amblyopia

Nanophthalmos 1

Clinical Characteristics
Ocular Features: 

The axial length ranges from 17.55 to 19.28 mm with a mean of 18.13 mm.  The mean refractive error was +9.88 in one reported family but ranged from +7.25 to +13.00.  More than half of reported patients have developed angle closure glaucoma.  Patients are at risk for strabismus and amblyopia.  Choroidal detachments are often seen in nanophthalmic eyes.

Histological studies on full thickness sclerotomy tissue from a nanophthalmic eye showed frayed and split collagen fibrils with lightly stained cores predominantly in the sclera and episcleral regions which may contribute to the anatomical changes.

Systemic Features: 

None have been reported.

Genetics

No mutation has been described but this autosomal dominant condition maps to 11p.

Another type of autosomal dominant nanophthalmos (NNO3) (611897) maps to 2q22-q14, and yet another, nanophthalmos AD, results from mutations in TMEM98.

Nanophthalmos may also be inherited in an autosomal recessive pattern.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Lifelong monitoring is required because of the risk of angle closure.  Intraocular surgery such as lens extractions carries a high risk of complications.

References
Article Title: 

Fibrosis of Extraocular Muscles, CFEOM1

Clinical Characteristics
Ocular Features: 

Hereditary CFEOM is a congenital, nonprogressive condition.  The eyes are usually fixed in the infraducted position about 20-30 degrees below the primary position.  Horizontal movement is absent or severely restricted.  Blepharoptosis is almost always present and patients exhibit a marked chin-up position of gaze.  Binocularity is usually absent.  Some patients have large amounts of astigmatism.  Amblyopia has been reported to occur on a refractive or strabismic basis.  However, careful examination of the optic nerve may reveal anomalies such as increased cupping, asymmetric cupping and hypoplasia and could be responsible for the reduced vision in some patients.

Neuropathologic studies in rare patients have shown defects in brainstem neural development including in one case absence of the superior division of the oculomotor nerve.  Fibrosis of extraocular muscles and Tenon's capsule as well as adhesions to the globe and between muscles have been described.   Anomalous insertions of EOMs may also occur.  An MRI can reveal atrophy of the levator palpebrae and the superior rectus muscles as well as absence or hypoplasia of the oculomotor and sometimes abducens nerves.  It is now considered that CFEOM disorders result from primary neuronal disease resulting in secondary myopathy. 

Systemic Features: 

Late onset gait abnormalities associated with MRI documented vermis atrophy have been reported in a single autosomal dominant pedigree.  The diagnosis of CFEOM1 was confirmed with molecular studies but only two older individuals aged 79 and 53 years had the cerebellar atrophy while a 33 year old in the same family had only CFEOM with no gait difficulties and no neuroimaging abnormalities.

Genetics

CFEOM1 is an autosomal dominant disorder caused by mutations in the KIF21A gene located at 12q12.  This is considered the classic form of congenital, restrictive strabismus but other types such as CFEOM2 (602078) and CFEOM3 (600638, 609384) have also been reported.  CFEOM3 is a clinically heterogeneous autosomal dominant condition and the label is usually applied to individuals who do not meet the criteria for the other two types.  A rare subtype (CFEOM3B) is also due to mutations in the KIF21A gene.  CFEOM3A (600638) is caused by mutations in the TUBB3 gene (16q24) while CFEOM3C (609384) maps to 13q.

The CFEOM2 (602078) phenotype is due to mutations in the PHOX2A (ARIX) gene and inherited in an autosomal recessive pattern.

Other nonsyndromal forms of congenital fibrosis of extraocular muscles include: CFEOM3C (609384), CFEOM5 (616219), and CFEOM with synergistic divergence (609612).  See also Tukel CFEOM syndrome (609428).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Normal ocular movements cannot be restored but large recessions of the inferior recti followed by frontalis suspension of the upper eyelids can improve severe ptosis and the compensatory chin-up gaze. Corneal lubrication must be maintained.  Refractive errors and amblyopia should be corrected.  

References
Article Title: 

Fibrosis of Extraocular Muscles, CFEOM2

Clinical Characteristics
Ocular Features: 

This is a congenital, autosomal recessive, nonprogressive type of CFEOM which has been described in several consanguineous Middle Eastern families.  The responsible mutations are in a different gene than the one responsible for autosomal dominant CFEOM1 cases although some of the clinical features are similar.  However, in CFEOM2 the eyes are less likely to be infraducted and instead are often fixed in extreme abduction.  In addition, the phenotype is more variable with some eyes fixed in the 'neutral' position and others having more mobility than usually seen in CFEOM1 but the clinical heterogeneity is less than that seen in CFEOM3.  Ptosis is part of both phenotypes.  All patients have severe restrictions in ocular motility.  It has been suggested that CEFOM2 patients are likely to have involvement of both superior and inferior divisions of the oculomotor nerve whereas only the superior division is abnormal in CFEOM1.  Binocular vision is absent and amblyopia is common.  The pupils may be small and respond poorly to light. Refractive errors are common.

