Showing papers in "American Journal of Medical Genetics Part A in 2005"

Clinical Features of 78 Adults With 22q11 Deletion Syndrome

Abstract: 22q11 Deletion Syndrome (22q11DS) is a common microdeletion syndrome with multisystem expression. Phenotypic features vary with age, ascertainment, and assessment. We systematically assessed 78 adults (36 M, 42 F; mean age 31.5, SD 10.5 years) with a 22q11.2 deletion ascertained through an adult congenital cardiac clinic (n = 35), psychiatric-related sources (n = 39), or as affected parents of subjects (n = 4). We recorded the lifetime prevalence of features requiring attention, with 95% confidence intervals (CI) not overlapping zero. Subtle learning difficulties, hypernasality and facial gestalt were not included. We investigated ascertainment effects using non-overlapping subgroups ascertained with tetralogy of Fallot (n = 31) or schizophrenia (n = 31). Forty-three features met inclusion criteria and were present in 5% or more patients, including several of later onset (e.g., hypothyroidism, cholelithiasis). Number of features per patient (median 9, range 3-22) correlated with hospitalizations (P = 0.0002) and, when congenital features were excluded, with age (P = 0.02). Adjusting for ascertainment, 25.8% (95% CI, 9.5-42.1%) of patients had cardiac anomalies and 22.6% (95% CI, 7.0-38.2%) had schizophrenia. Ascertainment subgroups were otherwise similar in median number and prevalence of features. Non-characteristic features are common in 22q11DS. Adjusting for ascertainment effects is important. Many treatable conditions may be anticipated and features may accumulate over time. The results have implications for clinical assessment and management, genetic counseling and research into pathophysiological mechanisms.

Precision and Error of Three-dimensional Phenotypic Measures Acquired from 3dMD Photogrammetric Images

Abstract: The genetic basis for complex phenotypes is currently of great interest for both clinical investigators and basic scientists. In order to acquire a thorough understanding of the translation from genotype to phenotype, highly precise measures of phenotypic variation are required. New technologies, such as 3D photogrammetry are being implemented in phenotypic studies due to their ability to collect data rapidly and non-invasively. Before these systems can be broadly implemented, the error associated with data collected from images acquired using these technologies must be assessed. This study investigates the precision, error, and repeatability associated with anthropometric landmark coordinate data collected from 3D digital photogrammetric images acquired with the 3dMDface System. Precision, error due to the imaging system, error due to digitization of the images, and repeatability are assessed in a sample of children and adults (n = 15). Results show that data collected from images with the 3dMDface System are highly repeatable and precise. The average error associated with the placement of landmarks is sub-millimeter; both the error due to digitization and due to the imaging system are very low. The few measures showing a higher degree of error include those crossing the labial fissure, which are influenced by even subtle movement of the mandible. These results suggest that 3D anthropometric data collected using the 3dMDface System are highly reliable and, therefore, useful for evaluation of clinical dysmorphology and surgery, analyses of genotype-phenotype correlations, and inheritance of complex phenotypes.

Updated diagnostic criteria for CHARGE syndrome: a proposal.

