Inherited Bone Marrow Failure Syndromes (IBMFS)

Most inherited bone marrow failure syndromes (IBMFS) are diagnosed in childhood. However, up to 9% of individuals may present in adulthood. Bone marrow failures (BMF) are generally caused by immune-related conditions or inherited due to germline abnormalities that cause decreased production of one or more cell lines. We will discuss when to suspect IBMFs and describe the most relevant cases that could be encountered in hematology.

When to Suspect an Inherited Bone Marrow Failure Syndrome

Bone marrow failure refers to the inability of the bone marrow to produce enough cells in one or more cell lines causing cytopenias and other clinical manifestations. Symptoms are related to the affected cell lines, and they have a variety of features that can include infection, symptomatic anemia, and bleeding, among others. Differentiating between immune-mediated BMF and inherited BMFS can be challenging. Therefore, patients presenting with new onset BMF should undergo genetic testing regardless of their age or clinical phenotype.

An inherited bone marrow failure is more likely if any of the following features is present:

• Positive family history of bone marrow failure or hematologic malignancy.
• Early-onset or long-standing cytopenias.
• Clinical features of an inherited BMF. For example, individuals with Fanconi Anemia can present with short stature, thumb/radial abnormalities, renal defects, and others.
• Cytopenias with unclear cause (rule out nutritional, infectious, malignant, drug-induced, and other causes).
• Presence of PNH clones in peripheral blood flow cytometry in a young patient without classical acquired aplastic anemia (AA).
• Somatic mutations in IBMFS-related genes (e.g. RUNX1, GATA2, DDX41, SAMD9, SAMD9L, MECOM).
• Inadequate response to immunosuppressive therapy (IST) since most immune-mediated BMF tend to respond well.

Overview of Inherited Bone Marrow Failure Syndromes (IBMFS)

Fanconi Anemia (FA)

• Autosomal recessive or X-linked DNA repair defect due to mutations in the Fanconi genes (at least 23 mutations) usually called FANC genes (FANCA, FANCB, etc.)
• Clinical features include bone marrow failure (pancytopenia) associated with skeletal abnormalities (radial abnormalities, short stature), renal defects, and increased risk for malignancies.

Dyskeratosis Congenita (DKC)

• Variable inheritance with X-linked (most common), autosomal dominant, and autosomal recessive defects in telomere maintenance and repair.
• Characterized by cytopenias associated with the classic triad of oral leukoplakia, nail dystrophy, and skin coloration abnormalities (hypopigmented or hyperpigmented lesions termed dyskeratosis).
• Pulmonary fibrosis and increased malignancy risk are also seen.

Diamond-Blackfan Anemia (DBA)

• Also known as congenital pure red cell aplasia.
• Variable inheritance including autosomal dominant and de novo mutations.
• Due to ribosomal protein gene mutations in the RPS (ribosomal protein synthesis) genes.
• Clinical features include pancytopenia associated with skeletal abnormalities (craniofacial, thumb abnormalities), cardiac abnormalities, and increased malignancy risk.

Shwachman-Diamond Syndrome (SDS)

• Autosomal recessive disorder due to mutations in the SBDS gene affecting the function of ribosomes (chromosome 7).
• Characterized by cytopenias and skeletal abnormalities, pancreatic insufficiency, and increased risk of hematologic malignancy.

Severe Congenital Neutropenia (SCN or Kostmann Syndrome)

• Variable inheritance, most commonly autosomal dominant due to ELANE (neutrophil elastase mutation).
• Presents with profound neutropenia (below 200/uL) associated with a significant risk of infections (particularly bacterial). Neurologic features such as cognitive delay and seizures can occur.

Congenital Amegakaryocytic Thrombocytopenia (CAMT)

• Autosomal recessive disorder due to MPL (thrombopoietin receptor gene) leads to defective platelet production and function.
• Absent or severely reduced megakaryocytes in the bone marrow.
• Clinical features include early-onset thrombocytopenia (usually <20.000/uL), other cytopenias, and no congenital deformities. Bleeding complications can occur.

Each of the inherited BMFs mentioned above will be described in future posts. Importantly, besides the clinical scenario that can point towards a particular inherited BMF, genetic testing is essential for all patients. Treatment of these conditions will include consideration for stem cell transplantation. In contrast, acquired BMFs in general are treated with immunosuppression.

---

We hope you enjoyed this post! Please, leave us any comments or questions below. Feel free to rate our post using the star system below if your time allows. Your feedback is important to us. Thank you!