Publications by authors named "Emanuela Scarano"

29 Publications

  • Page 1 of 1

Chondrodysplasia and growth failure in children after early hematopoietic stem cell transplantation for non-oncologic disorders.

Am J Med Genet A 2021 02 4;185(2):517-527. Epub 2021 Jan 4.

Division of Genetic Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.

Bone dysplasias (osteochondrodysplasias) are a large group of conditions associated with short stature, skeletal disproportion, and radiographic abnormalities of skeletal elements. Nearly all are genetic in origin. We report a series of seven children with similar findings of chondrodysplasia and growth failure following early hematopoietic stem cell transplantation (HSCT) for pediatric non-oncologic disease: hemophagocytic lymphohistiocytosis or HLH (five children, three with biallelic HLH-associated variants [in PRF1 and UNC13D] and one with HLH secondary to visceral Leishmaniasis), one child with severe combined immunodeficiency and one with Omenn syndrome (both children had biallelic RAG1 pathogenic variants). All children had normal growth and no sign of chondrodysplasia at birth and prior to their primary disease. After HSCT, all children developed growth failure, with standard deviation scores for height at or below -3. Radiographically, all children had changes in the spine, metaphyses and epiphyses, compatible with a spondyloepimetaphyseal dysplasia. Genomic sequencing failed to detect pathogenic variants in genes associated with osteochondrodysplasias. We propose that such chondrodysplasia with growth failure is a novel, rare, but clinically important complication following early HSCT for non-oncologic pediatric diseases. The pathogenesis is unknown but could possibly involve loss or perturbation of the cartilage-bone stem cell population.
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http://dx.doi.org/10.1002/ajmg.a.62021DOI Listing
February 2021

Adult phenotype in Koolen-de Vries/ haploinsufficiency syndrome.

J Med Genet 2020 Dec 24. Epub 2020 Dec 24.

Dipartimento Universitario Scienze della Vita e Sanità Pubblica, Sezione di Medicina Genomica, Università Cattolica del Sacro Cuore Facoltà di Medicina e Chirurgia, Roma, Italy

Background: Koolen-de Vries syndrome (KdVS) is a multisystem neurodevelopmental disorder caused by 17q21.31 deletions or mutations in . It was mainly described in children.

Methods: A retrospective study on 9 subjects aged 19-45 years and revision of 18 literature patients, with the purpose to get insights into the phenotypic evolution with time, and into the clinical manifestations in adulthood.

Results: Seven patients had a 17q21.31 deletion and two a point mutation in . All had intellectual disability, which was mild in five (56%) and moderate in four (44%). Epilepsy was diagnosed in four subjects (44%), with onset from 1 to 7 years and full remission before 9 years in 3/4 patients. Scoliosis affected seven individuals (77.7%) and it was substantially stable with age in 5/7 patients, allowing for simple daily activities. Two subjects had severely progressive scoliosis, which was surgically corrected. Overweight or true obesity did occur after puberty in six patients (67%). Behaviour abnormalities were recorded in six patients (67%). The facial phenotype slightly evolved with time to include thick eyebrows, elongated nose and pronounced pointed chin. Despite behaviour abnormalities, happy disposition and sociable attitudes were common. Half of patients had fluent language and were good at writing and reading. Rich language, although limited to single words or short sentences, and very limited or absent skills in writing and reading were observed in the remaining patients. Autonomy in daily activities and personal care was usually limited.

Conclusions: Distinctive features in adult KdVS subjects include intellectual disability, overweight/obesity, behaviour abnormalities with preserved social interest, ability in language, slight worsening of the facial phenotype and no seizures.
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http://dx.doi.org/10.1136/jmedgenet-2020-107225DOI Listing
December 2020

Variants of SOS2 are a rare cause of Noonan syndrome with particular predisposition for lymphatic complications.

Eur J Hum Genet 2021 Jan 12;29(1):51-60. Epub 2020 Aug 12.

Institute of Human Genetics, University Hospital Magdeburg, Magdeburg, Germany.

RASopathies are caused by variants in genes encoding components or modulators of the RAS/MAPK signaling pathway. Noonan syndrome is the most common entity among this group of disorders and is characterized by heart defects, short stature, variable developmental delay, and typical facial features. Heterozygous variants in SOS2, encoding a guanine nucleotide exchange factor for RAS, have recently been identified in patients with Noonan syndrome. The number of published cases with SOS2-related Noonan syndrome is still limited and little is known about genotype-phenotype correlations. We collected previously unpublished clinical and genotype data from 17 individuals carrying a disease-causing SOS2 variant. Most individuals had one of the previously reported dominant pathogenic variants; only four had novel changes at the established hotspots for variants that affect protein function. The overall phenotype of the 17 patients fits well into the spectrum of Noonan syndrome and is most similar to the phenotype observed in patients with SOS1-related Noonan syndrome, with ectodermal anomalies as common features and short stature and learning disabilities as relatively infrequent findings compared to the average Noonan syndrome phenotype. The spectrum of heart defects in SOS2-related Noonan syndrome was consistent with the known spectrum of cardiac anomalies in RASopathies, but no specific heart defect was particularly predominating. Notably, lymphatic anomalies were extraordinarily frequent, affecting more than half of the patients. We therefore conclude that SOS2-related Noonan syndrome is associated with a particularly high risk of lymphatic complications that may have a significant impact on morbidity and quality of life.
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http://dx.doi.org/10.1038/s41431-020-00708-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852574PMC
January 2021

Expanding the phenotype associated to KMT2A variants: overlapping clinical signs between Wiedemann-Steiner and Rubinstein-Taybi syndromes.

Eur J Hum Genet 2021 Jan 8;29(1):88-98. Epub 2020 Jul 8.

Genetica Medica e Biologia Applicata, Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milano, Italy.

