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WHIM syndrome 2(WHIMS2)

MedGen UID:
1785594
Concept ID:
C5543622
Disease or Syndrome
Synonym: WARTS, HYPOGAMMAGLOBULINEMIA, INFECTIONS, AND MYELOKATHEXIS SYNDROME 2
 
Gene (location): CXCR2 (2q35)
 
Monarch Initiative: MONDO:0030374
OMIM®: 619407

Definition

WHIM syndrome-2 (WHIMS2) is an autosomal recessive immunologic disorder characterized by chronic neutropenia and myelokathexis, which is impaired neutrophil mobilization from the bone marrow. Affected individuals have recurrent infections, usually bacterial (summary by Auer et al., 2014). In a review of WHIMS, Heusinkveld et al. (2019) noted that there is significant phenotypic variation among patients, such that some individuals may have an 'incomplete' form of the disorder in which 1 or more of the classic tetrad features are not present. In general, the WHIMS phenotype comprises a spectrum of manifestations with variable expressivity. For a discussion of genetic heterogeneity of WHIMS, see 193670. [from OMIM]

Clinical features

From HPO
Tetralogy of Fallot
MedGen UID:
21498
Concept ID:
C0039685
Congenital Abnormality
Each of the heart defects associated with CCHD affects the flow of blood into, out of, or through the heart. Some of the heart defects involve structures within the heart itself, such as the two lower chambers of the heart (the ventricles) or the valves that control blood flow through the heart. Others affect the structure of the large blood vessels leading into and out of the heart (including the aorta and pulmonary artery). Still others involve a combination of these structural abnormalities.\n\nSome people with treated CCHD have few related health problems later in life. However, long-term effects of CCHD can include delayed development and reduced stamina during exercise. Adults with these heart defects have an increased risk of abnormal heart rhythms, heart failure, sudden cardiac arrest, stroke, and premature death.\n\nAlthough babies with CCHD may appear healthy for the first few hours or days of life, signs and symptoms soon become apparent. These can include an abnormal heart sound during a heartbeat (heart murmur), rapid breathing (tachypnea), low blood pressure (hypotension), low levels of oxygen in the blood (hypoxemia), and a blue or purple tint to the skin caused by a shortage of oxygen (cyanosis). If untreated, CCHD can lead to shock, coma, and death. However, most people with CCHD now survive past infancy due to improvements in early detection, diagnosis, and treatment.\n\nCritical congenital heart disease (CCHD) is a term that refers to a group of serious heart defects that are present from birth. These abnormalities result from problems with the formation of one or more parts of the heart during the early stages of embryonic development. CCHD prevents the heart from pumping blood effectively or reduces the amount of oxygen in the blood. As a result, organs and tissues throughout the body do not receive enough oxygen, which can lead to organ damage and life-threatening complications. Individuals with CCHD usually require surgery soon after birth.\n\nPeople with CCHD have one or more specific heart defects. The heart defects classified as CCHD include coarctation of the aorta, double-outlet right ventricle, D-transposition of the great arteries, Ebstein anomaly, hypoplastic left heart syndrome, interrupted aortic arch, pulmonary atresia with intact septum, single ventricle, total anomalous pulmonary venous connection, tetralogy of Fallot, tricuspid atresia, and truncus arteriosus.
Myelokathexis
MedGen UID:
543867
Concept ID:
C0272173
Disease or Syndrome
Impaired egress of mature neutrophils from bone marrow causing neutropenia.
Chronic neutropenia
MedGen UID:
1671095
Concept ID:
C0746882
Disease or Syndrome
Neutropenia with an absolute neutrophil count (ANC) less than 1,500,000,000/L lasting for more than 3 months.
Severe infection
MedGen UID:
1700844
Concept ID:
C5139167
Disease or Syndrome
A type of infection that is regarded as a sign of a pathological susceptibility to infection because of unusual severity or intensity of the infection.
Recurrent gingivitis
MedGen UID:
1814411
Concept ID:
C5676847
Disease or Syndrome
Repeated occurrences of inflammatory condition of the gums (gingival tissue), most commonly caused by bacterial infection.

