Fanconi anaemia
FA; Fanconi syndrome (NB: not the renal Fanconi syndrome — distinct entity); congenital aplastic anaemia with multiple congenital anomalies
Fanconi anaemia is a rare inherited bone-marrow failure syndrome and DNA-repair disorder, caused by biallelic mutations in any of more than 22 known FA pathway genes (most commonly FANCA, FANCC, FANCG; X-linked FANCB). The syndrome combines progressive aplastic anaemia, characteristic congenital anomalies (radial-ray defects, café-au-lait macules, short stature, microcephaly) and a profoundly elevated lifetime cancer risk — most importantly head-and-neck and anogenital squamous cell carcinoma, with cumulative risks of 30–50% by age 50, and acute myeloid leukaemia and myelodysplastic syndrome. Allogeneic haematopoietic stem-cell transplantation cures the haematological component but, importantly, is associated with further markedly elevated post-transplant SCC risk because of conditioning chemoradiotherapy and chronic graft-versus-host disease. The dermatologist's role is critical lifelong surveillance for early SCC, particularly oral, oesophageal and anogenital, where routine prevention and early detection radically improve outcomes.
Genetics
- Biallelic mutations of any of >22 known Fanconi anaemia complementation group genes — FANCA (~60%), FANCC (~15%), FANCG (~10%) commonest; FANCD1 = BRCA2; FANCJ = BRIP1; FANCN = PALB2; FANCS = BRCA1.
- Autosomal recessive inheritance for most genes; X-linked recessive for FANCB.
- FA proteins form a complex that monoubiquitinates FANCD2 and FANCI, recruiting downstream homologous-recombination DNA-repair effectors (BRCA2, RAD51, etc.) to interstrand crosslinks.
- Loss of function → impaired interstrand crosslink repair → chromosomal instability → bone-marrow failure and cancer.
- Diagnosis confirmed by chromosome breakage (mitomycin C / diepoxybutane) test on peripheral blood lymphocytes followed by germline sequencing.
Clinical features
- Congenital anomalies (60–75%): short stature, microcephaly, radial-ray defects (absent / hypoplastic thumbs and radii), café-au-lait macules, generalised hyperpigmentation, abnormal genitalia, structural renal anomalies, congenital heart disease.
- Progressive bone-marrow failure — typically presenting in childhood (median age 7) with thrombocytopenia, then pancytopenia.
- Endocrine — growth hormone deficiency, hypothyroidism, glucose intolerance, primary gonadal failure.
- Skin — café-au-lait macules, generalised hyperpigmentation, areas of hypopigmentation.
Cancer risk
- Acute myeloid leukaemia / myelodysplastic syndrome — cumulative risk 30–50% by age 50 (without transplantation).
- Head-and-neck squamous cell carcinoma — cumulative risk 30–50% by age 50; tongue, gingiva, buccal mucosa, hypopharynx; younger age, multifocality and aggressive behaviour. Risk further amplified by post-transplant chronic GvHD and conditioning therapy.
- Anogenital SCC — vulva, anus, perianal skin, cervix; HPV-driven; markedly elevated risk.
- Cutaneous SCC and BCC — increased risk; particularly post-transplant.
- Oesophageal SCC — increased risk.
- Liver tumours — hepatocellular adenoma / carcinoma; particularly with anabolic steroid therapy for bone-marrow failure.
- Brain tumours — increased risk, especially in BRCA2 / FANCD1 patients.
Surveillance
- Multidisciplinary care — paediatric / adult haematology, dermatology, ENT / oral medicine, gynaecology, genetics; lifelong.
- Annual oral examination from age 10 — by ENT or oral-medicine specialist; biopsy of any white / red lesion or persistent ulcer.
- Annual gynaecological examination from late adolescence — including HPV vaccination if not already received.
- Annual full skin examination from late childhood; lower threshold for biopsy of any persistent lesion.
- Annual upper-GI endoscopy in adults with risk factors or symptoms.
- Marrow surveillance and management of cytopenias / leukaemia by haematology.
- Strict avoidance of tobacco and alcohol.
- Photoprotection — daily SPF 50+, sun-protective clothing.
- HPV vaccination for all FA patients regardless of age.
Management of skin / mucosal cancers
- Wide local excision is the cornerstone; reconstruction by plastic surgery / oral surgery.
- Radiotherapy is associated with severe toxicity in FA — markedly enhanced normal-tissue radiosensitivity due to defective DNA repair. Use only when essential and at reduced doses with specialist input.
- Conventional chemotherapy is also poorly tolerated — DNA-crosslinking agents (cisplatin, mitomycin C) and ionising radiation cause severe toxicity. Reduced-dose protocols required.
- Anti-PD-1 immunotherapy (cemiplimab) — emerging option for advanced cSCC / head-and-neck SCC; reasonable in FA given limited chemotherapy / RT options.
- Allogeneic haematopoietic stem-cell transplantation cures the marrow disease but does not reduce — and may increase — post-transplant solid tumour risk; strict surveillance after transplant.
References
- Auerbach AD. Fanconi anemia and its diagnosis. Mutat Res; 2009.
- Alter BP. Cancer in Fanconi anemia, 1927–2001. Cancer; 2003.
- Fanconi Anemia Research Fund / Fanconi Cancer Foundation. Fanconi Anemia Clinical Care Guidelines. 5th ed. 2020; online chapter updates accessed 18 May 2026.
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