corneal clouding

Anterior Segment, Brain, and Facial Anomalies

Clinical Characteristics
Ocular Features: 

The interpupillary distance appears abnormally wide.  VEP and ERG responses suggest abnormal retinal bipolar cells.  Specular microscopy reveals variable sizes and shapes of corneal endothelial cells with scattered vesicles and large 'holes' in the usual hexagonal array.  The iris may be malformed (no collarette, stromal hypoplasia) and there may be peripheral iridocorneal adhesions.  Elevated IOP, band keratopathy, corneal clouding, and keratoconus have been reported.  Visual acuity is impaired to some extent, from near normal (20/25) to NLP.  Progressive optic atrophy was observed in one patient.

Systemic Features: 

Four members of a 3 generation family had malformed pinnae (posterior placement and rotation).  Other features variably present were an empty sella turcica, posterior fossa cyst, and hydrocephalus. The propositus also was found to have abnormal auditory bipolar cells based on the audiogram and audio-evoked brainstem responses.

Genetics

Based on direct sequencing in one family (3 adults and 1 child), this condition seems to be caused by heterozygous variations or mutations in the VSX1 gene (20p11.21). 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Monitoring for glaucoma and appropriate treatment are indicated.  Hearing tests should be performed early.  The usual treatments for keratoconus should be considered.  Excess brain fluid may need surgical drainage.

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References
Article Title: 

Roberts Syndrome

Clinical Characteristics
Ocular Features: 

The eyes often appear prominent as the result of shallow orbits.  Hypertelorism and microphthalmia can be present.  The sclerae can have a bluish hue.   Cataracts and central corneal clouding plus scleralization and vascularization of the peripheral corneas are sometimes seen.  Lid colobomas and down-slanting palpebral fissures may be present.

Systemic Features: 

Failure of both membranous and long bones to grow properly lead to a variety of abnormalities such as craniosynostosis, hypomelia, syndactyly, oligodactyly, malar hypoplasia, short neck, micrognathia, and cleft lip and palate.  The long bones of the limbs may be underdeveloped or even absent.  Contractures of elbow, knee, and ankle joints are common as are digital anomalies.  Low birth weight and slow postnatal growth rates are usually result in short stature.  The hair is often sparse and light-colored. 

Mental development is impaired and some children are diagnosed to have mental retardation.  Cardiac defects are common.  Facial hemangiomas are often present as are septal defects and sometimes a patent ductus arteriosus.  External genitalia in both sexes appear enlarged.  The kidneys may be polycystic or horseshoe-shaped.

Genetics

This is an autosomal recessive condition caused by mutations in the ESCO2 gene (8p21.1).  Mutations in the same gene are also responsible for what some have called the SC phocomelia syndrome (269000) which has a similar but less severe phenotype.  Some consider the two disorders to be variants of the same condition and they are considered to be the same entity in this database.  The gene product is required for structural maintenance of centromeric cohesion during the cell cycle.  Microscopic anomalies of the centromeric region (puffing of the heterochromatic regions) are sometimes seen during cell division.

The Baller-Gerold syndrome (218600) has some phenotypic overlap with Roberts syndrome but is caused by mutations in a different gene (RECQL4).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Severely affected infants may be stillborn or die in infancy.  Other individuals live to adulthood.  There is no treatment for this condition beyond specific correction of individual anomalies.

References
Article Title: 

IFAP (BRESHECK) Syndrome

Clinical Characteristics
Ocular Features: 

The eyelashes and eyebrow hair is sparse or completely absent.  Keratitis with secondary photophobia is often seen during infancy and progresses to corneal vascularization and scarring, sometimes resembling trachomatous disease.  Cataracts do not seem to be part of this syndrome unlike some other genodermatoses.

Systemic Features: 

Dry, scaly skin and alopecia are usually evident at birth.  There is marked absence of hair throughout the body.  The skin is generally ichthyotic and erythematous, with continuous lamellar desquamation of surface skin.  Generalized follicular hyperkeratosis is present on the scalp, dorsal surface of the limbs and on the abdomen.  Most patients are completely bald.

In some patients the skin, hair and corneal disease is accompanied by severe internal anomalies such as kidney dysplasia, brain anomalies and mental retardation, Hirschsprung disease, cleft palate, external ear malformations, cryptorchidism, and skeletal deformities, a combination of signs that some have called BRESEK/BRESHECK syndrome.  Depending upon how extensive the organ involvement, the prognosis is usually guarded and patients may not live beyond early childhood. 

