Discerning clinicopathological features of congenital neutropenia syndromes: an approach to diagnostically challenging differential diagnoses

Abstract

The congenital neutropenia syndromes are rare haematological conditions defined by impaired myeloid precursor differentiation or function. Patients are prone to severe infections with high mortality rates in early life. While some patients benefit from granulocyte colony-stimulating factor treatment, they may still face an increased risk of bone marrow failure, myelodysplastic syndrome and acute leukaemia. Accurate diagnosis is crucial for improved outcomes; however, diagnosis depends on familiarity with a heterogeneous group of rare disorders that remain incompletely characterised. The clinical and pathological overlap between reactive conditions, primary and congenital neutropenias, bone marrow failure, and myelodysplastic syndromes further clouds diagnostic clarity.We review the diagnostically useful clinicopathological and morphological features of reactive causes of neutropenia and the most common primary neutropenia disorders: constitutional/benign ethnic neutropenia, chronic idiopathic neutropenia, cyclic neutropenia, severe congenital neutropenia (due to mutations inELANE,GFI1,HAX1,G6PC3,VPS45,JAGN1,CSF3R,SRP54,CLPBandWAS), GATA2 deficiency, Warts, hypogammaglobulinaemia, infections and myelokathexis syndrome, Shwachman-Diamond Syndrome, the lysosomal storage disorders with neutropenia: Chediak-Higashi, Hermansky-Pudlak, and Griscelli syndromes, Cohen, and Barth syndromes. We also detail characteristic cytogenetic and molecular factors at diagnosis and in progression to myelodysplastic syndrome/leukaemia.

Neutropenia in Childhood—A Narrative Review and Practical Diagnostic Approach

“…TAZ [63] X-linked/Xq28 Barth disease CXCR4 [64] Dominant/2q21 WHIM syndrome JAGN1 [65] Recessive/3p25.3 Severe congenital neutropenia VPS13B [66] Recessive/8q22-q23 Cohen syndrome GFI1 [67] Dominant/1p22 Severe congenital neutropenia HAX1 [68,69] Recessive/1q21.3 Kostmann disease AP3B1 [70] Recessive/5q14.1 Hermansky-Pudlak syndrome type 2 LAMTOR2 [49] Recessive/1q21 Chronic neutropenia USB1 [71] Recessive/16q21 Clericuzio-type poikiloderma VPS45 [72] Recessive/1q21.2 Severe congenital neutropenia TCIRG1 [73] Dominant/11q13.2 Severe congenital neutropenia…”