high myopia

Myopia 26, X-Linked, Female-Limited

Clinical Characteristics
Ocular Features: 

Affected females have high myopia with a tigroid fundus and temporal crescent of the optic nerve.  The eyes have an axial length of greater than 26 mm and a spherical refraction of -6 diopters or greater which are present before the age of 7 years.

Systemic Features: 

No systemic abnormalities have been found in this condition.

Genetics

Heterozygous missense and nonsense mutations in the ARR3 gene (Xq13.1) have been found in several Chinese families in which only females were affected.   Hemizygous males were not affected.

Treatment
Treatment Options: 

Correction of the refractive error improves vision.  Periodic eye examinations should be done to monitor for cataracts and retinal thinning.

References
Article Title: 

Marfan Lipodystrophy Syndrome

Clinical Characteristics
Ocular Features: 

The eyes are large resulting in high myopia and apparent proptosis.  The palpebral fissures usually slant downwards and ectopia lentis may be present.  

Systemic Features: 

This syndrome shares many features of Marfan syndrome (154700) such as tall stature, dislocated lenses, myopia, high arched palate, aortic root and valvular anomalies, arachnodactyly, high arched palate, lax and hyperextensible joints, and pectus excavatum.  In addition, MFLS patients have retrognathia, intrauterine growth retardation, scarce or absent subcutaneous fat, a progeroid facies, and sometimes macrocephaly.  Postnatal growth and psychomotor development have been reported to be normal albeit with slow weight gain.

Genetics

This condition is transmitted as an autosomal dominant as the result of heterozygous mutations in FBN1 (15q21.1).  The same gene is mutated in 6 other conditions in this database including Marfan Syndrome (154700) with which it shares some features.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no treatment for the overall condition but individual features such as ectopia lentis can be surgically corrected.  Patients with high myopia require frequent evaluation for retinal tears and detachments.  Cardiac monitoring likewise is important to monitor for aortic valve prolapse and dilation of the aortic root.

References
Article Title: 

Myopia and Deafness

Clinical Characteristics
Ocular Features: 

High myopia (6-11D) is usually diagnosed during infancy or in the first year of life.  Nine patients so far reported have ranged in age from 13 to 60 years if age.  Vitreoretinal degeneration has not been reported.

Systemic Features: 

Prelingual hearing loss has been identified in all patients, ranging in severity from moderate to severe.  No other neurological problems have been found.  CT scans of the temporal bone are normal.  No developmental delays or cognitive deficits have been identified.

Genetics

SLITRK family genes code for membrane proteins, expressed primarily in neural tissues. Mutations in SLITRK6 in the reported families cause loss of function.  In cultured cells from rodents the protein product impacts synapse induction and neurite modulation.  In Slitrk6 knockout mice, there is a reduction of cochlear innervations with reduced startle responses and impaired brainstem responses.  Axial length in these mice is normal at birth but adults have a significant increase in eye size.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

The refractive error should be corrected and assistive hearing devices may be helpful.

References
Article Title: 

SLITRK6 mutations cause myopia and deafness in humans and mice

Tekin M, Chioza BA, Matsumoto Y, Diaz-Horta O, Cross HE, Duman D, Kokotas H, Moore-Barton HL, Sakoori K, Ota M, Odaka YS, Foster J 2nd, Cengiz FB, Tokgoz-Yilmaz S, Tekeli O, Grigoriadou M, Petersen MB, Sreekantan-Nair A, Gurtz K, Xia XJ, Pandya A, Patton MA, Young JI, Aruga J, Crosby AH. SLITRK6 mutations cause myopia and deafness in humans and mice. J Clin Invest. 2013 May 1;123(5):2094-102.

PubMed ID: 
23543054

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: 

Myopia 2, Autosomal Dominant, Nonsyndromal

Clinical Characteristics
Ocular Features: 

Nonsyndromal, high myopia (over 6 D) has been found in multiple multigenerational families.  Most individuals have no other ocular problems but a small percentage develop degenerative changes in the retina, particularly in the macula (Fuchs spot).  A few individuals have posterior staphylomas with significant vitreoretinal changes conferring higher risks of retinal detachments and macular holes.  Vitreous traction is often present.  The macula in such cases is may be thickened and microcystic with areas of frank retinoschisis.  Of course, vitreous degeneration and retinal detachments are well known sequelae of high myopia. 

Systemic Features: 

There are no systemic features by definition. 

Genetics

Refractive errors are continuous traits with a wide range in most populations.  This suggests that many developmental and heritable (and perhaps environmental) components are responsible.  No specific mutation has been identified but a number of 'susceptibility' loci have been mapped.

Myopia 2 has been linked to a susceptibility locus at 18q11.31.

Evidence of heritability in both syndromal and isolated myopia comes from several sources.  For example, high myopia is a common feature in familial collagenopathies such as Marfan syndrome (154700), Kniest dysplasia (156550), and Stickler syndrome (108300). Multigenerational families with isolated myopia have been reported as well and mutations in multiple genes (at least 18) have been associated with these.  Heredibility studies using twin pairs have identified additional mutations (609256).  Further, the prevalence of myopia among children increases in the presence of parental myopia.