It is uncertain if IFAP refers to a single disorder or if two disorders are involved (see Genetics).

Genetics

This is generally considered to be an X-linked recessive disorder most likely due to mutations in MBTPS2, at least in patients considered to have the BRESHECK condition.  Female carrier may have some similar skin and hair signs albeit to a lesser degree than males.

Since the amount of MBTPS2 activity has been shown to vary with different mutations, it is possible that all cases of IFAP with or without the added BRESHECK findings are part of the clinical spectrum of a single disorder (variable expressivity).  

Other genodermatoses with severe keratitis are KID syndrome (148210) and Hereditary Mucoepithelial Dysplasia (158310).

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

No effective treatment is known.

References
Article Title: 

MBTPS2 mutation causes BRESEK/BRESHECK syndrome

Naiki M, Mizuno S, Yamada K, Yamada Y, Kimura R, Oshiro M, Okamoto N, Makita Y, Seishima M, Wakamatsu N. MBTPS2 mutation causes BRESEK/BRESHECK syndrome. Am J Med Genet A. 2012 Jan;158A(1):97-102.

PubMed ID: 
22105905

IFAP syndrome is caused by deficiency in MBTPS2, an intramembrane zinc metalloprotease essential for cholesterol homeostasis and ER stress response

Oeffner F, Fischer G, Happle R, Konig A, Betz RC, Bornholdt D, Neidel U, Boente Mdel C, Redler S, Romero-Gomez J, Salhi A, Vera-Casano A, Weirich C, Grzeschik KH. IFAP syndrome is caused by deficiency in MBTPS2, an intramembrane zinc metalloprotease essential for cholesterol homeostasis and ER stress response. Am J Hum Genet. 2009 Apr;84(4):459-67.

PubMed ID: 
19361614

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: 

Keratitis, Hereditary

Clinical Characteristics
Ocular Features: 

The disorder begins in the first year of life with a band of vascularized opacification inside the limbus.  Evidence of inflammation is seen in the anterior stroma and the Bowman membrane becomes replaced by fibrovascular tissue.  The disease is recurrent and progressive and there is usually asymmetry between the two eyes.  Non-penetrance and considerable variation in expression have been reported.  Acute episodes are characterized by photophobia, tearing, mucous discharge, and punctate keratitis.  The limbal opacification may progress centrally and eventually leads to a reduction in vision.  Deficits in visual acuity may lead to deprivation amblyopia and secondary esotropia.

In a 4 generation family, foveal hypoplasia, iris stromal defects, and ectropion uveae were seen in several of the fifteen affected individuals.  It has been suggested that this may be a variant of aniridia. 

Systemic Features: 

No systemic disease has been found. 

Genetics

This is an autosomal dominant disorder reported in several multigeneration families.  Mutations in the PAX6 gene (11p13) seem to be responsible.  The same gene is mutant in Gillespie syndrome (206700), aniridia (106210) and Peters anomaly (604229). 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no effective treatment.  Penetrating keratoplasty in several individuals has been followed by similar disease in the donor tissue. 

References
Article Title: 

Dominantly inherited keratitis

Kivlin JD, Apple DJ, Olson RJ, Manthey R. Dominantly inherited keratitis. Arch Ophthalmol. 1986 Nov;104(11):1621-3.

PubMed ID: 
3778274

GM1 Gangliosidosis

Clinical Characteristics
Ocular Features: 

Based on clinical manifestations, three types have been described: type I or infantile form, type II or late-infantile/juvenile form, and type III or adult/chronic form but all are due to mutations in the same gene.  Only the infantile form has the typical cherry red spot in the macula but is present in only about 50% of infants.  The corneal clouding is due to intracellular accumulations of mucopolysaccharides in corneal epithelium and keratan sulfate in keratocytes.  Retinal ganglion cells also have accumulations of gangliosides.  Decreased acuity, nystagmus, strabismus and retinal hemorrhages have been described. 

Systemic Features: 

Infants with type I disease are usually hypotonic from birth but develop spasticity, psychomotor retardation, and hyperreflexia within 6 months.  Early death from cardiopulmonary disease or infection is common.  Hepatomegaly, coarse facial features, brachydactyly, and cardiomyopathy with valvular dysfunction are common.  Dermal melanocytosis has also been described in infants in a pattern some have called Mongolian spots.  Skeletal dysplasia is a feature and often leads to vertebral deformities and scoliosis.  The ears are often large and low-set, the nasal bridge is depressed, the tongue is enlarged and frontal bossing is often striking.  Hirsutism, coarse skin, short digits, and inguinal hernias are common.

