CTNND1 is a gene located in 11q12.1, encoding for p120 catenin, a protein involved in maintaining adherent junctions, regulating the epithelial-mesenchymal transition, and transcriptional signaling of different cellular pathways. Pathogenic variants in CTNND1 are classically associated with isolated cleft palate and Blefaro-cheilo-dontic syndrome, an autosomal dominant condition characterized by abnormalities of the eyelid. Considering different signs and symptoms associated first with Blefaro-cheilo-dontic syndrome and later specifically with CTNND1, Ahlaratani and colleagues proposed a wider developmental role for CTNND1 than previously described, associating a broader phenotypic spectrum. This report describes a prenatal case in which a CTNND1 pathogenic variant and reverse phenotyping allowed a diagnosis of Blefaro-cheilo-dontic syndrome associated with characteristics never related to Blefaro-cheilo-dontic syndrome or CTNND1, such as hydrocephalus. This report is the first detailed fetal case of Blefaro-cheilo-dontic syndrome, and the new feature reported is consistent with CTNND1 developmental role and may add new insights into the phenotype spectrum that is being defined.

Neurofibromatosis type 1 (NF1) is an autosomal dominant condition caused by neurofibromin haploinsufficiency due to pathogenic variants in the NF1 gene. Tumor predisposition has long been associated with NF1, and an increased breast cancer (BC) incidence and reduced survival have been reported in recent years for women with NF1. As breast density is another known independent risk factor for BC, this study aims to evaluate the variability of breast density in patients with NF1 compared to the general population. Mammograms from 98 NF1 women affected by NF1, and enrolled onto our monocentric BC screening program, were compared with those from 300 healthy subjects to verify differences in breast density. Mammograms were independently reviewed and scored by a radiologist and using a Computer-Aided Detection (CAD) software. The comparison of breast density between NF1 patients and controls was performed through Chi-squared test and with multivariable ordinal logistic models adjusted for age, body mass index (BMI), number of pregnancies, and menopausal status.breast density was influenced by BMI and menopausal status in both NF1 patients and healthy subjects. No difference in breast density was observed between NF1 patients and the healthy female population, even after considering the potential confounding factors.Although NF1 and a highly fibroglandular breast are known risk factors of BC, in this study, NF1 patients were shown to have comparable breast density to healthy subjects. The presence of pathogenic variants in the NF1 gene does not influence the breast density value.

Silvia Tortora,1 Andrea Esposito,2 Gianmarco Della Pepa,1 Michele Paternò,1 Giulia Anna Cagnoli,3 Claudia Cesaretti,3 Federica Natacci,3 Gianpaolo Carrafiello2 1School of Diagnostic and Interventional Radiology, University of Milan, Milan, 20122, Italy; 2Radiology Department, Foundation IRCCS Ca’ Granda Maggiore Policlinico Hospital, Milan, 20122, Italy; 3Medical Genetics Unit, Woman-Child-Newborn Department, Foundation IRCCS Ca’ Granda Maggiore Policlinico Hospital, Milan, 20122, ItalyCorrespondence: Silvia TortoraSchool of Diagnostic and Interventional Radiology, University of Milan, Via Festa del Perdono 7, Milan, 20122, ItalyEmail silvia.tortora@unimi.itAndrea EspositoRadiology Department, Foundation IRCCS Ca’ Granda Maggiore Policlinico Hospital, Via F. Sforza 35, Milan, 20122, ItalyEmail andrea.esposito@policlinico.mi.itAbstract: Neurofibromatosis type 1 (NF1) is an autosomal dominant disease caused by the mutation of the tumour suppressor gene NF1 located on chromosome 17q11.2, occurring in approximately 1 in 2000– 2500 people. The diagnosis of NF1 is made according to the presence of two or more diagnostic criteria of the National Institute of Health Consensus Development Conference. We present six cases of NF1 with neck and thoraco-abdominal involvement that we studied with MRI. The patients we present in this case series are asymptomatic and have in common the presence of multiple neurofibromas ubiquitously distributed in various body districts, including nerve roots, mediastinum, abdominal cavity, skin and subcutaneous tissue. Currently, there are no clear indications on the use of imaging in the diagnosis and follow-up of patients with NF1, although there is increasing evidence of the usefulness of imaging techniques and in particular of MRI. MRI with DWI and ADC mapping is a technique that should be proposed as a new standard of care for patients with NF1 since it can be used to distinguish a benign from a malignant tumour in relation to tumour size and ADC map values.Keywords: neurofibromatosis 1, neurofibroma, plexiform neurofibroma, nerve sheath tumour, magnetic resonance imaging