Lysine-specific methyltransferase 2A (KMT2A) is responsible for methylation of histone H3 (K4H3me) and contributes to chromatin remodeling, acting as "writer" of the epigenetic machinery. Mutations in KMT2A were first reported in Wiedemann-Steiner syndrome (WDSTS). More recently, KMT2A variants have been described in probands with a specific clinical diagnosis comprised in the so-called chromatinopathies. Such conditions, including WDSTS, are a group of overlapping disorders caused by mutations in genes coding for the epigenetic machinery. Among them, Rubinstein-Taybi syndrome (RSTS) is mainly caused by heterozygous pathogenic variants in CREBBP or EP300. In this work, we used next generation sequencing (either by custom-made panel or by whole exome) to identify alternative causative genes in individuals with a RSTS-like phenotype negative to CREBBP and EP300 mutational screening. In six patients we identified different novel unreported variants in KMT2A gene. The identified variants are de novo in at least four out of six tested individuals and all of them display some typical RSTS phenotypic features but also WDSTS specific signs. This study reinforces the concept that germline variants affecting the epigenetic machinery lead to a shared molecular effect (alteration of the chromatin state) determining superimposable clinical conditions.
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http://dx.doi.org/10.1038/s41431-020-0679-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852672PMC
January 2021

Mowat-Wilson syndrome: growth charts.

Orphanet J Rare Dis 2020 06 15;15(1):151. Epub 2020 Jun 15.

Medical Genetics Unit, Department of Mother and Child, Azienda Unità Sanitaria Locale - IRCCS di Reggio Emilia, Viale Risorgimento, 80 42123, Reggio Emilia, Italy.

Background: Mowat-Wilson syndrome (MWS; OMIM #235730) is a genetic condition caused by heterozygous mutations or deletions of the ZEB2 gene. It is characterized by moderate-severe intellectual disability, epilepsy, Hirschsprung disease and multiple organ malformations of which congenital heart defects and urogenital anomalies are the most frequent ones. To date, a clear description of the physical development of MWS patients does not exist. The aim of this study is to provide up-to-date growth charts specific for infants and children with MWS. Charts for males and females aged from 0 to 16 years were generated using a total of 2865 measurements from 99 MWS patients of different ancestries. All data were collected through extensive collaborations with the Italian MWS association (AIMW) and the MWS Foundation. The GAMLSS package for the R statistical computing software was used to model the growth charts. Height, weight, body mass index (BMI) and head circumference were compared to those from standard international growth charts for healthy children.

Results: In newborns, weight and length were distributed as in the general population, while head circumference was slightly smaller, with an average below the 30th centile. Up to the age of 7 years, weight and height distribution was shifted to slightly lower values than in the general population; after that, the difference increased further, with 50% of the affected children below the 5th centile of the general population. BMI distribution was similar to that of non-affected children until the age of 7 years, at which point values in MWS children increased with a less steep slope, particularly in males. Microcephaly was sometimes present at birth, but in most cases it developed gradually during infancy; many children had a small head circumference, between the 3rd and the 10th centile, rather than being truly microcephalic (at least 2 SD below the mean). Most patients were of slender build.

Conclusions: These charts contribute to the understanding of the natural history of MWS and should assist pediatricians and other caregivers in providing optimal care to MWS individuals who show problems related to physical growth. This is the first study on growth in patients with MWS.
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http://dx.doi.org/10.1186/s13023-020-01418-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294656PMC
June 2020

Delineation of phenotypes and genotypes related to cohesin structural protein RAD21.

Hum Genet 2020 May 19;139(5):575-592. Epub 2020 Mar 19.

Department of Pediatrics, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, The Netherlands.

RAD21 encodes a key component of the cohesin complex, and variants in RAD21 have been associated with Cornelia de Lange Syndrome (CdLS). Limited information on phenotypes attributable to RAD21 variants and genotype-phenotype relationships is currently published. We gathered a series of 49 individuals from 33 families with RAD21 alterations [24 different intragenic sequence variants (2 recurrent), 7 unique microdeletions], including 24 hitherto unpublished cases. We evaluated consequences of 12 intragenic variants by protein modelling and molecular dynamic studies. Full clinical information was available for 29 individuals. Their phenotype is an attenuated CdLS phenotype compared to that caused by variants in NIPBL or SMC1A for facial morphology, limb anomalies, and especially for cognition and behavior. In the 20 individuals with limited clinical information, additional phenotypes include Mungan syndrome (in patients with biallelic variants) and holoprosencephaly, with or without CdLS characteristics. We describe several additional cases with phenotypes including sclerocornea, in which involvement of the RAD21 variant is uncertain. Variants were frequently familial, and genotype-phenotype analyses demonstrated striking interfamilial and intrafamilial variability. Careful phenotyping is essential in interpreting consequences of RAD21 variants, and protein modeling and dynamics can be helpful in determining pathogenicity. The current study should be helpful when counseling families with a RAD21 variation.
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http://dx.doi.org/10.1007/s00439-020-02138-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170815PMC
May 2020

Corrigendum to "Challenges in the clinical interpretation of small de novo copy number variants in neurodevelopmental disorders" [Gene 706 (2019) 162-171].

Gene 2020 04 6;735:144393. Epub 2020 Feb 6.

Unit of Medical Genetics, Department of Medical and Surgical Sciences, Policlinico St. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.gene.2020.144393DOI Listing
April 2020

Uniparental disomy and pretreatment IGF-1 may predict elevated IGF-1 levels in Prader-Willi patients on GH treatment.

Growth Horm IGF Res 2019 Oct - Dec;48-49:9-15. Epub 2019 Aug 28.

