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European Journal of Human Genetics :... Mar 2015We used exome sequencing to study a non-consanguineous family with two children who had anterior segment dysgenesis, sclerocornea, microphthalmia, hypotonia and...
We used exome sequencing to study a non-consanguineous family with two children who had anterior segment dysgenesis, sclerocornea, microphthalmia, hypotonia and developmental delays. Sanger sequencing verified two Peroxidasin (PXDN) mutations in both sibs--a maternally inherited, nonsense mutation, c.1021C>T predicting p.(Arg341*), and a paternally inherited, 23-basepair deletion causing a frameshift and premature protein truncation, c.2375_2397del23, predicting p.(Leu792Hisfs*67). We re-examined exome data from 20 other patients with structural eye defects and identified two additional PXDN mutations in a sporadic male with bilateral microphthalmia, cataracts and anterior segment dysgenesis--a maternally inherited, frameshift mutation, c.1192delT, predicting p.(Tyr398Thrfs*40) and a paternally inherited, missense substitution that was predicted to be deleterious, c.947 A>C, predicting p.(Gln316Pro). Mutations in PXDN were previously reported in three families with congenital cataracts, microcornea, sclerocornea and developmental glaucoma. The gene is expressed in corneal epithelium and is secreted into the extracellular matrix. Defective peroxidasin has been shown to impair sulfilimine bond formation in collagen IV, a constituent of the basement membrane, implying that the eye defects result because of loss of basement membrane integrity in the developing eye. Our finding of a broader phenotype than previously appreciated for PXDN mutations is typical for exome-sequencing studies, which have proven to be highly effective for mutation detection in patients with atypical presentations. We conclude that PXDN sequencing should be considered in microphthalmia with anterior segment dysgenesis.
Topics: Amino Acid Substitution; Antigens, Neoplasm; Child, Preschool; Exome; Eye Abnormalities; High-Throughput Nucleotide Sequencing; Humans; Infant; Male; Microphthalmos; Mutation; Pedigree; Peroxidases; Phenotype; Receptors, Interleukin-1
PubMed: 24939590
DOI: 10.1038/ejhg.2014.119 -
International Journal of Environmental... Mar 2019(1) Background: Oculo-facio-cardio-dental (OFCD) syndrome is a rare pathological condition with an X-linked dominant trait that only occurs in females; no males are born...
(1) Background: Oculo-facio-cardio-dental (OFCD) syndrome is a rare pathological condition with an X-linked dominant trait that only occurs in females; no males are born with OFCD syndrome. This syndrome is characterized by congenital cataracts with secondary glaucoma ocular defects, ventricular and atrial septal defects, or mitral valve prolapses. Facial traits are a long narrow face and a high nasal bridge with a bifid nasal tip. Dental anomalies include radiculomegaly, oligodontia, root dilacerations, malocclusion, and delayed eruption. (2) Methods: This clinical report describes a 26-year-old girl who suffers from OFCD syndrome and who was treated with a multidisciplinary approach. The treatment plan included orthodontic treatment, orthognathic surgery, namely LeFort I and a Bilateral Sagittal Split Osteotomy, and occlusal rehabilitation with implants. (3) Discussion: Early diagnosis and multidisciplinary treatment of orthodontic, orthognathic surgery and occlusal rehabilitation with implants make it possible to maintain tooth function and improve aesthetics with good prognoses for success. In this paper, we report a case of a female patient with OFCD syndrome, who was referred for orthodontic treatment and occlusal rehabilitation and treated with a multidisciplinary approach.
Topics: Adult; Cataract; Female; Heart Septal Defects; Humans; Malocclusion; Microphthalmos; Orthognathic Surgical Procedures
PubMed: 30875852
DOI: 10.3390/ijerph16060928 -
BMC Medical Genetics Sep 2018Autosomal recessive anophthalmia and microphthalmia are rare developmental eye defects occurring during early fetal development. Syndromic and non-syndromic forms of...
