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We describe the prenatal ultrasound findings and autopsy of three fetuses with multiple congenital anomalies (MCA) whose diagnostic workup suggested the same genetic etiology. We conducted a literature review to corroborate the molecular results and find evidence that the identified variants are responsible for the phenotype seen.Trio-based Exome Sequencing (ES) analysis was performed on chorionic villus samples. We reviewed available reports dealing with prenatal manifestations of genes involved in the Glycosylphosphatidylinositols (GPI) biosynthesis defects (GPIBDs).Prenatal findings shared by all the three pregnancies included facial dysmorphisms, brain malformations of the posterior fossa, skeletal and genitourinary anomalies. ES analysis identified homozygous variants of uncertain significance in PIGW in the three fetuses. Prenatal findings of the three pregnancies overlapped with those previously described for PIGW variants and with those associated with PIGN, PIGV and PIGA variants.Based on the phenotypic overlap between the prenatal findings in our three cases and other cases with pathogenic variants in other genes involved in GPIBDs, we speculate that the variants identified in the three fetuses are likely causal of their phenotype and that the PIGWclinical spectrum might extend to MCA, mainly involving brain, skeletal and genitourinary systems. Moreover, we suggest that also PIGW could be involved in Fryns/Fryns-like phenotypes.

To reach a molecular diagnosis for a family with two consecutive fetuses presenting with multiple congenital anomalies.The two fetuses underwent prenatal ultrasound, autopsy, radiologic, and genetic investigation. Genetic analysis included karyotype and array-CGH for both fetuses and trio-based whole exome sequencing (WES) only for the second fetus.WES results, initially focusing on recessive or dominant de novo variants, were negative.However, as a result of new relevant information regarding family history, the variant c.648_651dup in the PTCH1 gene was identified as causative of the fetal phenotype.This case further highlights how WES data analysis and interpretation strongly rely on family history and robust genotype-phenotype correlation. This is even more relevant in the prenatal setting, where access to fetal phenotype is limited and prenatal recognition of many morbid genes is not fully explored. We also provide a detailed description of the prenatal manifestations of Basal Cell Nevus Syndrome.

Spinal neurofibromatosis (SNF), a phenotypic subclass of neurofibromatosis 1 (NF1), is characterized by bilateral neurofibromas involving all spinal roots. In order to deepen the understanding of SNF’s clinical and genetic features, we identified 81 patients with SNF, 55 from unrelated families, and 26 belonging to 19 families with at least 1 member affected by SNF, and 106 NF1 patients aged >30 years without spinal tumors. A comprehensive NF1 mutation screening was performed using NGS panels, including NF1 and several RAS pathway genes. The main features of the SNF subjects were a higher number of internal neurofibromas (p < 0.001), nerve root swelling (p < 0.001), and subcutaneous neurofibromas (p = 0.03), while hyperpigmentation signs were significantly less frequent compared with the classical NF1-affected cohorts (p = 0.012). Fifteen patients underwent neurosurgical intervention. The histological findings revealed neurofibromas in 13 patients and ganglioneuromas in 2 patients. Phenotypic variability within SNF families was observed. The proportion of missense mutations was higher in the SNF cases than in the classical NF1 group (21.40% vs. 7.5%, p = 0.007), conferring an odds ratio (OR) of 3.34 (CI = 1.33–10.78). Two unrelated familial SNF cases harbored in trans double NF1 mutations that seemed to have a subclinical worsening effect on the clinical phenotype. Our study, with the largest series of SNF patients reported to date, better defines the clinical and genetic features of SNF, which could improve the management and genetic counseling of NF1.

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

Non-transfusion dependent thalassemia (NTDT) is an inherited hemoglobin disorder characterized by an ?/non-? globin chain imbalance of variable severity, resulting in a wide spectrum of clinical manifestations. The coinheritance of additional ? genes with a beta-thalassemia heterozygous mutation has a well-known negative effect. Triplication or quadruplication alone are mostly found by chance, but the coinheritance with ? mutations can worsen the very mild anemia to a more severe hematological and clinical phenotype causing NTDT, depending on the severity of beta mutations. We describe a case of a 38-year-old ?-thalassemia trait, pregnant woman at 33 weeks of gestation with supernumerary ?-globin genes and two ?-globin defects. J Med Cases. 2020;11(4):90-93 doi: https://doi.org/10.14740/jmc3335

Although several studies have shown the correlation between chromosomal rearrangements and the risk of developing psychotic disorders, such as schizophrenia, little attention has been given to identifying the genetic basis of pre-disposing personality so far. In this regard, a limited but significant number of studies seem to indicate an association between chromosomal anomalies and cluster A personality disorders (CAPD). Starting from the clinical description of two brothers affected by familial 16p11 deletion syndrome (OMIM #611913), both sharing cluster A and C personality traits, the aim of the present study is to critically review the literature regarding the correlation between chromosomal rearrangements and CAPD. A bibliographic search on PubMed has been conducted, and eight studies were finally included in our review. Most of the studies highlight the presence of schizotypal personality disorder in the 22q11.2 deletion syndrome, whose evolutionary course toward psychotic pictures is well-known. One study also identified a paranoid personality disorder in a patient with a deletion on chromosome 7q21.3. No studies have so far identified the presence of paranoid personality disorder in 16p11 deletion, as in the case of the two siblings we report, while its association with psychosis and autism is already known. Although further epidemiologic studies on broader populations are indicated, our observations might pave the way for the definition of new diagnostic subgroups of CAPD and psychotic disorders, in order to implement the clinical management of such complex conditions.

