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.
SIGNS AND SYMPTOMS
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.[3]
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[1]), 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.[3]
The frequent signs of severe chronic neutropenia, and profound lymphopenia may indicate that WHIM syndrome should be classified as both a congenital neutropenia and a combined primary immunodeficiency. The concentration of B lymphocytes is usually particularly low, and this probably prevents the immune system of some patients with WHIM syndrome from making sufficient immunoglobulins (hypogammaglobulinemia).
Mutations associated with WHIM syndrome may affect HPV-infected keratinocytes.[5] Warts experienced by these patients are typically treatment resistant, and generally appear before the age of 10 years.[1] Warts may be extensive, involve the ano-genital area, and may be related to human papillomavirus virus (HPV) infection (mean age of appearance, 12 yr); they may not occur at all).[3,4] These HPV-related warts are resistant to such treatments as freezing (cryotherapy), salicylic acid, or even surgical removal, which are typically effective in other patients with warts.[1,6]
In one review of reported cases,[6] the clinical features of WHIM were noticeable at a mean of 2 years of age, but a diagnosis was not made until the patients were 12 or 13 years old. Severe bacterial infection occurred in 78% of patients, with recurrent pneumonia in 61% of cases that was complicated with bronchiectasis in 27% of patients. Patients were a mean age of 11 years of age by the time cutaneous warts were observed (in 61% of children).[5] In the survey reported by Geier and colleagues,[3] the lifetime presence of warts in patients with WHIM syndrome was approximately 40%. These are generally driven by HPV, which also raises the potential concern for HPV-related carcinoma (see Complications of WHIM Syndrome).
WHIM Syndrome Etiology and Diagnosis
Philip M. Murphy, MD, Chief, Laboratory of Molecular Immunology, National Institute of Allergy and Infection, discusses the etiology and diagnosis of WHIM syndrome, a rare immunodeficiency disorder.
(Video length: 4 minutes)
Confirming a WHIM Syndrome Diagnosis
Experts discuss WHIM syndrome and how to confirm a proper diagnosis for this rare disease. This video is part of a longer Panel Discussion on WHIM Syndrome, which can be viewed here.
(Video length: 3 minutes)
DIAGNOSIS
Making an accurate diagnosis in the case of inborn errors of immunity can be challenging because of the multiple potential causes. Part of this challenge is how clinicians recognize the particular characteristics of the presentation and the likelihood of a genetic mutational etiology.[8] A systematic approach to accurate diagnosis of these inborn errors of immunity may be best summarized as three steps: (1) Recognition of the clinical presentation (phenotype), including clues of family history; (2) diagnostic laboratory evaluations, including immunological factors; and (3) confirmatory genetic analysis, seeking specific mutations and potential variants.[8]
Clinical Observations. Whereas recognition of the most notable clinical signs of WHIM syndrome may be straightforward, diagnosis is challenging because of its rarity and the heterogeneity of the clinical presentation.[3] Recurrent infections are the most common early clinical presentation. When information is obtained through a careful patient history, the clinician may find that the severity of the infections varies, and most infections (e.g., otitis media) may be otherwise unremarkable, because they resolve with antibiotic treatment.[2] Unless the patient has another obvious sign, such as warts, physical exam will not likely yield a diagnosis of WHIM syndrome. This places considerable onus on the clinician (often a pediatrician) to recognize that this may be the result ultimately of a genetic mutation.
Inheritance and Family History. The importance of a family history was demonstrated by Dale and colleagues,[9] who identified a total of 24 patients in nine families affected by WHIM syndrome. This emphasizes the need of obtaining a comprehensive family history in patients with recurrent infections, neutropenia, and lymphocytopenia.
