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a pattern of symptoms indicative of some disease
a complex of concurrent things; "every word has a syndrome of meanings"

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(疾患の徴候となる一群の)症徴候,症候群 / (事件・社会的状態などのパターンを示す)徴候形態
気まぐれ,でき心,むら気

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/09/06 01:15:48」(JST)

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WHIM Syndrome (or Warts, Hypogammaglobulinemia, Infections, and Myelokathexis syndrome) is a rare congenital immunodeficiency disorder characterized by chronic noncyclic neutropenia.

Diagnosis

Patients exhibit increased susceptibility to bacterial and viral infections, especially from common serotype human papilloma virus, resulting in warts on the hands and feet starting in childhood. Myelokathexis refers to retention (kathexis) of neutrophils in the bone marrow (myelo). In addition, lymphocytes and IgG antibody levels (gammaglobulins) are often deficient.

Pathophysiology

WHIM syndrome has an autosomal dominant pattern of inheritance.

WHIM syndrome results from autosomal dominant mutations in the gene for the chemokine receptor, CXCR4,^[1]^[2] resulting in a carboxy-terminus truncation of the receptor of between ten and 19 residues. The gene mutant is located on 2q21. The truncation of the receptor protein results in the inability of downregulation after stimulation. Thus, the receptor remain in an activated state.^[3] WHIM syndrome is one of only a few diseases directly and primarily caused by an aberrant chemokine, making its molecular biology important in understanding the role of cell signaling and trafficking.

An association with GRK3 has also been observed.^[4]

Treatment

Infusions of immune globulin can reduce the frequency of bacterial infections, and G-CSF or GM-CSF therapy improves blood neutrophil counts.^[5]

As WHIM syndrome is a molecular disease arising from gain-of-function mutations in CXCR4, preclinical studies identified plerixafor, a specific CXCR4 antagonist, as a potential mechanism-based therapeutic for the disease.^[6] Two subsequent clinical trials involving a handful of patients with WHIM syndrome demonstrated that plerixafor could increase white blood cell counts and continues to be a promising targeted therapy.^[7]^[8]

A woman with spontaneous remission of her WHIM syndrome due to Chromothripsis in one of her blood stem cells has been identified. ^[9]^[10]

References

^ Hernandez PA, Gorlin RJ, Lukens JN et al. (May 2003). "Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease". Nat. Genet. 34 (1): 70–4. doi:10.1038/ng1149. PMID 12692554.
^ Kawai T, Choi U, Cardwell L et al. (January 2007). "WHIM syndrome myelokathexis reproduced in the NOD/SCID mouse xenotransplant model engrafted with healthy human stem cells transduced with C-terminus-truncated CXCR4". Blood 109 (1): 78–84. doi:10.1182/blood-2006-05-025296. PMC 1785067. PMID 16946301.
^ Lagane B, Chow KY, Balabanian K et al. (July 2008). "CXCR4 dimerization and beta-arrestin-mediated signaling account for the enhanced chemotaxis to CXCL12 in WHIM syndrome". Blood 112 (1): 34–44. doi:10.1182/blood-2007-07-102103. PMID 18436740.
^ Balabanian K, Levoye A, Klemm L et al. (March 2008). "Leukocyte analysis from WHIM syndrome patients reveals a pivotal role for GRK3 in CXCR4 signaling". J. Clin. Invest. 118 (3): 1074–84. doi:10.1172/JCI33187. PMC 2242619. PMID 18274673.
^ Wetzler M, Talpaz M, Kleinerman ES et al. (1990). "A new familial immunodeficiency disorder characterized by severe neutropenia, a defective marrow release mechanism, and hypogammaglobulinemia.". Am. J. Med. 89 (5): 663–72. doi:10.1016/0002-9343(90)90187-i. PMID 2239986.
^ McDermott DH, Lopez J, Deng F et al. (2011). "AMD3100 is a potent antagonist at CXCR4(R334X), a hyperfunctional mutant chemokine receptor and cause of WHIM syndrome.". J. Cell. Mol. Med. 15 (10): 2071–81. doi:10.1111/j.1582-4934.2010.01210.x. PMC 3071896. PMID 21070597.
^ McDermott DH et al. (2011). "The CXCR4 antagonist plerixafor corrects panleukopenia in patients with WHIM syndrome.". Blood 118 (18): 4957–62. doi:10.1182/blood-2011-07-368084. PMID 21890643.
^ Dale DC et al. (Nov 2011). "The CXCR4 antagonist plerixafor is a potential therapy for myelokathexis, WHIM syndrome.". Blood 118 (18): 4963–6. doi:10.1182/blood-2011-06-360586. PMID 21835955.
^ Kaiser, Jocelyn (5 February 2015). "Shattered chromosome cures woman of immune disease". Science.
^ David H. McDermott, Ji-Liang Gao, Qian Liu, Marie Siwicki, Craig Martens, Paejonette Jacobs, Daniel Velez, Erin Yim, Christine R. Bryke, Nancy Hsu, Zunyan Dai, Martha M. Marquesen, Elina Stregevsky, Nana Kwatemaa, Narda Theobald, Debra A. Long Priel, Stefania Pittaluga, Mark A. Raffeld, Katherine R. Calvo, Irina Maric, Ronan Desmond, Kevin L. Holmes, Douglas B. Kuhns, Karl Balabanian, Françoise Bachelerie, Stephen F. Porcella, Harry L. Malech, Philip M. Murphy (5 February 2015). "Chromothriptic Cure of WHIM Syndrome". Cell. doi:10.1016/j.cell.2015.01.014. ISSN 0092-8674.

