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Koolen-de Vries syndrome (KdVS, MIM#610443) is a rare malformation condition mainly characterized by cognitive impairment in association with craniofacial and visceral anomalies. The core phenotype is caused by mutations in the chromatin remodeler KANSL1 (MSL1V1, KIAA1267, KAT8 Regulatory NSL Complex Subunit 1, MIM#612452), which maps to 17q21.31 critical genomic region (Koolen et al., Nature Genetics 2012;44:639-641). Considering its molecular basis, KdVS is included in the group of Developmental Disorders of Chromatin Remodeling (DDCRs), also termed chromatinopathies. We describe the first KdVS patient of Southern India ethnicity, harboring the typical de novo 17q21.31 microdeletion, including KANSL1. Observed facial features and congenital anomalies are in line with the already reported KdVS phenotype, suggesting that phenotypic features are consistent across different ethnicities., (© 2020 Wiley Periodicals LLC.)

Background: Escobar syndrome, a nonlethal variant of multiple pterygium syndromes (MPS), is a rare autosomal recessive disorder characterized by pterygia and multiple joint contractures along with other anomalies. Variants in cholinergic receptor nicotinic gamma subunit ( CHRNG ) have been previously reported in patients with Escobar syndrome. Objective: We studied a consanguineous Pakistani family affected with Escobar syndrome to identify the underlying genetic defect through short tandem repeat (STR) genotyping and direct DNA sequencing. Results: Genotyping with microsatellite markers (D2S427, D2S2344, and D2S206) revealed linkage of the disease phenotype in the family to the CHRNG locus. Using Sanger sequencing, we identified a homozygous nonsense CHRNG variant c.136C>T (p.R46*), predicted to produce a truncated protein that leads to acetylcholine receptor deficiency, causing MPS. The unaffected parents and siblings in the family were heterozygous carriers of this disease-causing variant. Conclusion: We report the identification of a nonsense CHRNG variant in a consanguineous Pakistani family affected with Escobar syndrome.

Background: Microtia is a congenital anomaly of the external ear that can appear in isolation or in association with other congenital anomalies. In this study, the authors identify the prevalence and phenotypes of associated congenital malformations in patients with microtia in a Chinese specialty clinic population., Methods: Data were collected from 672 patients seen between December of 2014 and February of 2016 in the Department of Auricular Reconstruction at the Plastic Surgery Hospital of Peking Union Medical College. All patients were examined by trained clinicians and classified into one of three grades of microtia. Co-occurring congenital anomalies were detected and recorded., Results: The majority of study participants were male patients (72 percent), and most participants had unilateral microtia (93 percent, 68 percent of whom had right-side microtia). Two hundred ninety-three patients (44 percent) had one or more associated anomalies. The most commonly occurring comorbid malformations were those of the ear, face, and neck (40 percent of all associated malformations); musculoskeletal system (35 percent); and cardiovascular system (11 percent)., Conclusions: These data represent the first detailed and thematic study of microtia and associated congenital anomalies in a Chinese clinical population. Substantial clinical heterogeneity was observed, and the prevalence of comorbid congenital malformations was high. Future studies investigating congenital anomalies associated with microtia are needed to improve understanding of its cause.

Conotruncal heart defects (CTDs) are severe malformations of outflow tract with heterogeneous morphology. Several missense variants of CITED2 have been identified to cause CTDs in recent researches. In this study, we screened the coding regions of CITED2 in 605 Chinese children with CTDs and found two possible pathogenic mutant sites: p.Q117L and p.T257A, both located in the conserved regions of CITED2. Then, we investigated the biological and functional alterations of them. Western blotting showed low level of protein expression of mutant Q117 and T257A compared with wild-type CITED2. Dual-luciferase reporter assay demonstrated that mutant Q117 and T257A decreased the ability of CITED2 to modulate the expression of paired-like homeodomain transcription factor 2 gamma (PITX2C), which are closely related to cardiac growth and left-right patterning. Meanwhile, T257A also exhibited impaired ability to mediate vascular endothelial growth factor expression, another gene closely associated with the normal development of cardiovascular system. Three-dimensional molecular conformation showed reduced hydrogen bond between Asp254 and mutant Thr257, indicating the weakened stability and binding ability of CITED2. All these results suggest that CITED2 mutations in conserved regions lead to disease-causing biological and functional changes and may contribute to the occurrence of CTDs.

Mesomelia-synostoses syndrome (MSS) is a rare, autosomal-dominant, syndromal osteochondrodysplasia characterized by mesomelic limb shortening, acral synostoses, and multiple congenital malformations due to a non-recurrent deletion at 8q13 that always encompasses two coding-genes, SULF1 and SLCO5A1. To date, five unrelated patients have been reported worldwide, and MMS was previously proposed to not be a genomic disorder associated with deletions recurring from non-allelic homologous recombination (NAHR) in at least two analyzed cases. We conducted targeted gene panel sequencing and subsequent array-based copy number analysis in an 11-year-old undiagnosed Japanese female patient with multiple congenital anomalies that included mesomelic limb shortening and detected a novel 590 Kb deletion at 8q13 encompassing the same gene set as reported previously, resulting in the diagnosis of MSS. Breakpoint sequences of the deleted region in our case demonstrated the first LINE-1s (L1s)-mediated unequal NAHR event utilizing two distant L1 elements as homology substrates in this disease, which may represent a novel causative mechanism of the 8q13 deletion, expanding the range of mechanisms involved in the chromosomal rearrangements responsible for MSS., (© 2017 Wiley Periodicals, Inc.)