As many as two-thirds of patients may have a family history of WHIM syndrome.[8] Yet, a positive family history of WHIM prompted diagnosis in only 20% of the patients in the survey by Geier and associates.[3] This may reflect a lack of awareness of the autosomal dominant inheritance of the mutations or undiagnosed family members as a result of heterogeneity of disease (which may imply a higher percentage of patients with a positive family history). For example, it may be more likely that a pediatrician recognizes that another family member has neutropenia, recurrent infections, or lymphocytopenia than one with a clinical diagnosis of WHIM syndrome.[9]
Laboratory Work-up. Laboratory testing is essential to gather additional clues over time to identify WHIM syndrome as the underlying cause of the clinical symptoms and signs. Complete blood count testing (with differential) will often yield neutrophil counts of below 300/mcL (unless bolstered during episodes of infection), low total white blood cells and low lymphocytes. About half of the patients have low IgG, IgM and/or IgA concentrations. One of the challenges to diagnosis is the temporary, normal levels of white blood cells during acute infections,[5,11,12] which is the moment when patients most commonly seek medical attention.[6] Therefore, blood counts drawn during an acute infection episode can lead clinicians to miss the key sign of low neutrophils and to a delayed diagnosis. Hemoglobin and platelet measurements will appear normal.[2]
Bone Marrow Biopsy. Myelokathexis, a strong determinant of a WHIM syndrome diagnosis, is obtained through bone marrow biopsy.[2,13] Myelokathexis is the abnormal retention of white blood cells in the bone marrow, where they “overmature.”[3] The result is a reduction of immune fighting white blood cells, and most notably the reduction of neutrophils and lymphocytes.
However, myelokathexis is not readily apparent, and may only be identified by an experienced pathologist when evaluating the bone marrow aspirate for its tell-tale signs: myeloid hyperplasia; abnormal, mature neutrophils with hypersegmentation of the nuclei and the presence of cytoplasmic vacuolization.[2]
Although a hallmark of patients with WHIM syndrome, myelokathexis is not the only confirmation of a WHIM diagnosis. Genetic testing can also be used to corroborate the findings.[3,14]
Genetic Testing. If WHIM syndrome is suspected, a patient’s diagnosis can be confirmed through genetic tests to identify gain-of-function mutations in the CXCR4 gene.[14]
Advances in genetic diagnostic techniques (such as Next-Generation-Sequencing) and rising awareness about the disease is expected to facilitate early recognition and diagnosis. Commercial as well as sponsored, no-charge genetic testing and counseling is available to aid in the molecular diagnosis of WHIM syndrome such as, PATH4WARD, detects for known mutations and variants in a panel of more than 550 genes in patients with primary immunodeficiency disorders and congenital neutropenia. Wider availability of genetic testing panels such as this may offer opportunities for early treatment or participation in interventional trials.[15]
Differential Diagnosis. The differential diagnosis of WHIM syndrome should consider inherited neutropenias and myelodysplastic syndromes.[2] One example is an autosomal recessive severe congenital neutropenia caused by G6PC3 deficiency.[16]
There may be crossover in identification of WHIM syndrome with other genetic disorders, like primary immunodeficiencies such as common variable immune deficiency (CVID). Like WHIM syndrome, patients with CVID may present with warts and hypogammaglobulinemia.[2] A study of 571 patients with CVID revealed a subset of individuals with CXCR4 variants similar to those with WHIM syndrome.[17]
In a French registry of patients with severe chronic neutropenia, genetic analyses amongst other studies revealed eight patients with WHIM syndrome.[4] Therefore, patients with chronic neutropenia of unknown origin also must be considered for further testing.
Patients with epidermodysplasia verruciformis will develop cutaneous warts, but immunologic abnormalities seen in WHIM syndrome will be absent.[2]
For more information about some of the clinical trials currently underway for WHIM, visit clinicaltrials.gov.
Diagnosing WHIM Syndrome
David Dale, MD at the University of Washington Medical Center in Seattle, discusses some of the challenges in diagnosing WHIM syndrome.
(Video length: 3 minutes)
Importance of Early Diagnosis of WHIM Syndrome
Jolan Walter, MD, PhD, University of South Florida at Johns Hopkins All Children’s Hospital, discusses the importance of early identification of patients with WHIM syndrome. The full Panel Discussion on WHIM Syndrome can be viewed here.
