CDH3

EEM Syndrome

Clinical Characteristics
Ocular Features: 

Granular pigmentation and a grayish coloration of the retina may be present.  The peripheral retina usually appears normal but the posterior pole and macula have pigmentary changes consisting of clumping and geographic atrophy.  Fluorescein angiography shows patchy areas of hyperfluorescence.  Patients in their 30s have been reported to have normal ERGs in one study.  Reduced acuity can be noted in the first decade but progression is slow.  Acuity levels in the 20/200 range may be seen in the fourth decade of life. 

Systemic Features: 

Ectodermal dysplasia with ectrodactyly and syndactyly are prominent features of this syndrome.  Hypotrichosis of the scalp, eyebrows and eyelashes is often seen.  Partial anodontia and diastema are also features.  Syndactyly of the toes is present more frequently than found among the fingers. 

Genetics

This is an autosomal recessive disorder resulting from mutations in the CDH3 gene (16q22.1).

EEM syndrome is allelic to the Hypotrichosis with Macular Dystrophy syndrome (601553).  However, the latter lacks the dental, limb, and digital anomalies as well as the hypotrichosis of eyebrows and eyelashes.  

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for this disease. 

References
Article Title: 

Hypotrichosis with Juvenile Macular Degeneration

Clinical Characteristics
Ocular Features: 

Macular dystrophy usually becomes symptomatic before the second decade of life but retinal evidence of macular degeneration can be seen in the first decade.   EOG is usually normal while the ERG responses are decreased early and with time decrease further in amplitude.  Pattern reversal VEPs are significantly subnormal even while vision is relatively good.  Visual acuity decreases slowly in spite of significant deterioration of cone- and rod-mediated retinal function.  Retinal pigmentary changes consisting of irregular clumping and areas of hypopigmentation are evident in the macular and perimacular areas and sometimes beyond.  Most patients eventually become blind. 

Systemic Features: 

Scalp hair loss occurs during the first months of life but the alopecia does not affect eyebrows or eyelashes unlike that seen in the EEM disorder (225280)  which in addition has digital and dental anomalies.  Partial regrowth may occur during puberty.  Light and electron microscopy of hair shafts may reveal pili torti, longitudinal ridging with scaling, and fusiform beading but these are not present in all patients. 

Genetics

This is an autosomal recessive disorder resulting from homozygous mutations in the CDH3 gene located at 16q22.1.

EEM syndrome (225280) is an allelic disorder with similar hair and retinal features plus dental, digital and limb anomalies.  The hypotrichosis also involves the eyebrows and eyelashes in this disorder, however. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no known treatment for this disorder. 

References
Article Title: 

Usher Syndrome Type I

Clinical Characteristics
Ocular Features: 

The fundus dystrophy of retinitis pigmentosa in Usher syndrome is indistinguishable from isolated retinitis pigmentosa.   Night blindness begins by about 10 years of age and the ERG by that time is often markedly diminished or absent.  Patches of hyperfluorescence are seen in younger individuals and these enlarge and coalesce with age.  Tunnel vision occurs early as the peripheral visual field is constricted to 5-10 degrees by midlife.  The retinal disease is progressive and blindness may be the final result.

Systemic Features: 

Type I Usher syndrome is characterized by profound hearing impairment beginning at birth, vestibular dysfunction, and unintelligible speech in addition to retinitis pigmentosa.  Vestibular areflexia is virtually complete and constitutes a defining feature.  Ataxic gait disturbances are common secondary to labyrinthine dysfunction and many children do not walk until 18-24 months of age.  Sitting alone may also be delayed.  Sperm motility is abnormal which is likely the basis for reduced fertility in male patients.  An abnormal exoneme morphology from ciliated progenitors is likely the common basis for these clinical findings.  MRI imaging has found a significant decrease in intracranial volume and brain size.  About 1 in 4 children have behavioral problems or psychosocial difficulties.

Genetics

Type I Usher syndrome is an autosomal recessive genetically heterogeneous disorder as mutations in at least 8 genes produce a similar disease.  These are: MYO7A (276900) at 11q13.5 causing USH1B (USH1A is now considered to be the same), USH1C at 11p15.1 causing USH1C (276904), CDH23 at 10q21-q22, causing USH1D (601067), PCDH15 at 10q21.1 causing USH1F (602083), and USH1G at 17q24-25 causing USH1G (606943).  Mutations in as yet unnamed genes in loci at 21q21 (USH1E; 602097), 10p11.21-q21.1 (USH1K), and 15q22-q23 (USH1H; 612632) may also cause this type I phenotype. They are discussed here as a single entity designated type I since the clinical features of each are indistinguishable.'

A varant of USH1C resulting from homozygous deletions in 11p15-p14, known as homozygous 11p15-p14 deletion syndrome, has the additional feature of severe hyperinsulinemia due to the involvement of ABCC8 and KCNJ11 genes (606528).

Clinical differences have led to the categorization of three types of Usher syndrome:  type I described here, type II (276901) caused by mutations in at least 4 genes, and type III (276902) caused by mutations in CLRN1.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

At-risk infants should have hearing evaluations as soon as possible after birth.  Assistive hearing devices are of little benefit.  Unless cochlear implants are placed in young children, speech may not develop.  Extra precautions during physical activities such as swimming, bicycling, and night-time driving are highly recommended. Speech therapy and low vision aids can be beneficial.

References
Article Title: 

Targeted exon sequencing in Usher syndrome type I

Bujakowska KM, Consugar MB, Place E, Harper S, Lena J, Taub DG, White J, Navarro-Gomez D, Weigel-DiFranco C, Farkas MH, Gai X, Berson EL, Pierce EA. Targeted exon sequencing in Usher syndrome type I. Invest Ophthalmol Vis Sci. 2014 Dec 2.  [Epub ahead of print].

PubMed ID: 
25468891

Heterogeneity in Phenotype of Usher-Congenital Hyperinsulinism Syndrome: Hearing Loss, Retinitis Pigmentosa, and Hyperinsulinemic Hypoglycemia Ranging from Severe to Mild with Conversion to Diabetes

Al Mutair AN, Brusgaard K, Bin-Abbas B, Hussain K, Felimban N, Al Shaikh A, Christesen HT. Heterogeneity in Phenotype of Usher-Congenital Hyperinsulinism Syndrome: Hearing Loss, Retinitis Pigmentosa, and Hyperinsulinemic Hypoglycemia Ranging from Severe to Mild with Conversion to Diabetes. Diabetes Care. 2012 Nov 12. [Epub ahead of print].

PubMed ID: 
23150283
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