Maternal isodisomy for 14q21-q24 in a man with diabetes mellitus

The association of craniosynostosis with ectopia lentis is extremely rare. This was recently reported in monozygotic twin sisters, supporting a genetic etiology for this syndromic association. We report on female first cousins once removed who were born with unilateral coronal synostosis. One cousin also had peripheral pulmonic branch stenosis at birth and was later found to have ectopia lentis and severe myopia. The other cousin had an atrial septal defect, mitral valve prolapse, and only mild myopia. Their intelligence is normal. The inheritance is likely autosomal dominant with variable expression and incomplete penetrance and further defines this syndrome to include congenital heart defects. These findings will have important implications for genetic counseling.     

Craniosynostosis associated with ectopia lentis in monozygotic twin sisters.

Ectopia lentis has rarely been reported to occur in association with craniosynostosis, and this was found only in sporadic cases. We report on twin sisters who underwent surgery for craniosynostosis and later on, at age 3 years, were found to have bilateral ectopia lentis. Molecular studies yielded a probability of monozygosity of more than 0.98. Inheritance of the syndrome may be autosomal dominant, possibly due to a new mutation, autosomal recessive, or X-linked with male lethality.     

Ectopia lentis et pupillae: the genetic aspects and differential diagnosis.

Two sib pairs and a fifth child are described with autosomal recessive ectopia lentis et pupillae. Patients with this disorder need regular ophthalmic review, but do not have the skeletal and metabolic complications associated with other syndromes with ectopia lentis.     

Craniosynostosis associated with ectopia lentis in monozygotic twin sisters

Ectopia lentis has rarely been reported to occur in association with craniosynostosis, and this was found only in sporadic cases. We report on twin sisters who underwent surgery for craniosynostosis and later on, at age 3 years, were found to have bilateral ectopia lentis. Molecular studies yielded a probability of monozygosity of more than 0.98. Inheritance of the syndrome may be autosomal dominant, possibly due to a new mutation, autosomal recessive, or X-linked with male lethality. Am. J. Med. Genet. 82:201–205, 1999. © 1999 Wiley-Liss, Inc.     

Clinical homogeneity and genetic heterogeneity in Weill-Marchesani syndrome

Weill-Marchesani syndrome (WMS) is a rare condition characterized by short stature, brachydactyly, joint stiffness, and characteristic eye abnormalities including microspherophakia, ectopia of lens, severe myopia, and glaucoma. Both autosomal recessive (AR) and autosomal dominant (AD) modes of inheritance have been described for WMS. A locus for AR WMS has recently been mapped to chromosome 19p13.3-p13.2 while mutation within the fibrillin-1 gene (15q21.1) was found in one AD WMS family. In order to answer the question of whether or not genetic heterogeneity could be related to a clinical heterogeneity, we reviewed 128 WMS patients from the literature (including 57 AR, 50 AD, and 21 sporadic cases), with a particular attention to clinical features. Statistical analyses using Fischer exact test were used to compare the proportions of 12 clinical parameters between AR and AD patients. There was no significant difference between both groups for myopia, glaucoma, cataract, short stature, brachydactyly, thick skin, muscular build, and mental retardation. Significant results were found for microspherophakia (94% in AR, 74% in AD, Fischer 0.007), ectopia lentis (64% in AR, 84% in AD, Fischer 0.016), joint limitations (49% in AR, 77% in AD, Fischer 0.010), and cardiac anomalies (39% in AR, 13% in AD, Fischer 0.004). Nevertheless, we failed to distinguish AR from AD inheritance in individual cases. These results support the clinical homogeneity but the genetic heterogeneity of WMS.     

Ectopia lentis in Loeys‐Dietz syndrome type 4

Loeys‐Dietz syndrome is a heritable disorder of the connective tissue leading to multisystem involvement including craniofacial features, skeletal abnormalities, cutaneous findings and early‐onset and aggressive disease of the aorta and its branches. There are multiple types of Loeys‐Dietz syndrome related to pathogenic variants in TGFBR1, TGFBR2, SMAD3, TGFB2, and TGFB3. Individuals with Loeys‐Dietz syndrome may be misdiagnosed as having Marfan syndrome due to shared phenotypic features and aortic root dilation. However, ectopia lentis has been an important discriminating feature, being unique to Marfan syndrome and not reported to be associated with Loeys‐Dietz syndrome. We report the case of a 46‐year‐old woman with Loeys‐Dietz syndrome type 4 due to a pathogenic variant in TGFB2 who was diagnosed with ectopia lentis at age 44. The patient underwent whole exome sequencing and no other pathogenic variants were found to explain the ectopia lentis. Our findings indicate that ectopia lentis may be an uncommon finding in Loeys‐Dietz syndrome type 4 and emphasize the importance of genetic testing in familial thoracic aortic aneurysm disease.     