(Video length: 1 minute)
PRIMARY IMMUNE DEFICIENCY ADVOCACY GROUPS AND NONPROFIT ORGANIZATIONS
Immune Deficiency Foundation
A national non-profit patient organization dedicated to improving the diagnosis, treatment and quality of life of persons with primary immunodeficiency diseases through advocacy, education and research.
International Patient Organisation for Primary Immunodeficiencies
An association of national patient organizations dedicated to improving awareness, access to early diagnosis and optimal treatments for primary immunodeficiency patients worldwide.
Jeffrey Modell Foundation
An international, non-profit, organization dedicated to helping individuals and family members affected by primary immunodeficiency disorders.
RARE DISEASE ORGANIZATIONS
EURORDIS
A non-governmental patient-driven alliance of patient organizations representing 724 rare disease patient organizations in 64 countries.
Genetic Alliance
A nonprofit health advocacy organization that engages individuals, families, and communities to transform health. They create ways to make it easier to find or build solutions in health services and research.
Global Genes
A rare disease patient advocacy organization that aims to build awareness, educate the global community and provide critical connections and resources that equip advocates to become activists for their disease.
National Organization for Rare Disorders
A rare disease patient advocacy organization providing a unified voice for the 30 million people who wake up every day to fight the battle with a rare disease, including parents and caregivers.
EveryLife Foundation for Rare Diseases
A rare disease patient advocacy organization dedicated to advancing the development of treatment and diagnostic opportunities for rare disease patients through science-driven public policy.
REFERRENCES
- WHIM syndrome. National Institutes of Health: Genetic and Rare Disease Information Center. December 2019. https://rarediseases.info.nih.gov/diseases/9297/whim-syndrome#).Accessed December 12, 2019.
- Diaz G, Gulino V. WHIM syndrome. June 2004. https://www.orpha.net/data/patho/GB/uk-Whim.pdf. Accessed December 13, 2019.
- Geier CB, Ellison M, Cruz R, et al. Disease progression of WHIM syndrome in an international cohort of 66 pediatric and adult patients. J Clin Immunol. 2022 https://doi.org/10.1007/s10875-022-01312-7.
- Cohen SB, Fenneteau O, Plouvier, et al. Description and outcome of a cohort of 8 patients with WHIM syndrome from the French Severe Chronic Neutropenia Registry. Orphanet J Rare Dis. 2012;7:71. doi: 10.1186/1750-1172-7-71
- Dotta L, Notarangelo LD, Moratto D, et al. Long-term outcome of WHIM syndrome in 18 patients: high risk of lung disease and HPV-related malignancies. J Allergy Clin Immunol Pract. 2019;7:1568-1577. doi: 10.1016/j.jaip.2019.01.045.
- Zampella J, Cohen B. Consideration of underlying immunodeficiency in refractory or recalcitrant warts: A review of the literature. Skin Health Dis. 2022;2:e98-e107. doi.org/10.1002/ski2.98.
- Abraham RS, Butte MJ. The new “wholly trinity” in the diagnosis and management of inborn errors of immunity. J Allergy Clin Immunol Pract. 2021;9:613-625. doi.org/10.1016/j.jaip.2020.11.044.
- Heusinkveld LE, Majumdar S, Gao JL, McDermott DH, Murphy PM. WHIM syndrome: from pathogenesis towards personalized medicine and cure. J Clin Immunol. 2019;39:532-556. doi: 10.1007/s10875-019-00665-w.
- Dale DC, Dick E, Kelley M, et al. Family studies of warts, hypogammaglobulinemia, immunodeficiency, myelokathexis syndrome. Curr Opin Hematol. 2020;27:11-17. doi: 10.1097/MOH.0000000000000554.
- Aghamohammadi A, Abolhassani H, Puchalka J, et al. Preference of genetic diagnosis of CXCR4 mutation compared with clinical diagnosis of WHIM syndrome. J Clin Immunol. 2017;37:282-286. doi: 10.1007/s10875-017-0387-5.
