream:
  - target: Decreased circulating immunoglobulin concentration
    causal_link_type: DIRECT
phenotypes:
- category: Immunologic
  name: Severe combined immunodeficiency
  description: >-
    The defining presentation: severe, recurrent and opportunistic infection
    beginning in the first months of life.
  phenotype_term:
    preferred_term: Severe combined immunodeficiency
    term:
      id: HP:0004430
      label: Severe combined immunodeficiency
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:10700239
    reference_title: "Mutations in the tyrosine phosphatase CD45 gene in a child with severe combined immunodeficiency disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient presented at 2 months of age with severe combined immunodeficiency disease."
    explanation: "Presentation and age of onset in the index patient."
- category: Immunologic
  name: Decreased total T cell count
  phenotype_term:
    preferred_term: Decreased total T cell count
    term:
      id: HP:0005403
      label: Decreased total T cell count
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:10700239
    reference_title: "Mutations in the tyrosine phosphatase CD45 gene in a child with severe combined immunodeficiency disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The population of peripheral blood T lymphocytes was greatly diminished and unresponsive to mitogen stimulation."
    explanation: "Records the T lymphopenia that defines the T-negative immunophenotype."
- category: Immunologic
  name: Decreased mitogen-induced T-cell proliferation
  phenotype_term:
    preferred_term: Decreased mitogen-induced T-cell proliferation
    term:
      id: HP:0031381
      label: Decreased mitogen-induced T-cell proliferation
  frequency: VERY_FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:10700239
    reference_title: "Mutations in the tyrosine phosphatase CD45 gene in a child with severe combined immunodeficiency disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The population of peripheral blood T lymphocytes was greatly diminished and unresponsive to mitogen stimulation."
    explanation: >-
      The functional assay result. This sentence carries both the count and the
      proliferation failure; they are recorded as separate phenotypes because a
      normal count with absent proliferation would still be diagnostic.
- category: Immunologic
  name: Decreased circulating immunoglobulin concentration
  description: >-
    Hypogammaglobulinaemia that worsens with age rather than being present from
    birth, reflecting failure of B-cell function rather than absence of B cells.
  phenotype_term:
    preferred_term: Decreased circulating immunoglobulin concentration
    term:
      id: HP:0004313
      label: Decreased circulating immunoglobulin concentration
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:10700239
    reference_title: "Mutations in the tyrosine phosphatase CD45 gene in a child with severe combined immunodeficiency disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "serum immunoglobulin levels decreased with age"
    explanation: "Establishes the progressive rather than congenital character of the hypogammaglobulinaemia."
genetic:
- name: PTPRC
  gene_term:
    preferred_term: PTPRC
    term:
      id: hgnc:9666
      label: PTPRC
  association: Causative
  relationship_type: CAUSATIVE
  notes: >-
    Biallelic loss-of-function variants in PTPRC on chromosome 1q31.3. Reported
    mechanisms are a large deletion in trans with an intervening-sequence 13 donor
    splice-site change, a homozygous in-frame six-base-pair deletion removing
    Glu339 and Tyr340, and uniparental isodisomy of chromosome 1 making a single
    maternal allele homozygous. The last of these is worth remembering as a
    general lesson: the patient looked homozygous for a variant found in only one
    parent.
  evidence:
  - reference: PMID:11145714
    reference_title: "A deletion in the gene encoding the CD45 antigen in a patient with SCID."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is the second description of a clinically relevant CD45 mutation, provides direct evidence for the importance of CD45 in immune function in humans, and suggests that abnormalities in CD45 expression are a possible cause of SCID in humans."
    explanation: >-
      The second independent human case, which is what moved CD45 deficiency from
      a single observation to an established cause.
  - reference: PMID:22689986
    reference_title: "CD45-deficient severe combined immunodeficiency caused by uniparental disomy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patient SNP array analysis revealed no change in copy number but loss of heterozygosity for the entire length of chromosome 1 (Chr1), indicating that disease was caused by uniparental disomy (UPD) with isodisomy of the entire maternal Chr1 bearing the mutant CD45 allele."
    explanation: >-
      Documents the uniparental isodisomy route to biallelic loss, and with it the
      diagnostic trap of an apparently homozygous variant present in one parent only.
- name: PTPRC C77G
  gene_term:
    preferred_term: PTPRC
    term:
      id: hgnc:9666
      label: PTPRC
  association: Susceptibility variant, not a cause of this disease
  relationship_type: SUSCEPTIBILITY
  notes: >-
    Recorded here specifically so it is not mistaken for a cause of this disease.
    C77G is a common isoform-altering polymorphism in PTPRC exon 4 that disrupts
    an exonic splicing silencer and causes aberrant retention of CD45RA on
    activated and memory T cells. It is enriched in autoimmune and infectious
    disease cohorts and alters CD45 isoform expression rather than abolishing the
    protein, so it belongs to a different mechanistic class from the biallelic
    null variants that cause immunodeficiency 105. A literature search on PTPRC
    returns the polymorphism far more often than the deficiency, which is why the
    distinction is worth making explicitly in the entry rather than leaving it to
    the reader.
  evidence:
  - reference: PMID:18312479
    reference_title: "PTPRC (CD45) variation and disease association studied using single nucleotide polymorphism tagging."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two polymorphisms (C77G and A138G), which alter CD45 isoform expression, are associated with autoimmune and infectious diseases."
    explanation: >-
      Establishes that these are isoform-altering susceptibility alleles, which is
      a different claim from causing severe combined immunodeficiency.
animal_models:
- name: Ptprc (CD45) null mouse
  species: Mouse
  genotype: Ptprc targeted null, all isoforms absent, homozygous
  publication: PMID:8666928
  description: >-
    Gene-targeted mouse lacking every CD45 isoform. It reproduces the human
    immunophenotype in the direction that matters, T cells reduced and B cells
    preserved or increased, and it is the only source of staged developmental and
    selection data for this disease, since the human cases are too few for that
    kind of analysis.
  modeled_mechanisms:
  - target: Arrest of Thymocyte Development
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      A two-stage developmental block with impaired T-cell-receptor-dependent
      selection, in the same cell type and at the same checkpoints proposed for
      the human disease.
    limitations: >-
      The mouse is a complete null of every isoform; the human alleles abolish
      surface expression by different routes and have not been shown to be
      equivalent nulls. Mouse T lymphopenia is partial, roughly a fivefold
      reduction in splenic T cells, whereas the human phenotype is described as
      T-negative severe combined immunodeficiency, so the model is milder than
      the disease it stands in for.
    readouts:
    - name: Splenic T cell number
      target: Arrest of Thymocyte Development
      direction: DECREASED
      interpretation: >-
        The peripheral consequence of the thymic block, measured against
        littermate controls.
      evidence:
      - reference: PMID:8666928
        reference_title: "CD45-null transgenic mice reveal a positive regulatory role for CD45 in early thymocyte development, in the selection of CD4+CD8+ thymocytes, and B cell maturation."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "The spleens from CD45-null mice contain approximately twice the number of B cells and one fifth the number of T cells found in normal controls."
        explanation: "Quantifies the T-cell reduction, and simultaneously the preserved B-cell compartment."
    - name: Thymocyte apoptosis on T-cell receptor crosslinking
      target: Arrest of Thymocyte Development
      direction: DECREASED
      interpretation: >-
        Impaired negative selection. Paired with a preserved response to
        non-receptor signals, this is what places the lesion in receptor-proximal
        signalling rather than in the apoptotic machinery itself.
      evidence:
      - reference: PMID:8666928
        reference_title: "CD45-null transgenic mice reveal a positive regulatory role for CD45 in early thymocyte development, in the selection of CD4+CD8+ thymocytes, and B cell maturation."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "we demonstrate that CD45-null thymocytes are severely impaired in their apoptotic response to cross-linking signals via T cell receptor (TCR) in fetal thymic organ culture. In contrast, apoptosis can be induced normally in CD45-null thymocytes by non-TCR-mediated signals."
        explanation: "The paired positive and negative result that makes this readout interpretable."
    evidence:
    - reference: PMID:8666928
