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FOXE3 forkhead transcription factor is essential to lens development in vertebrates. The eyes of Foxe3/foxe3-deficient mice and zebrafish fail to develop normally. In humans, autosomal dominant and recessive mutations in FOXE3 have been associated with variable phenotypes including anterior segment anomalies, cataract and microphthalmia. We undertook sequencing of FOXE3 in 116 probands with a spectrum of ocular defects ranging from anterior segment dysgenesis and cataract to anophthalmia/microphthalmia. Recessive mutations in FOXE3 were found in four of 26 probands affected with bilateral microphthalmia (15% of all bilateral microphthalmia and 100% of consanguineous families with this phenotype). FOXE3-positive microphthalmia was accompanied by aphakia and/or corneal defects; no other associated systemic anomalies were observed in FOXE3-positive families. The previously reported c.720C>A (p.C240X) nonsense mutation was identified in two additional families in our sample and therefore appears to be recurrent, now reported in three independent microphthalmia families of varied ethnic backgrounds. Several missense variants were identified at varying frequencies in patient and control groups with some apparently being race-specific, which underscores the importance of utilizing race/ethnicity-matched control populations in evaluating the relevance of genetic screening results. In conclusion, FOXE3 mutations represent an important cause of nonsyndromic autosomal recessive bilateral microphthalmia.

We report the case of a now 6-year-old girl who was born with different abnormalities in each eye. The right eye showed a total sclerocornea. At the age of 4 years we performed a perforating keratoplasty. On the left eye a large staphyloma developed. The staphyloma was excised and a cornea with a scleral rim was fixed in. This transplant became cloudy under a conjunctival flap and blepharoplasty. In addition to the clinical follow-up, histological and immun-histochemical examinations of the corneas were carried out.

Here we report on a 1-year-old Japanese girl with psychomotor retardation, bilateral congenital corneal opacity and bilateral postaxial polysyndactyly of the feet. Although she had a normal female karyotype, our in-house bacterial artificial chromosome (BAC)-based array-CGH analysis successfully detected at least a 2.7-Mb heterozygous deletion at 14q22.1-q22.3 harboring 18 protein-coding genes. Among the genes, BMP4 was a candidate for the gene causing the abnormalities of both the eye and digits. It was previously reported that the BMP family was correlated with the morphogenesis of digits and ocular development, and Bmp4 heterozygous null mice revealed skeletal abnormalities including polydactyly and ocular anterior segment abnormalities. Patients with a deletion including BMP4 also hadabnormalities of the eye and digits. These previous reports support that a haplo-insufficiency of the BMP4 gene likely caused the congenital ocular and digit abnormalities. Moreover, among the other genes contained in the deletion, GMFB is a candidate for the gene responsible for the psychomotor retardation.

Microphthalmia and anophthalmia are at the severe end of the spectrum of abnormalities in ocular development. Mutations in several genes have been involved in syndromic and non-syndromic anophthalmia. Previously, RAX recessive mutations were implicated in a single patient with right anophthalmia, left microphthalmia and sclerocornea. In this study, we report the findings of novel compound heterozygous RAX mutations in a child with bilateral anophthalmia. Both mutations are located in exon 3. c.664delT is a frameshifting deletion predicted to introduce a premature stop codon (p.Ser222ArgfsX62), and c.909C>G is a nonsense mutation with similar consequences (p.Tyr303X). This is the second report of a patient with anophthalmia caused by RAX mutations. These findings confirm that RAX plays a major role in the early stages of eye development and is involved in human anophthalmia.

We report on a male child with "apple peel" atresia, associated with microcephaly, with subsequent hydrocephalus, short stature, moderate global developmental delay and ocular abnormalities. A similar phenotype was previously reported by Stromme et al. in 1993 in female siblings, and this description of another affected individual provides further evidence for this being a distinct syndromic entity.

Purpose Outcomes of pediatric penetrating keratoplasties (PK) performed for various corneal anomalies in children. Methods Since 2000 56 PKs in children (6 months to 16 years) were performed. In infants group there were: 17 Peters Anomaly cases (24 eyes including 3 bilateral cases, 4 reoperations), 3 cases of sclerocornea. In older children surgeries were performed for 18 leucomas and 11 posttraumatic lesions. Follow up was at least 12 months. VA and graft transparency were analyzed. Results 59,2% of infant’s eyes had transparent corneas, VA ranged from 0.01 to 0.2. 19.2% of transplanted corneas were cloudy with blured vision. Other grafts were failed including one phthisis. In older children success rate with transparent cornea was achieved in 82,7% of cases. Mean VA was 0.3±0.12. Main complications were: immune rejection (11 eyes), stromal vascularisation (5 cases). Conclusion Keratoplasty is an effective procedure to safe vision in children.

Microphthalmia with linear skin defects (MLS) or microcornea, dermal aplasia and sclerocornea (MIDAS) syndrome is a rare X-linked-dominant disorder. We present a patient with agenesis of corpus callosum, ocular abnormalities, and multiple skin defects. The cytogenetic studies of the MLS critical region (Xp22.2) were normal, but a skewed X-chromosome inactivation pattern (85:15) was observed.

