Macular coloboma type Leber's congenital amaurosis

Three brothers, with the macular coloboma type Leber's congenital amaurosis aged 10, 8, and 6 years respectively, are described in this report. Only the two elder brothers were symptomatic while the third patient had no complaint at the time of diagnosis. The patients had no associated systemic or ocular disorders, including nystagmus. They had mild myopic astigmatism. All three had a relatively well-circumscribed bilateral macular atrophy with a seemingly normal peripheral retina. The electroretinogram was non recordable but the visualy evoked potential responses were within normal limits. During three years of follow-up, the macular lesions did not progress and the visual acuity did not deteriorate further. Our experience with these three familial cases supports the general view that the macular coloboma variant does not necessarily have the typical signs and symptoms and perhaps also the dismal prognosis of classic Leber's congenital amaurosis, and as such should stand as a distinct subtype of the disease.     

Spontaneous regression of retinoblastoma

Clinicopathologic evidence of bilateral spontaneous regression of retinoblastoma in three brothers is presented. The buphthalmic right eye and phthisical left eye of one of these persons were examined histopathologically. The two brothers of this patient both had phthisical left eyes, and those eyes were examined histopathologically. Both of those brothers also had clinically detected chorioretinal scars in their right eyes from regressed retinoblastoma. Three of eight children of one of the two brothers had bilateral retinoblastoma, and two of seven children of the other brother had bilateral retinoblastoma. Reports in the literature of 50 previous cases of total spontaneous regression of retinoblastoma from 1911 to 1975 are reviewed.     

Cockayne's syndrome with unusual retinal involvement (report of one family)

Cockayne's syndrome is a very rare autosomal recessive affection. Ocular involvement is an essential element for positive diagnosis; the retina shows a typical salt and pepper retinitis with optical atrophy. We report a family with four brothers who had Cockayne's syndrome with unusual retinal involvement. The patients' parents were first cousins. Ophthalmologic examination of the mother showed unilateral left pigmentary retinopathy localized in the peripapillary region. The father's ophthalmological examination was normal. The four brothers presented disharmonious dwarfism, cutaneous hyperpigmentation of skin areas exposed to sun with old-appearance of the skin, sensorineural deafness, kyphoscoliosis, a cerebellar syndrome and mental retardation. The ophthalmological examination showed hypermetropia in all four brothers and bilateral maculopathy with no papillary or vascular abnormalities. The electroretinogram was in favor of cone dystrophy. Computed tomography showed one case of calcifications of the basal ganglia and cerebral atrophy. The karyotypes of the four brothers and the mother were normal. We discuss the ocular symptoms and the etiopathogenesis of this syndrome.     

Familial non-syndromic macular pseudocoloboma secondary to homozygous CLDN19 mutation

Purpose: The purpose of this study is to uncover the genetic cause for non-syndromic macular “coloboma” (pseudocoloboma) in three brothers from a consanguineous family.

Methods: Homozygosity mapping for the three affected brothers and whole-exome sequencing in one affected brother, followed by confirmatory Sanger sequencing and segregation analysis of the candidate gene for all immediate family members; molecular modeling of the candidate mutation; and review of clinical, imaging, and laboratory findings.

Results: Three otherwise-healthy brothers (age 10, 10, and 6 years) had macular pseudocoloboma. Both parents and the fourth brother were not affected. Parents were first cousins. A novel homozygous missense variant in claudin 19 (CLND19: NM_148960.2:c. 263T>A; p.Val88Glu) segregated with the phenotype, and molecular modeling predicts an unfavorable effect to protein function. All prior reported biallelic CLND19 mutations cause symptomatic hypomagnesemia with hypercalciuria and nephrocalcinosis, often with concurrent macular pseudocoloboma. However, general physical assessment, metabolic profile, and renal imaging for the three affected brothers were normal.

Conclusions: A homozygous CLDN19 mutation can cause macular pseudocoloboma without evidence for systemic disease in children. This is the first reported family with CLDN19 mutations to have an ocular phenotype only; however, those identified to harbor biallelic CLDN19 mutations should be considered at risk for the extraocular manifestations that have previously been associated with mutations in the gene.     