BACKGROUND
Autosomal recessive anophthalmia and microphthalmia are rare developmental eye defects occurring during early fetal development. Syndromic and non-syndromic forms of anophthalmia and microphthalmia demonstrate extensive genetic and allelic heterogeneity. To date, disease mutations have been identified in 29 causative genes associated with anophthalmia and microphthalmia, with autosomal dominant, autosomal recessive and X-linked inheritance patterns described. Biallelic ALDH1A3 gene variants are the leading genetic causes of autosomal recessive anophthalmia and microphthalmia in countries with frequent parental consanguinity.
METHODS
This study describes genetic investigations in two consanguineous Pakistani families with a total of seven affected individuals with bilateral non-syndromic clinical anophthalmia.
RESULTS
Using whole exome and Sanger sequencing, we identified two novel homozygous ALDH1A3 sequence variants as likely responsible for the condition in each family; missense mutation [NM_000693.3:c.1240G > C, p.Gly414Arg; Chr15:101447332G > C (GRCh37)] in exon 11 (family 1), and, a frameshift mutation [NM_000693.3:c.172dup, p.Glu58Glyfs*5; Chr15:101425544dup (GRCh37)] in exon 2 predicted to result in protein truncation (family 2).
CONCLUSIONS
This study expands the molecular spectrum of pathogenic ALDH1A3 variants associated with anophthalmia and microphthalmia, and provides further insight of the key role of the ALDH1A3 in human eye development.
Topics: Aldehyde Oxidoreductases; Anophthalmos; Consanguinity; Exome; Exons; Female; Genes, Recessive; Humans; Male; Microphthalmos; Mutation; Pedigree; Sequence Analysis, DNA
PubMed: 30200890
DOI: 10.1186/s12881-018-0678-6 -
The Journal of Clinical Pediatric... 2005Hallerman Streif syndrome is a rare congenital disorder characterized by dyscephaly, dental anomalies, proportionate nazism, hypotrichosis, cutaneous atrophy limited to... (Review)
Review
Hallerman Streif syndrome is a rare congenital disorder characterized by dyscephaly, dental anomalies, proportionate nazism, hypotrichosis, cutaneous atrophy limited to the head, bilateral congenital cataracts and bilateral microphthalmia. Despite the marked craniofacial characteristics and oral findings, a relative lack of reports in the dental literature has been noted. In this article, a case of a 8 year old boy with dental problems is described.
Topics: Abnormalities, Multiple; Child; Craniofacial Abnormalities; Facies; Hallermann's Syndrome; Humans; Hypotrichosis; Male; Microphthalmos; Mouth Abnormalities; Tooth Abnormalities
PubMed: 16302604
DOI: 10.17796/jcpd.30.1.91036513g7u55705 -
Clinical Genetics Mar 2021Complex microphthalmia is characterized by small eyes with additional abnormalities that may include anterior segment dysgenesis. While many genes are known, a genetic...
Complex microphthalmia is characterized by small eyes with additional abnormalities that may include anterior segment dysgenesis. While many genes are known, a genetic cause is identified in only 4-30% of microphthalmia, with the lowest rate in unilateral cases. We identified four novel pathogenic loss-of-function alleles in PRR12 in families affected by complex microphthalmia and/or Peters anomaly, including two de novo, the first dominantly transmitted allele, as well as the first splicing variant. The ocular phenotypes were isolated with no additional systemic features observed in two unrelated families. Remarkably, ocular phenotypes were asymmetric in all individuals and unilateral (with structurally normal contralateral eye) in three. There are only three previously reported PRR12 variants identified in probands with intellectual disability, neuropsychiatric disorders, and iris anomalies. While some overlap with previously reported cases is seen, nonsyndromic developmental ocular anomalies are a novel phenotype for this gene. Additional phenotypic expansions included short stature and normal development/cognition, each noted in two individuals in this cohort, as well as absence of neuropsychiatric disorders in all. This study identifies new associations for PRR12 disruption in humans and presents a genetic diagnosis resulting in unilateral ocular phenotypes in a significant proportion of cases.
