Good syndrome is a rare adult-onset combined immunodeficiency occurring with thymoma. The laboratory picture is near-absent peripheral B cells with hypogammaglobulinemia, accompanied by variable T-cell abnormalities including CD4 lymphopenia and an inverted CD4:CD8 ratio. Patients present in middle age, most often with infection: recurrent sinopulmonary infection reflecting the humoral defect, and opportunistic infection with cytomegalovirus, Candida or Pneumocystis reflecting the cellular one. Autoimmune complications are common, pure red cell aplasia and myasthenia gravis among them, so the same patient can present with too little immunity and too much of it at once. The mechanism is genuinely unresolved, and this entry treats it that way rather than picking a story. The central difficulty is that the immunodeficiency frequently does not remit after the thymoma is removed, so the tumour cannot be assumed to sit simply upstream of the B-cell loss. Competing accounts are curated as `mechanistic_hypotheses` rather than as a single chain: an arrest of B-cell development in the bone marrow, autoantibody-mediated suppression of marrow precursors, and a shared underlying lesion of the thymic epithelium that gives rise to both the neoplasm and the immune failure.
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name: Good Syndrome
creation_date: "2026-09-04T00:00:00Z"
category: Complex
description: >-
Good syndrome is a rare adult-onset combined immunodeficiency occurring with
thymoma. The laboratory picture is near-absent peripheral B cells with
hypogammaglobulinemia, accompanied by variable T-cell abnormalities including
CD4 lymphopenia and an inverted CD4:CD8 ratio. Patients present in middle age,
most often with infection: recurrent sinopulmonary infection reflecting the
humoral defect, and opportunistic infection with cytomegalovirus, Candida or
Pneumocystis reflecting the cellular one. Autoimmune complications are common,
pure red cell aplasia and myasthenia gravis among them, so the same patient can
present with too little immunity and too much of it at once.
The mechanism is genuinely unresolved, and this entry treats it that way rather
than picking a story. The central difficulty is that the immunodeficiency
frequently does not remit after the thymoma is removed, so the tumour cannot be
assumed to sit simply upstream of the B-cell loss. Competing accounts are
curated as `mechanistic_hypotheses` rather than as a single chain: an arrest of
B-cell development in the bone marrow, autoantibody-mediated suppression of
marrow precursors, and a shared underlying lesion of the thymic epithelium that
gives rise to both the neoplasm and the immune failure.
notes: >-
Scope, and the relationship to the thymoma entry. `kb/disorders/Thymoma.yaml`
curates the neoplasm. This entry curates the immunodeficiency syndrome that
occurs with it, which is a different claim: most people with thymoma do not
develop Good syndrome, and removing the thymoma usually does not resolve it.
The two entries should be read together and neither subsumes the other.
Evidence discipline. One quotation offered by the deep-research report for this
disease, attributing the phrase about disrupting the balance between
host-defense and self-tolerance to PMID:34113351, could not be verified against
the cached record and is not used anywhere in this entry. Only quotations
verified against the reference cache appear here.
Correction. An earlier version of this entry omitted treatments and stated that
no cached reference carried a quotable statement about immunoglobulin
replacement. That was wrong, and the error was in the search rather than in the
cache: only the two references this entry already cited were checked, not the
repository-wide reference cache, which already held PMID:39180607 because
kb/disorders/Thymoma.yaml cites it. Treatments are now curated from it.
The same mistake, twice more. Two further claims in this entry turned out to be
answerable from references already sitting in this repository's cache, found
the same way as the immunoglobulin one above — by searching the whole cache
rather than the handful of references this entry happened to cite. The first
was the load-bearing observation that the immunodeficiency does not remit after
thymectomy, which was asserted in five places and cited in none. The second was
the decision to omit pure red cell aplasia and myasthenia gravis as phenotypes.
Both are now curated. Searching only what an entry already cites is the failure
mode; it has now produced three separate omissions here.
Phenotype frequencies. An earlier version of this paragraph said the reported
figures live in full text "not in this repository's cache", and a later
version said that was false because the cache "is 324 lines of full_text_xml
and has been since it was committed". Both were wrong, in opposite
directions, and the second was written while reading a locally upgraded copy
rather than the committed one.
What was actually true: `references_cache/PMID_34113351.md` was 43 lines and
`abstract_only` on `main`. The figures were therefore genuinely not quotable
from the committed cache, and the original paragraph was right about that
even though it was later contradicted. The full-text version is now fetched
and committed with the change that depends on it, so the figures are quotable
from the repository rather than from one worktree.
The CD4 lymphopenia (71.3%), inverted CD4:CD8 ratio (82.5%) and absent
peripheral B cell (95.2%) bands are all curated from it. The pure red cell
aplasia and myasthenia gravis figures are not, and that is now an ordinary
open item rather than a sourcing problem.
Absent still means unassessed rather than absent from the disease.
Where the thymectomy evidence came from, and why not from the source that was
suggested. Review of this entry pointed at PMID:38122866, the 2024 prospective
natural-history study, as stating that the immune compartments decline even
after thymectomy. It was fetched and read, and its cached abstract does not say
that; the "even after thymectomy" clause belongs to the deep-research report's
paraphrase, not to the paper. The claim is instead cited from three sources
that do state it, two of them as dissociations rather than bare negatives — a
cohort in which thymoma-associated red cell aplasia remits after thymectomy
while Good syndrome does not, and a single patient in whom ciclosporin
corrected the red cell aplasia and left the hypogammaglobulinemia untouched.
PMID:38122866 is used for what it does establish: a multidecade decline across
three haematopoietic lineages, which is evidence for the marrow hypothesis and
is the first evidence that hypothesis has carried.
disease_term:
preferred_term: Good syndrome
term:
id: MONDO:0015696
label: Good syndrome
synonyms:
- thymoma with immunodeficiency
- immunodeficiency with thymoma
- thymoma with hypogammaglobulinemia
parents:
- Combined Immunodeficiency
classifications:
iuis_category:
classification_value: phenocopy of IEI
notes: >-
IUIS 2022 phenotypic classification of inborn errors of immunity (Tangye et
al., PMID:35748970), Table 10 "Phenocopies of inborn errors of immunity",
second section, "Associated with autoantibodies". The row is "Thymoma with
hypogammaglobulinemia (Good syndrome)", with the presumed pathogenesis given
as autoantibodies to various cytokines and an immunological profile of
increased CD8+ T cells, absent B cells and decreased immunoglobulin. Good
syndrome is the clearest case in the table of why the phenocopy category
exists: the laboratory picture is that of a combined immunodeficiency, the
entry's own parent term, but it is acquired in adult life on the back of a
thymic epithelial tumour rather than inherited. Note that IUIS attributes it
to anticytokine autoantibodies, which is one mechanism among several
proposed; this entry's mechanistic_hypotheses section keeps the thymic
stromal account open alongside it, and the classification does not settle
that question. Distinct from Thymoma, which dismech curates as the neoplasm
and which carries no IUIS assignment.
evidence:
- reference: PMID:35748970
reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
supports: SUPPORT
evidence_source: OTHER
snippet: "Thymoma with hypogammaglobulinemia (Good syndrome) AutoAb to various cytokines"
explanation: >-
The Table 10 row for this disease, naming it by both its descriptive and
eponymous labels and giving its presumed pathogenesis as autoantibodies to
various cytokines, which is what places it among the phenocopies rather
than in the germline combined-immunodeficiency table. Graded OTHER because
the cited source is an expert-committee nosology, not a primary study.
references:
- reference: PMID:34113351
title: "When the Good Syndrome Goes Bad: A Systematic Literature Review."
findings: []
- reference: PMID:36175547
title: Human thymoma-associated mutation of the GTF2I transcription factor impairs thymic epithelial progenitor differentiation in mice.
findings: []
- reference: PMID:39180607
title: "Good syndrome combined with multiple microbial pulmonary infections: case report and review of the literature."
findings: []
mechanistic_hypotheses:
- hypothesis_group_id: gs_thymic_stromal_origin
hypothesis_label: A thymic epithelial lesion causes both the tumour and the immune failure
status: ALTERNATIVE
description: >-
On this account the thymoma is not upstream of the immunodeficiency at all.
A single lesion of the thymic epithelium, plausibly the recurrent GTF2I
mutation, produces the neoplasm and independently disturbs the stromal
environment on which lymphopoiesis and central tolerance depend. The
attraction of this account is that it explains the one observation that
embarrasses the simple causal story, namely that removing the thymoma does
not restore immunity, without needing the defect to be self-perpetuating. The
supporting evidence is a mouse carrying the human mutation, not a study of
Good syndrome patients, so this remains a hypothesis rather than an
established mechanism.
evidence:
- reference: PMID:36175547
reference_title: Human thymoma-associated mutation of the GTF2I transcription factor impairs thymic epithelial progenitor differentiation in mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: INDIRECT
snippet: "Co-dominant expression of wild-type and mutated forms of Gtf2i in the mouse thymic epithelium is associated with aberrant thymic architecture and reduced thymopoietic activity."
explanation: >-
Shows that the thymoma-associated transcription factor mutation is by
itself sufficient to disturb thymic epithelial architecture and output,
which is what this hypothesis requires.
