Coloboma Research Articles

Prevalence of Olfactory and Other Developmental Anomalies in Patients with Central Hypogonadotropic Hypogonadism

Introduction: Hypogonadotropic hypogonadism (HH) is a heterogeneous disease caused by mutations in several genes. Based on the presence of hyposmia/anosmia it is distinguished into Kallmann syndrome (KS) and isolated HH. The prevalence of other developmental anomalies is not well established.Methods: We studied 36 patients with HH (31 males, 5 females, mean age 41.5), 9 with familial and 27 with sporadic HH (33 congenital, 3 adult-onset), by physical examination, smell test (BSIT Sensonics), audiometry, renal ultrasound, and magnetic resonance imaging of the olfactory structures.Results: Based on the smell test, patients were classified as normosmic (n = 21, 58.3%) and hypo/anosmic (n = 15, 41.6%). Hypoplasia/agenesis of olfactory bulbs was found in 40% of patients (10/25; 75% hypo/anosmic, 7.6% normosmic, p < 0.01, Fisher’s test). Remarkably, olfactory structures were normal in two anosmic patients, while one normosmic patient presented a unilateral hypoplastic bulb. Fourteen of 33 patients (42.4%) presented neurosensorial hearing loss of various degrees (28.5% hypo/anosmic, 52.6% normosmic, p = NS). Renal ultrasound revealed 27.7% of cases with renal anomalies (26.6% hypo/anosmic, 28.5% normosmic, p = NS). At least one midline defect was found in 50% of the patients (53.3% hypo/anosmic, 47.6% normosmic, p = NS), including abnormal palate, dental anomalies, pectus excavatum, bimanual synkinesis, iris coloboma, and absent nasal cartilage. Anamnestically 4/31 patients reported cryptorchidism (25% hypo/anosmic, 5.2% normosmic, p = NS).Conclusion: Hypo/anosmia is significantly related to anatomical anomalies of the olfactory bulbs/tracts but the prevalence of other developmental anomalies, especially midline defects and neurosensorial hearing loss, is high both in HH and KS and independent of the presence of anosmia/hyposmia. From the clinical standpoint KS and normosmic HH should be considered as the same complex, developmental disease.

Exome Analysis Identified a Novel Mutation in the RBP4 Gene in a Consanguineous Pedigree with Retinal Dystrophy and Developmental Abnormalities

Retinitis Pigmentosa (RP) is a common form of retinal degeneration characterized by photoreceptor degeneration and retinal pigment epithelium (RPE) atrophy causing loss of visual field and acuities. Exome sequencing identified a novel homozygous splice site variant (c.111+1G>A) in the gene encoding retinol binding protein 4 (RBP4). This change segregated with early onset, progressive, and severe autosomal recessive retinitis pigmentosa (arRP) in an eight member consanguineous pedigree of European ancestry. Additionally, one patient exhibited developmental abnormalities including patent ductus arteriosus and chorioretinal and iris colobomas. The second patient developed acne from young age and extending into the 5th decade. Both patients had undetectable levels of RBP4 in the serum suggesting that this mutation led to either mRNA or protein instability resulting in a null phenotype. In addition, the patients exhibited severe vitamin A deficiency, and diminished serum retinol levels. Circulating transthyretin levels were normal. This study identifies the RBP4 splice site change as the cause of RP in this pedigree. The presence of developmental abnormalities and severe acne in patients with retinal degeneration may indicate the involvement of genes that regulate vitamin A absorption, transport and metabolism.

Molecular Characterization of De Novo Unbalanced 5;21 Translocation Associated With Multiple Congenital Abnormalities and Developmental Delay by Array-Based Comparative Genomic Hybridization

Chromosomal imbalances are a significant cause of congenital disorders. Microarray-based comparative genomic hybridization, also known as chromosomal microarray (CMA), is a relatively new technology that can identify microscopic and submicroscopic chromosomal imbalances. We report the case of a 12-year-old boy with multiple congenital abnormalities referred for cytogenetic and CMA evaluation. The patient had developmental delay, microcephaly, bilateral iris colobomas, ventricular septal defect, …

Bilateral microphthalmos with unilateral superior cyst in a child with autism and CHARGE syndrome

