Leukocyte Disorders
Hereditary Leukocyte Anomalies
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An inherited leukocyte anomaly usually announces itself as an unexpected CBC pattern or blood-film finding: neutrophilia with no inflammatory explanation, hyposegmented nuclei, giant cytoplasmic granules, or Döhle-like inclusions beside large platelets. The International Union of Immunological Societies 2024 classification lists 559 inborn errors of immunity, and a selected subset carries distinctive hematologic clues.1,2 The immunology topics own the immune mechanisms and the immune-diagnostic workup; this page covers the laboratory recognition tasks that belong to the hematology bench: seeing the pattern on the film, separating it from reactive and clonal mimics, and routing confirmatory testing to the right pathway.
Nuclear segmentation anomalies
Pelger-Huët anomaly is an autosomal dominant disorder of the lamin B receptor gene in which nuclear segmentation is reduced. The classic mature neutrophil carries two rounded lobes joined by a thin filament, a pince-nez shape, with coarse chromatin clumping; band-shaped nuclei and round nuclei occur as well. Prevalence is commonly reported as about 1 in 4,785 in United States populations. Neutrophil function is normal, and eosinophils, basophils, and monocytes can show the same nuclear pattern. A practical discriminator is the fraction of affected cells: true Pelger-Huët anomaly typically involves well over half of circulating neutrophils, with a commonly taught threshold above 68%, while acquired forms usually affect a smaller fraction.2
Hyposegmented neutrophils are a misclassification trap. An automated or manual differential that calls Pelger-Huët cells metamyelocytes, myelocytes, or bands invents a left shift and can suggest infection or a myeloid neoplasm that is not there. Recommended practice is to report the cells as segmented neutrophils with an interpretive comment naming the anomaly.
Acquired (pseudo) Pelger-Huët anomaly produces the same nuclear appearance in a subset of neutrophils, typically below 35% of the count, and it is neutrophil-restricted except in myelodysplastic neoplasms, where eosinophils, basophils, and monocytes can be involved. Recognized settings include myelodysplastic and myeloid neoplasms, severe bacterial infection, HIV, tuberculosis, mycoplasma pneumonia, and selected drugs such as immunosuppressants, chemotherapy, valproate, sulfisoxazole, fluconazole, ganciclovir, hematopoietic growth factors, and ibuprofen. Clinical context, a drug review, and the affected fraction separate pseudo-Pelger-Huët from the true anomaly; a film review of family members supports the hereditary form.2
Hereditary neutrophil hypersegmentation is a rare benign finding in which neutrophils carry more than the normal 3 to 5 lobes. The rest of the CBC is normal and the cells are normal in size, which separates it from the two major causes of hypersegmentation: megaloblastic anemia, where neutrophils are also large and anemia dominates, and myelodysplasia, where hypersegmentation is one dysplastic feature among others.2
Cytoplasmic granule and inclusion anomalies
Chédiak-Higashi syndrome is an autosomal recessive disorder of the LYST gene at 1q42.3 that disrupts lysosome-related organelle formation across cell types. Granulocytes, monocytes, and lymphocytes carry giant, darkly staining lysosomal granules, a finding that is unmistakable on a Wright-stained film. Partial oculocutaneous albinism, severe recurrent infection, neurologic decline, and platelet dense-granule deficiency with bleeding complete the syndrome, and about 85% of patients with classic disease develop a life-threatening hemophagocytic accelerated phase, so a suspicious film warrants urgent follow-up.3 Pseudo-Chédiak-Higashi granules, a similar but distinct finding, occur in AML, CML, and MDS and are resolved by the full morphology picture and disease workup.
Alder-Reilly anomaly produces large, darkly staining metachromatic cytoplasmic granules, called Reilly bodies, in granulocytes and sometimes monocytes and lymphocytes. It is classically described with the mucopolysaccharidoses and also occurs in otherwise healthy people. Leukocyte function is unaffected. The distinction from toxic granulation rests on distribution and context: Reilly bodies also appear in eosinophils, basophils, and monocytes, and they arrive without the neutrophilia, left shift, and clinical signs of infection.2
May-Hegglin anomaly and the MYH9 disorder spectrum are autosomal dominant disorders of the nonmuscle myosin heavy chain IIA gene (MYH9) at 22q12.3. The film shows basophilic, Döhle-body-like inclusions in neutrophils, eosinophils, basophils, and monocytes together with giant platelets and variable thrombocytopenia. The inclusions are precipitated myosin heavy chains, a different substance from the rough-endoplasmic-reticulum remnants of true Döhle bodies, and their presence in multiple leukocyte lines distinguishes them. Most patients are asymptomatic; in the minority who bleed, bleeding correlates with the degree of thrombocytopenia, and extrahematologic features such as presenile cataracts, nephropathy, and progressive hearing loss can appear over time.4
Inborn errors of immunity with leukocyte findings
The disorders below are recognized in the hematology laboratory through their count patterns, cell populations, and film clues. The immunology topics own the underlying mechanisms and the immune-diagnostic workflows that confirm them.1
| Disorder | Gene | Hematologic and laboratory clues | Recognition notes |
|---|---|---|---|
