INDEX OF SUSPICION

Neutropenia, Recurrent Infections, and Warts in a

6-year-old Boy
Haig H. Manougian, MD,* Brinda Mehta, MD,* Michele K. Beekman, MD,* Philip M. Murphy, MD,†
David H. McDermott, MD†
*Department of Pediatrics, University of Illinois College of Medicine Peoria, OSF Children’s Hospital of Illinois, Peoria, IL
†
Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD

PRESENTATION
A 6-year-old boy presents to the emergency department with acute onset of ab-
dominal pain, fever, hematuria, cough, and rhinorrhea. Blood was noticed in his
urine in the morning, with right flank and abdominal pain developing in the
evening just before presentation. He additionally complains of left ear pain of
2 days’ duration, having developed a runny nose, congestion, and cough during
that time. A temperature of up to 101 F (38.3 C) was measured at home. His sis-
ter is also noted to be ill with cough and cold symptoms. The family denies re-
cent changes in bowel habits, similar past abdominal symptoms, blood in stools,
changes in diet, or changes in appetite. The family denies similar past urinary
symptoms, current sore throat, or recent strep throat infection. His medical his-
tory is remarkable for laryngomalacia diagnosed at 3 months of age that resolved
spontaneously and recurrent ear infections during winter months. The family
history is remarkable for Hodgkin lymphoma in a grandfather diagnosed in the
third decade of life.
Physical examination reveals a nontoxic-appearing boy. Vital signs are remarkable
for temperature elevation to 102.5 F (39.2 C) and tachycardia to 120 beats/min. Re-
spiratory rate and blood pressure are normal. Review of growth parameters reveals
weight at the 19th percentile for age (decreased from the 52nd percentile seen ap-
proximately 2 years earlier) and height at the 29th percentile (trending appropriately AUTHOR DISCLOSURE: Drs Manougian,
Mehta, Beekman, Murphy, and
from the 30th percentile approximately 2 years earlier). Ear examination is remark-
McDermott have disclosed no financial
able for an erythematous and bulging left tympanic membrane. Eye, nose, throat, relationships relevant to this article. This
and neck examination findings are normal. Cardiac evaluation findings are normal commentary does contain a discussion of
an unapproved/investigative use of a
except for tachycardia. Pulmonary examination findings are normal. Capillary refill,
commercial product/device.
peripheral pulses, and skin turgor are normal. Abdominal examination reveals ten-
derness to palpation throughout the abdomen, suprapubic region, and the patient’s Acknowledgments: This project was
partially supported by the Division of
flanks bilaterally. Bowel sounds are normal, and no abdominal distention, hepatos- Intramural Research, National Institute of
plenomegaly, or masses are appreciated. He has no adenopathy. Evaluation of the Allergy and Infectious Diseases, National
extremities reveals paronychia of the left index finger. Institutes of Health. The content of this
publication does not necessarily reflect
On laboratory evaluation, a complete blood cell count reveals a normocytic anemia the views or policies of the Department
with a hemoglobin level of 10.5 g/dL (105 g/L) (lower limit of normal 5 11.5 g/dL of Health and Human Services, and
[115 g/L]), leukopenia with a white blood cell count of 2050/mL (2.05 × 109/L) consist- neither does the mention of trade names,
commercial products, or organizations
ing of a low absolute neutrophil count (ANC) of 800/mL (0.80 × 109/L), and a low ab- imply endorsement by the US
solute lymphocyte count of 150/mL (0.15 × 109/L). His platelet count is normal at Government.