- Wetzler M, Talpaz M, Kleineman ES, et al. A new familial immunodeficiency disorder characterized by severe neutropenia, a defective marrow release mechanism, and hypogammaglobulinemia. Am J Med. 1990;89(5):663-72.
- Beaussant Cohen S, Fenneteau O, et al. Description and outcome of a cohort of 8 patients with WHIM syndrome from the French Severe Chronic Neutropenia Registry. Orphanet J Rare Dis. 2012;7:71.
- Heusinkveld LE, Yim E, Yang A. Pathogenesis, diagnosis and therapeutic strategies in WHIM syndrome immunodeficiency. Expert Opin Orphan Drugs. 2017;5:813-825. doi: 10.1080/21678707.2017.1375403.
- WHIM syndrome. National Organization for Rare Disorders. 2016. https://rarediseases.org/rare-diseases/whim-syndrome/. Accessed December 12, 2019.
- McLaughlin H, Connelly J, Neri L, et al. PATH4WARD: A genetic testing program to aid in molecular diagnosis of congenital neutropenia and other primary immunodeficiencies including WHIM syndrome. Poster presented at the 2022 annual meeting of Clinical Immunology Society, March 31-April 3, 2022, Charlotte, NC.
- WHIM syndrome: Summary. Orphanet. October 2014. https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=51636.
- Abolhassani H, Hammarstrom L, Cunningham-Rundles C. Current genetic landscape in common variable immune deficiency. Blood. 2020;135:656-667.
- Badolato R, Donadieu J, and the WHIM Research Group. How I treat warts, hypogammaglobulinemia, infections, and myelokathexis syndrome. Blood. 2017;130:2491-2498. Doi: 10.1182/blood-2017-02-708552.
- Zhang A, Chen X, Li Z, et al. Acute myeloid leukemia arising after Hodgkin lymphoma in a patient with WHIM syndrome. Pediatr Blood Cancer. 2019;66:e27951. doi: 10.1002/pbc.27951.
- Donadieu J. WHIM syndrome is associated with a high incidence malignancies mainly related to HPV- and EBV- infections. Presented at the 2019 Focused Meeting of the European Society for Immunodeficiencies; Brussels, Belgium; Sept 18-21, 2019. https://cslide.ctimeetingtech.com/esid19/attendee/person/35
- McDermott DH, Heusinkveld LE, Zein WM, et al. Case report: Ocular toxoplasmosis in a WHIM syndrome immunodeficiency patient. Version 2. F1000Res. 2019 Jan 2 [revised 2019 Jul 17];8:2. doi: 10.12688/f1000research.16825.2.
- Mozobil prescribing information. Sanofi-Genzyme. 2019. http://products.sanofi.us/Mozobil/mozobil.html. Accessed December 16, 2019
- Plerixafor versus G-CSF in the treatment of people with WHIM syndrome. ClinicalTrials.gov March 12, 2021. https://www.clinicaltrials.gov/ct2/show/NCT02231879?term=plerixafor&cond=WHIM+syndrome&draw=2&rank=1.
- Efficacy and safety study of mavorixafor in participants with Warts, Hypogammaglobinemia, Infections, and Myelokathexis (WHIM) syndrome. September 14, 2022. https://www.clinicaltrials.gov/ct2/show/NCT03995108?term=Mavorixafor&draw=2&rank=2.
- McDermott DH, Gao JL, Murphy PM. Chromothriptic cure of WHIM syndrome: implications for bone marrow transplantation. Rare Diseases. 2015;3:e1073430
- Gao JL, Owusu-Ansah A, Paun A, et al. Low-level Cxcr4-haploinsufficient HSC engraftment is sufficient to correct leukopenia in WHIM syndrome mice. JCI Insight. 2019 Nov 5. pii: 132140. doi: 10.1172/jci.insight.132140. [Epub ahead of print].
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