corneal clouding

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

Keratoconus 4

Clinical Characteristics
Ocular Features: 

The cornea progressively thins in the lower portion, usually in juveniles and young adults.  The cornea may appear normal by slit lamp examination in early stages but keratoscopy can show steepening or distortion of the mires.  Retinoscopy through dilated pupils often yields a ‘scissoring’ pattern.  Early symptoms include uncorrectable blurring of vision and visual distortion.  The central and lower cornea progressively thins with formation of a cone.  A subepithelial iron line can sometimes be seen around the conical portion of the cornea (Fleischer ring).  Vertical lines may be found in the deep portions of the stroma and in Descemet membrane (Vogt striae).  The disease can progress for some years but there may also be periods of stability.  Individuals with advanced disease may suffer acute painful episodes following breaks in the Descemet membrane with edema and opacification in the cone (hydrops), followed by stromal scarring.

Systemic Features: 

Keratoconus has been found in a large number of systemic conditions, such as connective tissue disorders, Down syndrome, and chromosomal disorders.  It has been blamed on eye rubbing as is often seen in Leber congenital amaurosis and other ocular disorders as well as in atopic conditions and in individuals who have worn contact lenses for many years.  Cause and effect in these situations is difficult to prove and it is likely that keratoconus is an etiologically heterogeneous disorder.  Only keratoconus associated with single gene mutations are considered here.

Recent evidence suggests that corneal hydrops is strongly associated with mitral valve prolapse. 

Genetics

Less than 10% of keratoconus cases have a positive family history and several mutations seem to be responsible.  Mutations at the 2p24 locus on chromosome 2 seem to cause KTCN4 based on genome-wide linkage analysis in families from multiple out-bred populations.  The pattern of inheritance is autosomal dominant.

Other forms of hereditary keratoconus caused by different mutations are:  Mutations in VSX1 (20p11.2) cause KTCN1, KTCN2 (608932) is linked to a mutation on chromosome 16 (16q22.3-q23.1), and KTCN3 (608586) results from a mutation on chromosome 3 (3p14-q13).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Contact lenses may correct vision satisfactorily in early stages of the disease but up to 20% of patients will eventually need a corneal transplant.

References
Article Title: 

Keratoconus 3

Clinical Characteristics
Ocular Features: 

The cornea progressively thins in the lower portion, usually in juveniles and young adults.  The cornea may appear normal by slit lamp examination in early stages but keratoscopy can show steepening or distortion of the mires.  Retinoscopy through dilated pupils often yields a 'scissoring' pattern.  Early symptoms include uncorrectable blurring of vision and visual distortion.  The central and lower cornea progressively thins with formation of a cone.  A subepithelial iron line can sometimes be seen around the conical portion of the cornea (Fleischer ring).  Vertical lines may be found in the deep portions of the stroma and in Descemet membrane (Vogt striae).  The disease can progress for some years but there may also be periods of stability.  Individuals with advanced disease may suffer acute painful episodes following breaks in the Descemet membrane with edema and opacification in the cone (hydrops), followed by stromal scarring.

Systemic Features: 

Keratoconus has been found in a large number of systemic conditions, such as connective tissue disorders, Down syndrome, and chromosomal disorders.  It has been blamed on eye rubbing as is often seen in Leber congenital amaurosis and other ocular disorders as well as in atopic conditions and in individuals who have worn contact lenses for many years.  Cause and effect in these situations is difficult to prove and it is likely that keratoconus is an etiologically heterogeneous disorder.  Only keratoconus associated with single gene mutations are considered here.

Recent evidence suggests that corneal hydrops is strongly associated with mitral valve prolapse. 

Genetics

Less than 10% of keratoconus cases have a positive family history and several mutations seem to be responsible.  KTCN3 seems to be caused by a mutation located at 3p14-q13 as determined from linkage studies in a 2 generation Italian family.  It is inherited in an autosomal dominant pattern.

Other forms of hereditary keratoconus caused by different mutations are:  KTCN1 (148300) caused by mutations in the VSX1 gene at 20p11.2), KTCN2 (608932) from a mutation on chromosome 16 (16q22.3-q23.1), and KTCN4 (609271) caused by a mutation on chromosome 2 (2p24).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Contact lenses may correct vision satisfactorily in early stages of the disease but up to 20% of patients will eventually need a corneal transplant.