Abstract: Alain Verloes*Clinical Genetics Unit, Hoˆpital Robert Debre´, Paris, France‘‘CHARGE association’’ is a well-known entity of unknownorigin. It was originally delineated by Bryan Hall [1979] in17 children with multiple congenital anomalies (MCA) includ-ingchoanal atresiaand,independently by Hittneretal.[1979]in 10 MCA patients with coloboma, hence the eponymic Hall–Hittner syndrome which is sometimes used for it Graham,2001. Pagon et al. [1981] coined ‘‘CHARGE,’’ an acronym sum-marizing the five cardinal clinical features: ocular Coloboma,Heart defects of any type, Atresia of the choanae, Retardation(ofgrowthand/orofdevelopment), Genitalanomalies,andEaranomalies (abnormal pinnae or hearing loss). Classically, tomake a diagnosis of CHARGE complex, 4/7 signs need to bepresent [Oley et al., 1988], and one should be either choanalatresiaoracoloboma[Pagonetal.,1981].Manyotherdevelop-mental anomalies have been reported in CHARGE beyond theacronymic components [Pagon et al., 1981; Oley et al., 1988;Blake et al., 1998; Tellier et al., 1998; Gorlin et al., 2001].Amongthose,oticmalformations,anomaliesofthecranialandCNS midline structures, hypophyseal disorders, and brain-stem dysfunctions have to be stressed as emerging problemshidden beyond the historical cardinal features.Terminological Difficulty: Charge is notan Association, but a SyndromeAn association is the nonrandom cluster of developmentalanomalies that results from early teratogenic events thatoverlap in time and space. Whereas the term association isappropriate for VATER, which is a generalized blastogenicdefect, CHARGE is characterized by very specific develop-mentalanomaliesoftheopticvesicle,oticcapsule,midlineCNSstructures,andupperpharynx.CHARGEissupposedtoresultfrom abnormal differentiation of cephalic mesoderm andectoderm (otic placode and 1st branchial cleft), abnormalsetting (differentiation, migration, survival) of neural crestcells, abnormal interaction of neural crests (forming e.a. 1stand 2nd arch) with the cephalic mesoderm and the developingforebrain, and concomitant disorder in the development ofthe rhombencephalon out of which the neural crest cells havemigrated. CHARGE is thus a complex neurocristopathy, thetiming of which extends from blastogenesis (3rd week) to afterthe9thweekofgestation[Siebertetal.,1985;KirbyandWaldo,1990;Linetal.,1990].Eventhoughthecauseisnotknown,theterm ‘‘CHARGE syndrome’’ [Lubinsky, 1994; Amiel et al.,2001]isprobablymoreappropriate,andtheterm‘‘association’’should be dropped.Semicircular Canals in Charge Syndrome:An Underweighted and Overlooked Diagnostic ClueCochleovestibular abnormalities have recently been showntobeanimportantadditionaldysplasiainCHARGEsyndrome[Morgan et al., 1993; Murofushi et al., 1997; Dhooge et al.,1998; Amiel et al., 2001] In CHARGE, semicircular canals canbe aplastic and vestibular functions may be severely reduced.Cranial imaging frequently reveals absence or abnormality ofthe semicircular canals and, less frequently, hypoplasia of theupper turn of the cochlea or, in more severe cases, Mondinianomaly. In middle ear, hypoplastic long process of the incus,abnormal/absent oval window, and absence of stapediusmuscle are described. Facial nerve may show aberrant coursein the temporal bone, sometimes related with facial palsy.From an embryological point of view, inner ear develops fromthe ectodermally-derived otic placode, whereas middle andouter ear develop between the 5th and the 9th week from theectodermally-derived 1st branchial cleft and from the mesen-chyme (of neural crest origin) of the 1st and 2nd arches.Anatomical anomalies of middle and inner ear were notdirectly considered at the time where CHARGE was coined,probably because technical limits of medical imaging did notallow evaluation of these signs. Anomalies of the semicircularcanals are present in more than 80% of scanned CHARGEchildren [Morgan et al., 1993]. In another recent review ofcongenitalaplasiaofsemi-circularcanalswith‘‘relativelywell-formed cochlea’’ retrospectively selected in a population ofchildren candidate for inner ear implant electrode, Satar et al.[2003] presented a series of 15 patients. Ten of them werediagnosed as CHARGE syndrome. Among those, 85% of thecochleas were mildly or moderately dysplastic. Combined,those two series illustrate the high frequency and the highspecificity of canalar anomalies in CHARGE, a point furtherstressed in a recent review [Stjernholm, 2003]. Although theimportance of inner ear anomalies has been stressed, thepracticalconclusionshavenotbeencompletelydrawnintermsof diagnostic rules and syndrome definition.Variability of Expression in Charge:No Rules for an Old ProblemCHARGEwascoined22yearsagoandhasbeenshowntobeasuccessful acronym giving a simple rule of the thumb formaking or rejecting a diagnosis. Nevertheless, any dysmor-phologist knows how often he/she is led to the diagnosis of‘‘partial’’ or ‘‘atypical’’ CHARGE in patients who, usually,presents only with choanal atresia and some other signs.Curiously, this point has never been adequately discussed in*Correspondence to: Alain Verloes, Clinical Genetics Unit,Hoˆpital Robert Debre´, Paris, France.E-mail: alain.verloes@rdb.ap-hop-paris.frReceived 9 April 2004; Accepted 2 June 2004DOI 10.1002/ajmg.a.30559 2005 Wiley-Liss, Inc.

Clinical and genetic epidemiology of Bardet-Biedl syndrome in Newfoundland: A 22-year prospective, population-based, cohort study

Abstract: Bardet-Biedl syndrome (BBS) and Laurence-Moon syndrome (LMS) have a similar phenotype, which includes retinal dystrophy, obesity, and hypogenitalism. They are differentiated by the presence of spasticity and the absence of polydactyly in LMS. The aims of this study were to describe the epidemiology of BBS and LMS, further define the phenotype, and examine genotype-phenotype correlation. The study involved 46 patients (26 males, 20 females) from 26 families, with a median age of 44 years (range 1-68 years). Assessments were performed in 1986, 1993, and 2001 and included neurological assessments, anthropometric measurements, and clinical photographs to assess dysmorphic features. The phenotype was highly variable within and between families. Impaired co-ordination and ataxia occurred in 86% (18/21). Thirty percent (14/46) met criteria for psychiatric illness; other medical problems included cholecystectomy in 37% (17/46) and asthma in 28% (13/46). Dysmorphic features included brachycephaly, large ears, and short, narrow palpebral fissures. There was no apparent correlation of clinical or dysmorphic features with genotype. Two patients were diagnosed clinically as LMS but both had mutations in a BBS gene. The features in this population do not support the notion that BBS and LMS are distinct. The lack of a genotype-phenotype correlation implies that BBS proteins interact and are necessary for the development of many organs.

Essential versus complex autism: Definition of fundamental prognostic subtypes

Abstract: Heterogeneity within the autism diagnosis obscures the genetic basis of the disorder and impedes our ability to develop effective treatments. We found that by using two readily available tests, autism can be divided into two subgroups, "essential autism" and "complex autism," with different outcomes and recurrence risks. Complex autism consists of individuals in whom there is evidence of some abnormality of early morphogenesis, manifested by either significant dysmorphology or microcephaly. The remainder have "essential autism." From 1995 to 2001, 260 individuals who met DSM-IV criteria for autistic disorder were examined. Five percent (13/260) were microcephalic and 16% (41/260) had significant physical anomalies. Individually, each trait predicted a poorer outcome. Together they define the "complex autism" subgroup, comprising 20% (46/233) of the total autism population. Individuals with complex autism have lower IQs (P=0.006), more seizures (P=0.0008), more abnormal EEGs (46% vs. 30%), more brain abnormalities by MRI (28% vs. 13%). Everyone with an identifiable syndrome was in the complex group. Essential autism defines the more heritable group with higher sib recurrence (4% vs. 0%), more relatives with autism (20% vs. 9%), and higher male to female ratio (6.5:1 vs. 3.2:1). Their outcome was better with higher IQs (P=0.02) and fewer seizures (P=0.0008). They were more apt to develop autism with a regressive onset (43% vs. 23%, P=0.02). Analysis of the features predictive of poor outcome (IQ<55, functionally non-verbal) showed that microcephaly was 100% specific but only 14% sensitive; the presence of physical anomalies was 86% specific and 34% sensitive. The two tests combined yielded 87% specificity, 47% sensitivity, and an odds ratio of 4.8:1 for poor outcome. Separating essential from complex autism should be the first diagnostic step for children with autism spectrum disorders as it allows better prognostication and counseling. Definition of more homogeneous populations should increase power of research analyses.