Metabolic Diseases, Clinical Genetics and Diabetology Unit, Giovanni XXIII Children's Hospital, Bari, Italy. Electronic address:

Pediatric patients with Prader-Willi syndrome (PWS) can be treated with recombinant human GH (rhGH). These patients are highly sensitive to rhGH and the standard doses suggested by the international guidelines often result in IGF-1 above the normal range. We aimed to evaluate 1 the proper rhGH dose to optimize auxological outcomes and to avoid potential overtreatment, and 2 which patients are more sensitive to rhGH. In this multicenter real-life study, we recruited 215 patients with PWS older than 1 year, on rhGH at least for 6 months, from Italian Centers for PWS care. We collected auxological parameters, rhGH dose, IGF-1 at recruitment and (when available) at start of treatment. The rhGH dose was 4.3 (0.7/8.4) mg/m/week. At recruitment, IGF-1 was normal in 72.1% and elevated in 27.9% of the patients. In the group of 115 patients with IGF-1 available at start of rhGH, normal pretreatment IGF-1 and uniparental disomy were associated with elevated IGF-1 during the therapy. No difference in height and growth velocity was found between patients treated with the highest and the lowest range dose. The rhGH dose prescribed in Italy seems lower than the recommended one. Normal pretreatment IGF-1 and uniparental disomy are risk factors for elevated IGF-1. The latter seems to be associated with higher sensitivity to GH. In case of these risk factors, we recommend a more accurate titration of the dose to avoid overtreatment and its potential side effects.
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http://dx.doi.org/10.1016/j.ghir.2019.08.003DOI Listing
May 2020

Anthropometric characteristics of newborns with Prader-Willi syndrome.

Am J Med Genet A 2019 10 30;179(10):2067-2074. Epub 2019 Jul 30.

Department of Human Pathology of the Adult and of the Developmental Age "Gaetano Barresi", University of Messina, Messina, Italy.

This is a retrospective multicenter nationwide Italian study collecting neonatal anthropometric data of Caucasian subjects with Prader-Willi syndrome (PWS) born from 1988 to 2018. The aim of the study is to provide percentile charts for weight and length of singletons with PWS born between 36 and 42 gestational weeks. We collected the birth weight and birth length of 252 male and 244 female singleton live born infants with both parents of Italian origin and PWS genetically confirmed. Percentile smoothed curves of birth weight and length for gestational age were built through Cole's lambda, mu, sigma method. The data were compared to normal Italian standards. Newborns with PWS showed a lower mean birth weight, by 1/2 kg, and a shorter mean birth length, by 1 cm, than healthy neonates. Females with a 15q11-13 deletion were shorter than those with maternal uniparental maternal disomy of chromosome 15 (p < .0001). The present growth curves may be useful as further traits in supporting a suspicion of PWS in a newborn. Because impaired prenatal growth increases risk of health problems later in life, having neonatal anthropometric standards could be helpful to evaluate possible correlations between the presence or absence of small gestational age and some clinical and metabolic aspects of PWS.
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http://dx.doi.org/10.1002/ajmg.a.61304DOI Listing
October 2019

A novel mutation in gene causes a severe neurodevelopmental delay due to mitochondrial dysfunction with complex I impairments and altered pyruvate metabolism.

FASEB J 2019 10 7;33(10):11284-11302. Epub 2019 Aug 7.

Department of Medical and Surgical Sciences (DIMEC), St. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.

Loss-of-function mutations in the gene cause Troyer syndrome, a recessive form of spastic paraplegia resulting in muscle weakness, short stature, and cognitive defects. encodes for Spartin, a protein linked to endosomal trafficking and mitochondrial membrane potential maintenance. Here, we identified with whole exome sequencing (WES) a novel frameshift mutation in the gene in 2 brothers presenting an uncharacterized developmental delay and short stature. Functional characterization in an SH-SY5Y cell model shows that this mutation is associated with increased neurite outgrowth. These cells also show a marked decrease in mitochondrial complex I (NADH dehydrogenase) activity, coupled to decreased ATP synthesis and defective mitochondrial membrane potential. The cells also presented an increase in reactive oxygen species, extracellular pyruvate, and NADH levels, consistent with impaired complex I activity. In concordance with a severe mitochondrial failure, Spartin loss also led to an altered intracellular Ca homeostasis that was restored after transient expression of wild-type Spartin. Our data provide for the first time a thorough assessment of Spartin loss effects, including impaired complex I activity coupled to increased extracellular pyruvate. In summary, through a WES study we assign a diagnosis of Troyer syndrome to otherwise undiagnosed patients, and by functional characterization we show that the novel mutation in leads to a profound bioenergetic imbalance.-Diquigiovanni, C., Bergamini, C., Diaz, R., Liparulo, I., Bianco, F., Masin, L., Baldassarro, V. A., Rizzardi, N., Tranchina, A., Buscherini, F., Wischmeijer, A., Pippucci, T., Scarano, E., Cordelli, D. M., Fato, R., Seri, M., Paracchini, S., Bonora, E. A novel mutation in gene causes a severe neurodevelopmental delay due to mitochondrial dysfunction with complex I impairments and altered pyruvate metabolism.
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http://dx.doi.org/10.1096/fj.201802722RDOI Listing
October 2019

Novel Mutations and Unreported Clinical Features in KBG Syndrome.

Mol Syndromol 2019 May 15;10(3):130-138. Epub 2019 Jan 15.

Rare Disease Unit, Department of Pediatrics, St. Orsola-Malpighi Hospital, Bologna, Italy.