References
Article Title: 

Keratoconus 2

Clinical Characteristics
Ocular Features: 

The cornea progressively thins in the lower portion, usually in juveniles and young adults.  The cornea may appear normal by slit lamp examination in early stages but keratoscopy can show steepening or distortion of the mires.  Retinoscopy through dilated pupils often yields a 'scissoring' pattern.  Early symptoms include uncorrectable blurring of vision and visual distortion.  The central and lower cornea progressively thins with formation of a cone.  A subepithelial iron line can sometimes be seen around the conical portion of the cornea (Fleischer ring).  Vertical lines may be found in the deep portions of the stroma and in Descemet membrane (Vogt striae).  The disease can progress for some years but there may also be periods of stability.  Individuals with advanced disease may suffer acute painful episodes following breaks in the Descemet membrane with edema and opacification in the cone (hydrops), followed by stromal scarring.

Systemic Features: 

Keratoconus has been found in a large number of systemic conditions, such as connective tissue disorders, Down syndrome, and chromosomal disorders.  It has been blamed on eye rubbing as is often seen in Leber congenital amaurosis and other ocular disorders as well as in atopic conditions and in individuals who have worn contact lenses for many years.  Cause and effect in these situations is difficult to prove and it is likely that keratoconus is an etiologically heterogeneous disorder.  Only keratoconus associated with single gene mutations are considered here.

Recent evidence suggests that corneal hydrops is strongly associated with mitral valve prolapse. 

Genetics

Less than 10% of keratoconus cases have a positive family history and several mutations seem to be responsible.  KTCN2 seems to be caused by a mutation located at 16q22.3-q23.1 as determined from linkage studies in 20 Finnish families.  It is inherited in an autosomal dominant pattern.

Other forms of hereditary keratoconus caused by different mutations are:  KTCN1 (148300) caused by a mutation in the VSX1 gene (20p11.2), KTCN3 (608586) from a mutation on chromosome 3 (3p14-q13), and KTCN4 (609271) caused by a mutation on chromosome 2 (2p24).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Contact lenses may correct vision satisfactorily in early stages of the disease but up to 20% of patients will eventually need a corneal transplant.

References
Article Title: 

Keratoconus 1

Clinical Characteristics
Ocular Features: 

The cornea progressively thins mostly in the lower portion, usually in juveniles and young adults.  The cornea may appear normal by slit lamp examination in early stages but keratoscopy may show steepening or distortion of the mires.  Retinoscopy through dilated pupils often yields a 'scissoring' pattern.  Early symptoms include uncorrectable blurring of vision and visual distortion.  The central and lower cornea progressively often thins with formation of a cone.  A subepithelial iron line can sometimes be seen around the conical portion of the cornea (Fleischer ring).  Vertical lines may be found in the deep portions of the stroma and in Descemet membrane (Vogt striae).  The disease can progress for some years but there may also be periods of stability.  Individuals with advanced disease may suffer acute painful episodes following breaks in the Descemet membrane with edema and opacification in the cone (hydrops), followed by stromal scarring.

Systemic Features: 

Recent evidence suggests that corneal hydrops is strongly associated with mitral valve prolapse.

Genetics

Keratoconus has been found in a large number of systemic conditions, such as connective tissue disorders, Down syndrome, and other chromosomal disorders. It has been blamed on eye rubbing as is often seen in Leber congenital amaurosis and other ocular disorders as well as in atopic conditions and in individuals who have worn contact lenses for many years. Cause and effect in these situations is difficult to prove and it is likely that keratoconus is an etiologically heterogeneous disorder. Only keratoconus associated with single gene mutations are considered here.

Less than 10% of keratoconus cases have a positive family history and several mutations seem to be responsible.  Mutations in the VSX1 homeobox gene (20p11.2) have been found in what is called KTCN1 keratoconus (the same gene is mutant in posterior polymorphous corneal dystrophy 1 [122000]), inherited as an autosomal dominant trait.

