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Disease Progression of WHIM Syndrome in an International Cohort of 66 Pediatric and Adult Patients.

ABSTRACT: Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome (WS) is a combined immunodeficiency caused by gain-of-function mutations in the C-X-C chemokine receptor type 4 (CXCR4) gene. We characterize a unique international cohort of 66 patients, including 57 (86%) cases previously unreported, with variable clinical phenotypes. Of 17 distinct CXCR4 genetic variants within our cohort, 11 were novel pathogenic variants affecting 15 individuals (23%). All variants affect the same CXCR4 region and impair CXCR4 internalization resulting in hyperactive signaling. The median age of diagnosis in our cohort (5.5 years) indicates WHIM syndrome can commonly present in childhood, although some patients are not diagnosed until adulthood. The prevalence and mean age of recognition and/or onset of clinical manifestations within our cohort were infections 88%/1.6 years, neutropenia 98%/3.8 years, lymphopenia 88%/5.0 years, and warts 40%/12.1 years. However, we report greater prevalence and variety of autoimmune complications of WHIM syndrome (21.2%) than reported previously. Patients with versus without family history of WHIM syndrome were diagnosed earlier (22%, average age 1.3 years versus 78%, average age 5 years, respectively). Patients with a family history of WHIM syndrome also received earlier treatment, experienced less hospitalization, and had less end-organ damage. This observation reinforces previous reports that early treatment for WHIM syndrome improves outcomes. Only one patient died; death was attributed to complications of hematopoietic stem cell transplantation. The variable expressivity of WHIM syndrome in pediatric patients delays their diagnosis and therapy. Early-onset bacterial infections with severe neutropenia and/or lymphopenia should prompt genetic testing for WHIM syndrome, even in the absence of warts.

SUBMITTER: Geier CB

PROVIDER: S-EPMC9700649 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Disease Progression of WHIM Syndrome in an International Cohort of 66 Pediatric and Adult Patients.

Geier Christoph B CB Ellison Maryssa M Cruz Rachel R Pawar Sumit S Leiss-Piller Alexander A Zmajkovicova Katarina K McNulty Shannon M SM Yilmaz Melis M Evans Martin Oman MO Gordon Sumai S Ujhazi Boglarka B Wiest Ivana I Abolhassani Hassan H Aghamohammadi Asghar A Barmettler Sara S Bhar Saleh S Bondarenko Anastasia A Bolyard Audrey Anna AA Buchbinder David D Cada Michaela M Cavieres Mirta M Connelly James A JA Dale David C DC Deordieva Ekaterina E Dorsey Morna J MJ Drysdale Simon B SB Ehl Stephan S Elfeky Reem R Fioredda Francesca F Firkin Frank F Förster-Waldl Elizabeth E Geng Bob B Goda Vera V Gonzalez-Granado Luis L Grunebaum Eyal E Grzesk Elzbieta E Henrickson Sarah E SE Hilfanova Anna A Hiwatari Mitsuteru M Imai Chihaya C Ip Winnie W Jyonouchi Soma S Kanegane Hirokazu H Kawahara Yuta Y Khojah Amer M AM Kim Vy Hong-Diep VH Kojić Marina M Kołtan Sylwia S Krivan Gergely G Langguth Daman D Lau Yu-Lung YL Leung Daniel D Miano Maurizio M Mersyanova Irina I Mousallem Talal T Muskat Mica M Naoum Flavio A FA Noronha Suzie A SA Ouederni Monia M Ozono Shuichi S Richmond G Wendell GW Sakovich Inga I Salzer Ulrich U Schuetz Catharina C Seeborg Filiz Odabasi FO Sharapova Svetlana O SO Sockel Katja K Volokha Alla A von Bonin Malte M Warnatz Klaus K Wegehaupt Oliver O Weinberg Geoffrey A GA Wong Ke-Juin KJ Worth Austen A Yu Huang H Zharankova Yulia Y Zhao Xiaodong X Devlin Lisa L Badarau Adriana A Csomos Krisztian K Keszei Marton M Pereira Joao J Taveras Arthur G AG Beaussant-Cohen Sarah L SL Ong Mei-Sing MS Shcherbina Anna A Walter Jolan E JE

Journal of clinical immunology 20220810 8

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome (WS) is a combined immunodeficiency caused by gain-of-function mutations in the C-X-C chemokine receptor type 4 (CXCR4) gene. We characterize a unique international cohort of 66 patients, including 57 (86%) cases previously unreported, with variable clinical phenotypes. Of 17 distinct CXCR4 genetic variants within our cohort, 11 were novel pathogenic variants affecting 15 individuals (23%). All variants affect the same C ...[more]