Topics: Adolescent; Adult; Alleles; Anterior Eye Segment; Child; Child, Preschool; Corneal Opacity; Eye Abnormalities; Female; Genetic Predisposition to Disease; Genetic Variation; Humans; Male; Membrane Proteins; Microphthalmos; Mutation; Pedigree; Phenotype
PubMed: 33314030
DOI: 10.1111/cge.13897 -
American Journal of Medical Genetics Jan 2001Lenz microphthalmia syndrome is a rare X-linked recessive condition first described by Lenz in 1955 and comprises of anophthalmia, microcephaly, mental retardation,... (Review)
Review
Lenz microphthalmia syndrome is a rare X-linked recessive condition first described by Lenz in 1955 and comprises of anophthalmia, microcephaly, mental retardation, external ear, digital, cardiac, skeletal, and urogenital anomalies. We present three brothers (ages 15 years, 9 years, and 18 months) and a maternal uncle (age 27 years) with congenital anophthalmia, delayed motor development, hypotonia, and moderate to severe mental retardation. They also have abnormally modeled ears, high-arched palate, pectus excavatum, finger and toe syndactyly, clinodactyly, fetal pads, scoliosis, cardiac, and renal abnormalities. An obligate carrier had abnormally modeled ears and syndactyly of the 2nd to 3rd toes bilaterally. Linkage and haplotype analysis in this family indicates that the gene is located in a 17.65-cM region on chromosome region Xq27-Xq28.
Topics: Abnormalities, Multiple; Adolescent; Adult; Child; Craniofacial Abnormalities; Family Health; Genetic Linkage; Haplotypes; Heterozygote; Humans; Infant; Intellectual Disability; Lod Score; Male; Microphthalmos; Pedigree; Physical Chromosome Mapping; X Chromosome
PubMed: 11426460
DOI: No ID Found -
Molecular Vision 2011To further explore the spectrum of mutations in the Visual System Homeobox 2 (VSX2/CHX10) gene previously found to be associated with autosomal recessive microphthalmia.
PURPOSE
To further explore the spectrum of mutations in the Visual System Homeobox 2 (VSX2/CHX10) gene previously found to be associated with autosomal recessive microphthalmia.
METHODS
We screened 95 probands with syndromic or isolated developmental ocular conditions (including 55 with anophthalmia/microphthalmia) for mutations in VSX2.
RESULTS
Homozygous mutations in VSX2 were identified in two out of five consanguineous families with isolated microphthalmia. A novel missense mutation, c.668G>C (p.G223A), was identified in a large Pakistani family with multiple sibships affected with bilateral microphthalmia. This p.G223A mutation affects the conserved CVC motif that was shown to be important for DNA binding and repression activities of VSX2. The second mutation, c.249delG (p.Leu84SerfsX57), was identified in an Iranian family with microphthalmia; this mutation has been previously reported and is predicted to generate a severely truncated mutant protein completely lacking the VSX2 homeodomain, CVC domain and COOH-terminal regions.
CONCLUSIONS
Mutations in VSX2 represent an important cause of autosomal recessive microphthalmia in consanguineous pedigrees. Identification of a second missense mutation in the CVC motif emphasizes the importance of this region for normal VSX2 function.
Topics: Amino Acid Sequence; Animals; Anophthalmos; Asian People; Base Sequence; Case-Control Studies; Child; Consanguinity; Conserved Sequence; DNA Mutational Analysis; Female; Genes, Recessive; Homeodomain Proteins; Homozygote; Humans; Male; Mice; Microphthalmos; Molecular Sequence Data; Mutation; Pedigree; Retina; Sequence Alignment; Transcription Factors; Zebrafish
PubMed: 21976963
DOI: No ID Found -
Proceedings of the Royal Society of... Oct 1948
Topics: Cysts; Eye Abnormalities; Humans; Microphthalmos; Orbital Diseases
PubMed: 18225097
DOI: No ID Found -
International Journal of Surgery Case... Feb 2021Choristomas are benign growth of normal tissue in abnormal location and in the ophthalmic practice, they are more commonly found in the epibulbar region. Intraocular...