- hypothesis_group_id: gs_marrow_b_cell_arrest
hypothesis_label: The B-cell defect is a bone marrow precursor arrest
status: ALTERNATIVE
description: >-
On this account the block sits in the bone marrow, at or before the pre-B
stage, rather than in the periphery or the thymus. The evidence cited for it
is the reported absence of transitional B cells and loss of unswitched B-cell
subsets in patients, which places the lesion early in development. This
hypothesis accounts naturally for the failure of thymectomy to restore B
cells, since the marrow is untouched by the operation. It does not by itself
explain why the marrow defect should accompany a thymic tumour.
evidence:
- reference: PMID:38122866
reference_title: "Unraveling the Natural History of Good's Syndrome: A Progressive Adult Combined Immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: "We also report a statistically significant, multidecade progressive decline in lymphocytes, platelets, hemoglobin, and red blood cells in our cohort, suggesting gradual bone marrow failure."
explanation: >-
A prospective cohort followed for up to 37 years finds progressive decline
across three haematopoietic lineages, not the lymphoid one alone, and its
authors read that as gradual marrow failure. A defect confined to the
thymus or to the peripheral B-cell pool does not predict falling platelets
and red cells. INDIRECT because the marrow was not assayed for a precursor
arrest: this is the pattern the hypothesis predicts, not the block itself.
notes: >-
The transitional-B-cell finding this hypothesis was originally built on is
still not quotable from any reference cached here, and the evidence item
above is not it. What that item supplies is a different and weaker argument
from the same hypothesis: a multi-lineage decline that a thymus-confined
account does not predict. Curating the transitional-B-cell data remains
outstanding.
- hypothesis_group_id: gs_autoantibody_mediated
hypothesis_label: Autoantibodies against precursors and cytokines drive the cytopenias
status: ALTERNATIVE
description: >-
On this account the immune failure is itself autoimmune: autoantibodies
directed against marrow precursors and against cytokines suppress
haematopoiesis and lymphocyte development. Its appeal is parsimony, since it
uses one process, loss of self-tolerance, to explain both halves of a syndrome
that otherwise needs two, and pure red cell aplasia in these patients is an
established antibody- and T-cell-mediated suppression of erythroid precursors
of exactly this kind. Roughly half of patients have a concurrent autoimmune
disorder, which is the observation this hypothesis leans on.
evidence:
- reference: PMID:34113351
reference_title: "When the Good Syndrome Goes Bad: A Systematic Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: "Type AB was the most common histological subtype of thymoma, and infections as well as concurrent autoimmune disorders were identified in 92.6% and 51.2% patients, respectively."
explanation: >-
Establishes the high frequency of concurrent autoimmunity that this
hypothesis takes as its starting point. INDIRECT because co-occurrence of
autoimmune disease does not establish that autoantibodies cause the
immunodeficiency.
pathophysiology:
- name: Thymic Epithelial Neoplasia
biological_scale: TISSUE
description: >-
A thymic epithelial tumour arises, most often of the mixed type AB
histology. In thymoma generally, a recurrent somatic missense mutation in the
general transcription factor GTF2I is characteristic of some subtypes, and is
one of very few pathognomonic transcription-factor mutations in human
tumours. Whether this lesion is upstream of the immunodeficiency in Good
syndrome specifically, or merely accompanies it, is exactly what is
unresolved.
genes:
- preferred_term: GTF2I
term:
id: hgnc:4659
label: GTF2I
evidence:
- reference: PMID:34113351
reference_title: "When the Good Syndrome Goes Bad: A Systematic Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Type AB was the most common histological subtype of thymoma, and infections as well as concurrent autoimmune disorders were identified in 92.6% and 51.2% patients, respectively."
explanation: >-
Establishes the predominant thymoma histology in a 162-patient systematic
review, and the accompanying infection and autoimmunity frequencies.
downstream:
- target: Disrupted Thymic Epithelial Architecture and Medullary Differentiation
description: >-
The neoplastic epithelium replaces or distorts the normal thymic
microenvironment.
- target: Thymoma
description: >-
The tumour is itself one of the two defining findings of the syndrome.
- name: Disrupted Thymic Epithelial Architecture and Medullary Differentiation
biological_scale: TISSUE
description: >-
The best mechanistic evidence available for this step is not from patients
but from a mouse carrying the human thymoma-associated GTF2I mutation, in
which co-dominant expression with the wild-type allele produces aberrant
thymic architecture and reduced thymopoietic activity, with medullary
differentiation particularly affected. Medullary epithelium is where
AIRE-dependent negative selection happens, which is what makes this step
relevant to the autoimmune half of the syndrome as well as the immunodeficient
half.
cell_types:
- preferred_term: thymic epithelial cell
term:
id: CL:0002293
label: epithelial cell of thymus
evidence:
- reference: PMID:36175547
reference_title: Human thymoma-associated mutation of the GTF2I transcription factor impairs thymic epithelial progenitor differentiation in mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: INDIRECT
snippet: "Co-dominant expression of wild-type and mutated forms of Gtf2i in the mouse thymic epithelium is associated with aberrant thymic architecture and reduced thymopoietic activity."
explanation: >-
Supplies the architectural and thymopoietic consequence of the human
thymoma mutation. INDIRECT because it is a mouse carrying the human allele
and was not studied in Good syndrome patients.
downstream:
- target: Reduced Thymopoietic Output
description: >-
Reduced thymopoiesis follows directly from the disturbed epithelium.
- target: Failed Central Tolerance in the Thymic Medulla
description: >-
Defective medullary selection follows from the same lesion but leads to the
opposite clinical problem.
- target: Peripheral B Cell Depletion
description: >-
One of the competing accounts routes the B-cell defect through the
disturbed thymic microenvironment, though this step is not established in
patients.
- name: Reduced Thymopoietic Output
biological_scale: CELLULAR
description: >-
Reduced production of naive T cells from a disturbed thymus. Patients show
CD4 lymphopenia and an inverted CD4:CD8 ratio, and the laboratory picture is
that of a combined rather than a purely humoral immunodeficiency, which is
what separates this syndrome from common variable immunodeficiency.
cell_types:
- preferred_term: CD4-positive, alpha-beta T cell
term:
id: CL:0000624
label: CD4-positive, alpha-beta T cell
evidence:
- reference: PMID:34113351
reference_title: "When the Good Syndrome Goes Bad: A Systematic Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Laboratory workup showed typical findings of combined immunodeficiency."
explanation: >-
Establishes that the defect is combined rather than purely humoral.
- reference: PMID:36175547
reference_title: Human thymoma-associated mutation of the GTF2I transcription factor impairs thymic epithelial progenitor differentiation in mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: INDIRECT
snippet: "Co-dominant expression of wild-type and mutated forms of Gtf2i in the mouse thymic epithelium is associated with aberrant thymic architecture and reduced thymopoietic activity."
explanation: >-
Supplies the reduced thymopoietic activity this node names, in a mouse
carrying the human thymoma-associated allele.
downstream:
- target: Recurrent infection
description: >-
Impaired cell-mediated immunity permits viral, fungal and opportunistic
infection.
- target: CD4 T-cell lymphopenia
description: >-
Falling thymic output depletes the CD4 compartment preferentially. This
is the measurable form of the cellular defect this node describes; the
opportunistic infections it permits are reached through the Recurrent
infection edge above rather than through this one.
evidence:
- reference: PMID:34113351
reference_title: "When the Good Syndrome Goes Bad: A Systematic Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
as well as low absolute CD4 count in 77 of 108 patients (71.3%)
explanation: >-
Quantifies the CD4 depletion this edge asserts, in the largest
published series.
- target: Inverted CD4:CD8 ratio
description: >-
The same preferential CD4 loss, expressed as the ratio in which it is
usually reported. Drawn as its own edge because the ratio is a separate
measurement from the count, not a restatement of it.
evidence:
- reference: PMID:34888060
reference_title: >-
Good's syndrome presenting with CMV pneumonitis and oesophageal
candidiasis: A case report.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: >-
It is characterized by a combined T‐ and B‐cell immunodeficiency
including hypogammaglobulinaemia, reduced or absent B cells, CD4 T‐cell
lymphopenia leading to decreased CD4:CD8 T‐cell ratio and impaired
T‐cell mitogenic response.
explanation: >-
States the CD4 lymphopenia and the resulting ratio inversion as
characteristic features, which is the claim this edge makes.
