Fanconi anaemia Clinical features

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Since the first description by Fanconi in 1927, FA has become to be recognized as an autosomal recessive disorder in which there is progressive BM failure and an increased predisposition

Table 12.2 Characteristics ofthe bone marrow failure syndromes.

FA DC SDS DBA TAR SCN IAA

Inheritance pattern AR XLR, AR, AD AR AD and AR AR AD, AR ?

Somatic abnormalities Yes Yes Yes Yes Yes Rare ? None

Bone marrow failure AA (> 90%) AA (~80%) AA (20%) RCA Megs Neutropenia Yes (100%)

Short telomeres Yes Yes Yes ? ? ? Yes

Malignancy Yes Yes Yes Yes ? No Yes Yes

Chromosome instability Yes Yes Yes ? ? ? Yes

Number of genes At least 7 At least 3 ?1 At least three ? ? ?

Genes identified 7 2 11 No 1 ?

AA, aplastic anaemia; AD, autosomal dominant; AR, autosomal recessive; DBA, Diamond-Blackfan anaemia; DC, dyskeratosis congenita; FA, Fanconi anaemia; IAA, idiopathic AA; Megs, low megakaryocytes; RCA, red cell aplasia; SCN, severe congenital neutropenia; SDS, Shwachman-Diamond syndrome; TAR, thrombocytopenia with absent radii; XLR, X-linked recessive.

to malignancy, especially acute myeloid leukaemia. Most, but not all, affected individuals also have one or more somatic abnormalities including skin (cafe-au-lait spots), skeletal (absent thumbs, radial hypoplasia, scoliosis), genitourinary (underdeveloped gonads, horseshoe kidneys), gastrointestinal, cardiac and neurological anomalies (Table 12.3). Some of these somatic abnormalities are shown in Figure 12.1. The course of the disease and the pattern of somatic abnormalities show considerable variation, with approximately one-third of patients having no somatic abnormalities. This makes diagnosis based on clinical criteria alone difficult and unreliable.

Table 12.3 Somatic abnormalities in FA (modified from Auerbach etal. 1998).

Abnormality

Percentage

of patients

Skeletal (radial ray, hip, vertebral, scoliosis, rib)

71

Skin pigmentation (café-au-lait, hyper- and

64

hypopigmentation)

Short stature

63

Eyes (microphthalmia)

38

Renal and urinary tract

34

Male genital

20

Mental retardation

16

Gastrointestinal (e.g. anorectal, duodenal atresia)

14

Heart

13

Hearing

11

Central nervous system (e.g. hydrocephalus,

8

septum pellucidum)

No abnormalities

30

The cumulative incidence of BM failure by the age of 40 years is 90%. At birth the blood count is usually normal. Pancytopenia develops insidiously and presents in most cases between the ages of 5 and 10 years (median age 7 years). However, in some cases the pancytopenia develops in adolescence or even in adult life. The haemoglobin (Hb) and platelet count are usually first to fall; the granulocytes are usually well preserved in the early stages. As the pancytopenia develops, the BM becomes progressively hypocellular. There is often a marked increase in macrophage activity with evidence of haemophagocytosis. BM failure leading to fatal haemorrhage or infection is the main cause of death in FA patients. In a recent analysis from the International Fanconi Anemia Registry (IFAR), the median survival time was 24 years.

FA is associated with an increased risk of leukaemia and other malignancies. The leukaemias are usually of the acute myeloid type, particularly FAB types M4 (myelomonocytic) and M5 (monocytic). In some cases, leukaemia may be the initial event leading to the diagnosis of FA. The cumulative incidence of haematological malignancy by the age of 40 years is 33%. Besides these haematological malignancies, there is a significant risk of hepatic tumours and squamous cell carcinoma, including squamous cell carcinomas of the vulva, oesophagus, head and neck. The cumulative incidence of solid tumours is calculated to be 28% by the age of 40 years. The impression is that malignancies occur mainly in patients with late-onset BM failure and longer survival, with a median age of 13 years for leukaemia and 25 years for solid tumours. Furthermore, long-term follow-up in FA patients who have been treated by haemopoietic stem cell transplantation (SCT) is showing a higher incidence of non-haematological malignancies in patients with FA than patients with other types of BM failure who underwent SCT, again emphasizing the predisposition to malignancy.

Fanconi Anemia Image Cafe Lait Spots

Figure 12.1 (a) Photographs of FA patients (A1-A3) with small mouth and chin ('Fanconi facies'). (b) Abnormalities of pigmentation (hyper- and hypopigmentation) on the abdomen (B1) with a close-up (B2) of a cafe-au-lait spot and a hypopigmented patch. The bottom photograph (B3) shows the back of a FA patient, demonstrating lumbar scoliosis. (c) Hands/forearms of FA children showing hypoplastic thumbs (C1), rudimentary ('dangling') thumbs (C2) and a radiograph (C3) showing rudimentary thumb (skeletal) development.

Figure 12.1 (a) Photographs of FA patients (A1-A3) with small mouth and chin ('Fanconi facies'). (b) Abnormalities of pigmentation (hyper- and hypopigmentation) on the abdomen (B1) with a close-up (B2) of a cafe-au-lait spot and a hypopigmented patch. The bottom photograph (B3) shows the back of a FA patient, demonstrating lumbar scoliosis. (c) Hands/forearms of FA children showing hypoplastic thumbs (C1), rudimentary ('dangling') thumbs (C2) and a radiograph (C3) showing rudimentary thumb (skeletal) development.

Figure 12.2 (a and b) Chromosomal abnormalities seen in FA lymphocytes following incubation with diepoxybutane. ctb, chromatid break; ctg, chromatid gap; mci, multiple chromatid

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