      reference_title: "CD45-null transgenic mice reveal a positive regulatory role for CD45 in early thymocyte development, in the selection of CD4+CD8+ thymocytes, and B cell maturation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We have employed gene targeting to create a strain of transgenic mice that completely lacks expression of all isoforms of CD45."
      explanation: "Establishes the model as a complete null, which is what makes it informative for a loss-of-function disease."
  - target: B Cell Signalling Failure Despite Normal B Cell Numbers
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      B-cell numbers preserved or increased with selective failure of
      antigen-receptor signalling, matching the human picture of normal B-cell
      counts and declining immunoglobulins.
    limitations: >-
      The mouse readout is proliferation to surface IgM and IgD crosslinking in
      vitro; the human readout is serum immunoglobulin concentration falling over
      years. These are different measurements and the correspondence between them
      is an inference, not an observation.
    evidence:
    - reference: PMID:8666928
      reference_title: "CD45-null transgenic mice reveal a positive regulatory role for CD45 in early thymocyte development, in the selection of CD4+CD8+ thymocytes, and B cell maturation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We conclude that CD45 is not required at any stage during the generation of mature peripheral B cells, however its loss reveals a previously unrecognized role for CD45 in the regulation of certain subpopulations of B cells."
      explanation: "States the model's own conclusion: B-cell generation intact, B-cell regulation not."
treatments:
- name: Allogeneic Hematopoietic Stem Cell Transplantation
  description: >-
    The only curative treatment for severe combined immunodeficiency, including
    CD45 deficiency: donor haematopoiesis supplies leukocytes carrying CD45 and
    reconstitutes antigen-receptor signalling. Outcome depends heavily on whether
    the diagnosis was made before infection had accumulated.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: allogeneic haematopoietic stem cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_mechanisms:
  - target: Loss of CD45 Surface Expression
    description: >-
      Donor-derived haematopoietic cells express CD45, so the lesion is corrected
      at its origin rather than downstream.
  evidence:
  - reference: PMID:40374985
    reference_title: "Newborn Screening Followed By Early Treatment is Essential to Improve Survival in SCID."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The 2-year overall survival (OS) of the late group was 29.2%, in contrast to the 2-year OS of the early diagnosis group of 71.4%"
    explanation: >-
      Quantifies how strongly outcome depends on the timing of diagnosis. This is a
      general severe combined immunodeficiency cohort, not a CD45-specific one.
  - reference: PMID:22689986
    reference_title: "CD45-deficient severe combined immunodeficiency caused by uniparental disomy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nonlymphoid blood cells and other mesoderm- and ectoderm-derived tissues retained UPD of the entire maternal Chr1 in this patient, who had undergone successful bone marrow transplantation."
    explanation: >-
      The only genotype-specific transplant datum in the literature: a
      molecularly confirmed CD45-deficient patient who was successfully
      transplanted. It is a single patient reported in passing by a paper about
      something else, so it establishes feasibility rather than outcome.
  notes: >-
    No CD45-deficiency-specific transplant series exists, so the survival figures
    above are for severe combined immunodeficiency as a whole. There is, however,
    one genotype-specific datum: the uniparental-disomy patient was successfully
    transplanted, which is recorded in the evidence above. So the recommendation
    rests on that single case plus the general reasoning that a haematopoietic
    defect is correctable by replacement, not on nothing.
- name: Immunoglobulin Replacement Therapy
  description: >-
    Supportive replacement for the progressive hypogammaglobulinaemia, used
    before and around transplantation.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: immunoglobulin replacement therapy
    term:
      id: NCIT:C121331
      label: Intravenous Immunoglobulin Therapy
  target_phenotypes:
  - preferred_term: Decreased circulating immunoglobulin concentration
    term:
      id: HP:0004313
      label: Decreased circulating immunoglobulin concentration
  notes: >-
    Left without evidence deliberately. Immunoglobulin replacement in severe
    combined immunodeficiency is standard supportive care rather than a finding
    reported in the CD45 literature, and no source among the papers cited by this
    entry states it in a form that could be quoted for this genotype.
diagnosis:
- name: Absent surface CD45 on leukocyte immunophenotyping
  description: >-
    Because CD45 is carried by every nucleated haematopoietic cell, its absence
    from the leukocyte surface is directly visible on routine flow cytometry.
    That makes the confirmatory step for this disease unusually accessible once
    it is suspected, and it is the one diagnostic finding here that is specific
    to the genotype rather than shared with severe combined immunodeficiency in
    general. Molecular confirmation is by PTPRC sequencing.
  diagnosis_term:
    preferred_term: leukocyte immunophenotyping by flow cytometry
    term:
      id: NCIT:C113003
      label: Immunological Flow Cytometry
  evidence:
  - reference: PMID:11145714
    reference_title: "A deletion in the gene encoding the CD45 antigen in a patient with SCID."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We investigated the first SCID patient to be described with minimal cell surface expression of the leukocyte common (CD45) Ag."
    explanation: >-
      Establishes that the diagnosis was made on absent surface CD45, which is
      what this diagnostic step detects.
  - reference: PMID:11145714
    reference_title: "A deletion in the gene encoding the CD45 antigen in a patient with SCID."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "is associated with failure of surface expression of CD45 and SCID"
    explanation: >-
      Links the loss of surface expression to the disease, which is the inference
      the flow-cytometry result licenses.
definitions:
- name: Newborn screening by T-cell receptor excision circle quantification
  definition_type: DIAGNOSTIC_CRITERIA
  derivation_basis: ESTABLISHED_CRITERIA
  description: >-
    CD45 deficiency produces T lymphopenia from birth, so it falls within the
    population detectable by universal newborn severe combined immunodeficiency
    screening, which quantifies T-cell receptor excision circles in dried blood
    spots. Confirmation is by flow cytometry, where absent surface CD45 on all
    leukocytes is directly visible and effectively pathognomonic, followed by
    PTPRC sequencing.
  evidence:
  - reference: PMID:42079620
    reference_title: "SCID newborn screening: seven-year performance and outcomes including T-cell lymphopenia in Catalonia (Spain)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Severe combined immunodeficiency (SCID) can be detected at birth through T-cell receptor excision circles (TREC) analysis in dried blood spots."
    explanation: "Establishes the screening modality that would detect this disease presymptomatically."
  notes: >-
    This describes the screening pathway for severe combined immunodeficiency in
    general. No published case of immunodeficiency 105 has been reported as
    detected by newborn screening, so the applicability here is inferred from the
    T-lymphopenic immunophenotype rather than demonstrated.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Only a handful of unrelated patients have been reported: the index case with
    a deletion and a splice-site variant, the homozygous six-base-pair deletion
    case, and the uniparental isodisomy case. No incidence or prevalence estimate
    exists for this genotype, and none is attempted here. For scale, universal
    newborn screening in Catalonia gives an incidence of roughly 1 in 46,753 live
    births for severe combined immunodeficiency of all causes, of which CD45
    deficiency is a very small fraction.
  evidence:
  - reference: PMID:42079620
    reference_title: "SCID newborn screening: seven-year performance and outcomes including T-cell lymphopenia in Catalonia (Spain)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "corresponding to an overall incidence of 1:46,753 live births"
    explanation: >-
      Provides the all-cause severe combined immunodeficiency incidence used here
      only as an upper bound for context, not as an estimate for this disease.
discussions:
- discussion_id: human_thymocyte_staging_unobserved
  kind: KNOWLEDGE_GAP
  prompt: >-
    Does human CD45 deficiency arrest thymocyte development at the same two
    checkpoints identified in the Ptprc-null mouse?
  attaches_to:
  - pathophysiology#Arrest of Thymocyte Development
  rationale: >-
    The staged block, a halved double-negative to double-positive transition
    followed by a four to fivefold failure of single-positive maturation, comes
    entirely from the mouse. The human patients are too few, and were studied by
    peripheral blood immunophenotyping rather than thymic analysis, for the
    staging to have been tested in people. The entry states the mechanism at the
    level the mouse supports and this gap records that the human staging is
    unobserved rather than confirmed.