Based on visual field testing and ERG findings, it has been suggested that subnormal vision in CFEOM2 may be due to undescribed retinal dysfunction.  

Systemic Features: 

Mild facial muscle weakness may be apparent. 

Genetics

This is an autosomal recessive disorder caused by homozygous mutations in the PHOX2A gene at 11q13.3-q13.4.  Another more common form of CFEOM is the autosomal dominant CFEOM1 type (135700) in which the primary fixed deviation is infraduction. The third type is CFEOM3 (600638, 609384) which is clinically more heterogeneous. 

Other nonsyndromal forms of congenital fibrosis of extraocular muscles include: CFEOM3C (609384), CFEOM5 (616219), and CFEOM with synergistic divergence (609612).  See also Tukel CFEOM syndrome (609428).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Restoration of normal ocular motility is difficult but cosmetic improvement is possible by correcting some of the ptosis with frontalis slings.  Corneal lubrication must be maintained and amblyopia should be treated. 

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

Noonan Syndrome

Clinical Characteristics
Ocular Features: 

Noonan syndrome has prominent anomalies of the periocular structures including downward-slanting lid fissures, hypertelorism, epicanthal folds, high upper eyelid crease, and some limitation of ocular mobility most commonly of the levator.  Ptosis and strabismus are present in nearly half of patients. Amblyopia has been found in one-third of patients and almost 10% have nystagmus.  Corneal nerves are prominent and a substantial number of individuals have optic nerve abnormalities including drusen, hypoplasia, colobomas and myelinated nerves.  Evidence of an anterior stromal dystrophy, cataracts, or panuveitis is seen in a minority of patients.  About 95% of patients have some ocular abnormalities.

Systemic Features: 

Patients are short in stature.  Birth weight and length may be normal but lymphedema is often present in newborns.  The neck is usually webbed (pterygium colli) and the ears low-set.  The sternum may be deformed.  Cardiac anomalies such as coarctation of the aorta, pulmonary valve stenosis, hypertrophic cardiomyopathy, and septal defects are present in more than half of patients.  Dysplasia of the pulmonic valve has been reported as well.  Thrombocytopenia and abnormal platelet function with abnormalities of coagulation factors are found in about 50% of cases resulting in easy bruising and prolonged bleeding.  Cryptorchidism is common in males.  Some patients have intellectual disabilities with speech and language problems.  Most have normal intelligence.   

Parents of affected children often have subtle signs of Noonan Syndrome.

Genetics

This is an autosomal dominant disorder that can result from mutations in at least 8 genes.  Nearly half are caused by mutations in the PTPN11 gene (12q24.1) (163950).  Mutations in the SOS1 gene (2p22-p21) cause NS4 (610733) and account for 10-20% of cases, those in the RAF1 gene (3p25) causing NS5 (611553) for about the same proportion, and mutations in the KRAS gene (12p12.1) (NS3; 609942) cause about 1%.  Mutations in BRAF (7q34) causing NS7 (613706), NRAS (1p13.2) responsible for NS6 (613224), and MEK1 genes have also been implicated and it is likely that more mutations will be found.  The phenotype is similar in all individuals but with some variation in the frequency and severity of specific features.  New mutations are common. 

Several families with autosomal recessive inheritance (NS2) (605275) patterns have been reported with biallelic mutations in LZTR1.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment for most of the developmental problems but some patients benefit from special education. Cardiac surgery may be required in some cases to correct the developmental defects.  Bleeding problems can be treated with supplementation of the defective coagulation factor.  Growth hormone therapy can increase the growth velocity.

References
Article Title: 

Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants

Johnston JJ, van der Smagt JJ, Rosenfeld JA, Pagnamenta AT, Alswaid A, Baker EH, Blair E, Borck G, Brinkmann J, Craigen W, Dung VC, Emrick L, Everman DB, van Gassen KL, Gulsuner S, Harr MH, Jain M, Kuechler A, Leppig KA, McDonald-McGinn DM, Can NTB, Peleg A, Roeder ER, Rogers RC, Sagi-Dain L, Sapp JC, Schaffer AA, Schanze D, Stewart H, Taylor JC, Verbeek NE, Walkiewicz MA, Zackai EH, Zweier C; Members of the Undiagnosed Diseases Network, Zenker M, Lee B, Biesecker LG. Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants. Genet Med. 2018 Oct;20(10):1175-1185.

