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Item does not contain fulltext De novo variants are a leading cause of neurodevelopmental disorders (NDDs), but because every monogenic NDD is different and usually extremely rare, it remains a major challenge to understand the complete phenotype and genotype spectrum of any morbid gene. According to OMIM, heterozygous variants in KDM6B cause "neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities." Here, by examining the molecular and clinical spectrum of 85 reported individuals with mostly de novo (likely) pathogenic KDM6B variants, we demonstrate that this description is inaccurate and potentially misleading. Cognitive deficits are seen consistently in all individuals, but the overall phenotype is highly variable. Notably, coarse facies and distal skeletal anomalies, as defined by OMIM, are rare in this expanded cohort while other features are unexpectedly common (e.g., hypotonia, psychosis, etc.). Using 3D protein structure analysis and an innovative dual Drosophila gain-of-function assay, we demonstrated a disruptive effect of 11 missense/in-frame indels located in or near the enzymatic JmJC or Zn-containing domain of KDM6B. Consistent with the role of KDM6B in human cognition, we demonstrated a role for the Drosophila KDM6B ortholog in memory and behavior. Taken together, we accurately define the broad clinical spectrum of the KDM6B-related NDD, introduce an innovative functional testing paradigm for the assessment of KDM6B variants, and demonstrate a conserved role for KDM6B in cognition and behavior. Our study demonstrates the critical importance of international collaboration, sharing of clinical data, and rigorous functional analysis of genetic variants to ensure correct disease diagnosis for rare disorders.

Background: Mowat–Wilson syndrome (MWS; OMIM #235730) is a genetic condition caused by heterozygous mutations or deletions of the ZEB2 gene. It is characterized by moderate-severe intellectual disability, epilepsy, Hirschsprung disease and multiple organ malformations of which congenital heart defects and urogenital anomalies are the most frequent ones. To date, a clear description of the physical development of MWS patients does not exist. The aim of this study is to provide up-to-date growth charts specific for infants and children with MWS. Charts for males and females aged from 0 to 16 years were generated using a total of 2,865 measurements from 99 MWS patients of different ancestries. All data were collected through extensive collaborations with the Italian MWS association (AIMW) and the MWS Foundation. The GAMLSS package for the R statistical computing software was used to model the growth charts. Height, weight, body mass index (BMI) and head circumference were compared to those from standard international growth charts for healthy children.Results: In newborns, weight and length were distributed as in the general population, while head circumference was slightly smaller, with an average below the 30th centile. Up to the age of 7 years, weight and height distribution was shifted to slightly lower values than in the general population; after that, the difference increased further, with 50% of the affected children below the 5th centile of the general population. BMI distribution was similar to that of non-affected children until the age of 7 years, at which point values in MWS children increased with a less steep slope, particularly in males. Microcephaly was sometimes present at birth, but in most cases it developed gradually during infancy; many children had a small head circumference, between the 3rd and the 10th centile, rather than being truly microcephalic (at least 2 SD below the mean). Most patients were of slender build. Conclusions: These charts contribute to the understanding of the natural history of MWS and should assist pediatricians and other caregivers in providing optimal care to MWS individuals who show problems related to physical growth. This is the first study on growth in patients with MWS.

Morquio A syndrome (MPS IVA) is a systemic lysosomal storage disorder caused by the deficiency of N-acetylgalactosamine-6-sulfatase (GALNS), encoded by the GALNS gene. We studied 37 MPS IV A patients and defined genotype-phenotype correlations based on clinical data, biochemical assays, molecular analyses, and in silico structural analyses of associated mutations. We found that standard sequencing procedures, albeit identifying 14 novel small GALNS genetic lesions, failed to characterize the second disease-causing mutation in the 16% of the patients' cohort. To address this drawback and uncover potential gross GALNS rearrangements, we developed molecular procedures (CNV [copy-number variation] assays, QF-PCRs [quantitative fluorescent-PCRs]), endorsed by CGH-arrays. Using this approach, we characterized two new large deletions and their corresponding breakpoints. Both deletions were heterozygous and included the first exon of the PIEZO1 gene, which is associated with dehydrated hereditary stomatocitosis, an autosomal-dominant syndrome. In addition, we characterized the new GALNS intronic lesion c.245-11C>G causing m-RNA defects, although identified outside the GT/AG splice pair. We estimated the occurrence of the disease in the Italian population to be approximately 1:300,000 live births and defined a molecular testing algorithm designed to help diagnosing MPS IVA and foreseeing disease progression. © 2014 WILEY PERIODICALS, INC.

