enophthalmos

Nanophthalmos 3

Clinical Characteristics
Ocular Features: 

A six generation Chinese family has been reported in which 12 affected members had small eyes, ptosis, apparent enophthalmos, shallow anterior chambers, and small corneas.  Hyperopic refractive errors ranged from +6.00 to +11.25 (mean +8.25).  

Systemic Features: 

None reported.

Genetics

The transmission pattern for this 6 generation family strongly suggests autosomal dominant inheritance.  No mutation has been identified but the 2q11-14 locus is strongly associated with the phenotype.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Treatment has not been reported but monitoring for narrow angle glaucoma is advised.

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

Leber Congenital Amaurosis

Clinical Characteristics
Ocular Features: 

Leber congenital amaurosis is a collective term applied to multiple recessively inherited conditions with early-onset retinal dystrophy causing infantile or early childhood blindness.  There are no established diagnostic criteria.  First signs are usually noted before the age of 6 months.  These consist of a severe reduction in vision accompanied by nystagmus, abnormal pupillary responses, and photophobia.  Ametropia in the form of hyperopia is common.  Keratoconus (and keratoglobus) is frequently found in older children but it is uncertain if this is a primary abnormality or secondary to eye rubbing as the latter is commonly observed.  Repeated pressure on the eye may also be responsible for the relative enophthalmos often seen in these patients.  The ERG is reduced or absent early and permanently.  Final visual acuity is seldom better than 20/400 and perhaps one-third of affected individuals have no light perception.  Some individuals experience a period of vision improvement.

The retina usually has pigmentary changes but these are not diagnostic.  Retinal vessels are generally attenuated.  The RPE may have a finely granulated appearance or, in some cases, whitish dots, and even 'bone spicules'.

Systemic Features: 

A variety of metabolic and physical abnormalities have been reported with LCA but many publications are from the pre-genomic era and the significance of such associations remains uncertain.  Most extraocular signs result from delays in mental development but it is uncertain what role, if any, that visual deprivation plays.  Perhaps 20% of patients are mentally retarded or have significant cognitive deficits.

Genetics

Leber congenital amaurosis is genetically heterogeneous with at least 18 known gene mutations associated with the phenotype.  It is also clinically heterogeneous both within and among families and this is the major obstacle to the delineation of individual clinicogenetic entities.  As more patients are genotyped, it is likely that more precise genotype-phenotype correlations will emerge.  At the present time, however, it is not possible to use clinical findings alone to distinguish individual conditions.

Below are links to the genotypic and phenotypic features of the 19 known types of LCA.  All cause disease in the homozygous or compound heterozygous state. 

LCA type               OMIM#                 Locus              Gene Symbol   

LCA 1                    204000                 7p13.1                 GUCY2D

LCA 2                    204100                 1p31                    RPE65**

LCA 3                    604232                 14q31.3               SPATA7

LCA 4                    604393                 17p13.1               AIPL1

LCA 5                    604537                 6q14.1                 LCA5

LCA 6                    613826                 14q11                  RPGRIP1

LCA 7                    613829                19q13.1                CRX*

LCA 8                    613835                 1q31-q32             CRB1

LCA 9                    608553                 1p36                    NMNAT1

LCA 10                  611755                 12q21                  CEP290

LCA 11                  613837                 7q31.3-q332        IMPDH1

LCA 12                  610612                 1q32.3                 RD3

LCA 13                  612712                 14q24.1               RDH12

LCA 14                  613341                 4q31                    LRAT

LCA 15                  613843                 6p21-31              TULP1

LCA 16                  614186                 2q37                    KCNJ13

LCA 17                  615360                 8q22.1                 GDF6

LCA 18                  608133                 6p21.1                 PRPH2***

It is likely that more mutant genes will be identified since these are found in only about half of patients studied in large series.  

*(Heterozygous mutations in CRX may also cause a cone-rod dystrophy).

**(Mutations in RPE65 has been described as also causing retinitis pigmentosa (RP20; 613794)  with choroidal involvement.)

***Mutations in PRPH2 (RDS) has also been reported to cause retinitis pigmentosa 7, choroidal dystrophy, and vitelliform macular dystrophy (179605) among others.