BACKGROUND: Neurofibromatosis type 1 (NF1) is a human autosomal dominant disorders that affects approximately 1 in 3,500 individuals worldwide. The most common features of NF1 are pigmentary abnormalities, such as café-au-lait macules, skinfold freckling, Lisch nodules and cutaneous and plexiform neurofibromas (PNs). These signs are age-dependent and present high variability in penetrance and expressivity even between affected members of a family. NF1 is the most common cancer predisposing syndrome affecting the nervous system. Glioma is the most common central nervous system neoplasia in NF1 patients: 15-20% NF1 children develop low grade optic gliomas. PNs occur in 30% of NF1 patients in peripheral nervous system. Patients with PNs have a 20-fold higher risk of developing malignant peripheral nerve sheath tumours (MPNSTs) than other NF1 patients. NF1 is caused by mutations in the neurofibromin gene encoding a negative regulator of Ras guanosine triphosphate (GTP)ase proteins: for this reason is considered a tumor suppressor gene. Mutation detection in the NF1 gene is complex, due to the large size of the gene (>350 kb), the presence of pseudogenes, the lack of hot spots, and the great variety of possible mutations. Hence, the clinical and molecular diagnosis of NF1 may be challenging and its fine-tuning is desirable. METHODS: During 2003-2013 NF1 mutation analysis of genomic DNA was performed in 458 patients using the multiplex ligation-dependent probe amplification (MLPA) to look for deletions or insertions located inside the NF1 gene. Subjects who tested negative for MLPA were investigated using denaturing high pressure liquid chromatography (DHPLC) and sequencing DNA. RNA-based cDNA-PCR sequencing was used in a limited group of patients. RESULTS: 299 of 458 patients were diagnosed according to NIH criteria. 54% were children and about 53% of all NF1 patients were found to have sporadic mutations. We identified 197 single mutations and more than 57% were novel. This genetic protocol permitted us to find mutations in 210 of 299 of clinically diagnosed patients (detection rate: 70%). To improve such detection rate we have recently developed a sensitive, integrated genetic protocol using MLPA and RNA-based cDNA-PCR sequencing. This protocol was validated in a cohort of 33 blood samples from NF1 patients with complete NF1 features, identifying the mutations in 30 cases (91% detection rate). CONCLUSIONS: These data suggest that integrated DNA/RNA-based protocols can improve detection rate in patients suspected to have NF1.

American Journal of Medical Genetics Part AVolume 132A, Issue 3 p. 329-330 Research Letter Cumming syndrome with heterotaxia, campomelia and absent uterus/fallopian tubes M.F. Bedeschi, Corresponding Author M.F. Bedeschi geneticamedica@icp.mi.it Medical Genetics Unit, ICP, Clinica Mangiagalli, Milan, ItalyMedical Genetics Unit, Istituti Clinici di Perfezionamento, Via Commenda 12, 20122 Milano, Italy.Search for more papers by this authorL. Spaccini, L. Spaccini Medical Genetics Unit, ICP, Clinica Mangiagalli, Milan, ItalySearch for more papers by this authorT. Rizzuti, T. Rizzuti Pathology Unit, ICP, Clinica Mangiagalli, Milan, ItalySearch for more papers by this authorD.A. Coviello, D.A. Coviello Prenatal Diagnosis Unit, Ospedale Buzzi, ICP, Milan, ItalySearch for more papers by this authorP. Castorina, P. Castorina Medical Genetics Unit, ICP, Clinica Mangiagalli, Milan, ItalySearch for more papers by this authorF. Natacci, F. Natacci Medical Genetics Unit, ICP, Clinica Mangiagalli, Milan, ItalySearch for more papers by this authorF. Lalatta, F. Lalatta Medical Genetics Unit, ICP, Clinica Mangiagalli, Milan, ItalySearch for more papers by this author M.F. Bedeschi, Corresponding Author M.F. Bedeschi geneticamedica@icp.mi.it Medical Genetics Unit, ICP, Clinica Mangiagalli, Milan, ItalyMedical Genetics Unit, Istituti Clinici di Perfezionamento, Via Commenda 12, 20122 Milano, Italy.Search for more papers by this authorL. Spaccini, L. Spaccini Medical Genetics Unit, ICP, Clinica Mangiagalli, Milan, ItalySearch for more papers by this authorT. Rizzuti, T. Rizzuti Pathology Unit, ICP, Clinica Mangiagalli, Milan, ItalySearch for more papers by this authorD.A. Coviello, D.A. Coviello Prenatal Diagnosis Unit, Ospedale Buzzi, ICP, Milan, ItalySearch for more papers by this authorP. Castorina, P. Castorina Medical Genetics Unit, ICP, Clinica Mangiagalli, Milan, ItalySearch for more papers by this authorF. Natacci, F. Natacci Medical Genetics Unit, ICP, Clinica Mangiagalli, Milan, ItalySearch for more papers by this authorF. Lalatta, F. Lalatta Medical Genetics Unit, ICP, Clinica Mangiagalli, Milan, ItalySearch for more papers by this author First published: 02 November 2004 https://doi.org/10.1002/ajmg.a.30398Citations: 5Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume132A, Issue330 January 2005Pages 329-330 RelatedInformation

