Neonatal-Onset Congenital Ectropion Uveae May Be Caused by a Distinct CYP1B1 Pathologic Variant.

PURPOSE: To report underlying genetic variants of recently described distinct phenotype of newborn glaucoma: neonatal-onset congenital ectropion uveae (NO-CEU). DESIGN: Prospective cohort study. METHODS: Setting: tertiary care teaching institute. SUBJECTS: Thirteen children with clinical diagnosis of NO-CEU who had completed 1-year follow-up after glaucoma surgery and had undergone clinical exome sequencing (CES) by selective capture and sequencing of the protein-coding regions of the genes including 19 candidate genes for NO-CEU were assessed. The same criteria were applied for evaluating pathogenicity of variants to all the candidate genes. OUTCOME MEASURES: primary-genetic variants found on CES keeping in view the clinical indication of congenital glaucoma; secondary-corneal clarity and intraocular pressure (IOP) at baseline and 1-year follow-up, interventions required to control IOP, and postoperative visual acuity. The genetic variants were correlated with the outcome. RESULTS: All 13 patients diagnosed with NO-CEU had onset of glaucoma at birth and severe bilateral disease. Twelve of 13 (92.3%) patients harbored CYP1B1 variants. Nine of these 12 patients (83.3%) were homozygous for [c.1169G>A(p.Arg390His)] in exon-3 of CYP1B, with 5 common homozygous single-nucleotide polymorphisms flanking the pathogenic variant. They had intractable glaucoma and required multiple surgeries. Six patients had persistent corneal opacities, necessitating optical iridectomies. Three patients were compound heterozygous for CYP1B1 variants, showing [c.1169G>A(p.Arg390His)] along with [c.1103G>A(p.Arg368His)], [c.1103G>A (p.Arg368His)] along with [c.1403_1429dup(p.Arg468_Ser476dup)], and [(c.1063C>T(p.Arg355Ter)] along with [c.1325del(p.Pro442GlnfsTer15)]. These patients had better visual outcomes. CONCLUSIONS: NO-CEU appears to be a phenotypic marker for specific CYP1B1 genotypes, one of which is [c.1169G>A(p.Arg390His)] in our study population. Phenotype recognition is helpful to characterize the underlying genetic variants.

CDH1-related blepharocheilodontic syndrome is associated with diffuse gastric cancer risk.

We report the first case of diffuse gastric cancer in an individual with familial blepharocheilodontic syndrome (BCD) due to a germline CDH1 likely pathogenic variant. To date, other BCD affected relatives are nonpenetrant for diffuse gastric cancer posing challenges to counseling regarding gastric and breast cancer surveillance, and preventative total gastrectomy.

Novel truncating mutations in CTNND1 cause a dominant craniofacial and cardiac syndrome.

CTNND1 encodes the p120-catenin (p120) protein, which has a wide range of functions, including the maintenance of cell-cell junctions, regulation of the epithelial-mesenchymal transition and transcriptional signalling. Due to advances in next-generation sequencing, CTNND1 has been implicated in human diseases including cleft palate and blepharocheilodontic (BCD) syndrome albeit only recently. In this study, we identify eight novel protein-truncating variants, six de novo, in 13 participants from nine families presenting with craniofacial dysmorphisms including cleft palate and hypodontia, as well as congenital cardiac anomalies, limb dysmorphologies and neurodevelopmental disorders. Using conditional deletions in mice as well as CRISPR/Cas9 approaches to target CTNND1 in Xenopus, we identified a subset of phenotypes that can be linked to p120-catenin in epithelial integrity and turnover, and additional phenotypes that suggest mesenchymal roles of CTNND1. We propose that CTNND1 variants have a wider developmental role than previously described and that variations in this gene underlie not only cleft palate and BCD but may be expanded to a broader velocardiofacial-like syndrome.

Clinical spectrum and pleiotropic nature of CDH1 germline mutations.