Neurofibromatosis type 1 (NF1) displays overlapping phenotypes with other neurocutaneous diseases such as Legius Syndrome. Here, we present results obtained using a next generation sequencing (NGS) panel including NF1, NF2, SPRED1, SMARCB1, and LZTR1 genes on Ion Torrent. Together with NGS, the Multiplex Ligation-Dependent Probe Amplification Analysis (MLPA) method was performed to rule out large deletions/duplications in NF1 gene, we validated the MLPA/NGS approach using Sanger sequencing on DNA or RNA of both positive and negative samples. In our cohort, a pathogenic variant was found in 175 patients, the pathogenic variant was observed in NF1 gene in 168 cases. A SPRED1 pathogenic variant was also found in one child and in a one year old boy, both NF2 and LZTR1 pathogenic variants were observed, in addition, we identified five LZTR1 pathogenic variants in three children and two adults. Six NF1 pathogenic variants, that the NGS analysis failed to identify, were detected on RNA by Sanger. NGS allows the identification of novel mutations in five genes in the same sequencing run, permitting unambiguous recognition of disorders with overlapping phenotypes with NF1 and facilitating genetic counseling and a personalized follow-up.

Neurofibromatosis type 1 (NF1) displays overlapping phenotypes with other neurocutaneous diseases such as Legius Syndrome. Here, we present results obtained using a next generation sequencing (NGS) panel including NF1, NF2, SPRED1, SMARCB1, and LZTR1 genes on Ion Torrent. Together with NGS, the Multiplex Ligation-Dependent Probe Amplification Analysis (MLPA) method was performed to rule out large deletions/duplications in NF1 gene; we validated the MLPA/NGS approach using Sanger sequencing on DNA or RNA of both positive and negative samples. In our cohort, a pathogenic variant was found in 175 patients; the pathogenic variant was observed in NF1 gene in 168 cases. A SPRED1 pathogenic variant was also found in one child and in a one year old boy, both NF2 and LZTR1 pathogenic variants were observed; in addition, we identified five LZTR1 pathogenic variants in three children and two adults. Six NF1 pathogenic variants, that the NGS analysis failed to identify, were detected on RNA by Sanger. NGS allows the identification of novel mutations in five genes in the same sequencing run, permitting unambiguous recognition of disorders with overlapping phenotypes with NF1 and facilitating genetic counseling and a personalized follow-up.

Interest in α-globin point mutations has increased in the past few years because nondeletional variations can affect protein function and stability, giving rise to hemoglobin (Hb) variants that present a wide spectrum of phenotypes, from asymptomatic forms to hemolytic anemia. We describe a novel α1-globin gene variant, which we have named Hb Milano [α109(G16)Leu→Pro (CTG>CCG); HBA1: c.329T>C]. We performed high performance liquid chromatography (HPLC) to carry out Hb analysis, capillary electrophoresis (CE) for Hb separation and quantitation of Hb subtypes, two tests on stroma-free lysates for evaluating Hb stability, multiplex ligation-dependent probe amplification (MLPA) to detect deletions/duplications within the α gene cluster and Sanger sequencing of the α-globin genes. No abnormal Hb variants were identified by HPLC and CE. Isopropanol and stability tests were negative. The peripheral blood film showed no inclusions such as Hb H or Heinz bodies. Multiplication ligation-dependent probe amplification of the α-globin gene cluster detected a heterozygosity for the -α3.7 (rightward) deletion. Direct sequencing of the α-globin genes identified the Hb Milano variant on the HBA1 gene. No mutations were found on the HBA2 gene. The clinical consequences of the Hb Milano variant differ based on the genotype: according to our study, the hematological parameters range from a marked microcythemia with mild anemia if the variant is coinherited with an α gene deletion, to mild microcytosis when the variant is not associated with α gene deletions.

The occurrence of optic pathway gliomas (OPGs) in children with neurofibromatosis type 1 (NF1) still raises many questions regarding screening and surveillance because of the lack of robust prognostic factors. Recent studies of an overall cohort of 381 patients have suggested that the genotype may be the main determinant of the development of OPG, with the risk being higher in patients harbouring NF1 mutations in the 5&rsquo, tertile and the cysteine/serine-rich domain. In an attempt to confirm this hypothesis, we used strict criteria to select a large independent cohort of 309 NF1 patients with defined constitutional NF1 mutations and appropriate brain images (255 directly enrolled and 54 as a result of a literature search). One hundred and thirty-two patients had OPG and 177 did not. The association of the position (tertiles and functional domains) and type of NF1 mutation with the development of OPG was analysed using the &chi, 2 test and Fisher&rsquo, s exact probability test, odds ratios (ORs) with 95% confidence intervals were calculated, and Bonferroni&rsquo, s correction for multiple comparisons was applied, multiple logistic regression was also used to study genotype&ndash, phenotype associations further. Our findings show no significant correlation between the site/type of NF1 mutation and the risk of OPG, and thus do not support the hypothesis that certain constitutional mutations provide prognostic information in this regard. In addition, we combined our cohort with a previously described cohort of 381 patients for a total of 690 patients and statistically re-analysed the results. The re-analysis confirmed that there were no correlations between the site (tertile and domain) and the risk of OPG, thus further strengthening our conclusions.

