cataracts

Congenital Disorder of Glycosylation, Type Ij

Clinical Characteristics
Ocular Features: 

Bilateral cataracts are present at birth.  Nystagmus, strabismus, and long eyelashes have been reported.

Systemic Features: 

This is a disorder of glycosylation important to the formation of glycoproteins and glycolipids.  Neurological signs such as tremor, clonus, and muscle fasiculations may be seen soon after birth.  Other neurological abnormalities eventually include psychomotor retardation, seizures, mental retardation, hyperexcitabilty, and ataxia.  Failure to thrive and feeding difficulties are evident early.  Progressive microcephaly is a feature.  Liver dysfunction can lead to coagulopathy and hypoproteinemia with hepatomegaly is sometimes present.  Some patients have facial anomalies, inverted nipples, and subcutaneous fat pads.  The MRI may show areas of brain atrophy, ischemia, and focal necrosis.

Longevity is limited with 2 of 3 reported patients dying within 2 years of life.

Genetics

This is a rare autosomal recessive disorder resulting from mutations in DPAGT1 (11q23.3) resulting in defective N-glycosylation.  There are numerous other types of glycosylation defects with variations in the clinical manifestations.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment consists of fluid and caloric intake management.  Hypoproteinemia and coagulation defects may respond to oral mannose administration.

References
Article Title: 

Retinitis Pigmentosa and Mental Retardation

Clinical Characteristics
Ocular Features: 

The lenses may have pleomorphic white axial opacities but in other patients can be totally opacified.  Optic atrophy is present and vision may be reduced to light perception but nystagmus is absent.  Evidence suggests that vision loss is progressive.  Some patients have extensive posterior synechiae while others have been noted to have sluggish pupils.  High myopia is a feature. The retinal pigmentation has a typical retinitis pigmentosa picture with attenuated retinal vessels and equatorial bone spicule pigmentation located in the midperiphery while the macula can have a bull’s eye appearance.   

Systemic Features: 

Early development may seem normal but developmental milestones are usually delayed.  Postnatal microcephaly and growth deficiency with mental retardation and early hypotonia are typical features.  The mental retardation may be severe.  Scoliosis and arachnodactyly have been noted and hypogonadism has been reported.  Speech may not develop and mobility is sometimes limited.

Genetics

The family pattern suggests autosomal recessive inheritance.  Homozygosity mapping has identified in a region of chromosome 8 (8q21.2-22.1) that overlaps the region for Cohen syndrome () but no specific mutated gene has been identified.      

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

None.

References
Article Title: 

Leukoencephalopathy with Vanishing White Matter

Clinical Characteristics
Ocular Features: 

Optic atrophy is a common feature and blindness is often the result.

Systemic Features: 

Onset of symptoms may occur at any time from 1.5 years of age to adulthood.  Early psychomotor development may be normal but developmental milestones such as walking and crawling are often delayed.  Patients with a later onset often have a milder course.  Progression is chronic but often episodic with exacerbations following infection and blunt head trauma. Mental stress, even of a relatively minor nature such as fright, may likewise cause a worsening of symptoms.  Such episodes can lead to loss of consciousness or even coma.  Cerebellar ataxia and spasticity are common.  Epilepsy may occur but is uncommon.  Motor function is more severely impaired compared with mental deterioration.  The MRI reveals a diffuse leukoencephalopathy as well as focal and cystic degeneration of white matter which may be present before the onset of symptoms.  Cerebellar atrophy primarily involving the vermis is common.  Behavioral problems, psychiatric symptoms, and even signs of dementia have been reported.  The vast majority of patients have cognitive disabilities and many become severely handicapped and immobile.  Early onset disease in children often leads to death within a few years whereas adults with later onset may live for many years.       

Females with leukoencephalopathy who live to puberty may experience ovarian failure, a condition sometimes called ovarioleukodystrophy.

Genetics

This is an autosomal recessive disorder secondary to homozygous mutations in one of a group of five genes (EIF2B) located on chromosomes 1,2,3,12, and 14 encoding subunits of translation initiation factor 2B.    

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no effective treatment for the neurologic disease.  Ocular treatment for cataracts has not been reported.

References
Article Title: 

Retinitis Pigmentosa 2, X-Linked

Clinical Characteristics
Ocular Features: 

Retinitis pigmentosa consists of a group disorders with great clinical and genetic heterogeneity.  The ocular disease is characterized by night blindness, field constriction, and pigmentary changes in the retina.  The later is sometimes described as having a 'bone corpuscle' appearance with a perivascular distribution.  A ring scotoma is sometimes evident.  Age of onset and rate of progression is highly variable, even within families.

