Neutropenia, Recurrent Infections, and Warts in a 6-year-old Boy

A 6-year-old boy presents to the emergency department with acute onset of abdominal 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 sister is also noted to be ill with cough and cold symptoms. The family denies recent 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 history 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. Respiratory rate and blood pressure are normal. Review of growth parameters reveals weight at the 19th percentile for age (decreased from the 52nd percentile seen approximately 2 years earlier) and height at the 29th percentile (trending appropriately from the 30th percentile approximately 2 years earlier). Ear examination is remarkable for an erythematous and bulging left tympanic membrane. Eye, nose, throat, and neck examination findings are normal. Cardiac evaluation findings are normal except for tachycardia. Pulmonary examination findings are normal. Capillary refill, peripheral pulses, and skin turgor are normal. Abdominal examination reveals tenderness to palpation throughout the abdomen, suprapubic region, and the patient's flanks bilaterally. Bowel sounds are normal, and no abdominal distention, hepatosplenomegaly, or masses are appreciated. He has no adenopathy. Evaluation of the extremities reveals paronychia of the left index finger.On laboratory evaluation, a complete blood cell count reveals a normocytic anemia with a hemoglobin level of 10.5 g/dL (105 g/L) (lower limit of normal = 11.5 g/dL [115 g/L]), leukopenia with a white blood cell count of 2050/µL (2.05 × 109/L) consisting of a low absolute neutrophil count (ANC) of 800/µL (0.80 × 109/L), and a low absolute lymphocyte count of 150/µL (0.15 × 109/L). His platelet count is normal at 293 × 103/µL (293 × 109/L). Results of the serum electrolyte panel, creatinine level, and liver function panel are all normal. Urinalysis reveals 3+ blood (21–50 urine red blood cells), 1+ protein, and the presence of calcium oxalate crystals but is negative for leukocyte esterase, nitrites, ketones, and glucose. Urine microanalysis is negative for white blood cells. The patient is admitted to the hospital with febrile neutropenia and is started on intravenous ceftriaxone after obtaining a blood culture. Epstein-Barr virus and cytomegalovirus titers obtained to evaluate for viral-induced neutropenia show no recent or past exposure. Uric acid and lactate dehydrogenase levels in the serum are unrevealing. Quantitative immunoglobulin analysis reveals a borderline low IgM level of 38 mg/dL (0.38 g/L) (lower limit of normal = 41 mg/dL [0.41 g/L]). The ANC decreased from 800/µL (0.80 × 109/L) to 80/µL (0.08 × 109/L) on subsequent days. Peripheral blood flow cytometry for acute leukemia is normal, and antineutrophil antibodies are not detected. Creatine phosphokinase, complement 3, and complement 4 levels are normal. An antistreptolysin O assay, a rapid streptococcal antigen test with culture, and a polymerase chain reaction test for adenovirus and a panel of other respiratory pathogens are all negative. To evaluate the patient's hematuria, renal ultrasonography is performed and is normal; however, the urinary calcium to creatinine ratio is noted to be elevated. The hematuria and abdominal pain resolve spontaneously and are attributed to possible transient urolithiasis, although a definitive cause is not found. The patient's urine and blood cultures do not isolate any organisms, the upper respiratory tract symptoms gradually improve, ceftriaxone is discontinued, and the patient is discharged with amoxicillin/clavulanate to complete a therapeutic course for paronychia.In the ensuing months, an anemia evaluation reveals iron deficiency, which resolves with iron supplementation. At baseline, the patient continues to have severe neutropenia with an ANC ranging from 80/µL to 100/µL (0.08–0.10 × 109/L). He presents to the hospital twice more during this period with febrile neutropenia in the absence of localizing symptoms or clinical decompensation, during which he has an increase in his ANC within 24 hours of admission (from 80/µL [0.08 × 109/L] to 500/µL [0.50 × 109/L] and from 50/µL [0.05 × 109/L] to 2,940/µL [2.94 × 109/L]) without granulocyte colony-stimulating factor (G-CSF) support. On both admissions, the patient is observed with febrile neutropenia precautions, receiving cefepime, and is promptly discharged after normal evaluation results for sepsis. With continued follow-up evaluation, the patient is noted to develop refractory warts of his hands and feet, with repeated quantitative immunoglobulin testing revealing a persistently low IgM level.The differential diagnosis for chronic neutropenia includes acquired and congenital conditions. Our patient's initial presentation suggested an acquired cause, given his largely normal medical history consisting of only a few episodes of acute otitis media. Examples of acquired etiologies include immune neutropenia, viral