Nicolaides-Baraitser syndrome (NCBRS) is an intellectual disability (ID)/multiple congenital anomalies syndrome caused by non-truncating mutations in the ATPase region of SMARCA2, which codes for one of the two alternative catalytic subunits of the BAF chromatin remodeling complex. We analyzed 61 molecularly confirmed cases, including all previously reported patients (n = 47) and 14 additional unpublished individuals. NCBRS is clinically and genetically homogeneous. The cardinal features (ID, short stature, microcephaly, typical face, sparse hair, brachydactyly, prominent interphalangeal joints, behavioral problems and seizures), are almost universally present. There is variability however, as ID can range from severe to mild, and sparse hair may be present only in certain age groups. There may be a correlation between the severity of the ID and presence of seizures, absent speech, short stature and microcephaly. SMARCA2 mutations causing NCBRS are likely to act through a dominant-negative effect. There may be some genotype-phenotype correlations (mutations at domain VI with severe ID and seizures; mutations affecting residues Pro883, Leu946, and Ala1201 with mild phenotypes) but numbers are still too small to draw definitive conclusions.

Alterazioni del gene responsabile dell'Incontinentia pigmenti possono provocare, in età scolare, difficoltà nella lettura e nel calcolo. Lo suggerisce, per la prima volta, uno studio dell'Igb-Cnr di Napoli, in collaborazione con l'Irccs-Fondazione Santa Lucia di Roma. I risultati sono stati pubblicati su Plos One

Ophthalmo-acromelic syndrome (OAS), also known as Waardenburg Anophthalmia syndrome, is defined by the combination of eye malformations, most commonly bilateral anophthalmia, with post-axial oligosyndactyly. Homozygosity mapping and subsequent targeted mutation analysis of a locus on 14q24.2 identified homozygous mutations in SMOCI (SPARC-related modular calcium binding 1) in eight unrelated families. Four of these mutations are nonsense, two frame-shift, and two missense. The missense mutations are both in the second Thyroglobulin Type-1 (Tg1) domain of the protein. The orthologous gene in the mouse, Smoc1, shows site-and stage-specific expression during eye, limb, craniofacial, and somite development. We also report a targeted pre-conditional gene-trap mutation of SmoCI (Smoc(1tm1a)) that reduces mRNA to similar to 10% of wild-type levels. This gene-trap results in highly penetrant hindlimb post-axial oligosyndactyly in homozygous mutant animals (Smoc(1tm1a/tm1a)). Eye malformations, most commonly coloboma, and cleft palate occur in a significant proportion of Smoc(1tm1a/tm1a) embryos and pups. Thus partial loss of Smoc-1 results in a convincing phenocopy of the human disease. SMOC-1 is one of the two mammalian paralogs of Drosophila Pentagone, an inhibitor of decapentaplegic. The orthologous gene in Xenopus laevis, Smoc-1, also functions as a Bone Morphogenic Protein (BMP) antagonist in early embryogenesis. Loss of BMP antagonism during mammalian development provides a plausible explanation for both the limb and eye phenotype in humans and mice.

The screening of the usually tested CYP21 gene alterations (the large gene deletion/conversion and the P30L, IVS2-13A/C>G, Ex 3 D8nt, Ex6 cluster, I172N, V281L, 1766-1767insT, Q318X, R356Q, P453S) by means of Southern blotting and Allele-Specific PCR in an Italian population of 284 patients with 21-hydroxylase deficiency led us to characterize 461 of the total 506 different alleles (91.1%), while 45 (8,9 %) remained uncharacterized. Some incongruent genotype/phenotype correlation was also observed. In order to reduce the number of uncharacterized alleles and possibly to identify additional alterations in some patients’ alleles, we reanalysed the entire population (128 classic and 156 nonclassic forms selected for stimulated 17-HP level>10 ng/ml) by complete sequencing of the CYP21 gene, promoter included. Identified mutations were verified in the available parents to confirm allele segregation. Result a: of the 461 characterized alleles, 10 present an additional/different known mutation from that previously identified (2.1% false positive/negative results); 7 showed a conversion extending from the promoter to the P30L mutation (3 cases) or the IVS2 (4 cases). Result b: of the 34 uncharacterized alleles, 16 showed rare mutations (1 M283V, 1 R316X, 4 R341P, 4 R356Q, 1 R426H, 4 P482S, 1 R483P); 7 showed as far as we know unique mutations, 2 (W19X, L480Xfs) with an obvious implication in the phenotype, and 5 affecting residues L142, I171, R341, V358, L446 currently being studied; 11 remained uncharacterized. A total of 43 (23 of pseudogene origin) SNPs, 15 in the promoter, 3 in the 3’ UTR and 25 in introns were identified: further studies will verify their frequency in controls and the possible implication in the phenotypes. The high frequence of complex, rare or unique alleles in the Italian population underlines the importance to routinely analyse the CY21 gene by complete sequencing to avoid false/incomplete results, identify new mutations or sequence variations and to improve the genotype/phenotype correlation, genetic counselling and treatment.