Other forms of hereditary keratoconus caused by different mutations are:  KTCN2 (608932) linked to a mutation on chromosome 16 (16q22.3-q23.1), KTCN3 (608586) by a mutation on chromosome 3 (3p14-q13), KTCN4 (609271) caused by a mutation on chromosome 2 (2p24), KTCN5 (614622) mapped to 5q14.1-q21.3, KTCN6 (614623) mapped to 9q34, KTCN7 (614629) mapped to 13q32, KTCN8 (614628) mapped to 14q24, and KTCN9 (617928) associated with a mutation in the TUBA3D gene located at 2q21.1.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Contact lenses may correct vision satisfactorily in early stages of the disease but up to 20% of patients will eventually need a corneal transplant.

References
Article Title: 

VSX1: a gene for posterior polymorphous dystrophy and keratoconus

Heon E, Greenberg A, Kopp KK, Rootman D, Vincent AL, Billingsley G, Priston M, Dorval KM, Chow RL, McInnes RR, Heathcote G, Westall C, Sutphin JE, Semina E, Bremner R, Stone EM. VSX1: a gene for posterior polymorphous dystrophy and keratoconus. Hum Mol Genet. 2002 May 1;11(9):1029-36.

PubMed ID: 
11978762

Hunter Syndrome (MPS II)

Clinical Characteristics
Ocular Features: 

Corneal clouding may be noted as early as 6 months of age but is usually absent. When present it is milder than in some other forms of mucopolysaccharidosis.  A pigmentary retinopathy with variable severity is often present.  The disc may be elevated and appears swollen.  Secondary optic atrophy may be seen in long standing cases.

Systemic Features: 

Mild to severe developmental delays are common and mental retardation has been reported in some cases.  There is often 'pebbling' of the skin over the neck and chest.  Joint stiffness, short stature, and skeletal deformities are common.   Many have short necks, a protuberant abdomen, a broad chest, and facial coarseness.  Hepatosplenomegaly, hearing loss, hernias, and carpal tunnel syndrome are often present.  The skull is large with a J-shaped sella, the vertebral bodies are hypoplastic anteriorly, the pelvis and femoral heads are hypoplastic and the diaphyses are expanded.

A severe form, type A, has its onset in the first two to four years of life, with more rapid progression and death commonly by adolescence.  Many patients have obstructive pulmonary disease and heart failure.  The IDS deficiency is similar to that of type B which is less severe and compatible with life into the 7th decade.  Intelligence is often normal in type B.

Genetics

Hunter syndrome, or MPS II, is one of seven lysosomal enzyme deficiencies responsible for the degradation of mucopolysaccharides, and the only one known to be X-linked (Xq28).  The mutation in IDS leads to a deficiency of iduronate sulfatase resulting in accumulation of dermatan and heparin sulfate.  Rare affected females may have chromosomal deletions instead of a simple mutation in IDS.

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

Various therapies are under development including enzyme replacement, gene transfers, and bone marrow transplantation.  Human iduronate-2-sulfatase (Idursulfase) has been used with encouraging signs but it is too early to determine the long term effectiveness.

References
Article Title: 

Dermochondrocorneal Dystrophy

Clinical Characteristics
Ocular Features: 

A corneal dystrophy is part of this syndrome.  Patients develop confluent, drop-like subepithelial whitish-brown infiltrates of the central cornea with some anterior stromal involvement together with stellate anterior cortical cataracts.  The intervening stroma appears hazy.  The epithelial surface remains intact but may be irregular over the superficial stromal infiltrates. The corneal opacities follow the skin and hand deformities and may be accompanied by a vascularized pannus.  Diagnosis can usually be made in the first decade of life.  Visual acuity in young adults may be reduced to the 20/80 - 20/100 range.

Systemic Features: 

Xanthomatous nodules are primarily located on the pinnae, hands, elbows, and nose.  Most of the nodules are small and primarily of cosmetic significance.  They have also been reported in oral mucosa and gingival tissue.  Hyperplasia of the oral mucosa is common.  Deformities of the hands and feet are also seen.

Genetics

Both autosomal dominant and autosomal recessive modes of inheritance have been proposed but insufficient numbers of families have been reported to be conclusive.