A novel mutation of the OPA1 gene responsible for isolated autosomal dominant optic atrophy in two brothers

Autosomal dominant optic atrophy, or Kjer disease, is the most frequent form of autosomal dominant optic neuropathy. We report a novel mutation of the OPA1 gene in two brothers with autosomal dominant optic atrophy and describe their clinical features. The two patients, aged 41 and 37, presented with a bilateral visual impairment that had been detected at the age of 4 in both of them. Their ophthalmoscopic examinations disclosed a bilateral optic atrophy and their Goldmann visual fields showed cecocentral scotomas. The patients thought their disease might be a Leber's hereditary optic neuropathy; however, mutations had ever been sought. When first seen by us, they wished to know whether their disorder might be transmitted to their children. They had a family history of visual impairment. We carried out mtDNA sequencing but we did not identify any primary or rare Leber's hereditary optic neuropathy mutations. On the other hand, the 30 coding exons of the OPA1 gene and the intron-exon junctions were amplified by polymerase chain reaction and sequenced. A novel mutation of the OPA1 gene was found in both brothers: a deletion of four nucleotides in intron 19, associated with anomalous splicing, demonstrating the pathogenicity of the mutation. These molecular analyses contributed to identifying a novel mutation of the OPA1 gene with a clinical phenotype of isolated optic atrophy.     

Familiar case of granular dystrophy and oculocutaneous albinism

CLINICAL CASE: A 35-year-old female patient with blurred vision since childhood, for which no treatment had been given, presented with poor visual acuity. She had white skin and fair yellow hair. There were several well circumscribed deposits in the central and anterior corneal stroma, and iris transillumination and foveal hypoplasia were evident. The clinical diagnosis was oculo-cutaneous albinism and granular corneal dystrophy. We found oculo-cutaneous albinism in two brothers and granular dystrophy in three brothers, the mother and a son. DISCUSSION: Corneal dystrophy is an autosomal dominant disorder inherited independently of oculocutaneous albinism, which is inherited as an autosomal recessive condition. This is the first case report of granular dystrophy concurrent with oculocutaneous albinism.     

Congenital ocular malformations (lens subluxation,pupillary displacement,cataract, myopia) and classic galactosaemia associated with Q188R and /or G1391A mutations

Purpose: Observations of multiple ocular malformations together with heterozygosity for galactosaemia in siblings and homozygosity in one child are highly unusual. In these case histories, a series of investigations in one family are reported. Methods: Members of a family of two brothers and one sister and their children were pre‐ and post‐surgically examined over several years. Blood examination was carried out in a laboratory specializing in investigation into genetic diseases (Dr Podskarbi, Munich). Results: Two brothers and one sister suffered from cataract‐induced visual deterioration at 38, 34 and 35 years of age, respectively. All three siblings reported having had bilateral poor vision since early childhood. The three siblings’ parents had no congenital ocular malformations, nor was there any parental consanguinity. One child, the 10‐year‐old son of the 35‐year‐old sister, exhibited classic galactosaemia and normal ocular findings. This sister’s other child was healthy. All three siblings presented congenital lens luxa‐tion, axial myopia, cataract and iridodonesis. In addition, the 34‐year‐old brother showed unilateral right corectopia and left coloboma adjacent to the optic disc. The 38‐year‐old brother revealed myopic fundus changes, but no coloboma. The three siblings experienced a distinct increase in visual acuity after cataract surgery. Both eyes of the patients were partially or distinctly amblyopic, respectively. We assume an autosomal‐recessive transmission. Molecular genetic examination of the 10‐year‐old child with classic galactosaemia showed homozygosity for the mutation Q188R with a complete galactose‐1‐phosphate‐uridyltransferase (GALT) deficiency. Because of his galactose‐free diet, the child showed normal values for galactose‐1‐phosphate. The 35‐year‐old mother showed compound heterozygosity for Q188R and G1391A (D2/G). The 10‐year‐old boy’s father also revealed heterozygosity for galactosaemia caused by GALT deficiency. The two children of the 38‐year‐old brother were heterozygous for G1391A. They did not show any clinical abnormality. None of the family members had clinical signs of Marfan’s syndrome or homocysteinuria. The three siblings’ parents were not consanguineous. Conclusions: Patients with worsening cataracts occurring at a pre‐senile age should be examined for galactosaemia. We describe for the first time the molecular genetic findings in congenital ectopia lentis et pupillae. Early treatment in conjunction with a galactose‐free diet is mandatory in patients with galactosaemia. Members of a family with heterozygosity for galactosaemia should be advised to attend a human genetic consultation.     