| Severe combined immunodeficiency, γc (X-linked) type | IL2RG | T and NK lymphocytes nearly absent; B cells present in normal number but nonfunctional | Most common SCID form; symptomatic at 3 to 6 months as maternal immunoglobulin wanes; lymphopenia on the CBC is the clue |
| 22q11.2 deletion syndrome | TBX1 microdeletion | Variable T-cell deficiency from thymic hypoplasia | Prevalence about 1 in 3,000 to 6,000 births; cardiac and palatal findings usually point to the diagnosis first5 |
| X-linked agammaglobulinemia | BTK | Profoundly decreased or absent B cells; all serum immunoglobulin isotypes reduced | Antibody deficiency appears at 4 to 6 months; the CBC clue is a low or absent B-cell fraction |
| Wiskott-Aldrich syndrome | WAS | T cells decreased; thrombocytopenia with small platelets | Small platelets on the film are the diagnostically important hematologic clue |
| Chronic granulomatous disease | CYBB and other NADPH oxidase genes | Normal counts with defective respiratory burst | About two-thirds of cases are X-linked; the dihydrorhodamine flow assay confirms the functional defect6 |
| Leukocyte adhesion deficiency I | ITGB2 (CD18) | Marked neutrophilia without pus; cells cannot leave the circulation | Severe disease has CD18 expression below 2% of normal and moderate disease 2 to 30%; delayed umbilical-cord separation and recurrent infection begin in infancy7 |
| Leukocyte adhesion deficiency II | SLC35C1 | Neutrophilia from defective selectin-ligand fucosylation | Infections are milder than LAD I; growth retardation and coarse facial features accompany it |
| Leukocyte adhesion deficiency III | FERMT3 (kindlin-3) | Mild LAD-I-like infection pattern | Normal integrin expression with failed inside-out activation; platelet GPIIb/IIIa activation also fails, producing Glanzmann-like bleeding |
| Congenital neutropenias | ELANE most common; HAX1 autosomal recessive | Isolated or cyclic neutropenia | First-year presentation with recurrent, often life-threatening fever and infection; carries a risk of leukemic transformation8 |
| Shwachman-Diamond syndrome | SBDS | Marrow failure with cytopenias, myelodysplasia, and leukemia risk | Exocrine pancreatic insufficiency with malabsorption and failure to thrive accompanies the marrow picture9 |
| WHIM syndrome | CXCR4 | Neutropenia, lymphopenia, monocytopenia, hypogammaglobulinemia | Myelokathexis, marrow neutrophil retention with pyknotic degenerative change, despite abundant mature marrow myeloid cells; extensive warts mark the phenotype10 |
Separating anomaly from reactive and clonal findings
Persistence, family pattern, and the rest of the CBC do the sorting work:
| Question | Suggests hereditary anomaly | Suggests reactive or clonal process |
|---|---|---|
| Is the finding stable across serial specimens? | Persists unchanged over months | Varies with illness, treatment, or recovery |
| Do family members share the pattern? | Positive family films support autosomal dominant forms such as Pelger-Huët and May-Hegglin | Negative, or the patient is the only affected member |
| Which cells carry the change? | Multiple leukocyte lines in Pelger-Huët, Alder-Reilly, and May-Hegglin | Toxic granulation stays in neutrophils; pseudo-Pelger-Huët is usually neutrophil-restricted outside MDS |
| Is there infection, inflammation, or a drug explanation? | Absent | Present and quantitatively plausible |
| Are blasts, dysplasia, or other cytopenias present? | Absent | Present in myeloid neoplasia; pseudo-Chédiak-Higashi granules and pseudo-Pelger-Huët both occur there |
The platelet findings sharpen the routing: small platelets point to Wiskott-Aldrich syndrome, giant platelets with leukocyte inclusions point to the MYH9 spectrum, and dense-granule deficiency contributes to bleeding in Chédiak-Higashi syndrome. The platelet disorder topics cover those count and function patterns.
Reporting considerations
Report an anomaly as an observed pattern with a comment, and keep the count interpretation honest: Pelger-Huët nuclei are segmented neutrophils, and calling them bands fabricates a left shift. Suggested next steps belong in the comment when the pattern is unexplained: film review of family members for suspected Pelger-Huët or May-Hegglin anomaly, repeat testing to confirm persistence, and referral to the immune-deficiency pathway for count and function patterns such as sustained lymphopenia in an infant, neutrophilia without pus, or unexplained early-onset neutropenia. Newborns and infants carry the highest-consequence findings: delayed cord separation with neutrophilia, giant granules on a film, and small platelets with lymphopenia each justify urgent escalation under the laboratory’s notification procedure.2
References
- Bousfiha AA, Jeddane L, Moundir A, et al. The 2024 update of IUIS phenotypic classification of human inborn errors of immunity. J Hum Immun. 2025;1(1):e20250002. doi:10.70962/jhi.20250002.
- Keohane EM, Preston MM, Mirza KM, Walenga JM, eds. Rodak's Hematology: Clinical Principles and Applications. 7th ed. Elsevier; 2025. Accessed August 31, 2026.
- Chediak-Higashi syndrome. GeneReviews. Accessed August 31, 2026.
- MYH9-related disease. GeneReviews. Accessed August 31, 2026.
- 22q11.2 deletion syndrome. GeneReviews. Accessed August 31, 2026.
- Chronic granulomatous disease. GeneReviews. Accessed August 31, 2026.
- Justiz Vaillant AA, Ahmad F. Leukocyte adhesion deficiency. StatPearls. Updated July 3, 2023. Accessed August 31, 2026.
- ELANE-related neutropenia. GeneReviews. Accessed August 31, 2026.
- Shwachman-Diamond syndrome. GeneReviews. Accessed August 31, 2026.
- Hernandez PA, Gorlin RJ, Lukens JN, et al. Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease. Nat Genet. 2003;34(1):70-74. doi:10.1038/ng1149.