34  Acquired & Inherited WBC Disorders

Key Points

• SCN: ELANE (AD) most common; ↑ AML risk; G-CSF ↓ infections
• Monocyte disorders: Congenital monocytopenia (GATA2, GCSFR3 mutations), immunodeficiency
• Inherited neutropenias: SCN, cyclic, LAD, MPO deficiency, CGD
• LCH: BRAF clonal disorder; multisystem; organ-directed therapy
• HLH: Life-threatening immune dysregulation; fever, ↓ cytopenias; early HSCT
• Acquired neutropenias: Drug-induced, autoimmune, ↓ infection/splenomegaly; stop agent, G-CSF if severe

34.1 Monocytopenia & Related Disorders

34.1.1 Definition & Pathophysiology

• Monocytes 1-9% of leukocytes; normal ANC 0.2-0.8 × 10³/μL
• Monocytopenia <0.1 × 10³/μL; seen w/ hematologic & infection
• Dendritic cell dysfunction → ↓ T cell activation & antigen presentation

34.1.2 Severe Congenital Neutropenia (SCN)

• Genetics: ELANE mutations (AD, most common); HAX1, CSF3R, WAASF (X-linked variants)
• Pathophysiology: Mutant protein → apoptosis in immature myeloid precursors
• Treatment: G-CSF 3-5 μg/kg/d; ↓ infections but ~10% progress to AML
  • Monitor for leukemoid reaction w/ G-CSF discontinuation

34.1.3 WHIM Syndrome

• Features: Warts, hypogammaglobulinemia, infections, myelokathexis (AD)
• Presentation: Neutropenia, B-cell lymphopenia, HPV infection; recurrent bacterial infections
• Pathophysiology: CXCR4 mutations → enhanced G-CSF signaling, eosinophil retention
• Treatment: G-CSF effective; IVIG if lacking CXCR4 mutations

34.2 Acquired Neutropenias

34.2.1 Primary Autoimmune Neutropenia (AIN)

• Presentation: Children & adults; ANC 500-1000/μL; infrequent serious infections
• BM findings: Minimal abnormalities or maturation defect
• Diagnosis: Anti-granulocyte antibodies or ANCA positive

34.2.2 Drug-Induced Neutropenia

• Epidemiology: Incidence 5-15.4/million; mortality ~5%; risk ↑ w/ age
• Onset: Usually <3 mo after starting drug; fever, pharyngitis, pneumonia, sepsis
• Mechanism: Immune-mediated destruction or impaired production (often unclear)
• Management:
  • Prompt withdrawal of offending agent
  • Recovery typically within 1 week
  • G-CSF if sepsis or delayed recovery; progression to AML rare
  • RUNX1 mutations → ↑ leukemic risk

Selected drugs associated w neutropenia

Drug	Immune-mediated	Non-immune
Anti-inflammatory agents	Aminopyrine	Ampicillin
	Doxepin	Cephalothin
	Doxorubicin	Chloramphenicol
	Trimethoprim	Penicillin
	Ibuprofen	Phenothiazine
	Gold salts	Sulfonamides
Cardiovascular agents	Penicillamine	Niacin
	Phenothiazine	Oxacillin
Psychotropic agents	Chlorpromazine	Quinidine
	Antitrypsilin	Tocainide
	Chlorpromazine	Chlorpromazine
Hypoglycemic agents	Tolbutamide	Chlorpropamide
	Chlorpropamide	Gliclazide

34.2.3 Secondary Autoimmune Neutropenia

• Associations: Felty syndrome, SLE (~50%), RA (esp. w/ LGL clonal expansion)
• Presentation: Usually mild; minimal impact on prognosis
• Pathophysiology: Accelerated apoptosis of mature neutrophils (SLE)
• Treatment: Manage underlying autoimmune disease

34.2.4 Chronic Idiopathic Neutropenia

• Definition: Persistent neutropenia w/o immune markers, cytogenetic abnormalities, or antibodies
• Course: Generally benign; infrequent infections; no treatment required

34.2.5 Neonatal Alloimmune Neutropenia

• Pathophysiology: Maternal IgG antibodies → transplacental passage; targets HNA antigens (HNA1, HNA3, HNA5)
• Presentation: Recurrent infections in healthy infant; confused w/ sepsis
• BM findings: Normal cellularity w/ delayed maturation
• Diagnosis: Clinical + ↓ ANC; serology not routinely needed

34.3 Inherited Disorders of Neutrophil Function

34.3.1 Red Flags

• Severe or unusual bacterial/fungal infections
• Recurrent infections
• Chronic/recurrent aphthous ulcers