The juvenile form, type II, has a later onset with psychomotor deterioration, seizures and skeletal changes apparent between 7 and 36 months and death in childhood.  Visceral involvement and cherry-red spots are usually not present. 

Type III, or adult form, is manifest later in the first decade or even sometime by the 4th decade.  Symptoms and signs are more localized.  Neurological signs are evident as dystonia or speech and gait difficulties.  Dementia, parkinsonian signs, and extrapyramidal disease are late features.  No hepatosplenomegaly, facial dysmorphism, or cherry red spots are present in most individuals. Lifespan may be normal in this type. 

Genetics

This is an autosomal recessive lysosomal storage disease secondary to a mutations in GLB1 (3p21.33).  It is allelic to Morquio B disease (MPS IVB) (253010).  The mutations in the beta-galactosidase-1 gene result in intracellular accumulation of GM1 ganglioside, keratan sulfate, and oligosaccharides.  The production of the enzyme varies among different mutations likely accounting for the clinical heterogeneity. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment that effectively alters the disease course. 

References
Article Title: 

Hurler and Scheie Syndromes (MPS IH, IS, IH/S)

Clinical Characteristics
Ocular Features: 

Progressive corneal clouding is a major feature and appears early in life.  Intracellular accumulations of heparan and dermatan sulfate are responsible for the ground glass appearance.  However, congenital glaucoma also occurs in MPS I and must be considered as a concomitant cause of a diffusely cloudy cornea.

Abnormal storage of mucopolysaccharides has been found in all ocular tissues and in the retina leads to a pigmentary retinopathy.  The ERG may be abolished by 5 or 6 years of age.  Papilledema is often followed by optic atrophy.  Photophobia is a common symptom.  Shallow orbits give the eyes a prominent appearance.

Systemic Features: 

This group of lysosomal deficiency diseases is probably the most common.  MPS I is clinically heterogeneous encompassing three clinical entities: Hurler, Hurler-Scheie, and Scheie.  In terms of clinical severity, Hurler is the most severe and Scheie is the mildest.  Infants generally appear normal at birth and develop the typical coarse facial features in the first few months of life.  Physical growth often stops at about 2 years of age.  Skeletal changes of dysostosis multiplex are often seen and kyphoscoliosis is common as vertebrae become flattened.  The head is large with frontal bossing and a depressed nasal bridge.  Cranial sutures, especially the metopic and sagittal sutures, often close prematurely.  The lips are prominent and an open mouth with an enlarged tongue is characteristic.  The neck is often short.  Odontoid hypoplasia increases the risk of vertebral subluxation and cord compression.  Joints are often stiff and arthropathy eventually affects all joints.  Claw deformities of the hands and carpal tunnel syndrome are common.  Most patients are short in stature and barrel-chested.

Cardiac valves often are thickened and endocardial fibroelastosis is frequently seen.  The coronary arteries are often narrowed.  Respiratory obstructions are common and respiratory infections can be serious problems.  Hearing loss is common.

Most patients reach a maximum functional age of 2 to 4 years and then regress.  Language is limited.  Untreated, many patients die before 10 years of age.

Genetics

The Hurler/Scheie phenotypes are all the result of mutations in the IDUA gene (4p16.3).  They are inherited in an autosomal recessive pattern.  A deficiency in alpha-L-iduronidase causes three phenotypes: Hurler (607014; MPS IH), Hurler-Scheie (607015; MPS IH/S), and Scheie (607016; MPS IS) syndromes.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Various treatments have had some success.  Enzyme replacement using laronidase (Aldurazyme©) has been shown to reduce organomegaly and improve motor and respiratory functions.  It has been used alone and in combination with bone marrow transplantation but therapeutic effects are greater if given to younger patients.  It does not improve skeletal defects or corneal clouding.  MRI imaging has documented improvement in CNS signs.  Gene therapy has shown promise but remains experimental.  Regular lifelong monitoring is important using a multidisciplinary approach to identify potential problems.  Joint problems may be surgically correctable with special emphasis on the need for atlanto-occipital stabilization.  Corneal transplants may be helpful in the restoration of vision in selected patients.

References
Article Title: 

Sanfilippo Syndrome (MPS IIIA, B, C, D)

Clinical Characteristics
Ocular Features: 

This form of mucopolysaccharidosis causes little or no corneal clouding.  Abnormal retinal pigmentation can be seen.

