myopia

Knobloch Syndrome 2

Clinical Characteristics
Ocular Features: 

In an 18 month infant, ectopia lentis, cataract, and myopia with poor vision were noted.  This individual subsequently developed retinal degeneration and a serous retinal detachment.

Systemic Features: 

Only one patient has been reported.  While the clinical signs resemble Knobloch 1 syndrome, brain imaging does not reveal malformations in this syndrome.  The only systemic sign, in addition to an occipital encephalocele, is a minor delay in fine motor skills.

Genetics

This autosomal recessive disorder results from homozygous loss of function mutations in the ADAMTS18 gene (16q23.1).  The gene product has been found in the lens and retina in the murine eye.

Mutations in ADAMTS18 have also been found in the syndrome of Micorcornea, Myopia, Chorioretinal atrophy, and Telecanthus.  It may also be responsible for a retinal dystrophy.

Knobloch 2 syndrome was identified in a single female born to consanguineous parents.

This disorder is separate to Knobloch 1 syndrome (267750) based on the causative mutations.  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: 

The skull defect can be closed and the lenses can be removed if indicated.

References
Article Title: 

Congenital Disorder of Glycosylation, Type Ia

Clinical Characteristics
Ocular Features: 

Strabismus, roving eye movements (and nystagmus), and visual inattention are found in nearly all patients. Esotropia with defective abduction seems to be the most common oculomotor finding and may be present at birth.  Cataracts, ocular colobomas, oculomotor apraxia, disc pallor, and glaucoma have also been reported.  Vision is always subnormal. Reports of ocular disease before modern genotyping are not specific to the subtypes of CDG I now recognized.

This is a congenital, progressive disorder of photoreceptor degeneration with a later onset of progressive pigmentary retinopathy.  It is described in some cases as a typical retinitis pigmentosa.  The ERG is abnormal in all patients even if the pigmentary pattern is atypical for RP.  Rod responses are usually absent while the cone b-wave implicit time is delayed.  The degree of photoreceptor damage is variable, however.  Extended retinal function among younger patients suggest that the ‘on-pathway’ evolving synapses in the outer plexiform layer among photoreceptors, bipolar cells, and horizontal cells is severely dysfunctional.

Systemic Features: 

This is a multisystem disorder, often diagnosed in the neonatal period by the presence of severe encephalopathy with hypotonia, hyporeflexia, and poor feeding.  Failure to thrive, marked psychomotor retardation, delayed development, growth retardation, and ataxia become evident later in those who survive.  Cerebellar and brainstem atrophy with a peripheral neuropathy can be demonstrated during late childhood.  Some older patients have a milder disease, often with muscle atrophy and skeletal deformities such as kyphoscoliosis and a fusiform appearance of the digits.  Maldistribution of subcutaneous tissue is often seen resulting in some dysmorphism, especially of the face.  Hypogonadism and enlargement of the labia majora are commonly present.  Some patients have evidence of hepatic and cardiac dysfunction which together with severe infections are responsible for a 20% mortality rate in the first year of life.

Genetics

This is one of a group of genetically (and clinically) heterogeneous autosomal recessive conditions caused by gene mutations that result in enzymatic defects in the synthesis and processing of oligosaccharides onto glycoproteins. This type (Ia) is the most common.   The mutation lies in the PMM2 gene (16p13.2).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Most children require tube feeding with nutritional supplements.  The risk of systemic infections is high.  Those patients who survive into the second decade and beyond may require orthopedic procedures and are confined to wheelchairs.  Physical, occupational, and speech therapy along with parental support are important.

References
Article Title: 

Sengers Syndrome

Clinical Characteristics
Ocular Features: 

This is a mitochondrial DNA depletion syndrome in which congenital cataracts are the hallmark ocular feature.  The bilateral lens opacification is usually total at birth or within the first few weeks of life as manifested by leucocoria. Lens extraction is necessary within the first 6 months of life but visual rehabilitation is nearly always compromised postoperatively by nystagmus and strabismus.  In one series only one eye recovered to 20/40 but the average postoperative acuity was in the range of 20/200 and virtually all students require special education in schools for the visually impaired.  Axial myopia is common with most patients having myopic fundus changes and requiring less than +10 diopters of aphakic correction.  Pale optic disks and a pigmentary retinopathy were noted among 8 of 18 eyes in one series.  Mild and inconsistent dyschromatopsia has been reported in a few patients.  The ERG sometimes shows diminished rod and cone function.

Systemic Features: 

Hypertrophic cardiomyopathy is often diagnosed within a fews days after birth but 40% may escape detection until the second or third decade of life.  It is usually progressive and often fatal in the neonatal period.  Myopathy involves both cardiac and skeletal muscles.  Generalized hypotonia, exercise intolerance, and delayed motor development are important features in the majority of patients.  Metabolic lactic acidosis occurs with relatively minimal excercise.  Skeletal muscle biopsies show ragged-red fibers with combined deficiencies of mitochondrial complexes I, III, and IV along with severe depletion of mtDNA.  Increased urine levels of 3-methylglutaconic have been reported.