Interest in α-globin point mutations has increased in the past few years because nondeletional variations can affect protein function and stability, giving rise to hemoglobin (Hb) variants that present a wide spectrum of phenotypes, from asymptomatic forms to hemolytic anemia. We describe a novel α1-globin gene variant, which we have named Hb Milano [α109(G16)Leu→Pro (C

INTRODUCTION Spinal Neurofibromatosis (SNF), a distinct clinical entity of NF1, characterized by bilateral neurofibromas involving all spinal roots and a few, if any, cutaneous manifestations, entails greater morbidity than the classical form of disease. Nevertheless, there are no reliable patterns to sort out patients at risk for developing SNF. MATERIALS AND METHODS We investigated 19 NF1 families with at least one SNF member, 37 sporadic SNF patient and 100 NF1 patients with classical form of disease. We applied Targeted NGS using a panel consisting of 139 genes encoding RAS pathway effectors, neurofibromin interactors and genes mapping at 17q11.2 region. RESULTS In SNF patients we found a higher percentage of missense (21% versus 8%, p=0 0.016, OR 3.13 (95% CI 01.1 -8.2) and a lower percentage of nonsense NF1 mutations (12.5% versus 28%,, p= 0.026, OR 0.36 (95% CI 0.14–0.9) than in classical NF1 cases. Furthermore, we evaluated rare variants with damaging potential predictors in genes of the RAS pathway and in neurofibromin interactors. In more than one sporadic case possible pathogenic variants were found in LIMK2 (neurofibromin interactor), RASAL1, RASAL3, SOS1, A2ML1, MAP3K1 (RAS pathway effectors), while in more than one SNF family were detected RASAL1, RASAL3, MAP3K1 genes variations. CONCLUSIONS Our results confirm the correlation between NF1 genotype and SNF phenotype as previously reported (Ruggieri, 2015), suggesting that neurofibromin gain-of-functions mutations are associated to SNF. In some patients, the co-occurrence of potential pathogenic variants in NF1 related genes with severe phenotypes was detected supporting their role as modifier genes and promising therapeutic targets.

We read with great interest the research of Wang and colleagues who found a high prevalence ( n = 9/13, 69%) of human epidermal growth factor receptor (HER)2-enriched tumors in neurofibromin ( NF )1-altered breast cancers ([1][1]). The notion that NF1 mutations and HER2 copy number (CN) gain/

The 5q14.3 duplication is a rare condition comprising speech and developmental delay, microcephaly, and mild ventriculomegaly. The region 5q14.3 contains several genes but the predominant role for the onset of the neurodevelopmental phenotype has been attributed to MEF2C. We describe the prenatal identification of 5q14.3 duplication, including MEF2C, in a monochorionic twin pregnancy with corpus callosum anomalies, confirmed by autopsy. To the best of our knowledge, this cerebral finding has been observed for the first time in 5q14.3 duplication patients, possibly widening the neurological picture of this scarcely known syndrome. A pathogenetic role of MEF2C overexpression in brain development may be assumed, but further studies are needed.

BACKGROUND AND PURPOSE: Agenesis of the corpus callosum, even when isolated, may be characterized by anatomic variability. The aim of this study was to describe the types of other forebrain commissures in a large cohort of randomly enrolled fetuses with apparently isolated agenesis of the corpus callosum at prenatal MR imaging. MATERIALS AND METHODS: All fetuses with apparent isolated agenesis of the corpus callosum undergoing prenatal MR imaging from 2004 to 2014, were evaluated for the presence of the anterior or a vestigial hippocampal commissure assessed in consensus by 2 pediatric neuroradiologists. RESULTS: Overall, 62 cases of agenesis of the corpus callosum were retrieved from our data base. In 3/62 fetuses (4.8%), no forebrain commissure was visible at prenatal MR imaging, 23/62 fetuses (37.1%) presented with only the anterior commissure, and 20/62 fetuses (32.3%) showed both the anterior commissure and a residual vestigial hippocampal commissure, whereas in the remaining 16/62 fetuses (25.8%), a hybrid structure merging a residual vestigial hippocampal commissure and a rudiment of the corpus callosum body was detectable. Postnatal MR imaging, when available, confirmed prenatal forebrain commissure findings. CONCLUSIONS: Most fetuses with apparent isolated agenesis of the corpus callosum showed at least 1 forebrain commissure at prenatal MR imaging, and approximately half of fetuses also had a second commissure: a vestigial hippocampal commissure or a hybrid made of a hippocampal commissure and a rudimentary corpus callosum body. Whether such variability is the result of different genotypes and whether it may have any impact on the long-term neurodevelopmental outcome remains to be assessed. AC : anterior commissure ACC : agenesis of the corpus callosum CC : corpus callosum GA : gestational age HC : hippocampal commissure HS : hybrid structure

Rhombencephalosynapsis is a hindbrain malformation characterized by complete or partial absence of the cerebellar vermis, with varying degrees of midline continuity of cerebellar hemispheres, dentate nuclei, and in some patients of the superior cerebellar peduncles. Partial rhombencephalosynapsis usually consists of a segmental deficiency of posterior vermis. Although prenatal diagnosis of rhombencephalosynapsis is feasible by ultrasound and magnetic resonance imaging both, partial rhombencephalosynapsis might be difficult to detect, especially at an early gestational age. We report two fetal cases of atypical partial rhombencephalosynapsis, with deficiency of anterior vermis, detected by prenatal magnetic resonance imaging at 21st and 23rd week of gestation, respectively.

