Successful umbilical cord blood stem cell transplantation in a child with WHIM syndrome

Kriván, Gergely; Erdős, Melinda; Kállay, Krisztián; Benyó, Gábor; Tóth, Ágnes; Sinkó, János; Goda, Vera; Töth, Beáta; Maródi, László

doi:10.1111/j.1600-0609.2009.01368.x

Cited by 35 publications

(26 citation statements)

References 10 publications

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“…Two were cured by allogeneic stem cell transplantation [10,11], and one was cured by chromothripsis, a naturally-occurring, spontaneous and in this case highly fortuitous shattering and rearrangement of one copy of chromosome 2, which selectively deleted the WHIM allele as well as one copy of 163 other genes in HSCs and myeloid but not lymphoid cells (Figure 4) [2]. The molecular mechanisms leading to chromothripsis have not yet been defined.…”

Section: 5 Treatmentmentioning

confidence: 99%

“…Three patients have been cured to date: two by bone marrow transplantation and one by chromothripsis (chromosome shattering) involving fortuitous deletion of the disease allele in an HSC that gained a relative growth advantage [2,10,11]. Two CXCR4 antagonists, plerixafor (AMD3100, trade name Mozobil marketed by Sanofi) given subcutaneously and X4P-001-LD (under development by X4-Pharma) given orally, are currently undergoing clinical trials.…”

Section: 1 Introductionmentioning

confidence: 99%

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Pathogenesis, diagnosis and therapeutic strategies in WHIM syndrome immunodeficiency

Heusinkveld

Yim

Yang

et al. 2017

Expert Opinion on Orphan Drugs

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2.1 Introduction WHIM syndrome is a rare combined primary immunodeficiency disorder caused by autosomal dominant gain-of-function mutations in the chemokine receptor CXCR4. It is the only Mendelian condition known to be caused by mutation of a chemokine or chemokine receptor. As such, it provides a scientific opportunity to understand chemokine-dependent immunoregulation in humans and a medical opportunity to develop mechanism-based treatment and cure strategies. 2.2 Areas covered This review covers the clinical features, genetics, immunopathogenesis and clinical management of WHIM syndrome. Clinical trials of targeted therapeutic agents and potential cure strategies are also included. 2.3 Expert opinion WHIM syndrome may be particularly amenable to mechanism-based therapeutics for three reasons: 1) CXCR4 has been validated as the molecular target in the disease by Mendelian genetics; 2) the biochemical abnormality is excessive CXCR4 signaling; and 3) antagonists selective for CXCR4 have been developed. Plerixafor is FDA-approved for hematopoietic stem cell (HSC) mobilization and has shown preliminary safety and efficacy in phase I clinical trials in WHIM syndrome. Gene editing may represent a viable cure strategy, since chromothriptic deletion of the disease allele in HSCs resulted in clinical cure of a patient and because CXCR4 haploinsufficiency enhances engraftment of transplanted HSCs in mice.

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Section: 5 Treatmentmentioning

confidence: 99%

Section: 1 Introductionmentioning

confidence: 99%

Pathogenesis, diagnosis and therapeutic strategies in WHIM syndrome immunodeficiency

Heusinkveld

Yim

Yang

et al. 2017

Expert Opinion on Orphan Drugs

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“…There is evidence that HPV vaccine does not represent a risk to immune-compromised persons and it can be safely recommended for WHIM patients. Indeed, one WHIM patient immunized with the tetravalent HPV vaccine was able to mount HPV-specific antibody titers to the vaccine types, although the extent of the response was significantly lower than immune- [51]. According to the evidence that mutated CXCR4 hyperfunction is the main pathogenetic mechanism in WHIM syndrome, a new therapeutic strategy may be postulated considering the CXCR4 antagonist plerixafor (also called Mozobil, former known as AMD3100) [52].…”

Section: Treatmentmentioning

confidence: 99%

Clinical and Genetic Features of Warts, Hypogammaglobulinemia, Infections and Myelokathexis (WHIM) Syndrome

