- WHIM Syndrome Panel Discussion
- The Importance of Early Identification
- Burden of Disease: Warts and HPV Disease
- Risk of Malignancy
- Warts Due to HPV Infection
- Confirming a Diagnosis
- Importance of Early Diagnosis
- Frequent Types of Cancer
- Long-Term Risk and Unmet Needs
WHIM Syndrome Panel Discussion
Jean Donadieu, MD, French Severe Chronic Neutropenia Registry
David Dale, MD, University of Washington, Seattle
Jolan Walters, MD, PhD, University of South Florida at Johns Hopkins All Children’s Hospital
Raffaele Badolato, MD, PhD, University of Brescia, Italy discuss diagnosing and treating WHIM syndrome.
WHIM syndrome is a rare, congenital primary immunodeficiency disorder associated with severe neutropenia that affects all ages. However, due to the heterogeneous presentation of the disease, coupled with lack of awareness of the condition, the diagnosis may be delayed, sometimes even into adulthood. The acronym “WHIM” stands for (W)arts, (H)ypogammaglobulinemia, (I)nfections, and (M)yelokathexis. Myelokathexis refers to an abnormal retention of white blood cells, in the bone marrow, that causes a reduction of immune fighting white blood cells, and most notably the reduction of neutrophils and lymphocytes. Importantly, the acronym WHIM can be misleading because most patients will NOT present with all the symptoms associated with the four letters of the term (W.H.I. or M.), and therefore the diagnosis of the disease may be delayed, or misdiagnosed and, consequently, underdiagnosed.
For more information on WHIM syndrome, visit the WHIM Syndrome Learning Center.
Jolan Walter, MD, PhD, Division Chief, Pediatric Allergy/Immunology; University of South Florida at Johns Hopkins All Children’s Hospital, discusses the importance of early identification of patients with WHIM syndrome.
WHIM syndrome is a rare, congenital primary immunodeficiency disorder associated with neutropenia that typically presents in childhood or adolescence. However, due to the heterogeneous presentation of the disease, coupled with lack of awareness of the condition, recognition and diagnosis is often delayed, sometimes even into adulthood. Consequently, WHIM syndrome may be misdiagnosed and underdiagnosed.
To an extent, the name WHIM syndrome is a misnomer. The symptoms listed in the acronym (W)arts, (H)ypogammaglobulinemia, (I)nfections, and (M)yelokathexis do not describe the most common manifestations of the disorder, and only 23% of patients present with all four symptoms comprising WHIM.
In fact, the most common symptoms in patients diagnosed with WHIM syndrome are the laboratory findings of neutropenia (98%) and lymphopenia (88%).[3] Warts were seen in only 42% of one 66-patient cohort (though in more than half in another study), hypogammaglobulinemia in 65%, and recurrent infections in 92%. Myelokathexis, revealed via bone marrow biopsy, is often used to confirm the diagnosis, along with genetic testing.
The initial clinical sign of WHIM syndrome is recurrent infection. In a survey of patients with WHIM syndrome, Geier and colleagues[3] found that recurrent infection was the first recognizable symptom in 88% of patients (most commonly bacterial respiratory infections [49%] or otitis media [23%]). Skin infections were seen initially in 13%, and HPV-related infections (including warts) were the first recognized symptom in only 2% of patients. In this survey, 96% of patients with WHIM syndrome presented their initial symptom by age 5 years; 70% presented by 1 year of age.
David Dale, MD, Professor in the Department of Medicine at the University of Washington in Seattle, discussed the burden of disease with WHIM syndrome as it relates to the warts and HPV disease.
WHIM syndrome is a rare, congenital primary immunodeficiency disorder associated with neutropenia that typically presents in childhood or adolescence. However, due to the heterogeneous presentation of the disease, coupled with lack of awareness of the condition, recognition and diagnosis is often delayed, sometimes even into adulthood. Consequently, WHIM syndrome may be misdiagnosed and underdiagnosed.
The acronym “WHIM” stands for (W)arts, (H)ypogammaglobulinemia, (I)nfections, and (M)yelokathexis; however, patients rarely experience all of these symptoms, and if they do, they may not appear at the same time. Of these, recurrent infection and hypogammaglobulinemia are the most common presentations along with neutropenia and lymphocytopenia. Myelokathexis refers to an abnormal retention of white blood cells, in the bone marrow, that causes a reduction of immune fighting white blood cells, and most notably the reduction of neutrophils and lymphocytes; less a presenting symptom than a confirmatory sign, myelokathexis may not be obvious with bone marrow biopsy. Immediate long-term treatment strategies, careful monitoring, and timely intervention for complications may control the frequency of bacterial infections and prevent future complications. Disease understanding and awareness is improving as is the discovery and development of novel treatment approaches.
Jean Donadieu, MD, Director of the French Severe Chronic Neutropenia Registry, discusses the risk of malignancy in WHIM syndrome and how he manages this risk in patients with this rare disease.
