chorioretinal dysplasia

Chorioretinopathy with Microcephaly 3

Clinical Characteristics
Ocular Features: 

The eyes are not notably small although several patients have been reported to have significant hyperopia.  Vision can be impaired and some individuals have early-onset nystagmus.  The ERG responses are attenuated and may be absent.  The retina is dysplastic with multiple atrophic punched-out lesions, attenuated retinal vessels, and sparse pigmentation. Large retinal folds have been described and one patient developed a retinal detachment.  Optic atrophy was noted in one individual.

Systemic Features: 

Microcephaly of 3-4 standard deviations below normal is a constant feature.  Motor and language abilities can be mildly delayed and  several patients have had mild learning difficulties.   Brain imaging has been normal in most individuals but a shortened and thin corpus callosum was present in one patient.

Genetics

Family and genetic evidence suggest autosomal recessive inheritance.  Compound heterozygous mutations in the TUBGCP4 gene (15q15.3) code for part of a protein complex involved in microtubule organization.

For a somewhat similar condition with a different mutation involving the same microtubule complex see Chorioretinopathy with Microcephaly 1 (251270).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Low vision aids may be helpful in selected patients.

References
Article Title: 

Mutations in TUBGCP4 Alter Microtubule Organization via the γ-Tubulin Ring Complex in Autosomal-Recessive Microcephaly with Chorioretinopathy

Scheidecker S, Etard C, Haren L, Stoetzel C, Hull S, Arno G, Plagnol V, Drunat S, Passemard S, Toutain A, Obringer C, Koob M, Geoffroy V, Marion V, Strahle U, Ostergaard P, Verloes A, Merdes A, Moore AT, Dollfus H. Mutations in TUBGCP4 Alter Microtubule Organization via the g-Tubulin Ring Complex in Autosomal-Recessive Microcephaly with Chorioretinopathy. Am J Hum Genet. 2015 Apr 2;96(4):666-74.

PubMed ID: 
25817018

Chorioretinal dysplasia, lymphedema, and microcephaly

Clinical Characteristics
Ocular Features: 

The congenital lymphedema results in thickened and ptotic eyelids with prominent epicanthal folds.  Congenital ptosis is not uncommon in the general population in the absence of lymphedema so that this feature by itself is insufficient to diagnose this syndrome.  Retinal folds with variable degrees of pigmentary changes are often present.  Narrowed retinal vessels, atrophic nerve heads and progressive chorioretinopathy have been reported.  Visual acuity is often reduced, sometimes severely, and nystagmus may be present.

Systemic Features: 

Coarse hair follicles over the dorsum of the hands and feet and white nails when combined with the thickened, ptotic eyelids suggest the presence of lymphedema.  The hair pattern is often altered on the arms, nape of the neck, and the back.  White lines in the palms are also suggestive.  The 'facial phenotype' includes full cheeks, flat nasal bridge and underdeveloped supraorbital ridges, up slanting palpebral fissures, broad nose with rounded tip, anteverted nares, and a long philtrum, thin upper lip, and sometimes micrognathia. The ears may appear large.  Children with this syndrome are often hypotonic during the newborn period but this feature is less evident later in childhood and improves more rapidly than the resolution of the lymphedema. The lymphedema usually improves during early childhood and is often confined to the dorsum of the hands and feet at that time.  Psychomotor development is variably delayed and some but not all patients are mentally retarded. Microcephaly is a consistent feature.

Not all features are present in all patients and, specifically, there are often microcephalic relatives who lack other signs.

Genetics

This is an autosomal dominant disorder which may consist of more than one entity but at least some cases result from heterozygous mutations in KIF11 (10q23.33).  The gene encodes a member of the kinesin family of proteins responsible for cytoplasmic mechanisms that are essential for spindle assembly and function as well in transportation of other intracellular organelles.  Mutations in this gene have also been implicated in familial exudative vitreoretinopathy (FEVR) and there is phenotypic overlap with the condition described here.

It is not unusual for microcephalic individuals to also have chorioretinal dysplasia and/or pigmentary retinopathy.  See microcephaly, chorioretinal dysplasia, mental retardation (156590), for a somewhat similar autosomal dominant condition, as well as microcephaly with chorioretinopathy, AR (251270) for an autosomal recessive condition with this combination.  Neither of these conditions is associated with congenital lymphedema, however.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 

Phenotypic Overlap Between Familial Exudative Vitreoretinopathy and Microcephaly, Lymphedema, and Chorioretinal Dysplasia Caused by KIF11 Mutations

Robitaille JM, Gillett RM, LeBlanc MA, Gaston D, Nightingale M, Mackley MP, Parkash S, Hathaway J, Thomas A, Ells A, Traboulsi EI, Heon E, Roy M, Shalev S, Fernandez CV, MacGillivray C, Wallace K, Fahiminiya S, Majewski J, McMaster CR, Bedard K. Phenotypic Overlap Between Familial Exudative Vitreoretinopathy and Microcephaly, Lymphedema, and Chorioretinal Dysplasia Caused by KIF11 Mutations. JAMA Ophthalmol. 2014 Aug 14.