📚

References & Deep Research

Deep Research

1

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

Evaluations and curation notes (1)

Create: Immunodeficiency 105 (CD45 deficiency) · 2026-09-09T19:34:19Z · View source

New entry for claim #11553 (immunodeficiency 105, MONDO:0800104, PTPRC/CD45 deficiency). Preflight confirmed nothing in kb/ bound hgnc:9666 or described CD45 deficiency; the only prior PTPRC mention was a vitiligo GWAS snippet. Curated from one OpenScientist deep-research report (research/Immunodeficiency_105-deep-research-openscientist.md; 12/12 references resolved, 23/23 quotes verified, term validation needs_review true) plus the primary case reports. No GeneReviews chapter exists for this disease. Pathophysiology is a four-node chain: loss of CD45 surface expression, failure of Lck activation, arrest of thymocyte development, and B-cell signalling failure despite normal B-cell numbers. The human evidence base is three unrelated patients, so the entry is explicit about which claims rest on the Ptprc-null mouse: the two-checkpoint thymic block and the selection defects are model-organism evidence only, and a KNOWLEDGE_GAP discussion records that the human staging is unobserved rather than confirmed. The PTPRC C77G isoform-altering polymorphism is recorded as a separate SUSCEPTIBILITY genetic record precisely so it is not mistaken for a cause, since it dominates the PTPRC literature. The report's ontology suggestions were checked and three were wrong: HP:0410354 offered for reduced T-cell count is Increased sialylated N-glycan level, CL:0000807 offered for CD4/CD8 double-positive thymocyte is DN3 thymocyte, and HP:0005415 offered for T lymphopenia is Decreased total CD8+ T cell proportion. HP:0005403 and CL:0000809 were used instead. Every CURIE in the entry was resolved through OLS at the point of writing. Two claims are left deliberately without evidence, each with a notes line saying why: immunoglobulin replacement is standard supportive care not reported in the CD45 literature, and the newborn-screening definition describes the general SCID pathway since no case of this disease has been reported as screen-detected. Validated with just validate, just validate-terms, just check-entity-refs, just check-causal-targets, just check-enum-values, just check-duplicate-keys and just validate-disorders.

OpenScientist ▸

Immunodeficiency 105 (IMD105 / CD45 Deficiency SCID): Comprehensive Disease Characteristics Report

openscientist-autonomous 10 citations 2026-09-09T19:14:40.968960

Immunodeficiency 105 (IMD105 / CD45 Deficiency SCID): Comprehensive Disease Characteristics Report

Disease: Immunodeficiency 105 · MONDO: MONDO:0800104 · OMIM: #619924 (phenotype), 151460 (gene) · Gene: PTPRC (CD45) · Category: Mendelian (autosomal recessive)

Summary

Immunodeficiency 105 (IMD105) is an ultra-rare autosomal recessive severe combined immunodeficiency (SCID) caused by biallelic loss-of-function mutations in PTPRC, the gene encoding the leukocyte common antigen CD45. CD45 is an abundant, hematopoietic-specific, receptor-type transmembrane protein tyrosine phosphatase (UniProt P08575; EC 3.1.3.48) expressed on all nucleated blood cells. Its principal function is to activate the Src-family kinases Lck and Fyn — by dephosphorylating their inhibitory C-terminal tyrosine — which are indispensable for T-cell-receptor (TCR) and B-cell-receptor (BCR) proximal signaling. When CD45 is absent, Lck remains locked in an inhibited conformation, antigen-receptor signaling collapses, and thymic T-cell development arrests. The clinical result is a T-cell-negative, B-cell-positive, NK-variable (T−B+NK±) SCID that presents in early infancy (~2 months) with severe, recurrent, opportunistic infections and progressive hypogammaglobulinemia despite normal B-cell numbers.

The disease was defined by only a small number of human patients. The first (Kung et al., 2000) carried a large deletion on one PTPRC allele plus an IVS13 splice-site mutation on the other; the second (Tchilian et al., 2001) was homozygous for a 6-bp in-frame deletion removing Glu339/Tyr340 in the first fibronectin type III module of the CD45 extracellular domain, abolishing surface CD45. A Ptprc-null mouse faithfully recapitulates the human immunophenotype (T-low, B-normal-to-high) with a two-stage block in thymic T-cell development, providing strong mechanistic corroboration. Importantly, the common PTPRC C77G isoform-altering polymorphism — associated with autoimmune and infectious-disease susceptibility — is mechanistically and clinically separate from the biallelic null mutations that cause IMD105.

Diagnosis begins with universal newborn screening for T-cell receptor excision circles (TRECs); affected infants are T-lymphopenic with low/absent TRECs. Confirmation relies on lymphocyte immunophenotyping (T−B+NK± with the diagnostically distinctive absence of surface CD45 on all leukocytes), absent mitogen proliferation, and molecular sequencing of PTPRC. The only curative therapy is allogeneic hematopoietic stem cell transplantation (HSCT); untreated disease is fatal in early childhood. Survival is markedly better when disease is detected pre-symptomatically by newborn screening. This report compiles the etiology, phenotype spectrum, molecular mechanism, anatomy, epidemiology, diagnostics, prognosis, treatment, prevention, and model-organism data with supporting ontology terms and primary-literature citations.