bone marrow suppression, bone marrow failure, and malignancy. However, the laboratory evaluation was not consistent with these etiologies; antineutrophil antibodies that suggest an immunogenic cause and peripheral flow cytometry that suggests malignancy were both negative. Our patient's neutropenia persisted after the patient recovered to his clinical baseline (in which he appeared well), remaining low for many months of observation, beyond the duration expected with viral suppression. Bone marrow failure was not likely with only 1 affected cell line, and the patient had no identifiable drug-induced causes. Thus, congenital neutropenia was considered. Such causes include cyclic neutropenia (due to neutrophil elastase gene [ELANE] mutation); variable neutropenia typically within a 21 day cycle (due to ELANE gene mutation); severe congenital neutropenia/Kostmann syndrome (due to ELANE gene mutations or HAX1 gene mutations); and Schwachman-Diamond syndrome (due to SBDS gene mutations). Our patient's history was not consistent with the cyclical nature of cyclic neutropenia, lacked neurologic problems seen in some cases of Kostmann syndrome, and lacked the associated features of Schwachman-Diamond syndrome, such as exocrine pancreatic insufficiency or skeletal abnormalities. There are many other rare causes of congenital neutropenia, such as GATA2 deficiency/MonoMAC syndrome, Chediak-Higashi syndrome, glycogen storage disease type Ib, G-CSF receptor mutations, G6PC3 deficiency, and warts, hypogammaglobulinemia, recurrent infections, myelokathexis (WHIM) syndrome. With the presence of a low IgM level, refractory warts, and recurrent respiratory tract infections, our patient's clinical phenotype suggested a diagnosis of WHIM syndrome.A bone marrow aspiration and a biopsy were performed (Fig), which revealed trilineage hematopoiesis with an increased myeloid to erythroid ratio of 5:1 (normal ratio is 4:1) and a right shift of the neutrophil lineage resulting in accumulation of mature neutrophils. Some neutrophils appeared dysmorphic, with an increased number of nuclear lobes, long chromatin strands connecting the lobes, and hypervacuolation. This hematopathologic neutropenic picture is referred to as myelokathexis (bone marrow retention) and is nearly pathognomonic of WHIM syndrome. Consistent with this, a congenital neutropenia immunodeficiency genetic panel revealed a novel heterozygous mutation in the patient's leukocyte DNA in the gene CXCR4 encoding the C-X-C motif chemokine receptor 4 (CXCR4), which is the gene known to be mutated in almost all reported cases of WHIM syndrome. Like most other WHIM mutations, the patient's mutation (c.988_989delTC = p.Ser330Glnfs*13) resulted in a frameshift and premature truncation of the C-terminus of CXCR4. This finding was confirmed by Sanger sequencing, and both parents were negative for a CXCR4 mutation, indicating a diagnosis of a de novo case of WHIM syndrome. (1)WHIM syndrome is an extremely rare combined primary immunodeficiency with approximately 180 reported cases worldwide since 1964, although it is likely underdiagnosed 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 characteristics of WHIM syndrome are warts, hypogammaglobulinemia, 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 myeloid hyperplasia in the bone marrow. As originally described, there is also a characteristic cytologic abnormality in many cases of myelokathexis involving hypervacuolated neutrophils with hyperlobulated 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 neutropenia 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 receptor 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 β-arrestin–mediated desensitization after activation, resulting in neutrophil retention in the bone marrow. (4) No other causative gene mutations have been discovered for full-blown WHIM syndrome to date. (3) Despite retention of WHIM neutrophils in the marrow, they appear to function appropriately when released into the peripheral circulation during physiologically stressful and inflammatory states, presumably due to increased peripheral chemokine attraction by interleukin-8 (IL-8/CXCL8) or other chemoattractant molecules. (3) Diagnosis is often delayed due to incomplete penetrance of the clinical manifestations and the ability of the neutrophil count to increase during acute infection. Neutropenia is therefore not always immediately evident on patient admission, with release of marrow neutrophil stores during the acute illness period. Patients express associated traits with varying degrees, resulting in substantial phenotypic variability reported in the literature, including warts, cellulitis, recurrent otitis media, recurrent respiratory infections, congenital heart defects (especially tetralogy of Fallot), human papillomavirus (HPV)–dependent malignancies, and lymphoma. (5) The finding of myelokathexis on bone marrow examination is the key to diagnosis. Refractory warts