PubMed ID: 
25124931

Microcephaly with or without chorioretinopathy, lymphoedema, or mental retardation (MCLMR): review of phenotype associated with KIF11 mutations

Jones GE, Ostergaard P, Moore AT, Connell FC, Williams D, Quarrell O, Brady AF, Spier I, Hazan F, Moldovan O, Wieczorek D, Mikat B, Petit F, Coubes C, Saul RA, Brice G, Gordon K, Jeffery S, Mortimer PS, Vasudevan PC, Mansour S. Microcephaly with or without chorioretinopathy, lymphoedema, or mental retardation (MCLMR): review of phenotype associated with KIF11 mutations. Eur J Hum Genet. 2013 Nov 27.  [Epub ahead of print).

PubMed ID: 
24281367

Mutations in KIF11 Cause Autosomal-Dominant Microcephaly Variably Associated with Congenital Lymphedema and Chorioretinopathy

Ostergaard P, Simpson MA, Mendola A, Vasudevan P, Connell FC, van Impel A, Moore AT, Loeys BL, Ghalamkarpour A, Onoufriadis A, Martinez-Corral I, Devery S, Leroy JG, van Laer L, Singer A, Bialer MG, McEntagart M, Quarrell O, Brice G, Trembath RC, Schulte-Merker S, Makinen T, Vikkula M, Mortimer PS, Mansour S, Jeffery S. Mutations in KIF11 Cause Autosomal-Dominant Microcephaly Variably Associated with Congenital Lymphedema and Chorioretinopathy. Am J Hum Genet. 2012 Jan 24. [Epub ahead of print].

PubMed ID: 
22284827

Chorioretinopathy with Microcephaly 1

Clinical Characteristics
Ocular Features: 

The ocular features have not been well described.  Small corneas, hyperopia, pale optic nerves and a variety of pigmentary changes in the retina have been reported.  The latter may consist of diffuse, fine or granular pigmentary changes.  Areas of pigmentary atrophy are often associated with patchy areas of pigmentary clumping.  These changes are usually located posterior to the equator.  Choroidal vessels may be sparse where the RPE is absent.  It has been suggested that the patchy pattern of retinal pigmentation resembles ocular toxoplasmosis.  Strabismus is common.  One report suggests microphthalmos in a patient.  Vision has been reported as subnormal from the first year of life but no quantitative data are available.

Systemic Features: 

Microcephaly is a consistent feature.  The forehead is steeply sloped but facial size appears normal.  The palate is highly arched.  Patients often have hyperactive deep tendon reflexes and walk with a shuffling gait.  Children are often hyperactive and highly social.  Intelligence quotients are usually subnormal. No lymphedema has been reported.  At least some patients have cutis marmorata.

On MRI diffuse pachygryria is seen.  The vermis is hypoplastic and the surface area of the corpus callosum is reduced to half of normal. 

Genetics

 Parental consanguinity was present in two reported families and pedigrees are consistent with autosomal recessive inheritance with homozygous mutations of TUBGCP6 (22p22) responsible.

This presumed recessive disorder appears to be different than the autosomal dominant disorder of lymphedema, microcephaly, and chorioretinal dysplasia  (MCLMR) (152950) although molecular confirmation is lacking.

For somewhat similar disorder see Chorioretinopathy with Microcephaly 2 (616171).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment is supportive.

References
Article Title: 

Genetic mapping and exome sequencing identify variants associated with five novel diseases

Puffenberger EG, Jinks RN, Sougnez C, Cibulskis K, Willert RA, Achilly NP, Cassidy RP, Fiorentini CJ, Heiken KF, Lawrence JJ, Mahoney MH, Miller CJ, Nair DT, Politi KA, Worcester KN, Setton RA, Dipiazza R, Sherman EA, Eastman JT, Francklyn C, Robey-Bond S, Rider NL, Gabriel S, Morton DH, Strauss KA. Genetic mapping and exome sequencing identify variants associated with five novel diseases. PLoS One. 2012;7(1):e28936. Epub 2012 Jan 17. PubMed PMID: 22279524.