The central nervous system is usually not involved and mental development is normal if lactic acidosis is controlled.  However, several children with mental retardation have been reported.

Genetics

Homozygous or compound heterozygous mutations in AGK (7p34), a lipid metabolism gene, are responsible for this condition.  There is considerable variation in the severeity of the phenotypic features but no ocular or cardiac disease has been found in heterozygotes. 

The same gene was found to be mutated in an autosomal recessive congenital cataract (614691) in a single reported sibship. Thorough systemic evaluation found no evidence of cardiac and skeletal muscle disease.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Surgical removal of cataracts may be indicated.

References
Article Title: 

Lack of the mitochondrial protein acylglycerol kinase causes Sengers syndrome

Mayr JA, Haack TB, Graf E, Zimmermann FA, Wieland T, Haberberger B, Superti-Furga A, Kirschner J, Steinmann B, Baumgartner MR, Moroni I, Lamantea E, Zeviani M, Rodenburg RJ, Smeitink J, Strom TM, Meitinger T, Sperl W, Prokisch H. Lack of the mitochondrial protein acylglycerol kinase causes Sengers syndrome. Am J Hum Genet. 2012 Feb 10;90(2):314-20.

PubMed ID: 
22284826

Microcornea, Myopia, Telecanthus and Posteriorly-Rotated Ears

Clinical Characteristics
Ocular Features: 

Small corneas measuring 9.8 – 10.5 mm are characteristic.  Acuity is usually 20/60 or better in older children but even younger children maintain steady fixation.  Refractive errors of -6 to -12.75 diopters are usually present but may be much less in other children.  Axial lengths range from 22.42 to 26.84 mm corresponding to the amount of myopia.  The degree of myopic chorioretinal change correlates roughly with the amount of axial myopia.  Telecanthus is present in all individuals.  

Systemic Features: 

The ears are rotated posteriorly.

Genetics

Five males with this syndrome occurred in four consanquineous/endogamous Saudi families suggesting autosomal recessive inheritance.  Homozygous mutations in ADAMTS18 (16q23.1) have been found in these four families.  However, one child had a similarly affected father suggesting to some that this may be a pseudodominant disorder.

Mutations in the same gene are responsible for Knobloch syndrome 2 (KNO2) (608454).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported although correction of the refractive error should be made in early childhood.  It would seem prudent to monitor the vitreoretinal system for further degeneration.

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: 

Spherophakia with Inguinal Hernia

Clinical Characteristics
Ocular Features: 

Individuals with this condition have small spherical lenses that are usually displaced superiorly.  Myopia, both lenticular and axial, is often present and retinal detachments can occur.  Glaucoma was reported in one patient but this followed surgery for a retinal detachment.  Iridodenesis and nystagmus may be present.  The single report mentions strong zonules that created difficulties during intracapsular lens removal.  None of the spherical lenses were reported to migrate into the anterior chamber nor was lens-induced glaucoma present.

Systemic Features: 

Inguinal hernias are the only systemic manifestation of this disorder.  Four of 11 affected individuals in the family reported required surgery.  Physical examination and skeletal measurements were used to rule out the Marfan and Weill Marchesani syndromes.

Genetics

A single family with 11 affected individuals in 4 generations has been reported.  The four generation pedigree suggested autosomal dominant inheritance but nothing is known regarding the mutation or locus.

Spherophakia is a clinically and genetically heterogeneous disorder and usually found in association with systemic findings.  It is commonly seen in the Weill-Marchesani syndrome 1 (277600), in Weill Marchesani syndrome 2 (608328), in the Weill-Marchesani-Like syndrome (613195), in a condition known as ‘megalocornea, ectopia lentis, and spherophakia’ (?), and in a syndrome known as ‘spherophakia and metaphyseal dysplasia’ (157151).  Autosomal recessive isolated spherophakia (251750) has been found in several families.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Lens extraction may be necessary for vision rehabilitation if it is partially displaced.

References
Article Title: 

Dominant microspherophakia

Johnson VP, Grayson M, Christian JC. Dominant microspherophakia. Arch Ophthalmol. 1971 May;85(5):534-7.

PubMed ID: 
5087595

Weill-Marchesani-Like Syndrome

Clinical Characteristics
Ocular Features: 

Several families have been reported in which the ocular features were similar to Weill-Marchesani syndromes WMS1 and WMS2 but lacked most of the skeletal features.  The ocular abnormalities included: myopia, ectopia lentis, spherophakia, and glaucoma.  Shallow anterior chambers and peripheral iris synechiae are often present. Axial length ranges from 21 to 23 mm.