The X-linked form described here is a pigmentary retinopathy but sometimes labeled chorioretinal degeneration because of the extensive involvement of the choroid.  The clinical picture is sometimes referred to by the out-dated term 'choroidal sclerosis'.  It is often apparent in males during early childhood and they usually have early deterioration in central vision.  Some carrier females experience vision loss and have mild fundus abnormalities but these do no usually appear until middle age and are usually slowly progressive.  The ERG shows abnormalities in both sexes but these are highly variable.  Older males may have a waxy pallor of the optic nerve.  Posterior subcapsular cataracts are common.  The vitreous may contain fine, colorless particles even before fundus changes are evident.  Prognosis is highly variable but many patients eventually become legally blind by the age of 30 years.

Systemic Features: 

None.

Genetics

Mutations in more than 100 genes may be responsible for retinitis pigmentosa but sporadic disease occurs as well.  Between 5 and 10% of individuals have X-linked disease.

In this form of X-linked retinitis pigmentosa mutations in RP2 (Xp11.3) have been found.  The frequent occurrence of mild disease in females can cause diagnostic confusion with autosomal dominant RP but the disease in females in the latter disorder is usually as severe as in males.

This type of X-linked retinitis pigmentosa is far less common than RP3 (300029)caused by mutations in RPGR.  The two are clinically similar and genotyping is necessary to distinguish them.

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

High doses of vitamin A palmitate slow the rate of vision loss but plasma levels and liver function need to be checked at least annually.  Oral acetazolamide can be helpful in reducing macular edema.  Low vision aids and mobility training can be facilitating for many patients.  Cataract surgery may restore several lines of vision at least temporarily.

Several pharmaceuticals should be avoided, including isotretinioin, sildenafil, and vitamin E.

References
Article Title: 

Comprehensive survey of mutations in RP2 and RPGR in patients affected with distinct retinal dystrophies: genotype-phenotype correlations and impact on genetic counseling

Pelletier V, Jambou M, Delphin N, Zinovieva E, Stum M, Gigarel N, Dollfus H, Hamel C, Toutain A, Dufier JL, Roche O, Munnich A, Bonnefont JP, Kaplan J, Rozet JM. Comprehensive survey of mutations in RP2 and RPGR in patients affected with distinct retinal dystrophies: genotype-phenotype correlations and impact on genetic counseling. Hum Mutat. 2007 Jan;28(1):81-91.

PubMed ID: 
16969763

Microphthalmia, Syndromic 2

Clinical Characteristics
Ocular Features: 

Microphthalmia with congenital cataracts are the outstanding ocular features of this syndrome.  Some patients have glaucoma.  Blepharophimosis, ptosis, and ankyloblepharon have also been reported.

Systemic Features: 

Facial dysmorphism, dental anomalies and cardiac defects are consistently present.  The face may appear elongated while the nose can be short with a broad tip and long philtrum.  The primary teeth often persist into the second decade but oligodontia, hyperdontia, and dental radiculomegaly may be seen as well.  Reported cardiac defects include ASD, VSD and floppy valves.  Some patients have cleft palate.  Renal, and intestinal malformations have also been described and some patients exhibit psychomotor delays.

Genetics

This is an X-linked disorder secondary to a mutation in the BCOR gene at Xp11.4.  Because virtually all patients are female, it has been suggested that this is an X-linked dominant mutation with lethality in hemizygous males (mother-daughter transmission has been reported).  This is one of several disorders [others being Incontinentia pigmenti (308300)and focal dermal hypoplasia (305600)] in which skewed X-chromosome inactivation has been demonstrated.

Pedigree: 
X-linked dominant, father affected
X-linked dominant, mother affected
Treatment
Treatment Options: 

Cataracts can be removed and glaucoma requires treatment.

