Genotype-Phenotype Associations in Patients With Type-1, Type-2, and Atypical NF1 Microdeletions.

Neurofibromatosis type 1 is a tumor predisposition syndrome inherited in autosomal dominant manner. Besides the intragenic loss-of-function mutations in NF1 gene, large deletions encompassing the NF1 gene and its flanking regions are responsible for the development of the variable clinical phenotype. These large deletions titled as NF1 microdeletions lead to a more severe clinical phenotype than those observed in patients with intragenic NF1 mutations. Around 5-10% of the cases harbor large deletion and four major types of NF1 microdeletions (type 1, 2, 3 and atypical) have been identified so far. They are distinguishable in term of their size and the location of the breakpoints, by the frequency of somatic mosaicism with normal cells not harboring the deletion and by the number of the affected genes within the deleted region. In our study genotype-phenotype analyses have been performed in 17 mostly pediatric patients with NF1 microdeletion syndrome identified by multiplex ligation-dependent probe amplification after systematic sequencing of the NF1 gene. Confirmation and classification of the NF1 large deletions were performed using array comparative genomic hybridization, where it was feasible. In our patient cohort 70% of the patients possess type-1 deletion, one patient harbors type-2 deletion and 23% of our cases have atypical NF1 deletion. All the atypical deletions identified in this study proved to be novel. One patient with atypical deletion displayed mosaicism. In our study NF1 microdeletion patients presented dysmorphic facial features, macrocephaly, large hands and feet, delayed cognitive development and/or learning difficulties, speech difficulties, overgrowth more often than patients with intragenic NF1 mutations. Moreover, neurobehavior problems, macrocephaly and overgrowth were less frequent in atypical cases compared to type-1 deletion. Proper diagnosis is challenging in certain patients since several clinical manifestations show age-dependency. Large tumor load exhibited more frequently in this type of disorder, therefore better understanding of genotype-phenotype correlations and progress of the disease is essential for individuals suffering from neurofibromatosis to improve the quality of their life. Our study presented additional clinical data related to NF1 microdeletion patients especially for pediatric cases and it contributes to the better understanding of this type of disorder.

Antiphospholipid antibodies in relation to sterility/infertility.

Of the systemic autoimmune diseases that lead to sterility/infertility, antiphospholipid syndrome (APS) has an outstanding importance; it may be associated with abortion and premature birth which are included in its diagnostic criteria, as well as preeclampsia, pregnancy-induced hypertension, foetal retardation, miscarriage, stillbirth and sterility. Between 2004 and 2009, on the Department of Immunology in the Zala County Hospital, 100 female patients with sterility (st)/infertility (if) (33/67), (mean age: 34.08 years) underwent, in addition to history taking and physical examination, an assessment by immune-serologic tests (ANA, anti-dsDNA, ENA-Profile, anti-TPO, a-sperm, aCL, aPS, aß2GP1, aANX, and aPT). Positive aCL on two occasions could be demonstrated in 27/100 cases (27%) (st/if: 7/20). Among them 4 cases of primary APS have been diagnosed respectively. In the remaining 17 patients the clinical picture did not fulfil criteria. In addition to the twofold positive aCL, unusual antiphospholipid antibodies including aß2GP1, aPS or both were present in 1/27, 2/27 and 1/27 patients, as well as aANX and aPT in 3/26 and 1/27 patients respectively. One-time positive aCL occurred in 16/100 women (16%) (st/if: 5/11); among them aPT and aß2GP1 could be detected in 1/16 patient each. Based on the clinical picture, we raised the possibility of primary APS in 2/16 patients. Among the aCL-negative women, we found the unusual antibodies of APS in 8/57 patients (14%) including positivity of aß2GP1, aPS, aPT and aANX in 4/57, 4/57, 2/57 and 3/57 patients respectively; taking the clinical criteria of APS into consideration, primary APS could be stated in 2/57 patients of them. The 32 pregnancies developed in the follow-up period upon administration of acetylsalicylic acid (ASA) and maintenance dose low molecular weight heparin (LMWH), together with prednisolone in patients with secondary APS, resulted in 23 deliveries and 5 miscarriages; 4 pregnancies are currently in progress. The results of our investigations highlight the significance of demonstrating latent autoimmune diseases in female patients with sterility/infertility, as barrenness can be terminated by the appropriate treatment of these conditions.

[Phenotypic variants of A3243G mitochondrial DNA mutation in a Hungarian family]. / A mitokondriális DNS A3243G mutációja egy magyar családban.

The first Hungarian case with typical features of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) in a young girl is presented. MELAS is a multisystem disorder inherited by the mitochondrial DNA with onset typically in childhood. Our patient presented the first symptoms at the age of 6 years with recurrent vomiting, nausea and transient visual loss. Several stroke-like episodes followed gradually impairing motor abilities and mental development. Molecular analysis of the mitochondrial DNA confirmed a heteroplasmic A3243G transition. The maternal family members were also tested for the mutation in peripheral blood DNA. In the mother of the proband, who suffers from bilateral hypacusis the mutation was detected in 20% of heteroplasmy, while in one of her asymptomatic sisters the mutation was present in 10% only. The bilateral hypacusis of the mother may be associated with this mutation and seems to differentiate the pedigree reported here from others published in the literature.