Sequence of abnormal dendritic spine development in primary somatosensory cortex of a mouse model of the fragile X mental retardation syndrome.

Abstract: Anatomical analyses of occipital and temporal cortex of patients with fragile X mental retardation syndrome (FXS) and in a mouse model of the syndrome (FraX mice) compared to controls have suggested that the fragile X mental retardation protein (FMRP) is important for normal spine structural maturation and pruning. However, a recent analysis of spine properties in somatosensory cortex of young FraX mice has suggested that this region may not exhibit spine abnormalities. While spine abnormalities were present 1 week after birth in somatosensory cortex, by 4 weeks almost all spine abnormalities had disappeared, suggesting that adult spine abnormalities observed in other cortical regions may not persist post-developmentally in somatosensory cortex. To resolve this discrepancy we examined spine properties in somatosensory cortex of young (day 25) and adult (day 73-76) FraX compared to wild-type (WT) mice. Spine properties in young FraX and WT mice did not consistently differ from each other, consistent with the recent analysis of developing somatosensory cortex. However, adult FraX mice exhibited increased spine density, longer spines, more spines with an immature-appearing structure, fewer shorter spines, and fewer spines with a mature structure, a pattern consistent with prior analyses from other adult cortical brain regions in humans and mice. These findings (1) support the previous report of the absence of major spine abnormalities in the fourth postnatal week, (2) demonstrate normal spine development in WT mice, (3) demonstrate abnormal spine development after the fourth postnatal week in FraX mice, and (4) demonstrate spine abnormalities in somatosensory cortex of adult FraX compared to adult WT mice. In doing so, these findings resolve a potential conflict in the literature and more thoroughly describe the role of FMRP in spine development.

An epidemiological analysis of CHARGE syndrome: preliminary results from a Canadian study.

Abstract: CHARGE syndrome is a well-characterized clinical diagnosis with recent data supporting a genetic etiology. A 3-year national surveillance coordinated by the Canadian Pediatric Surveillance Program (CPSP) was started in September 2001. Physicians notified the CPSP if they had cared for individuals with CHARGE syndrome within their practice, and then completed a detailed reporting form. To date, there are 77 confirmed cases of CHARGE syndrome. The highest provincial prevalence of CHARGE syndrome in Canada was estimated at 1 in 8,500 live births. Subgroups of cases with particular clusters of anomalies were identified. In older individuals, bilateral posterior choanal atresia (BPCA) was predictive of the presence of the three other major criteria and of aortic arch anomalies. Individuals with CHARGE syndrome who demonstrated a less extensive phenotype (≤3 major criteria) were more likely to present with minor cardiovascular malformations, including small atrial or ventricular septal defects (VSD) or patent ductus arteriosus (PDA). A significant cause of morbidity was severe feeding difficulty, including problems with chewing, swallowing, and gastroesophageal reflux, which were prevalent throughout childhood. Infant mortality is high in individuals with CHARGE syndrome. However, life expectancy has improved for those surviving their first year. Increased mortality was associated with distinct cardiovascular malformations or ventriculomegaly combined with brainstem or cerebellar anomalies. From this study, revised diagnostic criteria are proposed for infants, children, and adolescents to help identify a group of individuals who represent CHARGE syndrome with more of the classical features as apposed to the boarder association. © 2005 Wiley-Liss, Inc.

SOX2 anophthalmia syndrome

Abstract: Heterozygous, de novo, loss-of-function mutations in SOX2 have been shown to cause bilateral anophthalmia. Here we provide a detailed description of the clinical features associated with SOX2 mutations in the five individuals with reported mutations and four newly identified cases (including the first reported SOX2 missense mutation). The SOX2-associated ocular malformations are variable in type, but most often bilateral and severe. Of the nine patients, six had bilateral anophthalmia and two had anophthalmia with contralateral microphthalmia with sclerocornea. The remaining case had anophthalmia with contralateral microphthalmia, posterior cortical cataract and a dysplastic optic disc, and was the only patient to have measurable visual acuity. The relatively consistent extraocular phenotype observed includes: learning disability, seizures, brain malformation, specific motor abnormalities, male genital tract malformations, mild facial dysmorphism, and postnatal growth failure. Identifying SOX2 mutations from large cohorts of patients with structural eye defects has delineated a new, clinically-recognizable, multisystem disorder and has provided important insight into the developmental pathways critical for morphogenesis of the eye, brain, and male genital tract.

