Cornelia de Lange syndrome (CdLS) is a dominant multisystemic malformation syndrome due to mutations in five genes-NIPBL, SMC1A, HDAC8, SMC3, and RAD21. The characteristic facial dysmorphisms include microcephaly, arched eyebrows, synophrys, short nose with depressed bridge and anteverted nares, long philtrum, thin lips, micrognathia, and hypertrichosis. Most affected individuals have intellectual disability, growth deficiency, and upper limb anomalies. This study looked at individuals from diverse populations with both clinical and molecularly confirmed diagnoses of CdLS by facial analysis technology. Clinical data and images from 246 individuals with CdLS were obtained from 15 countries. This cohort included 49% female patients and ages ranged from infancy to 37 years. Individuals were grouped into ancestry categories of African descent, Asian, Latin American, Middle Eastern, and Caucasian. Across these populations, 14 features showed a statistically significant difference. The most common facial features found in all ancestry groups included synophrys, short nose with anteverted nares, and a long philtrum with thin vermillion of the upper lip. Using facial analysis technology we compared 246 individuals with CdLS to 246 gender/age matched controls and found that sensitivity was equal or greater than 95% for all groups. Specificity was equal or greater than 91%. In conclusion, we present consistent clinical findings from global populations with CdLS while demonstrating how facial analysis technology can be a tool to support accurate diagnoses in the clinical setting. This work, along with prior studies in this arena, will assist in earlier detection, recognition, and treatment of CdLS worldwide.

Pallister‐Killian syndrome (PKS) is a tissue limited mosaic disorder, characterized by variable degrees of neurodevelopmental delay and intellectual disability, typical craniofacial findings, skin pigmentation anomalies and multiple congenital malformations. The wide phenotypic spectrum of PKS in conjunction with the mosaic distribution of the i(12p) makes PKS an underdiagnosed disorder. Recognition of prenatal findings that should raise a suspicion of PKS is complicated by the fragmentation of data currently available in the literature and challenges in diagnosing a mosaic diagnosis on prenatal testing. Ultrasound anomalies, especially congenital diaphragmatic hernia, congenital heart defects, and rhizomelic limb shortening, have been related to PKS, but they are singularly not specific and are not present in all affected fetuses. We have combined prenatal data from 86 previously published reports and from our cohort of 114 PKS probands (retrospectively reviewed). Summarizing this data we have defined a prenatal growth profile and identified markers of perinatal outcome which collectively provide guidelines for early recognition of the distinctive prenatal profile and consideration of a diagnosis of PKS as well as for management and genetic counseling.

Facial analysis systems are becoming available to healthcare providers to aid in the recognition of dysmorphic phenotypes associated with a multitude of genetic syndromes. These technologies automatically detect facial points and extract various measurements from images to recognize dysmorphic features and evaluate similarities to known facial patterns (gestalts). To evaluate such systems' usefulness for supporting the clinical practice of healthcare professionals, the recognition accuracy of the Cornelia de Lange syndrome (CdLS) phenotype was examined with FDNA's automated facial dysmorphology novel analysis (FDNA) technology. In the first experiment, 2D facial images of CdLS patients with either an NIPBL or SMC1A gene mutation as well as non‐CdLS patients which were assessed by dysmorphologists in a previous study were evaluated by the FDNA technology; the average detection rate of experts was 77% while the system's detection rate was 87%. In the second study, when a new set of NIPBL, SMC1A and non‐CdLS patient photos was evaluated, the detection rate increased to 94%. The results from both studies indicated that the system's detection rate was comparable to that of dysmorphology experts. Therefore, utilizing such technologies may be a useful tool in a clinical setting.

