Publications by authors named "Simonetta Rosato"

21 Publications

  • Page 1 of 1

Expanding the phenotype of Wiedemann-Steiner syndrome: Craniovertebral junction anomalies.

Am J Med Genet A 2020 12 11;182(12):2877-2886. Epub 2020 Oct 11.

Medical Genetics Unit, Meyer Children's University Hospital, Florence, Italy.

Wiedemann-Steiner syndrome (WDSTS) is a rare autosomal dominant condition caused by heterozygous loss of function variants in the KMT2A (MLL) gene, encoding a lysine N-methyltransferase that mediates a histone methylation pattern specific for epigenetic transcriptional activation. WDSTS is characterized by a distinctive facial phenotype, hypertrichosis, short stature, developmental delay, intellectual disability, congenital malformations, and skeletal anomalies. Recently, a few patients have been reported having abnormal skeletal development of the cervical spine. Here we describe 11 such individuals, all with KMT2A de novo loss-of-function variants: 10 showed craniovertebral junction anomalies, while an 11th patient had a cervical abnormality in C7. By evaluating clinical and diagnostic imaging data we characterized these anomalies, which consist primarily of fused cervical vertebrae, C1 and C2 abnormalities, small foramen magnum and Chiari malformation type I. Craniovertebral anomalies in WDSTS patients have been largely disregarded so far, but the increasing number of reports suggests that they may be an intrinsic feature of this syndrome. Specific investigation strategies should be considered for early identification and prevention of craniovertebral junction complications in WDSTS patients.
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http://dx.doi.org/10.1002/ajmg.a.61859DOI Listing
December 2020

Improving the phenotype description of Basel-Vanagaite-Smirin-Yosef syndrome, MED25-related: polymicrogyria as a distinctive neuroradiological finding.

Neurogenetics 2021 03 20;22(1):19-25. Epub 2020 Aug 20.

Medical Genetics Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.

Basel-Vanagaite-Smirin-Yosef syndrome (BVSYS) is an extremely rare autosomal recessive genetic disorder caused by variants in the MED25 gene. It is characterized by severe developmental delay and variable craniofacial, neurological, ocular, and cardiac anomalies. Since 2015, through whole exome sequencing, 20 patients have been described with common clinical features and biallelic variants in MED25, leading to a better definition of the phenotype associated with BVSYS. We report two young sisters, born to consanguineous parents, presenting with intellectual disability, neurological findings, and dysmorphic features typical of BVSYS, and also with bilateral perisylvian polymicrogyria. The younger sister died at the age of 1 year without autoptic examination. Whole exome sequencing detected a homozygous frameshift variant in the MED25 gene: NM_030973.3:c.1778_1779delAG, p.(Gln593Argfs). This report further delineates the most common clinical features of BVSYS and points to polymicrogyria as a distinctive neuroradiological feature of this syndrome.
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http://dx.doi.org/10.1007/s10048-020-00625-2DOI Listing
March 2021

Alazami syndrome: the first case of papillary thyroid carcinoma.

J Hum Genet 2020 Jan 28;65(2):133-141. Epub 2019 Oct 28.

Medical Genetics Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.

Alazami syndrome (MIM#615071) is a rare developmental disorder caused by biallelic variants in the LARP7 gene. Hallmark features include short stature, global developmental delay, and distinctive facial features. To date, 23 patients from 11 families have been reported in the literature. Here we describe a 19-year-old man who, in association with the typical features of Alazami syndrome, was diagnosed at the age of 14 years with papillary thyroid carcinoma, harboring the somatic BRAF V600E mutation. Whole exome sequencing revealed two novel LARP7 variants in compound heterozygosity, whereas only common variants were detected in genes associated with familial nonmedullary thyroid cancer (MIM#188550). LARP7 acts as a tumor suppressor in breast and gastric cancer, and possibly, according to recent studies, in thyroid tumors. Since thyroid cancer is rare among children and adolescents, we hypothesize that the LARP7 variants identified in our patient are responsible for both Alazami syndrome and tumor susceptibility. We also provide an overview of the clinical findings in all Alazami syndrome patients reported to date and discuss the possible pathogenetic mechanism that may underlie this condition, including the role of LARP7 in tumor susceptibility.
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http://dx.doi.org/10.1038/s10038-019-0682-5DOI Listing
January 2020

Van Maldergem syndrome and Hennekam syndrome: Further delineation of allelic phenotypes.