Van der Woude syndrome (VWS) is an autosomal dominant malformation syndrome characterized by orofacial clefting (OFC) and lower lip pits. The clinical presentation of VWS is variable and can present as an isolated OFC, making it difficult to distinguish VWS cases from individuals with non-syndromic OFCs. About 70% of causal VWS mutations occur in IRF6, a gene that is also associated with non-syndromic OFCs. Screening for IRF6 mutations in apparently non-syndromic cases has been performed in several modestly sized cohorts with mixed results. In this study, we screened 1521 trios with presumed non-syndromic OFCs to determine the frequency of causal IRF6 mutations. We identified seven likely causal IRF6 mutations, although a posteriori review identified two misdiagnosed VWS families based on the presence of lip pits. We found no evidence for association between rare IRF6 polymorphisms and non-syndromic OFCs. We combined our results with other similar studies (totaling 2472 families) and conclude that causal IRF6 mutations are found in 0.24-0.44% of apparently non-syndromic OFC families. We suggest that clinical mutation screening for IRF6 be considered for certain family patterns such as families with mixed types of OFCs and/or autosomal dominant transmission., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Joubert syndrome (JS) and related disorders (JSRD), Meckel syndrome (MKS) and Bardet-Biedl syndrome (BBS) are autosomal recessive ciliopathies with a broad clinical and genetic overlap. In our multiethnic cohort of 88 MKS, 61 JS/JSRD and 66 BBS families we performed genetic analyses and were able to determine mutation frequencies and detection rates for the most frequently mutated MKS genes. On the basis of determined mutation frequencies, a next generation gene panel for JS/JSRD and MKS was established. Furthermore 35 patients from 26 unrelated consanguineous families were investigated by SNP array-based homozygosity mapping and subsequent DNA sequencing of known candidate genes according to runs of homozygosity size in descending order. This led to the identification of the causative homozygous mutation in 62% of unrelated index cases. Based on our data we discuss various strategies for diagnostic mutation detection in the syndromic ciliopathies JS/JSRD, MKS and BBS., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Peters plus syndrome is an autosomal recessive rare disorder comprising ocular anterior segment dysgenesis, short stature, hand abnormalities, distinctive facial features, and often other major/minor additional defects. Peters plus syndrome is related to mutations in the B3GALTL gene with only seven recently reported mutations, leading to the inactivation of the B1, 3-glucosyltransferase. In this study, we screened the B3GALTL gene in two unrelated patients with typical Peters plus syndrome. A novel homozygous c.597-2A>G mutation was identified in both patients. Bioinformatic analyses showed that this mutation modulates the pre mRNA secondary structure of the gene, and decreases the score value related to the formation of splicing loops. Moreover, the c.597-2A>G mutation is located in a CpG Island of the B3GALTL gene, suggesting a potential epigenetic role of this position including gene's methylation and regulation. These data confirm an important role of the B3GALTL gene test that provides diagnosis confirmation and improves genetic counseling for the families., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The WNT4 gene plays a crucial role in sexual differentiation and female genital tract development. This study screened WNT4 for mutation in 189 Chinese women with Müllerian duct abnormalities (10 Mayer-Rokitansky-Küster-Hauser syndrome, five Müllerian aplasia and 174 incomplete Müllerian fusion) and detected no perturbation that would indicate a major role for WNT4. Only one novel synonymous mutation (c.1091G>A) in exon 5 and one known single-nucleotide polymorphism (rs16826648) in exon 2 were found. The results suggest that WNT4 might not contribute to the aetiology of Müllerian duct abnormalities in Chinese women., (Copyright © 2012 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Cohen syndrome (CS) (OMIM#216550) is an uncommon autosomal recessive developmental disorder that has been attributed to mutations in the COH1 gene in at least 200 patients of diverse ethnic background so far. The clinical heterogeneity of CS is evident when comparing patients of different ethnic backgrounds, especially when evaluating specific system phenotypes separately, such as the ophthalmic and central nervous systems. We reviewed the available clinical data on CS cohorts of patients who share a founder effect and demonstrated that most features associated so far with CS are less than those always present in the patients who share a founder mutation thus representing clinical heterogeneity. Furthermore, there is a wide clinical variability of CS in the distinct founder mutation cohorts, the Finnish, Greek/Mediterranean, Amish and Irish travelers. The Greek/Mediterranean founder mutation is correlated to a CS phenotype characterized by specific and persistent skeletal features, corneal changes, periodontal disease, a distinct neurocognitive phenotype for the high recurrence of autism and non-verbal communication and inconstant microcephaly., (© 2011 John Wiley & Sons A/S.)