Key Findings

Finding 1 — IMD105 is CD45 deficiency SCID caused by biallelic PTPRC mutations

IMD105 (OMIM #619924; MONDO:0800104) is a severe combined immunodeficiency caused by homozygous or compound-heterozygous loss-of-function mutations in PTPRC (CD45; HGNC:9666; NCBI Gene 5788) on chromosome 1q31.3. Inheritance is autosomal recessive. The immunophenotype is T− B+ NK-variable SCID with onset of recurrent infections in early infancy. The disorder sits within the OMIM Autosomal Recessive SCID Phenotypic Series (PS601457).

The first CD45-deficient patient (Kung et al., 2000) presented at 2 months with SCID, carrying a large deletion on one allele and an IVS13 donor splice-site point mutation on the other; peripheral T cells were greatly diminished and mitogen-unresponsive, B-cell numbers were normal, but serum immunoglobulins declined with age. The second patient (Tchilian et al., 2001) was homozygous for a 6-bp deletion causing loss of Glu339 and Tyr340 in the first fibronectin type III module of the extracellular domain, which prevented CD45 surface expression.

"The patient presented at 2 months of age with severe combined immunodeficiency disease." — PMID: 10700239

"Thus, CD45 deficiency in humans results in T- and B-lymphocyte dysfunction." — PMID: 10700239

"a homozygous 6-bp deletion in the gene encoding CD45 (PTPRC, gene map locus 1q31-32), which results in a loss of glutamic acid 339 and tyrosine 340 in the first fibronectin type III module of the extracellular domain of CD45, is associated with failure of surface expression of CD45 and SCID" — PMID: 11145714

Finding 2 — Mechanism: CD45 activates Src-family kinases (Lck/Fyn) required for antigen-receptor signaling

CD45 is an abundant, hematopoietic-specific transmembrane tyrosine phosphatase on all leukocytes. It dephosphorylates the inhibitory C-terminal tyrosine of Lck (Y505) to relieve autoinhibition and permit the active, open conformation. The phospho-balance at Lck's inhibitory versus activating tyrosines is set jointly by CD45 (activating) and Csk (inhibitory). Loss of CD45 therefore leaves Lck hyperphosphorylated and inactive, abrogating TCR- and BCR-proximal signaling and blocking thymocyte and T-cell development. CD45 additionally has a negative role — it can dephosphorylate the TCR itself — and its spatial exclusion from TCR clusters tunes the net signaling outcome (reconstituted-membrane studies).

"The hematopoietic-specific transmembrane protein tyrosine phosphatase CD45 functions to regulate Src kinases required for T- and B-cell antigen receptor signal transduction." — PMID: 10700239

"The balance of phosphorylation at the inhibitory and activating Tyr residues is maintained by a balance between CD45 and Csk" — PMID: 32794043

"CD45 is an abundant transmembrane tyrosine phosphatase, expressed on all leukocytes, and is required for efficient lymphocyte signaling." — PMID: 11145714

Finding 3 — CD45-null mouse recapitulates human T−B+ immunophenotype (model organism)

Ptprc (Cd45) knockout mice (Byth et al., 1996) completely lack all CD45 isoforms and display an immunophenotype closely matching the human disease: ~5-fold reduction in splenic T cells and ~2-fold increase in B cells versus controls. T-cell development is blocked at two stages — a reduced double-negative→double-positive (DN→DP) transition (~2-fold) and a severely impaired DP→single-positive maturation (~4–5-fold). CD45-null thymocytes are severely impaired in TCR-crosslinking-induced apoptosis (negative selection) yet respond normally to non-TCR signals, and show defective superantigen (SEB)-mediated deletion. CD45 is expressed highest on large, cycling, positively-selected DP thymocytes and enhances positive selection. Mouse Ptprc = NCBI Gene 19264, ortholog of human PTPRC (NCBI Gene 5788).

"The spleens from CD45-null mice contain approximately twice the number of B cells and one fifth the number of T cells found in normal controls." — PMID: 8666928

"T cell development is significantly inhibited in CD45-null animals at two distinct stages." — PMID: 8666928

Finding 4 — PTPRC C77G is a distinct isoform-altering susceptibility polymorphism, NOT a cause of IMD105

The C77G polymorphism in PTPRC exon 4/exon A disrupts an exonic splicing silencer (ESS1/ARS motif), preventing hnRNP L/K/E2-mediated repression and causing aberrant retention of CD45RA isoforms on activated/memory T cells (Motta-Mena 2011). C77G occurs at low frequency in healthy individuals but is enriched in multiple sclerosis, systemic sclerosis, autoimmune hepatitis, hepatitis C, and HIV-1 cohorts; it enhances TCR signaling and alters cytokine (IL-2/Jak1) responsiveness and adhesion. A second isoform-altering polymorphism, A138G, is associated with Graves' disease. The MS association is inconsistent across populations (no association in an Australian cohort). This is a partial gain/alteration-of-function susceptibility allele — mechanistically and clinically separate from the biallelic loss-of-function that causes IMD105 SCID. This distinction is essential for correctly curating the disease entry.

"An enhanced frequency of C77G individuals has been reported in cohorts of patients suffering from multiple sclerosis, systemic sclerosis, autoimmune hepatitis, hepatitis C and human immunodeficiency virus (HIV)-1." — PMID: 17903220

"the C77G polymorphism, which correlates with autoimmune disease susceptibility in humans, disrupts exon silencing by preventing the redundant activity of hnRNPs K and E2 to compensate for the weakened function of hnRNP L" — PMID: 21507955

"Two polymorphisms (C77G and A138G), which alter CD45 isoform expression, are associated with autoimmune and infectious diseases." — PMID: 18312479

Finding 5 — Diagnostics: TREC newborn screening detects CD45-deficiency SCID; confirmed by flow cytometry and PTPRC sequencing

SCID, including CD45 deficiency, is detectable at birth by quantifying T-cell receptor excision circles (TRECs) in dried blood spots; CD45-deficient infants are T-lymphopenic and will have low/absent TRECs. In the Catalonia program (2017–2023), among 420,263 newborns, 105 screened positive (0.02%) using the EnLite Neonatal TREC assay (cut-off 20 copies/µL), yielding an overall SCID incidence of 1:46,753 live births. Combined TREC/KREC assays additionally flag B-cell lymphopenia. Confirmatory workup: lymphocyte immunophenotyping by flow cytometry (T−/B+/NK-variable; absent surface CD45 on all leukocytes is diagnostic and distinctive), mitogen proliferation assays (absent), serum immunoglobulins (hypogammaglobulinemia), and molecular confirmation by PTPRC sequencing (single-gene, gene panels, or WES/WGS).

"Severe combined immunodeficiency (SCID) can be detected at birth through T-cell receptor excision circles (TREC) analysis in dried blood spots." — PMID: 42079620

"is associated with failure of surface expression of CD45 and SCID" — PMID: 11145714

Finding 6 — Treatment & prognosis: Allogeneic HSCT is the only curative therapy; early diagnosis markedly improves survival

Allogeneic hematopoietic stem cell transplantation (HSCT/HCT) is the only curative treatment for SCID including CD45 deficiency; without immune reconstitution, death occurs in early childhood. Outcome is strongly time-dependent. In a Brazilian cohort, 2-year overall survival was 71.4% for early-diagnosed (newborn-screened/family history) versus 29.2% for late clinically-diagnosed SCID (p = 0.053). In a 100-patient single-center HSCT cohort, overall survival was 68% (84% excluding first-month mortality), and NBS-identified cases had superior OS (93%) versus clinically-identified cases (p = 0.04); better outcomes were associated with bone-marrow stem-cell source, matched related donors, and use of conditioning. Supportive care before transplant: protective isolation, antimicrobial/antifungal/anti-Pneumocystis prophylaxis, immunoglobulin replacement, avoidance of live vaccines, and use of irradiated/CMV-safe/leukoreduced blood products. Gene therapy is investigational for other SCID subtypes but not established for PTPRC.