Am J Med Genet A 2018 05;176(5):1166-1174

Department of Pediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.

Biallelic variants in FAT4 are associated with the two disorders, Van Maldergem syndrome (VMS) (n = 11) and Hennekam syndrome (HS) (n= 40). Both conditions are characterized by a typical facial gestalt and mild to moderate intellectual disability, but differ in the occurrence of neonatal hypotonia and feeding problems, hearing loss, tracheal anomalies, and osteopenia in VMS, and lymphedema in HS. VMS can be caused by autosomal recessive variants in DCHS1 as well, and HS can also be caused by autosomal recessive variants in CCBE1 and ADAMTS3. Here we report two siblings with VMS and one girl with HS, all with FAT4 variants, and provide an overview of the clinical findings in all patients reported with FAT4 variants. Our comparison of the complete phenotypes of patients with VMS and HS indicates a resemblance of several signs, but differences in several other main signs and symptoms, each of marked importance for affected individuals.
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http://dx.doi.org/10.1002/ajmg.a.38652DOI Listing
May 2018

Complex cranio-vertebral malformation: disruption sequence or iniencephaly?

Clin Dysmorphol 2018 Jul;27(3):105-108

Department of Pediatrics, University of Lausanne and Lausanne University Hospital, Lausanne, Switzerland.

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http://dx.doi.org/10.1097/MCD.0000000000000218DOI Listing
July 2018

Phenotype and genotype of 87 patients with Mowat-Wilson syndrome and recommendations for care.

Genet Med 2018 09 4;20(9):965-975. Epub 2018 Jan 4.

Neuropsychiatric Department, Spedali Civili Brescia, Brescia, Italy.

Purpose: Mowat-Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype-phenotype correlations of MWS.

Methods: In a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations.

Results: All anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluation of MWS to date, we define its clinical evolution occurring with age and derive suggestions for patient management. Furthermore, we observe that its severity correlates with the kind of ZEB2 variation involved, ranging from ZEB2 locus deletions, associated with severe phenotypes, to rare nonmissense intragenic mutations predicted to preserve some ZEB2 protein functionality, accompanying milder clinical presentations.

Conclusion: Knowledge of the phenotypic spectrum of MWS and its correlation with the genotype will improve its detection rate and the prediction of its features, thus improving patient care.
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http://dx.doi.org/10.1038/gim.2017.221DOI Listing
September 2018

Endocrinological Abnormalities Are a Main Feature of 17p13.1 Microduplication Syndrome: A New Case and Literature Review.

Mol Syndromol 2016 Nov 14;7(6):337-343. Epub 2016 Oct 14.

Clinical Genetics Unit, Università degli Studi di Parma, Parma, Italy.

To date, 5 cases of 17p13.1 microduplications have been described in the literature. Intellectual disability was reported as the core feature, together with minor facial dysmorphisms and obesity, but a characteristic phenotype for 17p13.1 microduplication has not been delineated. Here, we describe a patient with a 1.56-Mb de novo duplication in 17p13.1, affected by mild intellectual disability, facial dysmorphisms, obesity, and diabetes. By comparing the different phenotypes of currently described cases, we delineated the main clinical features of 17p13.1 microduplication syndrome. All patients described to date had variable facial dysmorphisms; therefore, it was difficult to define a common facial gestalt. Furthermore, we stress endocrinological abnormalities as important features and the need to monitor these over time.
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http://dx.doi.org/10.1159/000450718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5131335PMC
November 2016

Natural history and life-threatening complications in Myhre syndrome and review of the literature.

Eur J Pediatr 2016 Oct 25;175(10):1307-15. Epub 2016 Aug 25.

Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Rome, Italy.

Unlabelled: Myhre syndrome (OMIM 139210) is a rare developmental disorder inherited as an autosomal dominant trait and caused by a narrow spectrum of missense mutations in the SMAD4 gene. The condition features characteristic face, short stature, skeletal anomalies, muscle pseudohypertrophy, restricted joint mobility, stiff and thick skin, and variable intellectual disability. While most of the clinical features manifest during childhood, the diagnosis may be challenging during the first years of life. We report on the evolution of the clinical features of Myhre syndrome during childhood in a subject with molecularly confirmed diagnosis. The clinical records of 48 affected patients were retrospectively analysed to identify any early clinical signs characterizing this disorder and to better delineate its natural history. We also note that pericarditis and laryngotracheal involvement represent important life-threatening complications of Myhre syndrome that justify the recommendation for cardiological and ENT follow-up for these patients.

