vitreoretinal degeneration

Knobloch Syndrome 1

Clinical Characteristics
Ocular Features: 

The ocular findings include high myopia, vitreoretinal degeneration, dislocated lenses, cataracts, and retinal detachment.  Some patients have early onset (2-4 years old) night blindness and progress to total blindness before 20 years of age.  Nystagmus, strabismus, small optic discs, glaucoma, and cataracts have been reported.  Poor vision and progressive loss of acuity are common.  The vitreous appears to be condensed into sheets and there may be distortion of the vitreoretinal interface with irregular white dots and lines.  Pigmentary changes are common in the retina which some have described as consistent with choroidal sclerosis and chorioretinal atrophy.  Atrophic changes are often seen in the macula.

Systemic Features: 

The degree of skull and brain defects is variable.  Some patients have only occipital scalp defects while others have occipital encephaloceles.  The scalp defect may contain heterotopic neuronal tissue suggesting neuronal migratory defects.  Brain imaging has revealed a variety of defects and some patients have cognitive deficits and personality changes.  Cerebellar atrophy with ataxia is found in some patients.

Genetics

This is an autosomal recessive disorder secondary to homozygous mutations in the COL18A1 gene (21q22.3).  Mutated COL18A1 leads to defects in type XVIII collagen which is a component of basement membranes throughout the body, especially in the eye.

In spite of some clinical similarities, this disorder is genetically distinct from Knobloch 2 syndrome (608454).  A third type, KNO3, has been proposed since the Knobloch clinical features were found in a 4-generation consanguineous Pakistani family but the phenotype mapped to 17q11.2.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment is largely supportive.  Attempts at repair of retinal detachments often fail and phthisis bulbi is not uncommon.

References
Article Title: 

Myopia, AR, with Cataracts and Vitreoretinal Degeneration

Clinical Characteristics
Ocular Features: 

Axial myopia and poor vision are noted during childhood.  Most individuals have refractive errors in the range of-5 to -18 diopters with a mean spherical equivalent of -11.3 diopters.  The axial length ranges from 25.1 and 30.5 mm.  Peripheral vitreoretinal degeneration and cataracts are usually present after the onset of myopia.  Lenticular opacities may necessitate cataract surgery in 11 of the 13 myopic patients in one kindred, usually by the second decade of life.  Lens instability or frank subluxation was noted in 8 patients.  At least five eyes suffered retinal detachments secondary to retinal dialyses and blindness of at least one eye occurred in 23% of patients.

Systemic Features: 

Deafness was reported in a single patient.

Genetics

This condition results from homozygous mutations in the gene LEPREL1 (3q28) encoding prolyl 3-hydroxylase.  It was identified in a large consanguineous Israeli Bedouin kindred containing seven affected males and 6 affected females.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Cataract and retinal surgery may be indicated. However, the instability of the lens can lead to complications. The nature and location of retinal tears likewise make repairs difficult and blindness is a relatively frequent complication.

References
Article Title: 

Stickler Syndrome, Type IV

Clinical Characteristics
Ocular Features: 

Evidence of vitreoretinal degeneration is common and the risk of retinal detachment is high.  High myopia is common.  Cataracts are not a feature in contrast to types I and II Stickler syndrome.

It is likely that the ocular phenotype will be expanded with the report of additional families.

Systemic Features: 

Sensorineural hearing loss and short stature are often present. The latter is not usually a feature in other types of Stickler syndrome.  However, midface hypoplasia and micrognathia may be present in all types as well as in Marshall syndrome.  Midline clefting usually does not occur.

Genetics

A reported pedigree suggests autosomal recessive inheritance based on parental consanguinity and the lack of parent-to-child transmission.  Affected individuals have homozygous deletion mutations leading to loss of function in COL9A2 (1p33-p32) while parents are heterozygous.  A family with mutations in COL9A1 (6q12-q14), usually causing multiple epiphyseal dysplasia, has been reported to have autosomal recessive Stickler syndrome as well.  Homozygous individuals had typical ocular and auditory findings of autosomal dominant Stickler syndrome but with evidence of epiphyseal dysplasia.

Type I Stickler syndrome (108300, 609508) is an autosomal dominant disorder with somewhat similar ocular manifestations resulting from mutations in COL2A1.

Type II Stickler syndrome (604841) with a somewhat similar ocular phenotype is also an autosomal dominant disorder but caused by mutations in COL11A1.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

The myopia and hearing loss can be corrected.  Lifelong vigilance and prompt treatment are required for the vitreoretinal disease.

References
Article Title: 

Kniest Dysplasia

Clinical Characteristics
Ocular Features: 

High myopia and vitreoretinal degeneration are characteristic ocular features in this disorder.   The myopia is in the range of -7.5 to -15.25 with most patients having about -11 diopters.  Acuity may be normal but inoperable retinal detachments can lead to blindness.  The vitreous demonstrates liquefaction and syneresis and often detaches posteriorly forming a retrolental curtain.  About half of affected eyes have perivascular lattice degeneration and the same proportion of patients at some point develop a retinal detachment.  Giant tears and retinal dialysis are commonly the cause.  The lens is often dislocated and cataracts are common.

Systemic Features: 

Short stature, cleft palate, stiff joints, and conductive hearing loss are characteristic extraocular features of Kniest dysplasia.  Some patients develop frank joint contractures and many are unable to make a tight fist due to inflexibility of the interphalangeal joints.  Lumber kyphoscoliosis is common.  Epiphyseal cartilage has a 'Swiss cheese appearance' with prominent lacunae.  The facies are round and the midface is underdeveloped with a flat nasal bridge.  Mild psychomotor retardation is sometimes seen.  