Background: This study reports on a hitherto undescribed autosomal recessive syndrome characterised by dysmorphic features and multiple congenital anomalies together with severe neurological impairment, chorea and seizures leading to early death, and the identification of a gene involved in the pathogenesis of the disease., Methods: Homozygosity mapping was performed using Affymetrix Human Mapping 250k NspI arrays. Sequencing of all coding exons of the candidate genes was performed with primer sets designed using the Primer3 program. Fluorescence activated cell sorting was performed using conjugated antibody to CD59. Staining, acquisition and analysis were performed on a FACSCalibur flow cytometer., Results: Using homozygosity mapping, the study mapped the disease locus to 18q21.32-18q22.1 and identified the disease-causing mutation, c.2126G→A (p.Arg709Gln), in PIGN, which encodes glycosylphosphatidylinositol (GPI) ethanolamine phosphate transferase 1, a protein involved in GPI-anchor biosynthesis. Arginine at the position 709 is a highly evolutionarily conserved residue located in the PigN domain. The expression of GPI linked protein CD59 on fibroblasts from patients as compared to that in a control individual showed a 10-fold reduction in expression, confirming the pathogenic consequences of the mutation on GPI dependent protein expression., Conclusions: The abundant expression of PIGN in various tissues is compatible with the diverse phenotypic features observed in the patients and with the involvement of multiple body systems. The presence of developmental delay, hypotonia, and epilepsy combined with multiple congenital anomalies, especially anorectal anomalies, should lead a clinician to suspect a GPI deficiency related disorder.

Background: A novel phenotype consisting of cataract, mental retardation, erythematous skin rash and facial dysmorphism was recently described in an extended pedigree of Australian Aboriginal descent. Large scale chromosomal re-arrangements had previously been ruled out. We have conducted a genome-wide scan to map the linkage region in this family., Methods: Genome-wide linkage analysis using Single Nucleotide Polymorphism (SNP) markers on the Affymetrix 10K SNP array was conducted and analysed using MERLIN. Three positional candidate genes (ZBTB17, EPHA2 and EPHB2) were sequenced to screen for segregating mutations., Results: Under a fully penetrant, dominant model, the locus for this unique phenotype was mapped to chromosome 1p35.3-p36.32 with a maximum LOD score of 2.41. The critical region spans 48.7 cM between markers rs966321 and rs1441834 and encompasses 527 transcripts from 364 annotated genes. No coding mutations were identified in three positional candidate genes EPHA2, EPHB2 or ZBTB17. The region overlaps with a previously reported region for Volkmann cataract and the phenotype has similarity to that reported for 1p36 monosomy., Conclusions: The gene for this syndrome is located in a 25.6 Mb region on 1p35.3-p36.32. The known cataract gene in this region (EPHA2) does not harbour mutations in this family, suggesting that at least one additional gene for cataract is present in this region.

Background: Nonsyndromic cleft lip with or without cleft palate is a common birth defect. Although a number of susceptibility loci have been reported, replication has often been lacking. This is likely due, in part, to the heterogeneity of datasets and methodologies. Two independent genome-wide association studies of individuals of largely western European extraction have identified a possible susceptibility locus on 8q24.21., Methods: To determine the overall effect of this locus, we genotyped six of the previously associated single nucleotide polymorphisms in our Hispanic and non-Hispanic white family-based datasets and evaluated them for linkage and association. In addition, we genotyped a large African American family with nonsyndromic cleft lip with or without cleft palate that we had previously mapped to the 8q21.3-24.12 region to test for linkage., Results: There was no evidence for linkage to this region in any of the three ethnic groups. Nevertheless, strong evidence for association was noted in the non-Hispanic white group, whereas none was detected in the Hispanic dataset., Conclusion: These results confirm the previously reported association and provide evidence suggesting that there is ethnically based heterogeneity for this locus., ((c) 2010 Wiley-Liss, Inc.)

Background: Children with 22q11.2 deletion syndrome (22q11.2DS) have a wide range of clinical features. TBX1 has been proposed as a candidate gene for some of the features in this condition. Polymorphisms in the nondeleted TBX1, which may affect the function of the sole TBX1 gene in individuals with the 22q11.2DS, may be a key to understanding the phenotypic variability among individuals with a shared deletion. Comprehensive single nucleotide polymorphism (SNP) discovery by resequencing candidate genes can identify genetic variants that influence a given phenotype. The purpose of this study was to further characterize the sequence variability in TBX1 by identifying all common SNPs in this gene., Methods: We resequenced TBX1 in 29 children with a documented 22q11.2 deletion and 95 nondeleted, healthy individuals. We estimated allele frequencies, performed tagSNP selection, and inferred haplotypes. We also compared SNP frequencies between 22q11.2DS and control samples., Results: We identified 355 biallelic markers among the 190 chromosomes resequenced in the control panel. The vast majority of the markers identified were SNPs (n = 331), and the remainder indels (n = 24). We did not identify SNPs or indels in the cis- regulatory element (FOX-binding site) upstream of TBX1. In children with 22q11.2DS we detected 187 biallelic markers, six of which were indels. Four of the seven coding SNPs identified in the controls were identified in children with 22q11.2DS., Conclusions: This comprehensive SNP discovery data can be used to select SNPs to genotype for future association studies assessing the role of TBX1 and phenotypic variability in individuals with 22q11.2DS., (Copyright 2009 Wiley-Liss, Inc.)