34.3.2 Chronic Granulomatous Disease (CGD)

• Genetics: CYBB X-linked (2/3 of cases); AR mutations in oxidase complex proteins
• Pathophysiology: ↓ NADPH oxidase → ↓ superoxide, H₂O₂, reactive O₂ species
• Presentation: Recurrent bacterial/fungal infections (skin, lungs, LN, liver); diagnosed in childhood
• Diagnosis: DHR test → absent/abnormal respiratory burst by flow cytometry
• Treatment:
  • TMP-SMX prophylaxis
  • Itraconazole
  • IFN-γ (↓ infection incidence)
  • HSCT (when available); gene therapy in development

34.3.3 Leukocyte Adhesion Deficiency (LAD)

• Genetics: AR; defects in β2-integrin (CD18) type 1; selectin type 2; other integrins type 3
• Pathophysiology: ↓ neutrophil chemotaxis & migration; delayed umbilical cord separation
• Features: Recurrent infections; neutrophilia; bleeding diathesis (platelet integrin defect)
• Treatment: Allogeneic HSCT (5-year survival ~75%)

34.3.4 Myeloperoxidase (MPO) Deficiency

• Epidemiology: Most common enzyme deficiency; 1 in 2,000-4,000 (complete deficiency)
• Pathophysiology: Catalyzes H₂O₂ → hypochlorous acid & toxic intermediates
• Presentation: Asymptomatic most; ↑ Candida infections
• Diagnosis: MPO-negative by histochemistry or flow cytometry

34.4 Histiocyte & Dendritic Cell Disorders

Spectrum of disorders: infiltration of histiocytes, dendritic cells, macrophages in tissues/organs. Range from unifocal to multiorgan involvement.

34.4.1 Langerhans Cell Histiocytosis (LCH)

• Definition: Neoplastic disorder of CD1a+/CD207+ (Langerin) dendritic cells
• Genetics: BRAF V600E in >70%; other mutations causing genetic heterogeneity
• Pathology: LCH cells w/ eosinophils, neutrophils, lymphocytes background
• Classification:
  • SS-LCH (single-system): Bone > skin, LN, lung (smokers)
  • MS-LCH (multisystem): Multiple organ involvement
• Presentation: Bone pain/swelling, skin rash, dyspnea, cough, bleeds; DI if CNS
• Treatment:
  • SS-LCH: Topical steroids, nitrogen mustard, curettage
  • MS-LCH: Systemic chemo ± biologic agents
  • BRAF-mutant w/ moderate/severe or refractory: Vemurafenib

34.4.2 Malignant Histiocytosis

• Epidemiology: Rare; hundreds of cases reported; adults > children
• Types: Primary (histiocytic sarcoma) or secondary (other hematologic malignancy)
• Presentation: Constitutional symptoms; GI & skin most common; aggressive course
• Sites: Retroperitoneal, GI, CNS, pancreas; >80% abnormal cytology
• Diagnosis: Biopsy required; assess BRAF status
• Treatment: IFN-α (first-line, improves survival); vemurafenib if BRAF V600E

34.4.3 Rosai-Dorfman Disease

• Definition: Sinus histiocytosis w/ massive lymphadenopathy; nonmalignant
• Pathology: Histiocyte proliferation in LN sinuses & extranodal sites; phagocytosis of lymphocytes/plasma cells
• Presentation: Children & young adults; massive lymphadenopathy, splenomegaly, fever
• Course: Spontaneous resolution common; extramedullary disease requires treatment
• Treatment: Surgery, corticosteroids, radiotherapy, systemic chemo, or clinical trials

34.4.4 Hemophagocytic Lymphohistiocytosis (HLH)

• Definition: Abnormal activation & proliferation of cytotoxic T cells & macrophages
• Hemophagocytosis: Macrophages engulf leukocytes, RBCs, platelets, & precursors
• Associations: Hemolytic anemias, rheumatologic disease, infection, malignancy
• Genetics: Familial HLH (F-HLH) or secondary to immune deficiency
• Presentation: Fever, ↓ cytopenias, splenomegaly, ↑ ferritin, ↑ sIL-2R
• Diagnosis: ≥5 of 8 HLH criteria OR familial disease OR genetic abnormality
  • Hemophagocytosis in marrow/spleen/LN (non-required)
• Prognosis: Untreated F-HLH uniformly fatal in 1-2 months
• Treatment:
  • HLH-94 protocol: Dexamethasone + etoposide (8 weeks) → continuation until HSCT
  • Refractory/progressive: Emapalumab (anti-IFN-γ antibody)
  • HSCT only curative option

34.5 Clinical Pearls

• SCN: ELANE most common; G-CSF effective; monitor for AML; distinguish from leukemoid reaction
• LCH: BRAF V600E >50%; vemurafenib for multisystem or refractory; organ-directed therapy critical
• HLH: Life-threatening; early recognition mandatory; HLH-94 protocol; HSCT only curative option
• CGD: Recurrent bacterial/fungal infections; DHR test diagnostic; TMP-SMX + itraconazole + IFN-γ
• LAD: Delayed cord separation; ↑ infections; ↓ CD18; HSCT only curative