References
Article Title: 

Vitreoretinal Degeneration, Snowflake Type

Clinical Characteristics
Ocular Features: 

The retina and vitreous are primarily affected in this disorder.  The age of onset is unknown but characteristic signs can be seen early in the second decade of life.   Early changes include thickening of the cortical vitreous and white dots in the superficial layers of the retina.  The latter are minute yellow-white crystalline deposits more common in the peripheral retina.  Many (83%) patients have early onset cataracts.  Corneal guttae are common (80% of patients).  The vitreous undergoes fibrillar degeneration with liquefaction and eventually appears optically empty.  Many patients experience symptoms of floaters.  The vitreous changes most closely resemble that seen in Wagner syndrome (143200) but with important differences.  In the latter disorder the vitreous changes are membranous, the retinal changes are deeper in location, RPE changes are evident, the choroid and RPE are involved, and the risk of retinal detachment is much higher.  Only 21% of patients with snowflake vitreoretinal degeneration have retinal detachments compared with about 50% in Wagner syndrome.  Retinal vasculature change such as perivascular sheathing and attenuation of arterioles may be seen in both disorders but occur far less commonly in snowflake degeneration.

Based on lack of visual symptoms, the photoreceptors are minimally involved.  Electrophysiologic studies reveal an elevated dark adaptation and reduced scotopic B waves.  Most patients retain excellent vision.  However, the optic nerve may have a waxy pallor and frequently appears flat and lacks a visible cup. 

Systemic Features: 

None.

Genetics

Snowflake vitreoretinal degeneration is an autosomal dominant disorder.   Heterozygous missense mutations have been found in KCNJ13 (2q37) in a single family.  Mutations in the same gene have been identified in rare cases of Leber congenital amaurosis.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Visually significant cataracts may be removed.  Patients need to be observed throughout life to enable prompt intervention when retinal detachments occur.

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: 

Cockayne Syndrome, Type B

Clinical Characteristics
Ocular Features: 

The eyes are deep-set.  Congenital cataracts are present in 30% of infants.  The aggressive course of this form of CS has precluded full delineation of the ocular features but infants have been described with microphthalmos, microcornea and iris hypoplasia. 

Systemic Features: 

Evidence of somatic and neurologic delays is present at birth or shortly thereafter with microcephaly and short stature.  Infants never develop normal milestones and may not grow in size beyond that of a 6 month-old child.  Communication skills are minimal.  They have a progeroid appearance, age rapidly, and most do not live beyond 5 years of age.   Feeding problems are common with considerable risk of aspiration, a common cause of respiratory infections and early death.  Severe flexion contractures develop early and may interfere with motor function.  Tremors and weakness contribute as well.  The skin is sensitive to UV radiation in some but not all patients.  However, the frequency of skin cancer is not increased.  Endogenous temperature regulation may be a problem. 

At least some cases with what has been called cerebro-oculo-facio-skeletal syndrome have been genotypically documented to have type B CS, the severe form of Cockayne syndrome.

Genetics

This is an autosomal recessive disorder resulting from mutations in ERCC6 (10q11) rendering the excision-repair cross-complementing protein ineffective in correcting defects during DNA replication.  Mutations in this gene account for about 75% of CS patients.  However, using date of onset and clinical severity, type A CS (216400) disease is far more common even though the ERCC8 mutations are found in only 25% of individuals.  Type A CS (216400) also has a somewhat later onset and is less severe in early stages.

Type III (216411) is poorly defined but seems to have a considerably later onset and milder disease.  The mutation is type III is unknown.

Some patients have combined  phenotypical features of cerebrooculofacioskeletal syndrome (214150) and xeroderma pigmentosum (XP) known as the XP-CS complex (216400).  Defective DNA repair resulting from mutations in excision-repair cross-complementing or ERCC genes is common to both disorders.  Two complementation groups have been identified in CS and seven in XP.  XP patients with CS features fall into only three (B, D, G) of the XP groups.  XP-CS patients have extreme skin photosensitivity and a huge increase in skin cancers of all types.  They also have an increase in nervous system neoplasms. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Feeding tubes may be necessary to maintain nutrition.  Protection from the sun is important.  Physical therapy can be used to minimize contractures.  Cataract surgery might be considered in selected cases as well as assistive devices for hearing problems but the limited lifespan should be considered. 

References
Article Title: 

The Cockayne Syndrome Natural History (CoSyNH) study: clinical findings in 102 individuals and recommendations for care

Wilson BT, Stark Z, Sutton RE, Danda S, Ekbote AV, Elsayed SM, Gibson L, Goodship JA, Jackson AP, Keng WT, King MD, McCann E, Motojima T, Murray JE, Omata T, Pilz D, Pope K, Sugita K, White SM, Wilson IJ. The Cockayne Syndrome Natural History (CoSyNH) study: clinical findings in 102 individuals and recommendations for care. Genet Med. 2015 Jul 23. doi: 10.1038/gim.2015.110. [Epub ahead of print].