A case of autism with CHARGE syndrome with microphthalmos and a superior colobomatous cyst arising from the optic disc is reported. A 7-year-old boy presented with a gradually increasing mass, involving the superior orbit and upper eyelid of right eye of 3 years' duration. Clinical examination revealed bilateral microphthalmos with typical iris coloboma, posterior synechiae, and cataractous lens. Imaging revealed bilateral optic disc colobomas with a superior cyst in the right orbit. Intraoperatively, a single cystic lesion was seen in the superior orbit arising from the optic disc region. Histopathology was suggestive of a colobomatous cyst, positive for glial tissue [glial fibrillary acidic protein (GFAP) positive] and neuroretinal elements (synaptophysin positive) on immunohistochemistry. Genetic analysis revealed a normal karyotype (46, XY).

Neurotrophic keratopathy associated with congenital agenesis of the corpus callosum

AbstractPurpose The corpus callosum (CC), with its central position in the cerebrum, has an essential role in relaying sensory, motor, and cognitive information from homologous brain regions across cerebral hemispheres. Corpus callosum agenesis (CCA) is a rare congenital malformation which is caused by an alteration in embryonic development.Methods We report the case of a 3 year old child who was diagnosed of complete corpus callosum agenesis with a normal karyotype. The neurological findings were spastic tetraparesis with dystonia, several delayed psychomotor and epilepsy. In ophthalmology examination he presented esotropia, bilateral optic nerve hypoplasia, delayed visual evoked potential flash type and altered corneal sensibility in both eyes which is manifested clinically by recurrent corneal ulcers and epithelial disruption associated with stromal edema.Results After Neurotrophic keratopathy suspected, treatment with autologous serum was decided and response to treatment was favorable in both eyes with closure of ulcers and good management of symptoms. CCA has also been described in association with other ocular abnormalities such as optic nerve hypoplasia, retinal detachments, cataracts, morning glory syndrome, iris and optic nerve colobomas, among many others.Conclusion In all patients diagnosed with agenesis of the corpus callosum, the possible alteration of corneal sensitibility is a fact that will be suspected to perform early diagnosis and appropriate treatment and follow‐up.

Partial duplication of chromosome 4 in a patient with bilateral ocular coloboma

Partial trisomy 4q is a rare chromosomal disease. It involves duplication of a portion (particularly the distal one) of the long arm of chromosome 4. In most cases results from a balanced translocation on one single progenitor. The de novo appearance is less common. Depending on the size and location of duplicated genetic material, patients may have different clinical manifestations. Associated eye pathology has been scarcely informed. We report on a novel case of a male infant with a proximal de novo 4q12-q22 duplication and bilateral iris, retinal and optic nerve coloboma.

Duplicación parcial del cromosoma 4 asociada con coloboma ocular bilateral

Partial trisomy 4q is a rare chromosomal disease. It involves duplication of a portion (particularly the distal one) of the long arm of chromosome 4. In most cases results from a balanced translocation on one single progenitor. The "de novo" appearance is less common. Depending on the size and location of duplicated genetic material, patients may have different clinical manifestations. Associated eye pathology has been scarcely informed. We report on a novel case of a male infant with a proximal "de novo" 4q12-q22 duplication and bilateral iris, retinal and optic nerve coloboma.

Phenotype of congenital cataract accompanied with iris dysplasia

Background Certain relationship has been found between phenotype and genes mutation of congenital cataract.It is clear that different genetic mutations can cause the same complication in congenital cataract,meanwhile,different complications may be caused by the same gene mutation.However,their mechanism is still remained unclear.Objective This study was to observe the phenotype of congenital cataract accompanied with iris dysplasia.Methods Fifteen patients with congenital cataract accompanied with iris dysplasia were included in this study.The slit lamp,gonioscope and ophthalmoscope were used for the examination of the anterior ocular segment,the anterior chamber angle and fundus on all the patients.This study was approved by the Ethic Committee of Second People' s Hospital of Yunnan Province.Written informed consent was obtained from each patient or the custodian prior to any medical procedure.Results All the patients showed binocular involvement.Congenital nuclear cataract with whole coloboma of iris was seen in 7 cases,and 2 cases showed an entire cataract associated with incomplete coloboma of iris.Entire cataract with aniridia was diagnosed in 5 patients,and suture cataract complicated with aniridia was in 1 patient.Conclusions Some regular patterns can be implied between the morphological type of cataract and iris dysplasia,which may be helpful for further study of these diseases. Key words: Cataract/congenital; Congenital aniridia; Congenital coloboma of iris; Clinical phenotype