PubMed ID: 
29469822

Update on turner and noonan syndromes

Chacko E, Graber E, Regelmann MO, Wallach E, Costin G, Rapaport R. Update on turner and noonan syndromes. Endocrinol Metab Clin North Am. 2012 Dec;41(4):713-34. Epub 2012 Sep 28.

PubMed ID: 
23099266

Cataracts, Congenital, Posterior Polar

Clinical Characteristics
Ocular Features: 

Posterior polar cataracts are likely to occur congenitally but there is often a delay in detection until childhood or even adolescence.  Many patients with a late diagnosis develop nystagmus and strabismus.  Opacification usually begins bilaterally as disc-shaped plaques of opacification in the posterior polar region and progresses relatively rapidly to complete opacification.  Some patients require lens surgery in the first year of life while others not until they are young adults.

Systemic Features: 

This type of congenital cataract is not associated with systemic symptoms.

Genetics

Autosomal dominant posterior polar cataracts may result from mutations in the EPHA2 gene located at 1pter-p36.1.  Interestingly, an area with a likely locus adjacent to but outside the coding region of this gene has been associated with age-related cataracts.

This type of lens opacity may be allelic to Volkmann cataract (115665).

Other forms of autosomal dominantly inherited, congenital, progressive lens opacities include congenital cerulean (115660, 601547, 608983, 610202), Coppock-like (604307), and lamellar (116800) cataracts. Due to clinical heterogeneity, it is not always possible to classify specific families based on the appearance and natural history of the lens opacities alone.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Serial monitoring and timely surgery are important for the prevention of amblyopia, strabismus, and nystagmus.

References
Article Title: 

Duane Retraction Syndrome 1

Clinical Characteristics
Ocular Features: 

Duane retraction syndrome is a clinically and genetically heterogeneous condition with a highly variable phenotype.  Most cases occur sporadically but others are familial and about 30% of affected individuals have other congenital anomalies.  It is also seen as part of other syndromes such as Goldenhar (164210), and Wildervanck (314600).  In the absence of other anomalies, it is called isolated Duane syndrome.  In addition, three types with autosomal dominant inheritance have been defined.  The clinical features are highly variable making distinction difficult.  Intrafamilial variation may be less than interfamilial differences.  Patients with type 1 discussed here are more likely to have esotropia with a head turn to the involved side in unilateral cases whereas those with type 2 are considered more likely to have an exotropia with a head turn toward the uninvolved side. 

This is a congenital and non-progressive strabismus syndrome.  Sporadic cases are mostly unilateral while familial ones are more likely to be bilateral.  The essential features are globe retraction upon adduction with narrowing of the lid fissure, and some limitation of abduction. Vertical deviation during adduction is sometimes seen.  Frank strabismus in primary position is evident in as many as 76% of individuals and a compensatory head turn is often adopted but amblyopia still occurs in at least 10% of individuals.  Females are affected more frequently than males.

At one point the syndrome was considered to be a myopathic disorder based on histologic changes in the lateral rectus but current thought based on MRI and neurohistologic studies favors a neuropathic etiology.  The abducens motor neurons and the sixth nerve may be absent or dysplastic.  Branches of the third nerve may also co-innervate the lateral and medial rectus muscles.  EMG studies have documented simultaneous activation of the two muscles which likely accounts for at least some of the globe retraction.  However, hypoplastic muscles, including the superior oblique, superior rectus, and levator, have also been visualized on MRI.

Systemic Features: 

None.

Genetics

Duane syndrome 1 described here follows an autosomal dominant pattern.  No specific mutant gene has been found but a locus has been identified at 8q13.

Individuals having Duane Retraction Syndrome 2 (DURS2) (604356) are often found in autosomal dominant pedigrees also.  Multiple mutations in CHN1 have been found among such individuals.  Pedigrees consistent with autosomal recessive inheritance have also been reported but the responsible genes are unknown.  Duane Retraction Syndrome (DURS3) (617041) patients with mutations in MAFB may have sensorineural hearing loss.

Features of Duane syndrome are also part of the Duane-Radial Ray Syndrome (607323).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Various treatments can be useful, ranging from prisms for mild cases to muscle surgery for a severe head turn or vertical deviations.  Patients should be followed carefully in the first decade of life for the onset of amblyopia and appropriate treatment instituted.  Because of the variability in signs, each patient requires individualized treatment.

