WHIM Syndrome 1

Mendelian MONDO:8000006 Pathograph 31 Show in embeddings browser

WHIM syndrome 1 is the CXCR4 form of WHIM syndrome, a rare autosomal dominant combined primary immunodeficiency named for its tetrad of warts, hypogammaglobulinemia, infections and myelokathexis. It is caused by heterozygous gain-of-function variants in CXCR4, most of them nonsense or frameshift variants that truncate the cytoplasmic carboxy-terminal tail of the receptor (R334X is the most common), and more rarely a charge-changing missense substitution in the same domain. The tail carries the phosphorylation sites that normally terminate signaling, so the mutant receptor resists CXCL12-induced desensitization and internalization and signals in an enhanced, prolonged fashion. The exaggerated response to CXCL12, the chemokine that holds leukocytes in the bone marrow, produces the defining hematopathology. Mature neutrophils are retained in the marrow (myelokathexis), where they become hypersegmented and degenerate, while the blood shows chronic severe neutropenia. Most patients are panleukopenic: lymphocytes (especially B cells), monocytes and plasmacytoid dendritic cells are also reduced, reflecting both leukocyte sequestration and defective B and T lymphopoiesis. Humoral immunity is impaired, with poor class switching, reduced memory B cells and variable hypogammaglobulinemia. Clinically, bacterial infections of the ears, sinuses, lungs and skin begin in infancy or early childhood, and recurrent pneumonia leads to bronchiectasis. Susceptibility to human papillomavirus is disproportionate: cutaneous and anogenital warts are refractory to treatment and can progress to HPV-associated squamous cell carcinoma, and EBV-associated lymphomas also occur. Conotruncal heart defects, including tetralogy of Fallot, and autoimmune complications are uncommon additional features. Standard care is G-CSF, immunoglobulin replacement and antibiotic prophylaxis; mechanism-based therapy with CXCR4 antagonists (plerixafor, and the oral agent mavorixafor, approved by the FDA in 2024 for patients aged 12 years and older) corrects the leukopenia by releasing sequestered leukocytes. Hematopoietic stem cell transplantation is curative in selected patients.

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Inheritance

Autosomal dominant HP:0000006

Disease results from a single heterozygous gain-of-function CXCR4 allele acting dominantly over the wild-type receptor. Familial transmission and de novo cases both occur; affected relatives can differ in which features of the tetrad they show.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:29066537 SUPPORT REVIEW SYNTHESIS Other

"The disorder, which is inherited as an autosomal dominant trait, is caused by heterozygous mutations of the chemokine receptor CXCR4."

Expert clinical review stating the autosomal dominant inheritance and the heterozygous CXCR4 cause.

PMID:22596258 SUPPORT Human Clinical

"We have identified a family with autosomal dominant inheritance of WHIM syndrome that is caused by a missense mutation in CXCR4, E343K (1027G → A)."

A family study documenting autosomal dominant transmission with a CXCR4 variant.

Discussions and Knowledge Gaps

Why is susceptibility to human papillomavirus so disproportionate in WHIM syndrome relative to other immunodeficiencies, and how much is due to the plasmacytoid dendritic cell / type I interferon defect versus a cell-intrinsic keratinocyte CXCR4 effect?

KNOWLEDGE GAP OPEN pdc_interferon_wart_susceptibility

Attached to

pathophysiology#Plasmacytoid Dendritic Cell Deficiency pathophysiology#CXCR4-Driven HPV Keratinocyte Transformation

HPV susceptibility in WHIM syndrome exceeds what neutropenia and antibody deficiency alone predict. Two non-exclusive mechanisms are proposed: loss of plasmacytoid dendritic cell type I interferon output, and a cell-intrinsic effect of the gain-of-function receptor in HPV-infected keratinocytes that promotes transformation. Their relative contributions in patients are not established, and it is not settled why HPV in particular, rather than other viruses, dominates.

Show evidence (2 references)

PMID:20736454 SUPPORT Human Clinical

"we hypothesized that the susceptibility of WHIM patients to warts is related to the abnormal homeostasis of plasmacytoid dendritic cells."

States the interferon/pDC hypothesis for HPV susceptibility.

PMID:21147466 SUPPORT In Vitro

"These results establish a pivotal role for CXCL12 signaling in HPV-mediated transformation and provide a mechanistic basis for understanding HPV pathogenesis in WHIM syndrome."

Provides the competing cell-intrinsic keratinocyte mechanism.

Does the mesenchymal stromal niche mechanism of B and T lymphopenia defined in the R334X mouse operate the same way in human WHIM syndrome bone marrow?

HUMAN MODEL MISMATCH OPEN human_model_mismatch_lymphopoiesis

Attached to

pathophysiology#Impaired B and T Lymphopoiesis

The switch from an adipogenic to an osteolineage-prone marrow stroma with reduced IL-7, and the rescue of B-cell development by LTbetaR or CXCR4 blockade, are defined in the CXCR4 R334X mouse. Human lymphopenia is concordant at the level of reduced early B-progenitor output, but the stromal transcriptional mechanism has not been demonstrated directly in human marrow, so its translational validity is the open question.

Show evidence (1 reference)

PMID:36149943 SUPPORT Model Organism

"Blocking LTβR or CXCR4 signaling restored IL-7 production and B cell development in WHIM mice."

The stromal mechanism and its rescue are established in the mouse, not yet in human tissue, which defines the mismatch.

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Pathophysiology

CXCR4 Carboxy-Terminal Gain-of-Function Variant

Mechanism confidence: Established

A heterozygous germline CXCR4 variant truncates or alters the cytoplasmic carboxy-terminal tail of the receptor, the region responsible for its negative regulation. The mutant receptor is expressed on leukocytes, hematopoietic progenitors and non-hematopoietic cells including keratinocytes.

Genetic context CXCR4 hgnc:2561 variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: GAIN_OF_FUNCTION

Heterozygous nonsense, frameshift or missense variants in the CXCR4 carboxy-terminal domain (for example R334X, E343K).

Downstream

Impaired CXCR4 Desensitization and Internalization Loss or alteration of the tail phosphorylation sites prevents the GRK/beta-arrestin-mediated shutoff of the ligand-bound receptor.

CXCR4-Driven HPV Keratinocyte Transformation The same gain-of-function receptor in HPV-infected keratinocytes amplifies the autocrine CXCL12 loop that the viral oncoproteins induce.

Show evidence (2 references)

PMID:22596258 SUPPORT Human Clinical

"This mutation is also located in the C-terminal domain, a region responsible for negative regulation of the receptor."

Locates the disease variants in the carboxy-terminal domain that negatively regulates the receptor.

PMID:30565238 SUPPORT REVIEW SYNTHESIS Other

"It results from heterozygous gain-of-function mutations in the chemokine receptor CXCR4 which is widely expressed on leukocytes and has profound influences on immune system homeostasis and organogenesis."

Review summarizing the heterozygous gain-of-function lesion and broad leukocyte expression of CXCR4.

Impaired CXCR4 Desensitization and Internalization

Mechanism confidence: Established

After binding CXCL12 the mutant receptor is not efficiently desensitized or internalized, so it stays on the surface in a signaling-competent state. Recruitment of GRK6 and beta-arrestin 2 is impaired. The degree of the internalization defect across variants correlates with the severity of leukopenia and infection susceptibility.

desensitization of G protein-coupled receptor signaling pathway GO:0002029 ↓ DECREASED G protein-coupled receptor internalization GO:0002031 ↓ DECREASED

Downstream

Enhanced CXCL12-CXCR4 Signaling A receptor that is not switched off after ligand binding produces enhanced and prolonged G protein- and beta-arrestin-dependent signaling.

Show evidence (6 references)

PMID:15536153 SUPPORT In Vitro

"This phenomenon relies on the refractoriness of CXCR4 to be both desensitized and internalized in response to CXCL12."

Patient leukocytes show the enhanced responses depend on failure of CXCR4 desensitization and internalization.

PMID:35947323 SUPPORT Human Clinical

"All variants affect the same CXCR4 region and impair CXCR4 internalization resulting in hyperactive signaling."

Across 17 variants in a 66-patient cohort, all impair internalization.

PMID:36089616 SUPPORT In Vitro

"A strong correlation was found between CXCR4 internalization defect and severity of blood leukocytopenias and infection susceptibility"

Links the magnitude of the internalization defect to clinical severity.

+ 3 more references

Enhanced CXCL12-CXCR4 Signaling

Mechanism confidence: Established

Neutrophils and lymphocytes from patients respond to CXCL12 with enhanced G protein-dependent signaling, increased calcium flux and increased chemotaxis. Because CXCL12 is the principal bone marrow retention signal, the result is an exaggeration of the normal homeostatic functions of the receptor.

neutrophil CL:0000775 T cell CL:0000084 B cell CL:0000236

CXCL12-activated CXCR4 signaling pathway GO:0038160 ↑ INCREASED

Downstream

Neutrophil Retention in Bone Marrow Excess responsiveness to the marrow CXCL12 gradient opposes egress of mature neutrophils into the blood.

Lymphocyte and Monocyte Sequestration The same retention signal holds lymphocytes and monocytes out of the blood, producing panleukopenia rather than isolated neutropenia.

Impaired B and T Lymphopoiesis Desensitization-resistant CXCR4 disturbs lymphoid progenitor development in the marrow and thymus, partly through altered stromal niche function.

Plasmacytoid Dendritic Cell Deficiency Plasmacytoid dendritic cell generation and motility partly depend on CXCR4; how the gain-of-function receptor depletes them is not established.

Show evidence (4 references)

PMID:15536153 SUPPORT In Vitro

"Circulating lymphocytes and neutrophils from all patients displayed similar functional alterations of CXCR4-mediated responses featured by a marked enhancement of G-protein-dependent responses."

Patient neutrophils and lymphocytes show enhanced G protein-dependent CXCR4 responses.

PMID:12692554 SUPPORT In Vitro

"Lymphoblastoid cell lines carrying a 19-residue truncation mutation show significantly greater calcium flux relative to control cell lines in response to the CXCR4 ligand, SDF-1, consistent with dysregulated signaling by the mutant receptor."

Increased calcium flux in patient-derived cells carrying a truncating variant.

PMID:15026312 SUPPORT In Vitro

"However, the chemotactic response of both polymorphonuclear cells and T lymphocytes in response to CXCL12 is increased."

Enhanced chemotaxis of patient neutrophils and T cells toward CXCL12.

+ 1 more reference

Neutrophil Retention in Bone Marrow

Mechanism confidence: Established

Myelokathexis: mature neutrophils accumulate in a hypercellular marrow with a shift toward mature forms and degenerate there, showing cytoplasmic vacuolation and hyperlobulated pyknotic nuclei, instead of being released into the blood. It is close to pathognomonic for WHIM syndrome.

neutrophil CL:0000775

neutrophil chemotaxis GO:0030593 ↕ DYSREGULATED

bone marrow UBERON:0002371

Downstream

Chronic severe neutropenia Neutrophils retained in the marrow do not reach the blood.

Myelokathexis Marrow retention of mature neutrophils is the pathological process the bone marrow finding of myelokathexis records.

Show evidence (2 references)

PMID:12692554 SUPPORT Human Clinical

"Despite the peripheral neutropenia, bone marrow aspirates from affected individuals contain abundant mature myeloid cells, a condition termed myelokathexis."

Describes marrow retention of mature myeloid cells in patients.

PMID:31313072 SUPPORT REVIEW SYNTHESIS Other

"Myelokathexis is a unique form of non-cyclic severe congenital neutropenia caused by accumulation of mature and degenerating neutrophils in the bone marrow"

Defines myelokathexis as marrow accumulation of mature, degenerating neutrophils.

Lymphocyte and Monocyte Sequestration

Mechanism confidence: Established

Beyond neutrophils, CXCR4-dependent retention holds lymphocytes and monocytes in the marrow and lymphoid organs, so most patients are panleukopenic. CXCR4 antagonists mobilize all three lineages within hours, with lymphocytes most responsive, showing the cells exist but are sequestered.

T cell CL:0000084 B cell CL:0000236 monocyte CL:0000576

leukocyte migration GO:0050900 ↕ DYSREGULATED

Animal models

CXCR4 R334X knock-in WHIM mouse Mouse recapitulates The knock-in mouse reproduces the peripheral leukopenia and its reversal by CXCR4 antagonists, matching the human sequestration mechanism.

Downstream

Lymphopenia

Monocytopenia

Show evidence (2 references)

PMID:21890643 SUPPORT Human Clinical

"Plerixafor increased absolute lymphocyte, monocyte, and neutrophil counts in blood to normal without significant side effects in all 3 patients."

Rapid normalization of three lineages by CXCR4 blockade shows the cells are sequestered rather than absent.

PMID:21890643 SUPPORT Human Clinical

"All 3 cell types increased in a dose-dependent manner with the rank order of responsiveness absolute lymphocyte > monocyte > neutrophil."

Lymphocytes and monocytes are mobilized as readily as neutrophils.

Impaired B and T Lymphopoiesis

Mechanism confidence: Provisional

Lymphopenia is evident at early progenitor stages. In knock-in mice the gain-of-function receptor impairs thymopoiesis and B-cell development; in the R334X mouse, marrow mesenchymal stromal cells switch from an adipogenic to an osteolineage-prone program with reduced IL-7 production, limiting lymphopoiesis. Human data are consistent but the stromal mechanism rests mainly on mouse work.