- name: Failed Central Tolerance in the Thymic Medulla
biological_scale: CELLULAR
description: >-
A separate consequence of the same disturbed epithelium, and separated from
reduced output because the two lead to opposite clinical problems. Medullary
epithelium is where AIRE-dependent negative selection removes self-reactive
thymocytes, and the mouse data show medullary differentiation is the lineage
particularly affected. Failure here is the proposed origin of the autoimmune
half of the syndrome, which is what makes a patient present with
immunodeficiency and autoimmunity at once.
cell_types:
- preferred_term: thymic epithelial cell
term:
id: CL:0002293
label: epithelial cell of thymus
evidence:
- reference: PMID:36175547
reference_title: Human thymoma-associated mutation of the GTF2I transcription factor impairs thymic epithelial progenitor differentiation in mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: INDIRECT
snippet: "Phenotypic and molecular characterization of the mutant epithelium indicates that medullary differentiation is particularly affected as a result of impaired differentiation"
explanation: >-
Identifies medullary differentiation as the affected lineage, which is the
compartment central tolerance depends on. INDIRECT because negative
selection itself was not assayed and the link to human autoimmunity is
inferred.
downstream:
- target: Concurrent autoimmune disorder
description: >-
Loss of central tolerance is the proposed origin of the autoimmune
phenotype.
- target: Pure red cell aplasia
description: >-
One of the two characteristic named autoimmune manifestations, and the one
whose effector mechanism — antibody- and T-cell-mediated suppression of
erythroid precursors — is best established.
- target: Myasthenia gravis
description: >-
The other characteristic manifestation. Acetylcholine receptor is a
medullary self-antigen, so a failure of medullary negative selection is the
proposed route to it.
- name: Peripheral B Cell Depletion
biological_scale: CELLULAR
description: >-
Near-absent circulating B cells with low IgG, IgA and IgM is the defining
laboratory abnormality. What is not established is where the block sits.
Because the deficiency persists after thymectomy in most patients, an
explanation confined to the thymic microenvironment is insufficient on its
own, and a marrow-level or autoantibody-mediated lesion has to be part of the
account.
cell_types:
- preferred_term: B cell
term:
id: CL:0000236
label: B cell
evidence:
- reference: PMID:34113351
reference_title: "When the Good Syndrome Goes Bad: A Systematic Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Good syndrome is a rare adult-onset immunodeficiency characterized by thymoma and hypogammaglobulinemia."
explanation: >-
Establishes hypogammaglobulinemia as definitional for the syndrome.
- reference: PMID:34888060
reference_title: "Good's syndrome presenting with CMV pneumonitis and oesophageal candidiasis: A case report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Despite thymectomy, the immunodeficiencies persist and lifelong immunoglobulin replacement is necessary to prevent infections."
explanation: >-
States the persistence of the immunodeficiency after thymectomy directly
and in Good syndrome specifically. This is the observation the whole entry
turns on, and it was previously asserted in prose without a citation.
- reference: PMID:34966753
reference_title: "Pure Red Cell Aplasia and Other Haematological Diseases Associated With Thymoma: A Case Series and Systematic Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Forty-four percent of patients were diagnosed with PRCA after thymoma, and 61% achieved remission with thymectomy plus IST; however, Good's syndrome was unaffected."
explanation: >-
The strongest form of the claim, because it is a dissociation rather than a
bare negative: in the same cohort and systematic review, one
thymoma-associated paraneoplastic condition remits after thymectomy while
Good syndrome does not. That rules out a general failure of the operation
and localizes the persistence to this syndrome.
- reference: PMID:38836142
reference_title: "Good's Syndrome With Pure Red Cell Aplasia and Subclinical Myasthenia Gravis: A Case Report and Review of Literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "While thymectomy did not result in the improvement of any paraneoplastic syndromes, cyclosporine A (CsA) treatment successfully improved PRCA; however, hypoglobulinemia was not recovered, and anti-AchR Ab did not disappear by CsA treatment in our case."
explanation: >-
A second dissociation, this time within one patient and against a drug
rather than an operation: ciclosporin corrected the red cell aplasia and
left the hypogammaglobulinemia untouched. The B-cell defect is not simply
the most stubborn of the paraneoplastic manifestations; it fails to respond
to interventions that resolve the others.
downstream:
- target: Hypogammaglobulinemia
description: >-
Loss of the circulating B cell pool removes the source of plasma cells and
so of immunoglobulin.
- target: B lymphocytopenia
description: >-
The depletion is measured directly as absent or near-absent circulating
CD19-positive cells.
- target: Recurrent infection
description: >-
Loss of antibody permits infection by encapsulated sinopulmonary
pathogens.
genetic:
- name: GTF2I
notes: >-
GTF2I is not a germline cause of Good syndrome. It is carried here because a
recurrent somatic missense mutation in this general transcription factor is
characteristic of some thymoma subtypes, and because it is the lesion the
leading mechanistic hypothesis for this syndrome rests on: a mouse expressing
the mutated form alongside wild-type in thymic epithelium develops aberrant
thymic architecture with reduced thymopoiesis. Whether GTF2I-mutant thymomas
are the ones that give rise to Good syndrome has not been tested, and the
entry does not assert it.
That refusal has a visible consequence: because relationship_type is UNKNOWN,
the graph builder suppresses the gene-to-mechanism edge it would otherwise
infer, so GTF2I renders as an isolated node. That is the correct picture and
not a defect to route around. Adding GTF2I as a genes: descriptor on the
Thymic Epithelial Neoplasia node — done, and worth doing, since it makes the
node queryable by gene — does not connect it either, because the suppression
is keyed on this item rather than on the descriptor match. The only way to
draw the edge would be to give this item a contributing relationship_type,
which is the claim the entry declines to make.
gene_term:
preferred_term: GTF2I
term:
id: hgnc:4659
label: GTF2I
relationship_type: UNKNOWN
variant_origin: SOMATIC
evidence:
- reference: PMID:36175547
reference_title: Human thymoma-associated mutation of the GTF2I transcription factor impairs thymic epithelial progenitor differentiation in mice.
supports: SUPPORT
evidence_source: OTHER
snippet: "Thymomas are an exception, with the majority of some subtypes exhibiting a distinct somatically acquired missense mutation in the general transcription factor GTF2I."
explanation: >-
Establishes the somatic GTF2I mutation as characteristic of thymoma
subtypes, which is the basis for including the gene at all.
animal_models:
- name: Gtf2i mutant thymic epithelium mouse
species: Mouse
genotype: Co-dominant expression of wild-type and thymoma-associated mutant Gtf2i in thymic epithelium
publication: PMID:36175547
description: >-
The only experimental system bearing on any of this entry's mechanistic
hypotheses. It carries the human thymoma-associated GTF2I allele in thymic
epithelium and is the sole support for the shared-thymic-lesion account.
modeled_mechanisms:
- target: Disrupted Thymic Epithelial Architecture and Medullary Differentiation
relationship: PARTIALLY_RECAPITULATES
fidelity: MODERATE
model_scale: TISSUE
description: >-
Reproduces the thymic-developmental step: aberrant architecture, reduced
thymopoietic activity, and medullary differentiation particularly affected.
limitations: >-
Graded PARTIALLY_RECAPITULATES because the model addresses thymoma biology
rather than Good syndrome. It was not made or studied as a model of the
immunodeficiency, and it is not reported to develop B-cell depletion or
hypogammaglobulinemia, which are the features that define the human
syndrome. It therefore supports the upstream half of one hypothesis and
says nothing about the half that is actually contested.
evidence:
- reference: PMID:36175547
reference_title: Human thymoma-associated mutation of the GTF2I transcription factor impairs thymic epithelial progenitor differentiation in mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Co-dominant expression of wild-type and mutated forms of Gtf2i in the mouse thymic epithelium is associated with aberrant thymic architecture and reduced thymopoietic activity."
explanation: >-
Supports treating this model as informative for the thymic epithelial
node.
treatments:
- name: Immunoglobulin replacement therapy
description: >-
The cornerstone of management. It replaces the missing antibody rather than
correcting the B-cell defect, so it is lifelong and does not alter the
underlying immunodeficiency. It addresses only the humoral arm; the cellular
defect and the autoimmune complications are managed separately.
therapeutic_modality: PROTEIN_REPLACEMENT
treatment_term:
preferred_term: intravenous immunoglobulin therapy
term:
id: NCIT:C121331
label: Intravenous Immunoglobulin Therapy
target_mechanisms:
- target: Recurrent infection
description: >-
Replacing circulating immunoglobulin reduces the infection burden that
follows from the humoral defect, without acting on the B-cell depletion
upstream of it.
evidence:
- reference: PMID:39180607
reference_title: "Good syndrome combined with multiple microbial pulmonary infections: case report and review of the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "regular IVIG injections can reduce infection rates in GS patients"
explanation: >-
States the benefit of regular immunoglobulin replacement on infection rate
in Good syndrome specifically, from a review of 98 case reports.