"Hematopoietic cell transplantation (HCT) is the only curative treatment currently available in Brazil." — PMID: 40374985

"The 2-year overall survival (OS) of the late group was 29.2%, in contrast to the 2-year OS of the early diagnosis group of 71.4%" — PMID: 40374985

"SCID cases identified by NBS demonstrated superior OS (93%) compared to cases identified by clinical presentation" — PMID: 39900265

Finding 7 — Clinical phenotype spectrum with HPO terms

Per the OMIM #619924 clinical synopsis and the reported patients: onset in early infancy (~2 months) with recurrent/severe infections. Manifestations include recurrent respiratory infections/pneumonia, severe combined immunodeficiency, T-cell lymphopenia (decreased/absent nonfunctional T cells), normal-to-increased B cells (B+), hypogammaglobulinemia that worsens with age, absent lymphocyte proliferative response to mitogens, dermatitis/eczema, lymphadenopathy, and B-cell lymphoma in one patient. NK cells are normal or low. Severity is severe; the course is rapidly life-threatening without HSCT; expressivity is somewhat variable across the few cases. Typical opportunistic organisms include Pneumocystis jirovecii, CMV, and other viral/fungal pathogens.

Phenotype	HPO term	Frequency/notes
Severe combined immunodeficiency	HP:0004430	Defining feature
Reduced T-cell count / T lymphopenia	HP:0410354 / HP:0005415	Core; T−
Pneumonia	HP:0002090	Recurrent
Recurrent respiratory infections	HP:0002205	Frequent
Decreased circulating IgG level	HP:0004315	Progressive with age
Decreased circulating IgA level	HP:0002720	Variable
Abnormal T cell proliferation (mitogen-unresponsive)	HP:0031381	Consistent
Eczema / inflammatory skin abnormality	HP:0000964 / HP:0011123	Reported
Lymphadenopathy	HP:0002716	Reported
B-cell lymphoma	HP:0012191	1 patient

"The population of peripheral blood T lymphocytes was greatly diminished and unresponsive to mitogen stimulation." — PMID: 10700239

"Despite normal B-lymphocyte numbers, serum immunoglobulin levels decreased with age." — PMID: 10700239

Finding 8 — Gene/protein annotation: PTPRC/CD45 (UniProt P08575) with GO terms

Causal gene PTPRC (HGNC:9666; NCBI Gene 5788; Ensembl ENSG00000081237; chromosome 1q31.3; OMIM gene 151460). Protein: Receptor-type tyrosine-protein phosphatase C (CD45, leukocyte common antigen), UniProt P08575, EC 3.1.3.48. It is a single-pass type I transmembrane protein with a large N-glycosylated extracellular domain (residues 26–577; two fibronectin type-III domains at 391–483 and 484–576), a transmembrane helix (578–598), and a large cytoplasmic region (599–1306) containing two tandem PTP domains — a membrane-proximal, catalytically active D1 (653–912) and a membrane-distal, regulatory/inactive D2 (944–1228). Alternative splicing of exons 4/5/6 (A/B/C) generates the CD45RA, RB, RC, and RO isoforms. Disease-causing variants are germline loss-of-function (large deletion + splice IVS13; homozygous in-frame 6-bp deletion Glu339_Tyr340del) with autosomal recessive inheritance and complete penetrance.

Suggested GO annotations: - Molecular Function: transmembrane receptor protein tyrosine phosphatase activity (GO:0005001); protein tyrosine phosphatase activity (GO:0004725); protein tyrosine kinase inhibitor activity (GO:0030292) - Biological Process: T cell receptor signaling pathway (GO:0050852); positive regulation of antigen receptor-mediated signaling pathway (GO:0050857); T cell differentiation (GO:0030217); T cell activation (GO:0042110); B cell receptor signaling pathway (GO:0050853); B cell differentiation (GO:0030183); natural killer cell differentiation (GO:0001779); DN2 thymocyte differentiation (GO:1904155); protein dephosphorylation (GO:0006470) - Cellular Component: external side of plasma membrane (GO:0009897); membrane raft (GO:0045121); plasma membrane (GO:0005886)

"a loss of glutamic acid 339 and tyrosine 340 in the first fibronectin type III module of the extracellular domain of CD45, is associated with failure of surface expression of CD45" — PMID: 11145714

Finding 9 — Anatomical structures, cell types, and subcellular localization (UBERON / CL / GO-CC)

CD45 is expressed on all nucleated hematopoietic cells (leukocyte common antigen). The primary affected system is the immune/hematolymphoid system (UBERON:0002405 immune system; UBERON:0002390 hematopoietic system). Primary organs/tissues: thymus (UBERON:0002370) — the site where T-cell development arrests at the DP→SP transition; bone marrow (UBERON:0002371) — hematopoietic origin; spleen (UBERON:0002106); lymph nodes (UBERON:0000029, clinical lymphadenopathy); peripheral blood (UBERON:0000178). Secondary/complication organs: lung (UBERON:0002048; pneumonia) and skin (UBERON:0002097; dermatitis).

Cell types (Cell Ontology): T cell (CL:0000084), thymocyte (CL:0000893), CD4/CD8 double-positive thymocyte (CL:0000807), mature αβ T cell (CL:0000791), B cell (CL:0000236), natural killer cell (CL:0000623), leukocyte/hematopoietic cell (CL:0000738).

Subcellular localization (GO-CC): plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), membrane raft/microdomain (GO:0045121, GO:0098857) where CD45 regulates raft-associated Src kinases.

"T cell development is significantly inhibited in CD45-null animals at two distinct stages." — PMID: 8666928

"CD45 is an abundant transmembrane tyrosine phosphatase, expressed on all leukocytes" — PMID: 11145714

Finding 10 — Inheritance, epidemiology, and prevention

Inheritance is autosomal recessive with complete penetrance for biallelic loss-of-function; heterozygous carriers are clinically unaffected. IMD105 is ultra-rare — only ~3 unrelated patients are reported in OMIM — so no disease-specific prevalence/incidence exists; it is a molecularly rare subtype within the broader SCID category (overall SCID incidence ~1:46,753 to ~1:58,000 live births by TREC screening). Consanguinity/homozygosity is a risk context (e.g., the homozygous 6-bp deletion). No sex predilection is expected (autosomal). There is no environmental cause; infections are downstream consequences (opportunistic Pneumocystis jirovecii, CMV, other viruses/fungi), not triggers.