Bilateral choroidal osteoma in three siblings

Three siblings (a sister and two identical-twin brothers) had bilateral choroidal osteomas. The sister was seen at 11 years of age, and the tumor showed significant growth two years later. The twin brothers' tumors were diagnosed at 9 years of age, and their conditions remained stable over two years except for a new, isolated lesion that occurred in one eye of one brother. The siblings' mother had a yellow mottling situated nasal to the disk in each eye that was similar in appearance to that in one eye of one of the twins. She showed no evidence of calcium on ultrasonography. The appearance of osteomas in three siblings suggests a choristoma as the cause of this tumor.     

Familial ophthalmoplegia-plus syndrome with corneal endothelial disorder

The authors report two brothers with an ophthalmoplegia-plus syndrome characterized by chronic progressive external ophthalmoplegia associated with hypogonadism, primary testicular failure, neural deafness, cone-rod degeneration and mild optic atrophy. One brother, the proband, was a daily soft contact lens wearer who developed persistent epithelial and stromal edema of the right cornea and had bilaterally thickened corneas by ultrasonic pachymetry. Endothelial studies of both brothers revealed marked polymegathism, and pleomorphism. Stressing the inherently abnormal endothelium with contact lens wear may have resulted in further endothelial compromise and corneal edema in the proband.

Endothelial abnormalities may be another clinical finding within the spectrum of ophthalmoplegia-plus syndrome and should be searched for before fitting these individuals with contact lenses.     

Hereditary Diffuse Infiltrating Retinoblastoma

Retinoblastoma is one of the most common childhood cancers. The diffuse infiltrating retinoblastoma is a rare subtype of this neoplasm. The majority of cases of diffuse infiltrating retinoblastoma are unilateral and occur sporadically. Herein we report on a family with three children affected by retinoblastoma, among them one girl with diffuse infiltrating retinoblastoma. This girl was diagnosed at the age of 8 years with a unilateral diffuse infiltrating retinoblastoma. By contrast, the two brothers became clinically apparent in the first 2 years of life with bilateral retinoblastoma. The parents were clinically unremarkable. Genetic analysis of RB1 gene was performed. The girl with diffuse infiltrating RB was found to be heterozygous for an oncogenic mutation in the RB1 gene that was also carried by both brothers and the father of the family. These results show that diffuse infiltrating retinoblastoma can develop on the background of a hereditary predisposition to retinoblastoma.     

Q118X mutation of M1S1 gene caused gelatinous drop-like corneal dystrophy: the P501T of BIGH3 gene found in a family with gelatinous drop-like corneal dystrophy

PURPOSE: To analyze BIGH3 and M1S1 genes in two Japanese brothers with gelatinous drop-like corneal dystrophy and five unaffected family members. METHODS: DNA was extracted, and each part of the two genes was amplified and directly sequenced. RESULTS: On the BIGH3 gene, a heterozygous P501T mutation was found in the elder brother and three unaffected family members. On the M1S1 gene, both brothers with gelatinous drop-like corneal dystrophy showed a homozygous Q118X mutation, whereas all unaffected members were heterozygous. CONCLUSIONS: The Q118X mutation of M1S1 gene caused gelatinous drop-like corneal dystrophy. Although the P501T of the BIGH3 gene found in this pedigree was precisely the one reported for lattice corneal dystrophy IIIA, no clinical feature was shown, even in the 85-year-old father. This fact shows that the P501T mutation for LCDIIIA has low penetrance.     

