Bone marrow failure syndromes

Inherited bone marrow failure syndromes (IBMFS) present with single-lineage or multi-lineage cytopenias of variable severity, often emerging in childhood but possible at any age. The clinical spectrum encompasses both syndromic forms with characteristic extrahaematological features and largely nonsyndromic presentations in which marrow failure dominates the picture.

Syndromic manifestations include congenital anomalies and growth deficiency in , the mucocutaneous triad and pulmonary or hepatic involvement in dyskeratosis congenita and related telomere biology disorders, exocrine pancreatic insufficiency and skeletal abnormalities in , and early-onset macrocytic anaemia with congenital anomalies in Diamond-Blackfan anaemia syndrome.

Onset spans the first months of life through adulthood, and bone marrow failure may develop progressively over years; approximately one half of individuals with dyskeratosis congenita and related telomere biology disorders develop some degree of marrow failure by age 40 years. The overlap of inherited and acquired causes of hypocellular marrow failure, particularly in nonsevere disease, can pose a substantial diagnostic challenge.

Due to insufficient data, no reliable statement on prevalence can currently be made.

More than 60 genes appear in diagnostic gene panels for these syndromes, grouped into DNA-repair disorders, telomere biology disorders, and ribosomopathies. (FANCA and other complementation-group genes) is generally regarded as the most frequent of these. Other frequent causes include dyskeratosis congenita and related telomere biology disorders (DKC1, TINF2), Diamond-Blackfan anaemia syndrome (RPS19), and (SBDS).

Inheritance across these syndromes is heterogeneous, with all three Mendelian modes represented. is autosomal recessive, with rarer autosomal dominant (RAD51-related) and X-linked (FANCB-related) forms; is autosomal recessive or dominant depending on the gene; Diamond-Blackfan anaemia syndrome is most often autosomal dominant, with X-linked GATA1– and TSR2-related forms; and dyskeratosis congenita and related telomere biology disorders show autosomal dominant, recessive, or X-linked inheritance.

• Molecular genetic testing can identify the underlying condition and confirm a clinical suspicion.
• The identified entity guides further clinical management and is a prerequisite for targeted medical care; therapeutic options are evaluated individually by the treating physicians.
• Identification of the underlying pathogenic germline variant enables predictive testing of at-risk family members, provides information relevant to family planning and can help identify suitable donors for stem cell transplantation.

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