Genetic analysis of Neurofibromatosis type 1 (NF1) may facilitate the identification of patients in early phases of the disease. Here, we present an overview of our diagnostic research spanning the last 11 years, with a focus on the description of 225 NF1 mutations, 126 of which are novel, found in a series of 607 patients (513 unrelated) in Italy. Between 2003 and 2013, 443 unrelated patients were profiled by denaturing high pressure liquid chromatography (DHPLC) analysis of 60 amplicons derived from genomic NF1 DNA and subsequent sequencing of heterozygotic PCR products. In addition, a subset of patients was studied by multiplex ligation‐dependent probe amplification (MLPA) to identify any duplications, large deletions or microdeletions present at the locus. Over the last year, 70 unrelated patients were investigated by MLPA and sequencing of 22 amplicons spanning the entire NF1 cDNA. Mutations were found in 70% of the 293 patients studied by DHPLC, thereby fulfilling the NIH criterion for the clinical diagnosis of NF1 (detection rate: 70%); furthermore, 87% of the patients studied by RNA sequencing were genetically characterized. Mutations were also found in 36 of the 159 patients not fulfilling the NIH clinical criteria. We confirmed a higher incidence of intellectual disability in patients harboring microdeletion type 1 and observed a correlation between a mild phenotype and the small deletion c.2970_2972delAAT or the missense alteration in amino acid residue 1809 (p.Arg1809Cys). These data support the use of RNA‐based methods for genetic analysis and provide novel information for improving the management of symptoms in oligosymptomatic patients.

Correction to: Journal of Human Genetics advance online publication 27 July 2017; https://doi.org/10.1038/jhg.2017.78.

Neurofibromatosis type 1 (NF1) is an hereditary disorder characterized by abnormal proliferation of multiple tissues of neural crest origin, and presents mainly with multiple cafe-au-lait macules, axillary freckling and neurofibromas. Choroidal involvement in NF1 patients has been studied, thanks to the development of non-invasive tools such as infrared monochromatic light during fundus examination, which showed bright patchy lesions consistent with choroidal nodules. Choroidal abnormalities identified with near-infrared reflectance have reported with a frequency of up to 100% in NF1, and have been recently been proposed as a novel diagnostic criterion for NF1. Legius syndrome can be clinically indistinguishable from NF1 and results in a small percentage of individuals being misdiagnosed. We investigated the presence of choroidal abnormalities in Legius syndrome to determine their specificity to NF1 and their potential usefulness as a novel diagnostic criterion for NF1. We examined the fundus of 16 eyes by confocal scanning laser ophthalmoscopy with infrared monochromatic light in eight patients with molecularly confirmed Legius syndrome. No abnormalities were observed, confirming the diagnostic value of choroidal abnormalities for the diagnosis of NF1.

Arhinia, or absence of the nose, is a rare malformation of unknown etiology that is often accompanied by ocular and reproductive defects. Sequencing of 40 people with arhinia revealed that 84% of probands harbor a missense mutation localized to a constrained region of SMCHD1 encompassing the ATPase domain. SMCHD1 mutations cause facioscapulohumeral muscular dystrophy type 2 (FSHD2) via a trans-acting loss-of-function epigenetic mechanism. We discovered shared mutations and comparable DNA hypomethylation patterning between these distinct disorders. CRISPR/Cas9-mediated alteration of smchd1 in zebrafish yielded arhinia-relevant phenotypes. Transcriptome and protein analyses in arhinia probands and controls showed no differences in SMCHD1 mRNA or protein abundance but revealed regulatory changes in genes and pathways associated with craniofacial patterning. Mutations in SMCHD1 thus contribute to distinct phenotypic spectra, from craniofacial malformation and reproductive disorders to muscular dystrophy, which we speculate to be consistent with oligogenic mechanisms resulting in pleiotropic outcomes.

Hypochondroplasia (HCH) is a genetic skeletal dysplasia, inherited in an autosomal dominant fashion. About 50–70% of HCH patients have a mutation in FGFR3 gene and in the majority of cases it is a de novo mutation. Recent magnetic resonance imaging studies on relative large cohorts of HCH patients have showed a central nervous system involvement with a high incidence of characteristic temporal lobe and hippocampal abnormalities. To the best of our knowledge, this report shows the first magnetic resonance imaging prenatal detection of characteristic brain anomalies in a case of HCH, molecularly confirmed through postnatal FGFR3 analysis. © 2014 John Wiley & Sons, Ltd.