Altogether 429.139 consecutive births were surveyed during the eighteen years study period by the Emilia-Romagna Registry. Among these, 2147 newborns with congenital heart defects (CHD) (prevalence 5 per 1000) were detected within the first week of life. There were 1607 isolated CHDs and 540 cases had other associated defects. During the study period an increase in prevalence/rate of CHDs was observed (from 3.1 per 1000 in 1980 to over 7 per 1000 in 1998), particularly isolated CHDs increased from 2.2 to 6 per 1000, while the prevalence rate of CHDs cases with other associated anomalies was constant ranging from 1 to 2 per 1000. The increase of isolated CHDs was due to the increased number of "minor" lesions such as ventricular (VSD) and atrial septal defect. The apparent increase in birth prevalence of CHD mainly results from improved diagnosis due to widespread use of color-doppler ecocardiography. As in other studies, a significant shift in the sex-ratio has been documented: a male predominance in transposition of great arteries, left hypoplastic heart and aortic stenosis (male/female ratio 2.2, 2.3, 4.5 respectively) were found; while VSD had a slight female excess (male/female ratio 0.96). The study confirmed that the majority of the affected parents were mothers. The recurrence risk of a cardiac defect in first degree relatives was 2.3%, while the recurrence risk of isolated conotruncal defects was 3.9%. Out of 47 cases with isolated conotruncal defects 4 had microdeletion of chromosome 22q11.2 and concerning the first degree relatives in one case the father had the deletion without CHD.

Contains fulltext : 70803.pdf (Publisher’s version ) (Closed access) Oral-facial-digital type I (OFDI) syndrome is a male-lethal X-linked dominant developmental disorder belonging to the heterogeneous group of oral-facial-digital syndromes (OFDS). OFDI is characterized by malformations of the face, oral cavity, and digits. Central nervous system (CNS) abnormalities and cystic kidney disease can also be part of this condition. This rare genetic disorder is due to mutations in the OFD1 gene that encodes a centrosome/basal body protein necessary for primary cilium assembly and for left-right axis determination, thus ascribing OFDI to the growing number of disorders associated to ciliary dysfunction. We now report a mutation analysis study in a cohort of 100 unrelated affected individuals collected worldwide. Putative disease-causing mutations were identified in 81 patients (81%). We describe 67 different mutations, 64 of which represent novel mutations, including 36 frameshift, nine missense, 11 splice-site, and 11 nonsense mutations. Most of them concentrate in exons 3, 8, 9, 12, 13, and 16, suggesting that these exons may represent mutational hotspots. Phenotypic characterization of the patients provided a better definition of the clinical features of OFDI syndrome. Our results indicate that renal cystic disease is present in 60% of cases >18 years of age. Genotype-phenotype correlation did not reveal significant associations apart for the high-arched/cleft palate most frequently associated to missense and splice-site mutations. Our results contribute to further expand our knowledge on the molecular basis of OFDI syndrome.