Inheritance Analysis of Congenital Left Ventricular Outflow Tract Obstruction Malformations: Segregation, Multiplex Relative Risk, and Heritability

Abstract: The left ventricular outflow tract (LVOTO) malformations, aortic valve stenosis (AVS), coarctation of the aorta (COA), and hypoplastic left heart (HLH) constitute a mechanistically defined subgroup of congenital heart defects that have substantial evidence for a genetic component. Evidence from echocardiography studies has shown that bicuspid aortic valve (BAV) is found frequently in relatives of children with LVOTO defects. However, formal inheritance analysis has not been performed. We ascertained 124 families by an index case with AVS, COA, or HLH. A total of 413 relatives were enrolled in the study, of which 351 had detailed echocardiography exams for structural heart defects and measurements of a variety of aortic arch, left ventricle, and valve structures. LVOTO malformations were noted in 30 relatives (18 BAV, 5 HLH, 3 COA, and 3 AVS), along with significant congenital heart defects (CHD) in 2 others (32/413; 7.7%). Relative risk for first-degree relatives in this group was 36.9, with a heritability of 0.71-0.90. Formal segregation analysis suggests that one or more minor loci with rare dominant alleles may be operative in a subset of families. Multiplex relative risk analysis, which estimates number of loci, had the highest maximum likelihood score in a model with 2 loci (range of 1-6 in the lod-1 support interval). Heritability of several aortic arch measurements and aortic valve was significant. These data support a complex but most likely oligogenic pattern of inheritance. A combination of linkage and association study designs is likely to enable LVOTO risk gene identification. This data can also provide families with important information for screening asymptomatic relatives for potentially harmful cardiac defects.

Phenotypes with GATA4 or NKX2.5 mutations in familial atrial septal defect

Abstract: Recently, GATA4 and NKX2.5 were reported as the disease genes of atrial septal defect (ASD) but the relationship between the locations of their mutations and phenotypes is not clear. We analyzed GATA4 and NKX2.5 mutations in 16 familial ASD cases, including four probands with atrioventricular conduction disturbance (AV block) and two with pulmonary stenosis (PS), by PCR and direct sequencing, and examined their phenotypes clinically. Five mutations, including two GATA4 and three NKX2.5 mutations, were identified in 31.3% of the probands with ASD, and three of them were novel. The two GATA4 mutations in the probands without AV block were S52F and E359Xfs (c.1075delG) that was reported previously, and three NKX2.5 mutations in the probands with AV block were A88Xfs (c.262delG), R190C, and T178M. Additionally, we observed some remarkable phenotypes, i.e., dextrocardia with E359Xfs (c.1075delG) and cribriform type ASD with R190C, both of which are expected to be clues for further investigations. Furthermore, progressive, most severe AV block was closely related with a missense mutation in a homeodomain or with a nonsense/frame-shift mutation of NKX2.5 for which classification has not been clearly proposed. This pinpoints essential sites of NKX2.5 in the development of the conduction system.

Use of targeted array-based CGH for the clinical diagnosis of chromosomal imbalance: is less more?

Abstract: Chromosome analysis is an important component to the diagnosis of congenital anomalies, developmental delay, and mental retardation. Routine chromosome analysis identifies aneuploidy and structural rearrangements greater than 5 Mb but cannot identify abnormalities of the telomeric regions or microdeletions reliably. Molecular cytogenetic techniques were developed to overcome these limitations. High-resolution comparative genomic hybridization (CGH)-based microarrays (array CGH) were developed to increase the resolution of chromosomal studies and to provide a comprehensive assay by using large-insert clones as the target for analysis. We constructed a microarray for the clinical diagnosis of medically significant and relatively common chromosomal alterations. Nine hundred six bacterial artificial chromosome (BAC) clones were chosen, the chromosomal locations of which were confirmed by fluorescence in situ hybridization (FISH). FISH-testing showed that 7% of the clones were mismapped based on map locations obtained from two publicly available databases (58 mapped to the wrong chromosome and three mapped to a different locus on the same chromosome), 16% cross-hybridized to other chromosomes, and 12% did not hybridize or showed poor hybridization signals under uniform FISH conditions. Thus, from a total of 906 BAC clones that were evaluated, only 589 (65%) were deemed adequate for arraying on this clinical device. The performance of this array was tested in a set of blinded experiments on a cohort of phenotypically normal individuals and on individuals with known chromosome abnormalities. The array identified deletion/duplication polymorphisms not seen by FISH in the phenotypically normal individuals and detected single copy dosage differences in all of the cases with known chromosomal abnormalities. All abnormalities detected by the array were confirmed by FISH with BACs from the appropriate loci. Our data demonstrate that the rigorous assessment of BACs and their use in array CGH is especially important when the microarray is used for clinical diagnosis. In addition, this study illustrates that when constructed carefully with proper attention to the quality of the BACs that are arrayed, array CGH is an effective and efficient tool for delineating chromosomal aberrations and an important adjunct to FISH and conventional cytogenetics.

Reduction of birth prevalence rates of neural tube defects after folic acid fortification in Chile

Abstract: To verify whether the decreasing neural tube defects birth prevalence rates in Chile are due to folic acid fortification or to pre-existing decreasing trends, we performed a population survey using a network of Estudio Colaborativo Latino Americano de Malformaciones Congenitas (ECLAMC, Latin American Collaborative Study of Congenital Malformations) maternity hospitals in Chile, between the years 1982 and 2002. Within each maternity hospital, birth prevalence rates of spina bifida and anencephaly were calculated from two pre-fortification periods (1982-1989 and 1990-2000), and from one fortified period (2001-2002). There was no historical trend for spina bifida birth prevalence rates before folic acid fortification, and there was a 51% (minimum 27%, maximum 66%) decrease in the birth prevalence rates of this anomaly in the fortified period. The relative risks of spina bifida were homogeneous among hospitals in the two period comparisons. There was no historical trend for the birth prevalence of anencephaly comparing the two pre-fortified periods, but the relative risks were heterogeneous among hospitals in this comparison. There was a 42% (minimum 10%, maximum 63%) decrease in the birth prevalence rate of anencephaly in the fortified period as compared with the immediately pre-fortified period, with homogeneous relative risks among hospitals. Within the methodological constraints of this study we conclude that the birth prevalence rates for both spina bifida and anencephaly decreased as a result of folic acid fortification, without interference of decreasing secular trends.

Tumor risk in Beckwith-Wiedemann syndrome: A review and meta-analysis.

