Fanconi Anemia

Fanconi anaemia (FA) is an inherited DNA repair disorder with progressive bone marrow failure, congenital anomalies and cancer predisposition.

• Incidence about 1 in 130,000 births; autosomal recessive (23 FANC genes; FANCA 60 to 70%), X linked (FANCB).
• Defect in the FA/BRCA interstrand crosslink repair pathway, with chromosome breakage.
• Marrow failure by median age 7; AML risk 10 to 15% by age 40; solid tumours (head and neck squamous carcinoma, anogenital, liver).
• Congenital anomalies in 60 to 75%: radial ray defects (absent or hypoplastic thumbs), short stature, café au lait spots, microcephaly, renal malformations, hypogonadism.
• VACTERL-H like phenotype in some.

• Short stature, abnormal thumbs and radii, skin pigmentation, small eyes, renal anomalies, developmental delay.
• Pancytopenia developing at 5 to 10 years: bruising, pallor, infections.
• Endocrine: growth hormone deficiency, hypothyroidism, diabetes, osteoporosis, infertility.
• Squamous carcinoma of mouth, oesophagus, vulva, anus at young age.
• 25% have no obvious malformations.

• Chromosome breakage test with diepoxybutane or mitomycin C (peripheral lymphocytes, increased breaks and radial forms) is diagnostic.
• Complementation group and mutation analysis (FANCA and panel); mosaicism may need fibroblast testing.
• Full blood count (macrocytosis, raised HbF), marrow aspirate and cytogenetics (clonal abnormalities of 1q, 3q, monosomy 7).
• Baseline: renal ultrasound, echocardiography, audiology, thyroid, glucose, IGF 1, bone age.
• Screen siblings (HLA typing and breakage test).

• Androgens for marrow failure when not transplant candidate: oxymetholone 2 to 5 mg/kg/day, response in 50 to 75% (liver toxicity, peliosis, adenoma, virilisation), with liver ultrasound; add G CSF for neutropenia.
• Haematopoietic stem cell transplant (the only curative option): matched sibling donor transplant with fludarabine based low dose conditioning (cyclophosphamide 20 mg/kg, avoiding total body irradiation) offers over 80% survival; haploidentical or unrelated donors with ATG and fludarabine; gene therapy in trials.
• Transfusions with irradiated, leucodepleted products; avoid family donors.
• Cancer surveillance: oral and ENT examination every 6 months from age 10, gynaecological and anal examinations, annual marrow with cytogenetics, liver imaging; HPV vaccination.
• Endocrine replacement: growth hormone, levothyroxine, insulin, sex steroids, vitamin D and bisphosphonates for osteoporosis.
• Avoid radiation and alkylating agents, lower doses of chemotherapy for malignancy.
• Genetic counselling and prenatal diagnosis.