- name: Thymectomy
description: >-
Resection of the thymoma. It is performed for oncologic control of the
tumour, and it is curated here with that scope stated because the
immunodeficiency does not follow it: hypogammaglobulinemia and B-cell
depletion persist afterwards, and immunoglobulin replacement remains
lifelong. Recording it as a treatment matters precisely because it is the
intervention a reader would expect to be curative and is not — omitting it
left the entry offering immunoglobulin replacement as though it were the
only thing done for these patients.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: thymectomy
term:
id: NCIT:C29894
label: Thymectomy
target_mechanisms:
- target: Thymic Epithelial Neoplasia
description: >-
Removes the tumour itself. The link stops at this node deliberately: no
edge is drawn to the immunological nodes downstream of it, because the
cited evidence is that removing the tumour does not reverse them.
evidence:
- reference: PMID:34966753
reference_title: "Pure Red Cell Aplasia and Other Haematological Diseases Associated With Thymoma: A Case Series and Systematic Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Forty-four percent of patients were diagnosed with PRCA after thymoma, and 61% achieved remission with thymectomy plus IST; however, Good's syndrome was unaffected."
explanation: >-
Establishes both halves of what this treatment does and does not achieve:
remission of a companion paraneoplastic condition, and no effect on Good
syndrome.
- reference: PMID:34888060
reference_title: "Good's syndrome presenting with CMV pneumonitis and oesophageal candidiasis: A case report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Despite thymectomy, the immunodeficiencies persist and lifelong immunoglobulin replacement is necessary to prevent infections."
explanation: >-
States the persistence of the immunodeficiency after the operation, and
the consequence for management.
- name: Immunosuppressive therapy for the autoimmune complications
description: >-
Directed at the autoimmune arm of the syndrome, not at the immunodeficiency.
Both agents documented in Good syndrome specifically — rituximab and
ciclosporin — corrected the pure red cell aplasia while leaving the
hypogammaglobulinemia untouched, which is the same dissociation the
thymectomy evidence shows. Curated as its own treatment rather than folded
into supportive care because giving an immunosuppressant to a patient who
already has a combined immunodeficiency is a deliberate and uncomfortable
trade, not a routine addition.
therapeutic_modality: MONOCLONAL_ANTIBODY
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: rituximab
term:
id: NCIT:C1702
label: Rituximab
- preferred_term: ciclosporin
term:
id: CHEBI:4031
label: cyclosporin A
target_mechanisms:
- target: Pure red cell aplasia
description: >-
Both documented agents act on the red cell aplasia, restoring erythroid
maturation. No link is drawn to the B-cell or immunoglobulin nodes,
because both sources report that the hypogammaglobulinemia did not
respond.
evidence:
- reference: PMID:27408396
reference_title: "Thymoma with Concomitant Pure Red Cell Aplasia, Good's Syndrome and Myasthenia Gravis Responding to Rituximab."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "He responded to rituximab with restoration of bone marrow erythroid maturation and stabilization of red blood cell counts."
explanation: >-
Documents the rituximab response in a patient carrying Good syndrome,
pure red cell aplasia and myasthenia gravis together.
- reference: PMID:38836142
reference_title: "Good's Syndrome With Pure Red Cell Aplasia and Subclinical Myasthenia Gravis: A Case Report and Review of Literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A review of the literature on simultaneous Good's syndrome with PRCA also suggested the efficacy of CsA on PRCA but not hypoglobulinemia, suggesting the distinct underlying mechanisms between these two paraneoplastic symptoms with thymoma."
explanation: >-
Generalizes the ciclosporin result beyond the single case, and states the
inference this entry draws from it: the two paraneoplastic manifestations
have distinct mechanisms, which is why the treatment link stops at the red
cell aplasia.
diagnosis:
- name: Immunoglobulin monitoring in thymoma patients
description: >-
Because the immunodeficiency can appear at any point in a thymoma patient's
course, and because it is what determines their survival, serial
immunoglobulin measurement in known thymoma is the route to early diagnosis
rather than waiting for the infections to declare themselves.
diagnosis_term:
preferred_term: laboratory procedure
term:
id: NCIT:C25294
label: Laboratory Procedure
results: Low IgG, IgA and IgM in a patient with known thymoma.
evidence:
- reference: PMID:39180607
reference_title: "Good syndrome combined with multiple microbial pulmonary infections: case report and review of the literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Regular immunoglobulin monitoring in thymoma patients is essential for early GS diagnosis."
explanation: >-
States that serial immunoglobulin monitoring in thymoma is what enables
early diagnosis of the syndrome. The quote spans a line wrap in the cached
record; the earlier truncation at "essential for" stopped short of the
clause carrying the claim.
has_subtypes:
- name: Cluster 1
display_name: Cluster 1 (cellular immunity defect infections)
description: >-
The subgroup whose infections are those of a cellular immunity defect. It
carries the worst prognosis of the three: infection related to cellular
immunity defects is itself one of the independent prognostic factors for
survival in the same analysis.
review_notes: >-
These three subgroups are statistical clusters, derived by multiple
correspondence analysis and unsupervised hierarchical clustering over 162
published cases, and not nosological entities. They have no ontology term,
no separate MONDO concept and no genetic basis, so no subtype_term is bound
and none should be manufactured. They are curated as subtypes because the
source treats them as clinically distinct strata with distinct prognosis,
and because the entry's prognostic content is otherwise unqueryable.
evidence:
- reference: PMID:34113351
reference_title: "When the Good Syndrome Goes Bad: A Systematic Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Cluster analysis revealed three clinical subgroups with distinct characteristics and prognosis (cluster 1, infections related to cellular immunity defects; cluster 2, infections related to other immunity defects; cluster 3, infections related to humoral and phagocytic immunity defects)."
explanation: Defines cluster 1 by its infection type.
- reference: PMID:34113351
reference_title: "When the Good Syndrome Goes Bad: A Systematic Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "infections related to cellular immunity defects (OR 3.324, 95% CI 1.100-10.046, p = 0.033)"
explanation: >-
The infection type defining this cluster is independently prognostic,
which is what makes the stratum clinically meaningful rather than
descriptive.
- name: Cluster 2
display_name: Cluster 2 (other immunity defect infections)
description: >-
The subgroup whose infections are attributed to immunity defects other than
the cellular and the humoral/phagocytic patterns that define the other two
clusters.
evidence:
- reference: PMID:34113351
reference_title: "When the Good Syndrome Goes Bad: A Systematic Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Cluster analysis revealed three clinical subgroups with distinct characteristics and prognosis (cluster 1, infections related to cellular immunity defects; cluster 2, infections related to other immunity defects; cluster 3, infections related to humoral and phagocytic immunity defects)."
explanation: Defines cluster 2 by its infection type.
- name: Cluster 3
display_name: Cluster 3 (humoral and phagocytic immunity defect infections)
description: >-
The subgroup whose infections are those of humoral and phagocytic immunity
defects — the pattern the hypogammaglobulinemia predicts most directly.
evidence:
- reference: PMID:34113351
reference_title: "When the Good Syndrome Goes Bad: A Systematic Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Cluster analysis revealed three clinical subgroups with distinct characteristics and prognosis (cluster 1, infections related to cellular immunity defects; cluster 2, infections related to other immunity defects; cluster 3, infections related to humoral and phagocytic immunity defects)."
explanation: Defines cluster 3 by its infection type.
phenotypes:
- category: Immunologic
name: Hypogammaglobulinemia
description: >-
Low IgG, IgA and IgM, with near-absent circulating B cells. This is the
defining laboratory abnormality.
phenotype_term:
preferred_term: Hypogammaglobulinemia
term:
id: HP:0004313
label: Decreased circulating immunoglobulin concentration
frequency: OBLIGATE
evidence:
- reference: PMID:34113351
reference_title: "When the Good Syndrome Goes Bad: A Systematic Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Good syndrome is a rare adult-onset immunodeficiency characterized by thymoma and hypogammaglobulinemia."
explanation: Hypogammaglobulinemia is definitional for the syndrome.