±6.4 nmol/mL•min).Autotaxin protein content correlated with autotaxin activity (r = 0.62, p < 0.01).With a cut-off value of 30.0 nmol/mL•min, autotaxin had a sensitivity of 88% and specificity of 93% in diagnosing ICP from other pruritic disorders and a sensitivity of 80% and specificity of 85% from HELLP-syndrome and pre-eclampsia.In a subset of ICP women longitudinal studies during pregnancy revealed that autotaxin activity strongly rises in the third trimester of pregnancy.Sequential blood sampling in healthy controls showed that autotaxin displayed no circadian rhythm and was not influenced by oral food intake.Conclusion: Autotaxin activity represents a highly sensitive, specific and robust diagnostic tool in distinguishing ICP from other disorders of pregnancy and pregnancy-related liver diseases such as HELLPsyndrome, and (pre-)eclampsia.

The Cornelia de Lange syndrome (CdLS), also termed the Brachmann-de Lange syndrome (BDLS), is a complex dominant developmental disorder that is defined by characteristic facial features, mental and growth retardation, and limb, cardiac, gastrointestinal, audiologic, ophthalmologic, and genito-urinary abnormalities. IQs range from 30 to 86 with an average of 53. Many individuals demonstrate autistic behavior, including self-destructive tendencies, and they may avoid or reject social interactions and physical contact. Mutations in two genes involved in the chromosomal cohesin complex, NIPBL, SMC1A and SMC3, have been found to be causative of CdLS in over half of cases.

Cornelia de Lange syndrome (CdLS) (OMIM #122470, #300590 and #610759) is a dominant genetic disorder with multiple organ system abnormalities which is classically characterized by typical facial features, growth and mental retardation, upper limb defects, hirsutism, gastrointestinal and other visceral system involvement. Mutations in three cohesin proteins, a key regulator of cohesin, NIPBL, and two structural components of the cohesin ring SMC1A and SMC3, etiologically account for about 65% of individuals with CdLS. Cohesin controls faithful chromosome segregation during the mitotic and meiotic cell cycles. Multiple proteins in the cohesin pathway are also involved in additional fundamental biological events such as double‐strand DNA break repair and long‐range regulation of transcription. Moreover, chromosome instability was recently associated with defective sister chromatid cohesion in several cancer studies, and an increasing number of human developmental disorders is being reported to result from disruption of this pathway. Here, we will discuss the human disorders caused by alterations of cohesin function (termed ‘cohesinopathies’), with an emphasis on the clinical manifestations of CdLS and mechanistic studies of the CdLS‐related proteins.

Alagille syndrome (AGS) is caused by heterozygous mutations in JAG1, and mutations have been previously reported in about 70% of patients who meet clinical diagnostic criteria. We studied a cohort of 247 clinically well, defined patients, and using an aggressive and sequential screening approach we identified JAG1 mutations in 94% of individuals. Mutations were found in 232 out of 247 patients studied and 83 of the mutations were novel. This increase in the mutation rate was accomplished by combining rigorous clinical phenotyping, with a combination of mutation detection techniques, including fluorescence in situ hybridization (FISH), genomic and cDNA sequencing, and quantitative PCR. This higher rate of mutation identification has implications for clinical practice, facilitating genetic counseling, prenatal diagnosis, and evaluation of living-related liver transplant donors. Our results suggest that more aggressive screening may similarly increase the rate of mutation detection in other dominant and recessive disorders.

Objective To evaluate individuals with Cornelia de Lange syndrome previously screened for mutations in theNIPBLgene for genotype-phenotype correlations with regard to severity of ophthalmologic findings. Methods Fifty-four patients with Cornelia de Lange syndrome (26 mutation positive and 28 mutation negative) with varying extent and severity of ophthalmologic findings participated in the study. We conducted a retrospective analysis of ophthalmologic data obtained through survey responses and medical records. The severity of nasolacrimal duct obstruction, myopia, ptosis, and strabismus was classified. The severity of eye findings was compared relative to the presence vs the absence of mutations in the coding region ofNIPBLand relative to mutations predicted to result in a truncated protein (nonsense and frameshift mutations) vs missense mutations. Fisher exact test was used to determine the significance of these correlations. Results A trend toward increased ptosis severity was found among individuals with truncating (nonsense and frameshift) mutations compared with individuals with missense mutations (P = .07). Conclusion NIPBLmay be directly involved in ptosis pathogenesis. Clinical Relevance Elucidating the pathogenetic mechanisms of ophthalmologic morbidities in patients with de Lange syndrome may lead to more effective treatment.