N eurofibromatosis type 1 (NF1 [MIM 162200]) is a common autosomal dominant disorder that affects 1/3500 individuals and is caused by deletion or point mutations of NF1, a tumour suppressor gene mapping to 17q11.2. Its main features include café au lait spots, axillary and inguinal freckling, iris Lisch nodules, neurofibromas, and an increased risk of benign and malignant tumours, particularly optic glioma, neurofibrosarcoma, malignant peripheral nerve sheath tumours (MPNSTs), and childhood myeloid leukaemia. Over 70% of NF1 germline mutations cause truncation or loss of the encoded protein. Approximately 5–20% of all NF1 patients carry a heterozygous deletion of usually 1.5 Mb involving the NF1 gene and contiguous genes lying in its flanking regions, 4 which is caused by unequal homologous recombination of NF1 repeats (REPs). Known as the ‘‘NF1 microdeletion syndrome,’’ this condition is often characterised by a more severe phenotype than is observed in the general NF1 group. In particular, NF1 microdeleted patients often show variable facial dysmorphisms, mental retardation, developmental delay, and an excessive number of neurofibromas for age. 6–12 The severe phenotype of microdeleted patients may be explained by variations in the expression of the genes involved in the rearrangement, which may be caused by different mechanisms, such as gene interruptions, position effects, and decreased gene dosages. Although NF1 microdeleted patients generally have different characteristics from those of classic NF1 patients, it remains difficult to foresee the presence of the deletion at an individual level on the basis of clinical observations. Various studies have reported the clinical characterisation of NF1 deleted patients and the precise extent of the deletion has been characterised in a subset. 13 14 However, no study comparing the incidence of specific clinical signs in NF1 deleted and classical NF1 patients has yet been published. The only published comparative study concerned a single clinical sign (the development of an MPNST), for which a correlation between NF1 microdeletion and a high risk for this tumour was observed. Our aims in the present study were, first, to verify whether the incidence of specific clinical signs is different in NF1 microdeleted and general NF1 patients; and second, to indicate possible correlations between the onset of distinct clinical features and the haploinsufficiency of specific genes involved in the deletions. We considered the extra-NF1 clinical signs shown by a sample of 92 microdeleted patients (evaluated in this study or described in published reports), and estimated their incidence in comparison with the NF1 patient group as a whole. METHODS Patients In order to generate a database that was as comprehensive as possible, we data-mined the NCBI Entrez Pubmed and Med Miner repository and retrieved all the individually reported cases of patients affected by the NF1 microdeletion syndrome whose clinical phenotype was also described. Signs included among the diagnostic criteria for NF1 were excluded (with the exception of plexiform neurofibroma), as were minor sporadically present signs for which no incidence figures were available.

We describe a female affected by diaphragmatic hernia and nasopharyngeal teratoma. The case is compared with one already reported and possible diagnoses discussed. These cases appear to represent a new syndrome.