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by Carlos Funes Merida
 293 × 103/mL (293 × 109/L). Results of the serum electrolyte Differential Diagnosis
panel, creatinine level, and liver function panel are all normal. The differential diagnosis for chronic neutropenia in-
Urinalysis reveals 31 blood (21–50 urine red blood cells), 11 cludes acquired and congenital conditions. Our patient’s
protein, and the presence of calcium oxalate crystals but is initial presentation suggested an acquired cause, given his
negative for leukocyte esterase, nitrites, ketones, and glucose. largely normal medical history consisting of only a few ep-
Urine microanalysis is negative for white blood cells. The pa- isodes of acute otitis media. Examples of acquired etiolo-
tient is admitted to the hospital with febrile neutropenia and gies include immune neutropenia, viral bone marrow
is started on intravenous ceftriaxone after obtaining a blood suppression, bone marrow failure, and malignancy. How-
culture. Epstein-Barr virus and cytomegalovirus titers obtained ever, the laboratory evaluation was not consistent with
to evaluate for viral-induced neutropenia show no recent these etiologies; antineutrophil antibodies that suggest an
or past exposure. Uric acid and lactate dehydrogenase lev- immunogenic cause and peripheral flow cytometry that
els in the serum are unrevealing. Quantitative immuno- suggests malignancy were both negative. Our patient’s
globulin analysis reveals a borderline low IgM level of neutropenia persisted after the patient recovered to his
38 mg/dL (0.38 g/L) (lower limit of normal 5 41 mg/dL clinical baseline (in which he appeared well), remaining
[0.41 g/L]). The ANC decreased from 800/mL (0.80 × 109/L) low for many months of observation, beyond the duration
to 80/mL (0.08 × 109/L) on subsequent days. Peripheral blood expected with viral suppression. Bone marrow failure was
flow cytometry for acute leukemia is normal, and antineutro- not likely with only 1 affected cell line, and the patient had
phil antibodies are not detected. Creatine phosphokinase, no identifiable drug-induced causes. Thus, congenital neutro-
complement 3, and complement 4 levels are normal. An anti- penia was considered. Such causes include cyclic neutropenia
streptolysin O assay, a rapid streptococcal antigen test with (due to neutrophil elastase gene [ELANE] mutation); variable
culture, and a polymerase chain reaction test for adenovirus neutropenia typically within a 21 day cycle (due to ELANE
and a panel of other respiratory pathogens are all negative. gene mutation); severe congenital neutropenia/Kostmann syn-
To evaluate the patient’s hematuria, renal ultrasonography is drome (due to ELANE gene mutations or HAX1 gene muta-
performed and is normal; however, the urinary calcium to tions); and Schwachman-Diamond syndrome (due to SBDS
creatinine ratio is noted to be elevated. The hematuria and ab- gene mutations). Our patient’s history was not consistent with
dominal pain resolve spontaneously and are attributed to pos- the cyclical nature of cyclic neutropenia, lacked neurologic
sible transient urolithiasis, although a definitive cause is not problems seen in some cases of Kostmann syndrome, and
found. The patient’s urine and blood cultures do not isolate lacked the associated features of Schwachman-Diamond syn-
any organisms, the upper respiratory tract symptoms gradu- drome, such as exocrine pancreatic insufficiency or skeletal
ally improve, ceftriaxone is discontinued, and the patient is abnormalities. There are many other rare causes of congenital
discharged with amoxicillin/clavulanate to complete a thera- neutropenia, such as GATA2 deficiency/MonoMAC syndrome,
peutic course for paronychia. Chediak-Higashi syndrome, glycogen storage disease type Ib,
In the ensuing months, an anemia evaluation reveals iron G-CSF receptor mutations, G6PC3 deficiency, and warts, hypo-
deficiency, which resolves with iron supplementation. At base- gammaglobulinemia, recurrent infections, myelokathexis (WHIM)
line, the patient continues to have severe neutropenia with an syndrome. With the presence of a low IgM level, refractory
ANC ranging from 80/mL to 100/mL (0.08–0.10 × 109/L). He warts, and recurrent respiratory tract infections, our patient’s
presents to the hospital twice more during this period with clinical phenotype suggested a diagnosis of WHIM syndrome.
febrile neutropenia in the absence of localizing symptoms or
clinical decompensation, during which he has an increase Actual Diagnosis
in his ANC within 24 hours of admission (from 80/mL A bone marrow aspiration and a biopsy were performed
[0.08 × 109/L] to 500/mL [0.50 × 109/L] and from 50/mL (Fig), which revealed trilineage hematopoiesis with an in-
[0.05 × 109/L] to 2,940/mL [2.94 × 109/L]) without granulo- creased myeloid to erythroid ratio of 5:1 (normal ratio is 4:1)
cyte colony-stimulating factor (G-CSF) support. On both ad- and a right shift of the neutrophil lineage resulting in accu-
missions, the patient is observed with febrile neutropenia mulation of mature neutrophils. Some neutrophils appeared
precautions, receiving cefepime, and is promptly discharged dysmorphic, with an increased number of nuclear lobes, long
after normal evaluation results for sepsis. With continued chromatin strands connecting the lobes, and hypervacuolation.
follow-up evaluation, the patient is noted to develop refractory This hematopathologic neutropenic picture is referred to as
warts of his hands and feet, with repeated quantitative immu- myelokathexis (bone marrow retention) and is nearly pathogno-
noglobulin testing revealing a persistently low IgM level. monic of WHIM syndrome. Consistent with this, a congenital