KBG syndrome is an autosomal dominant disorder caused by pathogenic variants within or deletions of 16q24.3 which include . It is characterized by distinctive facial features, developmental delay, short stature, and skeletal anomalies. We report 12 unrelated patients where a clinical diagnosis of KBG was suspected and confirmed by targeted analyses. Nine patients showed a point mutation in (none of which were previously reported) and 3 carried a 16q24.3 deletion. All patients presented with typical facial features and macrodontia. Skeletal abnormalities were constant, and the majority of patients showed joint stiffness. Three patients required growth hormone treatment with a significant increase of height velocity. Brain malformations were identified in 8 patients. All patients showed behavioral abnormalities and most had developmental delay. Two patients had hematological abnormalities. We emphasize that genetic analysis of can easily reach a detection rate higher than 50% thanks to clinical phenotyping, although it is known that a subset of -mutated patients show very mild features and will be more easily identified through the implementation of gene panels or exome sequencing. Joint stiffness was reported previously in few patients, but it seems to be a common feature and can be helpful for the diagnosis. Hematological abnormalities could be present and warrant a specific follow-up.
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http://dx.doi.org/10.1159/000496172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6528090PMC
May 2019

Challenges in the clinical interpretation of small de novo copy number variants in neurodevelopmental disorders.

Gene 2019 Jul 11;706:162-171. Epub 2019 May 11.

Unit of Medical Genetics, Department of Medical and Surgical Sciences, Policlinico St. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy. Electronic address:

In clinical genetics, the need to discriminate between benign and pathogenic variants identified in patients with neurodevelopmental disorders is an absolute necessity. Copy number variants (CNVs) of small size can enable the identification of genes that are critical for neurologic development. However, assigning a definite association with a specific disorder is a difficult task. Among 328 trios analyzed over seven years of activity in a single laboratory, we identified 19 unrelated patients (5.8%) who carried a small (<500 kb) de novo CNV. Four patients had an additional independent de novo CNV. Nine had a variant that could be assigned as definitely pathogenic, whereas the remaining CNVs were considered as variants of unknown significance (VUS). We report clinical and molecular findings of patients harboring VUS. We reviewed the medical literature available for genes impacted by CNVs, obtained the probability of truncating loss-of-function intolerance, and compared overlapping CNVs reported in databases. The classification of small non-recurrent CNVs remains difficult but, among our findings, we provide support for a role of SND1 in the susceptibility of autism, describe a new case of the rare 17p13.1 microduplication syndrome, and report an X-linked duplication involving KIF4A and DLG3 as a likely cause of epilepsy.
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http://dx.doi.org/10.1016/j.gene.2019.05.007DOI Listing
July 2019

HDAC8 Loss of Function and SHOX Haploinsufficiency: Two Independent Genetic Defects Responsible for a Complex Phenotype.

Cytogenet Genome Res 2019 26;157(3):135-140. Epub 2018 Mar 26.

We report a patient with developmental delay, brachydactyly type E, short stature, and tetralogy of Fallot. Brachydactyly-mental retardation syndrome (BDMR) was suspected based on the phenotype; however, array CGH excluded a 2q37 deletion, but identified a deletion encompassing the SHOX gene. BDMR is characterized by cognitive impairment, skeletal abnormalities involving hands and feet, short stature, and overweight. Most affected individuals carry relatively large 2q37 deletions encompassing HDAC4. This gene encodes a histone deacetylase involved in epigenetic regulation of cell growth and differentiation, specifically during endochondral bone formation in chondrocyte hypertrophy. Since SHOX haploinsufficiency can cause skeletal defects and short stature but would not fully explain the clinical picture of this patient, exome sequencing was performed, and a heterozygous HDAC8 frameshift mutation was identified. HDAC8 is a distinct histone deacetylase involved in cohesin recycling and is responsible for an X-linked dominant Cornelia de Lange-like phenotype. A new blended clinical phenotype may be explained by the result of a dual molecular diagnosis, which represents a combination of 2 independent genetic defects, with relevant implications for genetic counseling, clinical management, and prognosis.
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http://dx.doi.org/10.1159/000499174DOI Listing
May 2019

The Discovery of a LEMD2-Associated Nuclear Envelopathy with Early Progeroid Appearance Suggests Advanced Applications for AI-Driven Facial Phenotyping.

Am J Hum Genet 2019 04 21;104(4):749-757. Epub 2019 Mar 21.

Faculty of Medicine, University of Cologne, Cologne, 50931, Germany; Institute of Human Genetics, University Hospital Cologne, Cologne, 50931, Germany. Electronic address:

Over a relatively short period of time, the clinical geneticist's "toolbox" has been expanded by machine-learning algorithms for image analysis, which can be applied to the task of syndrome identification on the basis of facial photographs, but these technologies harbor potential beyond the recognition of established phenotypes. Here, we comprehensively characterized two individuals with a hitherto unknown genetic disorder caused by the same de novo mutation in LEMD2 (c.1436C>T;p.Ser479Phe), the gene which encodes the nuclear envelope protein LEM domain-containing protein 2 (LEMD2). Despite different ages and ethnic backgrounds, both individuals share a progeria-like facial phenotype and a distinct combination of physical and neurologic anomalies, such as growth retardation; hypoplastic jaws crowded with multiple supernumerary, yet unerupted, teeth; and cerebellar intention tremor. Immunofluorescence analyses of patient fibroblasts revealed mutation-induced disturbance of nuclear architecture, recapitulating previously published data in LEMD2-deficient cell lines, and additional experiments suggested mislocalization of mutant LEMD2 protein within the nuclear lamina. Computational analysis of facial features with two different deep neural networks showed phenotypic proximity to other nuclear envelopathies. One of the algorithms, when trained to recognize syndromic similarity (rather than specific syndromes) in an unsupervised approach, clustered both individuals closely together, providing hypothesis-free hints for a common genetic etiology. We show that a recurrent de novo mutation in LEMD2 causes a nuclear envelopathy whose prognosis in adolescence is relatively good in comparison to that of classical Hutchinson-Gilford progeria syndrome, and we suggest that the application of artificial intelligence to the analysis of patient images can facilitate the discovery of new genetic disorders.
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http://dx.doi.org/10.1016/j.ajhg.2019.02.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451726PMC
April 2019

Altered modulation of lamin A/C-HDAC2 interaction and p21 expression during oxidative stress response in HGPS.