- category: Immunologic
name: B lymphocytopenia
description: >-
Absent or near-absent circulating CD19-positive B cells. This is arguably the
single feature that separates Good syndrome from common variable
immunodeficiency, in which B cells are typically present, and the entry's
description, pathophysiology and every one of its competing hypotheses turn
on it.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: B lymphocytopenia
term:
id: HP:0010976
label: Decreased total B cell count
evidence:
- reference: PMID:34113351
reference_title: "When the Good Syndrome Goes Bad: A Systematic Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Laboratory workup showed typical findings of combined immunodeficiency."
explanation: >-
Supports the laboratory picture of which B cell depletion is the defining
component. The percentage behind the frequency band is quoted in the
evidence item below.
- reference: PMID:34113351
reference_title: "When the Good Syndrome Goes Bad: A Systematic Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Absent or low peripheral B cells were shown in 118 of 124 patients (95.2%)
explanation: >-
Gives the 95.2% figure behind the VERY_FREQUENT band. This is the single
most consistent laboratory finding in Good syndrome, which is why it is
the one the diagnosis leans on.
- category: Immunologic
name: Recurrent infection
description: >-
Infection is present in over nine tenths of patients and spans both arms of
the defect: sinopulmonary infection by encapsulated organisms, and
opportunistic viral and fungal infection.
phenotype_term:
preferred_term: Recurrent infections
term:
id: HP:0002719
label: Recurrent infections
frequency: VERY_FREQUENT
evidence:
- reference: PMID:34113351
reference_title: "When the Good Syndrome Goes Bad: A Systematic Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Type AB was the most common histological subtype of thymoma, and infections as well as concurrent autoimmune disorders were identified in 92.6% and 51.2% patients, respectively."
explanation: Gives the infection frequency in the 162-patient cohort.
sequelae:
- target: Bronchiectasis
description: >-
Repeated sinopulmonary infection over the years that typically precede
diagnosis produces irreversible airway dilatation. Modelled as a sequela
rather than as a separate mechanism because the airway damage is the
accumulated consequence of the infections themselves, not of a distinct
pathway.
evidence:
- reference: PMID:38122866
reference_title: >-
Unraveling the Natural History of Good's Syndrome: A Progressive Adult
Combined Immunodeficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: >-
All presented to our center with recurrent bacterial sinopulmonary
infections, thymoma, hypogammaglobulinemia, and absence of B cells.
explanation: >-
Establishes recurrent bacterial sinopulmonary infection as the universal
presenting feature in the cohort in which five of eight went on to
progressive bronchiectasis. INDIRECT because the quoted sentence
establishes the infections, not the airway damage they cause; the
bronchiectasis figure is reported elsewhere in the same paper and the
causal step between them is an inference.
- category: Immunologic
name: Concurrent autoimmune disorder
description: >-
About half of patients have an autoimmune disorder alongside the
immunodeficiency, pure red cell aplasia and myasthenia gravis being the
characteristic ones.
phenotype_term:
preferred_term: Autoimmunity
term:
id: HP:0002960
label: Autoimmunity
frequency: FREQUENT
evidence:
- reference: PMID:34113351
reference_title: "When the Good Syndrome Goes Bad: A Systematic Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Type AB was the most common histological subtype of thymoma, and infections as well as concurrent autoimmune disorders were identified in 92.6% and 51.2% patients, respectively."
explanation: Gives the autoimmunity frequency in the 162-patient cohort.
- category: Neoplastic
name: Thymoma
description: >-
A thymic epithelial tumour is present by definition, most commonly of the
mixed type AB histology.
phenotype_term:
preferred_term: Thymoma
term:
id: HP:0100522
label: Thymoma
frequency: OBLIGATE
evidence:
- reference: PMID:34113351
reference_title: "When the Good Syndrome Goes Bad: A Systematic Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Good syndrome is a rare adult-onset immunodeficiency characterized by thymoma and hypogammaglobulinemia."
explanation: Thymoma is definitional for the syndrome.
- category: Hematologic
name: Pure red cell aplasia
description: >-
Selective failure of erythroid maturation, presenting as severe anemia. It is
one of the two named autoimmune manifestations that the entry's
"Concurrent autoimmune disorder" phenotype abstracts over, and it is worth
curating separately because it behaves differently from the immunodeficiency
under treatment: it remits with thymectomy plus immunosuppression, and with
ciclosporin, where the hypogammaglobulinemia does not.
phenotype_term:
preferred_term: pure red cell aplasia
term:
id: HP:0012410
label: Pure red cell aplasia
notes: >-
Deliberately carries no frequency band. The one cached source giving a
percentage counts patients with thymoma, not patients with Good syndrome, so
quoting it here would attach a thymoma denominator to a Good syndrome
phenotype. Absent means unassessed, which is the honest state; a
Good-syndrome-specific frequency awaits a full-text-cached cohort.
evidence:
- reference: PMID:38836142
reference_title: "Good's Syndrome With Pure Red Cell Aplasia and Subclinical Myasthenia Gravis: A Case Report and Review of Literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here, we report a rare case of a patient with Good's syndrome with simultaneous pure red cell aplasia (PRCA) and subclinical myasthenia gravis with detectable serum anti-acetylcholine receptor antibody (AChR Ab)."
explanation: >-
Documents both manifestations occurring together in a patient with Good
syndrome, which is what establishes them as manifestations of this
syndrome rather than of thymoma generally.
- reference: PMID:27408396
reference_title: "Thymoma with Concomitant Pure Red Cell Aplasia, Good's Syndrome and Myasthenia Gravis Responding to Rituximab."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "He was diagnosed with PRCA, myasthenia gravis and Good's syndrome."
explanation: A second patient carrying both manifestations alongside the syndrome.
- category: Neurologic
name: Myasthenia gravis
description: >-
Autoimmune neuromuscular transmission failure with detectable
anti-acetylcholine-receptor antibody. The second named autoimmune
manifestation, and the one that separates most cleanly from the
immunodeficiency in its response to treatment: myasthenia gravis remits after
thymectomy at roughly three times the rate of other thymoma-associated
autoimmune disease, while the Good syndrome immunodeficiency does not remit
at all.
phenotype_term:
preferred_term: myasthenia gravis
term:
id: MONDO:0009688
label: myasthenia gravis
notes: >-
No frequency band, for the same reason as pure red cell aplasia above.
evidence:
- reference: PMID:38836142
reference_title: "Good's Syndrome With Pure Red Cell Aplasia and Subclinical Myasthenia Gravis: A Case Report and Review of Literature."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here, we report a rare case of a patient with Good's syndrome with simultaneous pure red cell aplasia (PRCA) and subclinical myasthenia gravis with detectable serum anti-acetylcholine receptor antibody (AChR Ab)."
explanation: >-
Documents myasthenia gravis, serologically confirmed, in a patient with
Good syndrome.
- reference: PMID:34966753
reference_title: "Pure Red Cell Aplasia and Other Haematological Diseases Associated With Thymoma: A Case Series and Systematic Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: "Patients with MG had a significantly higher remission rate after thymectomy (50 vs. 17%; p = 0.0378) as compared to those with other autoimmune diseases."
explanation: >-
Quantifies the differential response to thymectomy that separates this
manifestation from the immunodeficiency. INDIRECT because the comparison
is across thymoma-associated autoimmune disease generally rather than
within Good syndrome.
- name: CD4 T-cell lymphopenia
category: Immunologic
description: >-
The cellular half of the defect. Good syndrome is a *combined*
immunodeficiency and the entry previously curated only its humoral arm —
hypogammaglobulinemia and B-cell depletion — leaving the T-cell deficit as
prose. CD4 T cells are depleted while CD8 cells are relatively spared, and
T-cell mitogenic responses are impaired. This is the arm that carries the
opportunistic-infection risk, and it is why immunoglobulin replacement
controls sinopulmonary infection without protecting against viral and
fungal disease.
frequency: FREQUENT
phenotype_term:
preferred_term: CD4 T-cell lymphopenia
term:
id: HP:5210418
label: Decreased total CD4+ T cell count
evidence:
- reference: PMID:34113351
reference_title: "When the Good Syndrome Goes Bad: A Systematic Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
as well as low absolute CD4 count in 77 of 108 patients (71.3%)
explanation: >-
Gives the 71.3% figure behind the FREQUENT band, from the largest
published series.
- reference: PMID:34888060
reference_title: >-
Good's syndrome presenting with CMV pneumonitis and oesophageal
candidiasis: A case report.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: >-
It is characterized by a combined T‐ and B‐cell immunodeficiency including
hypogammaglobulinaemia, reduced or absent B cells, CD4 T‐cell lymphopenia
leading to decreased CD4:CD8 T‐cell ratio and impaired T‐cell mitogenic
response.
explanation: >-
Names CD4 T-cell lymphopenia as a defining component of the disease.
Graded BACKGROUND because the sentence is a case report restating the
established definition rather than reporting its own measurement.