Two brothers with gelatinous drop-like dystrophy at different stages of the disease: role of mutational analysis

PURPOSE: A report of two Japanese brothers with gelatinous drop-like corneal dystrophy, one with and one without the typical gelatinous drop-like region. DESIGN: Interventional case report and observational case report. METHODS: After penetrating keratoplasty, the corneal button, right eye, of the elder brother, 39 years of age, was stained and examined by microscopy. The M1S1 and BIGH3 genes were examined for mutations using the polymerase chain reaction and direct sequencing. Corneal abnormalities in the younger brother, 37 years of age, were observed. RESULTS: The elder brother had bilateral gelatinous prominences and band-shaped corneal opacities, whereas the younger brother had only bilateral band-shaped opacities. Histologically, corneal deposits beneath the epithelium stained with Congo red. Molecular genetic analysis revealed that M1S1 was homozygously mutated in both brothers (Q118X). CONCLUSION: The Q118X mutation of the M1S1 gene can produce either a gelatinous drop-like region or band-shaped opacities.     

Nystagmus mimicking spasmus nutans as the presenting sign of Bardet-Biedl syndrome

PURPOSE: To investigate the nystagmus of twin brothers presenting with spasmus nutans later diagnosed as Bardet-Biedl syndrome. METHODS: The twins presented at the age of 14 months with a presumed diagnosis of spasmus nutans. They were followed clinically and with quantitative electro-oculographic eye movement recordings until the age of 6 years. RESULTS: Polydactyly, truncal obesity, mild delay in cognitive development, visual acuity of 20/100, attenuated retinal vessels and pale disks, and bilaterally almost extinguished scotopic and photopic electroretinograms were found in both brothers. They had fine, fast, pendular, disconjugate, intermittent, oblique nystagmus. No head nodding was observed. CONCLUSION: As described in patients with other retinal diseases such as achromatopsia and congenital stationary night blindness, nystagmus of patients with Bardet-Biedl syndrome can mimic spasmus nutans.     

Opto-chiasmatic arachnoiditis in brothers.

Six patients (3 couples of brothers) with adhesive arachnoiditis of the opto-chiasmatic cistern, surgically verified, are presented. Only one couple of brothers offered a possible family history of a similar condition in one maternal uncle. The visual damage had almost constantly a sudden onset and was predominantly of the axial type. No gross pathology, other than the arachnoiditic involvement of the chiasmal cistern and alterations of the anterior optic pathways, was found at surgery. Pneumocisternoencephalographic findings did not prove constantly reliable for a preoperative diagnosis of the condition when compared with surgical pathology. The overall results of the neurosurgical operations (exploration of the chiasm and removal of the adhesions) can be considered as favorable and this type of treatment is once again recommended as the therapy of choice without undue delay when general or local medical treatment proves of no avail after a reasonable length of time.     

Novel mutation in RP2 gene in two brothers with X-linked retinitis pigmentosa and mtDNA mutation of leber hereditary optic neuropathy who showed marked differences in clinical severity

PURPOSE: To report the identification of a novel mutation of the RP2 gene in two Japanese brothers with X-linked retinitis pigmentosa of a differing clinical severity. The mother was a carrier of both retinitis pigmentosa and optic atrophy. METHODS: The older brother had a severe form of retinitis pigmentosa associated with macular degeneration and total optic atrophy, whereas the younger brother presented typical X-linked retinitis pigmentosa. RESULTS: Each patient exhibited a novel 2-bp insertion at codon 278 in exon 3 of the RP2 gene as well as a 11778 mutation in mitochondrial DNA. This suggests that the older brother may have developed Leber hereditary optic neuropathy as well as retinitis pigmentosa. CONCLUSION: Molecular testing confirmed the clinical diagnosis in each case. However, such testing did not explain the differences in the severity of the ophthalmoscopic findings between the two brothers.     

