NF1 MICRODELETION SYNDROME: CLINICAL AND CYTOGENETIC CHARACTERIZATION OF A FAMILIAL DELETION.

GREES S A; GUTIÉRREZ M; VALLE L E; CASALI B; BOYWITT A; DE BELLIS R; DEL REY G

Buenos Aires, Argentina

Simposio; VI International Conference of Rare Diseases and Orphan Drugs. IInd Latin American and Caribbean Symposium on Rare Diseases; 2010

Fundación Geiser. Conferencia Internacional de Enfermedades Raras y Drogas Huérfanas

Neurofibromatosis type 1 ( NF1 MIM 162200) is an autosomal dominant disorder caused by deletion or point mutations of NF1, a tumour suppressor gene located to17q11.2 with marked variation in expression, affecting approximately 1/3500 individuals. The main clinical features are café au lait spots, axillary and inguinal freckling, cutaneous neurofibromas, hamartomas of the iris (Lisch nodules) and an increased risk of benign and malignant tumours, optic glioma, neurofibrosarcoma, malignant peripheral nerve sheath tumours and childhood myeloid leukaemia. Additional complications include central nervous system tumours, scoliosis, plexiform neurofibromas, learning difficulties, and epilepsy. Aproximately 5-20% of all NF1 patients carry a heterozygous deletion of usually 1.5Mb involving the NF1 gene and contiguous genes lying in the flanking regions resulted by unequal homologous recombination during the meiosis. The “NF1 microdeletion syndrome” is often characterised by a more severe phenotype than that observed in the classical group. NF1 microdeleted patients show variable facial dysmorphism, mental retardation, developmental delay and an excessive number of neurofibromas for age. The severity may be explained by variations in the expression of the genes involved in the rearrangement caused by different mechanisms such as gene interruptions or position effects with a decreased gene dosage. In this report we present three-generations on a large pedigree with 3 patients, mother, sister and son whose clinical and laboratory data are characteristic of the NF1 microdeletion. The patients show a large number of cutaneous neurofibromas, facial anomalies, large hands and head, and developmental impairment. The 4-year-old sister present plexiform neurofibromas and learning disability. At 10 months of age she showed 13 café au lait spots. The 2-year-old boy present renal malformations and psychomotor retardation. The histology study of both revealed juvenile xanthogranuloma. Furthermore, several other relatives of the patients have been affected with NF1 as well tumours, cardiac anomalies, hypertension, and other relatives died in the newborn period or during the young life without diagnosis. Peripheral blood of the three patients was cultured using standard techniques to perform cytogenetic preparations suitable for high resolution analysis. Karyotyping with GTG banding revealed a cytogenetically visible deletion at 17q11.2 subband. The deletioned chromosome was shorter than the normal chromosome 17. According to literature data this family shows the most common extra NF1 signs as cardiac anormalies, dysmorphism, and learnig disability indicating clinical NF1 microdeleted. We conclude the importance to carry out cytogenetic studies, molecular and FISH analysis with locus specific probes to confirm the deletion size at 17q11.2 in patients with suspected clinical “NF1 microdeleted”, such as improving the assessment and the multidiscipline management of the clinical problems in isolated individuals or in families with one or more members affected with this genetic disorder.