Inherited bone marrow failure syndromes
§ 25% of paediatrics and 10% of adults presenting with AA have an inherited aetiology § Mutated genes have been identified on all but TAR § Often have macrocytosis and increased fetal Hb
Fanconi anaemia § AR / XLR § Median age of diagnosis 6 / death 23 § Pancytopenia § Very high rate of secondary complications § Preaplastic and preleukaemic § Associated with solid tumours § Head and neck SCC, liver § Gynaecological § Brain § Characteristic birth defects (25% normal) § Café au lait / hyper/ hypopigmentation § Short stature § Microcephaly / Microphthalmia / triangular face § Abnormal thumbs with/ without hypoplastic radii § Hypogonadism and infertility (some reports of pregnancy / male fertility) § Ectopic kidneys § Diagnosis (median 6 years) § PB T-lymphocytes exposed to a DNA cross-linking agent eg. MMC, DEB (diepoxybutane) § Not on marrow, increased false negatives § Metaphase spreads have increased chromosomal breakages § Definitive proof is gene identification (13 genes to date FANCA to N) § Clinical course § 50% bone marrow failure causing death or transplant § 30% solid tumour § 10% leukaemia (mainly AML – excluding MDS) § Can spontaneously remit – due to repair of DNA defect – remain at risk of solid tumours. § Monitoring § FBC 3-4monthly § BM annually including cytogenetics § Solid tumour surveillance (head and neck / gynae) § Effects of HPV vaccine on solid tumour rates awaited with interest § Therapy § Androgens +/- GCSF / EPO for AA § SCT cures bone marrow failure § Recommended if HLA-matched sibling when (Hb<8 Plts <30 Neut <0.5) consider MUD § Increases risk of solid tumours (4 fold / 16 years earlier) § Recommended if BM failure and an HLA-matched sibling § Conditioning is specialised because of the chromosomal instability · Eg. Fludarabine, ATG § Siblings must be proven to not have FA § Solid tumours – modified chemo / radiotherapy
Dyskeratosis Congenita § AR, AD, XLR § Often diagnosed late (median 15 – range 0-75) death 45 § Pancytopenia § Characteristic features (often absent) § Lacey reticulated pigmentation § Dysplastic nails § Oral leukoplakia § Pulmonary / hepatic fibrosis § Preaplastic and preleukaemic § Assoc with solid tumours § Head and neck § Oesophageal and colorectal § Diagnosis § Telomere length in leucocyte subsets using Flow-FISH (reduced length) § Therapy is similar as for FA § Androgens § Not recommended with GCSF because of splenic peliosis and rupture § Conditioning for SCT difficult because of risk of pulmonary and liver fibrosis in DC
Diamond-Blackfan Anaemia § AD § Median age of diagnosis 3 months / death 39 § Anaemia (macrocytic) and erythroid hypoplasia (pancytopenia rare – should question diagnosis) § Preleukaemic, preaplastic rarely § Assoc with ostogenic sarcoma § Characteristic defects § Flattened thenar muscles § Short stature § Triphalangeal thumbs § Diagnosis § Increased red cell adenosine deaminase levels § Treatment § Good response to corticosteroids § 25% spontaneous remission § Poor response to steroids § Transfusions and iron chelation § SCT has been used successfully
Shwachman-Diamond Syndrome § AR § Median age at diagnosis 1 / death at 35 § Predominantly neutropenia but may evolve to AA, MDS or leukaemia § >70% develop leukaemia (median age18) § Not assoc with solid tumours § Characteristic features § Malabsorption § Short stature § Metaphyseal dysotosis § Learning difficulties § Diagnosis § Proof of exocrine pancreatic insufficiency (serum trypsinogen levels reduced) § Neutropenia of <1.5 on at least 2 occassions § >95% have mutations in SBDS gene (Shwachman-Bodie-Diamond Syndrome) § Treatment § Monitor with yearly bone marrows / regular FBC § Supplement pancreatic enzymes and vitamins ADEK § GSCF § SCT has been successfully used
Severe Congenital Neutropenia § Sporadic, AR, AD § Median age at diagnosis – 3 / death 50 § Neutropenia, marrow maturation arrest and pyogenic infections § Preleukaemic, not pre-aplastic (20-40% at 10 years) § No assoc solid tumours § No characteristic findings § Diagnosis § Neutrophil <0.5 on 3 occassions separated by 1 month § Exclude cyclical neutropenia § By testing fortnightly for 6 weeks § Usually a 3 week cycle § BM to demonstrate promyelocyte arrest § Most have mutation in neutrophil elastase ELA-2 (as do many patients with cyclical neutopenia) § Treatment § GCSF to get neutrophil >1.5 § Some evidence to suggest that patients who are poorly responsive to GCSF ie. require higher doses, have a higher rate of leukaemic transformation, and should be considered for SCT
Amegakaryocytic thrombocytopenia § AR § Diagnosed in infancy, median survival 16 § Evolves to aplastic anaemia (90% by age 13) and preleukaemic (55% AML by age 17) § Not assoc with solid tumours § No characteristic findings § Diagnosis § BM – absent/ abnormal megas cf. ITP § Due to homozygous mutations in MPL – the thrombopoietin receptor (variability in phenotype depending on the mutations – null/null = worse prognosis) § Treatment § Androgens § SCT (normal conditioning for AA) because of high rate of evolution
Thrombocytopenia Absent Radii § ? AR – gene not identified § Usually diagnosed at birth median survival 70+ years § Thrombocytopenia +/- transient leukaemoid reaction § Preleukaemic but not preaplastic § Not assoc with solid tumours § Characteristic features § Absent radii but thumbs present § Diagnosis § BM – absent/ abnormal megakaryocytes § Treatment § Not usually required – platelet count rises over first year of life
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