Professional guidelines

PubMed

Yilmaz M, Potts DE, Geier C, Walter JE
Am J Med Genet C Semin Med Genet 2022 Jun;190(2):215-221. Epub 2022 Oct 9 doi: 10.1002/ajmg.c.32002. PMID: 36210583
Lanini LL, Prader S, Siler U, Reichenbach J
Pediatr Allergy Immunol 2017 Mar;28(2):124-134. Epub 2016 Oct 13 doi: 10.1111/pai.12654. PMID: 27612320

Recent clinical studies

Etiology

Göschl L, Mrak D, Grabmeier-Pfistershammer K, Stiasny K, Haslacher H, Schneider L, Deimel T, Kartnig F, Tobudic S, Aletaha D, Burgmann H, Bonelli M, Pickl WF, Förster-Waldl E, Scheinecker C, Vossen MG
Front Immunol 2022;13:974987. Epub 2022 Sep 14 doi: 10.3389/fimmu.2022.974987. PMID: 36189225Free PMC Article
Dale DC, Firkin F, Bolyard AA, Kelley M, Makaryan V, Gorelick KJ, Ebrahim T, Garg V, Tang W, Jiang H, Skerlj R, Beaussant Cohen S
Blood 2020 Dec 24;136(26):2994-3003. doi: 10.1182/blood.2020007197. PMID: 32870250Free PMC Article
Dotta L, Notarangelo LD, Moratto D, Kumar R, Porta F, Soresina A, Lougaris V, Plebani A, Smith CIE, Norlin AC, Gòmez Raccio AC, Bubanska E, Bertolini P, Amendola G, Visentini M, Fiorilli M, Venuti A, Badolato R
J Allergy Clin Immunol Pract 2019 May-Jun;7(5):1568-1577. Epub 2019 Feb 2 doi: 10.1016/j.jaip.2019.01.045. PMID: 30716504
Cao XX, Meng Q, Cai H, He TH, Zhang CL, Su W, Sun J, Li Y, Xu W, Zhou DB, Li J
Ann Hematol 2017 Jun;96(6):971-976. Epub 2017 Mar 9 doi: 10.1007/s00277-017-2968-z. PMID: 28280994
Stiehm ER
Pediatr Res 1993 Jan;33(1 Suppl):S2-7; discussion S7-8. doi: 10.1203/00006450-199305001-00007. PMID: 8433870

Diagnosis

Yilmaz M, Potts DE, Geier C, Walter JE
Am J Med Genet C Semin Med Genet 2022 Jun;190(2):215-221. Epub 2022 Oct 9 doi: 10.1002/ajmg.c.32002. PMID: 36210583
Geier CB, Ellison M, Cruz R, Pawar S, Leiss-Piller A, Zmajkovicova K, McNulty SM, Yilmaz M, Evans MO 2nd, Gordon S, Ujhazi B, Wiest I, Abolhassani H, Aghamohammadi A, Barmettler S, Bhar S, Bondarenko A, Bolyard AA, Buchbinder D, Cada M, Cavieres M, Connelly JA, Dale DC, Deordieva E, Dorsey MJ, Drysdale SB, Ehl S, Elfeky R, Fioredda F, Firkin F, Förster-Waldl E, Geng B, Goda V, Gonzalez-Granado L, Grunebaum E, Grzesk E, Henrickson SE, Hilfanova A, Hiwatari M, Imai C, Ip W, Jyonouchi S, Kanegane H, Kawahara Y, Khojah AM, Kim VH, Kojić M, Kołtan S, Krivan G, Langguth D, Lau YL, Leung D, Miano M, Mersyanova I, Mousallem T, Muskat M, Naoum FA, Noronha SA, Ouederni M, Ozono S, Richmond GW, Sakovich I, Salzer U, Schuetz C, Seeborg FO, Sharapova SO, Sockel K, Volokha A, von Bonin M, Warnatz K, Wegehaupt O, Weinberg GA, Wong KJ, Worth A, Yu H, Zharankova Y, Zhao X, Devlin L, Badarau A, Csomos K, Keszei M, Pereira J, Taveras AG, Beaussant-Cohen SL, Ong MS, Shcherbina A, Walter JE
J Clin Immunol 2022 Nov;42(8):1748-1765. Epub 2022 Aug 10 doi: 10.1007/s10875-022-01312-7. PMID: 35947323Free PMC Article
Sharma P, Naseem S, Varma N, Malhotra P
Br J Haematol 2021 May;193(4):690. Epub 2021 Feb 17 doi: 10.1111/bjh.17355. PMID: 33598939Free PMC Article
Scala S
Clin Cancer Res 2015 Oct 1;21(19):4278-85. Epub 2015 Jul 21 doi: 10.1158/1078-0432.CCR-14-0914. PMID: 26199389
Dotta L, Badolato R
Immunol Lett 2014 Oct;161(2):222-5. Epub 2013 Dec 4 doi: 10.1016/j.imlet.2013.11.018. PMID: 24316408