CDH1 encodes E-cadherin, a key protein in adherens junctions. Given that E-cadherin is involved in major cellular processes such as embryogenesis and maintenance of tissue architecture, it is no surprise that deleterious effects arise from its loss of function. E-cadherin is recognised as a tumour suppressor gene, and it is well established that CDH1 genetic alterations cause diffuse gastric cancer and lobular breast cancer-the foremost manifestations of the hereditary diffuse gastric cancer syndrome. However, in the last decade, evidence has emerged demonstrating that CDH1 mutations can be associated with lobular breast cancer and/or several congenital abnormalities, without any personal or family history of diffuse gastric cancer. To date, no genotype-phenotype correlations have been observed. Remarkably, there are reports of mutations affecting the same nucleotide but inducing distinct clinical outcomes. In this review, we bring together a comprehensive analysis of CDH1-associated disorders and germline alterations found in each trait, providing important insights into the biological mechanisms underlying E-cadherin's pleiotropic effects. Ultimately, this knowledge will impact genetic counselling and will be relevant to the assessment of risk of cancer development or congenital malformations in CDH1 mutation carriers.

Variants in members of the cadherin-catenin complex, CDH1 and CTNND1, cause blepharocheilodontic syndrome.

Blepharocheilodontic syndrome (BCDS) consists of lagophthalmia, ectropion of the lower eyelids, distichiasis, euryblepharon, cleft lip/palate and dental anomalies and has autosomal dominant inheritance with variable expression. We identified heterozygous variants in two genes of the cadherin-catenin complex, CDH1, encoding E-cadherin, and CTNND1, encoding p120 catenin delta1 in 15 of 17 BCDS index patients, as was recently described in a different publication. CDH1 plays an essential role in epithelial cell adherence; CTNND1 binds to CDH1 and controls the stability of the complex. Functional experiments in zebrafish and human cells showed that the CDH1 variants impair the cell adhesion function of the cadherin-catenin complex in a dominant-negative manner. Variants in CDH1 have been linked to familial hereditary diffuse gastric cancer and invasive lobular breast cancer; however, no cases of gastric or breast cancer have been reported in our BCDS cases. Functional experiments reported here indicated the BCDS variants comprise a distinct class of CDH1 variants. Altogether, we identified the genetic cause of BCDS enabling DNA diagnostics and counseling, in addition we describe a novel class of dominant negative CDH1 variants.

Blepharocheilodontic syndrome is a CDH1 pathway-related disorder due to mutations in CDH1 and CTNND1.

PURPOSE: Blepharocheilodontic (BCD) syndrome is a rare autosomal dominant condition characterized by eyelid malformations, cleft lip/palate, and ectodermal dysplasia. The molecular basis of BCD syndrome remains unknown. METHODS: We recruited 11 patients from 8 families and performed exome sequencing for 5 families with de novo BCD syndrome cases and targeted Sanger sequencing in the 3 remaining families. RESULTS: We identified five CDH1 heterozygous missense mutations and three CTNND1 heterozygous truncating mutations leading to loss-of-function or haploinsufficiency. Establishment of detailed genotype-phenotype correlations was not possible because of the size of the cohort; however, the phenotype seems to appear more severe in case of CDH1 mutations. Functional analysis of CDH1 mutations confirmed their deleterious impact and suggested accelerated E-cadherin degradation. CONCLUSION: Mutations in CDH1 encoding the E-cadherin were previously reported in hereditary diffuse gastric cancer as well as in nonsyndromic cleft lip/palate. Mutations in CTNND1 have never been reported before. The encoded protein, p120ctn, prevents E-cadherin endocytosis and stabilizes its localization at the cell surface. Conditional deletion of Cdh1 and Ctnnd1 in various animal models induces features reminiscent of BCD syndrome and underlines critical role of the E-cadherin-p120ctn interaction in eyelid, craniofacial, and tooth development. Our data assert BCD syndrome as a CDH1 pathway-related disorder due to mutations in CDH1 and CTNND1 and widen the phenotypic spectrum of E-cadherin anomalies.Genet Med advance online publication 09 March 2017.