Trisomy 9p syndrome and XYY syndrome in siblings

Two brothers are described, who have the 9p+ syndrome, due to a balanced translocation (9:22) inherited from the mother, Another brother had an XYY karyotype. The 47,XYY case and his youngest trisomy 9p brother also had ectopia lentis.     

Ectopia lentis and aortic root dilatation in congenital contractural arachnodactyly

Congenital contractural arachnodactyly (CCA) was described by Beals and Hecht as an autosomal dominant disorder distinct from Marfan syndrome and comprising joint contractures, arachnodactyly, scoliosis, and a distinct “crumpled ear” deformity. While the disorder is similar to Marfan syndrome, it was split from it due to the distinct physical appearance of the patients and, more importantly, the lack of heart and eye findings. Since the original report, several CCA patients have been found to have mitral valve prolapse, structural cardiac anomalies, and occasionally aortic root dilatations similar to those seen in Marfan syndrome. We report on a patient with CCA with bilateral ectopia lentis and aortic root dilatation. Our review of the literature of CCA showed that serial echo-cardiography and careful eye examinations have not become a standard of medical practice in this condition. Partly this may be due to a lack of documented cases of CCA having severe ectopia lentis and cardiac complications. This patient underscores the need for periodic eye and echocardiographic evaluations of all CCA patients.     

Ectopia lentis and aortic root dilatation in congenital contractural arachnodactyly.

Congenital contractural arachnodactyly (CCA) was described by Beals and Hecht as an autosomal dominant disorder distinct from Marfan syndrome and comprising joint contractures, arachnodactyly, scoliosis, and a distinct "crumpled ear" deformity. While the disorder is similar to Marfan syndrome, it was split from it due to the distinct physical appearance of the patients and, more importantly, the lack of heart and eye findings. Since the original report, several CCA patients have been found to have mitral valve prolapse, structural cardiac anomalies, and occasionally aortic root dilatations similar to those seen in Marfan syndrome. We report on a patient with CCA with bilateral ectopia lentis and aortic root dilatation. Our review of the literature of CCA showed that serial echocardiography and careful eye examinations have not become a standard of medical practice in this condition. Partly this may be due to a lack of documented cases of CCA having severe ectopia lentis and cardiac complications. This patient underscores the need for periodic eye and echocardiographic evaluations of all CCA patients.     

Isolated congenital ectopia lentis with autosomal dominant inheritance

Although autosomal dominant inheritance of isolated ectopia lentis has been described, the literature contains old and unclear reports concerning the evaluation of skeletal or metabolic abnormalities. We report a family in which congenital isolated ectopia lentis occurs in five members of two generations in a pattern consistent with autosomal dominant inheritance.     

Mutations of FBN1 and genotype-phenotype correlations in Marfan syndrome and related fibrillinopathies

The Marfan syndrome (MFS) is a pleiotropic, autosomal dominant disorder of connective tissue with highly variable clinical manifestations including aortic dilatation and dissection, ectopia lentis, and a series of skeletal anomalies. Mutations in the gene for fibrillin-1 (FBN1) cause MFS, and at least 337 mainly unique mutations have been published to date. FBN1 mutations have been found not only in MFS but also in a range of connective tissue disorders collectively termed fibrillinopathies ranging from mild phenotypes, such as isolated ectopia lentis, to severe disorders including neonatal MFS, which generally leads to death within the first two years of life. The present article intends to provide an overview of mutations found in MFS and related disorders and to discuss potential genotype-phenotype correlations in MFS.     

Clinical utility of genetic testing in 201 preschool children with inherited eye disorders

PurposeA key property to consider in all genetic tests is clinical utility, the ability of the test to influence patient management and health outcomes. Here we assess the current clinical utility of genetic testing in diverse pediatric inherited eye disorders (IEDs).MethodsTwo hundred one unrelated children (0–5 years old) with IEDs were ascertained through the database of the North West Genomic Laboratory Hub, Manchester, UK. The cohort was collected over a 7-year period (2011–2018) and included 74 children with bilateral cataracts, 8 with bilateral ectopia lentis, 28 with bilateral anterior segment dysgenesis, 32 with albinism, and 59 with inherited retinal disorders. All participants underwent panel-based genetic testing.ResultsThe diagnostic yield of genetic testing for the cohort was 64% (ranging from 39% to 91% depending on the condition). The test result led to altered management (including preventing additional investigations or resulting in the introduction of personalized surveillance measures) in 33% of probands (75% for ectopia lentis, 50% for cataracts, 33% for inherited retinal disorders, 7% for anterior segment dysgenesis, 3% for albinism).ConclusionGenetic testing helped identify an etiological diagnosis in the majority of preschool children with IEDs. This prevented additional unnecessary testing and provided the opportunity for anticipatory guidance in significant subsets of patients.     

