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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.

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.

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.

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.

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.

Mowat–Wilson syndrome (MWS; OMIM #235730) is a genetic condition caused by heterozygous mutations or deletions of the ZEB2 gene, and characterized by typical face, moderate-to-severe mental retardation, epilepsy, Hirschsprung disease, and multiple congenital anomalies, including genital anomalies (particularly hypospadias in males), congenital heart defects, agenesis of the corpus callosum, and eye defects. Since the first delineation by Mowat et al. [Mowat et al. (1998); J Med Genet 35:617–623], ∼179 patients with ZEB2 mutations, deletions or cytogenetic abnormalities have been reported primarily from Europe, Australia and the United States. Genetic defects include chromosome 2q21–q23 microdeletions (or different chromosome rearrangements) in few patients, and ZEB2 mutations in most. We report on clinical and genetic data from 19 Italian patients, diagnosed within the last 5 years, including six previously published, and compare them with patients already reported. The main purpose of this review is to underline a highly consistent phenotype and to highlight the phenotypic evolution occurring with age, particularly of the facial characteristics. The prevalence of MWS is likely to be underestimated. Knowledge of the phenotypic spectrum of MWS and of its changing phenotype with age can improve the detection rate of this condition. © 2009 Wiley-Liss, Inc.

Holt-Oram syndrome (HOS) (OMIM 142900) is characterized by upper-extremity malformations involving the radial, thenar, or carpal bones and a personal and/or family history of congenital heart defects (CHDs). It is inherited in an autosomal dominant manner. The TBX5 gene located on chromosome 12 (12q24.1) is the only gene currently known to be associated with HOS and is associated with variable phenotypes. We report on the clinical and molecular characterization of a HOS family with three affected individuals and a novel mutation (Lys88ter). We discuss genotype-phenotype correlations, the presence of foot anomalies in one affected individual, and the role of atypical features in HOS differential diagnosis.

Myhre syndrome is a developmental disorder characterized by reduced growth, generalized muscular hypertrophy, facial dysmorphism, deafness, cognitive deficits, joint stiffness, and skeletal anomalies. Here, by performing exome sequencing of a single affected individual and coupling the results to a hypothesis-driven filtering strategy, we establish that heterozygous mutations in SMAD4, which encodes for a transducer mediating transforming growth factor β and bone morphogenetic protein signaling branches, underlie this rare Mendelian trait. Two recurrent de novo SMAD4 mutations were identified in eight unrelated subjects. Both mutations were missense changes altering Ile500 within the evolutionary conserved MAD homology 2 domain, a well known mutational hot spot in malignancies. Structural analyses suggest that the substituted residues are likely to perturb the binding properties of the mutant protein to signaling partners. Although SMAD4 has been established as a tumor suppressor gene somatically mutated in pancreatic, gastrointestinal, and skin cancers, and germline loss-of-function lesions and deletions of this gene have been documented to cause disorders that predispose individuals to gastrointestinal cancer and vascular dysplasias, the present report identifies a previously unrecognized class of mutations in the gene with profound impact on development and growth.