Conclusion: Short length/stature, short palpebral fissures, and brachydactyly with hyperconvex nails represent signs/features that might lead to the correct diagnosis in the first years of life and direct to the proper molecular analysis. We underline the clinical relevance of pericarditis and laryngotracheal stenosis as life-threatening complications of this disorder and the need for careful monitoring, in relation to their severity.

What Is Known: • The clinical and radiological signs of the disease in children older than 7-8 years. • Pericarditis, sometimes occurring with constrictive pericardium requiring pericardiectomy, has been reported as a recurrent feature but has not been adequately stressed in previous literature. What is New: • Short length/stature, short palpebral fissures, brachydactyly with hyperconvex nails represent clinical signs that might lead to diagnosis in the first years of life. • Review of the literature showed that pericarditis and laryngotracheal complications represent major recurrent issues in patients with Myhre syndrome.
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http://dx.doi.org/10.1007/s00431-016-2761-3DOI Listing
October 2016

RIN2 syndrome: Expanding the clinical phenotype.

Am J Med Genet A 2016 09 8;170(9):2408-15. Epub 2016 Jun 8.

Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium.

Biallelic defects in the RIN2 gene, encoding the Ras and Rab interactor 2 protein, are associated with a rare autosomal recessive connective tissue disorder, with only nine patients from four independent families reported to date. The condition was initially termed MACS syndrome (macrocephaly, alopecia, cutis laxa, and scoliosis), based on the clinical features of the first identified family; however, with the expansion of the clinical phenotype in additional families, it was subsequently coined RIN2 syndrome. Hallmark features of this condition include dysmorphic facial features with striking, progressive facial coarsening, sparse hair, normal to enlarged occipitofrontal circumference, soft redundant and/or hyperextensible skin, and scoliosis. Patients with RIN2 syndrome present phenotypic overlap with other conditions, including EDS (especially the dermatosparaxis and kyphoscoliosis subtypes). Here, we describe a 10th patient, the first patient of Caucasian origin and the oldest reported patient so far, who harbors the previously identified homozygous RIN2 mutation c.1878dupC (p. (Ile627Hisfs*7)). Besides the hallmark features, this patient also presents problems not previously associated with RIN2 syndrome, including cervical vertebral fusion, mild hearing loss, and colonic fibrosis. We provide an overview of the clinical findings in all reported patients with RIN2 mutations and summarize some of the possible pathogenic mechanisms that may underlie this condition. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.a.37789DOI Listing
September 2016

Cryptic 13q34 and 4q35.2 Deletions in an Italian Family.

Cytogenet Genome Res 2015 9;147(1):24-30. Epub 2015 Dec 9.

Regional Reference Centre for Inherited Bleeding Disorders, University Hospital of Parma, Parma, Italy.

Variations of DNA sequences in the human genome range from large, microscopically visible chromosome anomalies to single nucleotide changes. Submicroscopic genomic copy number variations, i.e. chromosomal imbalances which are undetectable by conventional cytogenetic analysis, play an intriguing clinical role. In this study, we describe the clinical consequences of the concurrent presence of an interstitial deletion in 13q34 and a terminal deletion in 4q35.2 in an Italian family. The index patient, a 19-year-old male, as well as his 12-year-old sister are carriers of both deletions, one of maternal and the other of paternal origin. The phenotype includes language delay, multiorgan involvement and bleeding diathesis with mild deficiency of factors X and VII. In the sister, the concomitant presence of Noonan syndrome may partly explain the clinical symptoms. The deleted region on chromosome 13 involves several genes (ATP11A, MCF2L, F7, F10, PROZ, PCID2, CUL4A, and LAMP1); some of these seem to play a role in the proband's phenotype. The terminal deletion in 4q35.2 contains other OMIM genes (FRG1, FRG2 and DBET); moreover, the 4q region is reported as a susceptibility locus for Crohn's disease, diagnosed in the proband's father. To our knowledge, this is the first report of a family with these 2 submicroscopic copy number changes. We tried to relate the clinical phenotype of the proband and his family to the molecular function of the involved genes.
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http://dx.doi.org/10.1159/000442068DOI Listing
June 2016

Noonan syndrome-like disorder with loose anagen hair: a second case with neuroblastoma.