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by Carlos Funes Merida
 due to disease heterogeneity. (2) Most reported cases from
Western Europe and North America are of white ancestry,
but cases have been reported in Black, Hispanic, and Asian
races. (2) As the name suggests, the 4 main clinical charac-
teristics of WHIM syndrome are warts, hypogammaglobuli-
nemia, infections, and myelokathexis. Myelokathexis is a
Greek neologism that means “retention in the bone marrow.” It
refers to defective release of neutrophils from bone marrow to
the blood, resulting in peripheral blood neutropenia and mye-
loid hyperplasia in the bone marrow. As originally described,
there is also a characteristic cytologic abnormality in many cases
of myelokathexis involving hypervacuolated neutrophils with hy-
perlobulated nuclei with the lobes connected by long, thin
strands of chromatin. These dysmorphic neutrophils are found
in the bone marrow and are thought to be apoptotic cells.
Impaired release of newly developed neutrophils from bone
marrow to blood and accelerated return of dying neutrophils
from blood to bone marrow together produce the picture of neu-
tropenia despite myeloid hyperplasia.
WHIM syndrome is due to heterozygous gain-of-function
mutations in CXCR4, which is expressed on the surface of
most leukocytes as well as many nonhematopoietic cells. (3)
CXCR4 is a 7-transmembrane domain G protein–coupled re-
ceptor that exerts downstream effects after binding its ligand,
the chemokine CXCL12, which is abundantly expressed in the
bone marrow. Gain-of-function mutations amplify receptor
signaling to CXCL12 by eliminating b-arrestin–mediated de-
Figure. High-power field (×1,000) view of the patient’s bone marrow aspirate
highlighting myelokathexis. A. The number of mature neutrophils seen high- sensitization after activation, resulting in neutrophil retention
lights myeloid hyperplasia. White arrows represent hyperlobular neutrophils. in the bone marrow. (4) No other causative gene mutations
Black arrow represents a neutrophil with a dysmorphic nucleus. B. White ar-
row represents a hypervacuolated neutrophil, another dysmorphic example have been discovered for full-blown WHIM syndrome to date.
of neutrophil appearance in warts, hypogammaglobulinemia, recurrent infec- (3) Despite retention of WHIM neutrophils in the marrow,
tions, myelokathexis syndrome. Courtesy of Dr Sean A. Fitzgerald (Clinical and
Laboratory Pathology), verified at the National Institutes of Health. they appear to function appropriately when released into the
peripheral circulation during physiologically stressful and in-
neutropenia immunodeficiency genetic panel revealed a novel flammatory states, presumably due to increased peripheral
heterozygous mutation in the patient’s leukocyte DNA in the chemokine attraction by interleukin-8 (IL-8/CXCL8) or other
gene CXCR4 encoding the C-X-C motif chemokine receptor 4 chemoattractant molecules. (3) Diagnosis is often delayed due
(CXCR4), which is the gene known to be mutated in almost to incomplete penetrance of the clinical manifestations and
all reported cases of WHIM syndrome. Like most other the ability of the neutrophil count to increase during acute in-
WHIM mutations, the patient’s mutation (c.988_989delTC 5 fection. Neutropenia is therefore not always immediately evi-
p.Ser330Glnfs*13) resulted in a frameshift and premature trun- dent on patient admission, with release of marrow neutrophil
cation of the C-terminus of CXCR4. This finding was con- stores during the acute illness period. Patients express associ-
firmed by Sanger sequencing, and both parents were negative ated traits with varying degrees, resulting in substantial phe-
for a CXCR4 mutation, indicating a diagnosis of a de novo notypic variability reported in the literature, including warts,
case of WHIM syndrome. (1) cellulitis, recurrent otitis media, recurrent respiratory infec-
tions, congenital heart defects (especially tetralogy of Fallot),
The Condition human papillomavirus (HPV)–dependent malignancies, and
WHIM syndrome is an extremely rare combined primary lymphoma. (5) The finding of myelokathexis on bone marrow
immunodeficiency with approximately 180 reported cases examination is the key to diagnosis. Refractory warts in this
worldwide since 1964, although it is likely underdiagnosed condition are due to a failure to clear cutaneous or anogenital