Background: Much remains unknown regarding extrathyroidal congenital malformations (ECMs) in patients with primary congenital hypothyroidism (PCH) and Down syndrome (DS). Here, we investigated the frequency of ECMs in patients with PCH, particularly among patients with or without DS., Methods: In a retrospective review of questionnaires based on medical records, ECMs were identified in 1520 patients with PCH and were compared with congenital malformations among nationwide live births or liveborn infants with DS. The ECMs in PCH patients with or without DS were then analyzed. The statistical analysis was based on the Poisson distribution. Ethnicity, sex, and familial and seasonal factors were also observed in relation to the ECMs., Results: The incidences of ECMs (222/1520, 14.6%) and DS (86/1520, 5.7%) were significantly higher among the PCH patients than among the general population. Among the 127 PCH patients without chromosomal abnormalities, 101 had a single ECM and 26 had multiple ECMs. Unlike previously reported American and Egyptian patients with PCH, a significantly higher incidence of cardiovascular malformations was observed in the Japanese PCH patients, and a female predominance was also observed, except in patients with multiple ECMs. Regarding the PCH patients with DS, a significantly higher, male-predominant incidence of duodenal atresia was observed, compared with data for liveborn infants with DS, whereas a male-predominant, significantly higher incidence of gastrointestinal malformations and a female-predominant, significantly higher incidence of cardiovascular malformations were found compared with data among PCH patients without DS. Moreover, urogenital and orofacial ECMs were absent among the PCH patients with DS. Regarding PCH patients without DS, a male-predominant, significantly higher incidence of urogenital malformations and a female-predominant, significantly higher incidence of cardiovascular and nervous malformations were found, compared with data for nationwide live births. In PCH patients with DS and in PCH patients with a single ECM, both familial and seasonal factors existed, while in PCH patients with multiple ECMs, only familial factors were observed., Conclusion: The incidence of ECMs in PCH patients was significantly higher than in the normal population, and ethnic-, sex-, and DS-related differences were observed. Genetic and environmental factors were also identified in PCH patients with ECMs.

Walker-Warburg syndrome (WWS) is a genetically heterogeneous autosomal recessive disease characterized by congenital muscular dystrophy, cobblestone lissencephaly, and ocular malformations. Mutations in six genes involved in the glycosylation of á-dystroglycan (POMT1, POMT2, POMGNT1, FCMD, FKRP and LARGE) have been identified in WWS patients, but account for only a portion of WWS cases. To better understand the genetics of WWS and establish the frequency and distribution of mutations across WWS genes, we genotyped all known loci in a cohort of 43 WWS patients of varying geographical and ethnic origin. Surprisingly, we reached a molecular diagnosis for 40% of our patients and found mutations in POMT1, POMT2, FCMD and FKRP, many of which were novel alleles, but no mutations in POMGNT1 or LARGE. Notably, the FCMD gene was a more common cause of WWS than previously expected in the European/American subset of our cohort, including all Ashkenazi Jewish cases, who carried the same founder mutation., ((c) 2008 Wiley-Liss, Inc.)

We describe four patients, two pairs of siblings, with a somewhat unique oro-facial-digital syndrome. The siblings come from the Navajo population which has undergone several genetic "bottlenecks." Thus, as would be anticipated, this syndrome seems to show autosomal recessive inheritance. The combination of the presence of retinal colobomata and the paucity of digital findings in these patients leads us to believe that their condition is best described as a variant of oro-facial-digital syndrome IX. In addition to retinal colobomata, these patients also show severe microcephaly, mental retardation and short stature., ((c) 2007 Wiley-Liss, Inc.)

Objective: To explore the prevalence of oral clefting in northern Iran., Setting: In the Dezyani hospital 37,951 live births from 1998 through 2003 were screened for oral clefts. Clinical and demographic factors of diagnosed cases, including birth date, ethnicity, type of oral cleft, parental consanguinity, and coexisting anomalies, were recorded for analysis., Results: The overall prevalence of oral clefting was 0.97 per 1000 live births. The prevalence of cleft lip with or without cleft palate and isolated cleft palate was 0.60 and 0.37 per 1000, respectively. The prevalence of oral clefting was 1.08 per 1000 male births and 0.86 per 1000 female births. With respect to parental ethnicity, the prevalence of oral clefting was 0.86, 0.88, and 1.47 per 1000 in Fars, Turkman, and Sistani, respectively., Conclusions: The prevalence of oral cleft among live births in the Dezyani hospital is similar to that reported in the previous studies for Iran and whites.

Currarino syndrome (CS) is a rare autosomal dominant disease that has been described as a triad of partial sacral agenesis, anorectal anomalies, and a presacral mass. Mutations in the HLXB9 gene have been suggested to be the genetic background of CS. In this study, sequence analysis of the HLXB9 gene was performed in two familial and two sporadic Korean patients showing the clinical features of CS, and two mutations in the HLXB9 gene were identified only in the two familial cases. One mutation (R295W) has been reported previously, and the other (H260_Q261delinsLELLELE) is novel. Consistent with previous observations, the phenotypic expression of the mutation carriers in the CS families varies from mild to severe, including the complete triad. This study confirms that familial CS patients in Korea have the same genetic background as other ethnicities and reaffirms the phenotype variability among CS patients with the same mutation.