Blepharo-cheilo-dontic (BCD) syndrome: expanding the phenotype, case report and review of literature.

The combination of lagophthalmia, euryblepharon, ectropion of lower eyelids, distichiasis, bilateral cleft lip and palate, and oligodontia comprises the blepharo-cheilo-dontic (BCD) syndrome. This combination has been found sporadically or with positive family history and inherited as an autosomal dominant condition with variable expression. We described a Saudi boy with the cardinal signs consistent with the BCD syndrome. In addition to the common components of BCD syndrome that involve eyelids, lip, and teeth abnormalities, this patient is the third reported BCD case with imperforate anus, the second with thyroid agenesis, and the first with lumbosacral meningomyelocele.

Molecular characterization of newborn glaucoma including a distinct aniridic phenotype.

PURPOSE: To characterize the underlying genetic defect in otherwise healthy Saudi newborns with buphthalmos, including those with iris abnormalities. METHODS: Prospective case series of affected Saudi Arabian probands who were referred for genetic counseling over a 4 year period. All had CYP1B1 sequencing. Selected patients with visible iris abnormalities had PAX6, FOXC1, and PITX2 sequencing. CYP1B1-negative patients had LTBP2 sequencing. RESULTS: All 67 probands had corneal enlargement with variable haze/scarring evident to caregivers at birth; 46 had a family history of infantile or early childhood glaucoma. All families were consanguineous except for 6, 2 of which were endogamous. Eight probands had mild ectropion uveae with partial aniridia; 2 probands had thick scarred corneas that precluded careful iris examination. Homozygous or compound heterozygous CYP1B1 mutations were identified in 91% (61/67), including all 8 probands with ectopion uveae and partial aniridia. The common Saudi mutation p.G61E occurred in most cases (38 homozygous, 8 compound heterozygous). Four novel mutations were identified (p.N252K, p.V460E, p.S485F, p.N519D). No mutations were identified in the other screened genes. CONCLUSIONS: Newborn glaucoma on the Arabian Peninsula is typically CYP1B1-related even in the setting of developmental iris abnormality. Mild iris ectropion with partial aniridia in a newborn with glaucoma suggests mutations in CYP1B1 rather than in other genes associated with anterior segment dysgenesis. On the Arabian Peninsula p.G61E mutations are the major cause of newborn glaucoma but novel CYP1B1 mutations continue to be documented. The fact that the 9% of cases that were CYP1B1-negative did not have mutations in LTBP2 suggests that there exists at least 1 additional locus for this condition.

Imperforate anus is a rare associated finding in blepharocheilodontic syndrome.

Blepharocheilodontic (BCD) syndrome is a rare autosomal-dominant condition that is characterized by lower eyelid ectropion, upper eyelid distichiasis, euryblepharon, bilateral cleft lip and palate, and conical teeth. It exhibits considerable phenotypic variability among affected individuals. An additional rare associated manifestation is imperforate a.u. (IA), which has been reported in three cases [Guyuron et al. (1995); J Craniofac Surg 6:392-394; Gorlin et al. (1996); Am J Med Genet 65:109-112; da Silva Lopes et al. (2003); Am J Med Genet Part A 121A:266-270]. Here we report on a family with BCD that includes IA, confirming that anorectal anomalies are a part of BCD syndrome.

[Congenital ectropion in ichthyosis congenita mitis and gravis]. / Angeborenes Ektropium bei Ichthyosis congenita mitis und gravis.

