Whim Syndrome

A number sign (#) is used with this entry because of evidence that WHIM syndrome (WHIMS) is caused by heterozygous mutation in the CXCR4 gene (162643) on chromosome 2q22.

Description

WHIM syndrome is an immunodeficiency disease characterized by neutropenia, hypogammaglobulinemia, and extensive human papillomavirus (HPV) infection. Despite the peripheral neutropenia, bone marrow aspirates from affected individuals contain abundant mature myeloid cells, a condition termed myelokathexis. The susceptibility to HPV is disproportionate compared with other immunodeficiency conditions (summary by Hernandez et al., 2003).

Clinical Features

Wetzler et al. (1990) described a family in which 2 sisters and their father had a combination of chronic papillomavirus and bacterial sinopulmonary infections, low immunoglobulin levels, and peripheral neutropenia in the face of bone marrow hypercellularity, shift to the right in granulopoiesis, and distinctive neutrophil morphology. The occurrence of neutropenia and retention of bone marrow neutrophils has been called myelokathexis (kathexis = retention) (Zuelzer, 1964; O'Regan et al., 1977). In addition to extensive verrucae vulgaris of the hands, both sisters, aged 23 and 22 years, had cervical papillomatosis with severe dysplasia of the cervix, and 1 had vulval condylomata acuminata. Neutrophils had cytoplasmic vacuoles and hypersegmented nuclei with dense, pycnotic lobes connected by long filaments. There were no morphologic abnormalities observed in lymphoid cells, erythroid series or megakaryocytes and the karyotype was normal in both. The father had severe neutropenia and warts as well as frequent episodes of pneumonia necessitating partial lung resection. He died at the age of 31 years of meningitis and septicemia. A sister of the father died at age 1 month of pneumonia. The same disorder appears to have been described by Mentzer et al. (1977). Wetzler et al. (1990) suggested that this disorder be designated the WHIM syndrome; the acronym stands for warts, hypogammaglobulinemia, infections, and myelokathexis.

Gorlin et al. (2000) reported a kindred with 6 affected individuals in 4 sibships in 3 generations; there was no instance of male-to-male transmission. Affected individuals showed chronic noncyclic neutropenia and hypercellular bone marrow. The hypermature neutrophils were bizarre in shape. Condensed nuclei connected by long, stringy filaments and vacuolated cytoplasms suggested apoptosis. Fever or other stress increased the release of neutrophils. Hypogammaglobulinemia was marked and associated with recurrent upper respiratory infections. The patients had numerous warts, some venereal, with resultant cervical and vulval premalignant dysplasia. Gorlin et al. (2000) found approximately 20 reported examples under various designations, and included the report by Krill et al. (1964) in that number. Because of the lack of male-to-male transmission, they performed a linkage search of the entire X chromosome including the pseudoautosomal region and found no evidence of linkage. The birth of an unaffected daughter to the propositus confirmed that the gene is not X-linked and by exclusion can be considered autosomal dominant. The sex ratio among reported patients, including the kindred of Gorlin et al. (2000), was 17 females to 8 males.

McDermott et al. (2015) reported follow-up of the original patient (WHIM-09) with WHIM syndrome reported by Krill et al. (1964) and Zuelzer (1964). The patient reported that from childhood through age 38, she had had many serious infections, often requiring hospitalization, but then none in the 20 subsequent years. She also had a history of confluent warts that spontaneously resolved also in her thirties. At the time of presentation, laboratory studies showed no neutropenia, but a mild leukocytosis with increased neutrophil and monocyte counts, and decreased B cells and naive T cells. These findings were consistent with spontaneous and durable complete clinical remission. Her 2 daughters were affected with classic WHIM syndrome, consistent with autosomal dominant inheritance. Genetic analysis showed that the proband (WHIM-09) was a genetic mosaic for the R334X CXCR4 mutation (162643.0001), with the mutation present in lymphocytes and skin fibroblasts, but not in neutrophils or monocytes. Analysis of patient bone marrow cells showed chromothripsis with deletion of the mutant CXCR4 gene and loss of 1 copy of 163 additional annotated genes and other complex abnormalities of chromosome 2. Further analysis indicated that this occurred in a hematopoietic stem cell that repopulated the myeloid and erythroid cell lineage, but not the lymphoid lineage. In competitive mouse bone marrow transplantation experiments, Cxcr4 haploinsufficiency was sufficient to confer a strong long-term engraftment advantage of donor bone marrow over bone marrow from either wildtype or WHIM syndrome model mice, suggesting a potential mechanism for the patient's remission. The findings suggested that partial inactivation of CXCR4 may have general utility as a strategy to promote hematopoietic stem cell engraftment in transplantation.