The first textbook of Pediatric Endocrinology in the early 1950s reported an association of neurofibromatosis type 1 (NF1) and precocious puberty (PP) and/or short stature. Recent studies have indicated that children with NF1 grow normally until puberty; thereafter height velocity and relative height (SDS or percentiles) decreases with respect to healthy peers, reaching a mean adult height close to the 25th percentile for the general population. Moreover, the percentage of patients with true short stature (3rd percentile) increases from childhood (5%) to late puberty (20-30% in literature, 18% in our study), and final height is significantly below the genetic target and predicted adult height calculated just before or at the beginning of puberty. Finally, among the shortest patients (10th percentile) there is a high incidence of severe complications, such as CNS tumors, huge plexiform neurofibromas and severe scoliosis. Precocious puberty is a frequent complication of NF1, and occurs mainly in association with optic pathway tumors (OPT); however, occasionally it has been reported in the absence of optic gliomas, probably with a similar incidence as in the general population. GnRH agonist therapy must be decided individually as in some patients further growth could be normal and/or treatment would not improve final height. In the presence of early pubertal signs, an OPT must be ruled out. In addition to PP, delayed puberty has been frequently reported in NF1. In a study of 123 girls with NF1, we found that the mean age at menarche (13.0 +/- 1.9 yr) was later than in their mothers (12.7 +/- 1.4 yr) and in the general population (12.4 +/- 1.2 yr; p0.05), with a very high incidence of delayed menarche (2 SD): 16% vs 6.8% (mothers) vs 3.4% (controls) (p0.01). In conclusion, growth and puberty present unusual patterns in NF1, often with true pathological findings increasing medical and psychological problems.

22q11.2 deletion syndrome is mainly characterized by conotruncal congenital heart defects, velopharyngeal insufficiency, hypocalcemia and a characteristic craniofacial appearance. The etiology in the majority of patients is a 3-Mb recurrent deletion in region 22q11.2. Nevertheless, recently some cases of infrequent deletions with various sizes have been reported with a different phenotype. We report on a patient with congenital heart disease (truncus arteriosus type 2) in whom a de novo 1.3-Mb 22q11.2 deletion was detected by array comparative genomic hybridization. The deletion described corresponds to an atypical and distal deletion which spans low copy repeat (LCR) 4 and is associated with breakpoint sites that do not correspond to known LCRs of 22q11.2. We examine the clinical phenotype of our case and compare our findings with those published in the literature. The most prevalent clinical features in this type of deletion are a history of prematurity, pre-natal and post-natal growth retardation, slight facial dysmorphic features, microcephaly and developmental delay, with a speech defect in particular. These are clearly different from those found in the classic 22q11.2 deletion syndrome, and we believe that the main differential diagnosis should be with Silver-Russel syndrome. In our case we observe the cardiac phenotype with truncus arteriosus communis usually seen in the classic 22q11.2 deletion syndrome, and so far associated with the TBX1 gene. Significantly, however, TBX1 is not included in our patient’s deletion. The possible roles of a position effect or other genes are discussed.

Background Epilepsy is a main feature of Mowat Wilson Syndrome (MWS), a congenital malformation syndrome caused by ZEB2 variants. The aim of this study was to investigate the long-term evolution of the electroclinical phenotype of MWS in a large population. Methods Forty-individuals with a genetically confirmed diagnosis were enrolled. Three age groups were identified (t1 = 0–4; t2 = 5–12; t3 = >13 years); clinical data and EEG records were collected, analyzed, and compared for age group. Video-EEG recorded seizures were reviewed. Results Thirty-six of 40 individuals had epilepsy, of whom 35/35 aged >5 years. Almost all (35/36) presented focal seizures at onset (mean age at onset 3.4 ± 2.3 SD) that persisted, reduced in frequency, in 7/22 individuals after the age of 13. Absences occurred in 22/36 (mean age at onset 7.2 ± 0.9 SD); no one had absences before 6 and over 16 years old. Paroxysmal interictal abnormalities in sleep also followed an age-dependent evolution with a significant increase in frequency at school age (p = 0.002) and a reduction during adolescence (p = 0.008). Electrical Status Epilepticus during Sleep occurred in 14/36 (13/14 aged 5–13 years old at onset). Seven focal seizure ictal video-EEGs were collected: all were long-lasting and more visible clinical signs were often preceded by prolonged electrical and/or subtle (erratic head and eye orientation) seizures. Valproic acid was confirmed as the most widely used and effective drug, followed by levetiracetam. Conclusions Epilepsy is a major sign of MWS with a characteristic, age-dependent, electroclinical pattern. Improvement with adolescence/adulthood is usually observed. Our data strengthen the hypothesis of a GABAergic transmission imbalance underlying ZEB2-related epilepsy.