See also Mannucci PM. Red cells playing as activated platelets in thalassemia intermedia. This issue, pp 2149–51. Summary. Background: Hypercoagulability in splenectomized patients with thalassemia intermedia (TI) has been extensively evaluated. However, clinical and laboratory characteristics of patients who eventually develop overt thromboembolic events (TEE) are poorly studied. Patients/Methods: Three Groups of TI patients (n = 73 each) were retrospectively identified from a registry involving six centers across the Middle East and Italy: Group I, all splenectomized patients with a documented TEE; Group II, age- and sex-matched splenectomized patients without TEE; and Group III, age- and sex-matched non-splenectomized patients without TEE. Retrieved data included demographics, laboratory parameters, clinical complications, and received treatments that may influence TEE development, and reflected the period prior to TEE occurrence in Group I. Results: The mean age of Group I patients at development of TEE was 33.1 ± 11.7 years, with a male to female ratio of 33:40. TEE were predominantly venous (95%) while four patients (5%) had documented stroke. Among studied parameters, Group I patients were more likely to have a nucleated red blood cell (NRBC) count ≥ 300 × 106 L−1, a platelet count ≥ 500 × 109 L−1 and evidence of pulmonary hypertension (PHT), or be transfusion naive. The median time to thrombosis following splenectomy was 8 years. Patients with an NRBC count ≥ 300 × 106 L−1, a platelet count ≥ 500 × 109 L−1, or who were transfusion naive also had a shorter time to thrombosis following splenectomy. Conclusion: Splenectomized TI patients who will develop TEE may be identified early on by high NRBC and platelet counts, evidence of PHT, and transfusion naivety.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare and lethal developmental disorder of the lung that affect both acinar structure and the intrinsic pulmonary vasculature. We report prenatal and postnatal imaging with histopathological findings of this rare condition. We, first, describe MR imaging features and discuss its role in prenatal imaging.

Ganglionic eminence (GE) is a transient fetal brain structure that harvests a significant amount of precursors of cortical GABA-ergic interneurons. Prenatal magnetic resonance (MR) imaging features of GE anomalies (i.e., cavitations) have already been reported associated with severe micro-lissencephaly. The purpose of this report was to illustrate the MR imaging features of GE anomalies in conditions other than severe micro-lissencephalies. Among all the fetuses submitted to prenatal MR imaging at our center from 2005 to 2014, we collected eight cases with GE anomalies and only limited associated brain anomalies. The median gestational age at the time of MR imaging was 21 weeks ranging from 19 to 29 weeks. Two senior pediatric neuroradiologists categorized the anomalies of the GE region in two groups: group one showing cavitation in the GE region and group two showing enlarged GE region. For each fetal case, associated cranial anomalies were also reported. Five out of the eight cases were included in group one and three in group two. Besides the GE region abnormality, all eight cases had additional intracranial anomalies, such as mild partial callosal agenesis, vermian hypoplasia and rotation, cerebellar hypoplasia, ventriculomegaly, enlarged subarachnoid spaces, molar tooth malformation. Ultrasound generally detected most of the associated intracranial anomalies, prompting the MR investigation; on the contrary in none of the cases, GE anomalies had been detected by ultrasound. Our observation expands the spectrum of human GE anomalies, demonstrating that these may take place also without associated severe micro-lissencephalies.

Prenatal features of isolated cerebellar haemorrhagic lesions have not been sufficiently characterised. We aimed to better define their MR imaging characteristics, documenting the location, extension, evolution stage and anatomic sequelae, and to better understand cerebellar haemorrhage pathophysiology. We screened our foetal MR imaging database (3200 cases) for reports of haemorrhagic lesions affecting only the cerebellum (without any supratentorial bleeding or other clastic lesions), defined as one of the following: T2-weighted hypointense or mixed hypo-/hyperintense signal; rim of T2-weighted hypointense signal covering the surface of volume-reduced parenchyma; T1-weighted hyperintense signal; increased DWI signal. Seventeen cases corresponded to the selection criteria. All lesions occurred before the 26th week of gestation, with prevalent origin from the peripheral-caudal portion of the hemispheres and equal frequency of unilateral/bilateral involvement. The caudal vermis appeared affected in 2/3 of cases, not in all cases confirmed postnatally. Lesions evolved towards malformed cerebellar foliation. The aetiology and pathophysiology were unknown, although in a subset of cases intra- and extracranial venous engorgement seemed to play a key role. Onset from the peripheral and caudal portion of the hemispheres seems characteristic of prenatal cerebellar haemorrhagic lesions. Elective involvement of the peripheral germinal matrix is hypothesised. • The cerebellum can be vulnerable to bleeding during foetal development. • Isolated cerebellar haemorrhages can be seen on prenatal MRI. • In our cohort, isolated foetal cerebellar haemorrhages occurred before the 26th gestational week. • Haemorrhagic lesions happening in utero could look like malformations on post-natal MRI. • Venous engorgement could have a role in causing cerebellar haemorrhagic lesions.

Hypochondroplasia (HCH) is a genetic skeletal dysplasia, inherited in an autosomal dominant fashion. About 50-70% of HCH patients have a mutation in FGFR3 gene and in the majority of cases it is a de novo mutation. Recent magnetic resonance imaging studies on relative large cohorts of HCH patients have showed a central nervous system involvement with a high incidence of characteristic temporal lobe and hippocampal abnormalities. To the best of our knowledge, this report shows the first magnetic resonance imaging prenatal detection of characteristic brain anomalies in a case of HCH, molecularly confirmed through postnatal FGFR3 analysis.