INTRODUCTION AND IMPORTANCE
Choristomas are benign growth of normal tissue in abnormal location and in the ophthalmic practice, they are more commonly found in the epibulbar region. Intraocular choristoma has been reported in different ocular structures but it is very rare especially in association with microphthalmos.
CASE PRESENTATION
We present a 13-month-old child with bilateral microphthalmia with the left side being more significantly smaller than the right that required enucleation for introducing a larger silicone implant. The histopathological examination revealed an intraocular choristoma consisting of chondroid and adipose tissue with surrounding fibrosis. Other areas in the globe were also underdeveloped and dysplastic including the optic nerve, which was replaced by dense wavy collagen fibers and fibrovascular tissue.
DISCUSSION
Even though choristomas are benign, they may be extensive interfering with visual development especially the ones involving the epibulbar area. Systemic disease can have choristomas as an ocular feature such as in Goldenhar-Gorlin syndrome. Choristomas inside the eye are rare and they commonly involve the uveal tissue and the optic nerve head mostly in the form of ectopic glandular tissue and choroidal osseous choristoma. Our case is unique in its intraocular retrolental location, composition of chondroid tissue and fat, in addition to the fact that it was found within a microphthalmic globe with other interesting histopathological findings.
CONCLUSION
We report a case of an incidental finding of intraocular choristoma with associated microphthalmia, genetic testing may be useful for establishing a genetic etiology in such cases even in the absence of dysmorphic features.
PubMed: 33434772
DOI: 10.1016/j.ijscr.2021.01.010 -
European Journal of Medical Genetics Nov 2019Microphthalmia with limb anomalies (MLA, OMIM, 206920) is a rare autosomal-recessive disease caused by biallelic pathogenic variants in the SMOC1 gene. It is...
Microphthalmia with limb anomalies (MLA, OMIM, 206920) is a rare autosomal-recessive disease caused by biallelic pathogenic variants in the SMOC1 gene. It is characterized by ocular disorders (microphtalmia or anophtalmia) and limb anomalies (oligodactyly, syndactyly, and synostosis of the 4th and 5th metacarpals), variably associated with long bone hypoplasia, horseshoe kidney, venous anomalies, vertebral anomalies, developmental delay, and intellectual disability. Here, we report the case of a woman who interrupted her pregnancy after ultrasound scans revealed a depression of the frontal bone, posterior fossa anomalies, cerebral ventricular enlargement, cleft spine involving the sacral and lower-lumbar vertebrae, and bilateral microphthalmia. Micrognathia, four fingers in both feet and a slight tibial bowing were added to the clinical picture after fetal autopsy. Exome sequencing identified two variants in the SMOC1 gene, each inherited from one of the parents: c.709G>T - p.(Glu237*) on exon 8 and c.1223G>A - p.(Cys408Tyr) on exon 11, both predicted to be pathogenic by different bioinformatics software. Brain histopathology showed an abnormal cortical neuronal migration, which could be related to the SMOC1 protein function, given its role in cellular signaling, proliferation and migration. Finally, we summarize phenotypic and genetic data of known MLA cases showing that our case has some unique features (Chiari II malformation; focal neuropathological alterations) that could be part of the variable phenotype of SMOC1-associated diseases.
Topics: Adult; Alleles; Brain; Cell Movement; Child; Consanguinity; Exons; Female; Fetus; Homozygote; Humans; Infant; Limb Deformities, Congenital; Male; Micrognathism; Microphthalmos; Mutation; Neurons; Osteonectin; Pedigree; Sequence Analysis, DNA
PubMed: 30445150
DOI: 10.1016/j.ejmg.2018.11.012