B cell CL:0000236 T cell CL:0000084

B cell differentiation GO:0030183 ↓ DECREASED T cell differentiation in thymus GO:0033077 ↓ DECREASED

Animal models

CXCR4 R334X knock-in WHIM mouse Mouse recapitulates The knock-in mouse shows defective thymopoiesis and B-cell development, reproducing the developmental component of the human lymphopenia.

Downstream

Decreased B cell count

Lymphopenia

Defective B Cell Memory and Isotype Switching A small, oligoclonal B-cell pool with disturbed germinal center trafficking generates few switched memory B cells.

Show evidence (2 references)

PMID:22438253 SUPPORT Model Organism

"In contrast, Cxcr4(+/1013) mice show defective thymopoiesis and B-cell development, accounting for circulating lymphopenia."

Knock-in mouse evidence that desensitization-resistant CXCR4 impairs lymphoid development.

PMID:36149943 SUPPORT Model Organism

"Using a CXCR4 R334X GOF mouse model of WHIM syndrome, we showed that lymphopoiesis is reduced because of a dysregulated mesenchymal stem cell (MSC) transcriptome characterized by a switch from an adipogenic to an osteolineage-prone program with limited lymphopoietic activity."

Identifies a stromal niche mechanism for reduced lymphopoiesis in the R334X mouse.

Defective B Cell Memory and Isotype Switching

Mechanism confidence: Provisional

The circulating B-cell pool is small and oligoclonal, memory B cells are reduced, and switching from IgM to IgG after immunization is markedly impaired. Altered CXCR4 signaling in germinal center trafficking has been proposed as the cause. The defect is incomplete: vaccine responses can occur, which is why hypogammaglobulinemia is variable rather than constant.

memory B cell CL:0000787

isotype switching GO:0045190 ↓ DECREASED

Downstream

Hypogammaglobulinemia

Show evidence (2 references)

PMID:20226738 SUPPORT Human Clinical

"Isotype switching from phage specific neutralizing antibody of the IgM class to IgG was markedly reduced."

Neoantigen immunization in a patient shows impaired IgM-to-IgG switching.

PMID:15026312 SUPPORT Human Clinical

"immunophenotypic analysis of circulating T and B lymphocytes reveals a decreased number of memory B cells and of naive T cells"

Reduced memory B cells in patient blood.

Plasmacytoid Dendritic Cell Deficiency

Mechanism confidence: Provisional

Patients have a striking reduction in circulating plasmacytoid dendritic cells and a partial reduction in myeloid dendritic cells, and their mononuclear cells produce no detectable interferon-alpha after herpes simplex virus or TLR9 stimulation. This antiviral defect is a proposed contributor to the disproportionate susceptibility to papillomavirus.

plasmacytoid dendritic cell CL:0000784

type I interferon production GO:0032606 ↓ DECREASED

Downstream

Cutaneous warts Hypothesized: reduced plasmacytoid dendritic cell interferon output weakens antiviral control of papillomavirus.

Show evidence (2 references)

PMID:20736454 SUPPORT Human Clinical

"Analysis of the myeloid and plasmacytoid dendritic cell blood counts in WHIM patients revealed a striking defect in the number of plasmacytoid dendritic cells as well as a partial reduction of the number of myeloid dendritic cells, compared with healthy subjects."

Documents the plasmacytoid dendritic cell deficit in patients.

PMID:20736454 SUPPORT In Vitro

"the production of interferon-α by mononuclear cells in response to herpes simplex infection, or after stimulation with the Toll-like receptor 9 ligand CpG, was undetectable in WHIM patients."

Patient mononuclear cells fail to make type I interferon.

CXCR4-Driven HPV Keratinocyte Transformation

Mechanism confidence: Provisional

Oncogenic HPV16 and HPV18 induce CXCL12 and its receptors in keratinocytes through the E6 and E7 oncoproteins, and the autocrine loop controls motility and survival of infected cells. Expression of a WHIM gain-of-function CXCR4 mutant confers transforming capacity on HPV18-immortalized keratinocytes, offering a cell-intrinsic contribution to HPV-associated dysplasia and carcinoma alongside the immune defect.

keratinocyte CL:0000312

Downstream

HPV-associated squamous cell carcinoma Proposed on in vitro grounds; the relative contributions of keratinocyte CXCR4 signaling and impaired immune surveillance to carcinoma in patients are not established.

Show evidence (1 reference)

PMID:21147466 SUPPORT In Vitro

"Strikingly, expression of a WHIM syndrome-related gain-of-function CXCR4 mutant confers transforming capacity to HPV18-immortalized keratinocytes."

Cell-culture evidence that the mutant receptor promotes transformation of HPV-infected keratinocytes.

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Pathograph

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Phenotypes

Blood 7

Myelokathexis VERY_FREQUENT HP:0031160

Show evidence (2 references)

PMID:12692554 SUPPORT Human Clinical

"Despite the peripheral neutropenia, bone marrow aspirates from affected individuals contain abundant mature myeloid cells, a condition termed myelokathexis."

Documents myelokathexis in marrow aspirates from affected individuals.

PMID:31313072 SUPPORT REVIEW SYNTHESIS Other

"which demonstrates statistically that myelokathexis is almost pathognomonic for WHIM syndrome."

Literature analysis showing myelokathexis is nearly specific to WHIM syndrome.

Chronic severe neutropenia VERY_FREQUENT Persistently decreased total neutrophil count HP:0410252

Sequelae: Recurrent bacterial infections

Show evidence (2 references)

PMID:30716504 SUPPORT Human Clinical

"All the patients had severe neutropenia (195 ± 102 cells/mm3 at onset)"

Severe neutropenia in every patient of an 18-patient international cohort.

PMID:35947323 SUPPORT Human Clinical

"infections 88%/1.6 years, neutropenia 98%/3.8 years, lymphopenia 88%/5.0 years, and warts 40%/12.1 years"

Neutropenia in 98% of a 66-patient cohort, recognized at a mean age of 3.8 years.

Lymphopenia VERY_FREQUENT Decreased total lymphocyte count HP:0001888

Show evidence (2 references)

PMID:30716504 SUPPORT Human Clinical

"lymphopenia and hypogammaglobulinemia were detected in 88% and 58% of patients, respectively."

Lymphopenia in 88% of an international cohort.

PMID:23009155 SUPPORT Human Clinical

"In addition to neutropenia and myelokathexis, all patients presented deep monocytopenia and lymphopenia."

Lymphopenia in every patient of the French registry cohort.

Decreased B cell count Decreased total B cell count HP:0010976

Show evidence (1 reference)

PMID:20226738 SUPPORT Human Clinical

"We confirmed profound B-cell lymphopenia and demonstrated oligoclonality of the circulating B-cell pool by HCDR3 spectratyping."

Documents profound B lymphopenia in patients.

Monocytopenia VERY_FREQUENT Decreased total monocyte count HP:0012312

Show evidence (1 reference)

PMID:23009155 SUPPORT Human Clinical

"In addition to neutropenia and myelokathexis, all patients presented deep monocytopenia and lymphopenia."

Monocytopenia in every patient of the French registry cohort.

Hypogammaglobulinemia FREQUENT Decreased circulating immunoglobulin concentration HP:0004313

Sequelae: Recurrent bacterial infections

Show evidence (1 reference)

PMID:30716504 SUPPORT Human Clinical

"lymphopenia and hypogammaglobulinemia were detected in 88% and 58% of patients, respectively."

Hypogammaglobulinemia in 58% of an international cohort.

Lymphoma HP:0002665

Show evidence (1 reference)

PMID:38442908 SUPPORT Human Clinical

"Malignancies included EBV-associated lymphoproliferative disorders and HPV-positive genital and anal cancers as in the French cohort."

Documents EBV-associated lymphoproliferative disorders among WHIM malignancies.

Cardiovascular 1

Tetralogy of Fallot VERY_RARE HP:0001636

Show evidence (1 reference)

PMID:31313072 SUPPORT REVIEW SYNTHESIS Other

"especially Tetralogy of Fallot (ToF), a severe cardiovascular malformation that has a prevalence in the general population of only 1 in 3000, yet has occurred in 4 out of the 105 reported WHIM patients, all from different pedigrees"

Reports tetralogy of Fallot in 4 of 105 reported patients, far above the population rate.

Head and Neck 1

Recurrent bacterial upper respiratory tract infections VERY_FREQUENT HP:0031949

Show evidence (1 reference)

PMID:23009155 SUPPORT Human Clinical

"Seven patients presented repeated bacterial Ears Nose Throat as well as severe bacterial infections that were curable with antibiotics."

Repeated bacterial ENT infections in seven of eight registry patients.

Immune 3

Recurrent bacterial infections VERY_FREQUENT HP:0002718

Sequelae: Recurrent pneumonia Recurrent bacterial upper respiratory tract infections

Show evidence (2 references)

PMID:35947323 SUPPORT Human Clinical

"The prevalence and mean age of recognition and/or onset of clinical manifestations within our cohort were infections 88%/1.6 years"

Infections in 88% of patients with onset at a mean age of 1.6 years.

PMID:30716504 SUPPORT Human Clinical

"Patients with WHIM commonly presented with a severe bacterial infection (78%)."

Severe bacterial infection is the common presentation.

Recurrent pneumonia FREQUENT HP:0006532

Sequelae: Bronchiectasis

Show evidence (1 reference)

PMID:30716504 SUPPORT Human Clinical

"Pneumonia recurrence was observed in 61% of patients and was complicated with bronchiectasis in 27%."

Recurrent pneumonia in 61% of patients.

Autoimmunity HP:0002960

Show evidence (1 reference)

PMID:35947323 SUPPORT Human Clinical

"However, we report greater prevalence and variety of autoimmune complications of WHIM syndrome (21.2%) than reported previously."

Autoimmune complications in 21.2% of the 66-patient cohort.

Integument 2

Cutaneous warts FREQUENT Verrucae HP:0200043

Sequelae: HPV-associated squamous cell carcinoma

Show evidence (2 references)

PMID:30716504 SUPPORT Human Clinical

"Skin warts were observed in 61% of patients at a mean age of 11 years"

Warts in 61% of patients with a mean onset age of 11 years.

PMID:35947323 SUPPORT Human Clinical

"infections 88%/1.6 years, neutropenia 98%/3.8 years, lymphopenia 88%/5.0 years, and warts 40%/12.1 years"

Warts in 40% of a larger cohort at a mean age of 12.1 years, reflecting the variable penetrance.

HPV-associated squamous cell carcinoma HP:0002860

Show evidence (2 references)

PMID:38442908 SUPPORT Human Clinical

"Immunocompromised WHIMS patients appear to be particularly susceptible to developing early malignancy, mainly HPV-induced carcinomas, followed by EBV-related lymphomas."

Establishes WHIM syndrome as a predisposition to HPV-induced carcinoma and EBV lymphoma.

PMID:30716504 SUPPORT Human Clinical

"human papilloma virus (HPV)-related malignancies manifested in 16% of patients."

HPV-related malignancy in 16% of an international cohort.

Respiratory 1

Bronchiectasis OCCASIONAL HP:0002110

Show evidence (1 reference)

PMID:30716504 SUPPORT Human Clinical

"Pneumonia recurrence was observed in 61% of patients and was complicated with bronchiectasis in 27%."

Bronchiectasis in 27% of an international cohort.

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Genetic Associations

CXCR4 (CXCR4 encodes C-X-C chemokine receptor type 4, the G protein-coupled receptor for CXCL12 that retains hematopoietic cells in the bone marrow and directs lymphocyte development and trafficking. Disease alleles are heterozygous gain-of-function variants clustered in the carboxy-terminal cytoplasmic tail, which carries the phosphorylation sites for receptor desensitization and internalization. They were the first chemokine receptor variants shown to cause a human disease.)

Gene: CXCR4 hgnc:2561 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:12692554 SUPPORT Human Clinical

"We describe here the localization of the gene associated with WHIM syndrome to a region of roughly 12 cM on chromosome 2q21 and the identification of truncating mutations in the cytoplasmic tail domain of the gene encoding chemokine receptor 4 (CXCR4)."

The gene-discovery study mapping the disease to 2q21 and identifying truncating CXCR4 tail variants.

Variants (2)

Carboxy-terminal truncating CXCR4 variants Pathogenic

Nonsense and frameshift variants that truncate the CXCR4 carboxy-terminus by 10 to 19 amino acids, removing negative regulatory phosphorylation sites. R334X is the most common allele.

Show evidence (2 references)

PMID:22596258 SUPPORT Human Clinical

"Gain-of-function mutations that truncate the C-terminus of the chemokine receptor CXCR4 by 10-19 amino acids cause WHIM syndrome."

States the truncating, gain-of-function character of the typical disease alleles.

PMID:21890643 SUPPORT Human Clinical

"we enrolled 3 unrelated adult patients with the most common WHIM mutation, CXCR4(R334X), in a phase 1 dose-escalation study."

Identifies R334X as the most common WHIM allele.

E343K Pathogenic

A missense variant in the same carboxy-terminal domain (c.1027G>A) segregating with autosomal dominant WHIM syndrome in one family; it increases signaling about twofold, like R334X, but has a weaker effect on blocking receptor down-regulation. Nomenclature follows the source.