References
Article Title: 

Duane Retraction Syndrome 2

Clinical Characteristics
Ocular Features: 

Duane retraction syndrome is a clinically and genetically heterogeneous condition with a highly variable phenotype.  It is a congenital and non-progressive strabismus syndrome.  Most cases occur sporadically but others are familial and about 30% of affected individuals have other congenital anomalies.  It is also seen as part of other syndromes such as Goldenhar (164210), and Wildervanck (314600).  In the absence of other anomalies, it is called isolated Duane syndrome.  Three heritable types with autosomal dominant familial patterns have also been defined.  Patients with type 2 discussed here are more likely to have an exotropia with a head turn toward the uninvolved side when only one eye is involved compared with Duane syndrome type 1 (126800) in which an esotropia with a head turn to the involved side is more common.  However, the clinical features are highly variable although intrafamilial differences may be less than those between families.

Sporadic cases are mostly unilateral while familial ones are more likely to be bilateral.  The essential features are globe retraction upon adduction with narrowing of the lid fissure and some limitation of abduction. Vertical deviation during adduction is sometimes seen.  Frank strabismus in primary position is evident in as many as 76% of individuals and a compensatory head turn is often adopted. Still, amblyopia occurs in at least 10% of individuals.  Females are affected more frequently than males.

At one point the syndrome was considered to be a myopathic disorder based on histologic changes in the lateral rectus but current thought based on MRI and neurohistologic studies favors a neuropathic etiology.  The abducens motor neurons and the sixth nerve may be absent or dysplastic.  Branches of the third nerve may also co-innervate the lateral and medial rectus muscles.  EMG studies have documented simultaneous activation of the two muscles which likely accounts for at least some of the globe retraction.  However, hypoplastic muscles, including the superior oblique, superior rectus, and levator, have also been visualized on MRI.

Systemic Features: 

A variety of skeletal and uroglogic anomalies have been found in association with the ocular findings of Duane syndrome but no consistent pattern has been documented.

Genetics

Familial isolated Duane syndrome 2 individuals usually appear in an autosomal dominant pattern of inheritance caused by a mutation in CHN1 (2q31-q32.1).  The protein products appear to be involved in early neurological development and are critical to the formation of the cranial nerves that innervate the extraocular muscles.

Mutations in CHN1 are usually absent in nonfamilial cases of Duane syndrome.

For other forms of autosomal dominant Duane syndrome, see Duane Retraction Syndrome 1 (126800) and Duane Retraction Syndrome 3 (617041).

Pedigrees consistent with presumed autosomal recessive inheritance have also been reported but the responsible genes are unknown.

Features of Duane syndrome are also part of the Duane-Radial Ray Syndrome (607323).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Various treatments can be useful, ranging from prisms for mild cases to muscle surgery for a severe head turn or vertical deviations.  Patients should be followed carefully in the first decade of life for the onset of amblyopia and appropriate treatment instituted.  Because of the variability in signs, each patient requires individualized treatment.

References
Article Title: 

Apert Syndrome

Clinical Characteristics
Ocular Features: 

In 10% of patients, keratitis and corneal scarring occur from the sometimes marked proptosis and corneal exposure.  Optic atrophy is present in over 20% of patients.  Strabismus, primarily exotropia, is found in more than 70% and various extraocular muscle anomalies may be detectable.  Usually the exotropia has a V-pattern with overaction of the inferior oblique muscles while the superior oblique is weak.  Amblyopia occurs in nearly 20%.  The lid fissures often slant downward and the eyebrows may be interrupted.

Systemic Features: 

This brachysphenocephalic type of acrocephaly is associated with syndactyly in the hands and feet.  Pre- and postaxial polydactyly may be present.  There is considerable variation in expression with some patients so mildly affected that they appear virtually normal, whereas others have extreme degrees of brachycephaly with high foreheads, midface hypoplasia, and proptosis secondary to shallow orbits.  Imaging often reveals one or more CNS anomalies such as defects of the corpus callosum, partial absence of the septum pellucidum, ventriculomegaly, and sometimes hydrocephalus.  A small but significant proportion of patients have some developmental delay and cognitive impairment.  Over 39% of patients have a normal IQ.

Genetics

This type of craniosynostosis is caused by mutations in the fibroblast growth factor receptor-2 gene, FGFR2, located at 10q26.13.  It is generally considered an autosomal dominant disorder based on familial cases but most occur sporadically.  A paternal age effect on mutations has been found.  The same gene is mutant in allelic disorders sometimes clinically separated and labeled Crouzon (123500) and Pfeiffer (some cases) (101600) syndromes.  Jackson-Weiss syndrome (123150) maps to the same locus.  However, this entire group has many overlapping features making classification on clinical grounds alone difficult.  Only Apert syndrome is caused by mutations in a single gene whereas other syndromes seem to result from mutations in multiple genes.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No specific treatment is available for this disorder but exposure keratitis may require surveillance and therapy.

References
Article Title: 
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