Abstract: Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome associated with macroglossia, abdominal wall defects, ear anomalies, and an increased risk for embryonic tumors. Reported tumor risk estimates vary between 4% and 21%. It has been hypothesized that tumor predisposition in BWS is related to the imprinting status of the H19 and LIT1 genes on chromosome 11p15. A loss of imprinting (LOI) of H19 implies a higher tumor risk. However, a systematic analysis of available data is lacking. Therefore, we performed a review and meta-analysis of reported associations between the imprinting status of the LIT1 and H19 genes and the risk for tumor development in BWS. Five publications suitable for meta-analysis were identified by electronic database searches. Sufficient data were available for 402 out of 520 patients. Patients were divided into four groups based on the imprinting status of H19 and LIT1: group I with LOI of LIT1 (45%); group II with LOI of H19 (9%); group III with LOI of LIT1 and LOI of H19 (21%); and group IV with normal imprinting patterns (26%). Differences in tumor risk between groups were studied with random effects meta-analysis. Tumors occurred in 55 patients. The odds of tumor development was significantly lower in group I when compared to group II (OR=0.06; 95% CI: 0.02-0.21) and group III (OR=0.12; 95% CI: 0.04-0.37). Tumor risk did not differ significantly between groups II and III (OR=1.40; 95% CI: 0.56-3.50). Compared to group IV, tumor risk was significantly lower in group I (OR=0.33; 95% CI: 0.12-0.87) and higher in groups II (OR=4.0; 95% CI: 1.5-10.4) and III (OR=2.6; 95% CI: 1.2-5.7). Tumor incidence rate for group IV was 10.6% (95% CI: 3.6-17.7). Calculated absolute risks were 3% for group I, 43% for group II, and 28% for group III, respectively. No Wilms tumor was seen in group I. In total, other tumors were seen with comparable frequencies in groups I-III. The results show a strong association between a LOI of H19 and especially Wilms tumor development in BWS.

Threshold effect of urinary glycosaminoglycans and the walk test as indicators of disease progression in a survey of subjects with Mucopolysaccharidosis VI (Maroteaux-Lamy syndrome).

Abstract: A cross-sectional survey in individuals affected with the lysosomal storage disease Mucopolysaccharidosis VI (MPS VI) was conducted to establish demographics, urinary glycosaminoglycan (GAG) levels, and clinical progression of the disease. The survey evaluated 121 bona fide MPS VI-affected individuals over the age of 4 years from 15 countries across the Americas, Europe, and Australasia representing greater than 10% of the estimated world prevalence of the disease. A medical history, complete physical exam, urinary GAG determination, and assessment of several clinical measures related to physical endurance, pulmonary function, joint range of motion, strength, and quality of life were completed for each participant. Although a wide variation in clinical presentation was observed, several general findings were obtained reflecting progression of the disease. Impaired physical endurance, as measured by the distance achieved in a 6-min walk, could be demonstrated across all age groups of MPS VI-affected individuals. High urinary GAG values (>200 mug/mg creatinine) were associated with an accelerated clinical course comprised of age-adjusted short stature and low body weight, impaired endurance, compromised pulmonary function, and reduced joint range of motion. An unexpected result was the predominance of urinary GAG values <100 mug/mg creatinine for those participants over the age of 20 years. Pending the collection of longitudinal data, these results suggest that urinary GAG levels predict clinical morbidity, and longer-term survival is associated with urinary GAG levels below a threshold of 100 mug/mg creatinine.

Uniparental disomy (UPD) other than 15: Phenotypes and bibliography updated

Abstract: Uniparental disomy (UPD) describes the inheritance of a pair of chromosomes from only one parent. The concept was introduced in Medical Genetics by Engel (1980); Am J Med Genet 6:137-143. Aside UPD 15, which is the most frequent one, up to now (February 2005) 197 cases with whole chromosome maternal UPD other than 15 (124 X heterodisomy, 59 X isodisomy, and 14 cases without information of the mode of UPD) and 68 cases with whole chromosome paternal UPD other than 15 (13 X heterdisomy, 53 X isodisomy, and 2 cases without information of the mode of UPD) have been reported. In this review we discuss briefly the problems associated with UPD and provide a comprehensive clinical summary with a bibliography for each UPD other than 15 as a guide for genetic counseling.

Down syndrome and comorbid autism-spectrum disorder: Characterization using the aberrant behavior checklist

Abstract: To report on the cognitive and behavioral attributes of 61 children with Down syndrome (DS) and autistic-spectrum disorder (ASD) according to DSM-IV criteria; to determine the utility of the aberrant behavior checklist (ABC) to characterize these subjects for research purposes; and to test the hypothesis that subjects with DS + ASD could be distinguished from their typical DS peers using the ABC. Cross-sectional design. Cases with DS + ASD (N = 61), comparison group of DS + stereotypy movement disorder (SMD) (N = 26) and typical DS controls without behavior problems (N = 44) were ascertained and enrolled sequentially upon presentation to a DS clinic at an academic medical center over a 10-year period from 1991 to 2001. All subjects underwent neurodevelopmental and medical evaluation, and standardized cognitive testing. The parents provided responses to standardized behavioral questionnaires. Cognitive function (IQ) differed markedly across the three groups. The Lethary and Stereotypy subscales of the ABC were highly significant (P PDD, P = 0.005; PDD < CDD, P = 0.002). Using a multivariate regression model, the ABC scales alone explained 62% of variance of ASD outcome; addition of demographic variables explained up to 68% of the variance. There is good correlation between DSM-IV criteria for autism and subscales scores on the ABC in subjects with DS. This study demonstrates the feasibility of using the ABC to characterize the neurobehavioral phenotype of a cohort of children with trisomy 21 and ASD for ongoing research purposes. © 2005 Wiley-Liss, Inc.