Aging Cell 2018 Oct 15;17(5):e12824. Epub 2018 Aug 15.

CNR Institute of Molecular Genetics, Unit of Bologna, Bologna, Italy.

Defects in stress response are main determinants of cellular senescence and organism aging. In fibroblasts from patients affected by Hutchinson-Gilford progeria, a severe LMNA-linked syndrome associated with bone resorption, cardiovascular disorders, and premature aging, we found altered modulation of CDKN1A, encoding p21, upon oxidative stress induction, and accumulation of senescence markers during stress recovery. In this context, we unraveled a dynamic interaction of lamin A/C with HDAC2, an histone deacetylase that regulates CDKN1A expression. In control skin fibroblasts, lamin A/C is part of a protein complex including HDAC2 and its histone substrates; protein interaction is reduced at the onset of DNA damage response and recovered after completion of DNA repair. This interplay parallels modulation of p21 expression and global histone acetylation, and it is disrupted by LMNAmutations leading to progeroid phenotypes. In fact, HGPS cells show impaired lamin A/C-HDAC2 interplay and accumulation of p21 upon stress recovery. Collectively, these results link altered physical interaction between lamin A/C and HDAC2 to cellular and organism aging. The lamin A/C-HDAC2 complex may be a novel therapeutic target to slow down progression of progeria symptoms.
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http://dx.doi.org/10.1111/acel.12824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156291PMC
October 2018

New insights on diabetes in Turner syndrome: results from an observational study in adulthood.

Endocrine 2018 03 7;59(3):651-660. Epub 2017 Jun 7.

Division of Endocrinology, Department of Medical & Surgical Sciences, University Alma Mater Studiorum, S. Orsola-Malpighi Hospital, Bologna, Italy.

Objective: To explore the characteristics of diabetes mellitus in adults with Turner syndrome.

Design: Observational study consisting of a prospective phase after the access of adults with Turner syndrome to the Endocrinology Unit (median period of follow-up 15.6, interquartile range: 12.0-24.5 months) and a retrospective collection of data from the diagnosis of Turner syndrome until the time of access to the Endocrinology Unit. A total of 113 Italian Turner syndrome patients were included in the study. During the prospective phase of the study, each patient underwent physical examination, fasting blood sampling, and an oral glucose tolerance test on a yearly basis. Oral glucose tolerance test was used to perform the diagnosis of diabetes mellitus.

Results: Before access to the Endocrinology Unit, diabetes mellitus was diagnosed in two Turner syndrome patients. Another five cases of diabetes mellitus were diagnosed at the first access to the Endocrinology Unit, whereas seven new cases of diabetes mellitus were diagnosed during the prospective phase of the study. At the diagnosis of diabetes mellitus, only one patient had fasting glucose above 126 mg/dL, and only two had an HbA1c value >6.5% (48 mmol/mol). When compared to normo-glucose tolerant patients, the diabetic patients had a significantly lower insulin-to-glucose ratio at 30 and 60 min of the oral glucose tolerance test. In the regression analyses, only age was associated with the development of diabetes mellitus.

Conclusions: This study confirms that diabetes mellitus is frequent in Turner syndrome and suggests that it is specific to the syndrome. In addition, this study demonstrates that oral glucose tolerance test is a more sensitive test than HbA1c for the diagnosis of diabetes mellitus in Turner syndrome.
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http://dx.doi.org/10.1007/s12020-017-1336-zDOI Listing
March 2018

From Whole Gene Deletion to Point Mutations of EP300-Positive Rubinstein-Taybi Patients: New Insights into the Mutational Spectrum and Peculiar Clinical Hallmarks.

Hum Mutat 2016 Feb 4;37(2):175-83. Epub 2015 Nov 4.

Genetica Medica, Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milano, Italia.

Rubinstein-Taybi syndrome (RSTS) is a rare congenital neurodevelopmental disorder characterized by growth deficiency, skeletal abnormalities, dysmorphic features, and intellectual disability. Causative mutations in CREBBP and EP300 genes have been identified in ∼55% and ∼8% of affected individuals. To date, only 28 EP300 alterations in 29 RSTS clinically described patients have been reported. EP300 analysis of 22 CREBBP-negative RSTS patients from our cohort led us to identify six novel mutations: a 376-kb deletion depleting EP300 gene; an exons 17-19 deletion (c.(3141+1_3142-1)_(3590+1_3591-1)del/p.(Ile1047Serfs*30)); two stop mutations, (c.3829A>T/p.(Lys1277*) and c.4585C>T/p.(Arg1529*)); a splicing mutation (c.1878-12A>G/p.(Ala627Glnfs*11)), and a duplication (c.4640dupA/p.(Asn1547Lysfs*3)). All EP300-mutated individuals show a mild RSTS phenotype and peculiar findings including maternal gestosis, skin manifestation, especially nevi or keloids, back malformations, and a behavior predisposing to anxiety. Furthermore, the patient carrying the complete EP300 deletion does not show a markedly severe clinical picture, even if a more composite phenotype was noticed. By characterizing six novel EP300-mutated patients, this study provides further insights into the EP300-specific clinical presentation and expands the mutational repertoire including the first case of a whole gene deletion. These new data will enhance EP300-mutated cases identification highlighting distinctive features and will improve the clinical practice allowing a better genotype-phenotype correlation.
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http://dx.doi.org/10.1002/humu.22922DOI Listing
February 2016

Response to long-term growth hormone therapy in patients affected by RASopathies and growth hormone deficiency: Patterns of growth, puberty and final height data.

Am J Med Genet A 2015 Nov 31;167A(11):2786-94. Epub 2015 Jul 31.