Marfan syndrome caused by a novel FBN1 mutation with associated pigmentary glaucoma

Mutations in fibrillin‐1 (FBN1) cause a wide spectrum of disorders, including Marfan syndrome, which have in common defects in fibrillin‐1 microfibrils. Ectopia lentis and myopia are frequently observed ocular manifestations of Marfan syndrome. Glaucoma is also associated with Marfan syndrome, though the form of glaucoma has not been well‐characterized. In this report, ocular examination of a patient diagnosed with Marfan syndrome based on family history and aortic dilatation was performed, including measurement of facility of aqueous humor outflow by tonography. The patient did not have ectopia lentis at the age of 42 years. Based on optic nerve appearance, reduced outflow facility, elevated IOP with open angles and clear signs of pigment dispersion, the patient was diagnosed with pigmentary glaucoma. The patient was heterozygous for a novel truncating mutation in FBN1, p.Leu72Ter. Histology of normal human eyes revealed abundant expression of elastic fibers and fibrillin‐1 in aqueous humor outflow structures. This is the first report of a patient with Marfan syndrome that is caused by a confirmed FBN1 mutation with associated pigmentary glaucoma. In addition to identifying a novel mutation of FBN1 and broadening the spectrum of associated ocular phenotypes in Marfan syndrome, our findings suggest that pigmentary glaucoma may involve defects in fibrillin‐1 microfibrils. © 2013 Wiley Periodicals, Inc.     

Genetic linkage of the Marfan syndrome, ectopia lentis, and congenital contractural arachnodactyly to the fibrillin genes on chromosomes 15 and 5. The International Marfan Syndrome Collaborative Study.

BACKGROUND. The large glycoprotein fibrillin is a structural component of elastin-containing microfibrils found in many tissues. The Marfan syndrome has been linked to the fibrillin gene on chromosome 15, but congenital contractural arachnodactyly, which shares some of the physical features of the syndrome, has been linked to the fibrillin gene on chromosome 5. METHODS. Using specific markers for the fibrillin genes, we performed genetic linkage analysis in 28 families with the Marfan syndrome and 8 families with four phenotypically related disorders--congenital contractural arachnodactyly (3 families), ectopia lentis (2), mitral-valve prolapse syndrome (2), and annuloaortic ectasia (1). RESULTS. Genetic linkage was established between the Marfan syndrome and only the fibrillin gene on chromosome 15, with a maximum lod score of 25.6 (odds for linkage, 10(25.6):1). Ectopia lentis was also linked to the fibrillin gene on chromosome 15, whereas congenital contractural arachnodactyly was linked to the fibrillin gene on chromosome 5. There was no linkage of mitral-valve prolapse to the fibrillin gene on chromosome 5; studies of chromosome 15 were not informative. Annuloaortic ectasia was not linked to either fibrillin gene. CONCLUSIONS. The Marfan syndrome appears to be caused by mutations in a single fibrillin gene on chromosome 15. Diagnosis of the Marfan syndrome by genetic linkage and analysis is now feasible in many families.     

Clinical and genetic analysis of Korean patients with Marfan syndrome: possible ethnic differences in clinical manifestation

Yoo E‐H, Woo H, Ki C‐S, Lee HJ, Kim D‐K, Kang I‐S, Park P, Sung K, Lee CS, Chung T‐Y, Moon JR, Han H, Lee S‐T, Kim J‐W. Clinical and genetic analysis of Korean patients with Marfan syndrome: possible ethnic differences in clinical manifestation. Marfan syndrome (MFS) is an autosomal dominant disorder of the fibrous connective tissue caused by mutations in the fibrillin‐1 (FBN1) gene. Although clinical and genetic analyses have been performed in various populations, there have been few studies in Korea. The aim of this study was to investigate the clinical characteristics and genetic background of Korean patients with MFS. In 39 Korean patients with MFS who met the Ghent criteria, the most common clinical finding was aortic dilatation and/or dissection (94.9%), whereas only 35.9% of patients had ectopia lentis. The majority of MFS patients had fewer than four of the skeletal findings required to fulfill the major skeletal Ghent criterion for MFS. Only 21% of Korean patients had major skeletal abnormalities and most cases showed only minor skeletal involvement. FBN1 gene mutations were detected in 35 out of 39 patients (89.7%), which is similar to rates presented in the previous reports. These results suggest that some clinical features in Korean patients with MFS differed from those reported in Western MFS patients.     