UpToDate Contents

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1. 複合免疫不全 combined immunodeficiencies
2. 先天性好中球減少症 congenital neutropenia
3. ウィスコット・オルドリック症候群 wiskott aldrich syndrome
4. 白血球増多症および好中球増多症の定義およびメカニズム definition and mechanisms of leukocytosis and neutrophilia
5. 感染症を繰り返す小児に対するアプローチ approach to the child with recurrent infections

English Journal

Filamin A interaction with the CXCR4 third intracellular loop regulates endocytosis and signaling of WT and WHIM-like receptors.

Gómez-Moutón C1, Fischer T1, Peregil RM1, Jiménez-Baranda S1, Stossel TP2, Nakamura F2, Mañes S1.
Blood.Blood.2015 Feb 12;125(7):1116-25. doi: 10.1182/blood-2014-09-601807. Epub 2014 Oct 29.
Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare congenital immunodeficiency often caused by mutations in the last 10 to 19 C-terminal amino acids of CXCR4. These mutations impair CXCR4 internalization and increase responsiveness to CXCL12. The CXCR4 C-terminal d
PMID 25355818

Chromothriptic cure of WHIM syndrome.

McDermott DH1, Gao JL1, Liu Q1, Siwicki M1, Martens C2, Jacobs P1, Velez D1, Yim E1, Bryke CR3, Hsu N3, Dai Z4, Marquesen MM5, Stregevsky E6, Kwatemaa N5, Theobald N5, Long Priel DA7, Pittaluga S8, Raffeld MA8, Calvo KR9, Maric I9, Desmond R10, Holmes KL6, Kuhns DB7, Balabanian K11, Bachelerie F11, Porcella SF2, Malech HL5, Murphy PM12.
Cell.Cell.2015 Feb 12;160(4):686-99. doi: 10.1016/j.cell.2015.01.014. Epub 2015 Feb 5.
Chromothripsis is a catastrophic cellular event recently described in cancer in which chromosomes undergo massive deletion and rearrangement. Here, we report a case in which chromothripsis spontaneously cured a patient with WHIM syndrome, an autosomal dominant combined immunodeficiency disease cause
PMID 25662009

Primary cutaneous follicle center lymphoma in a patient with WHIM syndrome.

Yoshii Y1, Kato T, Ono K, Takahashi E, Fujimoto N, Kobayashi S, Kimura F, Nonoyama S, Satoh T.
Journal of the European Academy of Dermatology and Venereology : JEADV.J Eur Acad Dermatol Venereol.2015 Jan 8. doi: 10.1111/jdv.12927. [Epub ahead of print]
PMID 25571909