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by Carlos Funes Merida
 HPV infection, which is likely due to a poor immune re- risks of dental infections and recurrent ear infections that
sponse, the cause of which is not completely understood. may in turn increase the risk of hearing loss and tooth
Uncontrolled HPV infection can develop into precancer- loss; dermatology for skin warts; urology due to risks of re-
ous lesions and fatal carcinomas. (3) Hypogammaglobuli- calcitrant HPV infection of the genitalia; and cardiology
nemia is likely due to ineffective adaptive immune system due to associated congenital cardiac disorders (which were
response, particularly in helper T cells, resulting in inef- not found in our patient). He also developed intermittent
fective B- and T-cell activation, decreased cell survival, and dysuria and hematuria, and his evaluation revealed neph-
decreased immunoglobulin production. (4) rolithiasis due to hypocitraturia, but this is not associated
with the WHIM phenotype. Our patient initially underwent
Treatment/Management a complete blood cell count every 2 weeks but was transi-
Therapy for WHIM syndrome focuses on correcting neu- tioned to every 2 months after an appropriate dose of G-CSF
tropenia and hypogammaglobulinemia and preventing in- was determined. His immunoglobulin levels are monitored
fections. G-CSF is used in the lowest dose possible for bone bi-yearly, IgG remaining normal through this duration
marrow neutrophil proliferation and release to increase pe- (hence not requiring supplementation), with consistently
ripheral neutrophil counts without causing adverse effects, low IgM levels, falling to a low of 18 mg/dL (0.18 g/L) (ref-
such as bone pain, and while minimizing the risk of myelo- erence range, 41–183 mg/dL [0.41–1.83 g/L]). Follow-up of
fibrosis and myeloid malignancy. The effective dose is often growth parameters revealed appropriate trending of weight
much less than is typically needed in other causes of severe at the 30th percentile, and appropriate trending of length
congenital neutropenia. Immunoglobulin is also used for at the 40th percentile. Our patient’s diagnosis and lack of
passive antibody replacement, especially for patients present- consensus management recommendations stress the im-
ing with persistently low IgG levels. There are currently no portance of collaboration with experts in the field to im-
studies evaluating the treatment efficacy of these interven- prove patient outcomes and further research efforts.
tions. (1) Of note, due to the refractory nature of warts in Evaluation of vaccine titer response revealed inadequate
WHIM syndrome, which do not respond well to topical ther- pneumococcal immunity. Strong recommendations were
apy, repeated physical interventions are often used, including made to the family to start HPV vaccination at 9 years of
cryotherapy, surgical excision, or laser ablation. (1) Prophylactic age to help prevent refractory anogenital warts caused by
antibiotics may also be helpful in some cases. Current ongo- cancer-causing strains of HPV. (11) Standard yearly influ-
ing experimental therapy includes plerixafor and mavorixafor enza vaccinations were also strongly recommended. The
(CXCR4 inhibitors), (6) umbilical cord blood stem cell trans- patient will benefit from genetic counseling in the future
plant, (7) and hematopoietic stem cell transplant. (8) An un- because the disease is transmitted in an autosomal domi-
expected case of spontaneous disease reversion involving nant manner.
chromothripsis (chromosomal shattering) in a single hema-
topoietic stem cell has been documented, raising hope of fu- Lessons for the Clinician
ture gene therapy directed at repair or removal of the mutant • Warts, hypogammaglobulinemia, recurrent infections,
CXCR4 allele. (9) Murine WHIM models have been devel- myelokathexis (WHIM) syndrome is an extremely rare
oped using a knock-in of a human WHIM mutation into the primary immunodeficiency syndrome characterized by
mouse Cxcr4 gene. (10) neutropenia in the setting of mature neutrophil retention
in the bone marrow (referred to as myelokathexis), warts,
Patient Course hypogammaglobulinemia, and recurrent infections. Great
Our patient was initiated on a daily subcutaneous G-CSF phenotypic variability exists beyond these findings as well.
regimen of 0.5 to 1.0 mg/kg per day with the goal of main- • WHIM syndrome highlights the intimate relationship
taining an ANC of 500 to 1,000/mL (0.5–1.0 × 109/L) and between immunodeficiency syndromes and their herald-
preventing bacterial infection. Since therapy initiation, he ing hematologic anomalies.
has been followed for 24 months, during which he experi- • Congenital immunodeficiencies should remain on the
enced 2 febrile episodes before obtaining the previously differential diagnosis of acute neutropenic presentations
mentioned goal ANC, prompting admission for monitor- in late childhood.
ing with febrile neutropenic precautions per hospital pro-
tocol. His multidisciplinary care and follow-up includes References for this article can be found at
evaluation by dental, audiology, and otolaryngology due to https://doi.org/10.1542/pir.2021-005348.

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