Prevention/management: (1) secondary prevention via universal newborn TREC screening for presymptomatic detection; (2) genetic counseling for recurrence risk (25% for carrier couples), carrier testing of relatives, and prenatal/preimplantation genetic testing when the familial PTPRC variants are known; (3) tertiary prevention of complications pre-HSCT — protective isolation, antimicrobial/anti-Pneumocystis prophylaxis, IVIG replacement, only irradiated/CMV-safe/leukoreduced blood products, and strict avoidance of live vaccines (BCG, rotavirus, MMR, VZV, OPV).

"corresponding to an overall incidence of 1:46,753 live births" — PMID: 42079620

"a homozygous 6-bp deletion in the gene encoding CD45" — PMID: 11145714

Section-by-Section Report

1. Disease Information

IMD105 is an autosomal recessive severe combined immunodeficiency of the T−B+NK-variable type caused by complete deficiency of the leukocyte common antigen CD45 (gene PTPRC). It presents in early infancy with life-threatening opportunistic infections. Key identifiers: OMIM #619924 (phenotype), OMIM 151460 (gene); MONDO:0800104; part of OMIM Phenotypic Series PS601457 (autosomal recessive SCID). ICD-10 D81.x (combined immunodeficiencies); ICD-11 4A01.0Y (other combined immunodeficiencies). MeSH: Severe Combined Immunodeficiency (D016511); no CD45-specific MeSH descriptor. Synonyms: CD45 deficiency; SCID due to CD45 deficiency; leukocyte common antigen deficiency; PTPRC deficiency; T-cell-negative, B-cell-positive SCID due to CD45 deficiency. The information is derived from aggregated disease-level resources (OMIM, primary case reports) rather than EHR — the entire literature rests on ~3 individually reported patients plus mouse-model data.

2. Etiology

Causal factor: purely genetic — biallelic loss-of-function mutations in PTPRC (chromosome 1q31.3). Genetic risk factors: the only causal factor is inheriting two damaging PTPRC alleles; consanguinity increases homozygosity risk. There are no environmental risk factors for disease causation. The recurrent opportunistic infections (Pneumocystis jirovecii, CMV, other viruses/fungi) are downstream consequences of immune failure, not triggers. Protective factors: none genetic beyond simply not carrying biallelic null alleles. Gene–environment interactions: not applicable to disease causation; environment determines which opportunistic infections manifest. Note: the PTPRC C77G and A138G polymorphisms are isoform-altering susceptibility alleles for autoimmune/infectious diseases and are not part of IMD105 etiology (Finding 4).

3. Phenotypes

See Finding 7 table. Phenotype onset is neonatal-to-early-infancy (~2 months); severity is severe; progression is progressive and rapidly life-threatening without HSCT. Laboratory abnormalities (T lymphopenia, absent mitogen response, progressive hypogammaglobulinemia, absent surface CD45) are the most consistent features. Quality-of-life impact is profound: without treatment the disease is uniformly fatal in early childhood; with successful HSCT, survivors may achieve durable immune reconstitution. Behavioral phenotypes are not a feature.

4. Genetic / Molecular Information

Causal gene: PTPRC (HGNC:9666; NCBI Gene 5788; Ensembl ENSG00000081237; OMIM 151460). Pathogenic variants reported: (i) large deletion on one allele + IVS13 donor splice-site point mutation (compound heterozygous; Kung 2000); (ii) homozygous in-frame 6-bp deletion p.Glu339_Tyr340del in the first fibronectin type III module (Tchilian 2001). Variant classes: structural (large deletion), splice-site, and in-frame indel — all loss-of-function. Functional consequence: loss of function → absent or non-functional surface CD45. Classification: pathogenic per ACMG (null/LOF in a gene with established LOF mechanism, segregating with recessive disease). Allele frequency: the disease alleles are private/ultra-rare (absent from gnomAD at appreciable frequency). Origin: germline. Modifier genes: none established. Epigenetics/chromosomal abnormalities: none specific to IMD105 (though the causal lesions include a submicroscopic deletion detectable in principle by high-resolution methods).

5. Environmental Information

No environmental, lifestyle, toxicological, or radiation factors cause IMD105. Infectious agents are relevant only as downstream opportunistic complications — Pneumocystis jirovecii, cytomegalovirus, and other viral/fungal/opportunistic pathogens typical of SCID. Live vaccine organisms (e.g., BCG, rotavirus, OPV) pose iatrogenic infection risk and must be avoided.

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation):

Biallelic loss-of-function PTPRC mutation leads to absent or non-functional CD45 protein at the leukocyte surface (demonstrated: absent surface CD45; PMID 11145714).
Absence of CD45 phosphatase activity results in failure to dephosphorylate the inhibitory C-terminal tyrosine (Y505) of the Src-family kinase Lck (and Fyn) (demonstrated biochemically; PMID 32794043).
Persistent inhibitory phosphorylation causes Lck to remain in its closed, autoinhibited conformation, so active Lck is not generated (mechanistic, in vitro/reconstitution evidence).
Loss of active Lck leads to failure of TCR/CD3 (and BCR) proximal phosphorylation and ZAP70 activation — i.e., collapse of antigen-receptor signal transduction (PMID 10700239).
Failed TCR signaling in the thymus results in an arrest of T-cell development at the double-positive → single-positive transition (and reduced DN→DP), impairing both positive and negative selection (demonstrated in mouse; PMID 8666928).
Thymic developmental block leads to profound peripheral T-cell lymphopenia with non-functional, mitogen-unresponsive T cells (T−) (PMID 10700239).
Absent T-cell help, together with intrinsic BCR-signaling impairment, causes progressive hypogammaglobulinemia despite normal/increased B-cell numbers (B+) (PMID 10700239).
The resulting combined immune failure leads to early-infancy recurrent, severe, opportunistic infections and, in one case, lymphoproliferation/B-cell lymphoma — clinical SCID (inferred branch for lymphoma).

Molecular pathways: TCR and BCR signaling (Reactome/KEGG "T cell receptor signaling pathway"); the Csk–CD45–Lck regulatory node. Cellular processes: thymocyte selection (positive/negative selection), lymphocyte development and activation, TCR-induced apoptosis (defective). Protein dysfunction: loss of function of a tandem-domain receptor tyrosine phosphatase; extracellular fibronectin-III lesion abolishes surface expression. Immune system involvement: immunodeficiency (not autoimmunity) is the core. Cell types (CL): double-positive thymocyte (CL:0000807), T cell (CL:0000084), B cell (CL:0000236), NK cell (CL:0000623). GO biological processes: GO:0050852 (TCR signaling), GO:0030217 (T cell differentiation), GO:0006470 (protein dephosphorylation). Upstream = the PTPRC lesion and CD45 loss; downstream = defective thymopoiesis, infections, and antibody failure.

7. Anatomical Structures Affected

See Finding 9. Primary organs: thymus (developmental arrest), bone marrow, spleen, lymph nodes, peripheral blood — the hematolymphoid system. Secondary/complication organs: lung (pneumonia) and skin (dermatitis). Cell/tissue level: all nucleated hematopoietic cells express CD45; the functional lesion falls hardest on thymocytes and T cells. Subcellular: plasma membrane and membrane rafts. Involvement is systemic/bilateral (not lateralized).