Improved molecular diagnosis of dystrophinopathies in an unselected clinical cohort.

Abstract: Mutations in the DMD gene result in Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). Readily available clinical tests detect only deletions of one exon or greater, which are found in approximately 60% of cases. Mutational analysis of other types of DMD mutations, such as premature stop codons and small frameshifting insertions or deletions, has historically been hampered by the large size of the gene. We have recently reported a method that allows the rapid and economical sequencing of the entire coding region of the DMD gene, and that is more sensitive than methods based on single-strand conformational polymorphism (SSCP) screening or other preliminary screening steps. Here we use single condition amplification/internal primer (SCAIP) sequencing analysis, in combination with multiplex amplifiable probe hybridization (MAPH) analysis of duplications, to report the frequency of mutations in a large cohort of unselected dystrophinopathy patients from a single clinic. Our results indicate that 7% of dystrophinopathy patients do not have coding region mutations, suggesting that intronic mutations are not uncommon. The availability of rapid and thorough mutation analysis from peripheral blood samples, along with an improved estimate of the percentage of non-coding region mutations, will be of benefit for improved genetic counseling and in identification of cohorts for clinical trials.

DLX3 mutation associated with autosomal dominant amelogenesis imperfecta with taurodontism.

Abstract: Department of Dentistry, Royal Children’s Hospital, Melbourne, AustraliaAmelogenesis imperfecta hypoplastic-hypoma-turation with taurodontism (AIHHT) is an auto-somaldominant(AD)traitassociatedwithenameldefectsandenlargedpulpchambers.Inthisstudy,we mapped an AIHHT family to human chromo-some 17 q21-q22 (lod score 3.3) and identify a twobasepair deletion (CT) at nucleotide 560 in DLX3associated with the disease. This mutation causesa frameshift altering the last two amino acids ofthe DNA-binding homeodomain introducing apremature stop codon truncating the proteinby 88 amino acids. This is the first report of amutation within the homeodomain of DLX3.Previous studies have shown a DLX3 mutationoutside the homeodomain associated with tricho-dento-osseous syndrome (TDO) suggesting TDOand some forms of AIHHT are allelic.

High incidence of malformation syndromes in a series of 1,073 children with cancer

Abstract: Constitutional molecular defects are known to play a role in oncogenesis, as shown by the increased incidence of embryonic cancers in children with Beckwith-Wiedemann syndrome (BWS) or of leukemia in children with Down syndrome To establish the incidence and spectrum of malformation syndromes associated with childhood cancer we performed a clinical morphological examination on a series of 1,073 children with cancer We diagnosed a syndrome in 42 patients (39%) and suspected the presence of a syndrome in another 35 patients (33%), for a total of 72% This incidence of patients with a proven or suspected syndrome is high, and points to a possible association We describe new syndrome-tumor associations in several entities: cleidocranial dysostosis (Wilms tumor), Bardet-Biedl syndrome (BBS) (acute lymphoblastic leukemia), Kabuki syndrome (neuroblastoma), LEOPARD syndrome (neuroblastoma), Poland anomaly (osteosarcoma; Hodgkin disease), and blepharophimosis epicanthus inversus syndrome (Burkitt lymphoma) Twenty of the 42 syndrome diagnoses were not recognized in the patients prior to this study, indicating that these diagnoses are commonly missed We propose that all children with a malignancy should be examined by a clinical geneticist or a pediatrician skilled in clinical morphology to determine if the patients have a malformation syndrome

SOX2 mutation causes anophthalmia, hearing loss, and brain anomalies.

Abstract: The SOX2 transcription factor is expressed early in the embryonic stem cells of the blastocyst and later in the neural stem cells. It is a member of the SOX family of proteins that carry a DNA-binding high-mobility group domain and additional domains that regulate embryonic development and cell fate determinations. We surveyed 93 patients with severe eye malformations for mutations in SOX2. Here, we report a novel nonsense mutation in one female patient with bilateral clinical anophthalmia, absence of all optic pathways, and other neurological abnormalities. The mutation, Q155X, creates a premature termination codon early in the transcriptional activation domain and is likely to be a null allele. Our data show that mutations in SOX2 can cause not only anophthalmia, but also aplasia of the optic nerve, chiasm and optic tract, as well as modest bilateral sensorineural hearing loss, and global developmental delay, underscoring the importance of SOX2 in early human eye and brain development.

Variation in IRF6 contributes to nonsyndromic cleft lip and palate.

Abstract: Nonsyndromic cleft lip with or without cleft palate (NSCLP) is a common craniofacial birth defect which results in lifelong medical and social consequences. While there have been a number of attempts to identify the genes responsible for this disorder, the results have not been consistent among populations and no single gene has been identified as playing a major susceptibility role. Van der Woude syndrome, a disorder characterized by lower-lip pits with or without cleft lip/palate, results in many cases from mutations in the interferon regulatory factor 6 (IRF6) gene. Recently, Zucchero et al. [2004: N Engl J Med 351:769–780] detected an association between SNPs in IRF6 and NSCLP in a number of different populations. A subsequent study by Scapoli et al. [2005: Am J Hum Genet 76:180–183] confirmed this association in an Italian population. We examined the same SNPs as Scapoli et al. [2005] in our large, well-characterized sample of NSCLP families and trios, and also detected an altered transmission of IRF6 alleles. This additional confirmation further strengthens the IRF6 association and suggests that IRF6 plays a role in NSCLP susceptibility. © 2005 Wiley-Liss, Inc.

Stickler syndrome: clinical characteristics and diagnostic criteria.