Treatment
Treatment Options: 

Corneal grafts could be visually beneficial but the vascularized pannus increases the risk of rejection.  CO2 laser treatment can reduce the cutaneous chondromes.  Gingival lesions and hyperplasia of the oral mucosa may require surgical treatment.

References
Article Title: 

Cystinosis

Clinical Characteristics
Ocular Features: 

Cystinosis is a clinically heterogeneous disorder that has been divided into three allelic forms based on the age of onset and the amount of kidney disease.  Since the three types are caused by mutations in the same CTNS gene they are discussed here as a single entity with emphasis on the similarities and differences.  All three cause significant corneal disease secondary to crystalline cystine deposits.

The early onset and most common form of cystinosis (219800) causes severe photophobia and even corneal erosions from accumulation of refractile cystine crystals which can be seen in the first years of life.  Accumulation of cystine in the retina leads to peripheral pigmentary changes that progress centrally and is present to some degree in all patients by age 7 years.  Mottling of the retinal pigment epithelium is the most common finding but there are often alternating areas of hyperpigmentation and depigmentation as well.  Visual fields may be markedly constricted.  Photoreceptor damage eventually leads to decreased rod and cone responses as recorded by ERG.  Visual acuity ranges from near normal to NLP.

The late-onset juvenile nephropathic (219900) form has a similar corneal profile but the pigmentary retinopathy occurs later than in the infantile disease.

The adult nonnephropathic form (219750) likewise has visible cystine crystals in the cornea.  This disorder should be considered in all healthy adults with a crystalline dystrophy of the cornea.  The pigmentary retinopathy does not occur.

Systemic Features: 

In the more common infantile form of cystinosis, accumulation of cystine leads to dysfunction in many organs.  Nephropathy, hypothyroidism, and growth retardation in the infantile type are major complications.  The kidney disease leads to a Fanconi syndrome type pattern of kidney failure.  Pancreatic insufficiency, ovarian failure, myopathy, and central nervous system signs are often seen.  Patients require renal transplantation, often in the first decade of life.  Slow eating and dysphagia are common.  Heterozygotes may have elevated levels of free cystine in leukocytes.

The later onset juvenile form of cystinosis presents with kidney failure secondary to glomerular damage instead of tubular dysfunction.  The age of diagnosis varies widely, however, anywhere from 2-26 years of age, with end-stage kidney failure occurring generally in the third decade.  Aminoaciduria is usually not present and growth is normal.

The adult-onset or benign type is also uncommon.  Patients with this non-nephropathic type (219750), of course, do not develop kidney disease but have demonstrable cystine deposits in the cornea, buffy coat, and bone marrow.  No proteinuria or amino aciduria is detectable.

Genetics

Cystinosis is an autosomal recessive disease that is found in individuals homozygous for mutations in the CTNS gene (17p13) that encodes cystinosin.  The most common mutation among Caucasians of European descent is a 57-kb deletion which sometimes includes contiguous and regulatory genes.  Other sequence variants have also been found.  High cystine levels can be demonstrated in leucocytes of heterozygotes, at least in the infantile form.   A large number of mutations, both homozygous and compound heterozygous, have been found .  The accumulation of cystine seems to result from impaired cystine transport across the lysosomal membrane and it has been suggested that the severity of disease depends on the amount of functional cystinosin produced by various mutations in the CTNS gene.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Topical cysteamine eye drops can dramatically reduce the number of cornea crystals and improve symptoms such as photophobia and visual acuity.  Oral administration of the same drug can be beneficial for systemic disease as well, especially if initiated before the age of two years.  It can also reduce the frequency and severity of posterior segment disease with the most benefit occurring in those who begin the drug early in life.  Improved kidney function and quality of life may be dramatic.

The chronic nature and multisystem involvement require lifelong monitoring of ocular and systemic disease.

References
Article Title: 

Glaucoma, Congenital Primary B

Clinical Characteristics
Ocular Features: 

Type B congenital glaucoma is considerably more rare than type A and may be more common in Middle Eastern families.  Few families have been reported but the clinical features are similar: elevated intraocular pressure in infancy or early childhood, photophobia, and cloudy corneas (see Glaucoma, Congenital Primary A [231300] for a more complete description of the phenotype).