Few cases of mosaicism involving a normal cell line and an unbalanced autosomal translocation have been reported so far. No cases of partial trisomy 13 and partial monosomy 8 mosaicism have been published. The authors report a new patient with partial trisomy 13 and partial monosomy 8 mosaicism due to an unbalanced translocation (13/8). A postzygotic mitotic exchange of nonhomologous chromatids followed by the loss of one of the translocated chromatids has been hypothesized as the potential underlying mechanism. Although a clear correlation of the clinical features of the patient with his chromosomal abnormality can be challenging, dysmorphic features, hyperactive behavior, moderate developmental delay, and tonic-clonic seizures can be interpreted as secondary to the particular genotype of the patient. These findings should be taken into account in the diagnostic process of patients presenting with multiple congenital anomalies and/or mental retardation conditions.

Clinical genetics is the discipline which deals with hereditary diseases and implies a strong diagnostic approach without which all information conveyed by the counselling process has insecure foundation and the estimation of recurrence risk within the family may be misinterpreted. The ideal time for having a genetic counselling is before pregnancy. In this case the subsequent genetic evaluation and counselling may lead to the definition of a reproductive risk and thus to an early, even prenatal diagnosis in the offspring. However in some cases genetic conditions are under-recognized in the adult age and people are not referred to genetic services. This happens because of a variety of reasons both related to the health professionals (non-habit to the pre-conceptional genetic counselling, lack of attention/information on genetic themes, diagnostic difficulties related to the variability of gene expression, incomplete penetrance and late onset conditions) and to the patient’s psychological status, for example denial mechanisms. Six cases are presented in which a correct diagnosis in one parent was reached after the identification of a rare disease in the child with severe psychological and social consequences. Obviously the lack of the correct diagnosis in the parent implied that he/she was not only uninformed about the presence of the increased reproductive risk, but also unaware of the clinical variability of the condition. Anger and frustration was present in all affected parents asking why their family doctors never suspected the condition which, afterwards, seemed quite obvious. Legal actions were started in two out of six cases. Establishing the correct diagnosis, or at least the suspicion of a genetic disease, is therefore a priority that may be not considered an exclusive responsibility of the geneticist, but ideally involves other medical figures, for example primary care physician, pediatricians or other medical specialists who see a patient with a condition.

β thalassemia intermedia (TI) is a clinical definition referring to a heterogeneous group of hereditary anemias resulting from defective β chain production, an α/β globin chain imbalance, and anemia that lie in severity between that of thalassemia minor and the transfusion-dependent thalassemia

Transfusion-independent patients with β thalassemia intermedia (TI) experience a variety of clinical complications attributed to the underlying ineffective erythropoiesis and subsequent anemia, hemolysis, and iron overload. Growth differentiation factor-15 (GDF-15) was recently investigated as a marker of ineffective erythropoiesis in several anemias. In this work, we evaluated GDF-15 levels in 55 patients with TI. The mean GDF-15 level was 25,197.8±16,208.9pg/ml which is lower than values reported for patients with thalassemia major, yet considerably higher than those reported in patients with other congenital and acquired anemias. GDF-15 levels were significantly higher in splenectomized compared to non-splenectomized patients and correlated with anemia, markers of iron overload, and a pre-defined clinical severity score. Further studies are needed to determine the practical utility of GDF-15 measurement and its potential to reflect the severity of the clinical course in TI patients.

International audience; Cardiac involvement in patients with thalassemia intermedia (TI) is characterized by a high-output state and pulmonary hypertension, with systolic left ventricle function usually being preserved. Myocardial iron overload in patients with TI has not been extensively studied. We conducted a cross-sectional study of 49 Italian patients with TI. Patient charts were reviewed and data collected for transfusion and iron chelation history, status of the spleen, and comorbid illnesses or infections. Blood samples were obtained for assessment of hemoglobin, serum ferritin, and liver enzyme levels. Doppler echocardiography was done for all patients. Cardiac and hepatic iron levels were measured by magnetic resonance imaging T2*. The mean age was 40.5 ± 8.3 years, with a male to female ratio of 29:20. A total of 34 (69.4%) patients were splenectomized, and four patients had evidence of hepatitis C infection. Around 45% of patients were transfusion naïve while the rest received infrequent (47%) or regular (8%) transfusions. A total of 31 (63.3%) patients were maintained on iron chelation therapy. None of the patients had evidence of heart failure. Mean serum ferritin and liver iron concentration were 1,060.2 ng/ml and 8.2 mg Fe per gram dry weight, respectively. None of the patients had evidence of cardiac iron overload (mean cardiac T2* = 38.7 ± 11.0 ms). There were no statistically significant correlation between cardiac T2* values and liver iron concentration, serum ferritin, or any patient, disease, or treatment-related parameters. Patients with TI show absence of cardiac iron overload even if hepatic iron accumulation is significant.