ABSTRACT Objectives: To define the spectrum of intracranial events and cerebrovascular lesions in patients with Alagille syndrome using magnetic resonance imaging with angiography of the head and medical histories and to correlate the presence of lesions with the clinical outcome of bleeding or ischemic intracranial events. Methods: 26 patients with Alagille syndrome underwent magnetic resonance imaging with angiography of the head; 22 had no symptoms and underwent study for screening purposes and 4 were symptomatic with neurologic changes. The results of studies and the history of ischemic intracranial events were reviewed. Results: Cerebrovascular abnormalities were detected in 10 of 26 (38%) patients (9 by head magnetic resonance imaging with angiography and 1 by necropsy). The findings included stenoses of the internal carotid arteries unilaterally (n = 5) or bilaterally (n = 3), basilar artery aneurysm (n = 1) and middle cerebral artery aneurysm (n = 1). Among the 9 patients with cerebrovascular abnormalities detected by magnetic resonance imaging with angiography, 5 had no symptoms (23%, 5 of 22) and 4 were symptomatic. Thus, 100% of symptomatic patients had detected abnormalities and 23% of screened, asymptomatic patients had detected anomalies. Screening magnetic resonance imaging with angiography failed to detect vascular anomalies in 2 asymptomatic patients who had fatal ischemic intracranial events years later. There was evidence of progression of vascular abnormalities in 4 patients. Ischemic intracranial events occurred in 10 of 26 (38%) patients and were associated with cerebrovascular abnormalities in 6 of 10 patients. Conclusion: The cerebral vasculopathy of Alagille syndrome predominantly involves the internal carotid arteries. It is more prevalent than would be suggested by the number of symptomatic individuals, appears to be progressive and shares many similarities with moyamoya. Magnetic resonance imaging with angiography is useful to detect these lesions and may have a valuable role in screening for treatable lesions such as aneurysms.

Cornelia de Lange syndrome (CdLS; OMIM 122470) is a dominantly inherited disorder characterized by multisystem involvement, cognitive delay, limb defects, and characteristic facial features. Recently, mutations in NIPBL have been found in approximately 50% of individuals with CdLS. Numerous chromosomal rearrangements have been reported in individuals with CdLS. These rearrangements may be causative of a CdLS phenotype, result in a phenocopy, or be unrelated to the observed phenotype. We describe two half siblings with a der(3)t(3;12)(p25.3;p13.3) chromosomal rearrangement, clinical features resembling CdLS, and phenotypic overlap with the del(3)(p25) phenotype. Region-specific BAC probes were used to fine-map the breakpoint region by fluorescence in situ hybridization (FISH). FISH analysis places the chromosome 3 breakpoint distal to RP11-115G3 on 3p25.3; the chromosome 12 breakpoint is distal to BAC RP11-88D16 on 12p13.3. A review of published cases of terminal 3p deletions and terminal 12p duplications indicates that the findings in these siblings are consistent with the del(3)(p25) phenotype. Given the phenotypic overlap with CdLS, we have reviewed the reported cases of chromosomal rearrangements involved in CdLS to better elucidate other potential loci that could harbor additional CdLS genes. Additionally, to identify chromosome rearrangements, genome-wide array comparative genomic hybridization (CGH) was performed on eight individuals with typical CdLS and without identifiable deletion or mutation of NIPBL. No pathologic rearrangements were identified.