Gap-filling repair of traumatic corneal coloboma with autogenous Tenon' s capsule

Objective To explore the effect of gap-filling repair for traumatic corneal coloboma with autogenous Tenon' s capsule.Methods 11 cases( 11 eyes) with coneal coloboma due to ocular trauma were studied.The corneal wound was sutured on the bit,pre-placed suture,gap-filling repaired with autogenous Tenon' s capsule,covered up with conjunctival flap.Coneal smoothness,wound obturation,intraocular pressure and the local change of the patch were observed after surgery.Results All the coneal wound were watertight,no obvious plica appeared,the anterior chamber were formed normaly,the intraocular pressure recovered,and no wound infection or endophthalmitis occurred after surgery.In 1 ～ 6 month' s follow up,the Tenon's capsule tissue were alive and gradually scarring with neovascularization,and epithelium were repaired.No rejection,Tenon' capsule tissue autolysis or local corneal bulge occurred.Conclusion Gap-filling repair of the corneal coloboma due to ocular trauma with autogenous Tenon' s capsule is a ideal method.The Tenon' s capsule is easily obtained,and the surgical effect is reliable. Key words: Ocular trauma; Corneal coloboma; Tenon's capsule

Combined partial trisomy 11q and partial monosomy 10p in a 19‐year‐old female patient: Phenotypic and genotypic findings

Constitutional partial trisomy 11q in man mostly occurs in combination with partial trisomy 22 due to a balanced parental translocation t(11;22). Occasionally a chromosome other than 22 is involved in the parental translocation with chromosome 11, resulting in partial monosomy for the other participating chromosome. We report of a patient with partial trisomy 11q and partial monosomy 10p [46,XX,der(10)t(10;11)(p15;q22)] due to a paternal balanced translocation [46,XY,t(10;11)(p15;q22)]. Array CGH showed heterozygosity for a deletion of ∼3.46 Mb at 10p15.3p15.2 and gain of ∼32.21 Mb at 11q22.2q25. The patient, a 19-year-old woman, has a multiple congenital anomaly syndrome with severe developmental and growth delay, muscular hypotonia, iris coloboma, abnormal external ears, widely spaced nipples, atrial septum defect, clubfoot, and arthrogryposis multiplex congenita. Despite multiple health problems and numerous hospitalizations due to massive seizures, pulmonary insufficiency and recurrent infections the patient reached adulthood. The clinical features in our patient are compared to other cases reported in the literature of either partial monosomy 10p or partial trisomy 11q. To the best of our knowledge, this is the first report of the combination of partial trisomy 11q and partial monosomy 10p. Comparing the molecular karyotype and the phenotype of our patient to other patients, the clinical features of our patient are more likely due to partial trisomy 11q than to partial monosomy 10p.

Colobomas and Amblyopia—Reply

Colobomas and Amblyopia—Reply

Two novel mutations of the PAX6 gene causing different phenotype in a cohort of Chinese patients

Aniridia (AN) is a rare congenital panocular disorder caused by the mutations of the paired box homeotic gene 6(PAX6) gene. The PAX6gene is also involved in other anterior segment malformations including Peters anomaly. We studied the PAX6gene mutations in a cohort of affected individuals with different clinical phenotype including AN, coloboma of iris and choroid, or anterior segment malformations. Six unrelated families and 10 sporadic patients were examined clinically. After informed consent was obtained, genomic DNA was extracted from the venous blood of all participants. Mutation screening of all exons of the PAX6gene was performed by direct sequencing of PCR-amplified DNA fragments. Multiplex ligation-dependent probe amplification (MLPA) was performed to detect large deletions. By clinical examination, the patients and the pedigrees were divided into the following three groups: AN, coloboma of iris and choroids, and the anterior segment malformations including peters anomaly. Sequencing of the PAX6gene, three intragenic mutations including a novel heterozygous splicing-site mutations c.357-3C>G (p.Ser119fsX) were identified in the patients of the AN group. A novel missense mutation c.643T>C (p.S216P) was detected in the anterior segment malformation group. The mutation p.S216P located in the homeodomain region of the PAX6 caused the phenotype of Peters anomaly in family A6 with different expressing. Through MLPA analysis, a large deletion including the whole PAX6gene and DKFZ p686k1684gene was detected in one sporadic patient from the AN group. Neither intragenic mutation nor large deletion was identified in the group with coloboma of iris and choroid. Our findings further confirmed that different kind of mutations might cause different ocular phenotype, and clearly clinical phenotype classification might increase the mutation detection rate of the PAX6gene.