Abstract 4763 Background. Sickle Cell Disease (SCD) is one of the most common severe monogenic inherited disorder worldwide characterized by the presence of hemoglobin S (HbS). HbS causes Hb polimerization leading to hemolytic anemia and vaso-occlusion due to erythrocyte rigidity, and is responsible of clinical acute events and chronic progressive multiorgan damage, which becomes evident with increasing age. The term SCD is used to refer to all the different genotypes: Sickle Cell Anemia (SCA) referring to homozygosis for βS allele; HbS/β-thalassemia, compound of β-thal and βS allele (T-SCD); and HbSC disease, owing to the coinheritance of βS and βcalleles. In Italy T-SCD is more frequent than SCA (70% vs 30% of SCD patients). Aims. This retrospective study involved 63 adult SCD patients of the Hereditary Anemia Centre of the Foundation IRCCS “Ca' Granda” Ospedale Maggiore Policlinico, in Milan, Italy. The aim was to assess and compare splenic and liver involvement in SCA and T-SCD patients. Methods. Mutation analysis of the b globin gene was performed by direct DNA sequencing by the ABI Prism 310 genetic analyzer. Clinical and hematological parameters were evaluated by routine tests and physical examination according to guidelines for SCD follow-up. Results. Sixty-three adult SCD patients, 19 SCA and 44 T-SCD patients, were evaluated. The b mutations detected in T-SCD were severe (b°) in 69.8%, and moderate or mild (b+-b++) in 30.2% of patients. The mean age of SCA patients was 36±8 and 41±11 years for T-SCD patients. For both groups the mean follow-up was 20±6 years and the mean age at the presentation to our Centre was 32±8 years. Five out of 19 (26.3%) of SCA group and 17/44 (38.6%) of T-SCD group were male. HbF mean levels were 7.7±4.9% and 10.7±7.5% respectively in SCA and T-SCD; Hb total mean levels were lower in SCA (9.2±1.2 g/dl) than in T-SCD (10.3±3.2 g/dl) patients. Comparing SCA and T-SCD patients, there was not statistically significant difference in the prevalence of clinical manifestations, except for splenic features. Splenectomy was performed in 3/19 (15.8%) SCA patients vs 23/44 (52.3%) T-SCD patients (p-value < 0.001). For the remaining patients, splenomegaly was absent in SCA, while was detected in 11/21 (52.4%) T-SCD. All SCA patients (100%) had functional asplenia, which was absent in T-SCD patients. Splenic infarctions were present in 2/16 (12.5%) SCA patients and in 6/21 (28.6%) T-SCD patients, of whom 5 had splenomegaly and one normal spleen size (pvalue Conclusions. These data suggest that T-SCD patients, particularly those with severe b mutations, have similar clinical course than SCA patients. Splenomegaly is present only in T-SCD patients and seems to induce splenic infarctions. Only SCA patients experience functional asplenia. Liver involvement, a severe complication of the adult life, is characterized in both groups by sickle cholestatic liver involvement, that can lead to liver failure and, in some cases, to liver transplantation. Exchange transfusion, if started early at the diagnosis of liver disease, can avoid liver transplantation in some selected cases. Disclosures: Cappellini: Novartis Pharmaceuticals: Honoraria, Research Funding.

Concomitant HCV infection and iron overload are responsible for increased risk of chronic liver disease (CLD) in thalassemic patients. Liver biopsy remains so far the gold standard to assess histological activity and iron burden, although it is an invasive method poorly accepted by patients and it can not be repeated regularly. MRI ferriscan is a good tool recently introduced to estimate hepatic and cardiac iron load but it does not allow to evaluate the tissue liver damage. Transient Elastography (TE) is a new non-invasive device that measures liver stiffness (LSM) and assesses liver damage, namely fibrosis and cirrhosis. TE use in thalassemic patients is still limited, thus the aim of this study was to evaluate LSM by TE in a cohort of adults affected by Thalassemia Intermedia (TI) in order to assess the liver damage. Ninety consecutive TI patients followed at a single Italian tertiary Thalassemia Care Center in Milan were enrolled in this study. Eighteen patients (20%) were regularly transfused, 28 (31%) occasionally transfused, 44 (49%) never transfused. No one patient was on regular chelation treatment. Table 1 summarizes the demographic, clinical and laboratory features at time of TE evaluation. Males n° (%) 43 (47.8%) LDH U/l * 570±296 *Mean ± SD TE (FibroScan®) was performed according to Fraquelli et al. and was expressed in KPa. Only the examination with at least 10 validated measurements, a success rate greater than 60% and the interquartile range of all validated measurements lower than 30% of the mean value were considered reliable. TE cut-off to diagnose different stages of hepatic fibrosis was >7.9 kPa for F>2, >10.3 for F>3 and >11.9 for F>4 (cirrhosis). Forty-eight patients underwent T2* Magnetic Resonance Imaging (MRI) in order to estimate liver iron concentration (LIC). Forty-three patients (48%) had normal TE values (TE≤5.0 KPa), 35 (39%) had F>1 (5.02, 2 (2%) had F>3, 5 (6%) had F>4. Mean ± SD TE value was 6.0±2.8 KPa. A significant correlation (p Table 2 describes TE results based on transfusion regimen, ferritin levels and HCV-RNA positivity. TE (mean ± SD) Transfusion regimen Never 5.4±2.2 Occasionally 6.4±3.5 Regular 7.2±2.9 Ferritin levels ng/ml 1000 8.2±3.4 HCV-RNA Positive 7.7±2.9 Negative 5.9±2.8 Moreover, splenectomy (p=0.014) and cholecystectomy (p