Therapy

Badolato R, Alsina L, Azar A, Bertrand Y, Bolyard AA, Dale D, Deyà-Martínez À, Dickerson KE, Ezra N, Hasle H, Kang HJ, Kiani-Alikhan S, Kuijpers TW, Kulagin A, Langguth D, Levin C, Neth O, Olbrich P, Peake J, Rodina Y, Rutten CE, Shcherbina A, Tarrant TK, Vossen MG, Wysocki CA, Belschner A, Bridger GJ, Chen K, Dubuc S, Hu Y, Jiang H, Li S, MacLeod R, Stewart M, Taveras AG, Yan T, Donadieu J
Blood 2024 Jul 4;144(1):35-45. doi: 10.1182/blood.2023022658. PMID: 38643510Free PMC Article
Merati N, Sivachandran S, Jfri A, Ben-Shoshan M, Vinh DC, Popradi G, Litvinov IV
Skin Therapy Lett 2022 Mar;27(2):1-5. PMID: 35385630
Lanini LL, Prader S, Siler U, Reichenbach J
Pediatr Allergy Immunol 2017 Mar;28(2):124-134. Epub 2016 Oct 13 doi: 10.1111/pai.12654. PMID: 27612320
Scala S
Clin Cancer Res 2015 Oct 1;21(19):4278-85. Epub 2015 Jul 21 doi: 10.1158/1078-0432.CCR-14-0914. PMID: 26199389
Sri JC, Dubina MI, Kao GF, Rady PL, Tyring SK, Gaspari AA
J Am Acad Dermatol 2012 Feb;66(2):292-311. Epub 2011 May 14 doi: 10.1016/j.jaad.2010.12.011. PMID: 21571393

Prognosis

Göschl L, Mrak D, Grabmeier-Pfistershammer K, Stiasny K, Haslacher H, Schneider L, Deimel T, Kartnig F, Tobudic S, Aletaha D, Burgmann H, Bonelli M, Pickl WF, Förster-Waldl E, Scheinecker C, Vossen MG
Front Immunol 2022;13:974987. Epub 2022 Sep 14 doi: 10.3389/fimmu.2022.974987. PMID: 36189225Free PMC Article
Ma X, Wang Y, Wu P, Kang M, Hong Y, Xue Y, Chen C, Li H, Fang Y
Front Immunol 2022;13:857527. Epub 2022 Apr 13 doi: 10.3389/fimmu.2022.857527. PMID: 35493524Free PMC Article
McDermott DH, Pastrana DV, Calvo KR, Pittaluga S, Velez D, Cho E, Liu Q, Trout HH 3rd, Neves JF, Gardner PJ, Bianchi DA, Blair EA, Landon EM, Silva SL, Buck CB, Murphy PM
N Engl J Med 2019 Jan 10;380(2):163-170. doi: 10.1056/NEJMoa1808575. PMID: 30625055Free PMC Article
Doncker AV, Balabanian K, Bellanné-Chantelot C, de Guibert S, Revest M, Bachelerie F, Lamy T
Clin Microbiol Infect 2011 Feb;17(2):135-9. doi: 10.1111/j.1469-0691.2010.03187.x. PMID: 20148920
Imashuku S, Miyagawa A, Chiyonobu T, Ishida H, Yoshihara T, Teramura T, Kuriyama K, Imamura T, Hibi S, Morimoto A, Todo S
Ann Hematol 2002 Aug;81(8):470-3. Epub 2002 Jul 20 doi: 10.1007/s00277-002-0489-9. PMID: 12224006