Show evidence (1 reference)

PMID:22596258 SUPPORT In Vitro

"CXCR4(E343K) mediated approximately 2-fold increased signaling in calcium flux and chemotaxis assays relative to wild-type CXCR4"

Functional assays showing the missense variant is gain-of-function.

💊

Medical Actions

Mavorixafor

Action: Pharmacotherapy NCIT:C15986

Agent: mavorixafor CHEBI:138865

Platform: Small molecule

Dosing: once daily every 1 days

Oral, once-daily selective CXCR4 antagonist. In April 2024 it became the first therapy approved for WHIM syndrome (FDA), for patients aged 12 years and older, to increase circulating mature neutrophils and lymphocytes. In a phase 3 placebo-controlled trial it increased time above the neutrophil and lymphocyte thresholds and reduced annualized infection rate by about 60%.

Mechanism Target:

INHIBITS Enhanced CXCL12-CXCR4 Signaling — Mavorixafor blocks CXCL12 binding to CXCR4, antagonizing the hyperactive signaling and releasing sequestered leukocytes into the blood.

Show evidence (1 reference)

PMID:38643510 SUPPORT Human Clinical

"In 31 participants (mavorixafor, n = 14; placebo, n = 17), mavorixafor least squares (LS) mean TATANC was 15.0 hours and 2.8 hours for placebo (P < .001)."

The CXCR4 antagonist increased time above the neutrophil threshold versus placebo, showing mechanism-based mobilization.

Target Phenotypes: Chronic severe neutropenia HP:0410252 Lymphopenia HP:0001888 Cutaneous warts HP:0200043

Show evidence (3 references)

PMID:39004659 SUPPORT REVIEW SYNTHESIS Other

"In April 2024, it became the first therapy to be approved for WHIM syndrome"

Records the 2024 FDA approval of mavorixafor for WHIM syndrome.

PMID:38643510 SUPPORT Human Clinical

"Annualized infection rates were 60% lower with mavorixafor vs placebo (LS mean 1.7 vs 4.2; nominal P = .007)"

Phase 3 evidence of clinical benefit (reduced infection rate).

PMID:32870250 SUPPORT Human Clinical

"We observed an average 75% reduction in the number of cutaneous warts."

Open-label phase 2 study in 8 adults reporting fewer cutaneous warts on long-term treatment.

Plerixafor

Action: Pharmacotherapy NCIT:C15986

Agent: plerixafor CHEBI:125354

Platform: Small molecule

Parenteral small-molecule CXCR4 antagonist used off-label as mechanism-based therapy. Low-dose plerixafor corrects panleukopenia in WHIM syndrome by mobilizing sequestered leukocytes; a phase 3 crossover trial found it noninferior to G-CSF for neutrophil maintenance and superior for lymphocyte counts.

Mechanism Target:

INHIBITS Enhanced CXCL12-CXCR4 Signaling — Plerixafor competitively antagonizes CXCR4, releasing leukocytes retained by the hyperactive CXCL12-CXCR4 signal.

Show evidence (1 reference)

PMID:21890643 SUPPORT Human Clinical

"Plerixafor increased absolute lymphocyte, monocyte, and neutrophil counts in blood to normal without significant side effects in all 3 patients."

CXCR4 blockade restores all three depleted lineages, confirming the mechanism-based effect.

Target Phenotypes: Chronic severe neutropenia HP:0410252

Show evidence (1 reference)

PMID:37561579 SUPPORT Human Clinical

"plerixafor was noninferior to G-CSF for maintaining neutrophil counts of more than 500 cells/μL (P = 0.023) and was superior to G-CSF for maintaining lymphocyte counts above 1,000 cells/μL (P < 0.0001)."

Phase 3 crossover evidence for plerixafor efficacy relative to G-CSF.

Granulocyte Colony-Stimulating Factor

Action: colony-stimulating factor therapy Ontology label: Colony-Stimulating Factor Therapy NCIT:C15515

Agent: filgrastim NCIT:C1474

Platform: Protein replacement

G-CSF (filgrastim) raises the neutrophil count and has long been a standard treatment, but it does not correct the monocytopenia, lymphopenia or hypogammaglobulinemia, and long-term use can cause bone pain.

Mechanism Target:

MODULATES Chronic severe neutropenia — G-CSF drives residual granulopoiesis and neutrophil release, raising the blood neutrophil count without addressing the CXCR4 retention signal, so other cytopenias persist.

Show evidence (1 reference)

PMID:30625055 SUPPORT Human Clinical

"Patients with WHIM syndrome are often treated with granulocyte colony-stimulating factor (G-CSF), which can increase neutrophil counts but does not affect cytopenias other than neutropenia."

States that G-CSF raises neutrophils only and leaves the other cytopenias untreated.

Target Phenotypes: Chronic severe neutropenia HP:0410252

Show evidence (1 reference)

PMID:30716504 SUPPORT Human Clinical

"Approximately 50% of patients received antibiotic prophylaxis, whereas G-CSF and immunoglobulin treatments were used in 72% and 55% of patients, respectively."

Documents G-CSF as a widely used treatment in the international cohort.

Immunoglobulin Replacement

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

Agent: human immunoglobulin G NCIT:C80829

Platform: Protein replacement

Immunoglobulin replacement provides passive antibody and reduces bacterial infection frequency; it is recommended to help prevent chronic lung damage in patients with recurrent infection or hypogammaglobulinemia.

Target Phenotypes: Recurrent bacterial infections HP:0002718

Show evidence (1 reference)

PMID:30716504 SUPPORT Human Clinical

"We suggest that immunoglobulin therapy should be promptly considered to control the frequency of bacterial infections and prevent chronic lung damage."

Recommends immunoglobulin therapy to reduce infection frequency and prevent lung damage.

Antibiotic Prophylaxis

Action: antibiotic prophylaxis Ontology label: Antibiotic Prophylaxis NCIT:C51993

Agent: antibiotic NCIT:C258

Platform: Small molecule

Long-term antibacterial prophylaxis, especially when started in early childhood, reduces bacterial infections and the consequent obstructive lung disease.

Target Phenotypes: Recurrent bacterial infections HP:0002718

Show evidence (1 reference)

PMID:23009155 SUPPORT Human Clinical

"Continuous prophylactic anti-infective measures, when started in early childhood, seem to effectively prevent further bacterial infections and the consequent development of COPD."

Reports the benefit of early continuous antibiotic prophylaxis.

Hematopoietic Stem Cell Transplantation

Action: hematopoietic cell transplantation Ontology label: Hematopoietic Cell Transplantation NCIT:C15431

Platform: Cell therapy

Allogeneic hematopoietic stem cell transplantation is curative in selected patients, correcting the neutropenia and immunodeficiency and resolving autoimmunity, recurrent infections and warts; it carries transplant-related risk.

Mechanism Target:

BYPASSES CXCR4 Carboxy-Terminal Gain-of-Function Variant — Replacing the patient's hematopoietic system with donor cells that lack the CXCR4 gain-of-function allele removes the mutant receptor from the blood lineages, correcting the downstream cytopenias. The link covers hematopoietic cells only: keratinocytes keep the variant, so transplantation does not act on the CXCR4-Driven HPV Keratinocyte Transformation branch.

Show evidence (2 references)

PMID:34697698 SUPPORT Human Clinical

"HSCT in WHIM syndrome corrects neutropenia and immunodeficiency, and leads to resolution of autoimmunity and recurrent infections, including warts."

Multicenter evidence that transplantation corrects the disease phenotype.

PMID:25662009 SUPPORT INDIRECT Human Clinical

"In this patient, deletion of the disease allele, CXCR4(R334X), as well as 163 other genes from one copy of chromosome 2 occurred in a hematopoietic stem cell (HSC) that repopulated the myeloid but not the lymphoid lineage."

A spontaneous cure in which loss of the mutant allele from a single hematopoietic stem cell was enough to restore the myeloid lineage. It supports removing the variant from hematopoietic cells as the curative step, by a natural experiment rather than transplantation.

Show evidence (1 reference)

PMID:34697698 SUPPORT Human Clinical

"At last follow-up (median 6.7 years), all six surviving patients were alive with full donor chimerism."

Documents durable engraftment and survival after transplantation in a pediatric series.

📈

Progression

Early childhood presentation

Age: Onset in infancy or early childhood; diagnosis often delayed

Clinical features begin early (mean about 2 years) but diagnosis is frequently delayed by years because of the variable phenotype.

Show evidence (1 reference)

PMID:30716504 SUPPORT Human Clinical

"The clinical features manifested at 2.2 ± 2.6 years of age, whereas the disease diagnosis was delayed until 12.5 ± 10.4 years of age."

Documents early onset and the substantial diagnostic delay.

Adult complications

Age: Adulthood

Long-term morbidity is dominated by chronic obstructive lung disease from recurrent pneumonia and by HPV- and EBV-associated malignancies.

Show evidence (1 reference)

PMID:38442908 SUPPORT Human Clinical

"The 40-year risk of malignancy was 39% (95% confidence interval [CI]: 6%-74%)."

Quantifies the substantial cumulative cancer risk over adult life.

📊

Prevalence

France (French Severe Chronic Neutropenia Registry)

Birth Prevalence 0.023 per 100,000 live births <1 in 1,000,000 (births)

Estimated incidence of 0.23 per million births from the French registry; the disease is ultra-rare.

Show evidence (1 reference)

PMID:23009155 SUPPORT Human Clinical

"Estimated incidence for WS was of 0.23 per million births."

Registry-based estimate of WHIM syndrome birth prevalence.

⚖️

Clinical Burden

High

WHIM syndrome causes lifelong severe cytopenias with recurrent bacterial infection from infancy, progressive bronchiectasis and chronic lung disease, and a high cumulative risk of virus-associated malignancy. Standard care is only partially effective; mechanism-based CXCR4 antagonists and transplantation have improved outcomes but the disease and its complications remain serious.

Show evidence (2 references)

PMID:30716504 SUPPORT Human Clinical

"Patients with WHIM need careful monitoring and timely intervention for complications, mainly lung disease and HPV-related malignancies."

Establishes the major long-term morbidities driving the HIGH burden assessment.

PMID:38442908 SUPPORT Human Clinical

"The 40-year risk of malignancy was 39% (95% confidence interval [CI]: 6%-74%)."

The high cumulative malignancy risk supports the HIGH burden.

🔬

Clinical Trials

NCT03995108 PHASE_III COMPLETED

Randomized, double-blind, placebo-controlled phase 3 trial of the oral CXCR4 antagonist mavorixafor in patients aged 12 years and older with WHIM syndrome, with an open-label extension; the pivotal trial supporting FDA approval.

Target Phenotypes: Chronic severe neutropenia HP:0410252 Lymphopenia HP:0001888

Show evidence (1 reference)

clinicaltrials:NCT03995108 SUPPORT Human Clinical

"The primary objective of the Randomized Placebo-Controlled Period is to demonstrate the efficacy of mavorixafor in participants with WHIM syndrome as assessed by increasing levels of circulating neutrophils compared with placebo"

Registry record of the pivotal phase 3 mavorixafor trial in WHIM syndrome.

NCT02231879 PHASE_III COMPLETED

Investigator-initiated phase 3 crossover trial comparing the CXCR4 antagonist plerixafor with G-CSF for infection prevention in patients with CXCR4-mutated WHIM syndrome.

Target Phenotypes: Recurrent bacterial infections HP:0002718

Show evidence (1 reference)

clinicaltrials:NCT02231879 SUPPORT Human Clinical

"To compare plerixafor versus granulocyte colony stimulating factor (G-CSF) for preventing infections in people with WHIMS."

Registry record of the plerixafor-versus-G-CSF phase 3 crossover trial.

🐁

Animal Models

CXCR4 R334X knock-in WHIM mouse

A heterozygous Cxcr4 knock-in mouse expressing a desensitization-resistant receptor. It reproduces the enhanced leukocyte response to CXCL12, the leukopenia, and the defective B and T lymphopoiesis of WHIM syndrome, and the leukopenia is reversed by CXCR4 antagonists, establishing the causal role of the mutant receptor. A parallel R334X gain-of-function model was used to dissect the stromal niche contribution to lymphopenia.

Species

Mouse

Genotype

Cxcr4(+/1013) heterozygous knock-in (murine equivalent of human R334X)

Publication

PMID:22438253

Pathograph links

Lymphocyte and Monocyte Sequestration recapitulates fidelity: high observes: organism The knock-in mouse reproduces the peripheral leukopenia and its reversal by CXCR4 antagonists, matching the human sequestration mechanism.

Limitations: A murine 1013 truncation modeling the human R334X allele; species differences in marrow architecture and lymphoid compartments qualify the fit.

Show evidence (1 reference)

PMID:22438253 SUPPORT Model Organism

"Cxcr4(+/mutant(1013)) mice display leukocytes with enhanced responses to Cxcl12 and exhibit leukopenia as reported in patients."

The model recapitulates the enhanced CXCL12 response and leukopenia of patients.

Impaired B and T Lymphopoiesis recapitulates fidelity: moderate observes: organism The knock-in mouse shows defective thymopoiesis and B-cell development, reproducing the developmental component of the human lymphopenia.