Introduction: β-thalassemia intermedia (TI) patients either present with a severe disease between the ages of 2–6 years, or remain asymptomatic until they present with a milder disease during adult life. With the advances in assisted reproductive technology and medical management, pregnancy has become possible in most TI cases. Spontaneous abortions, intrauterine growth restriction (IUGR), and preterm labor are complications that face women with TI. This study aimed at evaluating the pregnancy outcome of women with TI in two tertiary care centers, one in Lebanon and another in Italy. Methods: Patient databases at the Chronic Care Center, Lebanon and at the Hereditary Anemia Center in Milan, Italy were reviewed. Maternal and neonatal charts of women with TI and documented pregnancy were identified and reviewed using a specially formulated questionnaire that focused on demographic characteristics (maternal age, gestational age (GA), parity, and abortions), past medical history related to thalassemia, course of pregnancy and complications, intrapartum events and neonatal outcome. Patients were then contacted by phone for any missing information. Results: A total of 44 pregnant TI patients, 11 in Lebanon and 33 in Italy were identified. Mean age at diagnosis of TI was 9.2 ± 9.7 years (range 1–42 years) with 34 (77.3%) splenectomized patients identified. Fourteen patients (31.8%) were frequently transfused, 25 (56.8%) occasionally transfused and only 4 (9.1%) never transfused. Mean age at pregnancy was 29.5 ± 3.9 years (range 21–38 years) with 11 patients (28.2%) receiving the first transfusion during pregnancy. Twenty eight patients were on chelation therapy: 21 (48.8%) received deferioxamine, 4 (9.3%) deferiprone and 3 (7%) deferasirox. After excluding 4 women with ongoing pregnancies, information on 79 pregnancies, all spontaneous, were available, 30 from Lebanon and 49 from Italy. These resulted in 60 live births (75.9%), 17 abortions (21.5%), and 2 intrauterine fetal deaths (2.5%), at 26 and 36 weeks of gestation, respectively. Three patients (7.5%) had recurrent abortions (≥3 abortions). Of women whose pregnancies progressed beyond 20 weeks of gestation (n=62), the following obstetrical complications were encountered: preterm delivery Conclusions: Preterm delivery complicates 29% of pregnancies with TI which are at a 23% risk of IUGR. Cesarean delivery is the most common route of delivery in these patients (70.9%). As with any chronic disease affecting different organs, TI presents a challenge for pregnant patients, their fetuses and physicians and requires close monitoring for any events that might compromise the patient or the newborn. Further studies comprising more patients need to be carried out to determine the effects of splenectomy and transfusions during pregnancy and on the outcome of those pregnancies.

Background: The reproductive and sexual health issues concerning persons affected by thalassemia major are complex. The study was planned to investigate the psychological attitudes and expectations in a group of thalassemic pregnant women attending hospital for regular blood transfusion. Methods: This is a preliminary cross-sectional study involving 20 consecutive thalassemic patients and a control group of 42 healthy pregnant volunteers. The personality structure was evaluated by Rorschach′s test and the presence of psychic symptoms by SCL-90-R and STAI. Results: Narcissism and sexual traumas are significantly higher in thalassemic women with respects to the control group. Also the percent of anxiety and depression observed with the SCL-90-R was significantly higher than in control group (45% vs. 3%, p < 0.001, mean and SD values are 1.65 ΁ 0.15 vs. 0.43 ± 0.18 for anxiety; 55% vs. 12%, p < 0.001, mean and SD values are 1.76 ± 0.18 vs. 0.85 ± 0.25 for depression). The score observed with the STAI shows that the trait of anxiety differed between thalassemic pregnant women and the control group, even though the score values aren′t pathologic in neither group (87% vs. 42%, p < 0.05, mean and SD values are 33 ± 0.8 vs. 22 ± 0.2). Conclusions: This study addresses the need for developing, implementing and evaluating proper psychological support for thalassemic pregnant patients. Moreover, psychological screening and support prior to, during and following pregnancy would be indicated.

BACKGROUND AND PURPOSE: In several countries, laws and regulations allow abortion for medical reasons within 24–25 weeks of gestational age. We investigated the diagnostic value of prenatal MR imaging for brain malformations within 25 weeks of gestational age. MATERIALS AND METHODS: We retrospectively included fetuses within 25 weeks of gestational age who had undergone both prenatal and postnatal MR imaging of the brain between 2002 and 2014. Two senior pediatric neuroradiologists evaluated prenatal MR imaging examinations blinded to postnatal MR imaging findings. With postnatal MR imaging used as the reference standard, we calculated the sensitivity, specificity, positive predictive value, and negative predictive value of the prenatal MR imaging in detecting brain malformations. RESULTS: One-hundred nine fetuses (median gestational age at prenatal MR imaging: 22 weeks; range, 21–25 weeks) were included in this study. According to the reference standard, 111 malformations were detected. Prenatal MR imaging failed to detect correctly 11 of the 111 malformations: 3 midline malformations, 5 disorders of cortical development, 2 posterior fossa anomalies, and 1 vascular malformation. Prenatal MR imaging misdiagnosed 3 findings as pathologic in the posterior fossa. CONCLUSIONS: The diagnostic value of prenatal MR imaging between 21 and 25 weeks9 gestational age is very high, with limitations of sensitivity regarding the detection of disorders of cortical development.