Quantitative fluorescent polymerase chain reaction (QF-PCR) has recently entered the field of prenatal diagnosis to overcome the need to culture fetal cells, hence to allow rapid diagnosis of some selected chromosomal anomalies. We reviewed the studies on the accuracy of QF-PCR in detecting chromosomal anomalies at prenatal diagnosis. Overall, 22 504 samples have been analysed. The detection rate of aneuploidies of the selected chromosomes (13, 18 and 21, and X and Y) was 98.6% (95% confidence interval 97.8-99.3). QF-PCR might play a major role and be considered a valid alternative to the full karyotype. Being less expensive, and almost entirely automated, more women could undergo invasive prenatal diagnosis without significant increase in health expenditure. By using QF-PCR as a stand-alone test, the chances of non diagnosing the commonest, and the only chromosome anomalies which do increase in frequency with maternal age, are approximately one in 150 abnormal karyotypes, or one in 10-30 000 samples, based on the age distribution. These error rates might be deemed acceptable, although most structural chromosomal anomalies will be missed. At present, women are rarely informed about the full spectrum of the conditions which might be diagnosed via amniocentesis or chorionic villous sampling. Some of these anomalies might be acceptable, in view of their limited or uncertain clinical relevance, and decision analysis might, in the majority of cases, confine the full karyotype to selected women who have specific indications.

Objectives The presence in the conceptus of a Robertsonian translocation predisposes to UPD formation, mainly by post-zygotic events of chromosome abnormality rescue. This is due to the increased risk of generating aneuploid zygotes because the rearranged chromosome and the respective homologues are prone to nondisjunction errors. Given this, carriers and karyotypically normal individuals conceived from a parent with a Robertsonian translocation are at risk for UPD. Abnormal phenotypes due to an imprinting effect have been found to be associated with UPD 14 and 15. The aim of the study was to refine, at the time of prenatal diagnosis, the risk for UPD 14 and 15 in a population with Robertsonian translocations involving these chromosomes.Methods Sixty-five cases of familial and de novo heterologous Robertsonian translocations involving chromosomes 14 and 15 and 18 fetuses with a normal karyotype, but conceived by a Robertsonian translocation carrier were prenatally studied to investigate the presence of UPD for chromosomes 14 and 15.Results Of the 65 Robertsonian translocation carriers, one fetus with a de novo der(14;21) showed maternal UPD 14. None of the 18 fetuses with a normal karyotype had UPD.Conclusion Our data, combined with other previous prenatal investigations provide a general risk estimate for UPD 14 and 15 of 0.6%. Nevertheless, combining our data and those previously reported, all three fetuses with UPD had a de novo Robertsonian translocation, thus suggesting a risk of UPD formation of about 3% for this specific group of translocation carriers. Copyright (C) 2004 John Wiley Sons, Ltd.

Partial trisomy 16p is a rare chromosomal anomaly in newborns: of the fewer than 30 carrier patients so far reported, most were born to parents with a balanced translocation involving the p arm of chromosome 16.1Pure partial trisomy 16p has been reported in seven patients,2–6 three of whom (all showing behavioural problems with autistic traits) carried a tandem duplication of the (16)(p11.2–p12) region4,6; minor dysmorphisms were reported in only one patient.4Linkage studies indicated chromosome 16p as a major location for autism susceptibility genes,7 while association was reported between autistic traits and attention deficit or hyperactivity disorders mapping to the 16p13 band.8 In addition TSC2, one of the genes responsible for tuberous sclerosis, a syndrome often associated with autistic traits, maps to the same cytogenetic band.9We report the clinical phenotype and refined molecular cytogenetic characterisation of a patient carrying a (16)(p11.2p12.2) duplication. By extending the FISH analysis to a previously described patient with an apparently similar chromosomal rearrangement,6 we found that low copy repeats map to the 16p11.2 and 16p12.2 duplication endpoints, suggesting non-allelic homologous recombination as the pathogenetic mechanism. This finding is consistent with the non-random occurrence of the observed chromosomal rearrangement and the high frequency of segmental duplications identified throughout chromosome 16.10–12 We also inferred from genotype-phenotype correlation studies that genes involved in autism susceptibility are located within the duplicated region.Patient 1 is a 25 year old man, the first son of unrelated parents. At the time of his birth, his mother was aged 30 and his father 29 years. He was born at term with a weight of 2.550 kg (3rd centile).The father suffered from alcohol misuse and left the family when the patient was 12 years old. Because of …