Clinical prediction guides

Badolato R, Alsina L, Azar A, Bertrand Y, Bolyard AA, Dale D, Deyà-Martínez À, Dickerson KE, Ezra N, Hasle H, Kang HJ, Kiani-Alikhan S, Kuijpers TW, Kulagin A, Langguth D, Levin C, Neth O, Olbrich P, Peake J, Rodina Y, Rutten CE, Shcherbina A, Tarrant TK, Vossen MG, Wysocki CA, Belschner A, Bridger GJ, Chen K, Dubuc S, Hu Y, Jiang H, Li S, MacLeod R, Stewart M, Taveras AG, Yan T, Donadieu J
Blood 2024 Jul 4;144(1):35-45. doi: 10.1182/blood.2023022658. PMID: 38643510Free PMC Article
Geier CB, Ellison M, Cruz R, Pawar S, Leiss-Piller A, Zmajkovicova K, McNulty SM, Yilmaz M, Evans MO 2nd, Gordon S, Ujhazi B, Wiest I, Abolhassani H, Aghamohammadi A, Barmettler S, Bhar S, Bondarenko A, Bolyard AA, Buchbinder D, Cada M, Cavieres M, Connelly JA, Dale DC, Deordieva E, Dorsey MJ, Drysdale SB, Ehl S, Elfeky R, Fioredda F, Firkin F, Förster-Waldl E, Geng B, Goda V, Gonzalez-Granado L, Grunebaum E, Grzesk E, Henrickson SE, Hilfanova A, Hiwatari M, Imai C, Ip W, Jyonouchi S, Kanegane H, Kawahara Y, Khojah AM, Kim VH, Kojić M, Kołtan S, Krivan G, Langguth D, Lau YL, Leung D, Miano M, Mersyanova I, Mousallem T, Muskat M, Naoum FA, Noronha SA, Ouederni M, Ozono S, Richmond GW, Sakovich I, Salzer U, Schuetz C, Seeborg FO, Sharapova SO, Sockel K, Volokha A, von Bonin M, Warnatz K, Wegehaupt O, Weinberg GA, Wong KJ, Worth A, Yu H, Zharankova Y, Zhao X, Devlin L, Badarau A, Csomos K, Keszei M, Pereira J, Taveras AG, Beaussant-Cohen SL, Ong MS, Shcherbina A, Walter JE
J Clin Immunol 2022 Nov;42(8):1748-1765. Epub 2022 Aug 10 doi: 10.1007/s10875-022-01312-7. PMID: 35947323Free PMC Article
Levy E, Reger R, Segerberg F, Lambert M, Leijonhufvud C, Baumer Y, Carlsten M, Childs R
Front Immunol 2019;10:1262. Epub 2019 Jun 5 doi: 10.3389/fimmu.2019.01262. PMID: 31231387Free PMC Article
Luo J, Busillo JM, Stumm R, Benovic JL
Mol Pharmacol 2017 Jun;91(6):554-566. Epub 2017 Mar 22 doi: 10.1124/mol.116.106468. PMID: 28331048Free PMC Article
Stiehm ER
Pediatr Res 1993 Jan;33(1 Suppl):S2-7; discussion S7-8. doi: 10.1203/00006450-199305001-00007. PMID: 8433870

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