Am J Med Genet A 2015 Aug 5;167A(8):1902-7. Epub 2015 Apr 5.

Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.

Noonan-like syndrome with loose anagen hair (NSLH), also known as Mazzanti syndrome, is a RASopathy characterized by craniofacial features resembling Noonan syndrome, cardiac defects, cognitive deficits and behavioral issues, reduced growth generally associated with GH deficit, darkly pigmented skin, and an unique combination of ectodermal anomalies. Virtually all cases of NSLH are caused by an invariant and functionally unique mutation in SHOC2 (c.4A>G, p.Ser2Gly). Here, we report on a child with molecularly confirmed NSLH who developed a neuroblastoma, first suspected at the age 3 months by abdominal ultrasound examination. Based on this finding, scanning of the SHOC2 coding sequence encompassing the c.4A>G change was performed on selected pediatric cohorts of malignancies documented to occur in RASopathies (i.e., neuroblastoma, brain tumors, rhabdomyosarcoma, acute lymphoblastic, and myeloid leukemia), but failed to identify a functionally relevant cancer-associated variant. While these results do not support a major role of somatic SHOC2 mutations in these pediatric cancers, this second instance of neuroblastoma in NSLAH suggests a possible predisposition to this malignancy in subjects heterozygous for the c.4A>G SHOC2 mutation.
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http://dx.doi.org/10.1002/ajmg.a.37082DOI Listing
August 2015

Multiple sulfatase deficiency with neonatal manifestation.

Ital J Pediatr 2014 Dec 17;40:86. Epub 2014 Dec 17.

Pediatrics Unit, UNIVPM, Ancona, Italy.

Multiple Sulfatase Deficiency (MSD; OMIM 272200) is a rare autosomal recessive inborn error of metabolism caused by mutations in the sulfatase modifying factor 1 gene, encoding the formylglycine-generating enzyme (FGE), and resulting in tissue accumulation of sulfatides, sulphated glycosaminoglycans, sphingolipids and steroid sulfates. Less than 50 cases have been published so far. We report a new case of MSD presenting in the newborn period with hypotonia, apnoea, cyanosis and rolling eyes, hepato-splenomegaly and deafness. This patient was compound heterozygous for two so far undescribed SUMF1 mutations (c.191C > A; p.S64X and c.818A > G; p.D273G).
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http://dx.doi.org/10.1186/s13052-014-0086-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4299397PMC
December 2014

Hydrops fetalis in a preterm newborn heterozygous for the c.4A>G SHOC2 mutation.

Am J Med Genet A 2014 Apr 23;164A(4):1015-20. Epub 2014 Jan 23.

Neonatologic Unit, Obstetric and Paediatric Department, Istituto di Ricovero e Cura a Carattere Scientifico, S. Maria Nuova Hospital, Reggio Emilia, Italy.

Fetal hydrops is a condition resulting from interstitial fluid accumulation in fetal compartments secondary to increased capillary permeability and characterized by high rates of perinatal mortality and morbidity. Clinical features include skin edema, hydrothorax, pericardial effusion, ascites with or without polyhydramnios, and placental edema. While it may occur as associated feature in multiple disorders, it has been documented to recur in Noonan syndrome, the most common disorder among RASopathies, but also in cardiofaciocutaneous and Costello syndromes. Here, we report on the occurrence of severe hydrops in a newborn heterozygous for the invariant c.4A>G missense change in SHOC2 which underlies Noonan-like syndrome with loose anagen hair, documenting that it represents a clinically relevant complication in this condition, shared by RASopathies.
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http://dx.doi.org/10.1002/ajmg.a.36376DOI Listing
April 2014

Multiple tumor types including leiomyoma and Wilms tumor in a patient with Gorlin syndrome due to 9q22.3 microdeletion encompassing the PTCH1 and FANC-C loci.

Am J Med Genet A 2013 Nov 7;161A(11):2894-901. Epub 2013 Oct 7.

Clinical Genetics Unit, Obstetric and Paediatric Department, Istituto di Ricovero e Cura a Carattere Scientifico, Arcispedale S Maria Nuova, Reggio Emilia, Italy.

