Clinical Characteristics of Patients with Fanconi Anemia in Complementation Group J.

Abstract Fanconi anemia (FA) is an inherited disorder characterized by chromosomal instability, developmental abnormalities, progressive bone-marrow failure, and cancer susceptibility. To date, twelve complementation groups have been described for FA (A, B, C, D1, D2, E, F, G, I, J, L and M) and eleven associated genes have already been identified (FANCA, FANCB, FANCC, FANCD1/BRCA2, FANCD2, FANCE, FANCF, FANCG/XRCC9, BRIP1/FANCJ, FANCL and FANCM/Hef). The FA complementation group J (FA-J) was first reported in 2004. FA-A is the most common group, accounting for approximately 65% of all affected individuals while FA-J is a rare group, comprising only 1.6% of all FA patients in the International Fanconi Anemia Registry (IFAR). To the best of our knowledge 11 FA-J patients have been reported in the IFAR. Patients with Fanconi anemia show extreme clinical heterogeneity. Thus, it is of interest to associate the phenotype with the complemantation group, since this could provide predictive information on clinical outcome. So far, in the Hospital La Fe, 4 patients (two siblings and two unrelated patients) belong to scarce FA-J complementation group. This represents the 4.5 % of the FA patients included in the Spanish Fanconi Anemia Registry. Subtyping was done by viral complementation. Cells from these patients were not complemented with a battery of vectors with FA genes (FANCA, FANCC, FANCG, FANCE, FANCF, and FANCD2). However, the characteristic cellular hypersensitivity to mitomycin C was reverted when a lentiviral vector encoding for BRIP1/FANCJ was used. Moreover, mutational studies confirmed the subtyping of FA-J in these Fanconi patients. The clinical course of the 4 FA-J patienst are shown in the Table. In conclusion, its noteworthy the high frequency of the FA-J genotype in Spain. The 75% of our patients have major congenital malformations and severe endocrinopathy. All our patients had short stature and 50% were mycrosomic. None of our patients had skin abnormalities, although this is present in 80% of the patients in other registries. Although two of these patients developed aplasia very early (5 years old), FA-J siblings developed severe aplasia at the age of 20 years but none of them developed leukemia or solid tumors. Clinical course of patients Patient 1* 2* 3 4 * Sibling sex male female male female Aplasia onset (years) 24 20.5 4.3 3.5 Survival (years) 28 31.5 6 alive Short stature Yes Yes Yes Yes Microsomy No Yes Yes No Skin pigmentation No No No No Eyes abnormalities No No microphthalmia Epiphora Skeletal malformations Syndactyly No Abnormal thumbs Abnormal thumbs Kidneys Agenesis, left No No Horseshoe Endocrinopathy failure puberty not available hypotiroidism hypopituitarysm Gastrointestinal malformations No No Esophageal atresia Onphalocele Malignacies No No No No Family cancers Not available Not available Liver Lung, brains and breast