Systemic Features: 

Sanfilippo syndrome differs from other forms of mucopolysaccharidoses in the severity of the neurologic degeneration compared to the amount of somatic disease.  Infants usually appear healthy but developmental delay becomes evident by 2 or 3 years of age and physical growth slows.  Deterioration in mental development is progressive and seizures occur in some.  Gait and speech are impaired and by age 10 years patients have severe disabilities.  Behavioral problems including hyperactivity and aggression are often severe.

There is some hepatosplenomegaly, mild coarseness of the facial features, claw hands and mild bony changes such as biconvexity of the vertebral bodies and thick calvaria.  Hirsutism and synophrys are common.  The hair is unusually coarse.  Joints are frequently stiff and more severely affected individuals may have hearing loss.  Diarrhea is frequently a problem and most patients have some airway obstruction and are susceptible to recurrent respiratory infections.  Some patients have cardiovascular problems.

Genetics

MPS III is a lysosomal storage disease and may be caused by mutations in 1 of 4 genes that result in defective enzymes unable to break down mucopolysaccharides (glycosaminoglycans).  MPS IIIA (252900)results from a defect in the heparan sulfate sulfatase gene SGSH (17q25.3), type IIIB (252920)from a defect in the N-acetyl-alpha-D-glucosaminidase gene NAGLU (17q21), type IIIC (252930) from a defect in the acetyl-CoA:alpha-glucosaminide acetyltransferase gene HGSNAT (8p11.1), and type IIID (252940) from a defect in the N-acetylglucosamine-6-sulfatase gene GNS (12q14).  Heparan sulfate is excreted in all types.  Because of their clinical similarities these are discussed as a group in this database.  All are inherited in autosomal recessive patterns.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment for the underlying disease.  Therapy is primarily supportive.  A multidisciplinary approach with neurologists, ophthalmologists, audiologists, cardiologists, gastroenterologists, and orthopedists is most likely to result in treatments that can improve quality of life.

References
Article Title: 

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 IVB)

Clinical Characteristics
Ocular Features: 

Corneal clouding may not be seen until 10 years of age and is sometimes associated with photophobia.  The stroma has fine dust-like particles most dense centrally.  Penetrating keratoplasty is rarely indicated. There is little retinal degeneration unlike that often seen in other mucopolysaccharidoses but the corneal clouding often precludes detailed examination.

Systemic Features: 

This form of mucopolysaccharidosis is characterized by the urinary excretion of keratin sulfate.  Age of onset is highly variable but most children are diagnosed by 6 years of age.  It is a milder disease than the somewhat similar but genetically distinct Morquio type A (253000)  disorder.  Intelligence is normal and there is no central nervous system involvement.  Hip joints are dysplastic and frequently painful.  Vertebral malformations lead to kyphoscoliosis and short trunk dwarfism.  Odontoid hypoplasia can cause cervical instability and increases the risk of myelopathy with secondary bowel and bladder dysfunction.  Coxa valgum, and narrow phalanges are common.  Many individuals have a characteristic gait secondary to genu valgum.  Patients with MPS IVB initially do not have the coarse facies seen in some other forms of MPS.  Further accumulation of cellular keratin sulfate may lead to some coarsening of facial features, increased corneal clouding, and hepatomegaly.  Some form of hearing loss is common.

Genetics

This is an autosomal recessive lysosomal storage disease caused by a mutation in the GLB1 gene (3p21.33) encoding beta-galactosidase.  It is allelic to GM1 gangliosidosis (230500).  Type A Morquio syndrome (253000) is a separate disorder secondary to a mutation in a different gene.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

A variety of treatments are under investigation including enzyme replacement, gene therapy, and bone marrow transplantation.  Supportive and palliative measures for respiratory difficulties and skeletal deformities can be used.  Atlantoaxial subluxation is a constant risk and some physicians recommend prophylactic vertebral fusion.  Intubation for general anesthesia carries special risks.

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

Mutation analyses in 17 patients with deficiency in acid beta-galactosidase: three novel point mutations and high correlation of mutation W273L with Morquio disease type B

Paschke E, Milos I, Kreimer-Erlacher H, Hoefler G, Beck M, Hoeltzenbein M, Kleijer W, Levade T, Michelakakis H, Radeva B. Mutation analyses in 17 patients with deficiency in acid beta-galactosidase: three novel point mutations and high correlation of mutation W273L with Morquio disease type B. Hum Genet. 2001 Aug;109(2):159-66.

PubMed ID: 
11511921

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