Gorlin syndrome or nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant condition mainly characterized by the development of mandibular keratocysts which often have their onset during the second decade of life and/or multiple basal cell carcinoma (BCC) normally arising during the third decade. Cardiac and ovarian fibromas can be found. Patients with NBCCS develop the childhood brain malignancy medulloblastoma (now often called primitive neuro-ectodermal tumor [PNET]) in 5% of cases. The risk of other malignant neoplasms is not clearly increased, although lymphoma and meningioma can occur in this condition. Wilms tumor has been mentioned in the literature four times. We describe a patient with a 10.9 Mb 9q22.3 deletion spanning 9q22.2 through 9q31.1 that includes the entire codifying sequence of the gene PTCH1, with Wilms tumor, multiple neoplasms (lung, liver, mesenteric, gastric and renal leiomyomas, lung typical carcinoid tumor, adenomatoid tumor of the pleura) and a severe clinical presentation. We propose including leiomyomas among minor criteria of the NBCCS.
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http://dx.doi.org/10.1002/ajmg.a.36259DOI Listing
November 2013

Dermoscopy of uncommon skin tumours.

Australas J Dermatol 2014 Feb 19;55(1):53-62. Epub 2013 Jul 19.

Skin Cancer Unit, Arcispedale Santa Maria Nuova IRCCS, Reggio Emilia.

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http://dx.doi.org/10.1111/ajd.12074DOI Listing
February 2014

Focal dermal hypoplasia (Goltz-Gorlin syndrome): a new case with a novel variant in the PORCN gene (c.1250T>C:p.F417S) and unusual spinal anomaly.

Am J Med Genet A 2013 Jul 21;161A(7):1750-4. Epub 2013 May 21.

Clinical Genetics Unit, Obstetric and Pediatric Department, Istituto di Ricovero e Cura a Carattere Scientifico, Arcispedale Santa Maria Nuova, Reggio Emilia, Italy.

Focal dermal hypoplasia (FDH; Goltz-Gorlin syndrome; OMIM 305600) is a disorder that features involvement of the skin, skeletal system, and eyes. It is caused by loss-of-function mutations in the PORCN gene. We report a young girl with FDH, microphthalmos associated with colobomatous orbital cyst, dural ectasia and cystic malformation of the spinal cord, and a de novo variant in PORCN. This association has not been previously reported, and based on these observations the phenotypic spectrum of FDH might be broader than previously appreciated. It would be prudent to alter the suggested surveillance for this rare disorder.
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http://dx.doi.org/10.1002/ajmg.a.35964DOI Listing
July 2013

Epilepsy in Mowat-Wilson syndrome: delineation of the electroclinical phenotype.

Am J Med Genet A 2013 Feb 15;161A(2):273-84. Epub 2013 Jan 15.

Child Neurology and Psychiatry Unit, S Orsola Malpighi Hospital, University of Bologna, Bologna, Italy.

Mowat-Wilson syndrome (MWS) is a genetic disease caused by heterozygous mutations or deletions of the ZEB2 gene and is characterized by distinctive facial features, epilepsy, moderate to severe intellectual disability, corpus callosum abnormalities and other congenital malformations. Epilepsy is considered a main manifestation of the syndrome, with a prevalence of about 70-75%. In order to delineate the electroclinical phenotype of epilepsy in MWS, we investigated epilepsy onset and evolution, including seizure types, EEG features, and response to anti-epileptic therapies in 22 patients with genetically confirmed MWS. Onset of seizures occurred at a median age of 14.5 months (range: 1-108 months). The main seizure types were focal and atypical absence seizures. In all patients the first seizure was a focal seizure, often precipitated by fever. The semiology was variable, including hypomotor, versive, or focal clonic manifestations; frequency ranged from daily to sporadic. Focal seizures were more frequent during drowsiness and sleep. In 13 patients, atypical absence seizures appeared later in the course of the disease, usually after the age of 4 years. Epilepsy was usually quite difficult to treat: seizure freedom was achieved in nine out of the 20 treated patients. At epilepsy onset, the EEGs were normal or showed only mild slowing of background activity. During follow-up, irregular, diffuse frontally dominant and occasionally asymmetric spike and waves discharges were seen in most patients. Sleep markedly activated these abnormalities, resulting in continuous or near-to-continuous spike and wave activity during slow wave sleep. Slowing of background activity and poverty of physiological sleep features were seen in most patients. Our data suggest that a distinct electroclinical phenotype, characterized by focal and atypical absence seizures, often preceded by febrile seizures, and age-dependent EEG changes, can be recognized in most patients with MWS.
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http://dx.doi.org/10.1002/ajmg.a.35717DOI Listing
February 2013

Simpson-Golabi-Behmel syndrome type 1 in a 27-week macrosomic preterm newborn: the diagnostic value of rib malformations and index nail and finger hypoplasia.