8. Temporal Development

Onset: neonatal-to-early-infancy (recurrent infections from ~2 months). Onset pattern: subacute/insidious, becoming acute with severe infection. Progression: rapidly progressive and, without immune reconstitution, fatal in early childhood. Course: chronic and progressive with acute infectious exacerbations. Remission: only treatment-induced, via successful HSCT (durable immune reconstitution). Critical period: the neonatal window before infectious/organ complications — pre-symptomatic detection by newborn screening and early transplant define outcome (Finding 6).

9. Inheritance and Population

Inheritance: autosomal recessive; complete penetrance for biallelic LOF; carriers unaffected. Expressivity: somewhat variable across the few cases (e.g., lymphoma in one). Epidemiology: ultra-rare — only ~3 unrelated reported families; no disease-specific prevalence. Sits within overall SCID incidence of ~1:46,753–1:58,000 live births by TREC screening. Consanguinity is a contributing context (homozygous 6-bp deletion). No founder effect established. Sex ratio ~1:1 (autosomal). Carrier frequency not defined given rarity. No population enrichment documented.

10. Diagnostics

Newborn screening: TREC assay on dried blood spots (low/absent TRECs in T-lymphopenic infants). Confirmatory clinical tests: lymphocyte immunophenotyping by flow cytometry (T−/B+/NK-variable) — absent surface CD45 on all leukocytes is the disease-specific pointer; mitogen proliferation assays (absent); serum immunoglobulins (progressive hypogammaglobulinemia). Genetic testing: PTPRC single-gene sequencing, SCID/IEI gene panels, or WES/WGS; deletion-spanning methods (MLPA/CMA) needed to detect the large-deletion allele. Differential diagnosis: other T−B+ SCID (IL2RG/X-linked, JAK3, IL7R deficiency) — distinguished by preserved surface CD45 in those disorders and by the specific gene defect; also RAG1/2, ADA, and reticular dysgenesis for broader SCID. Screening: newborn TREC screening; cascade carrier testing in families.

11. Outcome / Prognosis

Untreated: uniformly fatal in early childhood. With HSCT: curative, with survival strongly dependent on timing of diagnosis. Reported 2-year OS: 71.4% (early/NBS-diagnosed) vs 29.2% (late clinically-diagnosed) SCID; single-center OS 68% overall (93% for NBS-identified) (Finding 6). Complications: severe opportunistic infections, failure to thrive, and (in one CD45 case) B-cell lymphoma; transplant-related GVHD and graft failure. Prognostic factors: age/timing of diagnosis, pre-transplant infection status, donor matching, stem-cell source, and use of conditioning.

12. Treatment

Definitive: allogeneic HSCT — the only curative therapy (NCIT: Hematopoietic Cell Transplantation, C15431; Allogeneic Bone Marrow Transplantation). Supportive/bridging: immunoglobulin replacement (IVIG; NCIT C509), antimicrobial/antifungal/anti-Pneumocystis prophylaxis (e.g., trimethoprim-sulfamethoxazole), protective isolation, irradiated/CMV-safe/leukoreduced blood products, avoidance of live vaccines. Pharmacogenomics: conditioning agents (e.g., busulfan) are dose-adjusted; not PTPRC-specific. Advanced/experimental: gene therapy is investigational for other SCID subtypes but not established for PTPRC; antibody-based (anti-CD45-saporin) non-genotoxic conditioning is under study in models (PMID 32387109) but not a PTPRC therapy. Treatment strategy is genotype-agnostic beyond confirming diagnosis: proceed rapidly to HSCT with optimal supportive care.

13. Prevention

Primary prevention: not possible (monogenic); genetic counseling and reproductive options (PGT/prenatal testing) reduce recurrence for known-carrier families (25% recurrence risk). Secondary prevention: universal newborn TREC screening for presymptomatic detection — the single most impactful intervention (Findings 5–6). Tertiary prevention: anti-infective prophylaxis, IVIG, isolation, safe blood products, and avoidance of live vaccines to prevent complications before HSCT. Immunization: live vaccines contraindicated; killed vaccines generally ineffective pre-reconstitution. Counseling: genetic counseling and cascade carrier testing.

14. Other Species / Natural Disease

Taxonomy / orthologs: human PTPRC (NCBI Gene 5788); mouse Ptprc (NCBI Gene 19264; NCBI Taxon 10090). CD45 is highly conserved across mammals. Natural disease: no well-characterized spontaneous CD45-deficiency disease is documented in companion animals in OMIA within this investigation; CD45 biology is conserved and disease models are engineered rather than natural. Comparative biology: the mouse knockout closely mirrors the human immunophenotype, supporting strong evolutionary conservation of the CD45→Lck→TCR mechanism (Finding 3). Zoonotic potential: none (genetic disorder).

15. Model Organisms

Mouse (Mus musculus) is the principal model: the CD45/Ptprc-null knockout (Byth 1996) recapitulates T−B+ immunophenotype with a two-stage thymic block, defective negative selection/superantigen deletion, and CD45's role in enhancing positive selection (Finding 3). Model types: germline knockout; transgenic CD45RO-reconstitution lines used to dissect isoform effects. Phenotype recapitulation: high for the immunophenotype and developmental block. Limitations: mouse strain background and the engineered nature of alleles differ from the human private mutations; species differences in isoform usage; the lymphoma predisposition seen in one human patient is not a defining mouse phenotype. Resources: MGI (Ptprc), IMPC/IMSR for allele availability. In vitro reconstitution systems (supported lipid bilayers; PMID 25128530) and cell lines elucidate the CD45/Lck/TCR clustering mechanism.

Mechanistic Model / Interpretation

 Biallelic PTPRC LOF mutation
   (large del + IVS13 splice; or homozygous 6-bp del, Glu339_Tyr340del)
│  leads to
▼
 Absent / non-functional surface CD45 phosphatase
│  results in
▼
 Failure to dephosphorylate Lck inhibitory Y505  ◄── Csk keeps Y505 phosphorylated
│  causes                              (CD45 normally counteracts Csk)
▼
 Lck locked in closed, autoinhibited conformation  → no active Lck
│  leads to
▼
 Collapse of TCR/CD3 (and BCR) proximal signaling (ZAP70 not activated)
│  results in
      ┌─────────┴───────────────────────────┐
      ▼ (thymus)                             ▼ (periphery / B lineage)
 T-cell development arrests at DP→SP    Impaired T-cell help + BCR signaling
 (± reduced DN→DP); defective            → progressive hypogammaglobulinemia
 positive & negative selection             despite NORMAL/INCREASED B cells (B+)
      │                                     │
      ▼  leads to                           ▼
 Profound peripheral T-lymphopenia,    Antibody failure
 mitogen-unresponsive T cells (T−)
      └──────────────┬──────────────────────┘
     ▼  leads to
   Early-infancy severe recurrent opportunistic infections
   (Pneumocystis, CMV, viral/fungal); ± B-cell lymphoma (1 case)
     ▼  fatal in early childhood without
     ────────────────────────────────
     Allogeneic HSCT  → durable immune reconstitution (cure)

CD45 sits at a signaling rheostat: it activates Lck by removing the inhibitory phosphate (the dominant net effect in thymocytes) but can also dephosphorylate the TCR — a negative role blunted by CD45's spatial exclusion from TCR clusters. In complete deficiency the activating role is lost with no compensation, so the net outcome is a hard block in T-cell development. The mouse knockout, three human patients, and biochemical/reconstitution studies converge on the same causal chain, giving unusually high mechanistic confidence for such an ultra-rare disease.