Congenital malformations are among the major causes of perinatal mortality and morbidity at present. Research into the ethnic diversity of congenital malformations can form a basis both for aetiological studies and for health care advice and planning. This study compared the overall prevalence of congenital malformations, the prevalence in different organ systems and of several specific malformations between different maternal ethnic groups in the Netherlands using a 5-year national birth cohort (1996-2000) containing 881 800 births. Maternal ethnic groups considered were Dutch; Mediterranean (Moroccan/Turkish); other European; Black; Hindu and Asian. Mediterranean women had a 20% higher risk of having a child with a congenital malformation than Dutch women (age-adjusted OR = 1.21 [95% CI 1.16, 1.27]). They showed an increased risk of malformations in several organ systems such as the central nervous system and sensory organs, the urogenital system and skin and abdominal wall. Further, they had an increased risk of the group of chromosomal malformations/multiple malformations/syndromes. For the specific group of multiple malformations the maternal age adjusted OR was 1.80 [95% CI 1.47, 2.20]. The Black group showed a significantly increased risk of skeletal and muscular malformations (age adjusted OR = 1.76 [95% CI 1.53, 2.02]) with a sixfold increased risk of polydactyly compared with the Dutch group. For Mediterranean women, the largest and fastest growing group of immigrants in the Netherlands, this study demonstrated an increased risk of congenital malformations.

Walker-Warburg syndrome (WWS) is an autosomal recessive disorder of infancy characterized by hydrocephalus, agyria, retinal dysplasia, congenital muscular dystrophy, and over migration of neurons through a disrupted pial surface resulting in leptomeningeal heterotopia. Although previous work identified mutations in the o-mannosyl transferase, POMT1, in 6 out of 30 WWS families [Beltran-Valero de Bernabe et al., 2002], the incidence of POMT1 mutations in WWS is not known. We sequenced the entire coding region of POMT1 in 30 consecutive, unselected patients with classic WWS. Two novel heterozygous mutations were found in two patients from non-consanguineous parents, whereas 28 other patients failed to show any POMT1 mutations. One patient was found to be heterozygous for a transition, g.1233T > A, which predicts p.Y352X. A second patient was found also to be heterozygous for a transition g.1790C > G, which predicts p.S537R. As an additional determination of the frequency of the POMT1 mutations in WWS, we tested for linkage of WWS to POMT1 in six consanguineous families. All six demonstrated heterozygosity and negative LOD scores at the POMT1 locus. From these data we show that POMT1 is an uncommon cause of WWS, the incidence of coding region mutations in this population of WWS being less than 7%. We conclude that while the incidence of POMT1 mutations in WWS can be as high as 20% as reported by Beltran-Valero de Bernabe et al. [2002] and it can be as low as approximately 7%, as reported here., ((c) 2005 Wiley-Liss, Inc.)

Bowen-Conradi syndrome (BCS) is a lethal autosomal recessive disorder with an estimated incidence of 1 in 355 live births in the Hutterite population. A few cases have been reported in other populations. Here, we report the results of a genome-wide scan and fine mapping of the BCS locus in Hutterite families. By linkage and haplotype analysis the BCS locus was mapped to a 3.5 cM segment (1.9 Mbp) in chromosome region 12p13.3 bounded by F8VWF and D12S397. When genealogical relationships among the families were taken into account in the linkage analysis, the evidence for linkage was stronger and the number of potentially linked regions was reduced to one. Under the assumption that all the Hutterite patients were identical by descent for a disease-causing mutation, haplotype analysis was used to infer likely historical recombinants and thereby narrow the candidate region to a chromosomal segment shared in common by all the affected children. This study also demonstrates that BCS and cerebro-oculo-facial-skeletal syndrome (COFS) are genetically distinct.

Cohen syndrome is a rare autosomal recessive disorder with a variable clinical picture mainly characterized by developmental delay, mental retardation, microcephaly, typical facial dysmorphism, progressive pigmentary retinopathy, severe myopia, and intermittent neutropenia. A Cohen syndrome locus was mapped to chromosome 8q22 in Finnish patients, and, recently, mutations in the gene COH1 were reported in patients with Cohen syndrome from Finland and other parts of northern and western Europe. Here, we describe clinical and molecular findings in 20 patients with Cohen syndrome from 12 families, originating from Brazil, Germany, Lebanon, Oman, Poland, and Turkey. All patients were homozygous or compound heterozygous for mutations in COH1. We identified a total of 17 novel mutations, mostly resulting in premature termination codons. The clinical presentation was highly variable. Developmental delay of varying degree, early-onset myopia, joint laxity, and facial dysmorphism were the only features present in all patients; however, retinopathy at school age, microcephaly, and neutropenia are not requisite symptoms of Cohen syndrome. The identification of novel mutations in COH1 in an ethnically diverse group of patients demonstrates extensive allelic heterogeneity and explains the intriguing clinical variability in Cohen syndrome.

Background: Oralfacial clefting (OFC) disorders require expedient evaluation and treatment to obtain optimal outcome. In Florida, there is a statewide program targeted to the care of infants with OFC. We therefore sought to determine statewide referral and treatment patterns of children born with OFC identified through the Florida Birth Defects Registry., Methods: Using data for 1996 and 1997 and ICD-9 CM codes 749.00 - 749.25, we identified 539 OFC cases. All cases were matched with the evaluation and treatment records of the statewide Children's Medical Services' (CMS) craniofacial centers (CFC) and cleft palate clinics (CPC). The likelihood of CMS contact was examined with respect to demographic and other descriptive data characterizing the OFC cases., Results: 42% (227/539) of OFC cases were evaluated at or known to the CFC or CPC. Children with cleft lip and palate were more likely to have had contact than were those with cleft lip or cleft palate alone. The CFC and CPC programs were most likely to provide evaluation between age 2 months and 3 years. Of 12 counties with occurrences of more than 15 OFC cases, 2 had significantly lower contact rates, suggesting possible problems in accessibility or reporting of services., Conclusions: Statewide Birth Defect Registry data can be used in collaboration with statewide treatment programs to gain insight into referral patterns and provision of services. Factors influencing access to services and quality of care, though not addressed by this study, could be prospectively incorporated into such a project.