- reference: PMID:38122866
reference_title: >-
Unraveling the Natural History of Good's Syndrome: A Progressive Adult
Combined Immunodeficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The most notable clinical feature was opportunistic infections and in
vitro evidence of cellular immune deficiency, which resulted in the death
of 2 individuals.
explanation: >-
Ties the cellular deficit to its clinical consequence and its lethality in
a longitudinal cohort, which is why this arm is curated separately from
the humoral one rather than folded into it.
- name: Inverted CD4:CD8 ratio
category: Immunologic
description: >-
The consequence of CD4 depletion with relative CD8 sparing, and the form in
which the T-cell defect is usually reported. Curated separately from the CD4
count because the two are distinct measurements: a ratio can invert through
CD8 expansion as well as CD4 loss, and the same cited sentence reports both
independently.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Inverted CD4:CD8 ratio
term:
id: HP:0033222
label: Inverted CD4:CD8 ratio
evidence:
- reference: PMID:34113351
reference_title: "When the Good Syndrome Goes Bad: A Systematic Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Of 114 patients, 94 (82.5%) had an inverted CD4/8 ratio.
explanation: >-
Gives the 82.5% figure behind the VERY_FREQUENT band, and shows the ratio
inversion is commoner than the CD4 lymphopenia it is usually attributed
to.
- reference: PMID:34888060
reference_title: >-
Good's syndrome presenting with CMV pneumonitis and oesophageal
candidiasis: A case report.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: >-
It is characterized by a combined T‐ and B‐cell immunodeficiency including
hypogammaglobulinaemia, reduced or absent B cells, CD4 T‐cell lymphopenia
leading to decreased CD4:CD8 T‐cell ratio and impaired T‐cell mitogenic
response.
explanation: >-
States that the CD4 lymphopenia leads to a decreased CD4:CD8 ratio, which
is this record's claim. BACKGROUND for the same reason as above.
- name: Bronchiectasis
category: Respiratory
description: >-
Progressive bronchiectasis develops as structural damage accumulates from
recurrent sinopulmonary infection. It is the end-organ cost of the years
that typically pass before diagnosis — median age at diagnosis in the
longitudinal cohort was 57 — and it persists under immunoglobulin
replacement, which reduces infection frequency without reversing airway
damage already done.
phenotype_term:
preferred_term: Bronchiectasis
term:
id: HP:0002110
label: Bronchiectasis
clinical_course: PROGRESSIVE
evidence:
- reference: PMID:38122866
reference_title: >-
Unraveling the Natural History of Good's Syndrome: A Progressive Adult
Combined Immunodeficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
5 had progressive bronchiectasis and persistent splenomegaly
explanation: >-
Five of the eight patients followed longitudinally. No frequency band is
asserted from this: eight patients at a single referral centre is a
denominator too small and too selected to carry one.
prevalence:
- population: Worldwide, published cases 2010-2020
measure_type: CASES_IN_LITERATURE
prevalence_class: RARE
notes: >-
No population rate has been reported for Good syndrome; the source is a
systematic review that assembled 162 patients from the entire literature of
a decade, which is a case count and not a denominator-based estimate. The
RARE class is the source's own qualitative statement, not a numeric band
inferred from the case count.
evidence:
- reference: PMID:34113351
reference_title: "When the Good Syndrome Goes Bad: A Systematic Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Good syndrome is a rare adult-onset immunodeficiency characterized by thymoma and hypogammaglobulinemia."
explanation: The source's own qualitative rarity statement.
- reference: PMID:34113351
reference_title: "When the Good Syndrome Goes Bad: A Systematic Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Of 162 patients included in the current study, the median age at diagnosis was 58 years and 51% were male."
explanation: >-
Gives the case count assembled by the systematic review, which is what the
CASES_IN_LITERATURE measure records.
progression:
- phase: Adult onset with infection-driven mortality
notes: >-
Median age at diagnosis is in the late fifties and the sexes are affected
about equally. Ten-year overall survival is a little over half, and what
determines it is infection rather than the thymoma. Thymoma status,
infections related to cellular immunity defects, and sinopulmonary, central
nervous system and bloodstream infections were each independently prognostic
in the largest systematic review.
evidence:
- reference: PMID:34113351
reference_title: "When the Good Syndrome Goes Bad: A Systematic Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Of 162 patients included in the current study, the median age at diagnosis was 58 years and 51% were male."
explanation: Gives age at diagnosis and sex distribution.
- reference: PMID:34113351
reference_title: "When the Good Syndrome Goes Bad: A Systematic Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The 10-year overall survival was 53.7%."
explanation: Gives the survival figure for the cohort.
discussions:
- discussion_id: good_syndrome_thymectomy_does_not_remit
kind: KNOWLEDGE_GAP
prompt: >-
Why does removing the thymoma usually fail to restore B cells and
immunoglobulin, and what would distinguish the competing explanations?
rationale: >-
This is the observation that keeps the mechanism open, and every candidate
account is built to accommodate it. If the thymoma were simply upstream of
the immunodeficiency, thymectomy should be curative and it is not. Three
accounts survive that constraint and are curated as separate hypothesis
groups: a shared thymic epithelial lesion producing tumour and immune failure
in parallel, a bone marrow precursor arrest that surgery cannot reach, and
autoantibody-mediated suppression that persists after the tumour is gone.
They are not mutually exclusive. What would separate them is evidence nobody
has assembled: marrow B-cell precursor phenotyping in patients before and
after thymectomy, paired with autoantibody screening against precursors and
cytokines, and GTF2I genotyping of the same patients. Until that exists this
entry declines to name a canonical mechanism, and the absence of a CANONICAL
hypothesis group here is deliberate rather than an omission.
attaches_to:
- pathophysiology#Peripheral B Cell Depletion
- mechanistic_hypotheses#gs_thymic_stromal_origin
- mechanistic_hypotheses#gs_marrow_b_cell_arrest
- mechanistic_hypotheses#gs_autoantibody_mediated
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.
Record notes
Scope, and the relationship to the thymoma entry. `kb/disorders/Thymoma.yaml` curates the neoplasm. This entry curates the immunodeficiency syndrome that occurs with it, which is a different claim: most people with thymoma do not develop Good syndrome, and removing the thymoma usually does not resolve it. The two entries should be read together and neither subsumes the other. Evidence discipline. One quotation offered by the deep-research report for this disease, attributing the phrase about disrupting the balance between host-defense and self-tolerance to PMID:34113351, could not be verified against the cached record and is not used anywhere in this entry. Only quotations verified against the reference cache appear here. Correction. An earlier version of this entry omitted treatments and stated that no cached reference carried a quotable statement about immunoglobulin replacement. That was wrong, and the error was in the search rather than in the cache: only the two references this entry already cited were checked, not the repository-wide reference cache, which already held PMID:39180607 because kb/disorders/Thymoma.yaml cites it. Treatments are now curated from it. The same mistake, twice more. Two further claims in this entry turned out to be answerable from references already sitting in this repository's cache, found the same way as the immunoglobulin one above — by searching the whole cache rather than the handful of references this entry happened to cite. The first was the load-bearing observation that the immunodeficiency does not remit after thymectomy, which was asserted in five places and cited in none. The second was the decision to omit pure red cell aplasia and myasthenia gravis as phenotypes. Both are now curated. Searching only what an entry already cites is the failure mode; it has now produced three separate omissions here. Phenotype frequencies. An earlier version of this paragraph said the reported figures live in full text "not in this repository's cache", and a later version said that was false because the cache "is 324 lines of full_text_xml and has been since it was committed". Both were wrong, in opposite directions, and the second was written while reading a locally upgraded copy rather than the committed one. What was actually true: `references_cache/PMID_34113351.md` was 43 lines and `abstract_only` on `main`. The figures were therefore genuinely not quotable from the committed cache, and the original paragraph was right about that even though it was later contradicted. The full-text version is now fetched and committed with the change that depends on it, so the figures are quotable from the repository rather than from one worktree. The CD4 lymphopenia (71.3%), inverted CD4:CD8 ratio (82.5%) and absent peripheral B cell (95.2%) bands are all curated from it. The pure red cell aplasia and myasthenia gravis figures are not, and that is now an ordinary open item rather than a sourcing problem. Absent still means unassessed rather than absent from the disease. Where the thymectomy evidence came from, and why not from the source that was suggested. Review of this entry pointed at PMID:38122866, the 2024 prospective natural-history study, as stating that the immune compartments decline even after thymectomy. It was fetched and read, and its cached abstract does not say that; the "even after thymectomy" clause belongs to the deep-research report's paraphrase, not to the paper. The claim is instead cited from three sources that do state it, two of them as dissociations rather than bare negatives — a cohort in which thymoma-associated red cell aplasia remits after thymectomy while Good syndrome does not, and a single patient in whom ciclosporin corrected the red cell aplasia and left the hypogammaglobulinemia untouched. PMID:38122866 is used for what it does establish: a multidecade decline across three haematopoietic lineages, which is evidence for the marrow hypothesis and is the first evidence that hypothesis has carried.