Mowat-Wilson Syndrome (MWS) (OMIM # 235730) is a rare disorder due to ZEB2 gene defects (heterozygous mutation or deletion). The ZEB2 gene is a widely expressed regulatory gene, extremely important for the proper prenatal development. MWS is characterized by a specific facial gestalt and multiple musculoskeletal, cardiac, gastrointestinal, and urogenital anomalies. The nervous system involvement is extensive and constitutes one of the main features in MWS, heavily affecting prognosis and life quality of affected individuals. This review aims to comprehensively organize and discuss the neurological and neurodevelopmental phenotype of MWS. First, we will describe the role of ZEB2 in the formation and development of the nervous system by reviewing the preclinical studies in this regard. ZEB2 regulates the neural crest cell differentiation and migration, as well as in the modulation of GABAergic transmission. This leads to different degrees of structural and functional impairment that have been explored and deepened by various authors over the years. Subsequently, the different neurological aspects of MWS (head and brain malformations, epilepsy, sleep disorders, and enteric and peripheral nervous system involvement, as well as developmental, cognitive, and behavioral features) will be faced one at a time and extensively examined from both a clinical and etiopathogenetic point of view, linking them to the ZEB2 related pathways.

Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder characterized by prenatal and/or postnatal overgrowth, organomegaly, abdominal wall defects and tumor predisposition. CDKN1C is a maternally expressed gene of the 11p15.5 chromosomal region and is regulated by the imprinting control region IC2. It negatively controls cellular proliferation, and its expression or activity are frequently reduced in BWS. In particular, loss of IC2 methylation is associated with CDKN1C silencing in the majority of sporadic BWS cases, and maternally inherited loss-of-function variants of CDKN1C are the most frequent molecular defects of familial BWS. We have identified, using Sanger sequencing, novel CDKN1C variants in three families with recurrent cases of BWS, and a previously reported variant in a woman with recurrent miscarriages with exomphalos. Clinical evaluation of the patients showed variable manifestation of the disease. The frameshift and nonsense variants were consistently associated with exomphalos, while the missense variant caused a less severe phenotype. Pregnancy loss and perinatal lethality were found in the families segregating nonsense mutations. Intrafamilial variability of the clinical BWS features was observed, even between siblings. Our data are indicative of severe BWS phenotypes that, with variable expressivity, may be associated with both frameshift and nonsense variants of CDKN1C.

Objective Sleep disturbances are frequently reported in Mowat-Wilson Syndrome (MWS). The current study aimed to evaluate clinical and video-polysomnographic (VPSG) characteristics of the sleep architecture and abnormal electroencephalogram (EEG) patterns during sleep in MWS. Methods Sixteen individuals with MWS (range 16 months–25 years), attending the Department of Child Neurology and Psychiatry of the University of Bologna, were included. The “Sleep Disturbances Scale for Children (SDSC)” questionnaire was administered to all parents of MWS patients, and all patients underwent a VPSG recording. Results The analysis of the SDSC questionnaire revealed disturbances mainly at the sleep–wake transition and in initiating and maintaining sleep. Evaluation of sleep structure in MWS patients showed a significant reduction of total sleep time, an increase of wake after sleep onset and arousal index as compared to normal controls. An EEG pattern characterized by slowing of background activity and poverty of physiological sleep characterisitcs was observed in all patients. Moreover, in patients aged >7 years, anteriorly predominant spike and waves were observed, markedly activated by sleep configuring a sub-continuous or continuous activity. Conclusion Our data (both clinical and VPSG) documented the presence of significant and clinically relevant sleep disturbances in MWS patients. Moreover, we identified a characteristic age-dependent sleep EEG pattern that could provide a new element to assist in the management of MWS.

The basic genomic defect in Wolf–Hirschhorn syndrome (WHS), including isolated 4p deletions and various unbalanced de novo 4p;autosomal translocations and above all t(4p;8p), is heterogeneous. Olfactory receptor gene clusters (ORs) on 4p were demonstrated to mediate a group of WHS-associated t(4p;8p)dn translocations. The breakpoint of a 4-Mb isolated deletion was also recently reported to fall within the most distal OR. However, it is still unknown whether ORs mediate all 4p-autosomal translocations, or whether they are involved in the origin of isolated 4p deletions. Another unanswered question is whether a parental inversion polymorphism on 4p16 can act as predisposing factor in the origin of WHS-associated rearrangements. We investigated the involvement of the ORs in the origin of 73 WHS-associated rearrangements. No hotspots for rearrangements were detected. Breakpoints on 4p occurred within the proximal or the distal olfactory receptor gene cluster in 8 of 73 rearrangements (11%). These were five t(4p;8p) translocations, one t(4p;7p) translocation and two isolated terminal deletions. ORs were not involved in one additional t(4p;8p) translocation, in a total of nine different 4p;autosomal translocations and in the majority of isolated deletions. The presence of a parental inversion polymorphism on 4p was investigated in 30 families in which the 4p rearrangements, all de novo, were tested for parental origin (7 were maternal and 23 paternal). It was detected only in the mothers of 3 t(4p;8p) cases. We conclude that WHS-associated chromosome changes are not usually mediated by low copy repeats. The 4p16.3 inversion polymorphism is not a risk factor for their origin.