Oesophageal atresia (OA) is often associated with anomalies of other systems. The genetic contribution to the formation of the VACTERL association is not clear. The objective of this study was to evaluate the incidence of associated anomalies in two different racial populations. The associated anomalies in neonates with OA managed in an Asian and a European paediatric surgical centre from 1982 to 1998 were reviewed. Non-Asian and non-European patients were excluded from the respective centres. The incidence of anomalies was compared using Fisher's exact test, taking #E5/E5# below 0.05 as statistically significant. Forty-eight consecutive Asian (25 boys and 23 girls) and 34 consecutive European patients (20 boys and 14 girls) were included in the analysis. The percentage of patients with at least one associated anomaly was 50% and 74% in the Asian and European populations, respectively, which was significantly different (#E5/E5#=0. 04). There was no statistically significant difference in the incidence of associated cardiovascular (29% vs 39%), anorectal (11% vs 18%), and musculoskeletal (16% vs 22%) anomalies, duodenal atresia (4% vs 3%), or Down's syndrome (3% vs 6%) between the two populations. However, the European patients had a significantly higher incidence of urogenital (UG) anomalies (26% vs 4%, #E5/E5#=0.006), the most common being agenesis (n=4) and dysplasia (n=3) of one or both kidneys. Hereditary factors may influence the incidence of associated anomalies in children with OA, particularly of the UG system. However, environmental factors cannot be excluded.

Nine cases of Kabuki syndrome have been identified in Auckland and surrounding regions in the North Island, New Zealand since 1995. All have the characteristic facial dysmorphism and many of the well-described associated anomalies. Some of the abnormalities were unusual including a case with severe congenital mitral stenosis, two cases of eventration of the diaphragm, idiopathic thrombocytopaenic purpura and vitiligo. One child had an Arnold Chiari type 1 malformation and another had epibulbar dermoids, neither of which has previously been reported in this syndrome. There was a wide diversity of ethnic origin, with the syndrome being described in patients from the Pacific Islands for the first time. The cases described emphasize the broad range of associated anomalies found in Kabuki syndrome and further illustrate its presence in all ethnic groups.

This article explores the world of Sideshow Alley, which emerged from the ancient fair culture of Britain and took root in the agricultural show movement of Australia by the 1880s. There it flourished until the 1950s, when modernity and respectability caused its demise. The article also argues that Sideshow Alley was a place of power that helped to shape the identities of many Australians through the display of difference and that it also provided a site of agency for those displaying themselves.

Meckel syndrome (MKS) is a rare autosomal recessive lethal condition of unknown origin, characterized by (i) an occipital meningo-encephalocele with (ii) enlarged kidneys, with multicystic dysplasia and fibrotic changes in the portal area of the liver and with ductal proliferation, and (iii) postaxial polydactyly. A gene responsible for MKS in Finland has been mapped to chromosome 17q21-q24. Studying a subset of Middle Eastern and northern African MKS families, we have recently excluded the chromosome 17 region and have suggested a genetic heterogeneity. In the present study, we report on the mapping of a second MKS locus (MKS2) to chromosome 11q13, by homozygosity mapping in seven families that do not show linkage to chromosome 17q21-q24 (maximum LOD score 4.41 at recombination fraction .01). Most interestingly, the affected fetuses of southern Tunisian ancestry shared a particular haplotype at loci D11S911 and D11S906, suggesting that a founder effect is involved. Our observation gives support to the clinical and genetic heterogeneity of MKS.

Multiple congenital anomalies (MCA) in two siblings and digit abnormalities in four related individuals from a large highly inbred Muslim family are described. The pattern of MCA is consistent with the autosomal recessive Kaufman-McKusick syndrome [MIM 236700]. The present report reviews the previously published reports on this uncommon MCA dysmorphic syndrome and draws attention to the marked variation in the phenotype.

The paper describes associated malformations in infants born with neural tube defects (N = 3,809) from three large malformation registers and in fetuses aborted because of a diagnosed neural tube defect (N = 748) from two of the registers. In infants, upper spina bifida and encephalocele are more often associated with non-neural malformations than anencephaly or lower spina bifida. Aborted fetuses with spina bifida or encephalocele have associated malformations registered more often than infants with those neural tube defects, but the opposite is true for anencephaly. The degree of detail of the investigation of an aborted specimen or a perinatally dead infant will contribute to such differences but they can also depend on the fact that prenatal detection may be facilitated by the simultaneous presence of other malformations like body wall defects. Also, fetuses with many malformations may be more prone to abort spontaneously late in pregnancy. Variable prenatal diagnosis may, therefore, explain population differences in the pattern of associated malformations. The type of associated malformation differs with the level of the neural tube defect: this could be due to different causal mechanisms or be a question of cranio-caudal level and/or timing. For limb reduction defects, however, we did not find any association between upper limb and upper neural tube defects or lower limb and lower neural tube defects. These findings together with other epidemiological data support the idea that upper and lower neural tube defects may have different significance in epidemiological studies and should be treated separately.