X-linked mental retardation (XLMR) is genetically heterogeneous and clinically variable. We describe a new XLMR syndrome of severe mental retardation and multiple congenital anomalies. Two sisters have (with 3 different partners) 3 severely handicapped sons. In 2 cases, oligohydramnios and intrauterine growth retardation were noted. Common anomalies included a square-shaped face, high and broad forehead, frontal bossing, downward slant of palpebral fissures, hypertelorism, epicanthic folds, long philtrum, thin upper lip, and apparently low-set ears. One boy has bilateral microphthalmos and sclerocornea, and his cousin has atrophy of the optic nerve. All 3 patients are blind and have profound statomotor and mental retardation, seizures, and a grossly abnormal electroencephalographic pattern. Additional findings are short stature, delayed bone maturation, hydronephrosis, vesicorenal reflux, cryptorchidism, clinodactyly of the 5th fingers, and transverse palmar creases. The karyotype is normal (46,XY). Segregation analysis showed perfect coinheritance between the clinical phenotype and alleles at several loci in Xp22.3, whereas recombinants were identified with marker loci from Xp22.2-qter. Analysis of multiple informative meioses suggests that the disease locus maps in Xp22.3 distal to DXS16.

Twin brothers with microphthalmia, facial dermal hypoplasia, sclerocornea, and supraventricular tachycardia, are reported. Their clinical features are compatible with MIDAS syndrome, a known X-linked and hemizygous male lethal condition. Their karyotypes showed an XX sex chromosome modality with a subtle Xp/Yp translocation proven by the presence of SRY gene. The pregnancy was complicated with fetal supraventricular tachycardia, which was treated with digoxin prenatally. Postnatally, both twins required treatment with adenosine, digoxin, and propanolol to remain in normal sinus rhythm. The possible involvement of the heart, only in the form of cardiomyopathy with arrhythmia is emphasized. Both twins had a selective X-inactivation of the derivative chromosome X with Xp/Yp translocation.

Bilateral microphthalmia with blepharophimosis, linear lesions of dermal aplasia involving the face, and microcephaly were present in a newborn girl who died at age 9 months from cardiomyopathy resulting in ventricular fibrillation. Autopsy showed an atrial septum defect, persistent gross trabeculation of the left ventricle, and an arteria lusoria. This case represents a further example of a new entity for which we propose the term MIDAS syndrome. The acronym stands for microphthalmia, dermal aplasia, and sclerocornea. Our patient is the second with this syndrome to have a major congenital heart defect. Cytogenetic studies reported in previous cases indicate that the underlying gene defect can be assigned to Xp22.3. This new X-linked malelethal trait should be distinguished from focal dermal hypoplasia that will be found to map elsewhere on the X-chromosome. © 1993 Wiley-Liss, Inc.

Purpose To describe the evolution of a clinically useful classification of corneal developmental anomalies which has also allowed more accurate phenotype/genotype correlation. Methods The use of clinical documentation using anterior segment photography, normal ultrasound of the eyeball, and high frequency ultrasound and where available histology of host tissue has allowed detailed phenotypes to be developed . Intraoperative recordings of phenotype have also been noted. Genotyping of specific patterns groupings of corneal developmental anomaly phenotypes. Retrospective analysis of clnical outcome with or without surgical intervention. Results Corneal developmental anomalies are best considered in terms of primary corneal disease and secondary corneal disease. The former includes dystophies ( CHED, PPCD and X-L ECD) , corneal dermoids and isolated sclerocornea ( CNA 1 and 2 ).Secondary corneal disease includes secondary to, iridotrabecular anomalies ( eg congenital glaucoma, aniridia, axenfeld -rieger anomaly), kerato-irido-lenticular dysgenesis ( iridolenticular adhesions( Peters type I), failure of lens to form,separate or move away from the cornea). Conclusion Using this classification prognosis for intervention can be shown to be mor successful in primary corneal developmental anomalies. Also by considering groups of patients with similar disease eg primary aphakia, appropriate genotyping can be done eg FOXE3 analysis for children with primary aphakia . More acccurate phenotype allows better clinical classification and ultimately better genotyping of corneal developmental anomalies

Purpose To present a retrospective review of keratoprosthetic implantation and retention in patients with congenital corneal opacities. Methods Pediatric patients younger than seven years old, the average age of permanent visual loss from understimulation of the visual cortex, were selected from a single center Boston Type I keratoprosthesis database and categorized by 1) primary diagnosis, 2) short-term visual outcome, and 3) post-operative complications. Results Seventeen patients, with an age range of 41 days up to 6 years, were selected from a database of over one hundred and forty patients. Six had a primary diagnosis of sclerocornea and eleven had Peter’s anomaly. Visual outcome after one year improved in fourteen of the patients, with patients who previously could not detect light to subsequently being able to fixate and follow or even read allen cards. The remaining three patients showed no improvement in visual acuity but also no worsening from their baseline condition. In terms of post-operative complications of the optic, two had retroprosthetic membrane formation, and another patient required replacement of the keratoprosthesis due to phthisis and optic melting. From a retinal standpoint, four patients had retinal detachments. There were no cases of choroidal hemorrhaging or hypotony in these patients. Conclusion Based on visual outcome, the Boston Type I keratoprosthesis is a safe and effective procedure for patients with congenital corneal opacities. With great retention, the artificial cornea is a viable option for prevention of amblyopia. Due to comorbidities such as congenital cataracts, congenital glaucoma, and retinal detachments, it is crucial to have glaucoma and vitreo-retinal surgeons on hand when managing and implanting keratoprosthesis in a pediatric population.

We present a child with an MCA pattern of sclerocornea, hypertelorism, pterygium colli, upper limb syndactyly, ambiguous genitalia, abnormal ears and nose, umbilical hernia, congenital heart disease, and normal chromosomes (46,XX). Although the defects observed in this case follow the diagnostic criteria for Fraser syndrome proposed by Thomas et al. [1986: Am J Med Genet 25:85-98], we think that this is a different entity.