Clinical Management

Patients with WHIM syndrome can be treated with granulocyte colony-stimulating factor (GCSF; 138970), which can increase neutrophil counts but does not affect cytopenias other than neutropenia. McDermott et al. (2019) reported the treatment of 3 severely affected patients with WHIM syndrome who could not receive GCSF, but instead were treated with low-dose plerixafor, a CXCR4 antagonist, for 19 to 52 months. Myelofibrosis, panleukopenia, anemia, and thrombocytopenia were ameliorated, the wart burden and frequency of infection declined, human papillomavirus-associated oropharyngeal squamous cell carcinoma stabilized, and quality of life improved markedly. Adverse events were mainly infections attributable to the underlying immunodeficiency. One patient died from complications of elective reconstructive surgery.

Mapping

Hernandez et al. (2003) localized the gene mutant in WHIM syndrome to a region of roughly 12 cM on chromosome 2q21.

Inheritance

Hernandez et al. (2003) confirmed autosomal dominant inheritance of WHIM syndrome.

Molecular Genetics

In affected members of 5 unrelated families with WHIM syndrome, Hernandez et al. (2003) identified heterozygous truncating mutations in the cytoplasmic tail domain of the CXCR4 gene (162643.0001-162643.0003). They identified heterozygosity for one of these mutations (162643.0001) in affected members of a family with apparent recessive inheritance of isolated myelokathexis, which was thought to be explained by paternal somatic and gonadal mosaicism. The authors concluded that expression of the mutated allele in hematopoietic cells appeared to be required for disease occurrence. In affected members of another family with apparent autosomal recessive inheritance of isolated myelokathexis, no mutations in the CXCR4 gene were found, suggesting genetic heterogeneity for this aspect of the WHIM syndrome phenotype.

Balabanian et al. (2005) identified a heterozygous mutation in the CXCR4 gene (162643.0004) in 2 sibs with WHIM syndrome.

Pathogenesis

Balabanian et al. (2005) observed that cells derived from patients with WHIM syndrome showed impaired desensitization and internalization of CXCR4 in response to its ligand CXCL12 (600835). This lack of response was believed to result in enhanced CXCR4 activity and increased chemotactic responsiveness, ultimately resulting in immunohematologic clinical manifestations.

Lagane et al. (2008) demonstrated that the augmented CXCR4 responsiveness in WHIM leukocytes also resulted from enhanced ARRB2 (107941)-dependent signaling downstream from the mutant CXCR4 receptor. ARRB2 is involved in the desensitization and internalization of G protein-coupled receptors. An SHSK motif in CXCR4 was necessary for ARRB2-dependent signaling. Mutant CXCR4 proteins were found to form functional heterodimers with wildtype CXCR4, consistent with a dominant-negative effect.

In cells derived from 2 unrelated patients with WHIM syndrome who lacked CXCR4 mutations (Balabanian et al., 2005), Balabanian et al. (2008) found that the defect was similar to that observed in patients with mutations: impaired CXCL12-induced internalization and desensitization of CXCR4. Overexpression of GRK3 (ADRBK2; 109636) in both leukocytes and skin fibroblasts from these patients restored the CXCR4 defect and normalized chemotaxis, thus implicating GRK3 as a negative regulator of CXCR4 activation. Cells derived from 1 of the patients showed decreased GRK3 protein and mRNA synthesis, although no mutations were identified in the GRK3 gene. Cells from the other patient had normal GRK3 levels, but still responded to GRK3 overexpression. The results revealed a pivotal role for GRK3 in regulating CXCR4 attenuation and provided a mechanistic link between the GRK3 pathway and WHIM syndrome in patients without CXCR4 mutations.