PubMed ID: 
26204423

Cockayne syndrome and xeroderma pigmentosum

Rapin I, Lindenbaum Y, Dickson DW, Kraemer KH, Robbins JH. Cockayne syndrome and xeroderma pigmentosum. Neurology. 2000 Nov 28;55(10):1442-9. Review. PubMed PMID:

PubMed ID: 
11185579

Cockayne Syndrome, Type A

Clinical Characteristics
Ocular Features: 

A progressive pigmentary retinopathy of a salt-and-pepper type and optic atrophy are commonly seen.  Retinal vessels are often narrowed and older patients can have typical bone spicule formation.  Night blindness, strabismus, and nystagmus may be present as well.  Enophthalmos, hyperopia, poor pupillary responses, and cataracts have been observed.  The lens opacities may in the nucleus or in the posterior subcapsular area and are often present in early childhood.  The ERG is often flat but may show some scotopic and photopic responses which are more marked in older individuals.  Vision loss is progressive but is better than expected in some patients based on the retina and optic nerve appearance.  The cornea may have evidence of exposure keratitis as many patients sleep with their eyes incompletely closed.  Recurrent corneal erosions have been reported in some patients.

The complete ocular phenotype and its natural history have been difficult to document due to the aggressive nature of this disease.

Ocular histopathology in a single patient (type unknown) revealed widespread pigment dispersion, degeneration of all retinal layers as well as thinning of the choriocapillaris and gliosis of the optic nerve.  Excessive lipofuscin deposition in the RPE was seen.

Systemic Features: 

Slow somatic growth and neural development are usually noted in the first few years of life.  Young children may acquire some independence and motor skills but progressive neurologic deterioration is relentless with loss of milestones and eventual development of mental retardation or dementia.  Patients often appear small and cachectic, with a 'progeroid' appearance.  The hair is thin and dry, and the skin is UV-sensitive but the risk of skin cancer is not increased.  Sensorineural hearing loss and dental caries are common.  Skeletal features include microcephaly, kyphosis, flexion contractures of the joints, large hands and feet, and disproportionately long arms and legs.  Perivascular calcium deposits are often seen, particularly in various brain structures while the brain is small with diffuse atrophy and patchy demyelination of white matter.  Peripheral neuropathy is characterized by slow conduction velocities.  Poor thermal regulation is often a feature. 

Type A is considered the classic form of CS.  Neurological deterioration and atherosclerotic disease usually lead to death early in the 2nd decade of life but some patients have lived into their 20s.  

Genetics

There is a great deal of clinical heterogeneity in Cockayne syndrome.  Type A results from homozygous or heterozygous mutations in ERCC8 (5q12).  CS type B (133540), is caused by mutations in ERCC6, and has an earlier onset with more rapidly progressive disease.  Both mutations impact excision-repair cross-complementing proteins important for DNA repair during replication.

Type III (216411) is poorly defined but seems to have a considerably later onset and milder disease.  The mutation in type III is unknown. 

Some patients have combined phenotypical features of Cockayne syndrome (CS) and xeroderma pigmentosum (XP) known as the XP-CS complex (216400).  Defective DNA repair resulting from mutations in nucleotide excision-repair cross-complementing or ERCC genes is common to both disorders.  Two complementation groups have been identified in CS and seven in XP.  XP patients with CS features fall into only three (B, D, G) of the XP groups.  XP-CS patients have extreme skin photosensitivity and a huge increase in skin cancers of all types.  They also have an increase in nervous system neoplasms. 

There may be considerable overlap in clinical features and rate of disease progression among all types.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No specific treatment is available for Cockayne syndrome.  Supportive care for specific health problems, such as physical therapy for joint contractures, is important. 

Justification of cataract extraction should be made on a case by case basis.  Lagophthalmos requires that corneal lubrication be meticulously maintained.

References
Article Title: 

The Cockayne Syndrome Natural History (CoSyNH) study: clinical findings in 102 individuals and recommendations for care

Wilson BT, Stark Z, Sutton RE, Danda S, Ekbote AV, Elsayed SM, Gibson L, Goodship JA, Jackson AP, Keng WT, King MD, McCann E, Motojima T, Murray JE, Omata T, Pilz D, Pope K, Sugita K, White SM, Wilson IJ. The Cockayne Syndrome Natural History (CoSyNH) study: clinical findings in 102 individuals and recommendations for care. Genet Med. 2015 Jul 23. doi: 10.1038/gim.2015.110. [Epub ahead of print].