Pediatric Endocrinology and Rare Diseases Unit, Department of Pediatrics, S.Orsola-Malpighi University Hospital-University of Bologna, Bologna, Italy.

RASopathies are developmental disorders caused by heterozygous germline mutations in genes encoding proteins in the RAS-MAPK signaling pathway. Reduced growth is a common feature. Several studies generated data on growth, final height (FH), and height velocity (HV) after growth hormone (GH) treatment in patients with these disorders, particularly in Noonan syndrome, the most common RASopathy. These studies, however, refer to heterogeneous cohorts in terms of molecular information, GH status, age at start and length of therapy, and GH dosage. This work reports growth data in 88 patients affected by RASopathies with molecularly confirmed diagnosis, together with statistics on body proportions, pubertal pattern, and FH in 33, including 16 treated with GH therapy for proven GH deficiency. Thirty-three patients showed GH deficiency after pharmacological tests, and were GH-treated for an average period of 6.8 ± 4.8 years. Before starting therapy, HV was -2.6 ± 1.3 SDS, and mean basal IGF1 levels were -2.0 ± 1.1 SDS. Long-term GH therapy, starting early during childhood, resulted in a positive height response compared with untreated patients (1.3 SDS in terms of height-gain), normalizing FH for Ranke standards but not for general population and Target Height. Pubertal timing negatively affected pubertal growth spurt and FH, with IGF1 standardized score increased from -2.43 to -0.27 SDS. During GH treatment, no significant change in bone age velocity, body proportions, or cardiovascular function was observed.
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http://dx.doi.org/10.1002/ajmg.a.37260DOI Listing
November 2015

The association with Turner syndrome significantly affects the course of Hashimoto's thyroiditis in children, irrespective of karyotype.

Endocrine 2015 Dec 27;50(3):777-82. Epub 2014 Dec 27.

Department of Pediatric, Gynecological, Microbiological and Biomedical Sciences, University of Messina, Via Consolare Valeria, 98125, Messina, Italy.

Only few studies have investigated to now whether the association with Turner syndrome (TS) may affect the course of Hashimoto's thyroiditis (HT) in children. Aim of this study was to ascertain whether the presentation and long-term course of HT in TS children may be characterized by a peculiar and atypical pattern. The clinical and biochemical findings at HT diagnosis in 90 TS children (group A) were compared with those recorded in 449 girls with HT but without TS (group B); in group A patients, thyroid function tests were re-evaluated after a median time interval of 4.9 years. At HT diagnosis median TSH levels and the rate of cases presenting with a thyroid dysfunction picture were significantly lower in group A, irrespective of karyotype abnormalities. In group A only 34.8 % of the girls who had initially presented with euthyroidism remained euthyroid even at re-evaluation, whilst 67.7 % of those who had presented with subclinical hypothyroidism became overtly hypothyroid over time; also such evolutive pattern was irrespective of karyotype abnormalities. (1) In TS girls, HT presents with a milder hormonal pattern, which often deteriorates over time; (2) these biochemical features are not necessarily linked with a specific karyotype.
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http://dx.doi.org/10.1007/s12020-014-0513-6DOI Listing
December 2015

Epidemiology, presentation and long-term evolution of Graves' disease in children, adolescents and young adults with Turner syndrome.

Horm Res Paediatr 2014 31;81(4):245-50. Epub 2014 Jan 31.

Department of Pediatrics, University of Messina, Messina, Italy.

Background: Epidemiological studies on the association between Turner syndrome (TS) and Graves' disease (GD) are sparse and no studies are available on the clinical course of GD in TS.

Objectives: To retrospectively investigate the GD prevalence in children and young adults with TS and to compare the GD course in patients with or without TS who were followed up for 4.1 ± 0.6 and 4.5 ± 3.7 years, respectively.

Design: The prevalence of GD in 408 TS patients was evaluated; presentation and evolution of GD under therapy were evaluated both in 7 patients with TS (group A) and in 89 patients without TS (group B).

Results: (a) The prevalence of GD in TS patients was 1.7%; (b) GD in TS was not associated with a specific karyotype; (c) with respect to group B patients, those of group A exhibited at presentation more advanced age, a lower fT4 level and more frequent association with other autoimmune diseases, and (d) the clinical course under methimazole therapy was not different in the two groups.

Conclusions: The prevalence of GD in children and young adults with TS is 1.7% and in TS patients, GD presents later and its clinical course is not different than in those without TS.
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http://dx.doi.org/10.1159/000357130DOI Listing
January 2015

GH Therapy and first final height data in Noonan-like syndrome with loose anagen hair (Mazzanti syndrome).

Am J Med Genet A 2013 Nov 3;161A(11):2756-61. Epub 2013 Oct 3.

Pediatric Endocrinology and Rare Diseases, Department of Pediatrics, S.Orsola-Malpighi University Hospital - University of Bologna, Bologna, Italy.

Noonan-like syndrome with loose anagen hair (NS/LAH or Mazzanti Syndrome) is caused by a single missense mutation in SHOC2 promoting tN-myristoylation of the encoded protein. Cardinal features include facial features resembling NS, short stature often associated with proven growth hormone deficiency (GHD), typical ectodermal anomalies, and distinctive behavior. Overall, the clinical features are more severe than those generally observed in NS, even though the phenotype improves with age. We report on growth and pubertal trend in seven patients heterozygous for a mutated SHOC2 allele, treated with long-term GH-therapy, and final height (FH) in three of them. They were approximately -3 SDS below the Italian general population standards, they had very low IGF1 levels at baseline and GHD at pharmacological tests. All patients were treated with GH (0.035 mg/kg/day) for a mean period of 8.49 ± 5.72 years. After the 1st year of GH-therapy, IGF1 level and height velocity had increased. Three of 7 patients reached the FH (-2.34 ± 0.12 SDS) at 18.25 ± 0.73 years, after GH administration for 12.39 ± 2.12 years. Pubertal development was variable, showing a prolonged and delayed puberty or rapid pubertal progression that could impair the FH. Overall, our data in this small cohort suggest that NS/LAH patients benefit from long-term GH-therapy, although they do not show the characteristic catch-up growth of isolated GHD. While the observed growth and pubertal behavior is consistent with a dysfunction of the hypothalamic-pituitary-gonadal axis, the functional link between SHOC2 and the GH/IGF signaling pathways remains to be clarified.
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http://dx.doi.org/10.1002/ajmg.a.36255DOI Listing
November 2013

Turner syndrome strategies to improve care outcomes--cardiac evaluation using new imaging techniques.