Lens Coloboma and Associated Ocular Malformations

Lens coloboma is a rare congenital disorder of crystalline lens characterized by notching of the equator of the lens. Coloboma can occur in isolation or with other ocular malformations. The authors reported 5 cases of lens coloboma associated with some ocular malformations. Case reports. The clinical features, imaging findings and associated ocular malformations were reported. One case was not associated with ocular anomalies. One patient was involved with iris and choroid coloboma; another subject suffered from total cataract; and the fourth patient was affected by lens dislocation. The remaining case included aniridia. The pathogenic mechanisms and relationship of the ocular malformations have been discussed. Lens coloboma can be associated with other ocular malformations, such as iris coloboma, choroid colobma, localized or total caratact.

Occurrence and pattern of ocular disease in children with cholestatic disorders

To describe visual function and ocular manifestations in patients with onset of cholestasis during the neonatal period. Patients with neonatal cholestasis, either transitory or chronic, who came for assessment to our tertiary referral centre were included in a cross-sectional study and underwent ophthalmological examinations including fundus photography. A total of 57 patients (24 girls and 33 boys), aged 0.4-18.0 years, were included. Of these, 28 patients had biliary atresia, 11 had Alagille's syndrome, five had progressive familiar intrahepatic cholestasis and nine had different disorders such as pituitary insufficiency, alpha-1-antitrypsin deficiency, mitochondriopathy, congenital infections or cholestasis caused by unknown reasons. Visual dysfunction and/or one or several ocular manifestations occurred in 39 out of 57 patients. Major ocular malformations occurred in five patients. Out of three patients with biliary atresia, one patient had severe visual impairment caused by microphthalmia and chorioretinal coloboma, one patient with Cat Eye syndrome had bilateral uveochorioretinal coloboma and one patient had Rieger's anomaly. Two patients, both with pituitary deficiency and transient cholestasis, had severe unilateral visual impairment caused by optic nerve hypoplasia. The majority (68%) of the patients with cholestasis had ocular manifestations. Although the severity of ocular complications varied with diagnosis, and was most apparent among patients with biliary atresia or pituitary deficiency, no conclusion can be drawn regarding the connections between these conditions from the present study. Nevertheless, ocular assessment is important for diagnostic purposes and for early intervention in patients with cholestasis.

Clinical utility gene card for: renal coloboma (Papillorenal) syndrome

European Journal of Human Genetics (2011) 19, doi:10.1038/ejhg.2011.16; published online 16 February 20111. DISEASE CHARACTERISTICS1.1 Name of the disease (synonyms)Renal coloboma syndrome (Papillorenal syndrome).1.2 OMIM# of the disease120330.1.3 Name of the analyzed genes or DNA/chromosome segmentsPaired box gene 2 (PAX2 ).1.4 OMIM# of the gene(s)167409.1.5 Mutational spectrumTo date, there have been more than 25 published autosomal dominantmutations identifiedinthecoding regionofthe PAX2 gene.The majorityofthese mutations occurin exons2–4(encoding the paireddomain) andexons 7–9 (encoding the transact ivation domain). The most commonrecurrent mutations are frameshif t mutations within a homoguaninestretch (7Gs) in exon 2 (c.76dup, c.76del, c.75_76dup).

Congenital ectropion uveae with iris coloboma and telecanthus

Congenital ectropion uveae (CEU) is a rare, non progressive anomaly characterised by the presence of iris pigment epithelium on the anterior surface and is frequently associated with anterior iris insertion, dysgenesis of the drainage angle and glaucoma. This paper describes an unusual case of bilateral congenital ectropion uveae with iris coloboma and telecanthus. The anterior chamber angle was normal and there was no evidence of glaucoma. To the best of our knowledge, this association has not been reported previously.