BACKGROUND: Congenital ichthyosis is a generalized hyperkeratinization of the skin at birth. Depending on clinical aspects and severity, three forms of congenital ichthyosis have been defined: mitis, tarda, and gravis. Desquamation of the parchment-like hyperkeratinized skin begins shortly after birth and may require several weeks to complete. Skin alterations in the eyelid cause shortening of the anterior lamella, subsequently resulting in ectropion. This affects the upper eyelid more often than the lower and can lead to complications such as chronic palpebral or bulbar conjunctivitis and keratinization or exposure keratopathy. Here we present two case reports illustrating the course of ichthyosis congenita mitis and gravis. PATIENTS AND METHODS: Patient 1 (ichthyosis congenita mitis): a male baby prematurely born at 34+2 weeks of gestation was delivered by cesarean section. The entire body was covered by a parchment-like hyperkeratinized skin. Both eyes showed ectropion of the upper and the lower eyelid, which was more obvious with enforced lid closure. Frequent application of external ointment and spontaneous desquamation led to resolution of the ectropion. Patient 2 (ichthyosis congenita gravis): a male baby prematurely born at 35+4 weeks of gestation was delivered by cesarean section. At birth the child showed the signs of a collodion baby with ectropion of all four eyelids in combination with a characteristic "fish mouth" and rudimentary external ears. The child died on the 14th day of life of septicaemia. CONCLUSION: In mild forms of congenital ichthyosis surgical treatment of eyelid ectropion is not required. In more severe cases a skin graft may become necessary. Various although limited sources of graft material which are discussed can be considered.

Presence of the R1748X mutation in the NF1 gene in a Brazilian patient with ectropion uveae.

Congenital ectropion uveae is a rare, nonprogressive anomaly characterized by the presence of iris pigment epithelium on the anterior surface of the iris stroma and is occasionally associated with Rieger's anomaly, Prader-Willi syndrome and neurofibromatosis type 1 (NF1). The most important complication of ectropion uveae is congenital or juvenile glaucoma. We described a patient with ectropion and the mutation R1748X in the NF1 gene. This is the third report in the literature describing ectropion associated with neurofibromatosis. If this association is confirmed by other authors, the NF1 patients should be examined for the presence of ectropion and, consequently, for the development of glaucoma.

[Apert's syndrome: a case report]. / Le syndrome d'Apert: à propos d'une observation.

Apert's syndrome is a type of acrocephalosyndactylia that is from part of the great group of craniofacial synostoses. It is characterized by craniofacial dysmorphia and syndactylia on hands and feet, which differentiates it from Crouzon's disease. It is a rare affection that is often transmitted through an autosome dominant mode, but sporadic cases exist. We report the case of a 15-year-old girl who presented characteristic clinical signs of Apert's syndrome with normal karyotype without parental consanguinity. The Ser 252 Trp mutation of the FGFR2 gene was found, confirming the molecular diagnosis. This study illustrates the severity of ocular and neurological problems of untreated Apert's syndrome. The presence of hemoglobinopathy (Hb AS) is also a mark of its originality.

Familial clefting syndrome with ectropion and dental anomaly--without limb anomalies.

Three generations of a family are described in which cleft lip and/or cleft palate, ectropion of the lower eyelids and conical teeth, subject to premature carious decay, occur in various combinations in different family members, in a manner consistent with autosomal dominant inheritance.

Hereditary spinal arachnoid cysts, distichiasis, and lymphedema.

Familial congenital spinal arachnoid cysts causing progressive paraplegia are reported in two adolescent siblings as part of a hereditary syndrome. The other features of this unusual dominantly inherited disorder include double rows of eyelashes, partial ectropion of the lower eyelids, and acquired late-onset lymphedema of the lower extremities. The siblings' mother, who had roentgenographic evidence of a similar intraspinal lesion, was free of neurological symptoms but had the other characteristic features. Surgical treatment of the arachnoid cysts improves the progressive paraplegia.

Blepharophimosis with associated cup-lop ears.

Blepharophimosis is a rare congenital triad consisting of epicanthus inversus, blepharoptosis, and a wider than normal intercanthal distance. Attention has recently been drawn to abnormalities of the eyebrow and the poorly developed nasal bridge. I record 9 cases of blepharophimosis associated with cup-lop ears seen over the last 15 years. These include a father and his 4 children.