Am J Med Genet A 2012 Sep 17;158A(9):2245-9. Epub 2012 Jul 17.

Clinical Genetics Unit-Obstetric and Pediatric Department, Arcispedale Santa Maria Nuova, Istituto di Ricovero e Cura a Carattere Scientifico, Reggio Emilia, Italy.

The Simpson-Golabi-Behmel syndrome type 1 (SGBS1, OMIM #312870) is an X-linked overgrowth condition comprising abnormal facial appearance, supernumerary nipples, congenital heart defects, polydactyly, fingernail hypoplasia, increased risk of neonatal death and of neoplasia. It is caused by mutation/deletion of the GPC3 gene. We describe a macrosomic 27-week preterm newborn with SGBS1 who presents a novel GPC3 mutation and emphasize the phenotypic aspects which allow a correct diagnosis neonatally in particular the rib malformations, hypoplasia of index finger and of the same fingernail, and 2nd-3rd finger syndactyly.
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http://dx.doi.org/10.1002/ajmg.a.35474DOI Listing
September 2012

Disease family history and modification of breast cancer risk in common BRCA2 variants.

Oncol Rep 2008 Mar;19(3):783-6

Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), 47014 Meldola (FC), Italy.

A number of BRCA1 and BRCA2 polymorphisms have been extensively studied in order to test their association with breast cancer risk. Subsequently, discordant results were reported. In the present study, the genotypes of one BRCA1 (Q356R) and three BRCA2 (203G>A, N372H, IVS21-66T>C) common variants were evaluated in a series of 252 breast cancer patients, 155 age-matched controls and analysed in relation to family history (low- or high-risk) and BRCA1/2 mutation status. A complete analysis of the BRCA1/2 coding regions was performed on the 217 women from high-risk families and 44 BRCA1/2 mutation carriers were identifed. According to a dominant inheritance model, the BRCA2 IVS21-66T>C variant showed a 1.79-fold (95% CI, 1.16-2.78; P=0.009) increased breast cancer risk for the overall series. The BRCA2 N372H polymorphism was associated with a 2.29-fold (95% CI, 1.16-4.49; P=0.016) increased risk in the subgroup of high-risk families with no BRCA1/2 mutations. Conversely, the BRCA1 Q356R and BRCA2 203G>A polymorphisms did not show any significant associations with breast cancer risk. In conclusion, the analysis of some BRCA2 variants could help to identify women at a higher risk of developing breast cancer who could be candidates for chemoprevention protocols.
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March 2008

Results of a population-based screening for hereditary breast cancer in a region of North-Central Italy: contribution of BRCA1/2 germ-line mutations.

Breast Cancer Res Treat 2008 Nov 20;112(2):343-9. Epub 2007 Dec 20.

Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, FC, Italy.

BRCA1/2 mutation status is of paramount importance to identify families at risk of Hereditary Breast and Ovarian Cancer (HBOC). Most HBOC and BRCA1/2 mutation studies have focused on highly selected sub-populations, and few data are available for large population cohorts. For this reason, as part of a regional cancer prevention strategy in North-Central Italy, we set up a population-based screening programme to identify all resident HBOC families, and to determine their BRCA1/2 mutation status. To date, 44 different BRCA1/2 variants have been identified in 55 HBOC families. Of the seven newly reported mutations, only BRCA1 Q284X is clearly deleterious. The analysis of clinical disease characteristics in relation to age of disease onset and family history showed a difference between BRCA1/2 wild type and mutation carrier families. Interestingly, BRCA1/2 mutations were significantly more common in women who developed breast cancer
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http://dx.doi.org/10.1007/s10549-007-9846-7DOI Listing
November 2008
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