Limitations: Mouse lymphoid ontogeny differs from human; the stromal-niche mechanism is best characterized in the separate R334X model.

Show evidence (1 reference)

PMID:22438253 SUPPORT Model Organism

"In contrast, Cxcr4(+/1013) mice show defective thymopoiesis and B-cell development, accounting for circulating lymphopenia."

The model reproduces the defective lymphopoiesis underlying the lymphopenia.

Show evidence (1 reference)

PMID:22438253 SUPPORT Model Organism

"Treatment with CXCL12/CXCR4 antagonists transiently reverses blood anomalies, further demonstrating the causal role of the mutant receptor in the leukopenia."

Antagonist reversal in the model establishes it as informative for the human sequestration mechanism.

{ }

Source YAML

click to show

name: WHIM Syndrome 1
creation_date: "2026-09-24T19:23:48Z"
category: Mendelian
disease_term:
  preferred_term: WHIM syndrome 1
  term:
    id: MONDO:8000006
    label: WHIM syndrome 1
synonyms:
- WHIM syndrome
- WHIMS
- Warts, hypogammaglobulinemia, infections, and myelokathexis syndrome
- Warts-hypogammaglobulinemia-infections-myelokathexis syndrome
- Myelokathexis
- CXCR4-related WHIM syndrome
description: >-
  WHIM syndrome 1 is the CXCR4 form of WHIM syndrome, a rare autosomal dominant
  combined primary immunodeficiency named for its tetrad of warts,
  hypogammaglobulinemia, infections and myelokathexis. It is caused by
  heterozygous gain-of-function variants in CXCR4, most of them nonsense or
  frameshift variants that truncate the cytoplasmic carboxy-terminal tail of the
  receptor (R334X is the most common), and more rarely a charge-changing missense
  substitution in the same domain. The tail carries the phosphorylation sites that
  normally terminate signaling, so the mutant receptor resists CXCL12-induced
  desensitization and internalization and signals in an enhanced, prolonged
  fashion.

  The exaggerated response to CXCL12, the chemokine that holds leukocytes in the
  bone marrow, produces the defining hematopathology. Mature neutrophils are
  retained in the marrow (myelokathexis), where they become hypersegmented and
  degenerate, while the blood shows chronic severe neutropenia. Most patients are
  panleukopenic: lymphocytes (especially B cells), monocytes and plasmacytoid
  dendritic cells are also reduced, reflecting both leukocyte sequestration and
  defective B and T lymphopoiesis. Humoral immunity is impaired, with poor class
  switching, reduced memory B cells and variable hypogammaglobulinemia.

