Author Affiliations: Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital (Drs Halford, Holt, Németh, and Downes), Department of Clinical Genetics, Churchill Hospital (Dr Németh), and Oxford Eye Hospital (Dr Downes), Oxford, England.
Hypotrichosis associated with juvenile macular dystrophy (HJMD; OMIM 601553) is a rare autosomal recessive disorder characterized by short scalp hair from birth and progressive macular degeneration. Loss of central vision usually occurs between the second and fourth decades of life. Mutations in the P-cadherin gene (CDH3 ; GenBank NM_001793) were first reported to underlie HJMD by Sprecher et al1; splice, missense, and nonsense mutations have since been described.2- 5
A 48-year-old man had a 21-year history of deterioration of central vision. The original diagnosis was Stargardt disease. Initial symptoms at age 17 years included photosensitivity, abnormal color vision, and central scotomata. His sister has the same phenotype and the parents were likely to be related. The proband and his sister both gave a history of having very fine, sparse hair that never thickened, with a persistently visible scalp (Figure 1A). Funduscopy in the proband revealed bilateral symmetrical macular degeneration with sparing of the peripheral retina (Figure 1B and C). Visual acuities were 6/760 OD and 6/96 OS. Goldmann visual field testing showed bilateral central scotomata (Figure 1D). Electrophysiology showed extinguished pattern electroretinograms, normal scotopic responses, and significant reduction in amplitudes of both a and b waves in the standard flash electroretinogram and photopic responses. The electro-oculogram light rise was normal in both eyes.
Figure 1. Clinical spectrum of the patient with hypotrichosis associated with juvenile macular dystrophy. A, Sparse hair in the proband at age 48 years. B, Color fundus photograph showing macular degeneration. C, Color fundus photograph of the same eye showing degeneration confined to the macular and peripapillary regions, sparing the mid and peripheral retina. D, Left visual field showing extensive central scotoma (the findings are similar in the right eye).
The phenotype prompted us to undertake mutation screening of CDH3, which comprises 16 exons spanning approximately 55 kilobases of genomic DNA (Figure 2A). Exons 1 through 11 and 14 through 16 were successfully amplified using primers as described by Kjaer et al.6 No nucleotide changes were detected by sequencing. Failure to amplify exons 12 and 13 in the patient, compared with a control, led us to speculate that there could be a small intragenic deletion. Primers located in introns 11 and 14 amplified a 1607–base pair (bp) fragment from the patient, the expected size being 10 422 bp. Sequencing confirmed a homozygous deletion of 8815 bp in both siblings with break points in introns 11 and 13 resulting in loss of exons 12 and 13 (Figure 2A and B). Further examination of the region showed a 34-bp repeat (differing by only 1 bp) flanking the break points, suggesting homologous recombination as the mechanism for generating this deletion. The predicted result of this deletion would be that exon 11 splices directly to exon 14 and remains in frame, resulting in a protein of 685 amino acids, compared with the wild-type protein of 829 amino acids (Figure 2E). This was confirmed using complementary DNA from patient and control lymphocytes and sequencing the products (Figure 2C and D).
Figure 2. Mutation screening. A, Schematic diagram of the genomic structure of CDH3. Boxes indicate exons; lines, introns; and bp, base pairs. All are to scale except for regions of intronic DNA larger than 1 kilobase, which are represented as slashed lines. Exon and intron sizes are marked, as are the start and stop codons. The exons encoding the calcium-binding domains are shaded blue. B, Sequence of the deletion break point showing intron 11 spliced directly to intron 13 (not present in the Database of Genomic Variants). C, Expression of CDH3 in lymphocytes from the patient and a control by reverse transcription–polymerase chain reaction amplification of RNA using gene-specific primers spanning the junctions of exons 10 and 11 (forward) and 14 and 15 (reverse); human retinal complementary DNA was used as a control. The wild-type fragment should be 729 bp; the fragment amplified from the patient is 297 bp, lacking the 432 bp from exons 12 and 13. Lane 1 is the marker; 2, patient with reverse transcriptase; 3, patient without reverse transcriptase; 4, control with reverse transcriptase; 5, control without reverse transcriptase; 6, human retinal complementary DNA; 7, human genomic DNA; and 8, no-template control. D, Confirmation by sequence analysis. E, The domain structure of P-cadherin is represented diagrammatically. The protein consists of 5 extracellular calcium-binding domains (EC1-EC5), a transmembrane region, and a short intracellular tail that binds to β-catenin. The predicted mutant protein missing EC4, EC5, and part of the transmembrane domain is shown below.
Hypotrichosis associated with juvenile macular dystrophy is caused by mutations in CDH3, which encodes P-cadherin, a member of the classic cadherin family. We report here, to our knowledge for the first time, an intragenic deletion causing HJMD that results in the homozygous loss of exons 12 and 13 of CDH3. The resultant transcript has exon 11 spliced directly to exon 14, and although it remains in frame, the predicted protein loses extracellular calcium-binding domains 4 and 5 and part of the transmembrane domain and would therefore be nonfunctional.
Kjaer et al6 have shown that mutations in CDH3 also cause ectodermal dysplasia, ectrodactyly, and macular dystrophy (EEM; OMIM 225280); they also discuss possible mechanisms for this phenotypic variation. Both HJMD and EEM have very similar hair and retinal defects, but patients with EEM have additional limb abnormalities. Hypotrichosis associated with juvenile macular dystrophy is a rare condition with 1 previous report in the ophthalmology literature.7 This case highlights the importance of assessing patients with inherited retinal degeneration for extraocular features and the fact that HJMD should be considered if early-onset macular degeneration is diagnosed in the context of hypotrichosis.
Correspondence: Dr Halford, Nuffield Laboratory of Ophthalmology, Nuffield Department of Clinical Neurosciences, University of Oxford, Level 6 West Wing, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, England (email@example.com).
Author Contributions: All authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Conflict of Interest Disclosures: None reported.
Funding/Support: This work was supported by the Oxford Partnership Comprehensive Biomedical Research Centre funded by the Department of Health NIHR Biomedical Research Centre Programme and by Oxford Radcliffe Hospital Flexibility and Sustainability Funding.
Disclaimer: The views expressed in this article are those of the authors and not necessarily those of the Department of Health.
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