glaucoma

Megalocornea, Ectopia Lentis, and Spherophakia

Clinical Characteristics
Ocular Features: 

Patients have megalocornea and mobile lenses.  Corneal diameters are at least 13 mm in diameter.  Some lenses are spherophakic (refractive errors may be in the +11-12 diopter range) and sometimes displace into the anterior chamber or cause pupillary block glaucoma.  The clinical picture often resembles congenital glaucoma in young children but the elevated pressure is usually secondary to hypermobility of the lens and/or its spherical shape.  Haab striae are not present but cloudy corneas have been reported in a few patients.

Many patients develop phthisis or have severe reductions in vision.

Systemic Features: 

Some but not all patients have several physical features of the Marfan syndrome (154700) such as high arched palate, tall stature, and narrow face but those tested do not have mutations in the FBN1 gene.

Genetics

This is an autosomal recessive disorder.  Parental consanguinity is common.  Homozygous mutations in the LTBP2 gene (14q24.3) are found in affected individuals.

LTBP2 competes with LTBP1 (ADAMTSL2) for binding to the gene product of FBN1 in which mutations are associated with the Marfan syndrome (154700) and may account for the variable skeletal signs sometimes found in patients with this megalocornea syndrome.  Both gene products are important to the structure of the extracellular matrix proteins of the ciliary processes, lens capsule, and lens epithelial layer.  The different modes of inheritance and the unique mutations, of course, argue for separateness of the two disorders.

Mutations in LTBP2 have also been found in a family with microspherophakia and ectopia lentis but corneal diameters were described as normal suggesting clinical heterogeneity.

This is a unique disorder which previously has been classified as Glaucoma, Congenital Primary D (613086).  The usual occurrence of ectopia lentis,  the sometimes spherophakic nature of the lenses, the congenital presence of megalocornea without corneal edema in the absence of elevated intraocular pressure, and the lack of breaks in the Descemet membrane strongly suggest that this is not a primary congenital glaucoma.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Urgent lensectomy is necessary for lenses that migrate into the anterior chamber.  Patients have to be monitored as lens dislocations can occur at any age.

References
Article Title: 

Null mutations in LTBP2 cause primary congenital glaucoma

Ali M, McKibbin M, Booth A, Parry DA, Jain P, Riazuddin SA, Hejtmancik JF, Khan SN, Firasat S, Shires M, Gilmour DF, Towns K, Murphy AL, Azmanov D, Tournev I, Cherninkova S, Jafri H, Raashid Y, Toomes C, Craig J, Mackey DA, Kalaydjieva L, Riazuddin S, Inglehearn CF. Null mutations in LTBP2 cause primary congenital glaucoma. Am J Hum Genet. 2009 May;84(5):664-71.

PubMed ID: 
19361779

Cataracts, Congenital Zonular Pulverulent 1

Clinical Characteristics
Ocular Features: 

Bilateral lens opacities may be both nuclear and zonular.  The embryonic and fetal nuclei are usually involved and diffuse cortical opacities may also be seen in some patients.  The involved area is therefore larger than the somewhat similar Coppock-like cataract (604307) which is limited to the embryonic nucleus.  The lens opacities may be seen at birth or in early childhood and usually progress. There is considerable clinical variation in the degree and distribution of the usual dust-like opacities which may also be lamellar in distribution with a clear peripheral cortex and minimal nuclear involvement.  Microcornea has also been reported.  In mild cases the lens opacities are primarily clustered along the Y sutures resembling congenital zonular cataracts with sutural opacities (600881).

Three unrelated patients with mutations in GJA8 and total sclerocornea have been reported.  Two of these patients in addition had small abnormal lenses while the third had cataracts and micropthalmia.  Two of the three also develped glaucoma by one year of age.

The nature and morphology of the lens opacities in an adult have been studied by light and scanning electron microscopy.  They are located in the embryonic and fetal nuclei and appear "puffy" with lens fiber irregulaties and entanglement in adjacent areas. 

Systemic Features: 

None.