Bind the specific thymectomy term; treat the autoimmune arm · 2026-09-04T22:21:56Z · View source
Both IMPORTANT items from the third review round on PR #10923. Both were right and both drew on material already in the repository. 1. Thymectomy was bound to NCIT:C15329 (Surgical Procedure) when NCIT:C29894 (Thymectomy) exists, is already in cache/ncit/terms.csv and the treatmentactionterm enum cache, and is the binding five sibling entries already use — Thymoma, Thymic_Carcinoma, Thymus_Neoplasm, Myasthenia_Gravis and Adult-Onset_Myasthenia_Gravis. The deep-research report offered both the generic term and a thymectomy-specific one, and the generic half is what I took. Rebound; it validates offline against the existing cache with no new rows. 2. The entry gained pure red cell aplasia and myasthenia gravis as phenotypes in the previous round and then offered no treatment for either. An Immunosuppressive therapy treatment is added, carrying both agents documented in Good syndrome specifically: rituximab from PMID:27408396 and ciclosporin from PMID:38836142, the second of which also generalizes beyond its own case. Its target_mechanisms link stops at pure red cell aplasia and deliberately does not reach the B-cell or immunoglobulin nodes, because both sources report the hypogammaglobulinemia did not respond. That is the same dissociation the thymectomy evidence carries, from a second class of intervention, and the treatment description says so. It is curated as its own treatment rather than folded into supportive care because giving an immunosuppressant to a patient with an established combined immunodeficiency is a deliberate trade rather than a routine addition. The review's diagnosis of the pattern is correct and this is its third instance: PMID:27408396 was cached by this PR, cited for the phenotype from one sentence of its abstract, and the very next sentence — which is also the paper's title — went unread. The entry's notes already name this failure mode. One error caught by validation: CHEBI:4031's canonical label is 'cyclosporin A', not 'ciclosporin'. preferred_term keeps the INN spelling; the bound label matches the ontology. Validation: just validate passes with 37/37 snippets verified, up from 35/35; validate-terms, check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values, check-snippet-grading, check-title-snippets and check-snippet-length all clean; cache diff empty. Pathograph: 17 nodes, 16 edges, 0 orphan targets, one component apart from the deliberately isolated GTF2I node. Not taken, as the review agreed: antimicrobial prophylaxis (PMID:29878906 is not cached) and canine Good syndrome (no PMID exists for it).
Cite the thymectomy-failure claim; add thymectomy, PRCA and myasthenia gravis · 2026-09-04T21:43:18Z · View source
Addresses all four blocking items from the second review round on PR #10923. 1. The thymectomy-failure observation. It was asserted in five places — the description, two mechanistic_hypotheses descriptions, the Peripheral B Cell Depletion node, and the discussion rationale that explains why no hypothesis group is CANONICAL — and cited nowhere. It is now cited three times on that node. The review pointed at PMID:38122866 for it. That reference was fetched and read, and its cached abstract does not state it: the 'even after thymectomy' clause belongs to the deep-research report's paraphrase, not to the paper. Searching the repository-wide cache instead turned up three references that do state it, two as dissociations rather than bare negatives — PMID:34966753, a cohort plus systematic review in which thymoma-associated pure red cell aplasia remits after thymectomy while Good syndrome is unaffected, and PMID:38836142, one patient in whom ciclosporin corrected the red cell aplasia and left the hypogammaglobulinemia untouched. A dissociation is the stronger evidence because it rules out a general failure of the intervention. PMID:34888060 supplies the plain statement. PMID:38122866 is used for what it does establish, which the entry needed more: a statistically significant multidecade decline across lymphocytes, platelets, haemoglobin and red cells that its authors read as gradual marrow failure. That is the first evidence item the gs_marrow_b_cell_arrest hypothesis has ever carried. Its notes now say precisely what that item does and does not supply — it is not the transitional-B-cell finding the hypothesis was originally built on, which remains unquotable from anything cached here. 2. Thymectomy as a treatment. Added with SURGERY modality, scoped in its description to oncologic control, and with a target_mechanisms link that stops at Thymic Epithelial Neoplasia. No edge is drawn to the immunological nodes downstream, because the evidence is that removing the tumour does not reverse them. 3. Pure red cell aplasia (HP:0012410) and myasthenia gravis (MONDO:0009688), both wired off the central-tolerance node. The review's diagnosis of the earlier omission was right: the objection was to asserting an unquotable frequency, and that argues for omitting the band, not the phenotype — which is exactly what the entry already did for B lymphocytopenia. Both are curated with no frequency and a note saying why. 4. The diagnosis snippet stopped at 'essential for', one clause short of 'early GS diagnosis', which is the claim it was cited for. The truncation was working around a line wrap in the cached record; the validator normalizes the wrap, so the full sentence verifies. Suggestions taken: evidence_source on the genetic GTF2I item regraded HUMAN_CLINICAL to OTHER, since the quoted sentence is background tumour genetics inside a mouse study rather than that study's data; GTF2I added as a genes: descriptor on the Thymic Epithelial Neoplasia node. Suggestion taken but ineffective, and recorded as such: adding that descriptor does not connect the floating GTF2I node. src/dismech/graph.py suppresses the inferred gene-to-mechanism edge when relationship_type is UNKNOWN, and the suppression is keyed on the genetic item rather than on the descriptor match. The isolation is the correct picture — connecting it would mean giving the item a contributing relationship_type, which is the causal claim this entry declines to make. The genetic notes now say this. Declined again: canine Good syndrome. The research report cites a PMC identifier and a JAVMA abstract URL, and just fetch-reference has no source for a bare PMC id. Nothing quotable is reachable, so the model is not added. Entry notes record that all three of this entry's omissions — immunoglobulin replacement, the thymectomy claim, and the two autoimmune phenotypes — came from the same failure: searching only the references the entry already cited rather than the whole reference cache. Validation: just validate passes with 35/35 snippets verified, up from 25/25; validate-terms, check-duplicate-keys, check-entity-refs, check-causal-targets, check-enum-values, check-qualifier-terms, check-title-snippets, check-snippet-length and check-snippet-grading all clean; cache diff empty. Pathograph rebuilt: 16 nodes, 15 edges, 0 orphan targets, GTF2I isolated by design and everything else in one component.
Create: Good Syndrome (MONDO:0015696) · 2026-09-04T13:08:43Z · View source
New entry for Good syndrome, the adult-onset combined immunodeficiency occurring with thymoma, bound to MONDO:0015696 and curated as a DISEASE. The central curation decision was not to assert a mechanism. Good syndrome's pathophysiology is genuinely unresolved, and the observation that forces this is that the immunodeficiency usually does not remit after thymectomy, so the thymoma cannot be assumed to sit upstream of the B-cell loss. Rather than picking one story and writing it as a causal chain, three competing accounts are curated as separate mechanistic_hypotheses groups, all with status ALTERNATIVE: a shared thymic epithelial lesion producing the tumour and the immune failure in parallel, a bone marrow B-cell precursor arrest that surgery cannot reach, and autoantibody-mediated suppression of precursors and cytokines. The absence of a CANONICAL group is deliberate and is stated in the KNOWLEDGE_GAP discussion, which also sets out what evidence would separate the three: marrow B-cell precursor phenotyping before and after thymectomy, paired autoantibody screening, and GTF2I genotyping of the same patients. The pathophysiology chain is kept to steps that are actually supported, and the two branches, humoral and cellular, both feed the infection node so the combined nature of the defect is visible in the graph rather than only in prose. Evidence discipline, and the reason it mattered here. The deep-research report's reference validation flagged one quoted claim as not found in its cited source: the phrase about disrupting the balance between host-defense and self-tolerance, attributed to PMID:34113351. That quote is not used anywhere in this entry, and the entry's notes record that it was rejected. This is the first of the five reports in this session with a failing quote, and it is exactly the case the skill guidance describes, where a clean confabulation_rate says nothing about quote fidelity. The report resolved 28/28 references but 1 of 2 quotes failed, so needs_review would be true. Mouse evidence is graded MODEL_ORGANISM with directness INDIRECT. The GTF2I mouse carries the human thymoma-associated mutation but was not studied in Good syndrome patients, and the entry says so in the explanation rather than letting the grade carry it silently. One hypothesis, the marrow precursor arrest, is recorded with no evidence item at all, and its notes say why: no cached reference in this entry carries a quotable statement of the transitional-B-cell finding that the account rests on. Recording the hypothesis without evidence is more honest than attaching a quote that does not say what it would be cited for, and curating that evidence is the obvious next step for the entry. Prognosis is curated from the 162-patient systematic review, including the finding that infection type and site rather than the thymoma are what determine survival. Not done: no treatments section. Immunoglobulin replacement and thymectomy are both standard, but no cached reference in this entry carries a quotable statement about either, and a treatment entry asserting them from the research narrative alone would not survive snippet verification. No relationship modelled to kb/disorders/Thymoma.yaml beyond a notes cross-reference explaining that the two entries make different claims and neither subsumes the other. Validation: just validate, just validate-terms, just count-verified-snippets (14/14 verified), just check-duplicate-keys, just check-entity-refs, just check-causal-targets, just check-qualifier-terms, just check-enum-values and just check-stubs all pass.
