Bilateral adrenocortical carcinoma in a patient with multiple endocrine neoplasia type 1 (MEN1) and a novel mutation in the MEN1 gene

The incidence of adrenal involvement in MEN1 syndrome has been reported between 9 and 45%, while the incidence of adrenocortical carcinoma (ACC) in MEN1 patients has been reported between 2.6 and 6%. In the literature data only unilateral development of ACCs in MEN1 patients has been reported. We report a 31 years-old female MEN1-patient, in whom hyperplasia of the parathyroid glands, prolactinoma, non functioning pancreatic endocrine carcinoma and functioning bilateral adrenal carcinomas were diagnosed. Interestingly, a not previously described in the literature data, novel germline mutation (p.E45V) in exon 2 of MEN1 gene, was detected. The association of exon 2 mutation of the MEN1 gene with bilateral adrenal carcinomas in MEN1 syndrome, should be further investigated

MT-ND5 Mutation Exhibits Highly Variable Neurological Manifestations at Low Mutant Load.

Mutations in the m.13094T>C MT-ND5 gene have been previously described in three cases of Leigh Syndrome (LS). In this retrospective, international cohort study we identified 20 clinically affected individuals (13 families) and four asymptomatic carriers. Ten patients were deceased at the time of analysis (median age of death was 10years (range: 5·4months-37years, IQR=17·9years). Nine patients manifested with LS, one with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), and one with Leber hereditary optic neuropathy. The remaining nine patients presented with either overlapping syndromes or isolated neurological symptoms. Mitochondrial respiratory chain activity analysis was normal in five out of ten muscle biopsies. We confirmed maternal inheritance in six families, and demonstrated marked variability in tissue segregation, and phenotypic expression at relatively low blood mutant loads. Neuropathological studies of two patients manifesting with LS/MELAS showed prominent capillary proliferation, microvacuolation and severe neuronal cell loss in the brainstem and cerebellum, with conspicuous absence of basal ganglia involvement. These findings suggest that whole mtDNA genome sequencing should be considered in patients with suspected mitochondrial disease presenting with complex neurological manifestations, which would identify over 300 known pathogenic variants including the m.13094T>C

Physical and genetic mapping in the proximal short arm of the X chromosome

The aim of this thesis was to further develop the techniques of Fluorescence In Situ Hybridisation (FISH) for the localisation of markers on the X chromosome and to contribute to the physical mapping of the proximal short arm with particular emphasis on the region where the gene responsible for one form of Retinitis Pigmentosa (RP2) has been mapped by genetic linkage studies. FISH technique was initially used to sublocalise markers to X chromosome regions. Two-colour FISH was subsequently used to order selected X specific markers because of their position in proximal Xp relative to reference markers DXS7 and DXS426. These markers are known to be tightly linked to the RP2 locus. On the basis of the in situ results one of the newly isolated markers was eventually mapped genetically as it appeared to map in the region of interest. Therefore, a microsatellite was isolated from this cosmid and sequenced. The unique sequences flanking the repeat were used to design Polymerase Chain Reaction (PCR) amplification primers. After establishing allele number, length and frequency of this marker, its genetic position was defined by following its inheritance in twelve X linked Retinitis Pigmentosa families. These families had been previously analysed and linkage data for a number of other proximal short arm markers were available. The new marker eventually mapped distal to the region of interest and, therefore, was not included in further physical mapping studies. An alternative approach to generating markers was to construct a Yeast Artificial Chromosome (YAC) contig of the region using the DXS426 locus as a starting point for chromosome walking. A genomic YAC library was, therefore, screened by PCR and two YACs containing the DXS426 locus were isolated. The orientation of the two YACs was defined by end-cloning. Primers of the proximal end clone were used in order to isolate an overlapping YAC. The end clones of the overlapping YAC were isolated, sequenced and PCR amplification primers were designed. The above YAC clones covered a physical distance of approximately 1 Megabase and physically linked the DXS426 locus with the OATL1 locus in the proximal short arm of X chromosome. This work has contributed to the high resolution physical and genetic linkage map of the proximal short arm of the X chromosome and has provided a resource for the identification of candidate genes involved in inherited diseases localised to this part of the chromosome

Bilateral adrenocortical carcinoma in a patient with multiple endocrine neoplasia type 1 (MEN1) and a novel mutation in the MEN1 gene

Abstract The incidence of adrenal involvement in MEN1 syndrome has been reported between 9 and 45%, while the incidence of adrenocortical carcinoma (ACC) in MEN1 patients has been reported between 2.6 and 6%. In the literature data only unilateral development of ACCs in MEN1 patients has been reported. We report a 31 years-old female MEN1-patient, in whom hyperplasia of the parathyroid glands, prolactinoma, non functioning pancreatic endocrine carcinoma and functioning bilateral adrenal carcinomas were diagnosed. Interestingly, a not previously described in the literature data, novel germline mutation (p.E45V) in exon 2 of MEN1 gene, was detected. The association of exon 2 mutation of the MEN1 gene with bilateral adrenal carcinomas in MEN1 syndrome, should be further investigated.</p

A novel germline mutation of the VHL gene in a Greek family with Von Hippel–Lindau disease

Von Hippel–Lindau disease (VHL) is an autosomal dominant disorder, caused by mutations of the VHL gene showing a strong genotype–phenotype correlation. The present report concerns a 16-year-old girl with VHL (retinal, spinal cord and cerebellar haemangioblastomas and pancreatic cysts), her father (retinal and spinal cord haemangioblastomas) and the phenotypically healthy mother and younger brother and sister. DNA extraction, PCR and direct sequencing of the VHL entire coding and intronic flanking sequences, were performed according to standard procedures. In the index patient and her father a novel heterozygous germline was identified; nonsense mutation (p.145X) in exon 2 of VHL, leading to a truncated VHL protein lacking the last 66 amino acids. This is the first report of a novel VHL mutation in patients with VHL associated with haemangioblastomas and pancreatic cysts but not renal cell carcinoma

Multiple endocrine neoplasia type 2A in two families with the familial medullary thyroid carcinoma associated G533C mutation of the RET proto-oncogene

Introduction: Multiple endocrine neoplasia type 2A (MEN2A) is an autosomal domin ant hereditary disorder, associated with a cluster of germline gain-of-function mutations of the RET proto-oncogene (RET), mainly in exons 10-15. The G533C mutation in exon 8 of the RET is rare and has been mainly related to the familial medullary thyroid carcinoma. Patients-methods: We describe the RET G533C mutation in exon 8 of the RET in two unrelated female index patients, with MEN2A phenotype, consisting of pheochromocytoma which was the presenting feature and medullary thyroid carcinoma. In addition, 12 family members were also studied. DNA extraction, PCR, and sequencing of RET was performed in exons 7-19 and 21, following standard procedures. Results: The mutation was found in both index patients and in 6 out of 12 family members (50%). Three of them were biochemically affected with histologically proven medullary thyroid carcinoma in two of them while there are no certain clues regarding the other three members as they declined further evaluation. Conclusion: Patients with MEN2A should be also searched in exon 8 while positive carriers of this mutation should be screened annually for pheochromocytoma or other components of the syndrome

Case series: Pyramidal cataracts, intact irides and nystagmus from three novel PAX6 mutations

Purpose: To investigate the association between novel PAX6 mutations to bilateral anterior pyramidal congenital cataracts (APyC), complete and intact irides, and nystagmus. Observations: This is a retrospective observational case series in a multi-center setting with genetic testing. Three female patients were diagnosed with bilateral APyC, intact irides and nystagmus. Genetic testing identified the three patients had novel missense mutations in PAX6 – c.128C > T; p.Ser43Phe (S43F), c. 197T > A; p.Ile66Asn (I66N) and c.781C > G; p.Arg261Gly (R261G). Conclusions and importance: This study demonstrates a novel phenotype of bilateral APyC, intact irides, and nystagmus in whom genetic testing for PAX6 identified novel missense mutations (S43F, I66N, R261G) in highly conserved DNA-binding domains. Implications of understanding why the iris is present in these cases is discussed. Keywords: Pyramidal cataracts, Intact irides, Nystagmus, Novel PAX6 missense mutation