Genetics

Congenital zonular pulverulent cataracts are inherited in an autosomal dominant pattern resulting from missense mutations in the GJA8 gene (1q21.1) that codes for connexin 50.  These belong to a category of lens opacitites now designated "Cataract 1, Multiple Types" in OMIM (116200). They have been detected in multiple populations and ethnic groups around the world.

Mutations in CZP3 at 13q11-13 coding connexin 46 (601885) result in a similar phenotype (Cataracts, Congenital Zonular Pulverulent 3) suggesting that genetic heterogeneity is present.

This was the first disease locus to be linked on a human autosome, in this case to the Duffy blood group locus on chromosome 1.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Cataract surgery is indicated for visually significant lens opacities which may be required late in the first or early in the second decade of life.

References
Article Title: 

Cornea, Ring Dermoid

Clinical Characteristics
Ocular Features: 

Dermoids in this condition are found at the limbus extending onto the cornea anteriorly and into the conjunctiva posteriorly.  They may be unilateral or bilateral and some contain functional hair follicles.  They are present at birth and appear as raised yellow-white tissue which can be segmental or extend for the full limbal circumference.  Some present as a dark ring around the cornea.  The apophyses can be elevated 2-3mm and extend for 3-5mm laterally.  Corneal changes, primary or secondary, lead to progressive vision loss in older individuals. Corneal distortion can result in significant astigmatism.  Some patients have glaucoma and congenital cataracts.

Histological studies have not been reported.

Systemic Features: 

No systemic disease is part of this condition.

Genetics

Two families, one Peruvian and one Chinese, have been reported with autosomal dominant patterns of transmission.  A G185A substitution in the PITX2 gene (4q25) cosegregated with the ocular disease in the Chinese family.

PITX2 encodes a transcription factor important to the development of multiple organs including the eye.  Mutations in this gene have also been found in patients with Peters anomaly (604229), a form of iris hypoplasia with goniodysgenesis (IRID2) (137600), and in Type 1 Axenfeld-Rieger syndrome (180500).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Surgical excision may be necessary in patients with extensive disease.  Patients need to be monitored for cataracts, amblyopia, and glaucoma.

References
Article Title: 

Oculoauricular Syndrome

Clinical Characteristics
Ocular Features: 

This rare malformation syndrome affects primarily the eyes and ears.  The globes are small and usually have colobomas of both anterior and posterior segments.  The corneas likewise are small and often have opacities.  The anterior segment is dysplastic with anterior and/or posterior synechiae.  Glaucoma may be present.  The lenses may be small and often become cataractous.  There is a progressive rod-cone dystrophy associated with a pigmentary retinopathy.  Chorioretinal lacunae have been seen in the equatorial region.  The retinal degeneration is progressive, beginning with rod dysfunction but followed by deterioration of all receptors.  The onset in early childhood results in poor vision and nystagmus. 

Systemic Features: 

The external ears are abnormal.  The earlobes may have colobomas or may be aplastic.  The intertragic notch is often underdeveloped.  Audiograms and vestibular function tests, however, show normal function and MRI of the middle and inner ears likewise reveals no anatomic abnormalities.       

Among the few patients reported, dental anomalies, spina bifida oculta, and mild dyscrania have been noted in individual patients.

Genetics

This rare disorder has been reported in only a few families.  Based on parental consanguinity and homozygosity of mutations in the HMX1 gene (4p16.1) in affected sibs, this is an autosomal recessive disorder.  In one family there was a homozygous 26 bp deletion and in another a homozygous missense mutation.  The parents are heterozygous for the deletion.

HMX1 is a homeobox gene and the deletion abolishes its function by establishing a stop codon at position 112.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for the extraocular malformations.  Glaucoma treatment and cataract surgery should be considered although permanent visual rehabilitation is unlikely given the progressive nature of the rod-cone dystrophy.

References
Article Title: 

Microphthalmia with Coloboma, X-Linked

Clinical Characteristics
Ocular Features: 

Isolated colobomatous microphthalmia is caused multiple mutations and usually inherited in an autosomal dominant pattern.  Type 1 is an X-linked disorder with typical features of small eyes, small corneas, colobomas, and elevated intraocular pressures. 