PubMed ID: 
22279524

Chorioretinal dysplasia, microcephaly, and mental retardation

Clinical Characteristics
Ocular Features: 

The ocular phenotype has not been well defined in this condition since few families have been reported.  Microphthalmia is present in some patients.  The corneas may be small and there is often some conjunctival growth over the limbus.

The retinal features consist of lacunar depigmentation of the RPE and in some cases resemble the lesions of congenital toxoplasmosis.  Eighty to 90 per cent of patients have areas of atrophic and dysplastic-appearing lesions of the retina and choroid with vascular attenuation.  The edges of lacunae may have patchy hyperpigmentation.  These lesions are usually static but may show mild progression.  Visual acuity is generally stable or only mildly progressive.  However, other patients have a severe reduction in acuity.  ERG responses are reduced.

Systemic Features: 

The amount of microcephaly may be minimal and at least some patients have 'bulging' foreheads.  The amount of mental deficiency varies from mild to severe.  IQ levels are generally in the range of 60-70.   Hypotonia has been reported in more severe cases.  Skull size is usually 2-3 standard deviations below the mean and generally has some frontal prominence.

Genetics

This seems to be an autosomal dominant disorder although no loci or mutations have been identified.  It is likely that the category of disease known as microphthalmia-chorioretinal syndrome consists of a heterogeneous group of disorders.  No locus or specific mutation has been identified.

It differs from the microcephaly, lymphedema, chorioretinopathy syndrome (152950) in which retinal folds, ptosis and lymphedema are associated with a typical facial phenotype.  For other disorders in this database having a somewhat similar phenotype see: chorioretinopahty and microcephaly type 1 (251270) and type 2 (616171).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Treatment is supportive.  Low vision aids may be helpful.

References
Article Title: 

Aicardi Syndrome

Clinical Characteristics
Ocular Features: 

A variety of chorioretinal lesions have been described in Aicardi syndrome including lacunae ('holes') in 88%, and choroid plexus papillomas which are considered specific and characteristic.  These tend to be more common in the posterior pole. They are stable and do not enlarge.  They can usually be distinguished from post-infection scars by the absence of pigmentation.  A bull's eye maculopathy may be present.  Optic nerve colobomas (in 42%) and hypoplasia have been reported.   At least 61% of eyes have some optic nerve abnormalities.  Presumed microphthalmia has been noted in 25% of patients. A minority of patients have a persistent pupillary membrane.  Sparse lateral eyebrows have also been reported with .

There is evidence that the primary molecular defect involves Bruch's membrane resulting in damage to the RPE.

Congenital glaucoma has been diagnosed in several patients.

Systemic Features: 

Patients with Aicardi syndrome are considered to have a characteristic facial phenotype with a prominent premaxilla, upturned nasal tip, and decreased angle of the nasal bridge.  Several patients have been reported with vertebral anomalies as well as cleft lip and palate.  The most severe symptoms including infantile spasms, developmental delay, and seizures are the result of a generalized neuronal migration disorder evident on MRI as polymicrogyria, periventricular heterotopia, and various malformations of the corpus callosum.  The latter structure is absent in 72% of patients.  Intracranial cysts and cerebellar dysplasia have been reported in 95% of patients.  MRI of the brain often shows asymmetry and unilateral microphthalmia is often present on the side of the more severe brain lesions.  Most individuals have some intellectual disabilities and do not live beyond childhood.

Genetics

Since virtually all reported cases have been female this is considered to be a dominant X-linked disorder with lethality in hemizygous males.  The presumed locus is at Xp22 although no specific gene mutation has been identified. Interestingly, several affected XXY (Klinefelter syndrome) males have been reported which is consistent with the most likely mode of inheritance.  It has been proposed that the majority of cases results from new mutations since familial cases are exceedingly rare.

Aicard-Goutieres syndromes are separate disorders.

Pedigree: 
X-linked dominant, father affected
X-linked dominant, mother affected
Treatment
Treatment Options: 

No treatment is available for the syndrome.  However, specific features such as congenital glaucoma may require treatment.

References
Article Title: 

Laterality of brain and ocular lesions in aicardi syndrome

Cabrera MT, Winn BJ, Porco T, Strominger Z, Barkovich AJ, Hoyt CS, Wakahiro M, Sherr EH. Laterality of brain and ocular lesions in aicardi syndrome. Pediatr Neurol. 2011 Sep;45(3):149-54. PubMed PMID: 21824560.

PubMed ID: 
21824560

Neuroimaging aspects of Aicardi syndrome

Hopkins B, Sutton VR, Lewis RA, Van den Veyver I, Clark G. Neuroimaging aspects of Aicardi syndrome. Am J Med Genet A. 2008 Nov 15;146A(22):2871-8.

PubMed ID: 
18925666
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