Evidence Base

PMID	Title (abbrev.)	Role in this report
10700239	Mutations in the tyrosine phosphatase CD45 gene in a child with SCID	Founding human case; CD45 regulates Src kinases; T−B+ phenotype, progressive hypogammaglobulinemia
11145714	A deletion in the gene encoding the CD45 antigen in a patient with SCID	Second human case; homozygous 6-bp del; absent surface CD45; locus 1q31-32
8666928	CD45-null transgenic mice…	Mouse knockout recapitulates T−B+ phenotype and two-stage thymic block
32794043	The role of competing mechanisms on Lck regulation	CD45/Csk balance sets Lck activation state
25128530	Phosphatase CD45 both positively and negatively regulates TCR phosphorylation	Dual (activating/inhibitory) CD45 role; spatial exclusion
21507955	Disease-associated polymorphism alters CD45 splicing (hnRNPs)	Mechanism of C77G — distinct from LOF SCID
17903220	Altered CD45 isoform expression in C77G carriers…	C77G = autoimmune/infectious susceptibility, not SCID
18312479	PTPRC (CD45) variation and disease association…	C77G/A138G isoform-altering susceptibility alleles
42079620	SCID newborn screening, Catalonia	TREC screening; incidence 1:46,753
40374985	Newborn screening + early treatment in SCID	HCT only cure; 71.4% vs 29.2% 2-yr OS by timing
39900265	HSCT outcome & NBS impact (single center)	NBS-identified OS 93% vs clinical
32387109	Anti-CD45-saporin conditioning (RAG mice)	Investigational non-genotoxic conditioning (model, not PTPRC therapy)

Supporting mechanistic papers on Lck regulation and TCR clustering (PMIDs 28735895, 33225946, 25127865, 30745330, 25658352, 9052865, 9203971) reinforce the CD45→Lck→TCR axis and thymic selection biology.

Limitations and Knowledge Gaps

Extreme rarity: the human disease rests on only ~3 unrelated patients, so phenotype frequencies, expressivity range, and outcome statistics for PTPRC-specific SCID are imprecise; most prognosis/screening data are extrapolated from the broader SCID category.
No disease-specific epidemiology: prevalence/incidence, carrier frequency, and any founder effects are unknown.
Genotype–phenotype correlation cannot be established with so few alleles; the single lymphoma case may be incidental or mechanistically linked (uncertain).
Therapy: no PTPRC-specific gene/cell therapy exists; HSCT outcome data are not CD45-specific.
Ontology mapping for a few HPO/GO terms should be verified against current ontology releases before database ingestion.
Natural animal disease: no confirmed spontaneous CD45-deficiency disease documented in OMIA within this investigation.

Proposed Follow-up Experiments / Actions

Query OMIM/ClinVar/HGMD directly for any additional PTPRC SCID cases and variants beyond the three founding families to update the variant table and gnomAD allele-frequency checks.
Curate a differential-diagnosis matrix for T−B+ SCID (IL2RG, JAK3, IL7R vs PTPRC), emphasizing the flow-cytometry discriminator of absent surface CD45.
Assemble ontology cross-checks (HPO frequency annotations, GO evidence codes, UBERON/CL IDs) against current ontology versions for database ingestion.
Search GTR/GeneReviews for CD45-specific transplant management protocols and any conditioning-regimen recommendations.
Monitor ClinicalTrials.gov for gene-editing/HSCT trials that could extend to PTPRC SCID, and track anti-CD45-antibody conditioning translation.
Retrieve MGI/IMPC records for all Ptprc alleles to formalize the model-organism annotation (phenotype recapitulation and limitations).

Report compiled from 10 confirmed findings and 26 reviewed papers across a 5-iteration autonomous investigation. Evidence sources: human clinical case reports, mouse knockout studies, in vitro/biochemical reconstitution, and population screening cohorts.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	12
Resolved	12
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	23
Quoted claims found in source	23
Quoted claims not found in source	0
References weighed for topical relevance	12
On topic	7
Off topic	0

All extracted references resolved successfully.

Term Validation

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

Outcome	Count
Terms checked	46
Resolved	45
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	1
Terms whose name was checked	13
Terms named correctly	7
Terms named as a different term	0
Terms whose name is worth a second look	6

Terms whose name is worth a second look

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

HP:0004315 (1 mention) - the report calls it "Decreased circulating IgG level"; HP calls it Decreased circulating IgG concentration, and lists "Decreased circulating IgG level" among its other names
HP:0002720 (1 mention) - the report calls it "Decreased circulating IgA level"; HP calls it Decreased circulating IgA concentration, and lists "Decreased circulating IgA level" among its other names
HP:0031381 (1 mention) - the report calls it "Abnormal T cell proliferation (mitogen-unresponsive)"; HP calls it Decreased mitogen-induced T-cell proliferation, and lists "Reduced lymphocyte proliferation to mitogen" among its other names
GO:0005001 (1 mention) - the report calls it "Molecular Function: transmembrane receptor protein tyrosine phosphatase activity"; GO calls it transmembrane receptor protein tyrosine phosphatase activity**
GO:0050852 (2 mentions) - the report calls it "Biological Process: T cell receptor signaling pathway", "TCR signaling"; GO calls it T cell receptor signaling pathway**, and lists "TCR signaling pathway" among its other names
GO:0009897 (2 mentions) - the report calls it "Cellular Component: external side of plasma membrane"; GO calls it external side of plasma membrane**

Terms named inconsistently

The report gives these identifiers more than one name of its own:

GO:0050852 - called "Biological Process:** T cell receptor signaling pathway", "TCR signaling"

45 of 46 terms resolved to a current term; the rest could not be looked up either way.

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Immunodeficiency 105 (IMD105 / CD45 Deficiency SCID): Comprehensive Disease Characteristics Report

Summary

Key Findings

Finding 1 — IMD105 is CD45 deficiency SCID caused by biallelic PTPRC mutations

Finding 2 — Mechanism: CD45 activates Src-family kinases (Lck/Fyn) required for antigen-receptor signaling

Finding 3 — CD45-null mouse recapitulates human T−B+ immunophenotype (model organism)

Finding 4 — PTPRC C77G is a distinct isoform-altering susceptibility polymorphism, NOT a cause of IMD105

Finding 5 — Diagnostics: TREC newborn screening detects CD45-deficiency SCID; confirmed by flow cytometry and PTPRC sequencing

Finding 6 — Treatment & prognosis: Allogeneic HSCT is the only curative therapy; early diagnosis markedly improves survival

Finding 7 — Clinical phenotype spectrum with HPO terms

Finding 8 — Gene/protein annotation: PTPRC/CD45 (UniProt P08575) with GO terms

Finding 9 — Anatomical structures, cell types, and subcellular localization (UBERON / CL / GO-CC)

Finding 10 — Inheritance, epidemiology, and prevention

Section-by-Section Report

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Mechanistic Model / Interpretation

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Reference Validation

Term Validation

Terms whose name is worth a second look

Terms named inconsistently