Fanconi anemia-D1 due to homozygosity for the BRCA2 gene Cypriot founder mutation: A case report.

Fanconi anemia (FA) is a rare disorder characterized by multiple congenital malformations, progressive bone marrow failure and susceptibility to malignancies. Biallelic mutations in the breast cancer 2, early onset (BRCA2) gene are responsible for the FA-D1 subgroup, which accounts for ~3% of all the FA cases. Patients with biallelic BRCA2 mutations generally display a more severe phenotype, with earlier onset and increased incidence of leukaemia and other solid tumors, than other patients with FA. In the present report, the first Cypriot patient with FA-D1 is described, which is the fifth case of a homozygote for the same null allele reported thus far, and the third known case of neuroblastoma in association with FA-D1.

Novel GLA Deletion in a Cypriot Female Presenting with Cornea Verticillata.

Fabry disease is an X-linked lysosomal storage disorder resulting from a deficiency of the hydrolytic enzyme α-galactosidase A (α-Gal-A). It is characterized by progressive lysosomal accumulation of globotriaosylceramide (Gb3) and multisystem pathology, affecting the skin, nervous and cerebrovascular systems, kidneys, and heart. Heterozygous females typically exhibit milder symptoms and a later age of onset than males. Rarely, they may be relatively asymptomatic throughout a normal life span or may have symptoms as severe as those observed in males with the classic phenotype. We report on a 17-year-old female in whom cornea verticillata was found during a routine ophthalmological examination but with no other clinical symptoms. Leucocyte α-galactosidase activity was within the overlap range between Fabry heterozygotes and normal controls. Sanger sequencing of the GLA gene failed to reveal any pathogenic variants. Multiplex Ligation-dependent Probe Amplification (MLPA) analysis revealed a deletion of exon 7. Using a long-range PCR walking approach, we managed to identify the deletion breakpoints. The deletion spans 1182 bp, with its 5' end located within exon 6 of the GLA gene and its 3' end located 612 bp downstream of exon 7. This finding represents a novel deletion identified in the first reported Cypriot female carrier of Fabry disease.

Novel homozygous PANK2 mutation causing atypical pantothenate kinase-associated neurodegeneration (PKAN) in a Cypriot family.

Pantothenate kinase-associated neurodegeneration (PKAN) is the commonest, recessively inherited form of neurodegeneration with brain iron accumulation (NBIA) resulting from mutations in the pantothenate kinase 2 (PANK2) gene on chromosome 20. PKAN is usually rapidly progressive, presenting in the vast majority in the first decade of life (classic form). A rarer, later onset and slowly progressive (atypical) PKAN form also exists. We present two siblings of Cypriot descent, a 27-year-old man and his clinically asymptomatic younger sister, both of whom were found to be homozygous for a novel c.695A>G (p.Asp232Gly) missense mutation in exon 2 of the PANK2 gene. The index patient presented with a 5-year history of slowly progressive gait disturbance, dysarthria, mild axial rigidity and bradykinesia. His brain MRI scan revealed the characteristic "eye-of-the-tiger" sign. Atypical genetically confirmed PKAN cases are sparsely reported and should be considered in the differential diagnosis of patients presenting with a progressive extrapyramidal syndrome particularly if the radiographic findings are suggestive of iron accumulation. Effective treatment strategies for PKAN are not currently available and symptomatic therapy is often unsatisfactory. However, early diagnosis including the presymptomatic stage is important for genetic counseling and will be crucial for testing novel therapeutics in the future.