  Clinically, bacterial infections of the ears, sinuses, lungs and skin begin in
  infancy or early childhood, and recurrent pneumonia leads to bronchiectasis.
  Susceptibility to human papillomavirus is disproportionate: cutaneous and
  anogenital warts are refractory to treatment and can progress to HPV-associated
  squamous cell carcinoma, and EBV-associated lymphomas also occur. Conotruncal
  heart defects, including tetralogy of Fallot, and autoimmune complications are
  uncommon additional features. Standard care is G-CSF, immunoglobulin replacement
  and antibiotic prophylaxis; mechanism-based therapy with CXCR4 antagonists
  (plerixafor, and the oral agent mavorixafor, approved by the FDA in 2024 for
  patients aged 12 years and older) corrects the leukopenia by releasing
  sequestered leukocytes. Hematopoietic stem cell transplantation is curative in
  selected patients.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Disease results from a single heterozygous gain-of-function CXCR4 allele acting
    dominantly over the wild-type receptor. Familial transmission and de novo cases
    both occur; affected relatives can differ in which features of the tetrad they
    show.
  evidence:
  - reference: PMID:29066537
    reference_title: "How I treat warts, hypogammaglobulinemia, infections, and myelokathexis syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "The disorder, which is inherited as an autosomal dominant trait, is caused
      by heterozygous mutations of the chemokine receptor CXCR4."
    explanation: Expert clinical review stating the autosomal dominant inheritance and
      the heterozygous CXCR4 cause.
  - reference: PMID:22596258
    reference_title: WHIM syndrome caused by a single amino acid substitution in the carboxy-tail of chemokine receptor CXCR4.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We have identified a family with autosomal dominant inheritance of WHIM
      syndrome that is caused by a missense mutation in CXCR4, E343K (1027G → A)."
    explanation: A family study documenting autosomal dominant transmission with a CXCR4
      variant.
genetic:
- name: CXCR4
  gene_term:
    preferred_term: CXCR4
    term:
      id: hgnc:2561
      label: CXCR4
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  association: >-
    CXCR4 encodes C-X-C chemokine receptor type 4, the G protein-coupled receptor
    for CXCL12 that retains hematopoietic cells in the bone marrow and directs
    lymphocyte development and trafficking. Disease alleles are heterozygous
    gain-of-function variants clustered in the carboxy-terminal cytoplasmic tail,
    which carries the phosphorylation sites for receptor desensitization and
    internalization. They were the first chemokine receptor variants shown to cause
    a human disease.
  evidence:
  - reference: PMID:12692554
    reference_title: "Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe here the localization of the gene associated with WHIM syndrome
      to a region of roughly 12 cM on chromosome 2q21 and the identification of truncating
      mutations in the cytoplasmic tail domain of the gene encoding chemokine receptor
      4 (CXCR4)."
    explanation: The gene-discovery study mapping the disease to 2q21 and identifying
      truncating CXCR4 tail variants.
  variants:
  - name: Carboxy-terminal truncating CXCR4 variants
    description: >-
      Nonsense and frameshift variants that truncate the CXCR4 carboxy-terminus by
      10 to 19 amino acids, removing negative regulatory phosphorylation sites.
      R334X is the most common allele.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:22596258
      reference_title: WHIM syndrome caused by a single amino acid substitution in the carboxy-tail of chemokine receptor CXCR4.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Gain-of-function mutations that truncate the C-terminus of the chemokine
        receptor CXCR4 by 10-19 amino acids cause WHIM syndrome."
      explanation: States the truncating, gain-of-function character of the typical disease
        alleles.
    - reference: PMID:21890643
      reference_title: The CXCR4 antagonist plerixafor corrects panleukopenia in patients with WHIM syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "we enrolled 3 unrelated adult patients with the most common WHIM mutation,
        CXCR4(R334X), in a phase 1 dose-escalation study."
      explanation: Identifies R334X as the most common WHIM allele.
  - name: E343K
    description: >-
      A missense variant in the same carboxy-terminal domain (c.1027G>A) segregating
      with autosomal dominant WHIM syndrome in one family; it increases signaling
      about twofold, like R334X, but has a weaker effect on blocking receptor
      down-regulation. Nomenclature follows the source.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:22596258
      reference_title: WHIM syndrome caused by a single amino acid substitution in the carboxy-tail of chemokine receptor CXCR4.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "CXCR4(E343K) mediated approximately 2-fold increased signaling in calcium
        flux and chemotaxis assays relative to wild-type CXCR4"
      explanation: Functional assays showing the missense variant is gain-of-function.
pathophysiology:
- name: CXCR4 Carboxy-Terminal Gain-of-Function Variant
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    A heterozygous germline CXCR4 variant truncates or alters the cytoplasmic
    carboxy-terminal tail of the receptor, the region responsible for its negative
    regulation. The mutant receptor is expressed on leukocytes, hematopoietic
    progenitors and non-hematopoietic cells including keratinocytes.
  genetic_context:
    genes:
    - preferred_term: CXCR4
      term:
        id: hgnc:2561
        label: CXCR4
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: GAIN_OF_FUNCTION
    description: >-
      Heterozygous nonsense, frameshift or missense variants in the CXCR4
      carboxy-terminal domain (for example R334X, E343K).
  evidence:
  - reference: PMID:22596258
    reference_title: WHIM syndrome caused by a single amino acid substitution in the carboxy-tail of chemokine receptor CXCR4.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This mutation is also located in the C-terminal domain, a region responsible
      for negative regulation of the receptor."
    explanation: Locates the disease variants in the carboxy-terminal domain that negatively
      regulates the receptor.
  - reference: PMID:30565238
    reference_title: "WHIM syndrome: Immunopathogenesis, treatment and cure strategies."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "It results from heterozygous gain-of-function mutations in the chemokine
      receptor CXCR4 which is widely expressed on leukocytes and has profound influences
      on immune system homeostasis and organogenesis."
    explanation: Review summarizing the heterozygous gain-of-function lesion and broad
      leukocyte expression of CXCR4.
  downstream:
  - target: Impaired CXCR4 Desensitization and Internalization
    causal_link_type: DIRECT
    description: >-
      Loss or alteration of the tail phosphorylation sites prevents the
      GRK/beta-arrestin-mediated shutoff of the ligand-bound receptor.
    evidence:
    - reference: PMID:36089616
      reference_title: "Genotype-phenotype correlations in WHIM syndrome: a systematic characterization of CXCR4(WHIM) variants."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "All CXCR4 variants displayed impaired receptor trafficking, hyperactive
        downstream signaling, and enhanced chemotaxis in response to CXCL12."
      explanation: Cell-based analysis of 14 pathogenic variants showing every one impairs
        receptor trafficking.
  - target: CXCR4-Driven HPV Keratinocyte Transformation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      The same gain-of-function receptor in HPV-infected keratinocytes amplifies the
      autocrine CXCL12 loop that the viral oncoproteins induce.
- name: Impaired CXCR4 Desensitization and Internalization
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    After binding CXCL12 the mutant receptor is not efficiently desensitized or
    internalized, so it stays on the surface in a signaling-competent state.
    Recruitment of GRK6 and beta-arrestin 2 is impaired. The degree of the
    internalization defect across variants correlates with the severity of
    leukopenia and infection susceptibility.
  biological_processes:
  - preferred_term: desensitization of G protein-coupled receptor signaling pathway
    term:
      id: GO:0002029
      label: desensitization of G protein-coupled receptor signaling pathway
    modifier: DECREASED
  - preferred_term: G protein-coupled receptor internalization
    term:
      id: GO:0002031
      label: G protein-coupled receptor internalization
    modifier: DECREASED
  evidence:
  - reference: PMID:15536153
    reference_title: WHIM syndromes with different genetic anomalies are accounted for by impaired CXCR4 desensitization to CXCL12.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This phenomenon relies on the refractoriness of CXCR4 to be both desensitized
      and internalized in response to CXCL12."
    explanation: Patient leukocytes show the enhanced responses depend on failure of CXCR4
      desensitization and internalization.
  - reference: PMID:35947323
    reference_title: Disease Progression of WHIM Syndrome in an International Cohort of 66 Pediatric and Adult Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All variants affect the same CXCR4 region and impair CXCR4 internalization
      resulting in hyperactive signaling."
    explanation: Across 17 variants in a 66-patient cohort, all impair internalization.
  - reference: PMID:36089616
    reference_title: "Genotype-phenotype correlations in WHIM syndrome: a systematic characterization of CXCR4(WHIM) variants."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "A strong correlation was found between CXCR4 internalization defect and severity
      of blood leukocytopenias and infection susceptibility"
    explanation: Links the magnitude of the internalization defect to clinical severity.
  - reference: PMID:19956569
    reference_title: Impaired recruitment of Grk6 and beta-Arrestin 2 causes delayed internalization and desensitization of a WHIM syndrome-associated CXCR4 mutant receptor.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Recruitment of beta-Arrestin 2, but not beta-Arrestin 1, to the active WHIM-mutant
      receptor is delayed compared to the WT CXCR4 receptor."
    explanation: Supports the impaired beta-arrestin 2 recruitment step for a C-terminally
      truncated WHIM receptor.
  - reference: PMID:19956569
    reference_title: Impaired recruitment of Grk6 and beta-Arrestin 2 causes delayed internalization and desensitization of a WHIM syndrome-associated CXCR4 mutant receptor.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Grk6 fails to associate with the WHIM-mutant receptor whereas Grk3 associates
      normally"
    explanation: Supports the loss of GRK6 recruitment, the kinase step that normally
      initiates receptor desensitization and internalization.
  - reference: PMID:15026312
    reference_title: "Altered leukocyte response to CXCL12 in patients with warts hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome."
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: "We show that CXCR4 gene mutations in WHIM patients do not affect cell surface
      expression of the chemokine receptor and its internalization upon stimulation with
      CXCL12."
    explanation: An early study of leukocytes from three patients found normal CXCL12-induced
      internalization. Later patient-cell work (PMID:15536153), the biochemical study of
      GRK6 and beta-arrestin 2 recruitment (PMID:19956569) and a systematic analysis of
      14 variants (PMID:36089616) found impaired internalization, which the node follows.
  downstream:
  - target: Enhanced CXCL12-CXCR4 Signaling
    causal_link_type: DIRECT
    description: >-
      A receptor that is not switched off after ligand binding produces enhanced and
      prolonged G protein- and beta-arrestin-dependent signaling.
    evidence:
    - reference: PMID:31313072
      reference_title: "WHIM Syndrome: from Pathogenesis Towards Personalized Medicine and Cure."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "WHIM syndrome is usually caused by autosomal dominant mutations in the
        G protein-coupled chemokine receptor CXCR4 that impair desensitization, resulting
        in enhanced and prolonged G protein- and β-arrestin-dependent responses."
      explanation: Review of all 105 published cases stating the step from impaired desensitization
        to enhanced signaling.
- name: Enhanced CXCL12-CXCR4 Signaling
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Neutrophils and lymphocytes from patients respond to CXCL12 with enhanced
    G protein-dependent signaling, increased calcium flux and increased chemotaxis.
    Because CXCL12 is the principal bone marrow retention signal, the result is an
    exaggeration of the normal homeostatic functions of the receptor.
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  biological_processes:
  - preferred_term: CXCL12-activated CXCR4 signaling pathway
    term:
      id: GO:0038160
      label: CXCL12-activated CXCR4 signaling pathway
    modifier: INCREASED
  evidence:
  - reference: PMID:15536153
    reference_title: WHIM syndromes with different genetic anomalies are accounted for by impaired CXCR4 desensitization to CXCL12.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Circulating lymphocytes and neutrophils from all patients displayed similar
      functional alterations of CXCR4-mediated responses featured by a marked enhancement
      of G-protein-dependent responses."
    explanation: Patient neutrophils and lymphocytes show enhanced G protein-dependent
      CXCR4 responses.
  - reference: PMID:12692554
    reference_title: "Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Lymphoblastoid cell lines carrying a 19-residue truncation mutation show
      significantly greater calcium flux relative to control cell lines in response to
      the CXCR4 ligand, SDF-1, consistent with dysregulated signaling by the mutant receptor."
    explanation: Increased calcium flux in patient-derived cells carrying a truncating
      variant.
  - reference: PMID:15026312
    reference_title: "Altered leukocyte response to CXCL12 in patients with warts hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "However, the chemotactic response of both polymorphonuclear cells and T lymphocytes
      in response to CXCL12 is increased."
    explanation: Enhanced chemotaxis of patient neutrophils and T cells toward CXCL12.
  - reference: PMID:15026312
    reference_title: "Altered leukocyte response to CXCL12 in patients with warts hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome."
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: "Moreover, no significant differences in calcium mobilization in response to
      CXCL12 are found."
    explanation: The same three-patient study found no increase in calcium flux, which
      contradicts the increased calcium flux reported in lymphoblastoid cell lines
      (PMID:12692554). It still found increased chemotaxis, so it disputes the calcium
      readout rather than the enhanced CXCL12 response as a whole.
  downstream:
  - target: Neutrophil Retention in Bone Marrow
    causal_link_type: DIRECT
    description: >-
      Excess responsiveness to the marrow CXCL12 gradient opposes egress of mature
      neutrophils into the blood.
    evidence:
    - reference: PMID:15026312
      reference_title: "Altered leukocyte response to CXCL12 in patients with warts hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "we suggest that the altered leukocyte response to CXCL12 may account for
        the pathologic retention of mature polymorphonuclear cells in the bone marrow
        (myelokathexis)"
      explanation: Proposes the enhanced CXCL12 response as the cause of marrow neutrophil
        retention, later supported by the pharmacological rescue.
  - target: Lymphocyte and Monocyte Sequestration
    causal_link_type: DIRECT
    description: >-
      The same retention signal holds lymphocytes and monocytes out of the blood,
      producing panleukopenia rather than isolated neutropenia.
    evidence:
    - reference: PMID:21890643
      reference_title: The CXCR4 antagonist plerixafor corrects panleukopenia in patients with WHIM syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "These data provide the first pharmacologic evidence that panleukopenia
        in WHIM syndrome is caused by CXCL12-CXCR4 signaling-dependent leukocyte sequestration"
      explanation: Pharmacological blockade in patients shows the panleukopenia depends
        on CXCL12-CXCR4 signaling.
  - target: Impaired B and T Lymphopoiesis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Desensitization-resistant CXCR4 disturbs lymphoid progenitor development in the
      marrow and thymus, partly through altered stromal niche function.
    evidence:
    - reference: PMID:22438253
      reference_title: Proper desensitization of CXCR4 is required for lymphocyte development and peripheral compartmentalization in mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In contrast, Cxcr4(+/1013) mice show defective thymopoiesis and B-cell
        development, accounting for circulating lymphopenia."
      explanation: In a knock-in mouse carrying a desensitization-resistant receptor,
        lymphoid development is defective.
  - target: Plasmacytoid Dendritic Cell Deficiency
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Plasmacytoid dendritic cell generation and motility partly depend on CXCR4; how
      the gain-of-function receptor depletes them is not established.
    evidence:
    - reference: PMID:20736454
      reference_title: "Defect of plasmacytoid dendritic cells in warts, hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "These mutations confer an increased leukocyte response to the CXCR4-ligand
        CXCL12, resulting in abnormal homeostasis of many leukocyte types, including
        neutrophils and lymphocytes."
      explanation: Frames the dendritic cell defect as another consequence of the enhanced
        leukocyte response to CXCL12.
- name: Neutrophil Retention in Bone Marrow
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: >-
    Myelokathexis: mature neutrophils accumulate in a hypercellular marrow with a
    shift toward mature forms and degenerate there, showing cytoplasmic vacuolation
    and hyperlobulated pyknotic nuclei, instead of being released into the blood. It
    is close to pathognomonic for WHIM syndrome.
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  locations:
  - preferred_term: bone marrow
    term:
      id: UBERON:0002371
      label: bone marrow
  biological_processes:
  - preferred_term: neutrophil chemotaxis
    term:
      id: GO:0030593
      label: neutrophil chemotaxis
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:12692554
    reference_title: "Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite the peripheral neutropenia, bone marrow aspirates from affected individuals
      contain abundant mature myeloid cells, a condition termed myelokathexis."
    explanation: Describes marrow retention of mature myeloid cells in patients.
  - reference: PMID:31313072
    reference_title: "WHIM Syndrome: from Pathogenesis Towards Personalized Medicine and Cure."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Myelokathexis is a unique form of non-cyclic severe congenital neutropenia
      caused by accumulation of mature and degenerating neutrophils in the bone marrow"
    explanation: Defines myelokathexis as marrow accumulation of mature, degenerating
      neutrophils.
  downstream:
  - target: Chronic severe neutropenia
    causal_link_type: DIRECT
    description: >-
      Neutrophils retained in the marrow do not reach the blood.
    evidence:
    - reference: PMID:30625055
      reference_title: Plerixafor for the Treatment of WHIM Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Myelokathexis is neutropenia caused by neutrophil retention in bone marrow."
      explanation: States the peripheral neutropenia is caused by marrow retention.
  - target: Myelokathexis
    causal_link_type: DIRECT
    description: >-
      Marrow retention of mature neutrophils is the pathological process the bone
      marrow finding of myelokathexis records.
- name: Lymphocyte and Monocyte Sequestration
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  description: >-
    Beyond neutrophils, CXCR4-dependent retention holds lymphocytes and monocytes in
    the marrow and lymphoid organs, so most patients are panleukopenic. CXCR4
    antagonists mobilize all three lineages within hours, with lymphocytes most
    responsive, showing the cells exist but are sequestered.
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  - preferred_term: monocyte
    term:
      id: CL:0000576
      label: monocyte
  biological_processes:
  - preferred_term: leukocyte migration
    term:
      id: GO:0050900
      label: leukocyte migration
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:21890643
    reference_title: The CXCR4 antagonist plerixafor corrects panleukopenia in patients with WHIM syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Plerixafor increased absolute lymphocyte, monocyte, and neutrophil counts
      in blood to normal without significant side effects in all 3 patients."
    explanation: Rapid normalization of three lineages by CXCR4 blockade shows the cells
      are sequestered rather than absent.
  - reference: PMID:21890643
    reference_title: The CXCR4 antagonist plerixafor corrects panleukopenia in patients with WHIM syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All 3 cell types increased in a dose-dependent manner with the rank order
      of responsiveness absolute lymphocyte > monocyte > neutrophil."
    explanation: Lymphocytes and monocytes are mobilized as readily as neutrophils.
  downstream:
  - target: Lymphopenia
    causal_link_type: DIRECT
  - target: Monocytopenia
    causal_link_type: DIRECT
- name: Impaired B and T Lymphopoiesis
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: >-
    Lymphopenia is evident at early progenitor stages. In knock-in mice the
    gain-of-function receptor impairs thymopoiesis and B-cell development; in the
    R334X mouse, marrow mesenchymal stromal cells switch from an adipogenic to an
    osteolineage-prone program with reduced IL-7 production, limiting lymphopoiesis.
    Human data are consistent but the stromal mechanism rests mainly on mouse work.
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  biological_processes:
  - preferred_term: B cell differentiation
    term:
      id: GO:0030183