In WHIM patients, disease morbidity and mortality is highly dependent upon the frequency and severity of bacterial infections, the development of chronic lung disease, and the severity of HPV manifestations.
Reports underscore the importance of early diagnosis in patients with WHIM. Immediate long-term treatment strategies, careful monitoring, and timely intervention for complications may control the frequency of bacterial and viral infections and prevent future complications.
In addition to infections and warts, patients with WHIM syndrome may be prone to an increased risk of cancer (carcinoma), particularly when HPV warts are located in the anogenital region, although there have been reports of cancers in other parts of the body such as oral cavity and vulva.
Researchers conducting a long-term follow-up of 18 patients with WHIM syndrome observed HPV-related malignancy in three patients (17%). Although HPV vaccination may be considered (patients with WHIM syndrome can generate protective antibodies with active immunization, but seem to lose this protection over time.
Other non–HPV related malignancies have been reported in patients with WHIM syndrome. A 2019 report from China described a patient with acute myeloid leukemia that developed following Hodgkin’s lymphoma. The French registry reported that of a 14-patient cohort, five developed malignancy at median age of 37 years (2 HPV-induced vulvar cancers, 2 lymphomas [1 bone, 1 skin lymphoma, 1 basal-cell carcinoma]). The 40-year rate of malignancy was calculated to be 46%.
Beyond malignancies and the threat of recurrent infections, patients with WHIM may be subject to additional long-term complications. For example, recurrent otitis media infection can predispose these patients to perforated ear drums and hearing loss. Lung damage resulting from frequent infections can cause chronic bronchiectasis or other serious respiratory problems, and evidence exists that the frequency of irreversible, end-organ damage (e.g., bronchiectasis) may be underestimated.
Current Options to Manage Cutaneous and Anogenital Warts Due to HPV Infection
Raffaele Badolato, MD, PhD, Professor of Pediatrics, University of Brescia, Italy, discusses WHIM syndrome and the current options to manage cutaneous and anogenital warts due to HPV infection.
Physicians may choose to use therapies that replace antibodies (immunoglobulins) or increase the number of neutrophils (granulocyte–colony stimulating factor [G-CSF]), vaccinations (e.g., HPV), and prophylactic antibiotics to reduce the risk of infections in patients with WHIM syndrome.
The dose of G-CSF (e.g., filgrastim) should be individualized, based on each patient’s level of neutropenia. The effectiveness of these treatments, in patients with WHIM syndrome, has not been investigated in controlled trials, presumably because of the low number of study subjects available. However, based on drug trials in patients with other types of immune disorders, it is a recommended practice. In an international review of patient cases, roughly half of patients with WHIM syndrome were given antibiotic prophylaxis. Seventy-two percent of patients were administered granulocyte–colony stimulating factors ([G-CSF], e.g., filgrastim), and 55% were given intravenous immunoglobulin treatments.
Unfortunately, therapy with G-CSF does not help resolve either the lymphopenia or monocytopenia associated with WHIM syndrome and has no effect on HPV-induced warts. A review of 24 patients with WHIM syndrome in 9 families found that although G-CSF therapy is deemed controversial, it was effective in preventing and treating infections.[9]
Warts are classically reported to be resistant to treatment, may proliferate extensively, and affect the hands or feet, face, arms, or legs. Approximately 20 to 25% of WHIM patients report anogenital condyloma acuminata.
There are currently no approved treatments addressing HPV susceptibility and HPV vaccine response appears impaired with no substantial reduction in the burden of lesions. Standard treatment methods (cauterization, laser therapy) and more aggressive approaches (surgical removal, interferon, cidofovir, Imiquimod) have not proven effective against cutaneous or genital warts.
David Dale, MD, Raffaele Badolato, MD, PhD, and Jean Donadieu, MD, discuss WHIM syndrome and how to confirm a proper diagnosis for this rare disease.
WHIM syndrome is a rare, congenital primary immunodeficiency disorder associated with neutropenia that typically presents in childhood or adolescence. However, due to the heterogeneous presentation of the disease, coupled with lack of awareness of the condition, recognition and diagnosis is often delayed, sometimes even into adulthood. Consequently, WHIM syndrome may be misdiagnosed and underdiagnosed.
The acronym “WHIM” stands for (W)arts, (H)ypogammaglobulinemia, (I)nfections, and (M)yelokathexis; however, patients rarely experience all of these symptoms, and if they do, they may not appear at the same time. Of these, recurrent infection and hypogammaglobulinemia are the most common presentations along with neutropenia and lymphocytopenia. Myelokathexis refers to an abnormal retention of white blood cells, in the bone marrow, that causes a reduction of immune fighting white blood cells, and most notably the reduction of neutrophils and lymphocytes; less a presenting symptom than a confirmatory sign, myelokathexis may not be obvious with bone marrow biopsy. Immediate long-term treatment strategies, careful monitoring, and timely intervention for complications may control the frequency of bacterial infections and prevent future complications. Disease understanding and awareness is improving as is the discovery and development of novel treatment approaches.