in this condition are due to a failure to clear cutaneous or anogenital HPV infection, which is likely due to a poor immune response, the cause of which is not completely understood. Uncontrolled HPV infection can develop into precancerous lesions and fatal carcinomas. (3) Hypogammaglobulinemia is likely due to ineffective adaptive immune system response, particularly in helper T cells, resulting in ineffective B- and T-cell activation, decreased cell survival, and decreased immunoglobulin production. (4)Therapy for WHIM syndrome focuses on correcting neutropenia and hypogammaglobulinemia and preventing infections. G-CSF is used in the lowest dose possible for bone marrow neutrophil proliferation and release to increase peripheral neutrophil counts without causing adverse effects, such as bone pain, and while minimizing the risk of myelofibrosis and myeloid malignancy. The effective dose is often much less than is typically needed in other causes of severe congenital neutropenia. Immunoglobulin is also used for passive antibody replacement, especially for patients presenting with persistently low IgG levels. There are currently no studies evaluating the treatment efficacy of these interventions. (1) Of note, due to the refractory nature of warts in WHIM syndrome, which do not respond well to topical therapy, repeated physical interventions are often used, including cryotherapy, surgical excision, or laser ablation. (1) Prophylactic antibiotics may also be helpful in some cases. Current ongoing experimental therapy includes plerixafor and mavorixafor (CXCR4 inhibitors), (6) umbilical cord blood stem cell transplant, (7) and hematopoietic stem cell transplant. (8) An unexpected case of spontaneous disease reversion involving chromothripsis (chromosomal shattering) in a single hematopoietic stem cell has been documented, raising hope of future gene therapy directed at repair or removal of the mutant CXCR4 allele. (9) Murine WHIM models have been developed using a knock-in of a human WHIM mutation into the mouse Cxcr4 gene. (10)Our patient was initiated on a daily subcutaneous G-CSF regimen of 0.5 to 1.0 μg/kg per day with the goal of maintaining an ANC of 500 to 1,000/µL (0.5–1.0 × 109/L) and preventing bacterial infection. Since therapy initiation, he has been followed for 24 months, during which he experienced 2 febrile episodes before obtaining the previously mentioned goal ANC, prompting admission for monitoring with febrile neutropenic precautions per hospital protocol. His multidisciplinary care and follow-up includes evaluation by dental, audiology, and otolaryngology due to risks of dental infections and recurrent ear infections that may in turn increase the risk of hearing loss and tooth loss; dermatology for skin warts; urology due to risks of recalcitrant HPV infection of the genitalia; and cardiology due to associated congenital cardiac disorders (which were not found in our patient). He also developed intermittent dysuria and hematuria, and his evaluation revealed nephrolithiasis due to hypocitraturia, but this is not associated with the WHIM phenotype. Our patient initially underwent a complete blood cell count every 2 weeks but was transitioned to every 2 months after an appropriate dose of G-CSF was determined. His immunoglobulin levels are monitored bi-yearly, IgG remaining normal through this duration (hence not requiring supplementation), with consistently low IgM levels, falling to a low of 18 mg/dL (0.18 g/L) (reference range, 41–183 mg/dL [0.41–1.83 g/L]). Follow-up of growth parameters revealed appropriate trending of weight at the 30th percentile, and appropriate trending of length at the 40th percentile. Our patient's diagnosis and lack of consensus management recommendations stress the importance of collaboration with experts in the field to improve patient outcomes and further research efforts. Evaluation of vaccine titer response revealed inadequate pneumococcal immunity. Strong recommendations were made to the family to start HPV vaccination at 9 years of age to help prevent refractory anogenital warts caused by cancer-causing strains of HPV. (11) Standard yearly influenza vaccinations were also strongly recommended. The patient will benefit from genetic counseling in the future because the disease is transmitted in an autosomal dominant manner.Warts, hypogammaglobulinemia, recurrent infections, myelokathexis (WHIM) syndrome is an extremely rare primary immunodeficiency syndrome characterized by neutropenia in the setting of mature neutrophil retention in the bone marrow (referred to as myelokathexis), warts, hypogammaglobulinemia, and recurrent infections. Great phenotypic variability exists beyond these findings as well.WHIM syndrome highlights the intimate relationship between immunodeficiency syndromes and their heralding hematologic anomalies.Congenital immunodeficiencies should remain on the differential diagnosis of acute neutropenic presentations in late childhood.