      label: B cell differentiation
    modifier: DECREASED
  - preferred_term: T cell differentiation in thymus
    term:
      id: GO:0033077
      label: T cell differentiation in thymus
    modifier: DECREASED
  evidence:
  - reference: PMID:22438253
    reference_title: Proper desensitization of CXCR4 is required for lymphocyte development and peripheral compartmentalization in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In contrast, Cxcr4(+/1013) mice show defective thymopoiesis and B-cell development,
      accounting for circulating lymphopenia."
    explanation: Knock-in mouse evidence that desensitization-resistant CXCR4 impairs
      lymphoid development.
  - reference: PMID:36149943
    reference_title: Dysregulated stem cell niches and altered lymphocyte recirculation cause B and T cell lymphopenia in WHIM syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Using a CXCR4 R334X GOF mouse model of WHIM syndrome, we showed that lymphopoiesis
      is reduced because of a dysregulated mesenchymal stem cell (MSC) transcriptome
      characterized by a switch from an adipogenic to an osteolineage-prone program with
      limited lymphopoietic activity."
    explanation: Identifies a stromal niche mechanism for reduced lymphopoiesis in the
      R334X mouse.
  downstream:
  - target: Decreased B cell count
    causal_link_type: DIRECT
  - target: Lymphopenia
    causal_link_type: DIRECT
  - target: Defective B Cell Memory and Isotype Switching
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A small, oligoclonal B-cell pool with disturbed germinal center trafficking
      generates few switched memory B cells.
- name: Defective B Cell Memory and Isotype Switching
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    The circulating B-cell pool is small and oligoclonal, memory B cells are reduced,
    and switching from IgM to IgG after immunization is markedly impaired. Altered
    CXCR4 signaling in germinal center trafficking has been proposed as the cause.
    The defect is incomplete: vaccine responses can occur, which is why
    hypogammaglobulinemia is variable rather than constant.
  cell_types:
  - preferred_term: memory B cell
    term:
      id: CL:0000787
      label: memory B cell
  biological_processes:
  - preferred_term: isotype switching
    term:
      id: GO:0045190
      label: isotype switching
    modifier: DECREASED
  evidence:
  - reference: PMID:20226738
    reference_title: "Oligoclonality, impaired class switch and B-cell memory responses in WHIM syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Isotype switching from phage specific neutralizing antibody of the IgM class
      to IgG was markedly reduced."
    explanation: Neoantigen immunization in a patient shows impaired IgM-to-IgG switching.
  - reference: PMID:15026312
    reference_title: "Altered leukocyte response to CXCL12 in patients with warts hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "immunophenotypic analysis of circulating T and B lymphocytes reveals a decreased
      number of memory B cells and of naive T cells"
    explanation: Reduced memory B cells in patient blood.
  downstream:
  - target: Hypogammaglobulinemia
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20226738
      reference_title: "Oligoclonality, impaired class switch and B-cell memory responses in WHIM syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Overall, these data suggest that impaired CXCR4 signaling in WHIM syndrome
        results in defective B-cell function and abnormal isotype switching, possibly
        through effects on germinal center trafficking of lymphocytes."
      explanation: Links the B-cell functional defect to the antibody deficiency.
- name: Plasmacytoid Dendritic Cell Deficiency
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    Patients have a striking reduction in circulating plasmacytoid dendritic cells
    and a partial reduction in myeloid dendritic cells, and their mononuclear cells
    produce no detectable interferon-alpha after herpes simplex virus or TLR9
    stimulation. This antiviral defect is a proposed contributor to the
    disproportionate susceptibility to papillomavirus.
  cell_types:
  - preferred_term: plasmacytoid dendritic cell
    term:
      id: CL:0000784
      label: plasmacytoid dendritic cell
  biological_processes:
  - preferred_term: type I interferon production
    term:
      id: GO:0032606
      label: type I interferon production
    modifier: DECREASED
  evidence:
  - reference: PMID:20736454
    reference_title: "Defect of plasmacytoid dendritic cells in warts, hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Analysis of the myeloid and plasmacytoid dendritic cell blood counts in WHIM
      patients revealed a striking defect in the number of plasmacytoid dendritic cells
      as well as a partial reduction of the number of myeloid dendritic cells, compared
      with healthy subjects."
    explanation: Documents the plasmacytoid dendritic cell deficit in patients.
  - reference: PMID:20736454
    reference_title: "Defect of plasmacytoid dendritic cells in warts, hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome patients."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the production of interferon-α by mononuclear cells in response to herpes
      simplex infection, or after stimulation with the Toll-like receptor 9 ligand CpG,
      was undetectable in WHIM patients."
    explanation: Patient mononuclear cells fail to make type I interferon.
  downstream:
  - target: Cutaneous warts
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Hypothesized: reduced plasmacytoid dendritic cell interferon output weakens
      antiviral control of papillomavirus.
    evidence:
    - reference: PMID:20736454
      reference_title: "Defect of plasmacytoid dendritic cells in warts, hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "we hypothesized that the susceptibility of WHIM patients to warts is related
        to the abnormal homeostasis of plasmacytoid dendritic cells."
      explanation: The authors state this link as a hypothesis, which is why the edge is
        marked indirect.
- name: CXCR4-Driven HPV Keratinocyte Transformation
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    Oncogenic HPV16 and HPV18 induce CXCL12 and its receptors in keratinocytes
    through the E6 and E7 oncoproteins, and the autocrine loop controls motility and
    survival of infected cells. Expression of a WHIM gain-of-function CXCR4 mutant
    confers transforming capacity on HPV18-immortalized keratinocytes, offering a
    cell-intrinsic contribution to HPV-associated dysplasia and carcinoma alongside
    the immune defect.
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  evidence:
  - reference: PMID:21147466
    reference_title: "A pivotal role for CXCL12 signaling in HPV-mediated transformation of keratinocytes: clues to understanding HPV-pathogenesis in WHIM syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Strikingly, expression of a WHIM syndrome-related gain-of-function CXCR4 mutant
      confers transforming capacity to HPV18-immortalized keratinocytes."
    explanation: Cell-culture evidence that the mutant receptor promotes transformation
      of HPV-infected keratinocytes.
  downstream:
  - target: HPV-associated squamous cell carcinoma
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Proposed on in vitro grounds; the relative contributions of keratinocyte CXCR4
      signaling and impaired immune surveillance to carcinoma in patients are not
      established.
phenotypes:
- category: Hematological
  name: Myelokathexis
  description: >-
    Hypercellular marrow with retention of mature, degenerating neutrophils showing
    cytoplasmic vacuolation and hyperlobulated pyknotic nuclei. It is the most
    consistent finding and is close to pathognomonic for WHIM syndrome.
  phenotype_term:
    preferred_term: Myelokathexis
    term:
      id: HP:0031160
      label: Myelokathexis
  frequency: VERY_FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:12692554
    reference_title: "Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite the peripheral neutropenia, bone marrow aspirates from affected individuals
      contain abundant mature myeloid cells, a condition termed myelokathexis."
    explanation: Documents myelokathexis in marrow aspirates from affected individuals.
  - reference: PMID:31313072
    reference_title: "WHIM Syndrome: from Pathogenesis Towards Personalized Medicine and Cure."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "which demonstrates statistically that myelokathexis is almost pathognomonic
      for WHIM syndrome."
    explanation: Literature analysis showing myelokathexis is nearly specific to WHIM
      syndrome.
- category: Hematological
  name: Chronic severe neutropenia
  description: >-
    Chronic, non-cyclic severe neutropenia present from infancy in nearly all patients;
    neutrophils can be mobilized transiently by infection.
  phenotype_term:
    preferred_term: Chronic severe neutropenia
    term:
      id: HP:0410252
      label: Persistently decreased total neutrophil count
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:30716504
    reference_title: "Long-Term Outcome of WHIM Syndrome in 18 Patients: High Risk of Lung Disease and HPV-Related Malignancies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All the patients had severe neutropenia (195 ± 102 cells/mm3 at onset)"
    explanation: Severe neutropenia in every patient of an 18-patient international cohort.
  - reference: PMID:35947323
    reference_title: Disease Progression of WHIM Syndrome in an International Cohort of 66 Pediatric and Adult Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "infections 88%/1.6 years, neutropenia 98%/3.8 years, lymphopenia 88%/5.0
      years, and warts 40%/12.1 years"
    explanation: Neutropenia in 98% of a 66-patient cohort, recognized at a mean age of
      3.8 years.
  sequelae:
  - target: Recurrent bacterial infections
    causal_link_type: DIRECT
    description: >-
      Lack of circulating neutrophils impairs clearance of pyogenic bacteria.
- category: Hematological
  name: Lymphopenia
  description: >-
    Lymphopenia affecting B cells most, and T and NK cells to a lesser degree, is
    present in most patients.
  phenotype_term:
    preferred_term: Lymphopenia
    term:
      id: HP:0001888
      label: Decreased total lymphocyte count
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:30716504
    reference_title: "Long-Term Outcome of WHIM Syndrome in 18 Patients: High Risk of Lung Disease and HPV-Related Malignancies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "lymphopenia and hypogammaglobulinemia were detected in 88% and 58% of patients,
      respectively."
    explanation: Lymphopenia in 88% of an international cohort.
  - reference: PMID:23009155
    reference_title: Description and outcome of a cohort of 8 patients with WHIM syndrome from the French Severe Chronic Neutropenia Registry.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition to neutropenia and myelokathexis, all patients presented deep
      monocytopenia and lymphopenia."
    explanation: Lymphopenia in every patient of the French registry cohort.
- category: Hematological
  name: Decreased B cell count
  description: >-
    Profound B lymphopenia with an oligoclonal circulating B-cell pool.
  phenotype_term:
    preferred_term: B lymphopenia
    term:
      id: HP:0010976
      label: Decreased total B cell count
  evidence:
  - reference: PMID:20226738
    reference_title: "Oligoclonality, impaired class switch and B-cell memory responses in WHIM syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We confirmed profound B-cell lymphopenia and demonstrated oligoclonality
      of the circulating B-cell pool by HCDR3 spectratyping."
    explanation: Documents profound B lymphopenia in patients.
- category: Hematological
  name: Monocytopenia
  description: >-
    Monocytopenia accompanies the neutropenia and lymphopenia.
  phenotype_term:
    preferred_term: Monocytopenia
    term:
      id: HP:0012312
      label: Decreased total monocyte count
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:23009155
    reference_title: Description and outcome of a cohort of 8 patients with WHIM syndrome from the French Severe Chronic Neutropenia Registry.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition to neutropenia and myelokathexis, all patients presented deep
      monocytopenia and lymphopenia."
    explanation: Monocytopenia in every patient of the French registry cohort.
- category: Immunological
  name: Hypogammaglobulinemia
  description: >-
    Hypogammaglobulinemia is variable and incompletely penetrant; it may involve IgG
    alone or IgM and IgA, and is often only moderate.
  phenotype_term:
    preferred_term: Hypogammaglobulinemia
    term:
      id: HP:0004313
      label: Decreased circulating immunoglobulin concentration
  frequency: FREQUENT
  evidence:
  - reference: PMID:30716504
    reference_title: "Long-Term Outcome of WHIM Syndrome in 18 Patients: High Risk of Lung Disease and HPV-Related Malignancies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "lymphopenia and hypogammaglobulinemia were detected in 88% and 58% of patients,
      respectively."
    explanation: Hypogammaglobulinemia in 58% of an international cohort.
  sequelae:
  - target: Recurrent bacterial infections
    causal_link_type: DIRECT
    description: >-
      Deficient antibody, particularly against encapsulated bacteria, adds to the
      susceptibility created by neutropenia.
- category: Immunological
  name: Recurrent bacterial infections
  description: >-
    Bacterial infections begin in infancy or early childhood and involve mainly the
    ears, sinuses, lungs, oral cavity and skin; severe infections such as pneumonia,
    cellulitis, osteomyelitis and meningitis also occur.
  phenotype_term:
    preferred_term: Recurrent bacterial infections
    term:
      id: HP:0002718
      label: Recurrent bacterial infections
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:35947323
    reference_title: Disease Progression of WHIM Syndrome in an International Cohort of 66 Pediatric and Adult Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The prevalence and mean age of recognition and/or onset of clinical manifestations
      within our cohort were infections 88%/1.6 years"
    explanation: Infections in 88% of patients with onset at a mean age of 1.6 years.
  - reference: PMID:30716504
    reference_title: "Long-Term Outcome of WHIM Syndrome in 18 Patients: High Risk of Lung Disease and HPV-Related Malignancies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with WHIM commonly presented with a severe bacterial infection (78%)."
    explanation: Severe bacterial infection is the common presentation.
  sequelae:
  - target: Recurrent pneumonia
    causal_link_type: DIRECT
  - target: Recurrent bacterial upper respiratory tract infections
    causal_link_type: DIRECT
- category: Respiratory
  name: Recurrent bacterial upper respiratory tract infections
  description: >-
    Repeated bacterial ear, nose and throat infections.
  phenotype_term:
    preferred_term: Recurrent bacterial ear, nose and throat infections
    term:
      id: HP:0031949
      label: Recurrent bacterial upper respiratory tract infections
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:23009155
    reference_title: Description and outcome of a cohort of 8 patients with WHIM syndrome from the French Severe Chronic Neutropenia Registry.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seven patients presented repeated bacterial Ears Nose Throat as well as severe
      bacterial infections that were curable with antibiotics."
    explanation: Repeated bacterial ENT infections in seven of eight registry patients.
- category: Respiratory
  name: Recurrent pneumonia
  description: >-
    Recurrent pneumonia is common and is the main route to chronic lung damage.
  phenotype_term:
    preferred_term: Recurrent pneumonia
    term:
      id: HP:0006532
      label: Recurrent pneumonia
  frequency: FREQUENT
  evidence:
  - reference: PMID:30716504
    reference_title: "Long-Term Outcome of WHIM Syndrome in 18 Patients: High Risk of Lung Disease and HPV-Related Malignancies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pneumonia recurrence was observed in 61% of patients and was complicated
      with bronchiectasis in 27%."
    explanation: Recurrent pneumonia in 61% of patients.
  sequelae:
  - target: Bronchiectasis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30716504
      reference_title: "Long-Term Outcome of WHIM Syndrome in 18 Patients: High Risk of Lung Disease and HPV-Related Malignancies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Pneumonia recurrence was observed in 61% of patients and was complicated
        with bronchiectasis in 27%."
      explanation: Bronchiectasis complicated recurrent pneumonia in 27% of patients.
- category: Respiratory
  name: Bronchiectasis
  description: >-
    Chronic bronchiectasis and obstructive lung disease develop from repeated lower
    respiratory infection and are a major cause of long-term morbidity.
  phenotype_term:
    preferred_term: Bronchiectasis
    term:
      id: HP:0002110
      label: Bronchiectasis
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:30716504
    reference_title: "Long-Term Outcome of WHIM Syndrome in 18 Patients: High Risk of Lung Disease and HPV-Related Malignancies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pneumonia recurrence was observed in 61% of patients and was complicated
      with bronchiectasis in 27%."
    explanation: Bronchiectasis in 27% of an international cohort.
- category: Dermatological
  name: Cutaneous warts
  description: >-
    Refractory cutaneous and mucosal warts caused by human papillomavirus, typically
    appearing later than the hematologic features (mean age about 11-12 years) and
    incompletely penetrant.
  phenotype_term:
    preferred_term: Warts
    term:
      id: HP:0200043
      label: Verrucae
  frequency: FREQUENT
  evidence:
  - reference: PMID:30716504
    reference_title: "Long-Term Outcome of WHIM Syndrome in 18 Patients: High Risk of Lung Disease and HPV-Related Malignancies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Skin warts were observed in 61% of patients at a mean age of 11 years"
    explanation: Warts in 61% of patients with a mean onset age of 11 years.
  - reference: PMID:35947323
    reference_title: Disease Progression of WHIM Syndrome in an International Cohort of 66 Pediatric and Adult Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "infections 88%/1.6 years, neutropenia 98%/3.8 years, lymphopenia 88%/5.0
      years, and warts 40%/12.1 years"
    explanation: Warts in 40% of a larger cohort at a mean age of 12.1 years, reflecting
      the variable penetrance.
  sequelae:
  - target: HPV-associated squamous cell carcinoma
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Refractory HPV lesions can progress to invasive squamous cell carcinoma.
- category: Neoplastic
  name: HPV-associated squamous cell carcinoma
  description: >-
    HPV-driven squamous cell carcinomas, notably anogenital and oropharyngeal,
    develop in a substantial minority of patients over decades; EBV-associated
    lymphomas also occur.
  phenotype_term:
    preferred_term: HPV-associated squamous cell carcinoma
    term:
      id: HP:0002860
      label: Squamous cell carcinoma
  evidence:
  - reference: PMID:38442908
    reference_title: CXCR4 WHIM syndrome is a cancer predisposition condition for virus-induced malignancies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunocompromised WHIMS patients appear to be particularly susceptible to
      developing early malignancy, mainly HPV-induced carcinomas, followed by EBV-related
      lymphomas."
    explanation: Establishes WHIM syndrome as a predisposition to HPV-induced carcinoma
      and EBV lymphoma.
  - reference: PMID:30716504
    reference_title: "Long-Term Outcome of WHIM Syndrome in 18 Patients: High Risk of Lung Disease and HPV-Related Malignancies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "human papilloma virus (HPV)-related malignancies manifested in 16% of patients."
    explanation: HPV-related malignancy in 16% of an international cohort.
- category: Neoplastic
  name: Lymphoma
  description: >-
    EBV-associated lymphomas and lymphoproliferative disorders are part of the
    virus-driven cancer predisposition.
  phenotype_term:
    preferred_term: EBV-associated lymphoma
    term:
      id: HP:0002665
      label: Lymphoma
  evidence:
  - reference: PMID:38442908
    reference_title: CXCR4 WHIM syndrome is a cancer predisposition condition for virus-induced malignancies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Malignancies included EBV-associated lymphoproliferative disorders and HPV-positive
      genital and anal cancers as in the French cohort."
    explanation: Documents EBV-associated lymphoproliferative disorders among WHIM malignancies.
- category: Cardiovascular
  name: Tetralogy of Fallot
  description: >-
    Conotruncal congenital heart defects, notably tetralogy of Fallot, occur in a
    minority of patients at a rate well above the general population, consistent with
    a developmental role for CXCR4.
  phenotype_term:
    preferred_term: Tetralogy of Fallot
    term:
      id: HP:0001636
      label: Tetralogy of Fallot
  frequency: VERY_RARE
  evidence:
  - reference: PMID:31313072
    reference_title: "WHIM Syndrome: from Pathogenesis Towards Personalized Medicine and Cure."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "especially Tetralogy of Fallot (ToF), a severe cardiovascular malformation
      that has a prevalence in the general population of only 1 in 3000, yet has occurred
      in 4 out of the 105 reported WHIM patients, all from different pedigrees"
    explanation: Reports tetralogy of Fallot in 4 of 105 reported patients, far above
      the population rate.
- category: Immunological
  name: Autoimmunity
  description: >-
    Autoimmune complications, including cytopenias and arthritis, are increasingly
    recognized and were more common than previously reported in the largest cohort.
  phenotype_term:
    preferred_term: Autoimmunity
    term:
      id: HP:0002960
      label: Autoimmunity
  evidence:
  - reference: PMID:35947323
    reference_title: Disease Progression of WHIM Syndrome in an International Cohort of 66 Pediatric and Adult Patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, we report greater prevalence and variety of autoimmune complications
      of WHIM syndrome (21.2%) than reported previously."
    explanation: Autoimmune complications in 21.2% of the 66-patient cohort.
treatments:
- name: Mavorixafor
  description: >-
    Oral, once-daily selective CXCR4 antagonist. In April 2024 it became the first
    therapy approved for WHIM syndrome (FDA), for patients aged 12 years and older,