Abstract: The purpose of this study was to establish diagnostic criteria for Stickler syndrome. Ninety patients from 38 families had complete evaluations for possible Stickler syndrome. Molecular confirmation of COL2A1 mutation status (type I Stickler syndrome) was available on 25 patients from six families. In the remaining 65 patients, 47 from 25 families were affected with Stickler syndrome and 18 from seven families were unaffected with Stickler syndrome. A diagnostic nosology based on type I Stickler patients with known COL2A1 mutations was applied to clinically affected and unaffected patients. A diagnostic scale of 9 points evaluated molecular data or family history data and characteristic ocular, orofacial, auditory, and musculoskeletal findings. A score of > or =5 was diagnostic of Stickler syndrome. These criteria demonstrate 100% sensitivity when applied to type I Stickler syndrome patients with known COL2A1 mutations, 98% sensitivity when applied to clinically affected Stickler patients, and 86% specificity when applied to patients unaffected based on clinical and/or molecular analysis. We conclude that diagnostic criteria based on type I Stickler patients with molecularly confirmed COL2A1 mutations appear to be sensitive and specific for the diagnosis of this syndrome and should be helpful to clinicians when making the diagnosis.

Mayer–Rokitansky–Küster–Hauser anomaly and its associated malformations

Abstract: Mayer-Rokitansky-Kuster-Hauser (MRKHA) is a malformation complex comprising absent vagina and absent or rudimentary uterus. The aim of our study was to describe the type and frequency of anomalies associated with the MRKHA. Between 1975 and 2002, 25 patients with a diagnosis of MRKHA were identified at the Mayo Clinic. These charts were reviewed retrospectively. Two of the 25 patients were found to have absence of one ovary and two patients had unilateral oophorectomies performed for benign cysts. Four patients had minor anomalies and two had digital anomalies. The frequency of scoliosis (20%), unilateral renal agenesis (28%), non-vertebral skeletal anomalies (16%) and of the MURCS association (Mullerian agenesis, renal agenesis/ectopia and cervical somite dysgenesis), 16%, was similar compared to that of other published studies. Vertebral abnormalities were found more frequently in our patients (44%). Four patients had cardiac defects, an anomaly not previously described, including truncus arteriosus, patent ductus arteriosus and patent foramen ovale, mitral valve prolapse, and mild mitral regurgitation. We document cardiac anomalies in 16% of our patients with MRKHA suggesting that a search for associated anomalies including cardiac defects is indicated in all such patients.

Schizencephaly: heterogeneous etiologies in a population of 4 million California births.

Abstract: Schizencephaly is a rare congenital brain defect characterized by gray matter lined clefts of the cerebral mantle, frequently accompanied by other defects of the CNS such as absence of the corpus callosum. This study in a California population of >4 million births from 1985-2001 found a population prevalence of 1.54/100,000. Among 63 cases, there was an association with young parental age in isolated schizencephaly (RR 3.9 mothers; 5.8 fathers), which was also seen in mothers but not fathers of non-isolated cases (RR 3.2). Monozygotic twins may also be at increased risk for schizencephaly (RR 2.1). One third of cases had a non-CNS abnormality, over half of which could be classified as secondary to vascular disruption, including gastroschisis, bowel atresias, and amniotic band disruption sequence. Other apparent rare causes included chromosomal aneuploidy, non-random associations, and unusual syndromes. Our observations suggest that schizencephaly has heterogeneous etiologies many of which are vascular disruptive in origin.

Psychological benefit of diagnostic certainty for mothers of children with disabilities: lessons from Down syndrome.

Abstract: Diagnostic and prognostic uncertainty is one of the major psychological stressors for patients in acute and chronic illness, as well as for parents of children with disabilities or chronic disease. Whereas the parents' feeling of uncertainty is undoubtedly very strong shortly after the birth of a child with disabilities, the long-term effects on the parents of having or not having a precise genetic diagnosis, in terms of emotional stress, remain unclear. In this study, mothers of non-disabled children are compared to mothers of children with Down syndrome, and to mothers of children with a diagnostically unassigned mental retardation with regard to the level of anxiety, feelings of guilt, and emotional burden. While the mothers of children with Down syndrome score comparably to the mothers of non-disabled children, the results show broad psychoemotional disadvantages for mothers of children with a mental retardation of unknown etiology. Consequently, the value of genetic diagnosis of infantile disabilities encompasses, beyond clinical considerations like therapy planning and assignment of the recurrence risk for siblings, significant and long-lasting emotional relief for the parents.

Genotypic and phenotypic characterization of Noonan syndrome: New data and review of the literature

Abstract: Noonan syndrome (NS) is an autosomal dominant disorder, characterized by short stature, minor facial anomalies, and congenital heart defects. In approximately 50% of cases the condition is caused by missense mutations in the PTPN11 gene on chromosome 12, resulting in a gain of function of the protein SHP-2. In this study, PTPN11 mutation analysis was performed in 170 NS patients. In 76 (45%) of them a mutation was identified. We report on the distribution of these mutations, as well as on genotype-phenotype relationships. The benefit of the NS scoring system developed by van der Burgt et al. [(1994); Am J Med Genet 53:187-191] is shown, among physicians who consequently based their diagnosis on the NS scoring system the percentage mutation positive subjects was 54%, whereas this percentage was only 39% among physicians who made less use of the scoring system. In two patients with some uncommon manifestations mutations were found in the C-SH2 domain, a region in which defects are not often identified in NS. A trend was observed in patients carrying the 922A --> G change (Asn308Asp) receiving normal education. In one patient with NS and mild juvenile myelomonocytic leukemia (JMML) the mutation 218C --> T (Thr73Ile) was found. This confirms previous findings indicating that individuals with NS with specific mutations in PTPN11 are at risk of developing JMML.