Pediatr Endocrinol Rev 2012 May;9 Suppl 2:701-9

Rare Disease and Auxology Unit, Department of Paediatrics, University of Bologna, S.Orsola-Malpighi Hospital, Bologna, Italy.

Turner syndrome (TS) is at high risk for congenital heart diseases (CHD), aortic dilatation (AoDil) and dissection. New imaging techniques such as MRI have revealed the presence of vascular anomalies (VA) undetected at echo. MR angiography has shown a high prevalence of aortic and venous anomalies. The VA often coexist and interact to increase the risk of premature death in adulthood. AoDil and VA have been found also in asymptomatic individuals with no predisposing factors, but the prevalence is still unknown. We evaluated 100 TS subjects (15-35 yrs) with no aortic CHD at echocardiography with transthoracic MRA; 42 of them showed VA and 58 did not. Aortic diameters were indexed on BSA. At the sinuses of Valsalva a higher prevalence of AoDil was found in subjects with VA than without; 57% of them showed AoDil. The presence of VA (elongation of the transverse arch, bovine arch, left superior vena cava, PAPVD etc.) increased their relative risk of AoDil by more than 2 times. Excluding BSA influence, a severe phenotype influenced positively ascending AoDil. New imaging techniques enhance our ability to provide a prognosis for their adult age and in particular before they seek to become pregnant.
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May 2012

The empowerment of translational research: lessons from laminopathies.

Orphanet J Rare Dis 2012 Jun 12;7:37. Epub 2012 Jun 12.

The need for a collaborative approach to complex inherited diseases collectively referred to as laminopathies, encouraged Italian researchers, geneticists, physicians and patients to join in the Italian Network for Laminopathies, in 2009. Here, we highlight the advantages and added value of such a multidisciplinary effort to understand pathogenesis, clinical aspects and try to find a cure for Emery-Dreifuss muscular dystrophy, Mandibuloacral dysplasia, Hutchinson-Gilford Progeria and forms of lamin-linked cardiomyopathy, neuropathy and lipodystrophy.
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http://dx.doi.org/10.1186/1750-1172-7-37DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3458975PMC
June 2012

Correlations of phenotype and genotype in relation to morphologic remodelling of the aortic root in patients with Turner's syndrome.

Cardiol Young 2009 Jun 6;19(3):264-71. Epub 2009 Apr 6.

Pediatric Cardiology and Adult Congenital Unit, University of Bologna, Via Massarenti 9, Bologna, Italy.

Background: Patients with Turner's syndrome are at risk of aortic dilation and dissection. Currently, it is not known whether such dilation is related to associated cardiovascular abnormalities, or to the genetic anomaly itself.

Methods: We studied echocardiographically 107 patients with genetically proven Turner's syndrome, with heterogeneous underlying karyotypes, and without associated cardiac lesions. Their average age was 19.6 plus or minus 8.4 years. We compared the finding with those from 71 age-matched healthy female volunteers. The diameter of the aorta was measured at the level of the basal attachments of the aortic valvar leaflets, the sinuses of Valsalva, the sinutubular junction, and its ascending component.

Results: Compared to control subjects, the patients with Turner's syndrome had larger diameters of the aorta at the level of the sinuses of Valsalva, at 23.4+/-4.8 versus 25.5+/-4.1 millimetres (p = 0.0014), the sinutubular junction, at 19.9+/-3.8 versus 23.3+/-4.1 millimetres (p < 0.0001), and the ascending aorta, at 22.3+/-4.9 versus 24.6+/-4.4 millimetres (p = 0.0011). Dilation of the sinutubular junction, found in just over one-quarter of the patients, was more common than dilation of the ascending aorta, the latter found in less than one-tenth. The patients with Turner's syndrome, therefore, presented with remodelling of the aortic root, with relative dilation of the sinutubular junction. The underlying karyotype influenced both the dimensions of the sinutubular junction (p = 0.0054), and the ascending aorta (p = 0.0064), so that patients with the karyotype 45X had larger aortas. The karyotype was the strongest predictor by multivariate analysis for dilation at both these sites (p = 0.0138 and 0.0085, respectively).

Conclusions: Dilation at the sinutubular junction is frequent in patients with Turner's syndrome, and is more common than dilation of the ascending aorta. The syndrome is associated with a remodelling of the aortic root, with prominent dilation of the sinutubular junction. There seems to be a relation between aortic dilation and the underlying genotype.
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http://dx.doi.org/10.1017/S1047951109004016DOI Listing
June 2009

Developmental syndromes: growth hormone deficiency and treatment.

Endocr Dev 2009 27;14:114-34. Epub 2009 Feb 27.

Department of Pediatrics, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.