    to increase circulating mature neutrophils and lymphocytes. In a phase 3
    placebo-controlled trial it increased time above the neutrophil and lymphocyte
    thresholds and reduced annualized infection rate by about 60%.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: mavorixafor
      term:
        id: CHEBI:138865
        label: AMD 070
  dosing_interval: once daily
  dosing_interval_days: 1
  target_phenotypes:
  - preferred_term: Chronic severe neutropenia
    term:
      id: HP:0410252
      label: Persistently decreased total neutrophil count
  - preferred_term: Lymphopenia
    term:
      id: HP:0001888
      label: Decreased total lymphocyte count
  - preferred_term: Cutaneous warts
    term:
      id: HP:0200043
      label: Verrucae
  target_mechanisms:
  - target: Enhanced CXCL12-CXCR4 Signaling
    treatment_effect: INHIBITS
    description: >-
      Mavorixafor blocks CXCL12 binding to CXCR4, antagonizing the hyperactive
      signaling and releasing sequestered leukocytes into the blood.
    evidence:
    - reference: PMID:38643510
      reference_title: "A phase 3 randomized trial of mavorixafor, a CXCR4 antagonist, for WHIM syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In 31 participants (mavorixafor, n = 14; placebo, n = 17), mavorixafor
        least squares (LS) mean TATANC was 15.0 hours and 2.8 hours for placebo (P < .001)."
      explanation: The CXCR4 antagonist increased time above the neutrophil threshold
        versus placebo, showing mechanism-based mobilization.
  evidence:
  - reference: PMID:39004659
    reference_title: "Mavorixafor: First Approval."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "In April 2024, it became the first therapy to be approved for WHIM syndrome"
    explanation: Records the 2024 FDA approval of mavorixafor for WHIM syndrome.
  - reference: PMID:38643510
    reference_title: "A phase 3 randomized trial of mavorixafor, a CXCR4 antagonist, for WHIM syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Annualized infection rates were 60% lower with mavorixafor vs placebo (LS
      mean 1.7 vs 4.2; nominal P = .007)"
    explanation: Phase 3 evidence of clinical benefit (reduced infection rate).
  - reference: PMID:32870250
    reference_title: "Results of a phase 2 trial of an oral CXCR4 antagonist, mavorixafor, for treatment of WHIM syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We observed an average 75% reduction in the number of cutaneous warts."
    explanation: Open-label phase 2 study in 8 adults reporting fewer cutaneous warts
      on long-term treatment.
- name: Plerixafor
  description: >-
    Parenteral small-molecule CXCR4 antagonist used off-label as mechanism-based
    therapy. Low-dose plerixafor corrects panleukopenia in WHIM syndrome by
    mobilizing sequestered leukocytes; a phase 3 crossover trial found it noninferior
    to G-CSF for neutrophil maintenance and superior for lymphocyte counts.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: plerixafor
      term:
        id: CHEBI:125354
        label: plerixafor
  target_phenotypes:
  - preferred_term: Chronic severe neutropenia
    term:
      id: HP:0410252
      label: Persistently decreased total neutrophil count
  target_mechanisms:
  - target: Enhanced CXCL12-CXCR4 Signaling
    treatment_effect: INHIBITS
    description: >-
      Plerixafor competitively antagonizes CXCR4, releasing leukocytes retained by
      the hyperactive CXCL12-CXCR4 signal.
    evidence:
    - reference: PMID:21890643
      reference_title: The CXCR4 antagonist plerixafor corrects panleukopenia in patients with WHIM syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Plerixafor increased absolute lymphocyte, monocyte, and neutrophil counts
        in blood to normal without significant side effects in all 3 patients."
      explanation: CXCR4 blockade restores all three depleted lineages, confirming the
        mechanism-based effect.
  evidence:
  - reference: PMID:37561579
    reference_title: A phase III randomized crossover trial of plerixafor versus G-CSF for treatment of WHIM syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "plerixafor was noninferior to G-CSF for maintaining neutrophil counts of
      more than 500 cells/μL (P = 0.023) and was superior to G-CSF for maintaining lymphocyte
      counts above 1,000 cells/μL (P < 0.0001)."
    explanation: Phase 3 crossover evidence for plerixafor efficacy relative to G-CSF.
- name: Granulocyte Colony-Stimulating Factor
  description: >-
    G-CSF (filgrastim) raises the neutrophil count and has long been a standard
    treatment, but it does not correct the monocytopenia, lymphopenia or
    hypogammaglobulinemia, and long-term use can cause bone pain.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: colony-stimulating factor therapy
    term:
      id: NCIT:C15515
      label: Colony-Stimulating Factor Therapy
    therapeutic_agent:
    - preferred_term: filgrastim
      term:
        id: NCIT:C1474
        label: Filgrastim
  target_phenotypes:
  - preferred_term: Chronic severe neutropenia
    term:
      id: HP:0410252
      label: Persistently decreased total neutrophil count
  target_mechanisms:
  - target: Chronic severe neutropenia
    treatment_effect: MODULATES
    description: >-
      G-CSF drives residual granulopoiesis and neutrophil release, raising the blood
      neutrophil count without addressing the CXCR4 retention signal, so other
      cytopenias persist.
    evidence:
    - reference: PMID:30625055
      reference_title: Plerixafor for the Treatment of WHIM Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Patients with WHIM syndrome are often treated with granulocyte colony-stimulating
        factor (G-CSF), which can increase neutrophil counts but does not affect cytopenias
        other than neutropenia."
      explanation: States that G-CSF raises neutrophils only and leaves the other cytopenias
        untreated.
  evidence:
  - reference: PMID:30716504
    reference_title: "Long-Term Outcome of WHIM Syndrome in 18 Patients: High Risk of Lung Disease and HPV-Related Malignancies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Approximately 50% of patients received antibiotic prophylaxis, whereas G-CSF
      and immunoglobulin treatments were used in 72% and 55% of patients, respectively."
    explanation: Documents G-CSF as a widely used treatment in the international cohort.
- name: Immunoglobulin Replacement
  description: >-
    Immunoglobulin replacement provides passive antibody and reduces bacterial
    infection frequency; it is recommended to help prevent chronic lung damage in
    patients with recurrent infection or hypogammaglobulinemia.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: intravenous immunoglobulin therapy
    term:
      id: NCIT:C121331
      label: Intravenous Immunoglobulin Therapy
    therapeutic_agent:
    - preferred_term: human immunoglobulin G
      term:
        id: NCIT:C80829
        label: Human Immunoglobulin G
  target_phenotypes:
  - preferred_term: Recurrent bacterial infections
    term:
      id: HP:0002718
      label: Recurrent bacterial infections
  evidence:
  - reference: PMID:30716504
    reference_title: "Long-Term Outcome of WHIM Syndrome in 18 Patients: High Risk of Lung Disease and HPV-Related Malignancies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We suggest that immunoglobulin therapy should be promptly considered to control
      the frequency of bacterial infections and prevent chronic lung damage."
    explanation: Recommends immunoglobulin therapy to reduce infection frequency and prevent
      lung damage.
- name: Antibiotic Prophylaxis
  description: >-
    Long-term antibacterial prophylaxis, especially when started in early childhood,
    reduces bacterial infections and the consequent obstructive lung disease.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: antibiotic prophylaxis
    term:
      id: NCIT:C51993
      label: Antibiotic Prophylaxis
    therapeutic_agent:
    - preferred_term: antibiotic
      term:
        id: NCIT:C258
        label: Antibiotic
  target_phenotypes:
  - preferred_term: Recurrent bacterial infections
    term:
      id: HP:0002718
      label: Recurrent bacterial infections
  evidence:
  - reference: PMID:23009155
    reference_title: Description and outcome of a cohort of 8 patients with WHIM syndrome from the French Severe Chronic Neutropenia Registry.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Continuous prophylactic anti-infective measures, when started in early childhood,
      seem to effectively prevent further bacterial infections and the consequent development
      of COPD."
    explanation: Reports the benefit of early continuous antibiotic prophylaxis.
- name: Hematopoietic Stem Cell Transplantation
  description: >-
    Allogeneic hematopoietic stem cell transplantation is curative in selected
    patients, correcting the neutropenia and immunodeficiency and resolving
    autoimmunity, recurrent infections and warts; it carries transplant-related risk.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: hematopoietic cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_mechanisms:
  - target: CXCR4 Carboxy-Terminal Gain-of-Function Variant
    treatment_effect: BYPASSES
    description: >-
      Replacing the patient's hematopoietic system with donor cells that lack the
      CXCR4 gain-of-function allele removes the mutant receptor from the blood
      lineages, correcting the downstream cytopenias. The link covers hematopoietic
      cells only: keratinocytes keep the variant, so transplantation does not act on
      the CXCR4-Driven HPV Keratinocyte Transformation branch.
    evidence:
    - reference: PMID:34697698
      reference_title: Multicenter Experience of Hematopoietic Stem Cell Transplantation in WHIM Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "HSCT in WHIM syndrome corrects neutropenia and immunodeficiency, and leads
        to resolution of autoimmunity and recurrent infections, including warts."
      explanation: Multicenter evidence that transplantation corrects the disease phenotype.
    - reference: PMID:25662009
      reference_title: Chromothriptic cure of WHIM syndrome.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "In this patient, deletion of the disease allele, CXCR4(R334X), as well as
        163 other genes from one copy of chromosome 2 occurred in a hematopoietic stem
        cell (HSC) that repopulated the myeloid but not the lymphoid lineage."
      explanation: A spontaneous cure in which loss of the mutant allele from a single
        hematopoietic stem cell was enough to restore the myeloid lineage. It supports
        removing the variant from hematopoietic cells as the curative step, by a natural
        experiment rather than transplantation.
  evidence:
  - reference: PMID:34697698
    reference_title: Multicenter Experience of Hematopoietic Stem Cell Transplantation in WHIM Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At last follow-up (median 6.7 years), all six surviving patients were alive
      with full donor chimerism."
    explanation: Documents durable engraftment and survival after transplantation in a
      pediatric series.
clinical_trials:
- name: NCT03995108
  phase: PHASE_III
  status: COMPLETED
  description: >-
    Randomized, double-blind, placebo-controlled phase 3 trial of the oral CXCR4
    antagonist mavorixafor in patients aged 12 years and older with WHIM syndrome,
    with an open-label extension; the pivotal trial supporting FDA approval.
  target_phenotypes:
  - preferred_term: Chronic severe neutropenia
    term:
      id: HP:0410252
      label: Persistently decreased total neutrophil count
  - preferred_term: Lymphopenia
    term:
      id: HP:0001888
      label: Decreased total lymphocyte count
  evidence:
  - reference: clinicaltrials:NCT03995108
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The primary objective of the Randomized Placebo-Controlled Period is to demonstrate
      the efficacy of mavorixafor in participants with WHIM syndrome as assessed by increasing
      levels of circulating neutrophils compared with placebo"
    explanation: Registry record of the pivotal phase 3 mavorixafor trial in WHIM syndrome.
- name: NCT02231879
  phase: PHASE_III
  status: COMPLETED
  description: >-
    Investigator-initiated phase 3 crossover trial comparing the CXCR4 antagonist
    plerixafor with G-CSF for infection prevention in patients with CXCR4-mutated
    WHIM syndrome.
  target_phenotypes:
  - preferred_term: Recurrent bacterial infections
    term:
      id: HP:0002718
      label: Recurrent bacterial infections
  evidence:
  - reference: clinicaltrials:NCT02231879
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To compare plerixafor versus granulocyte colony stimulating factor (G-CSF)
      for preventing infections in people with WHIMS."
    explanation: Registry record of the plerixafor-versus-G-CSF phase 3 crossover trial.
animal_models:
- name: CXCR4 R334X knock-in WHIM mouse
  species: Mouse
  genotype: Cxcr4(+/1013) heterozygous knock-in (murine equivalent of human R334X)
  publication: PMID:22438253
  description: >-
    A heterozygous Cxcr4 knock-in mouse expressing a desensitization-resistant
    receptor. It reproduces the enhanced leukocyte response to CXCL12, the
    leukopenia, and the defective B and T lymphopoiesis of WHIM syndrome, and the
    leukopenia is reversed by CXCR4 antagonists, establishing the causal role of the
    mutant receptor. A parallel R334X gain-of-function model was used to dissect the
    stromal niche contribution to lymphopenia.
  modeled_mechanisms:
  - target: Lymphocyte and Monocyte Sequestration
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: ORGANISM
    description: >-
      The knock-in mouse reproduces the peripheral leukopenia and its reversal by
      CXCR4 antagonists, matching the human sequestration mechanism.
    limitations: >-
      A murine 1013 truncation modeling the human R334X allele; species differences
      in marrow architecture and lymphoid compartments qualify the fit.
    evidence:
    - reference: PMID:22438253
      reference_title: Proper desensitization of CXCR4 is required for lymphocyte development and peripheral compartmentalization in mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Cxcr4(+/mutant(1013)) mice display leukocytes with enhanced responses to
        Cxcl12 and exhibit leukopenia as reported in patients."
      explanation: The model recapitulates the enhanced CXCL12 response and leukopenia
        of patients.
  - target: Impaired B and T Lymphopoiesis
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      The knock-in mouse shows defective thymopoiesis and B-cell development,
      reproducing the developmental component of the human lymphopenia.
    limitations: >-
      Mouse lymphoid ontogeny differs from human; the stromal-niche mechanism is best
      characterized in the separate R334X model.
    evidence:
    - reference: PMID:22438253
      reference_title: Proper desensitization of CXCR4 is required for lymphocyte development and peripheral compartmentalization in mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In contrast, Cxcr4(+/1013) mice show defective thymopoiesis and B-cell
        development, accounting for circulating lymphopenia."
      explanation: The model reproduces the defective lymphopoiesis underlying the lymphopenia.
  evidence:
  - reference: PMID:22438253
    reference_title: Proper desensitization of CXCR4 is required for lymphocyte development and peripheral compartmentalization in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Treatment with CXCL12/CXCR4 antagonists transiently reverses blood anomalies,
      further demonstrating the causal role of the mutant receptor in the leukopenia."
    explanation: Antagonist reversal in the model establishes it as informative for the
      human sequestration mechanism.
prevalence:
- population: France (French Severe Chronic Neutropenia Registry)
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  rate_per_100000: 0.023
  rate_denominator: LIVE_BIRTHS
  notes: >-
    Estimated incidence of 0.23 per million births from the French registry; the
    disease is ultra-rare.
  evidence:
  - reference: PMID:23009155
    reference_title: Description and outcome of a cohort of 8 patients with WHIM syndrome from the French Severe Chronic Neutropenia Registry.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Estimated incidence for WS was of 0.23 per million births."
    explanation: Registry-based estimate of WHIM syndrome birth prevalence.
progression:
- phase: Early childhood presentation
  age_range: Onset in infancy or early childhood; diagnosis often delayed
  notes: >-
    Clinical features begin early (mean about 2 years) but diagnosis is frequently
    delayed by years because of the variable phenotype.
  evidence:
  - reference: PMID:30716504
    reference_title: "Long-Term Outcome of WHIM Syndrome in 18 Patients: High Risk of Lung Disease and HPV-Related Malignancies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical features manifested at 2.2 ± 2.6 years of age, whereas the disease
      diagnosis was delayed until 12.5 ± 10.4 years of age."
    explanation: Documents early onset and the substantial diagnostic delay.
- phase: Adult complications
  age_range: Adulthood
  notes: >-
    Long-term morbidity is dominated by chronic obstructive lung disease from
    recurrent pneumonia and by HPV- and EBV-associated malignancies.
  evidence:
  - reference: PMID:38442908
    reference_title: CXCR4 WHIM syndrome is a cancer predisposition condition for virus-induced malignancies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The 40-year risk of malignancy was 39% (95% confidence interval [CI]: 6%-74%)."
    explanation: Quantifies the substantial cumulative cancer risk over adult life.
clinical_burden:
  burden_level: HIGH
  rationale: >-
    WHIM syndrome causes lifelong severe cytopenias with recurrent bacterial
    infection from infancy, progressive bronchiectasis and chronic lung disease, and
    a high cumulative risk of virus-associated malignancy. Standard care is only
    partially effective; mechanism-based CXCR4 antagonists and transplantation have
    improved outcomes but the disease and its complications remain serious.
  evidence:
  - reference: PMID:30716504
    reference_title: "Long-Term Outcome of WHIM Syndrome in 18 Patients: High Risk of Lung Disease and HPV-Related Malignancies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with WHIM need careful monitoring and timely intervention for complications,
      mainly lung disease and HPV-related malignancies."
    explanation: Establishes the major long-term morbidities driving the HIGH burden assessment.
  - reference: PMID:38442908
    reference_title: CXCR4 WHIM syndrome is a cancer predisposition condition for virus-induced malignancies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The 40-year risk of malignancy was 39% (95% confidence interval [CI]: 6%-74%)."
    explanation: The high cumulative malignancy risk supports the HIGH burden.
discussions:
- discussion_id: pdc_interferon_wart_susceptibility
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Why is susceptibility to human papillomavirus so disproportionate in WHIM
    syndrome relative to other immunodeficiencies, and how much is due to the
    plasmacytoid dendritic cell / type I interferon defect versus a cell-intrinsic
    keratinocyte CXCR4 effect?
  attaches_to:
  - pathophysiology#Plasmacytoid Dendritic Cell Deficiency
  - pathophysiology#CXCR4-Driven HPV Keratinocyte Transformation
  rationale: >-
    HPV susceptibility in WHIM syndrome exceeds what neutropenia and antibody
    deficiency alone predict. Two non-exclusive mechanisms are proposed: loss of
    plasmacytoid dendritic cell type I interferon output, and a cell-intrinsic effect
    of the gain-of-function receptor in HPV-infected keratinocytes that promotes
    transformation. Their relative contributions in patients are not established, and
    it is not settled why HPV in particular, rather than other viruses, dominates.
  evidence:
  - reference: PMID:20736454
    reference_title: "Defect of plasmacytoid dendritic cells in warts, hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we hypothesized that the susceptibility of WHIM patients to warts is related
      to the abnormal homeostasis of plasmacytoid dendritic cells."
    explanation: States the interferon/pDC hypothesis for HPV susceptibility.
  - reference: PMID:21147466
    reference_title: "A pivotal role for CXCL12 signaling in HPV-mediated transformation of keratinocytes: clues to understanding HPV-pathogenesis in WHIM syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These results establish a pivotal role for CXCL12 signaling in HPV-mediated
      transformation and provide a mechanistic basis for understanding HPV pathogenesis
      in WHIM syndrome."
    explanation: Provides the competing cell-intrinsic keratinocyte mechanism.
- discussion_id: human_model_mismatch_lymphopoiesis
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Does the mesenchymal stromal niche mechanism of B and T lymphopenia defined in
    the R334X mouse operate the same way in human WHIM syndrome bone marrow?
  attaches_to:
  - pathophysiology#Impaired B and T Lymphopoiesis
  rationale: >-
    The switch from an adipogenic to an osteolineage-prone marrow stroma with reduced
    IL-7, and the rescue of B-cell development by LTbetaR or CXCR4 blockade, are
    defined in the CXCR4 R334X mouse. Human lymphopenia is concordant at the level of
    reduced early B-progenitor output, but the stromal transcriptional mechanism has
    not been demonstrated directly in human marrow, so its translational validity is
    the open question.
  evidence:
  - reference: PMID:36149943
    reference_title: Dysregulated stem cell niches and altered lymphocyte recirculation cause B and T cell lymphopenia in WHIM syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Blocking LTβR or CXCR4 signaling restored IL-7 production and B cell development
      in WHIM mice."
    explanation: The stromal mechanism and its rescue are established in the mouse, not
      yet in human tissue, which defines the mismatch.
notes: >-
  Scope. This entry is WHIM syndrome 1 (MONDO:8000006), the CXCR4 gain-of-function
  form, which accounts for nearly all molecularly confirmed cases. WHIM syndrome 2
  is a distinct disease caused by CXCR2 variants and is not curated here; rare
  clinically typical patients with a wild-type CXCR4 open reading frame (some with a
  GRK3 defect) also exist and are outside this CXCR4 entry. Several cited functional
  studies (PMID:15026312, PMID:15536153, PMID:18274673) include such CXCR4-wild-type
  patients; snippets used from them describe the shared enhanced-CXCL12-response
  biology rather than the CXCR4 genotype.