Dotta

Tassone

Badolato

2011

CMM

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WHIM syndrome is a dominantly inherited primary immunodeficiency disorder representing the first identified example of human disease caused by mutations in the gene encoding for the chemokine receptor CXCR4. Pathogenesis is mediated by CXCR4 hyperfunction, leading to increased responsiveness to its unique ligand CXCL12 (also known as SDF-1). The altered CXCR4/CXCL12 interaction likely impairs cellular homeostasis and trafficking, resulting in immunological dysfunctions. The acronym WHIM resumes the main features of the syndrome: Warts, Hypogammaglobulinemia, Infections and Myelokathexis, which is abnormal retention of mature neutrophils in the bone marrow. WHIM patients suffer from recurrent bacterial infections since childhood and manifest a specific susceptibility to HPV infections. Hematological findings include neutropenia, lymphopenia and hypogammaglobulinemia. Because of the rarity of the disease and the heterogeneity in clinical presentation, diagnosis is often delayed. In the majority of patients, the phenotype is incomplete at the onset and WHIM syndrome is not suspected. Early identification may improve clinical and therapeutic management. Symptomatic treatments include G-CSF, substitutive immunoglobulins and antibiotic prophylaxis. A new therapeutic strategy might include the potent inhibitor of CXCR4 function plerixafor (Mozobil), as an agent specifically targeting the molecular defect in order to attenuate the phenotypic manifestations of the syndrome.

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“…In the past 2 years, advances in this field have occurred in both myeloid and lymphoid immunodeficiencies. This review will address recent developments in these areas, with a primary focus on entities that lead to neutropenia as an isolated finding or in the context of other immune defects (Table 1) [2,3▪,4–7,8▪▪,9–34,35▪,36▪,37–43,44▪,45–47,48▪▪,49▪▪,50–58], excluding marrow disorders presenting as pancytopenia and disorders only described in single patients or kindreds. Treatment of neutropenia in the setting of PIDD will also be discussed.…”

Section: Introductionmentioning

confidence: 99%

Neutropenia in primary immunodeficiency

Sokolic

2013

Current Opinion in Hematology

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Purpose of review Neutropenia is a feature of several primary immunodeficiency diseases (PIDDs). Because of the diverse pathophysiologies of the PIDDs and the rarity of each disorder, data are often lacking, leading to the necessity of empiric treatment. Recent developments in the understanding of neutropenia in several of the PIDDs make a review of the data timely. Recent findings The category of severe congenital neutropenia continues to expand. Mutations in G6PC3 have been identified as the cause of neutropenia in a minority of previously molecularly undefined cases. Recent advances have broadened our understanding of the pathophysiology and the clinical expression of this disorder. A possible function of the C16orf57 gene has been hypothesized that may explain the clinical overlap between Clerucuzio-type poikiloderma with neutropenia and other marrow diseases. Plerixafor has been shown to be a potentially useful treatment in the warts, hypogammaglobulinemia, infection, and myelokathexis syndrome. Investigations of patients with adenosine deaminase deficient severe combined immunodeficiency have identified neutropenia, and particularly susceptibility to myelotoxins, as a feature of this disorder. Granulocyte-colony stimulating factor is the treatment of choice for neutropenia in PIDD, whereas hematopoietic cell transplantation is the only curative option. Summary The number of PIDDs associated with neutropenia has increased, as has our understanding of the range of phenotypes. Additional data and hypotheses have been generated helping to explain the diversity of presentations of neutropenia in PIDDs.

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Successful umbilical cord blood stem cell transplantation in a child with WHIM syndrome

Cited by 35 publications

References 10 publications

Pathogenesis, diagnosis and therapeutic strategies in WHIM syndrome immunodeficiency

Pathogenesis, diagnosis and therapeutic strategies in WHIM syndrome immunodeficiency

Clinical and Genetic Features of Warts, Hypogammaglobulinemia, Infections and Myelokathexis (WHIM) Syndrome

Neutropenia in primary immunodeficiency

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