Submicroscopic deletions and duplications in individuals with intellectual disability detected by array-CGH.

Abstract: Intellectual disability (ID) affects about 3% of the population (IQ < 70), and in about 40% of moderate (IQ 35-49) to severe ID (IQ < 34), and 70% of cases of mild ID (IQ 50-70), the etiology of the disease remains unknown. It has long been suspected that chromosomal gains and losses undetectable by routine cytogenetic analysis (i.e., less than 5-10 Mb in size) are implicated in ID of unknown etiology. Array CGH has recently been used to perform a genome-wide screen for submicroscopic gains and losses in individuals with a normal karyotype but with features suggestive of a chromosome abnormality. In two recent studies, the technique has demonstrated a approximately 15% detection rate for de novo copy number changes of individual clones or groups of clones. Here, we describe a study of 22 individuals with mild to moderate ID and nonsyndromic pattern of dysmorphic features suspicious of an underlying chromosome abnormality, using the 3 Mb and 1 Mb commercial arrays (Spectral Genomics). Deletions and duplications of 16 clones, previously described to show copy number variability in normal individuals [Iafrate et al., 2004; Lapierre et al., 2004; Schoumans et al., 2004; Vermeesch et al., 2005] were seen in 21/22 subjects and were considered polymorphisms. In addition, three subjects showed submicroscopic deletions and duplications not previously reported as normal variants. Two of these submicroscopic changes were of de novo origin (microdeletions at 7q36.3 and a microduplication at 11q12.3-13.1) and one was of unknown origin as parental testing of origin could not be performed (microduplication of Xp22.3). The clinical description of the three subjects with submicroscopic chromosomal changes at 7q36.3, 11q12.3-13.1, Xp22.3 is provided.

A patient with mutations in DNA Ligase IV: clinical features and overlap with Nijmegen breakage syndrome.

Abstract: The clinical phenotype of Ligase IV syndrome (LIG4 syndrome), an extremely rare autosomal recessive condition caused by mutations in the LIG4 gene, closely resembles that of Nijmegen breakage syndrome (NBS), and is characterized by microcephaly, characteristic facial features, growth retardation, developmental delay, and immunodeficiency. We report a 4½-year-old boy who presented with acute T-cell leukemia. The facial gestalt was strongly reminiscent of NBS. The patient died shortly after the onset of treatment for his T-cell leukemia. Subsequent chromosome breakage studies showed a high rate of breakage in a fibroblast culture. Radiosensitivity was assessed by a colony survival assay; the results showed radiosensitivity greater than is typically seen in NBS. Mutation screening of the NBS1 gene was negative. Sequencing of the LIG4 gene revealed a homozygous truncating mutation 2440 C>T (R814X). Although this mutation has been previously noted in LIG4 syndrome, this patient is the first reported homozygote for the mutation. In this study, we review the clinical features of this rare syndrome and provide suggestions for differential diagnosis. © 2005 Wiley-Liss, Inc.

Maladaptive behaviors and risk factors among the genetic subtypes of prader-willi syndrome

Abstract: Maladaptive behaviors among 65 people with Prader-Willi syndrome were assessed using the Reiss Screen for maladaptive behaviors. Young adults in their twenties were more likely to display aggressive behavior than adolescents and older adults. Differences in maladaptive behaviors between the typical deletion and uniparental disomy (UPD) subtypes were evaluated. The typical deletion subtype had higher self-injury and stealing scores than the UPD subtype. Subject characteristics were differentially related to maladaptive behavior among the typical deletion and UPD subtypes. Differences in maladaptive behavior were also examined between the typical deletion type I and type II subtypes. The type I deletion subtype had greater physical depression scores than the type II deletion subtype. The Reiss Screen cut-off scores were used to determine whether differences occurred between the subtypes at a clinically significant level. These findings offer insight into the health care needs of people with PWS.

Gonadoblastoma in Turner syndrome and Y-chromosome-derived material

Abstract: The identification of Y-chromosome material is important in females with Ullrich-Turner syndrome (UTS) due to the risk of developing gonadoblastoma or other gonadal tumors. There is controversy regarding the frequency of the Y-chromosome-derived material and the occurrence of gonadoblastoma in these patients. The aim of our study was to evaluate a large number of patients with UTS, followed before and during the pubertal age for the prevalence of Y-chromosome derived material, the occurrence of gonadoblastoma, and the incidence of possible neoplastic degeneration. An unselected series of 171 patients with UTS (1-34 years old), diagnosed cytogenetically, was studied for Y-chromosome markers (SRY and Y-centromeric DYZ3 repeats). The follow-up was of 2-22 years; 101 of these patients were followed during pubertal age. Y-chromosome material was found in 14 patients (8%): 12 of these were gonadectomized (2.8-25.9 years). A gonadoblastoma was detected in four patients under 16 years of age: in two, Y-material was detected only at molecular analysis (at conventional cytogenetic analysis, one was included in the 45,X group and one in the X + mar group) and one had also an immature teratoma and an endodermal sinus carcinoma. The prevalence of gonadoblastoma in our series of gonadectomized UTS patients with Y-positive material was of 33.3% (4/12). Our data suggest that the age of appearance and the possibility of malignant degeneration of gonadoblastoma can occur early in life. These patients, in particular those with 45,X or a marker chromosome may benefit from molecular screening to detect the presence of Y-chromosome material; PCR is a rapid and inexpensive technique. At the moment, laparoscopy and preventive gonadectomy performed as soon as possible remain the procedures of choice for patients with UTS, when Y-chromosome has been identified, as we are still unable to predict a future malignant evolution of gonadoblastoma.