Background—Alagille syndrome (AGS) is a dominantly inherited multisystem disorder involving the liver, heart, eyes, face, and skeleton, caused by mutations inJagged1. Intracranial bleeding is a recognized complication and cause of mortality in AGS. There are multiple case reports of intracranial vessel abnormalities and other vascular anomalies in AGS. The objective of this study was to characterize the nature and spectrum of vascular anomalies in AGS.Methods and Results—Retrospective chart review of 268 individuals with AGS was performed. Twenty-five patients (9%) had noncardiac vascular anomalies or events. Sixteen patients had documented structural vascular abnormalities. Two had basilar artery aneurysms, 7 had internal carotid artery anomalies, and another had a middle cerebral artery aneurysm. Moyamoya disease was described in 1 patient. Three of the 16 patients had aortic aneurysms, and 2 had aortic coarctations. One of the patients with a basilar artery aneurysm also had coarctation of the aorta. One of the individuals with an internal carotid artery anomaly also had renal artery stenosis. Nine more patients had intracranial events without documented vessel abnormalities. Vascular accidents accounted for 34% of the mortality in this cohort.Conclusions—The vascular anomalies described in our cohort of AGS individuals identify an underrecognized and potentially devastating complication of this disorder. It is a major cause of morbidity and mortality in this population, accounting for 34% of the mortality. We have also reviewed the body of evidence supporting a role forJagged1and the Notch signaling pathway in vascular development.

American Journal of Medical Genetics Part AVolume 124A, Issue 2 p. 222-223 Correspondence Reply to correspondence from Sokol Binita M. Kamath, Binita M. Kamath Division of Gastroenterology and Nutrition, The Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, PennsylvaniaSearch for more papers by this authorKathleen M. Loomes, Kathleen M. Loomes Division of Gastroenterology and Nutrition, The Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, PennsylvaniaSearch for more papers by this authorDavid A. Piccoli, David A. Piccoli Division of Gastroenterology and Nutrition, The Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, PennsylvaniaSearch for more papers by this authorKaran E.M. Emerick, Karan E.M. Emerick Division of Gastroenterology, Children's Memorial Hospital, Chicago, IllinoisSearch for more papers by this authorRebecca J. Oakey, Rebecca J. Oakey Division of Human Genetics and Molecular Biology, The Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, PennsylvaniaSearch for more papers by this authorNancy B. Spinner, Nancy B. Spinner Division of Human Genetics and Molecular Biology, The Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, PennsylvaniaSearch for more papers by this authorIan D. Krantz, Corresponding Author Ian D. Krantz [email protected] Division of Human Genetics and Molecular Biology, The Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, PennsylvaniaDivision of Human Genetics and Molecular Biology, The Children's Hospital of Pennsylvania and University of Pennsylvania School of Medicine, Philadelphia, PA.Search for more papers by this author Binita M. Kamath, Binita M. Kamath Division of Gastroenterology and Nutrition, The Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, PennsylvaniaSearch for more papers by this authorKathleen M. Loomes, Kathleen M. Loomes Division of Gastroenterology and Nutrition, The Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, PennsylvaniaSearch for more papers by this authorDavid A. Piccoli, David A. Piccoli Division of Gastroenterology and Nutrition, The Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, PennsylvaniaSearch for more papers by this authorKaran E.M. Emerick, Karan E.M. Emerick Division of Gastroenterology, Children's Memorial Hospital, Chicago, IllinoisSearch for more papers by this authorRebecca J. Oakey, Rebecca J. Oakey Division of Human Genetics and Molecular Biology, The Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, PennsylvaniaSearch for more papers by this authorNancy B. Spinner, Nancy B. Spinner Division of Human Genetics and Molecular Biology, The Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, PennsylvaniaSearch for more papers by this authorIan D. Krantz, Corresponding Author Ian D. Krantz [email protected] Division of Human Genetics and Molecular Biology, The Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, PennsylvaniaDivision of Human Genetics and Molecular Biology, The Children's Hospital of Pennsylvania and University of Pennsylvania School of Medicine, Philadelphia, PA.Search for more papers by this author First published: 09 June 2003 https://doi.org/10.1002/ajmg.a.20336Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. REFERENCES Kamath BM, Loomes KM, Oakey RJ, Emerick KE, Conversano T, Spinner NB, Piccoli DA, Krantz ID. 2002. Facial features in Alagille syndrome: Specific or cholestasis facies? Am J Med Genet 112: 163– 170. Sokol RJ, Heubi JE, Balistreri WF. 1983. Intrahepatic “cholestasis facies”: Is it specific for Alagille syndrome? J Pediatr 1032: 205– 208. Volume124A, Issue215 January 2004Pages 222-223 ReferencesRelatedInformation