See also Leber Congenital Amaurosis with Early-Onset Deafness.

Mutations in the GUCY2D gene seem to be the most common being present in about 21% of LCA patients with CRB1 next at 10%.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Until recently, no treatment was available for LCA.  However, results from early clinical trials with adeno-associated virus vector mediated gene therapy for RPE65 mutations in LCA 2 show promise.  Subretinal placement of recombinant  adeno-virus carrying RPE65 complementary DNA results in both subjective and objective improvements in visual function.  Patients generally report subjective improvement in light sensitivity and visual mobility.  Some recovery of rod and cone photoreceptor function has been documented.  Studies have also documented an improvement in visual acuity, size of visual field, pupillary responses, and in the amouunt of nystagmus.  More than 230 patients have now  been treated and improvements seem to be maintained for at least 3 or more years.  However, we have also learned that along with the enzymatic dysfunction of RPE65 that disrupts the visual cycle, there is also degeneration of photoreceptors which continues after treatment and the long term prognosis remains guarded. Multiple phase I clinical trials have demonstrated the safety of this approach and phase III trials are now underway.

It is crucial for patients to be enrolled early in sensory stimulation programs to ensure optimum neural development.  For patients with residual vision, low vision aids can be beneficial.  Vocational and occupational therapy should be considered for appropriate patients.

References
Article Title: 

Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease

Koenekoop RK, Wang H, Majewski J, Wang X, Lopez I, Ren H, Chen Y, Li Y,
Fishman GA, Genead M, Schwartzentruber J, Solanki N, Traboulsi EI, Cheng J, Logan
CV, McKibbin M, Hayward BE, Parry DA, Johnson CA, Nageeb M; Finding of Rare
Disease Genes (FORGE) Canada Consortium, Poulter JA, Mohamed MD, Jafri H, Rashid
Y, Taylor GR, Keser V, Mardon G, Xu H, Inglehearn CF, Fu Q, Toomes C, Chen R.
Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease
pathway for retinal degeneration. Nat Genet. 2012 Jul 29.
 

PubMed ID: 
22842230

A dominant mutation in RPE65 identified by whole-exome sequencing causes retinitis pigmentosa with choroidal involvement

Bowne SJ, Humphries MM, Sullivan LS, Kenna PF, Tam LC, Kiang AS, Campbell M, Weinstock GM, Koboldt DC, Ding L, Fulton RS, Sodergren EJ, Allman D, Millington-Ward S, Palfi A, McKee A, Blanton SH, Slifer S, Konidari I, Farrar GJ, Daiger SP, Humphries P. A dominant mutation in RPE65 identified by whole-exome sequencing causes retinitis pigmentosa with choroidal involvement. Eur J Hum Genet. 2011 Oct;19(10):1074-81. Erratum in: Eur J Hum Genet. 2011 Oct;19(10):1109.

PubMed ID: 
21654732

Treatment of leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial

Hauswirth WW, Aleman TS, Kaushal S, Cideciyan AV, Schwartz SB, Wang L, Conlon TJ, Boye SL, Flotte TR, Byrne BJ, Jacobson SG. Treatment of leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial. Hum Gene Ther. 2008 Oct;19(10):979-90.

PubMed ID: 
18774912

Effect of gene therapy on visual function in Leber's congenital amaurosis

Bainbridge JW, Smith AJ, Barker SS, Robbie S, Henderson R, Balaggan K, Viswanathan A, Holder GE, Stockman A, Tyler N, Petersen-Jones S, Bhattacharya SS, Thrasher AJ, Fitzke FW, Carter BJ, Rubin GS, Moore AT, Ali RR. Effect of gene therapy on visual function in Leber's congenital amaurosis. N Engl J Med. 2008 May 22;358(21):2231-9.

PubMed ID: 
18441371

Leber congenital amaurosis

Perrault I, Rozet JM, Gerber S, Ghazi I, Leowski C, Ducroq D, Souied E, Dufier JL, Munnich A, Kaplan J. Leber congenital amaurosis. Mol Genet Metab. 1999 Oct;68(2):200-8. Review.

PubMed ID: 
10527670
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