Pentalogy of Cantrell and ectopia cordis,a familial developmental field complex

The association of sternal fusion defects with various cardiac, diaphragmatic, and anterior body wall defects represents a developmental field complex that includes the Pentalogy of Cantrell and ectopia cordis. No familial cases have been reported previously. We present 3 consecutively born brothers with extensive diaphragmatic defects, 2 who had the Pentalogy of Cantrell. One of the 2 also had ectopia cordis.     

Pentalogy of Cantrell and ectopia cordis, a familial developmental field complex.

The association of sternal fusion defects with various cardiac, diaphragmatic, and anterior body wall defects represents a developmental field complex that includes the Pentalogy of Cantrell and ectopia cordis. No familial cases have been reported previously. We present 3 consecutively born brothers with extensive diaphragmatic defects, 2 who had the Pentalogy of Cantrell. One of the 2 also had ectopia cordis.     

LTBP2 null mutations in an autosomal recessive ocular syndrome with megalocornea, spherophakia, and secondary glaucoma

The latent TGFβ-binding proteins (LTBPs) and fibrillins are a superfamily of large, multidomain proteins with structural and TGFβ-signalling roles in the extracellular matrix. Their importance is underscored by fibrillin-1 mutations responsible for Marfan syndrome, but their respective roles are still incompletely understood. We report here on two families where children from healthy, consanguineous parents, presented with megalocornea and impaired vision associated with small, round, dislocated lenses (microspherophakia and ectopia lentis) and myopia, as well as a high-arched palate, and, in older children, tall stature with an abnormally large arm span over body height ratio, that is, associated features of Marfan syndrome. Glaucoma was not present at birth, but was diagnosed in older children. Whole genome homozygosity mapping followed by candidate gene analysis identified homozygous truncating mutations of LTBP2 gene in patients from both families. Fibroblast mRNA analysis was consistent with nonsense-mediated mRNA decay, with no evidence of mutated exon skipping. We conclude that biallelic null LTBP2 mutations cause the ocular phenotype in both families and could lead to Marfan-like features in older children. We suggest that intraocular pressures should be followed-up in young children with an ocular phenotype consisting of megalocornea, spherophakia and/or lens dislocation, and recommend LTBP2 gene analysis in these patients.     

Myopia as a latent phenotype of a pleiotropic gene positively selected for facilitating neurocognitive development, and the effects of environmental factors in its expression

Myopia has become an almost pandemic problem in many populations. There are compelling evidence to suggest that myopia is a hereditary condition. However, myopia would constitute a definite selection disadvantage during most stages of human evolution, which is incompatible with its moderate to high prevalence in most modern populations. The rapid upsurge of myopia over just a few decades also implies that its inheritance does not follow any of the usual patterns, and environmental factors may have an important role in precipitating its occurrence in those who are genetically predisposed. Previous studies showed that myopes were, on average, more intelligent than non-myopes, and this association had been attributed to a biological link between eye growth and brain development. We propose a pleiotropic genetic model to explain the atypical epidemiologic and inheritance pattern of myopia and its relationship with neurocognitive development. This pleiotropic gene was positively selected for its facilitation of human intelligence. The myopic component is a latent phenotype; myopia will not be expressed unless some novel external factors are encountered (i.e. a "quirk" phenomenon). Therefore, the myopic component was selectively neutral in our ancestral environment. The net gain in Darwinian fitness enables the pleiotropic gene to attain a high frequency in the human population, as reflected by our current prevalence of myopia.     

Fibrillin-1 mutations in Marfan syndrome and other type-1 fibrillinopathies

Fibrillin is the major component of extracellular microfibrils and is widely distributed in connective tissue throughout the body. Mutations in the fibrillin-1 FBN1) gene, on chromosome 15q21.1, have been found to cause Marfan syndrome, a dominantly inherited disorder characterised by clinically variable skeletal, ocular, and cardiovascular abnormalities. Fibrillin-1 mutations have also been found in several other related connective tissue disorders, such as severe neonatal Marfan syndrome, dominant ectopia lentis, familial ascending aortic aneurysm, isolated skeletal features of Marfan syndrome, and Shprintzen-Goldberg syndrome. Mutations are spread throughout the gene and, with the exception of neonatal Marfan syndrome, show no obvious clustering or phenotypic association. Hum Mutat 10:415–423, 1997. © 1997 Wiley-Liss, Inc.