Blood cytopenias as manifestations of inherited metabolic diseases: a narrative review

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TL;DR

This narrative review summarizes the inherited metabolic diseases (IMDs) that can present with cytopenias, including anemia, thrombocytopenia, neutropenia, and pancytopenia. It provides diagnostic algorithms and highlights key clinical scenarios where IMDs should be suspected, such as in cases of unexplained cytopenia, poor response to standard treatments, or multi-organ involvement. The review emphasizes that early recognition of these hematological manifestations can lead to specific treatments and improved outcomes.

Full summary

4,993 CHARS

**Background:** Inherited metabolic diseases (IMDs) are a heterogeneous group of over 1400 genetic conditions, often resulting from enzyme deficiencies, cofactor deficiencies, or impaired transporter proteins. These defects lead to the accumulation or deficiency of specific metabolites, causing a wide range of clinical and biological manifestations, including hematological abnormalities such as cytopenias, splenomegaly, and coagulation disorders. Despite their individual rarity, the overall birth prevalence of IMDs is as high as 1 in 784 live births in the United Kingdom, with an incidence of 40 cases per 100,000 live births. However, awareness of hematological features among specialists remains low; for example, only 20% of 406 hematology-oncology specialists considered Gaucher disease in the differential diagnosis for a patient with classic symptoms including cytopenia, hepatosplenomegaly, and bone pain. This narrative review, based on 20 years of experience at a reference center for IMDs and a literature review, aims to describe the spectrum of cytopenias associated with IMDs to improve diagnostic recognition and reduce diagnostic delay.

**Methods:** The authors conducted a narrative review of the literature, supplemented by their clinical experience as a reference center for IMDs in a tertiary hospital over 20 years. They focused on cytopenias—anemia, thrombocytopenia, neutropenia, and pancytopenia—associated with IMDs. The review includes diagnostic algorithms and tables summarizing key diseases, their clinical and biological signs, genetic causes, and diagnostic approaches.

**Key Results:** The review categorizes cytopenias by type and underlying IMD mechanisms.

**Anemia:** - **Microcytic anemia** is caused by iron transport disorders (e.g., IRIDA syndrome, DMT1 deficiency, aceruloplasminemia, atransferrinemia), sideroblastic anemias (e.g., X-linked sideroblastic anemia [XLSA], SIFD syndrome), and porphyrias (e.g., congenital erythropoietic porphyria [CEP], erythropoietic protoporphyria [EPP]). For example, in aceruloplasminemia, microcytic anemia occurs in 85% of patients, and in EPP, microcytic anemia occurs in 20–60% of patients. - **Hemolytic anemia** results from RBC enzyme defects (e.g., G6PD deficiency affecting over 500 million individuals worldwide, pyruvate kinase deficiency), cytotoxic metabolite accumulation (e.g., Wilson disease, porphyria), thrombotic microangiopathy (e.g., cobalamin C deficiency), Gaucher disease (autoimmune hemolytic anemia incidence 0.55–2.7%), and lipid metabolism disorders (e.g., LCAT deficiency, abetalipoproteinemia). In CEP, 60% of 128 cases had hemolytic anemia. - **Megaloblastic anemia** is due to impaired cobalamin metabolism (e.g., Imerslund-Gräsbeck syndrome, transcobalamin II deficiency, methylmalonic acidemias [MMA], propionic acidemia [PA]), impaired folate metabolism (e.g., MTHFD1 deficiency, DHFR deficiency), and thiamine-responsive megaloblastic anemia (TRMA). TRMA presents with a classic triad of megaloblastic anemia, diabetes mellitus, and deafness.

**Thrombocytopenia:** Causes include sitosterolemia (macrothrombocytopenia with stomatocytes), galactose epimerase deficiency (dysplastic megakaryocytes), Gaucher disease (thrombocytopenia in 10/15 patients in one study), and acid sphingomyelinase deficiency (ASMD) type B (associated with hypersplenism).

**Neutropenia:** Key IMDs include type Ib glycogen storage disease (GSD Ib) due to G6P translocase deficiency, Barth syndrome (variable neutropenia with 3-methylglutaconic aciduria), and Shwachman-Diamond syndrome (SDS) (neutropenia in 88–100% of patients).

**Pancytopenia:** Mechanisms include impaired medullary production (e.g., organic acidemias [OAD] like propionic acidemia, isovaleric acidemia, methylmalonic acidemia; lysinuric protein intolerance [LPI] with cytopenias in 37% of cases) and hypersplenism due to storage diseases (e.g., Gaucher disease, mucopolysaccharidoses, ASMD).

**Clinical Implications:** The review emphasizes that cytopenias can be the primary manifestation of an IMD (e.g., hemolytic anemia in G6PD deficiency) or part of a complex multisystemic picture (e.g., Gaucher disease). It highlights five "open and shut" clinical situations: G6PD deficiency (favism or rasburicase-induced hemolysis), Gaucher disease (hypersplenism in Ashkenazi Jewish descent, 1/450 births), IRIDA syndrome (iron deficiency unresponsive to oral iron), porphyria (cutaneous manifestations and anemia), and Wilson disease (hemolytic anemia with hepatic cytolysis or parkinsonism). Blood smear findings can aid diagnosis, such as Gaucher cells in Gaucher disease, hypersegmented neutrophils in megaloblastic anemia, and stomatocytes in sitosterolemia. The authors stress that physicians should suspect IMD in cases of cytopenia arising in childhood, without a definite diagnosis, not responding to usual treatment, or with signs of other organ involvement, as early identification can lead to specific treatments.