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.

The causative variant in a consanguineous family in which the three patients (two siblings and a cousin) presented with intellectual disability, Marfanoid habitus, craniofacial dysmorphisms, chronic diarrhea and progressive kyphoscoliosis, has been identified through whole exome sequencing (WES) analysis. WES study identified a homozygous DDC variant in the patients, c.1123C>T, resulting in p.Arg375Cys missense substitution. Mutations in DDC cause a recessive metabolic disorder (aromatic amino acid decarboxylase, AADC, deficiency, OMIM #608643) characterized by hypotonia, oculogyric crises, excessive sweating, temperature instability, dystonia, severe neurologic dysfunction in infancy, and specific abnormalities of neurotransmitters and their metabolites in the cerebrospinal fluid (CSF). In our family, analysis of neurotransmitters and their metabolites in patient's CSF shows a pattern compatible with AADC deficiency, although the clinical signs are different from the classic form. Our work expands the phenotypic spectrum associated with DDC variants, which therefore can cause an additional novel syndrome without typical movement abnormalities.

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).

Recently, mutations in the SMAD3 gene were found to cause a new autosomal dominant aneurysm condition similar to Loeys-Dietz syndrome (LDS), mostly with osteoarthritis, called aneurysms-osteoarthritis syndrome (AOS). Our 3-year-old propositus underwent correction of an inguinal hernia at 3 months and substitution of the ascending aorta for pathologic dilation at 12 months of age. Family history reveals aortic dilation in his mother at 30 years, death due to aortic dissection of an 18-year-old maternal aunt, surgical replacement of the ascending aorta because of aneurysm in a maternal uncle at 19 years, postpartum death of the maternal grandmother at 24 years and surgical intervention because of thoracic aortic aneurysm in a brother of the propositus' grandmother at 54 years. The affected individuals present with several other signs of connective tissue disease, but the two adult patients evaluated revealed no radiologic evidence of osteoarthritis. Molecular testing of the TGFBR1 and TGFBR2 genes, involved in LDS, resulted negative, but analysis of SMAD3 disclosed the novel heterozygous loss-of-function mutation c.1170_1179del (p.Ser391AlafsX7) in exon 9 in all affected family members, confirming the diagnosis of AOS. SMAD3 mutations should be considered in patients of all ages with LDS-like phenotypes and negative TGFBR1/2 molecular tests, especially in the presence of aortic root or ascending aortic aneurysms, even though signs of early onset osteoarthritis are absent. © 2013 Wiley Periodicals, Inc.

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.

The issue of adverse human health effects due to exposure to electromagnetic fields is still unclear, and congenital anomalies are among the outcomes that have been inconsistently associated with such exposure. We conducted a population-based, case–control study to examine the risk of congenital anomalies associated with maternal exposure to magnetic fields (MF) from high-voltage power lines during pregnancy in a community in northern Italy. We identified 228 cases of congenital malformations diagnosed in live births, stillbirths, and induced abortions among women living in the municipality of Reggio Emilia during the period 1998–2006, and a reference group of healthy newborns was matched for year of birth, maternal age, and hospital of birth. We identified maternal residence during early pregnancy and used Geographic Information System to determine whether the residences were within geocoded corridors with MF ≥0.1 µT near high-voltage power lines, then calculated the relative risk (RR) of congenital anomalies associated with maternal exposure. One case and 5 control mothers were classified as exposed, and the RR associated with MF ≥0.1 µT was 0.2 (95% CI: 0.0–2.0) after adjusting for maternal education. While small or moderate effects may have gone undetected due to low statistical power, the results of this study overall do not provide support for major effects of a teratogenic risk due to exposure to MF during early pregnancy. Bioelectromagnetics 33:405–409, 2012. © 2011 Wiley Periodicals, Inc.