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Description and outcome of a cohort of 8 patients with WHIM syndrome from the French Severe Chronic Neutropenia Registry.

Beaussant Cohen S, Fenneteau O, Plouvier E, Rohrlich PS, Daltroff G, Plantier I, Dupuy A, Kerob D, Beaupain B, Bordigoni P, Fouyssac F, Delezoide AL, Devouassoux G, Nicolas JF, Bensaid P, Bertrand Y, Balabanian K, Chantelot CB, Bachelerie F, Donadieu J - Orphanet J Rare Dis (2012)

Bottom Line: WHIM 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.In addition, two patients developed T cell lymphoma skin cancer and basal cell carcinoma at the age of 38 and 65 years.Continuous prophylactic anti-infective measures, when started in early childhood, seem to effectively prevent further bacterial infections and the consequent development of COPD.

View Article: PubMed Central - HTML - PubMed

Affiliation: AP-HP, Registre Français des Neutropénies Chroniques Sévères, Centre de Référence des Déficits Immunitaires Héréditaires, Service d'Hémato-Oncologie Pédiatrique Hôpital Trousseau, 26 avenue du Dr Netter, 75012 Paris, France.

ABSTRACT

Background: WHIM 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.

Objective: This study aims to describe the natural history of WS based on a French cohort of 8 patients.

Methods: We have reviewed the clinical, biological and immunological features of patients with WS enrolled into the French Severe Chronic Neutropenia Registry.

Results: We 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.

Conclusions: Continuous 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.

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Graphical representation of survival (A) and of the risk of cancer (B) after pooling the 52 published cases of patients with WHIM Syndrome and the 8 cases reported in this survey.
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Figure 2: Graphical representation of survival (A) and of the risk of cancer (B) after pooling the 52 published cases of patients with WHIM Syndrome and the 8 cases reported in this survey.

Mentions: The long-term outcome of WS patients from both our survey and the 52 previously reported patients indicated five deaths (Figure 2A). No death was reported before the age of 20 years with the exception of the medically terminated foetus described in this study. In addition to the two patients herein reported, whose deaths were caused by HPV-induced genital cancer and liver failure, the causes of deaths were lymphoma in two cases (at the ages of 26[28] and 54 years[41]) and bacterial meningitis in one case (at the age of 31 years[2]). Three other malignancies were reported including one patient who declared a non-lethal B lymphoma at the age of 31 years followed by a maxillary carcinoma[19], and another patient who developed a genital cancer of unspecified etiology at age of 20 years[5]. The overall cancer risk in this population is estimated to be about 30% by the age of 40 years, with an age of onset beyond the third decade (Figure 2B). Genital warts, which are reported for 23% of the literature cases and for 28.6% of cases herein described (2 cases), mark a turning point in the natural course of the disease due to their likelihood to progress to intractable multifocal dysplasia and invasive cancer with an early fatal course despite repeated aggressive surgical removal.


Description and outcome of a cohort of 8 patients with WHIM syndrome from the French Severe Chronic Neutropenia Registry.

Beaussant Cohen S, Fenneteau O, Plouvier E, Rohrlich PS, Daltroff G, Plantier I, Dupuy A, Kerob D, Beaupain B, Bordigoni P, Fouyssac F, Delezoide AL, Devouassoux G, Nicolas JF, Bensaid P, Bertrand Y, Balabanian K, Chantelot CB, Bachelerie F, Donadieu J - Orphanet J Rare Dis (2012)

Graphical representation of survival (A) and of the risk of cancer (B) after pooling the 52 published cases of patients with WHIM Syndrome and the 8 cases reported in this survey.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3585856&req=5

Figure 2: Graphical representation of survival (A) and of the risk of cancer (B) after pooling the 52 published cases of patients with WHIM Syndrome and the 8 cases reported in this survey.
Mentions: The long-term outcome of WS patients from both our survey and the 52 previously reported patients indicated five deaths (Figure 2A). No death was reported before the age of 20 years with the exception of the medically terminated foetus described in this study. In addition to the two patients herein reported, whose deaths were caused by HPV-induced genital cancer and liver failure, the causes of deaths were lymphoma in two cases (at the ages of 26[28] and 54 years[41]) and bacterial meningitis in one case (at the age of 31 years[2]). Three other malignancies were reported including one patient who declared a non-lethal B lymphoma at the age of 31 years followed by a maxillary carcinoma[19], and another patient who developed a genital cancer of unspecified etiology at age of 20 years[5]. The overall cancer risk in this population is estimated to be about 30% by the age of 40 years, with an age of onset beyond the third decade (Figure 2B). Genital warts, which are reported for 23% of the literature cases and for 28.6% of cases herein described (2 cases), mark a turning point in the natural course of the disease due to their likelihood to progress to intractable multifocal dysplasia and invasive cancer with an early fatal course despite repeated aggressive surgical removal.

Bottom Line: WHIM 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.In addition, two patients developed T cell lymphoma skin cancer and basal cell carcinoma at the age of 38 and 65 years.Continuous prophylactic anti-infective measures, when started in early childhood, seem to effectively prevent further bacterial infections and the consequent development of COPD.

View Article: PubMed Central - HTML - PubMed

Affiliation: AP-HP, Registre Français des Neutropénies Chroniques Sévères, Centre de Référence des Déficits Immunitaires Héréditaires, Service d'Hémato-Oncologie Pédiatrique Hôpital Trousseau, 26 avenue du Dr Netter, 75012 Paris, France.

ABSTRACT

Background: WHIM 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.

Objective: This study aims to describe the natural history of WS based on a French cohort of 8 patients.

Methods: We have reviewed the clinical, biological and immunological features of patients with WS enrolled into the French Severe Chronic Neutropenia Registry.

Results: We 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.

Conclusions: Continuous 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.

Show MeSH
Related in: MedlinePlus