– Jean Donadieu, MD, Director of the French Severe Chronic Neutropenia Registry
– Raffaele Badolato, MD, PhD, Professor of Pediatrics, University of Brescia, Italy
– Jolan Walter, MD, PhD, Division Chief, Pediatric Allergy/Immunology; University of South Florida at Johns Hopkins All Children’s Hospital
– David Dale, MD, Professor in the Department of Medicine at the University of
Washington in Seattle
Jolan Walter, MD, PhD, Division Chief, Pediatric Allergy/Immunology; University of South Florida at Johns Hopkins All Children’s Hospital, discusses the importance of early diagnosis of patients with WHIM syndrome.
WHIM syndrome is a rare, congenital primary immunodeficiency disorder associated with neutropenia that typically presents in childhood or adolescence. However, due to the heterogeneous presentation of the disease, coupled with lack of awareness of the condition, recognition and diagnosis is often delayed, sometimes even into adulthood. Consequently, WHIM syndrome may be misdiagnosed and underdiagnosed.
To an extent, the name WHIM syndrome is a misnomer. The symptoms listed in the acronym (W)arts, (H)ypogammaglobulinemia, (I)nfections, and (M)yelokathexis do not describe the most common manifestations of the disorder, and only 23% of patients present with all four symptoms comprising WHIM.
In fact, the most common symptoms in patients diagnosed with WHIM syndrome are the laboratory findings of neutropenia (98%) and lymphopenia (88%).[3] Warts were seen in only 42% of one 66-patient cohort (though in more than half in another study), hypogammaglobulinemia in 65%, and recurrent infections in 92%. Myelokathexis, revealed via bone marrow biopsy, is often used to confirm the diagnosis, along with genetic testing.
The initial clinical sign of WHIM syndrome is recurrent infection. In a survey of patients with WHIM syndrome, Geier and colleagues[3] found that recurrent infection was the first recognizable symptom in 88% of patients (most commonly bacterial respiratory infections [49%] or otitis media [23%]). Skin infections were seen initially in 13%, and HPV-related infections (including warts) were the first recognized symptom in only 2% of patients. In this survey, 96% of patients with WHIM syndrome presented their initial symptom by age 5 years; 70% presented by 1 year of age.
Jean Donadieu, MD, Director of the French Severe Chronic Neutropenia Registry, discusses frequent types of cancer in WHIM syndrome patients.
In addition to infections and warts, patients with WHIM syndrome may be prone to an increased risk of cancer (carcinoma), particularly when HPV warts are located in the anogenital region, although there have been reports of cancers in other parts of the body such as oral cavity and vulva.
Researchers conducting a long-term follow-up of 18 patients with WHIM syndrome observed HPV-related malignancy in three patients (17%). Although HPV vaccination may be considered (patients with WHIM syndrome can generate protective antibodies with active immunization, but seem to lose this protection over time.
Other non–HPV related malignancies have been reported in patients with WHIM syndrome. A 2019 report from China described a patient with acute myeloid leukemia that developed following Hodgkin’s lymphoma. The French registry reported that of a 14-patient cohort, five developed malignancy at median age of 37 years (2 HPV-induced vulvar cancers, 2 lymphomas [1 bone, 1 skin lymphoma, 1 basal-cell carcinoma]). The 40-year rate of malignancy was calculated to be 46%.
Beyond malignancies and the threat of recurrent infections, patients with WHIM may be subject to additional long-term complications. For example, recurrent otitis media infection can predispose these patients to perforated ear drums and hearing loss. Lung damage resulting from frequent infections can cause chronic bronchiectasis or other serious respiratory problems,[5] and evidence exists that the frequency of irreversible, end-organ damage (e.g., bronchiectasis) may be underestimated.
Jean Donadieu, MD, Director of the French Severe Chronic Neutropenia Registry, discusses the long-term risks and unmet needs of patients suffering from WHIM syndrome.
WHIM syndrome is a rare, congenital primary immunodeficiency disorder associated with neutropenia that typically presents in childhood or adolescence. However, due to the heterogeneous presentation of the disease, coupled with lack of awareness of the condition, recognition and diagnosis is often delayed, sometimes even into adulthood. Consequently, WHIM syndrome may be misdiagnosed and underdiagnosed.
The acronym “WHIM” stands for (W)arts, (H)ypogammaglobulinemia, (I)nfections, and (M)yelokathexis; however, patients rarely experience all of these symptoms, and if they do, they may not appear at the same time. Of these, recurrent infection and hypogammaglobulinemia are the most common presentations along with neutropenia and lymphocytopenia. Myelokathexis refers to an abnormal retention of white blood cells, in the bone marrow, that causes a reduction of immune fighting white blood cells, and most notably the reduction of neutrophils and lymphocytes; less a presenting symptom than a confirmatory sign, myelokathexis may not be obvious with bone marrow biopsy. Immediate long-term treatment strategies, careful monitoring, and timely intervention for complications may control the frequency of bacterial infections and prevent future complications. Disease understanding and awareness is improving as is the discovery and development of novel treatment approaches.