Systemic Features: 

No systemic abnormalities are associated.

Genetics

This is an autosomal recessive disorder caused by a mutation in GLC3B mapped to a locus at 1p36.2-p36.1.  Type A congenital glaucoma (231300) is caused by a mutation in CYP1B1 and type D by mutations in LTBP2 (613086).  A locus at 14q24.3 has been asssociated with another form of congenital glaucoma (613085; type C) but the nature of the gene is unknown.  Mutations in TEK are responsible for congenital glaucoma type GLC3E.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

As in other types of congenital glaucoma, pressure control is difficult and the best approach entails some form of glaucoma surgical filtration.

References
Article Title: 

Glaucoma, Congenital Primary A

Clinical Characteristics
Ocular Features: 

This may be the most common type of early (infantile, congenital) glaucoma.  Elevated intraocular pressure may be present at birth but sometimes is not evident until the first year of life or in some cases even later.  Irritability, photophobia, and epiphora are early signs.  The globe is often buphthalmic, the cornea is variably cloudy, and breaks in the Descemet membrane (Haab striae) may be present.  Frequently the iris root is inserted anteriorly in the region of the trabecular meshwork.  The anterior chamber often appears abnormally deep.  Early reports of a membrane covering the angle structures have not been confirmed histologically.  The mechanism causing elevated IOP seems to be excessive collagen tissue in the anterior chamber angle that impedes normal aqueous outflow.   The pressure is usually in the range of 25-35 mmHg but this is variable as the course can be intermittent.  It should be considered a bilateral disease although about one-fourth of patients have only unilateral elevations of pressure even though trabecular abnormalities are present.

Optic cupping may begin temporally but the more typical glaucomatous cupping eventually occurs.

Systemic Features: 

No consistent systemic abnormalities are associated with primary congenital glaucoma.  However, it is important to note that glaucoma is a feature of many congenital malformation syndromes and chromosomal aberrations.

Genetics

Congenital glaucoma of this type can result from both homozygous (25%) and compound heterozygous mutations (56%) in the CYP1B1 gene on chromosome 2 (2p22-p21) which codes for cytochrome P4501B1.

Evidence from many sources suggests that congenital glaucoma of this type is an autosomal recessive disorder. Parental consanguinity is common, the segregation ratio is approximately 25%, and the occurrence of congenital glaucoma among all offspring of two affected parents can be cited as support for this mode of inheritance.  Many cases occur sporadically but this is consistent with expectations in small human sibships.  Curiously, though, males are affected more often than females.

Another autosomal recessive infantile (congenital) glaucoma (600975), GLC3 or type B, is caused by mutations in GLC3B located at 1p36.2-p36.1.  A third locus at 14q24.3 has also been proposed  for GLC3, type C.  Autosomal recessive primary congenital glaucoma (so-called) type D (613086) is caused by a mutation in LTBP2 located at 14q24 near the GLC3C locus and heterozygous mutations in TEK are responsible for type E (617272).

Other modes of inheritance have been described and, for now, this form of glaucoma, like others, has to be considered a genetically and clinically heterogeneous disorder pending additional genotyping.  Early onset glaucoma is also a feature of numerous malformation and chromosomal disorders.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Some of the usual glaucoma drugs are ineffective as a result of obstruction to aqueous flow through the trabecular meshwork so that surgical treatment is the therapy of choice in most cases.   Monitoring of axial length has been proposed as helpful in gauging the effectiveness of pressure control.  In some patients the pressure normalizes spontaneously. 

It is important in the evaluation of patients with glaucoma that systemic evaluations be done because of the frequent syndromal associations.

References
Article Title: 

Congenital glaucoma and CYP1B1: an old story revisited

Alsaif HS, Khan AO, Patel N, Alkuraya H, Hashem M, Abdulwahab F, Ibrahim N, Aldahmesh MA, Alkuraya FS. Congenital glaucoma and CYP1B1: an old story revisited. Hum Genet. 2018 Mar 19. doi: 10.1007/s00439-018-1878-z.

PubMed ID: 
29556725

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