Systemic Features: 

By definition no systemic disease is present. 

Genetics

The combination of colobomas and microphthalmia is found in numerous heritable syndromes but also occurs in isolation.  X-linked syndromes with this combination usually include mental retardation and cataracts but these are absent in the isolated type described here.  A locus on the X chromosome was identified to lie either on the proximal short arm or the proximal long arm but no specific mutation or gene has been identified.  In the single multigenerational reported family, all affected individuals were male except for one female in whom non-random X-inactivation was postulated. 

Syndromal forms of X-linked microphthalmia with coloboma (309800 ) have also been reported.

Pedigree: 
X-linked recessive, carrier mother
X-linked recessive, father affected
Treatment
Treatment Options: 

No treatment is available for the malformations but low vision aids should be considered for appropriate individuals. 

References
Article Title: 

Pierson Syndrome

Clinical Characteristics
Ocular Features: 

Microcoria is the most consistent ocular feature but is not present in some families.  It is congenital and sometimes seen with iris hypoplasia.  Glaucoma and lens opacities (including posterior lenticonus sometimes) are present in one-fourth of patients.  Corneal size varies with some patients having apparent macrocornea which can lead to the mistaken diagnosis of buphthalmos.  Pigment mottling and clumping is common in the retina and the ERG can show changes characteristic of cone-rod dystrophy.  Retinal thinning is often present as well.  Non-rhegmatogenous retinal detachments occur in 24% of patients and optic atrophy is seen in some individuals.  There is considerable interocular, intrafamilial, and interfamilial variability in these signs. 

Systemic Features: 

The primary and most consistent systemic problem is progressive renal disease. Congenital nephrotic syndrome with proteinuria, hypoalbuminemia and hypertension is characteristic.  Renal failure eventually occurs although the rate of progression varies. Most patients require a renal transplant for end-stage kidney disease in the first decade of life.  Kidney histology shows glomerulosclerosis, peritubular scarring, and diffuse mesangial sclerosis.  Hypotonia and muscle weakness are sometimes present and congenital myasthenia has been reported.  Severe global psychomotor retardation is common and many infants never achieve normal milestones. 

Genetics

This is an autosomal recessive disorder resulting from homozygous mutations in the LAMB2 gene located at 3p21.  The normal gene encodes laminin beta-2 that is strongly expressed in intraocular muscles which may explain the hypoplasia of ciliary and pupillary muscles in Pierson syndrome.  Mutations in this gene are often associated with nephronophthisis but ocular abnormalities are not always present. 

Microcoria is also a feature of the autosomal dominant ocular condition known as congenital microcoria (156600).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Kidney replacement can restore renal function.  Glaucoma, cataracts, and retinal detachments require the usual treatment but patient selection is important due to the neurological deficits.  Lifelong monitoring is essential. 

References
Article Title: 

Ocular findings in a case of Pierson syndrome with a novel mutation in laminin ß2 gene

Arima M, Tsukamoto S, Akiyama R, Nishiyama K, Kohno RI, Tachibana T, Hayashida A, Murayama M, Hisatomi T, Nozu K, Iijima K, Ohga S, Sonoda KH. Ocular findings in a case of Pierson syndrome with a novel mutation in laminin ss2 gene. J AAPOS. 2018 Aug 16. pii: S1091-8531(18)30497-X. doi: 10.1016/j.jaapos.2018.03.016. [Epub ahead of print].

PubMed ID: 
30120985

Ophthalmological aspects of Pierson syndrome

Bredrup C, Matejas V, Barrow M, Bl?deghov?deg K, Bockenhauer D, Fowler DJ, Gregson RM, Maruniak-Chudek I, Medeira A, Mendon?ssa EL, Kagan M, Koenig J, Krastel H, Kroes HY, Saggar A, Sawyer T, Schittkowski M, Swietli?Nski J, Thompson D, VanDeVoorde RG, Wittebol-Post D, Woodruff G, Zurowska A, Hennekam RC, Zenker M, Russell-Eggitt I. Ophthalmological aspects of Pierson syndrome. Am J Ophthalmol. 2008 Oct;146(4):602-611.

PubMed ID: 
18672223

Maroteaux-Lamy Syndrome (MPS VI)

Clinical Characteristics
Ocular Features: 

Corneal clouding is the cardinal ocular feature and is often visible by 5 years of age.  Several adult patients have had glaucoma with both open and closed angles.  The mechanism is unknown.  Optic nerve compression or secondary edema can cause a relatively sudden loss of vision.

Systemic Features: 

The lysosomal accumulation of glycosaminoglycans is responsible for the widespread signs and symptoms found in this disease.  Bone destruction in shoulders, hips and skull is often seen by the second decade of life and may become evident later in the knees and spine.  Early growth may be normal but eventually slows resulting in short stature.  Dysplasia of bones comprising these joints leads to stiffness and restricted movement.  The face is dysmorphic with coarse features.  Bone dysplasia and facial dysmorphism may be seen at birth.  Myelopathy and even tetraplegia can result from vertebral compression.  Intelligence is often normal although more severely affected individuals may have some cognitive defects.  Hepatosplenomegaly is common and compromised respiratory function can result in reduced physical stamina.  The tongue is usually enlarged.  Accumulation of dermatan sulfate in heart valves may produce insufficiency or restriction of outflow.

Genetics

MPS VI is a lysosomal storage disease inherited in an autosomal recessive pattern.  The responsible mutations lie in ARSB (5q11-q13), the gene that encodes the enzyme arylsulfatase B.  The phenotype results from defective dermatan sulfate breakdown with lysosomal accumulation.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Enzyme replacement therapy with galsulfase (Naglazyme®) is beneficial in alleviating some of the manifestations of this disease.  Orthopedic surgery for specific deformities may be necessary.  Visually significant corneal opacification may require corneal transplantation.

References
Article Title: 

Threshold effect of urinary glycosaminoglycans and the walk test as indicators of disease progression in a survey of subjects with Mucopolysaccharidosis VI (Maroteaux-Lamy syndrome)

Swiedler SJ, Beck M, Bajbouj M, Giugliani R, Schwartz I, Harmatz P, Wraith JE, Roberts J, Ketteridge D, Hopwood JJ, Guffon N, S?deg Miranda MC, Teles EL, Berger KI, Piscia-Nichols C. Threshold effect of urinary glycosaminoglycans and the walk test as indicators of disease progression in a survey of subjects with Mucopolysaccharidosis VI (Maroteaux-Lamy syndrome). Am J Med Genet A. 2005 Apr 15;134A(2):144-50.

PubMed ID: 
15690405

Morquio Syndrome (MPS IVA)

Clinical Characteristics
Ocular Features: 

Corneal clouding in the form of fine deposits in the stroma is the major ocular manifestation but it may not be noted for several years after birth.  Penetrating keratoplasty is rarely needed.  Glaucoma occurs rarely.

Systemic Features: 

There is wide variation in the clinical disease in this disorder and some have grouped cases into severe, intermediate and mild categories.   Onset is about 2 years of age and three-quarters of patients are diagnosed by the age of 6 years.  Intelligence is usually normal and the central nervous system is spared similar to MPS IVB. However, the skeletal dysplasia can lead to neurologic complications.  In particular, odontoid hypoplasia raises the risk of atlantoaxial dislocation and spinal cord damage. The maxillary teeth are often abnormal with wide spacing and a flared appearance.  Truncal dwarfism is characteristic but the facies are often more fine-featured than in other mucopolysaccharidoses.  Lifespan is shortened in most patients.

Genetics

This is an autosomal recessive disorder resulting from mutations in the GALNS gene (16q24.3) encoding galactosamine-6-sulfate sulfatase.  Keratan sulfate and chondroitin-5-sulfate accumulates in lysosomes.  Urinary keratin sulfate excretion is increased.

A clinically similar disease, Morquio syndrome B (253010), is caused by a different mutation.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No specific treatment is available for this disease.  Some have recommended cervical spine fusion to stabilize the atlantoaxial joint. Orthopedic surgery may be indicated for joint and spine deformities.  Special precautions should be taken during intubation for general anesthesia.

Enzyme replacement therapies and hematopoietic stem cell transplantation techniques now being developed hold promise for more specific treatment for the underlying enzyme deficiencies in mucopolysaccharidoses.

References
Article Title: 

Mucopolysaccharidoses and the eye

Ashworth JL, Biswas S, Wraith E, Lloyd IC. Mucopolysaccharidoses and the eye. Surv Ophthalmol. 2006 Jan-Feb;51(1):1-17. Review.

PubMed ID: 
16414358

Histiocytic Dermatoarthritis

Clinical Characteristics
Ocular Features: 

This disorder has some ocular similarities to dermochondrocorneal dystrophy of Francois (221800) such as the presence of cataracts, but differs in the absence of corneal opacities.  All patients examined have had glaucoma, uveitis and lens opacities.  Gonioscopy in one patient showed multiple anterior synechiae and another patient, an adult, had buphthalmos.

Systemic Features: 

Skin lesions and stiff, painful joints develop between 4 and 15 years of age.   The cutaneous nodules are found primarily on the hands, ears and the upper extremities.  These are nonulcerating, tender, violaceous to brown in color, and firm in consistency.  Firm subcutaneous plaques apparent only on palpation are also present.  No mucosal lesions or xanthelasmata are present.  Deforming, symmetric arthritis of the hands, feet and elbows is frequently seen with periarticular bony resorption.  The skin of the legs and feet are thick and lichenified.  Histology of the skin lesions shows a granulomatous appearance with a chronic inflammatory infiltrate.  No multinucleated giant cells are seen.

Genetics

A single family with 4 affected sibs born to an affected male parent has been reported which suggests autosomal dominant inheritance.  The mutation, if any, is unknown.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

The glaucoma should, of course, be treated but no treatment is available for the systemic disease beyond orthopedic correction of the joint deformities.

References
Article Title: 

Osteoporosis-Pseudoglioma Syndrome

Clinical Characteristics
Ocular Features: 

Retrolental masses often present at birth have been mistaken for retinoblastomas.  Hyperplasias of the vitreous, corneal opacities, and secondary glaucoma have been described.  Band keratopathy may account for some of the corneal clouding and opacities.  Most patients are blind soon after birth although some retain some vision into the second decade.

Systemic Features: 

Some patients have been described as mentally retarded but others have normal intelligence.  Hypotonia and hyperflexible joints have been noted.  Bone fractures are common sometimes resulting in scoliosis, short stature and limb deformities.  Radiography of the skeletal reveals porotic and thin bones.

Genetics

This disorder, sometimes called the ocular form of osteogenesis imperfecta, results from mutations in LRP5 (11q13.4).  The same gene is mutant in the EVR4 type of familial exudative vitreoretinopathy (601813) which has some of the same ocular and bone features.  Most descriptions of OPPG were published before the gene mutation was found and many reports do not include detailed ocular examinations.  Certainly the two disorders are allelic and likely the same condition. 

Mutations in LRP5 lead to EVR4 disease in both the heterozygous and homozygous configuration but most cases of OPPG have homozygous or compound heterozygous mutations.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Bone fractures need to be repaired and glaucoma treated when present.  Bisphosphonate treatment may lead to increased bone density if initiated early.  The retrolental masses need to be carefully evaluated to rule out retinoblastoma.

References
Article Title: 

Osteoporosis-pseudoglioma syndrome, a disorder affecting skeletal strength and vision, is assigned to chromosome region 11q12-13

Gong Y, Vikkula M, Boon L, Liu J, Beighton P, Ramesar R, Peltonen L, Somer H, Hirose T, Dallapiccola B, De Paepe A, Swoboda W, Zabel B, Superti-Furga A, Steinmann B, Brunner HG, Jans A, Boles RG, Adkins W, van den Boogaard MJ, Olsen BR, Warman ML. Osteoporosis-pseudoglioma syndrome, a disorder affecting skeletal strength and vision, is assigned to chromosome region 11q12-13. Am J Hum Genet. 1996 Jul;59(1):146-51.

PubMed ID: 
8659519

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