We describe a large Acadian kindred including 8 Alstrom Syndrome (AS) patients, with an age range of 4 to 26 at the time of clinical assessment. The affected subjects come from 5 nuclear families within this kindred. The phenotype includes early childhood retinopathy, progressive sensorineural hearing loss, truncal obesity, and acanthosis nigricans. In addition, hyperinsulinemia and hypertriglyceridemia with normal cholesterol levels were observed in most affected individuals tested. Non-insulin dependent diabetes mellitus and growth retardation appear to be age-related manifestations that occur post-adolescence. Younger affected children are not overtly hyperglycemic and are normal or above average height for age. Although the AS patients in kindred 1 presumably carry the same mutation, many manifestations of the disease are variable. For example, of the 8 children in the Acadian kindred, 4 have scoliosis, 2 have had infantile cardiomyopathy, 2 are hypothyroid, 1 has had hepatic dysfunction and is hypertensive, and 4 have developed asthma. Seven subjects described in this kindred exhibit developmental delay. One additional manifestation not described widely in the literature, advanced bone age, was observed in all subjects tested. The clinical data from this large Acadian kindred, together with information obtained from 4 additional AS patients in 3 unrelated kindreds, confirm and extend clinical observations previously described. In addition, the Acadian kindred with multiple affected individuals, probably arising from a common founder, should allow for identification of the chromosomal localization of a gene causing AS.

Marinesco-Sjögren syndrome is rarely reported in the Middle East. This is the 2nd report of Marinesco-Sjögren syndrome in an Arab family. The clinical features of 2 affected brothers are described. Electrophysiological studies of the 2 patients showed primarily myopathic changes, whereas sural nerve biopsy revealed segmental demyelination and axonal degeneration. The role of tissue biopsy and the relationship to different electrophysiological studies are discussed. Both patients were noticed to have abnormally short lateral 3 metatarsals, a feature not present in other healthy members of the family. We suggest that this feature should be considered part of the syndrome profile.

Congenital hydrocephalus and/or open neural tube defect was present in at least one individual of 98 families out of the 2,000 Palestinian Arabic families who have visited the Genetic clinic at the Hadassah Medical Center. In 22 families the brain malformation was part of a syndrome: Meckel syndrome in 10, Warburg syndrome in another 5, Carpenter in one, and undiagnosed in 6 families. In 76 of the families the neural tube defect and/or the hydrocephalus were non-syndromal. It seems that most of the cases of isolated non-syndromal hydrocephalus represented autosomal recessive traits and that an abnormal allele is common among Palestinian Muslim Arabs.

Cartilage-hair hypoplasia (CHH) is an autosomal recessive disorder that presents with pleiotropic manifestations including impaired skeletal growth and cellular immunity. It is most prevalent among two founder populations, the Old Order Amish in the USA and the Finns. The gene has been localized to 9p13 by linkage analysis and linkage disequilibrium mapping. A statistically significant deficiency of affected members resulting in a lower than expected segregation ratio has been reported in the Amish, but was not found in a previous study in Finnish CHH families. Reduced penetrance was the mechanism suggested in the Amish, but could not be verified by haplotype analyses performed after the assignment of the CHH gene. Here we have carried out segregation analysis of 101 Finnish CHH families, but again, evidence of a significant deficiency of affected members was not found. Nevertheless, among 54 uniplex families, 2 patients with CHH and uniparental disomy (UPD) for chromosome 9 were discovered. UPD might contribute to low segregation ratios by increasing the number of families with only 1 affected individual. These observations show that UPD may occur in an unexpectedly high number of the patients and should be taken into account in the genetic counselling and prenatal diagnostics of CHH families.

We report a patient with a rudimentary uterine horn, fallopian tube and ovary in an inguinal hernia. Associated with this abnormality the patient had ipsilateral renal agenesis and a unicornuate uterus.

Study Objective: To ascertain the incidence and spectrum of congenital anomalies in neonates born in a rural hospital., Design: This was a prospective, hospital-based study, undertaken on liveborn neonates over the period 12 June 1989 - 31 December 1992., Setting: Mankweng Hospital, Sovenga, Northern Transvaal., Main Results: Of a total of 10,380 neonates born during this period, 7,617 (73.4%) were examined within the first 24 hours of life. On the basis of published observations, only 26.2% of severe congenital anomalies diagnosable by age 5 years are diagnosable at birth. In this South African study the finding at birth of severe, externally visible congenital anomalies in 14.97 per 1,000 livebirths could mean that by age 5 years the minimum cumulative incidence of severe congenital anomalies may involve 57.14 per 1,000 children. Extrapolating from other Third-World studies, the cumulative incidence of severe congenital anomalies in such communities may affect up to 84.85 per 1,000 children by the age of 5 years. High incidences of neural tube defects (3.55 per 1,000 livebirths) and Down syndrome (2.10 per 1,000 livebirths), both conditions which can be prevented by prenatal screening, were recorded., Conclusions: These figures indicate the necessity for inclusion of appropriate prenatal, genetic, family planning and paediatric facilities into the primary health care delivery system of rural areas, to manage such problems and to initiate programmes to reduce the incidence of selected congenital anomalies such as Down syndrome and neural tube defects.

We describe two Malay male term neonates with congenital limb reduction defects. The first neonate had hypodactyly of limbs associated with micrognathia, microstomia, glossopalatine ankylosis and congenital mitral stenosis. He developed gram-negative septicaemia and died on day 14 of life. The second neonate had tetraperomelia without any other associated congenital abnormality. He developed staphylococcal skin infection which was treated conservatively. Very few cases of congenital limb reduction defects have been reported in the Asian population and we are not aware of any other reports describing Malay infants with the congenital abnormalities described in this report.