  Mechanism confidence. The core chain, CXCR4 carboxy-terminal gain-of-function
  variant, impaired desensitization and internalization, enhanced CXCL12-CXCR4
  signaling and marrow leukocyte retention, is directly measured in patient cells
  and confirmed pharmacologically (leukocytes mobilize within hours of CXCR4
  blockade), and is graded established. An early three-patient study (PMID:15026312)
  reported no internalization defect and no difference in calcium flux while still
  finding enhanced chemotaxis; both results are recorded as REFUTE evidence on the
  relevant nodes. Later patient-cell work (PMID:15536153), the GRK6 and beta-arrestin 2
  recruitment study (PMID:19956569) and a systematic 14-variant analysis
  (PMID:36089616) found impaired internalization, which the entry follows. The lymphopoiesis, plasmacytoid
  dendritic cell and keratinocyte-transformation branches rest partly on mouse and
  in vitro work and are graded provisional.

  GeneReviews. No GeneReviews chapter for WHIM syndrome was found in PubMed
  (genereviews[book]) at the time of curation; myelokathexis and CXCR4 likewise
  returned none.
references:
- reference: PMID:12692554
  title: "Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease."
- reference: PMID:15026312
  title: "Altered leukocyte response to CXCL12 in patients with warts hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome."
- reference: PMID:15536153
  title: WHIM syndromes with different genetic anomalies are accounted for by impaired CXCR4 desensitization to CXCL12.
- reference: PMID:20226738
  title: "Oligoclonality, impaired class switch and B-cell memory responses in WHIM syndrome."
- reference: PMID:20736454
  title: "Defect of plasmacytoid dendritic cells in warts, hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome patients."
- reference: PMID:21147466
  title: "A pivotal role for CXCL12 signaling in HPV-mediated transformation of keratinocytes: clues to understanding HPV-pathogenesis in WHIM syndrome."
- reference: PMID:21890643
  title: The CXCR4 antagonist plerixafor corrects panleukopenia in patients with WHIM syndrome.
- reference: PMID:22438253
  title: Proper desensitization of CXCR4 is required for lymphocyte development and peripheral compartmentalization in mice.
- reference: PMID:22596258
  title: WHIM syndrome caused by a single amino acid substitution in the carboxy-tail of chemokine receptor CXCR4.
- reference: PMID:23009155
  title: Description and outcome of a cohort of 8 patients with WHIM syndrome from the French Severe Chronic Neutropenia Registry.
- reference: PMID:30565238
  title: "WHIM syndrome: Immunopathogenesis, treatment and cure strategies."
- reference: PMID:30625055
  title: Plerixafor for the Treatment of WHIM Syndrome.
- reference: PMID:30716504
  title: "Long-Term Outcome of WHIM Syndrome in 18 Patients: High Risk of Lung Disease and HPV-Related Malignancies."
- reference: PMID:31313072
  title: "WHIM Syndrome: from Pathogenesis Towards Personalized Medicine and Cure."
- reference: PMID:34697698
  title: Multicenter Experience of Hematopoietic Stem Cell Transplantation in WHIM Syndrome.
- reference: PMID:35947323
  title: Disease Progression of WHIM Syndrome in an International Cohort of 66 Pediatric and Adult Patients.
- reference: PMID:36089616
  title: "Genotype-phenotype correlations in WHIM syndrome: a systematic characterization of CXCR4(WHIM) variants."
- reference: PMID:36149943
  title: Dysregulated stem cell niches and altered lymphocyte recirculation cause B and T cell lymphopenia in WHIM syndrome.
- reference: PMID:37561579
  title: A phase III randomized crossover trial of plerixafor versus G-CSF for treatment of WHIM syndrome.
- reference: PMID:38442908
  title: CXCR4 WHIM syndrome is a cancer predisposition condition for virus-induced malignancies.
- reference: PMID:38643510
  title: "A phase 3 randomized trial of mavorixafor, a CXCR4 antagonist, for WHIM syndrome."
- reference: PMID:39004659
  title: "Mavorixafor: First Approval."

📚

References & Deep Research

References

PMID:12692554

Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease.