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Grossi A.,Bambino Gesu Childrens Hospital IRCCS | Palma A.,Immunology Area | Zanni G.,Unit of Molecular Medicine | Novelli A.,Institute CSS Mendel | And 3 more authors.
Gene | Year: 2013

Turner syndrome is a condition caused by numeric and structural abnormalities of the X chromosome, and is characterized by a series of clinical features, the most common being short stature and gonadal dysgenesis. An increased frequency of autoimmune diseases as well as an elevated incidence of autoantibodies has been observed in Turner patients.We present a unique case of mosaic Turner syndrome with a complex rearrangement consisting of a partial deletion of chromosome 2q and duplication of chromosome 10p {[46],XX,der(2)t(2;10)(2pter. →. 2q37::10p13. →. 10pter)[127]/45,X,der(2)t(2;10)(2pter. →. 2q37::10p13. →. 10pter)[23]}. The patient is affected by partial empty sella, in association with a group of multiorgan autoimmunity-related manifestations including Hashimoto's thyroiditis, celiac disease, insulin-dependent diabetes mellitus (Type 1 diabetes, T1D), possible autoimmune inner ear disease with sensorineural deficit, preclinical Addison disease and alopecia universalis. The patient was previously described at the age of 2.4. years and now re-evaluated at the age of 14. years after she developed autoimmune conditions. AIRE gene screening revealed heterozygous c.834 C>G polymorphism (p.Ser278Arg) and IVS9+6G>A variation, thus likely excluding autoimmune polyendocrine syndrome Type 1 (APECED). Heterozygous R620W polymorphism of the protein tyrosine phosphatase non receptor type 22 (. PTPN22) gene was detected in patient's DNA. SNP-array analysis revealed that autoimmunity-related genes could be affected by the partial monosomy 2q and trisomy 10p.These data suggest that early genetic analysis in TS patients with complex associations of multiorgan autoimmune manifestations would permit a precise diagnostic classification and also be an indicator for undiscovered pathogenetic mechanisms. © 2012 Elsevier B.V. Source

Zanni G.,Unit of Molecular Medicine | Opitz J.M.,University of Utah
American Journal of Medical Genetics, Part A | Year: 2013

Dedication: with highest respect and affection to Prof. Giovanni Neri on the eve of his official administrative retirement as Chair of the Institute of Medical Genetics of the Università Cattolica of Rome for leadership in medical genetics and medical science and friendship for decades. The concept "atavism," reversion, throwback, Rückschlag remains an epistemological challenge in biology; unwise or implausible over-interpretation of a given structure as such has led some to almost total skepticism as to its existence. Originating in botany in the 18th century it became applied to zoology (and humans) with increasing frequency over the last two centuries such that the very concept became widely discredited. Presently, atavisms have acquired a new life and reconsideration given certain reasonable criteria, including: Homology of structure of the postulated atavism to that of ancestral fossils or collateral species with plausible soft tissue reconstructions taking into account relationships of parts, obvious sites of origin and insertion of muscles, vascular channels, etc. Most parsimonious, plausible phylogenetic assumptions. Evident rudimentary or vestigial anatomical state in prior generations or in morphogenesis of a given organism. Developmental instability in prior generations, that is, some closely related species facultatively with or without the trait. Genetic identity or phylogenomic similarity inferred in ancestors and corroborated in more or less closely related species. Fluctuating asymmetry may be the basis for the striking evolutionary diversification and common atavisms in limbs; however, strong selection and developmental constraints would make atavisms in, for example, cardiac or CNS development less likely. Thus, purported atavisms must be examined critically in light of the above criteria. © 2013 Wiley Periodicals, Inc. Source

Poretti A.,University of Zurich | Poretti A.,Johns Hopkins University | Vitiello G.,IRCCS Casa Sollievo della Sofferenza Institute | Arrigoni F.,Scientific Institute E Medea | And 23 more authors.
Orphanet Journal of Rare Diseases | Year: 2012

Oral-Facial-Digital Syndrome type VI (OFD VI) represents a rare phenotypic subtype of Joubert syndrome and related disorders (JSRD). In the original report polydactyly, oral findings, intellectual disability, and absence of the cerebellar vermis at post-mortem characterized the syndrome. Subsequently, the molar tooth sign (MTS) has been found in patients with OFD VI, prompting the inclusion of OFD VI in JSRD. We studied the clinical, neurodevelopmental, neuroimaging, and genetic findings in a cohort of 16 patients with OFD VI. We derived the following inclusion criteria from the literature: 1) MTS and one oral finding and polydactyly, or 2) MTS and more than one typical oral finding. The OFD VI neuroimaging pattern was found to be more severe than in other JSRD subgroups and includes severe hypoplasia of the cerebellar vermis, hypoplastic and dysplastic cerebellar hemispheres, marked enlargement of the posterior fossa, increased retrocerebellar collection of cerebrospinal fluid, abnormal brainstem, and frequently supratentorial abnormalities that occasionally include characteristic hypothalamic hamartomas. Additionally, two new JSRD neuroimaging findings (ascending superior cerebellar peduncles and fused thalami) have been identified. Tongue hamartomas, additional frenula, upper lip notch, and mesoaxial polydactyly are specific findings in OFD VI, while cleft lip/palate and other types of polydactyly of hands and feet are not specific. Involvement of other organs may include ocular findings, particularly colobomas. The majority of the patients have absent motor development and profound cognitive impairment. In OFD VI, normal cognitive functions are possible, but exceptional. Sequencing of known JSRD genes in most patients failed to detect pathogenetic mutations, therefore the genetic basis of OFD VI remains unknown. Compared with other JSRD subgroups, the neurological findings and impairment of motor development and cognitive functions in OFD VI are significantly worse, suggesting a correlation with the more severe neuroimaging findings. Based on the literature and this study we suggest as diagnostic criteria for OFD VI: MTS and one or more of the following: 1) tongue hamartoma(s) and/or additional frenula and/or upper lip notch; 2) mesoaxial polydactyly of one or more hands or feet; 3) hypothalamic hamartoma. © 2012 Poretti et al; licensee BioMed Central Ltd. Source

Ginocchio V.M.,Bambino Gesu Childrens Hospital | D'Amico A.,Unit of Molecular Medicine | Bertini E.,Unit of Molecular Medicine | Ceravolo F.,Bambino Gesu Childrens Hospital | And 6 more authors.
Molecular Genetics and Metabolism | Year: 2013

Niemann-Pick disease type C (NPC) is a lysosomal storage disease characterized by progressive neurological degeneration. Miglustat is the first approved specific therapy and its efficacy in stabilizing or slowing disease progression has been demonstrated in previous studies. We evaluated data from 10 NPC patients treated with Miglustat in a single study centre. All disease manifestations were assessed and patients were stratified according to age at onset of neurological symptoms. Neurological data were recorded by using a modified version of the NP-C disability scale; a "composite score" and a "mean annual change" were calculated to evaluate disease progression. We observed a mean annual change of the composite score of 0.04 in our cohort, indicating slower progression of neurological symptoms if compared with the natural history of the disease. The evidence of slower disease evolution in patients treated with Miglustat suits with previous data and here it is also emphasized by the comparison between disease progression in two early-infantile onset patients receiving different Miglustat dosages. Evaluation of the mean annual change for individual subgroups of patients evidenced minor values in juvenile patients, highlighting better response in such class of patients. Among individual neurological parameters, swallowing showed the minor mean annual change (0.02), indicating better response to therapy. We underline the importance of using a standardized disability scale to quantify and compare neurological features and their evolution over time. © 2013 Elsevier Inc. Source

Wilmshurst J.M.,Red Cross | Lillis S.,Diagnostics Genetics Laboratory | Zhou H.,Institute of Child Health | Pillay K.,Red Cross | And 20 more authors.
Annals of Neurology | Year: 2010

Objective Centronuclear myopathy (CNM) is a rare congenital myopathy characterized by prominence of central nuclei on muscle biopsy. CNM has been associated with mutations in MTM1, DNM2, and BIN1 but many cases remain genetically unresolved. RYR1 encodes the principal sarcoplasmic reticulum calcium release channel and has been implicated in various congenital myopathies. We investigated whether RYR1 mutations cause CNM. Methods We sequenced the entire RYR1 coding sequence in 24 patients with a diagnosis of CNM from South Africa (n = 14) and Europe (n = 10) and identified mutations in 17 patients. The most common genotypes featured compound heterozygosity for RYR1 missense mutations and mutations resulting in reduced protein expression, including intronic splice site and frameshift mutations. Results The high incidence in South African patients (n = 12/14) in conjunction with recurrent RYR1 mutations associated with common haplotypes suggested the presence of founder effects. In addition to central nuclei, prominent histopathological findings included (often multiple) internalized nuclei and type 1 fiber predominance and hypotrophy with relative type 2 hypertrophy. Although cores were not typically seen on oxidative stains, electron microscopy revealed subtle abnormalities in most cases. External ophthalmoplegia, proximal weakness, and bulbar involvement were prominent clinical findings. Interpretation Our findings expand the range of RYR1-related phenotypes and suggest RYR1 mutations as a common cause of congenital myopathies with central nuclei. Corresponding to recent observations in X-linked CNM, these findings indicate disturbed assembly and/or malfunction of the excitation-contraction machinery as a key mechanism in CNM and related myopathies. © American Neurological Association. Source

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