Systemic Features: 

Short stature is a feature of this syndrome but brachydactyly and decreased joint mobility are not present.  Height is usually below the 25th percentile and often at the third or 5th percentile.

 

Genetics

This is an autosomal recessive disorder resulting from mutations in ADAMTS17 (15q26.3).  See also Weill-Marchesani Syndrome 1 (277600), and Weill-Marchesani Syndrome 2 (608328) for other conditions with clinical similarities but caused by different mutations.

Homozygous mutations in LTBP2 (14q24.3) have also been found in this disorder and in WMS1 (277600).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Glaucoma requires the usual treatments.  The lens may need to be removed for visual rehabilitation and/or lens induced glaucoma.

References
Article Title: 

LTBP2 mutations cause Weill-Marchesani and Weill-Marchesani-like syndrome and affect disruptions in the extracellular matrix

Haji-Seyed-Javadi R, Jelodari-Mamaghani S, Paylakhi SH, Yazdani S, Nilforushan N, Fan JB, Klotzle B, Mahmoudi MJ, Ebrahimian MJ, Chelich N, Taghiabadi E, Kamyab K, Boileau C, Paisan-Ruiz C, Ronaghi M, Elahi E. LTBP2 mutations cause Weill-Marchesani and Weill-Marchesani-like syndrome and affect disruptions in the extracellular matrix. Hum Mutat. 2012 Apr 26. doi: 10.1002/humu.22105. [Epub ahead of print] PubMed PMID: 22539340.

PubMed ID: 
22539340

Spherophakia and Metaphyseal Dysplasia

Clinical Characteristics
Ocular Features: 

The corneas and anterior chambers were normal in the son but the lenses were small and spherical and had colobomatous defects.  The father developed a retinal detachment in one eye and elevated intraocular pressure. The morphology of the lenses in the father is unknown.

Systemic Features: 

The diaphyses of the long bones are thickened with relative sparing of the small bones in the extremities.  The epiphyses become more irregular later in life.  The vertebrae are deformed with flattening.  The result is brachymelia and moderately severe dwarfism.  Pigeon breast deformity can be present.

Genetics

A father and son have been reported with this combination of findings suggesting autosomal dominant inheritance.  No locus or mutation has been identified.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Unknown.

References
Article Title: 

Brittle Cornea Syndrome 2

Clinical Characteristics
Ocular Features: 

Corneal thinning and extreme fragility are characteristic of BCS2.  Ruptures of the cornea may occur with minimal trauma and repair is often unsatisfactory due to the lack of healthy tissue.  Keratoconus, acute hydrops, keratoglobus, and high myopia are frequently present as well.  Some patients have sclerocornea that obscures the normal limbal landmarks.  The sclera is also thin and the underlying pigmented uveal tissue imparts a bluish discoloration to the globe which is especially evident in the area overlying the ciliary body creating what some call a blue halo.

Systemic Features: 

Skin laxity with easy bruisability, pectus excavatum, scoliosis, congenital hip dislocation, a high arched palate, mitral valve prolapse and recurrent shoulder dislocations are often present.  Hearing impairment with mixed sensorineural/conductive defects is common.

Genetics

This autosomal recessive disorder results from homozygous mutations in PRDM5 (4q27).  Heterozygous carriers may have blue sclerae, small joint hypermobility, and mild thinning of the central cornea. 

BCS2 has many clinical similarities to brittle cornea syndrome 1 (229200) which results from homozygous mutations in ZNF469.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment for specific defects such as joint dislocations and mitral valve malfunction may be helpful.

References
Article Title: 

Brittle cornea syndrome: recognition, molecular diagnosis and management

Burkitt Wright EM, Porter LF, Spencer HL, Clayton-Smith J, Au L, Munier FL, Smithson S, Suri M, Rohrbach M, Manson FD, Black GC. Brittle cornea syndrome: recognition, molecular diagnosis and management. Orphanet J Rare Dis. 2013 May 4;8(1):68. [Epub ahead of print]

PubMed ID: 
23642083

Mutations in PRDM5 in brittle cornea syndrome identify a pathway regulating extracellular matrix development and maintenance

Burkitt Wright EM, Spencer HL, Daly SB, Manson FD, Zeef LA, Urquhart J, Zoppi N, Bonshek R, Tosounidis I, Mohan M, Madden C, Dodds A, Chandler KE, Banka S, Au L, Clayton-Smith J, Khan N, Biesecker LG, Wilson M, Rohrbach M, Colombi M, Giunta C, Black GC. Mutations in PRDM5 in brittle cornea syndrome identify a pathway regulating extracellular matrix development and maintenance. Am J Hum Genet. 2011 Jun 10;88(6):767-77. Erratum in: Am J Hum Genet. 2011 Aug 12;89(2):346.

PubMed ID: 
21664999

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: 

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