Overview. Good syndrome (GS) — also called thymoma-associated immunodeficiency or thymoma with immunodeficiency — is a rare, adult-onset combined (B-cell and T-cell) primary immunodeficiency occurring in patients with a thymoma. It was first described by Robert A. Good in 1954–1955 after he noted the co-occurrence of thymoma and hypogammaglobulinemia. GS is now recognized by the WHO/International Union of Immunological Societies (as of 1999) as a distinct primary immunodeficiency, separate from common variable immunodeficiency (CVID), despite frequent misdiagnosis as CVID (PMC12647230; PMC8019250).
Key identifiers: - MONDO: MONDO:0015696 - Orphanet: ORPHA169105 (orpha.net) - ICD-10: D81.8 (Other combined immunodeficiencies) - ICD-11: 4B40.2 - OMIM: No dedicated OMIM entry exists (it is an acquired, not classically Mendelian, disorder) - MeSH/synonyms: Thymoma with immunodeficiency; thymoma-associated hypogammaglobulinemia; Good's syndrome; thymoma-associated combined immunodeficiency
Nature of evidence base. Because GS is exceedingly rare, the literature is dominated by individual case reports and small retrospective/cross-sectional case series pooled into systematic reviews, plus (as of 2023–2024) the first prospective longitudinal cohort study. There is essentially no large-scale EHR/claims-based epidemiology; most quantitative "prevalence" figures trace back to aggregated case counts rather than population registries.
Primary causal factor. GS requires the essentially simultaneous presence of a thymic epithelial tumor (thymoma) and acquired hypogammaglobulinemia with B-cell deficiency. There is no known Mendelian/germline genetic cause; it is an acquired (paraneoplastic-like) adult-onset immunodeficiency, distinguishing it from inherited agammaglobulinemias (e.g., XLA) and most forms of CVID.
Genetic risk factors (somatic, not germline): - Thymomas — especially WHO types A and AB, which predominate in GS — very frequently carry a recurrent somatic missense mutation in GTF2I (encoding transcription factor TFII-I), invariably p.L424H. This mutation is found in 82% of type A and 74% of type AB thymomas in large series (Nature Genetics, PMC7466068; PMID:37671056). - A mouse model of the human thymoma-associated GTF2I mutation shows that mutant TFII-I impairs thymic epithelial progenitor differentiation, producing aberrant thymic architecture and reduced thymopoietic activity, particularly of the medullary compartment (PMID:36175547; Communications Biology, PMC9522929) — a plausible mechanistic link between the thymoma's driver mutation and disrupted central tolerance/thymopoiesis. - A dedicated somatic variant profiling study of a GS-associated thymoma has been published, though comprehensive GS-specific genomic characterization (as distinct from thymoma genomics generally) remains limited (ScienceDirect S2772613424000039).
No established environmental/lifestyle causal or protective factors have been identified — GS is not linked to toxin exposure, infection, diet, or lifestyle in the literature reviewed. No GWAS, susceptibility-loci, or gene–environment interaction data exist, consistent with its status as a rare acquired tumor-associated condition rather than a polygenic disease.
| Feature | Frequency (pooled case series, n≈162) | Notes |
|---|---|---|
| Hypogammaglobulinemia | 100% | Median IgG ≈332 mg/dL (normal 700–1600 mg/dL); IgG can be as low as ~100 mg/dL |
| Low IgA | 86.0% | |
| Low IgM | 92.6% | (Some reports describe normal IgA/high IgM patterns in individual cases) |
| Absent/low peripheral B cells (CD19+) | 95.2% | Often near-complete absence; distinguishes GS from most CVID |
| Low CD4+ T-cell count | 71.3% | |
| Inverted CD4:CD8 ratio | 82.5% | e.g., ratio 0.45 vs. normal >1.1 in reported cases |
| Absent transitional B cells (CD38+CD24+) | Frequently reported | Suggests a B-cell precursor developmental defect |
| Loss of unswitched/CD21+ B cells, low CD19/CD20, near-absent surface IgD | Frequently reported | |
| Naïve CD8+CD45RA+ T-cell accumulation | Described as a hallmark finding |
Source: PMC8185358 (systematic review, 162 patients); PMC5937423; case reports.
Suggested HPO terms: HP:0002850 (Decreased circulating total IgG), HP:0002850-family Ig deficiency terms, HP:0005404 (Hypogammaglobulinemia), HP:0010976 (Abnormal B cell count / B lymphocytopenia), HP:0005400 (CD4 lymphopenia), HP:0002721 (Immunodeficiency), HP:0002960 (Autoimmunity).
No disease-specific validated QoL instrument was identified in the literature; QoL impact is inferred from the burden of recurrent hospitalization for infection, chronic diarrhea, and autoimmune complications, but formal EQ-5D/SF-36 GS-specific data were not found in this search.
No dietary, occupational, toxin, or infectious causal exposures for GS itself were identified — the "trigger" is the thymoma, not an external agent. Infections in this section are better understood as consequences (complications) of the immunodeficiency rather than causes; see Phenotypes and Diagnostics sections for the pathogen spectrum (CMV, Pseudomonas, Candida, Pneumocystis jirovecii).
Overall causal status: The Frontiers 2021 review explicitly states the pathophysiology "remains unclear," though it proposes the thymoma "disrupts the balance between host-defense and self-tolerance" (PMC8185358); another review states "many different theories were proposed on the pathogenesis of Good's syndrome but so far none has gained acceptance, making this syndrome still a mystery." Much of the mechanistic chain above (steps 2–5) is therefore inferential/hypothesis-level, built from a combination of a small number of tissue studies (e.g., B-cell depletion demonstrated directly within thymoma tissue — Discover Oncology 2024, showing complete B-cell absence in thymoma tissue of 4/5 GS patients) and mouse GTF2I models, rather than a fully demonstrated human causal pathway.
Molecular pathways/GO terms suggested: - GO:0033077 T cell differentiation in thymus - GO:0002519 natural killer cell tolerance induction / GO:0002377 immunoglobulin production - GO:0030217 T cell differentiation - GO:0042475 odontogenesis (n/a) — not relevant; instead: GO:0048538 thymus development - GO:0002250 adaptive immune response
Cell types (CL terms): - CL:0000236 B cell (depleted) - CL:0000899 Th cell / CL:0000624 CD4-positive, alpha-beta T cell (lymphopenic) - CL:0000625 CD8-positive, alpha-beta T cell (naïve accumulation) - CL:0002293 epithelial cell of thymus / thymic medullary epithelial cell - CL:0000980 plasmablast / CL:0000786 plasma cell (deficient)
Advanced/omics data: Single studies exist profiling "in-depth blood immune profiling of Good syndrome patients" (PMC10684950) and immunological signature studies of thymic epithelial tumor/GS patients (Frontiers 2022), but no large-scale transcriptomic (GEO), proteomic, or single-cell atlas specific to GS was identified — this remains a substantial evidence gap.
Minimal diagnostic criteria (used consistently across systematic reviews): presence of both thymoma and hypogammaglobulinemia, typically with absent/decreased B cells in most cases (PMC8185358).
Checked with linkml-reference-validator 0.2.1.
| Outcome | Count |
|---|---|
| References checked | 28 |
| Resolved | 28 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| Quoted claims checked | 2 |
| Quoted claims found in source | 1 |
| Quoted claims not found in source | 1 |
| References weighed for topical relevance | 28 |
| On topic | 24 |
| Off topic | 0 |
Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:
Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.
PMC:PMC8185358 (abstract only): "disrupts the balance between host-defense and self-tolerance"Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 32 |
| Resolved | 30 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 0 |
| Unverifiable | 2 |
| Terms whose name was checked | 1 |
| Terms named correctly | 1 |
| Terms named as a different term | 0 |
Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.
30 of 32 terms resolved to a current term; the rest could not be looked up either way.