title: Characterization of CDH3-Related Congenital Hypotrichosis With Juvenile Macular Dystrophy.
abstract: OBJECTIVE
  Congenital hypotrichosis with juvenile macular dystrophy (HJMD) is a rare disorder presenting in childhood and adolescence with central visual disturbance and sparse scalp hair. Reported retinal imaging is lacking, and whether the condition is progressive remains unclear.
  
  
  OBJECTIVE
  To investigate a series of patients with HJMD due to biallelic mutations in CDH3 and thereby characterize the disorder.
  
  
  METHODS
  Ten patients from 10 families underwent detailed clinical assessment, including serial retinal imaging and electrophysiologic evaluation, at Moorfields Eye Hospital, St James's University Hospital, and Calderdale Royal Infirmary. Patients ranged in age from 3 to 17 years at onset and 5 to 57 years at last assessment. The molecular genetic investigation included bidirectional Sanger sequencing of all exons and intron-exon boundaries of CDH3 and whole-exome sequencing in 2 patients. The study was conducted from June 5, 2013, to January 15, 2016, with final follow-up completed on December 15, 2015.
  
  
  METHODS
  Results of clinical assessment and molecular genetic testing.
  
  
  RESULTS
  All 10 patients (7 male and 3 female) presented with central visual disturbance in childhood and had lifelong sparse scalp hair with normal facial hair. Fundus examination revealed chorioretinal atrophy of the posterior pole contiguous with the disc in all but 1 patient that was associated with marked loss of autofluorescence on fundus autofluorescence imaging. Optical coherence tomography (OCT) demonstrated variable degrees of atrophy of the outer retina, retinal pigment epithelium, and choroid, with outer retinal tubulations frequently observed. One patient had mild disruption of the inner segment ellipsoid band on OCT and additional mild digit abnormalities. Electrophysiologic evaluation in 5 patients demonstrated macular dysfunction with additional mild, generalized retinal dysfunction in 2 patients. Eight patients had more than 1 evaluation; of these, 5 patients showed deterioration of visual acuity over time, 1 patient remained stable, and 2 patients had severe visual loss at presentation that precluded assessment of visual deterioration. The area of atrophy did not progress with time, but retinal thickness decreased on OCT. Electrophysiologic evaluation in 1 patient found deterioration of macular function after 13 years of follow-up, but the mild, generalized photoreceptor dysfunction remained stable. Biallelic mutations were identified in all patients, including 6 novel mutations.
  
  
  CONCLUSIONS
  These results suggest that CDH3-related disease is characterized by a childhood-onset, progressive chorioretinal atrophy confined to the posterior pole. The disease is readily distinguished from other juvenile macular dystrophies by the universally thin and sparse scalp hair. Patients may have additional limb abnormalities.
authors.affiliation: UCL (University College of London) Institute of Ophthalmology, London, England2Moorfields Eye Hospital, London, England.
authors.forename: Sarah
authors.initials: S
authors.lastname: Hull
authors.affiliation: UCL (University College of London) Institute of Ophthalmology, London, England2Moorfields Eye Hospital, London, England.
authors.forename: Gavin
authors.initials: G
authors.lastname: Arno
authors.affiliation: UCL (University College of London) Institute of Ophthalmology, London, England2Moorfields Eye Hospital, London, England.
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Robson
authors.affiliation: Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, England.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Broadgate
authors.affiliation: UCL Genetics Institute, London, England.
authors.forename: Vincent
authors.initials: V
authors.lastname: Plagnol
authors.affiliation: Department of Ophthalmology, St James's University Hospital, Leeds, England.
authors.forename: Martin
authors.initials: M
authors.lastname: McKibbin
authors.affiliation: Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, England.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Halford
authors.affiliation: UCL (University College of London) Institute of Ophthalmology, London, England2Moorfields Eye Hospital, London, England.
authors.forename: Michel
authors.initials: M
authors.lastname: Michaelides
authors.affiliation: UCL (University College of London) Institute of Ophthalmology, London, England2Moorfields Eye Hospital, London, England.
authors.forename: Graham E
authors.initials: GE
authors.lastname: Holder
authors.affiliation: UCL (University College of London) Institute of Ophthalmology, London, England2Moorfields Eye Hospital, London, England6Department of Ophthalmology, University of California, San Francisco, Medical Center.
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Moore
authors.affiliation: UCL (University College of London) Institute of Ophthalmology, London, England2Moorfields Eye Hospital, London, England5Department of Ophthalmology, St James's University Hospital, Leeds, England.
authors.forename: Kamron N
authors.initials: KN
authors.lastname: Khan
authors.affiliation: UCL (University College of London) Institute of Ophthalmology, London, England2Moorfields Eye Hospital, London, England.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Webster
mesh_terms: D000293:Adolescent; D000328:Adult; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D018450:Disease Progression; D004596:Electroretinography; D005260:Female; D005451:Fluorescein Angiography; D005654:Fundus Oculi; D006801:Humans; D007039:Hypotrichosis / Q000151:congenital* / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism; D008268:Macular Degeneration / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D012160:Retina; D055213:Retinal Pigment Epithelium / Q000473:pathology*; D041623:Tomography, Optical Coherence; D014792:Visual Acuity; D055815:Young Adult
chemical_list: C512197:CDH3 protein, human; D015820:Cadherins; D004247:DNA