The Kabuki (Niikawa-Kuroki) syndrome was reported in 1981 by Niikawa et al. and Kuroki et al. in a total of ten unrelated Japanese children with a characteristic array of multiple congenital anomalies and mental retardation. The syndrome is characterized by a distinct face, mild to moderate mental retardation, postnatal growth retardation, dermatoglyphic and skeletal abnormalities. In Japan, the syndrome appears to have an incidence of about 1:32,000 newborns. Outside of Japan, a growing number of patients have been recognized. Clinical data are presented on 29 Caucasian patients; the patients were diagnosed over a relatively short period of time, indicating that the incidence outside of Japan is probably not lower than in Japan. A literature review of 89 patients (60 Japanese and 29 non-Japanese) is given. In 66% of the non-Japanese patients serious neurological problems were present, most notably hypotonia and feeding problems (which were not only related to the cleft palate); this was not reported in the Japanese patients. Inheritance is not clear. Most patients are isolated, sex-ratio is equal. The syndrome can be recognized in patients with cleft (lip/)palate, with mild to moderate developmental delay and in young children with hypotonia and/or feeding problems. In counselling parents, the designation "Kabuki" syndrome seems to be more appropriate than "Kabuki make-up" syndrome.

Isolated neural tube defects (NTDs) appear to have different risk factors compared to nonisolated NTDs. To extend those observations, we explored routinely collected child and parental characteristics as possible risk factors among isolated versus nonisolated NTD cases, among high versus low spina bifida cases, and among open versus skin-covered spina bifida case. Fetuses and liveborn infants with anencephaly or spina bifida among the 1983-87 cohort of births and fetal deaths (n = 712,863) were ascertained by the California Birth Defects Monitoring Program. One hundred and ninety-three anencephalic cases and 272 spina bifida cases were compared to a random sample of 5,000 liveborn infants. Among anencephalic cases, 55% were livebirths and 85% were isolated. The proportion of males was similar to females across all subgroups. Increased risks were found for Hispanic whites, with risk estimates highest for nonisolated cases (odds ratio = 4.0, 95% confidence interval [1.5, 10.5]). Among spina bifida cases, 92% were livebirths, 81% isolated, 82% open, and 86% were low. More males were found among the group with isolated high open defects, and fewer males were found among the group of all closed defects. The proportion of males was similar to females in all other subgroups. Cases were more likely to be Hispanic with risks largest for high open defects (odds ratio = 2.9, [1.2,6.6]), particularly for nonisolated cases. This study provides some evidence that further classifications of NTDs may reveal subgroupings of cases with different etiologies.

We present a child with an MCA pattern of sclerocornea, hypertelorism, pterygium colli, upper limb syndactyly, ambiguous genitalia, abnormal ears and nose, umbilical hernia, congenital heart disease, and normal chromosomes (46,XX). Although the defects observed in this case follow the diagnostic criteria for Fraser syndrome proposed by Thomas et al. [1986: Am J Med Genet 25:85-98], we think that this is a different entity.

The recombinant 8[Rec(8)] syndrome [rec(8), (8qter-->8q22.1::8p23.1-->8qter] is due to a parental inv(8)(8pter-->8p23.1::8q22.1-->8p23.1::8q22+ ++.1-->8qter). All inv(8) parents we have studied were of Hispanic origin. The Rec(8) phenotype consists of a characteristic set of minor facial anomalies, cardiovascular and other major malformations, and moderate to severe mental retardation. The clinical phenotype is relatively consistent in all published cases; however the natural history of the condition has remained unknown. Retrospective and prospective information on 42 propositi, spanning a period from 5 days to 23 years, allowed us to define the natural history of this syndrome, tabulate the frequency and the evolution of phenotypic abnormalities, and share our experience with different therapeutic approaches.

Spondylothoracic dysplasia (STD) syndrome or the Jarcho-Levin syndrome has been seen commonly in Puerto Ricans. A case of STD syndrome in a Chinese baby which we believe is the first reported case in an Asian baby is reported. The skeletal disorder syndrome affecting the spine, ribs and thorax is an autosomal recessive disorder with associated non-skeletal anomalies. It should not be confused with the phenotypically similar skeletal disorder known as spondylocostal dysplasia, which is an autosomal dominant disease.

Kabuki make-up (Niikawa-Kuroki) syndrome has been described mainly in Japanese patients. In this paper we report sixteen new cases from Europe and North America, suggesting that Kabuki make-up syndrome may be more common outside of Japan than supposed. Their features are compared with those of the Japanese patients and most of our findings are similar to those previously reported. The facial phenotype is specific and easily recognizable, regardless of ethnic origin. Postnatal growth retardation and mild mental retardation are confirmed to be cardinal manifestations of the syndrome. Skeletal anomalies were present in all cases but most of the radiological changes were non-specific. The specificity of metacarpophalangeal pattern profile is not confirmed. Conversely, dermatoglyphic analysis is helpful in the diagnosis of this condition. Two differences have emerged between the Japanese patients and those in this study. Firstly, two-thirds of the patients in this series had significant neurological dysfunction other than mental retardation. Secondly, joint hypermobility appears more common in non-Japanese patients. Confirmation of these findings requires further studies.