The transmission pattern in most families to which susceptibility loci have been linked is autosomal dominant.  However, a susceptibility locus has been mapped to 14q22.1-q24.2 in several families with good evidence for autosomal recessive inheritance (255500).  In addition, two loci on the X chromosome have been linked to presumed X-linked myopia (MYP1 [310460] at Xq28 and MYP13 [300613] at Xq23-q25).  A patient with high myopia has been reported with a mutation in the NYX gene on the X-chromosome.  This patient did not have congenital stationary night blindness of the type CSNB1A (310500) in which NYX is usually mutated.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Correction of the refractive error is primary.  High myopes require periodic evaluation throughout life and prompt surgical intervention for retinal detachments.  In extreme myopia it may be especially prudent for individuals to avoid impact sports. 

References
Article Title: 

Cornelia de Lange Syndrome

Clinical Characteristics
Ocular Features: 

Many patients have few ocular findings beyond the usual synophyrs, a highly arched brow with hypertrichosis, and long eyelashes.  Synophrys is often prominent.  However, some also have significant ptosis, nystagmus, and high refractive errors.  Optic pallor and a poor macular reflex have also been reported.

Systemic Features: 

The facial features may be distinctive with low anterior hairline, anteverted nares, maxillary prognathism, long philtrum, crescent-shaped mouth and, of course, the bushy eyebrows and long lashes (in 98%).  Mental and growth retardation are common while many patients have features of the autism spectrum and tend to avoid social interactions.  The lips appear thin, the mouth is crescent-shaped, the head is often small, the teeth are widely spaced, and the ears are low-set.  The hands are often deformed with a proximally positioned thumb and metacarpophalangeal deformities.  It is stated that the middle phalanx of the index finger is always hypoplastic.  Other limb abnormalities of both upper (95%) and lower extremities are common.  Urinary tract abnormalities have been found in 41% of patients.  Middle ear effusions often lead to conductive hearing loss but 80% of patients have a sensorineural hearing deficit.

Genetics

This disorder is caused by mutations in genes encoding components of the cohesion complex.  Most cases occur sporadically but numerous familial cases suggest autosomal dominant inheritance. However, since at least three genes code for components of the cohesion complex including one located on the X-chromosome (610759), familial cases reported earlier without genotyping have created some confusion.  Hence, even autosomal recessive inheritance has been suggested in some families.  Genetic counseling should be family-specific based on the genotype and family pattern.

About 50% of cases result from mutations in the NIPBL gene (122470; 5p13.1) but less than 1% have an affected parent and the recurrence risk for sibs is similar.  The X-linked form of CDLS (300590; Xp11.22-p11.21) is caused by a mutation in the SMC1A gene, and a mild form (610759) results from mutations in the SMC3 gene (10q25).  Mutations in RAD21 (8q24) have been found in patients with milder disease and atypical presentations (614701).

A CDLS phenotype can also result from a specific duplication of a 3q 26-27 band.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

No genetic treatment is available.

References
Article Title: 

Spondyloepiphyseal Dysplasia Congenita

Clinical Characteristics
Ocular Features: 

Patients characteristically have vitreous abnormalities described as veils or stands.  The central vitreous may undergo liquefaction and the peripheral vitreous sometimes creates traction on the retina.  High myopia with progression is common and a significant proportion of patients suffer detachments of the retina even in the absence of myopia.  Lattice degeneration is frequently seen.  Most patients have 20/50 or better vision.

Systemic Features: 

Dwarfism with kyphosis and a barrel chest are characteristic.  The vertebrae are often flattened and malformed and the neck is short.  Delayed ossification in the epiphyses and the os pubis is common.  The disorder can be evident at birth but the full syndrome may not be evident until 3 or 4 years of age.  Radiologic studies are important in making the diagnosis.

Genetics

This is generally considered an autosomal dominant disorder secondary to mutations in the COL2A1 gene impacting type II collagen.  This type of collagen is found primarily in cartilage and vitreous and a number of type II collagenopathy disorders are associated with vitreoretinopathy and joint disease of which Stickler syndrome type I (609508, 108300) is the most common.  Other disorders in this database caused by mutations in COL2A1 are: Kniest dysplasia (156550), Stickler syndromes type I (609508, 108300 ) and II (604841), vitreoretinopathy with epiphyseal dysplasia (120140), and spondyloepiphyseal dysplasia congenita (183900).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Cervical fusion is sometimes used when odontoid hypoplasia leads to hypermobility of the cervical vertebrae.  Retinal detachments, of course, need to be repaired.

References
Article Title: 

Macrophthalmia, Colobomatous, with Microcornea

Clinical Characteristics
Ocular Features: 

Several families have been reported in which multiple family members had various ocular malformations including bilateral extensive colobomas from the iris to the optic nerve, increased axial length, microcornea, posterior staphylomas, and high myopia. In a three generation Turkish family with 13 affected individuals other features such as flatter than normal corneas, shallow anterior chambers and iridocorneal angle abnormalities with elevated intraocular pressures were described.  

Systemic Features: 

None have been reported.

Genetics

This is a contiguous gene deletion disorder located at 2p22.2 which involves the CRIM1 and FEZ2 genes.  Penetrance is high in this presumed autosomal dominant condition.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is known.
 

References
Article Title: 
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