Identification of XLRS1 gene mutation (608C > T) in a Portuguese family with juvenile retinoschisis

PURPOSE: To characterize electroretinogram (ERG) and molecular genetic findings in a family with XLRS1 mutation. The authors present two cases of a Portuguese family with juvenile retinoschisis with a mutation in exon 6. METHODS: Two brothers and their parents, grandmother, and uncle underwent a full ophthalmic examination. The two brothers with ophthalmic disease were evaluated with color fundus photography, fluorescein angiography, optical coherence tomography (OCT), molecular genetic study (Group VI of Retinoschisis Consortium), pattern visual evoked potential (PVEP), and full field ERG. RESULTS: Both patients presented funduscopic manifestations of vitre o retinal degeneration. They presented peripheral schisis and retinal detachment. However, foveal schisis had never been observed at funduscopy. A negative ERG was recorded in both. Six months after that, the younger brother showed a typical foveal schisis at fundus examination. A retinoschisis gene (XLRS1) mutation with transition of cytosine by thymine at position 608 (608C > T) had been identified in both. CONCLUSIONS: Negative ERG is the most secure clinical marker to establish the diagnosis of juvenile retinoschisis. XLRS1 gene 608C > T mutation was described for the first time in a Portuguese family.     

Visual Electrophysiologic Findings in Patients From an Extensive Brazilian Family with Leber's Hereditary Optic Neuropathy Visual electrophysiology in LHON

Leber's hereditary optic neuropathy (LHON) is a maternally inherited disease, associated with mitochondrial DNA (mtDNA) point mutations and characterized by bilateral, usually sequential, rapid loss of central vision. The purpose of this study was to investigate electrophysiologically a small cohort of members from an extensive Brazilian family affected by LHON. Pattern-reversal visual evoked potentials (PVEP), and full-field electroretinograms (ERG) were performed on the four index members, all carrying the 11778 homoplasmic mtDNA mutation. They were a 14-year-old recently affected male, his unaffected mother, and her two affected brothers. The three affected members all had bilateral profound visual loss with visual acuities that ranged from 20/250 to CF, cecocentral defects, and severe dyschromatopsia (by FM-100). The unaffected (carrier) female had normal visual acuities, visual fields and color discrimination. Severely prolonged P100 latencies and decreased N75-P100 peak amplitudes were found in pattern-reversal VEPs for three affected members. Normal PVEP responses were found in the carrier female. Rod and cone ERG responses were normal in two affected members, but both the carrier mother and her affected son showed reduced peak-to-peak amplitude for single-flash cone response and 30 Hz flicker, with normal b-wave implicit times. Thus, optic nerve function, evaluated by PVEP, was severely reduced in LHON affected members and normal in the carrier female. However, reduced ERG cone responses suggest that LHON can also affect retinal elements, even in the absence of fundus and other clinical changes that constitute the full and classical expression of LHON.     

Ocular onchocerciasis with living microfilariae in the anterior chamber in two Dutch boys

In 2 Dutch boys, 15 and 12-year-old brothers, living microfilariae were observed in the anterior chamber. Both boys had returned 4 years before from a hyperendemic onchocerciasis region where they had lived for 5 years. The pathogenesis and treatment of onchocerciasis are discussed.     

Extensive subretinal pigment epithelial deposit in two brothers suffering from dominant retinitis pigmentosa

The eyes of two brothers with retinitis pigmentosa were removed after death and examined by a variety of techniques, including conventional histology, fluorescence microscopy and both scanning and transmission electron microscopy. Their condition was considered to be of an autosomal dominant type but with some atypical clinical features. The outstanding histological feature in both pairs of eyes was a predominantly acellular deposit of amorphous material situated between the retinal pigment epithelium and Bruch's membrane. This material extended from the disc to beyond the ora serrata. In some regions of the retinae of both brothers, there was a cellular infiltrate into the deposit and this included multinucleate cells. In one brother the deposit was lined externally by a fibrovascular membrane in some few locations. All retinae were degenerate, but all showed preservation of abnormally short and sparse photoreceptor cells in both the peripheral and macular areas. There was only patchy loss of the choriocapillaris, which could have been age-dependent rather than disease-dependent, and the remaining choroidal vessels were patent in all cases. The widespread distribution of the deposit is unusual and suggests that it arises from disordered metabolism of the retinal pigment epithelium. We could not determine whether it was a primary disease process or if it arose as a secondary phenomenon.