PMID: 35947323

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Project description:BackgroundWHIM syndrome (WS), a rare congenital neutropenia due to mutations of the CXCR4 chemokine receptor, is associated with Human Papillomavirus (HPV)-induced Warts, Hypogammaglobulinemia, bacterial Infections and Myelokathexis. The long term follow up of eight patients highlights the clinical heterogeneity of this disease as well as the main therapeutic approaches and remaining challenges in the light of the recent development of new CXCR4 inhibitors.ObjectiveThis study aims to describe the natural history of WS based on a French cohort of 8 patients.MethodsWe have reviewed the clinical, biological and immunological features of patients with WS enrolled into the French Severe Chronic Neutropenia Registry.ResultsWe identified four pedigrees with WS comprised of eight patients and one foetus. Estimated incidence for WS was of 0.23 per million births. Median age at the last visit was 29 years. Three pedigrees encompassing seven patients and the fetus displayed autosomal dominant heterozygous mutations of the CXCR4 gene, while one patient presented a wild-type CXCR4 gene. Two subjects exhibited congenital conotruncal heart malformations. In addition to neutropenia and myelokathexis, all patients presented deep monocytopenia and lymphopenia. Seven patients presented repeated bacterial Ears Nose Throat as well as severe bacterial infections that were curable with antibiotics. Four patients with late onset prophylaxis developed chronic obstructive pulmonary disease (COPD). Two patients reported atypical mycobacteria infections which in one case may have been responsible for one patient's death due to liver failure at the age of 40.6 years. HPV-related disease manifested in five subjects and progressed as invasive vulvar carcinoma with a fatal course in one patient at the age of 39.5 years. In addition, two patients developed T cell lymphoma skin cancer and basal cell carcinoma at the age of 38 and 65 years.ConclusionsContinuous prophylactic anti-infective measures, when started in early childhood, seem to effectively prevent further bacterial infections and the consequent development of COPD. Long-term follow up is needed to evaluate the effect of early anti-HPV targeted prophylaxis on the development of skin and genital warts.

Project description:BackgroundMoyamoya is a rare progressive cerebral arteriopathy, occurring as an isolated phenomenon (moyamoya disease, MMD) or associated with other conditions (moyamoya syndrome, MMS), responsible for 6-10% of all childhood strokes and transient ischemic attacks (TIAs).MethodsWe conducted a retrospective multicenter study on pediatric-onset MMD/MMS in Italy in order to characterize disease presentation, course, management, neuroradiology, and outcome in a European country.ResultsA total of 65 patients (34/65 women) with MMD (27/65) or MMS (38/65) were included. About 18% (12/65) of patients were asymptomatic and diagnosed incidentally during investigations performed for an underlying condition (incMMS), whereas 82% (53/65) of patients with MMD or MMS were diagnosed due to the presence of neurological symptoms (symptMMD/MMS). Of these latter, before diagnosis, 66% (43/65) of patients suffered from cerebrovascular events with or without other manifestations (ischemic stroke 42%, 27/65; TIA 32%, 21/65; and no hemorrhagic strokes), 18% (12/65) of them reported headache (in 4/12 headache was not associated with any other manifestation), and 26% (17/65) of them experienced multiple phenotypes (≥2 among: stroke/TIA/seizures/headache/others). Neuroradiology disclosed ≥1 ischemic lesion in 67% (39/58) of patients and posterior circulation involvement in 51% (30/58) of them. About 73% (47/64) of patients underwent surgery, and 69% (45/65) of them received aspirin, but after diagnosis, further stroke events occurred in 20% (12/61) of them, including operated patients (11%, 5/47). Between symptom onset and last follow-up, the overall patient/year incidence of stroke was 10.26% (IC 95% 7.58-13.88%). At last follow-up (median 4 years after diagnosis, range 0.5-15), 43% (26/61) of patients had motor deficits, 31% (19/61) of them had intellectual disability, 13% (8/61) of them had epilepsy, 11% (7/61) of them had behavioral problems, and 25% (13/52) of them had mRS > 2. The proportion of final mRS > 2 was significantly higher in patients with symptMMD/MMS than in patients with incMMS (p = 0.021). Onset age <4 years and stroke before diagnosis were significantly associated with increased risk of intellectual disability (p = 0.0010 and p = 0.0071, respectively) and mRS > 2 at follow-up (p = 0.0106 and p = 0.0009, respectively).ConclusionsMoyamoya is a severe condition that may affect young children and frequently cause cerebrovascular events throughout the disease course, but may also manifest with multiple and non-cerebrovascular clinical phenotypes including headache (isolated or associated with other manifestations), seizures, and movement disorder. Younger onset age and stroke before diagnosis may associate with increased risk of worse outcome (final mRS > 2).

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Disease Progression of WHIM Syndrome in an International Cohort of 66 Pediatric and Adult Patients.

Publications

Disease Progression of WHIM Syndrome in an International Cohort of 66 Pediatric and Adult Patients.

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