PubMed ID: 
26204423

Ocular findings in Cockayne syndrome

Traboulsi EI, De Becker I, Maumenee IH. Ocular findings in Cockayne syndrome. Am J Ophthalmol. 1992 Nov 15;114(5):579-83.

PubMed ID: 
1443019

Cockayne syndrome and xeroderma pigmentosum

Rapin I, Lindenbaum Y, Dickson DW, Kraemer KH, Robbins JH. Cockayne syndrome and xeroderma pigmentosum. Neurology. 2000 Nov 28;55(10):1442-9. Review. PubMed PMID:

PubMed ID: 
11185579

Nance-Horan Syndrome

Clinical Characteristics
Ocular Features: 

Congenital cataracts are a feature of this X-linked disorder.  These consist of bilateral, dense nuclear opacification (in most males) but sutural opacities are also seen, especially in carrier females.  If the nuclear cataracts are not treated promptly, severe amblyopia, nystagmus, and strabismus may result.  Microcornea, congenital glaucoma, scleral staphylomas, and retinal cystoid degeneration may also be present.  Microphthalmia has been described. These ocular signs are present in 90% of heterozygous females but they may be subtle and careful examination is required to identify them.  Cataract surgery is usually not required in females. 

Systemic Features: 

This is a developmental disorder in which facial dysmorphism and dental anomalies are consistent systemic features in affected males.  Some patients (30%) also have some intellectual impairment while others have developmental delays and behavior problems.  The pinnae may be anteverted and often appear large while the nose and nasal bridge are prominent.  The teeth in males are small and pointed or 'screwdriver shaped' and are widely separated (sometimes called Hutchinson teeth).  The enamel may be hypoplastic and dental agenesis can be present.  Supernumerary incisors have been described.  The facial and dental features may be present in female carriers but are less pronounced.  Females do not have intellectual impairment. 

Genetics

This is an X-linked recessive (dominant?) disorder resulting from mutations in the NHS gene located at Xp22.13.  However, heterozygous females may have clinical manifestations, including dense cataracts, and all offspring of such females need ophthalmological evaluations at birth.

It is likely that at least some cases of X-linked congenital cataract (CXN; 302200) represent this disorder because the facial dysmorphism may be subtle and easily missed in Nance-Horan.  Of course, the two disorders may also be allelic.  A variety of alterations in the NHS gene, including copy number variations, intragenic deletions, and duplication/triplication arrangements, have been found.  The occasionally subtle facial dysmorphology and the dental abnormalities are easily missed in patients in whom congenital cataracts are the primary clinical concern.  

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

Visually significant cataracts should be removed early to allow for normal visual maturation.  Glaucoma must be treated appropriately.  At risk males and females should have dental X-rays and dental surgery may be required.  Special education may be beneficial in males. 

References
Article Title: 

X-linked cataract and Nance-Horan syndrome are allelic disorders

Coccia M, Brooks SP, Webb TR, Christodoulou K, Wozniak IO, Murday V, Balicki M, Yee HA, Wangensteen T, Riise R, Saggar AK, Park SM, Kanuga N, Francis PJ, Maher ER, Moore AT, Russell-Eggitt IM, Hardcastle AJ. X-linked cataract and Nance-Horan syndrome are allelic disorders. Hum Mol Genet. 2009 Jul 15;18(14):2643-55.

PubMed ID: 
19414485

Mutations in a novel gene, NHS, cause the pleiotropic effects of Nance-Horan syndrome, including severe congenital cataract, dental anomalies, and mental retardation

Burdon KP, McKay JD, Sale MM, Russell-Eggitt IM, Mackey DA, Wirth MG, Elder JE, Nicoll A, Clarke MP, FitzGerald LM, Stankovich JM, Shaw MA, Sharma S, Gajovic S, Gruss P, Ross S, Thomas P, Voss AK, Thomas T, Gecz J, Craig JE. Mutations in a novel gene, NHS, cause the pleiotropic effects of Nance-Horan syndrome, including severe congenital cataract, dental anomalies, and mental retardation. Am J Hum Genet. 2003 Nov;73(5):1120-30.

PubMed ID: 
14564667

Pages

Subscribe to RSS - cataracts