Developmental syndromes are characterized by numerous phenotypical signs and malformations. In most of them such as Turner, Noonan, Prader-Willi, Silver-Russel, Williams, Kabuki, Leri-Weill syndrome and skeletal dysplasias, short stature is a common feature. Growth defect is very often related to a defect in cellular growth, but some unknown abnormality in GH action is possible. Recently, the greater availability of recombinant GH has expanded the interest towards GH secretion and therapy also in developmental syndromes. We recognize syndromes associated with GH deficiency (GHD), showing a developmental midline defect such as Pallister-Hall syndrome, septo-optic dysplasia, but many of these conditions do not have a convincing link with GHD. Moreover, some conditions, in particular the well-studied Turner syndrome, that do not have a real GHD, have proven to benefit from GH therapy at supra-physiological doses obtaining a higher final height than the expected one according to the natural history. This has expanded the indications for GH therapy. The aim of our paper is to review the literature on GH secretion, on the effects and costs-benefits of GH therapy in many dysmorphic syndromes, presenting some results of GH secretion and therapy obtained in our experience.
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http://dx.doi.org/10.1159/000207481DOI Listing
May 2009

Strawberry plant relationship through the stolon.

Physiol Plant 2008 Nov 4;134(3):421-9. Epub 2008 Jun 4.

Department of Environmental and Crop Sciences, Polytechnic University of Marche, Ancona 60131, Italy.

Stolon is an elongated, two-node, vegetative, axillary shoot, which supports the ramet (rooted rosette) until it is completely independent on its own roots. The reciprocal capacity of the ramets, in a single runner chain, to sustain the growth and share locally abundant resources or to tolerate a local stress, is still in debate. This capacity may play an important role for improving nursery plant production and for better understanding the natural clonal multiplication. To describe strawberry stolon action, in plant-to-plant relationship, bare-rooted Camarosa ramets, joint in couples by their own stolons (generally, second and third ramet in a runner chain) were transplanted in two pots. The couples of ramets were treated in a factorial experiment with decortication (peeling a 2-mm ring of bark from the stolon), removal of root system or glyphosate application to one of the two ramets. In the studied system, the older ramet was referred as mother and the other as daughter. The two ramets were very similar in age and seem to act with a very limited hierarchic prevalence of the mother. When the root system of one ramet was eliminated, leaf number and chlorophyll content had a very slight decrease, independently in the mother ramet or in the daughter. The decortication did not reduce water integration, in any group of plants, but limited assimilate allocation towards the daughter ramet when the mother ramet had a severe root cut (not vice versa). The glyphosate action resulted localized in the sprayed ramet, which reduced chlorophyll content within 2 days and expired after 4 days.
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http://dx.doi.org/10.1111/j.1399-3054.2008.01145.xDOI Listing
November 2008

A de novo nonsense mutation of PAX6 gene in a patient with aniridia, ataxia, and mental retardation.

Am J Med Genet A 2007 Aug;143A(15):1802-5

O. di Genetica Medica, Dipartimento di Medicina Interna, Cardioangiologia ed Epatologia, Università degli Studi di Bologna, Bologna, Italy.

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http://dx.doi.org/10.1002/ajmg.a.31808DOI Listing
August 2007

Gonadoblastoma in Turner syndrome and Y-chromosome-derived material.

Am J Med Genet A 2005 Jun;135(2):150-4

Department of Pediatrics, Pediatric Clinic, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.

The identification of Y-chromosome material is important in females with Ullrich-Turner syndrome (UTS) due to the risk of developing gonadoblastoma or other gonadal tumors. There is controversy regarding the frequency of the Y-chromosome-derived material and the occurrence of gonadoblastoma in these patients. The aim of our study was to evaluate a large number of patients with UTS, followed before and during the pubertal age for the prevalence of Y-chromosome derived material, the occurrence of gonadoblastoma, and the incidence of possible neoplastic degeneration. An unselected series of 171 patients with UTS (1-34 years old), diagnosed cytogenetically, was studied for Y-chromosome markers (SRY and Y-centromeric DYZ3 repeats). The follow-up was of 2-22 years; 101 of these patients were followed during pubertal age. Y-chromosome material was found in 14 patients (8%): 12 of these were gonadectomized (2.8-25.9 years). A gonadoblastoma was detected in four patients under 16 years of age: in two, Y-material was detected only at molecular analysis (at conventional cytogenetic analysis, one was included in the 45,X group and one in the X + mar group) and one had also an immature teratoma and an endodermal sinus carcinoma. The prevalence of gonadoblastoma in our series of gonadectomized UTS patients with Y-positive material was of 33.3% (4/12). Our data suggest that the age of appearance and the possibility of malignant degeneration of gonadoblastoma can occur early in life. These patients, in particular those with 45,X or a marker chromosome may benefit from molecular screening to detect the presence of Y-chromosome material; PCR is a rapid and inexpensive technique. At the moment, laparoscopy and preventive gonadectomy performed as soon as possible remain the procedures of choice for patients with UTS, when Y-chromosome has been identified, as we are still unable to predict a future malignant evolution of gonadoblastoma.
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http://dx.doi.org/10.1002/ajmg.a.30569DOI Listing
June 2005

Noonan-like syndrome with loose anagen hair: a new syndrome?

Am J Med Genet A 2003 Apr;118A(3):279-86

Department of Pediatrics, University of Bologna, Bologna, Italy.

We present three children with short stature, the same facial phenotype, macrocephaly, enlarged cerebral spinal fluid spaces, short neck with redundant skin, severe GH deficiency, mild psychomotor delay with attention deficit/hyperactivity disorder (ADHD), mild dilatation of the pulmonary root in two of them, and a unique combination of ectodermal abnormalities. Their appearance, not completely typical of Noonan syndrome, the behavioral phenotype, GH deficiency, darkly pigmented and hairless skin, and the unusual aspect of the hair, defined as loose anagen hair syndrome did not fit any known condition. We postulate that these children may represent a distinct, previously unreported syndrome that we would name "Noonan-like syndrome with loose anagen hair".
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http://dx.doi.org/10.1002/ajmg.a.10923DOI Listing
April 2003