High levels of keratin sulfate are found in the urine.

Genetics

Mutations in the COL2A1 gene (12q13.11-q13.2) coding for type II collagen is responsible for this autosomal dominant disorder. This is one of a number of disorders known as type II collagenopathies (see Stickler syndrome I [609508]).  The clinical features arise from a defect in type II procollagen.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no treatment for the dysplasia.  Displaced lenses can be removed but the myopia and degenerated vitreous require a cautious approach.  Rhegmatogenous detachments demand prompt attention.

References
Article Title: 

Ophthalmic and molecular genetic findings in Kniest dysplasia

Sergouniotis PI, Fincham GS, McNinch AM, Spickett C, Poulson AV, Richards AJ, Snead MP. Ophthalmic and molecular genetic findings in Kniest dysplasia. Eye (Lond). 2015 Jan 16. doi: 10.1038/eye.2014.334. [Epub ahead of print].

PubMed ID: 
25592122

The Kniest syndrome

Siggers CD, Rimoin DL, Dorst JP, Doty SB, Williams BR, Hollister DW, Silberberg R, Cranley RE, Kaufman RL, McKusick VA. The Kniest syndrome. Birth Defects Orig Artic Ser. 1974;10(9):193-208.

PubMed ID: 
4214536

Stickler Syndrome, Type I

Clinical Characteristics
Ocular Features: 

High myopia and vitreous degeneration dominate the ocular manifestations of Stickler syndrome, type I.  The vitreous often appears optically empty as it liquefies and the fibrils degenerate.  The vitreous is sometimes seen to form 'veils', especially in the retrolenticular region but they may also float throughout the posterior chamber.  They are often attached to areas of lattice degeneration in the retina as well as other areas.  Posterior vitreous detachments are common.  Vitreoretinal degeneration is progressive and by the second decade rhegmatogenous detachments occur in half of affected patients.  As many as three quarters of adult patients have retinal breaks.  The retina has pigmentary changes with deposition circumferentially near the equator and more peripherally.  Hypopigmentation is more common early creating a tessellated appearance.  Lenticular opacities occur also early with cortical flecks and wedge-shaped changes.

The ERG may be normal early but evidence of rod and cone dysfunction soon appears and is progressive.  Dark adaptation is defective later in the course of the disease.  The EOG is virtually always depressed.  The visual field is constricted and may show a ring scotoma coincident with the equatorial chorioretinal atrophy.

Glaucoma is not uncommon and may be infantile in onset and difficult to control.  

Phthisis is a significant risk especially for individuals who have multiple surgical procedures for retinal detachments. 

Systemic Features: 

It has been suggested that there is a nonsyndromic or ocular type of Stickler syndrome lacking many of the extraocular features characteristic of the complete syndrome.  However, the evidence for the ocular type described here as a distinct entity remains slim and the clinical picture may simply reflect variable expressivity of mutations in the same gene.  Type I Stickler syndrome has multiple systemic features such as cleft palate, hearing impairment, premature arthritis, micrognathia, kyphoscoliosis, and some signs such as arachnodactyly that are found in the Marfan syndrome.

Genetics

This is an autosomal dominant disease of collagen formation as a result of mutations in the COL2A1 gene (12q13.11-q13.2). The mutations causing both syndromal and the suggested nonsyndromal ocular type of Stickler disease are in the same gene.  Mutations in the same gene are known to cause autosomal dominant rhegmatogenous retinal detachments in patients who have none of the systemic clinical signs (609508).  These patients may lack the signs of vitreous degeneration seen in Kniest dysplasia (156550)  and in the disorder described here.

There is better evidence for a second type of Stickler syndrome, STL2 or type II (604841) based on phenotypic differences and the fact that a second locus (1p21) containing mutations in COL11A1 has been linked to it. 

Type III is caused by mutations in COL11A2 and has systemic features similar to types I and II but lacks the eye findings since this gene is not expressed in the eye.

Type IV also has important ocular features but is an autosomal recessive disorder caused by mutations in COL9A2.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

The combination of progressive vitreoretinal degeneration, frequency of posterior vitreous detachments, and axial myopia creates a lifelong threat of retinal tears and detachments.   Half to three quarters of all patients develop retinal tears and detachments.  Certainly all patients with Stickler syndrome deserve repeated and thorough retinal exams throughout their lives.  In addition to prompt treatment of tears and detachments, some have advocated prophylactic scleral banding to reduce vitreous traction, or applying 360 degree cryotherapy.

References
Article Title: 

Stickler syndrome in children: a radiological review

McArthur N, Rehm A, Shenker N, Richards AJ, McNinch AM, Poulson AV, Tanner J, Snead MP, Bearcroft PWP. Stickler syndrome in children: a radiological review. Clin Radiol. 2018 Apr 13. pii: S0009-9260(18)30118-1. doi: 10.1016/j.crad.2018.03.004. [Epub ahead of print].

PubMed ID: 
29661559

High efficiency of mutation detection in type 1 stickler syndrome using a two-stage approach: vitreoretinal assessment coupled with exon sequencing for screening COL2A1

Richards AJ, Laidlaw M, Whittaker J, Treacy B, Rai H, Bearcroft P, Baguley DM, Poulson A, Ang A, Scott JD, Snead MP. High efficiency of mutation detection in type 1 stickler syndrome using a two-stage approach: vitreoretinal assessment coupled with exon sequencing for screening COL2A1. Hum Mutat. 2006 Jul;27(7):696-704. Erratum in: Hum Mutat. 2006 Nov;27(11):1156.

PubMed ID: 
16752401
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