The Development of Recurrent Choroidal Neovascularization in a Patient with Choroidal Coloboma

We report a case of recurrent choroidal neovascularization (CNV) in an eye with chorioretinal coloboma. A 36-year-old woman presented complaining of decreased visual acuity (VA) in her left eye. Best corrected visual acuity (BCVA) was 20/200 and iris coloboma was observed. Funduscopy and fluorescein angiography (FA) showed CNV in the superior extrafoveal region with chorioretinal coloboma reaching just inferior to the optic disc. No other cause for CNV was observed except for the chorioretinal coloboma. BCVA improved to 20/30 after laser photocoagulation. She revisited our clinic for deteriorating VA (20/400) in the same eye 3 years after treatment. Funduscopy and FA demonstrated recurrent CNV with subfoveal hemorrhage. Photodynamic therapy (PDT) was followed by three consecutive intravitreal bevacizumab injections (IVB) for the subfoveally-located CNV. However, the CNV persisted with the appearance of a fresh subretinal hemorrhage. Additional PDT was combined with IVB on the same day 6 months after the initial PDT. The CNV regressed 3 months after treatment and has not recurred as of 8 months after the last treatment. The patient's BCVA improved to 20/60. This case suggests that PDT combined with IVB can be an alternative treatment for the management of recurrent CNV after laser photocoagulation in eyes with chorioretinal coloboma.

Goltz syndrome (focal dermal hypoplasia) with unilateral ocular, cutaneous and skeletal features: case report

BackgroundGoltz syndrome or focal dermal hypoplasia (FDH) is an uncommon multisystem disorder. Herein, we report a typical case of FDH with unilateral ocular, cutaneous and skeletal features.Case Presentationa 4-year-old girl presented with microphthalmos and iris coloboma of the left eye, facial asymmetry, and a low-set protruding ear. Cutaneous changes included hypopigmented atrophic macules on the left side of the face, chest, abdomen and limbs. Characteristic lobster claw deformity of left hand and oligodactyly and syndactyly of left foot were present.ConclusionsFDH usually affects both sides of the body. This case represents the unusual unilateral manifestation of the syndrome.

Baraitser–Winter syndrome: An additional Arab patient

An Arab child is presented herein with a phenotype that fits the rare Baraitser–Winter syndrome. Her clinical features included a unilateral iris coloboma, ptosis, hypertelorism, epicanthic folds, broad nasal bridge, full cheeks, pointed chin, low set abnormal ears and short neck. In addition, she had cardiac defect, previously undescribed brain anomaly, seizures, hypotonia and developmental delay. Chromosomal analysis of the peripheral lymphocytes and FISH study revealed a normal 46, XX karyotype. To date, Baraitser–Winter syndrome has only been reported in 19 patients of different ethnic families. The present case adds a new finding to the spectrum of malformations published before.

P09.04: Prenatal diagnosis of Pai syndrome

PAI syndrome is a rare disorder characterized by midline anomalies such as cleft lip and cleft palate of variable complexity, associated with benign facial tumors represented by simple or multiple sessile or pedunculated polyps of the skin and nasal mucosa. Often these patients show mild hypertelorism, interhemispheric lipoma, with or without corpus callosum agenesis/dysgenesis, and normal neuropsychologic development. Seldom associations with ventricular septal defect or ocular abnormalities such as iris coloboma have been reported. Case report: An 18 year old primigravida woman, with no history of abnormalities in the family, was sent to our institution at 34 weeks gestation for further diagnosis. She presented with normal volume of amniotic fluid, a normally growing female fetus with median cleft upper lip, cleft palate and polyps of the facial skin and nasal mucosa. An interhemispheric lipoma, with corpus callosum dysgenesis. A muscular and also a perimembranous septal defects were also detected. Given the fetal phenotypic features, Pai Syndrome was suspected and confirmed after birth. 4D render did not helped in the final diagnosis, but allowed a better understanding of the anomalies by the mother. It is believed that a genetic defect in mesodermal differentiation and penetration would result in these particular type of anomalies. At present, the cause of this syndrome is unknown, although autosomal dominant inheritance has been suggested. Also a balanced X; 16 translocation has been reported. To our knowledge this is the second case of Pai Syndrome with prenatal diagnosis. In these particular case we want to emphasize the association with ventricular septal defect, although it is still not clear if this can be a feature of the syndrome.