Hypotrichosis with juvenile macular dystrophy : a case report with molecular study

Hypotrichosis with juvenile macular dystrophy is a rare autosomal recessive disorder characterized by sparse scalp hair caused by hair follicle abnormalities as well as progressive retinal degeneration leading to blindness in the second or third decade of life. It is associated with mutations of the cadherin 3 (CDH3) gene, which result in abnormal expression of P-cadherin. Mutations in CDH3 are related to ectodermal dysplasia, ectrodactyly, and macular dystrophy. In this report, we describe an 11-year-old Iranian boy born with a missing left index fingernail and sparse scalp hair who later displayed macular pigmentary changes. Genetic testing of the CDH3 gene revealed a homozygous gene variant at exon 6 (640A>T). This novel in-frame mutation converts a lysine to a premature stop codon, altering synthesis of P-cadherin on chromosome 16q22.


Descritores: Hipotricose; Degeneração macular; Caderinas/genética; Humanos; Re latos de casos
The proband began wearing glasses at 5 years of age when his teachers referred him for eye care because of trouble seeing the board.His visual acuity at the age of 8 years was 20/40 +2 for both eyes, which was stable for 2 years.The dilated fundus examination at that time showed stable, primarily macular pigmentary, changes (Figure 3).Electroretinography (ERG; Espion; Diagnosys LLC) was performed at the age of 9 years and showed decreased a and b wave amplitudes for the rod-, mixed rod-cone-, cone-, and flicker-mediated responses for both eyes.Another ERG was performed 6 months later and showed decreased rod-mediated responses for OD and borderline responses for the OS.The mixed rod-cone-mediated responses were borderline for both eyes, and the cone and flicker responses for both eyes were diminished.An ERG performed 1 year later showed no downward progression of the responses compared with the previous year.Goldmann visual field testing demonstrated full peripheral isopters and a marginally enlarged blind spot in both eyes.Optical coherence tomography (OCT; Stratus; Carl Zeiss Meditec) testing de monstrated mild macular region attenuation (Figure 4).Both tests were conducted at the age of 9 years.
Sanger sequencing was performed to specifically screen for a mutation in the CDH3 gene, which encodes for the P-cadherin protein.A homozygous in-frame nonsense mutation was found in exon 6 (640A>T), resulting in the substitution of a lysine for a premature stop codon, thus leading to the synthesis of a truncated protein unable to fulfill its physiologic functions.

DISCUSSION
Several authors have described different families with this condition found in remote areas of the Middle East (2,(4)(5)(6)(7) .All the families studied by these authors shared mutations in the CDH3 gene.Symptom   severity varies for each individual, but all share common features of sparse scalp hair with limited growth throughout life and retinal degeneration.
Naqvi et al. (4) studied a family from a remote region of Pakistan.The family was consanguineous, with six affected members delineated in an autosomal recessive state.All affected individuals had sparse scalp hair.Their finger and toenails, teeth, and skin were normal, with normal growth.The affected individuals had progressive vision loss starting at 12-20 years of age.Fundus examination revealed pigmentary abnormalities of the posterior pole as in the patient in our study.Both ERG and fundus inspections were consistent with macular dystrophy (4) .
Jelani et al. (2) studied another large consanguineous pedigree from Pakistan with nine affected individuals.They were born with sparse scalp hair but otherwise normal integumentary and teeth.Examination showed degeneration of the macular pigmented epithelium.ERG testing of two of the affected individuals showed severe retinal dysfunction (2) .Despite a different genotype (IVS10-1 G→T), the phenotype was similar to that in the present report.
Sprecher et al. (5) studied four large consanguineous families from Israel, with 11 affected individuals.At birth, they had seemingly normal hair growth but developed alopecia at 3 months of age.Scalp skin biopsies were taken and showed "reduced ratio of terminal versus vellus hair follicles." They observed "distinct structural aberrations of the hair shaft." Progressive macular degeneration started between 3 and 21 years of age.Electrophysiological evaluation was also conducted and showed anomalies consistent with impaired macular function (5) .The authors identified a homozygous deletion in exon 8 (981delG) of the CDH3 gene in all families, identifying cadherin molecule pathogenesis resulting in a human hair and retinal disorder for the first time.In the present study, the age of onset was 8 years, and mild macular region attenuation on OCT was observed at 9 years.Indelman et al. reported, in four members with HJMD of a consanguineous family, a homozygous missense mutation (R503H) resulting in a single amino acid substitution at position 503 of the P-cadherin sequence.The affected individuals were born with sparse scalp hair.Retinal degeneration manifested in all of the affected individuals with decreased visual acuity during the first decade of life (6) .These clinical findings were similar to those of the patient in the current study.
Leibu et al. evaluated retinal function in 16 patients with HJMD.Fundus examination showed pigmentary abnormalities with atrophic changes extending to regions beyond the macula.ERG revealed subnormal responses in light-and dark-adapted tests.The electrooculography responses were normal.Pattern-reversal visual evoked potential showed abnormal waveforms even in patients with relatively good visual acuity.The flash demonstrated abnormal waveform architecture but subnormal amplitudes.Follow-up visual acuity and ERG testing indicated a slowly progressive retinal disorder affecting cone and rod-mediated vision; therefore, the authors suggested that

Figure 2 .
Figure 2. Picture of proband with sparse scalp hair.

Figure 3 .
Figure 3.Primary macular pigmentary changes and atrophy of the retinal pigment epithelium.

Figure 4 .
Figure 4. Optical coherence tomography demonstrating a mild decrease in macular thickness bilaterally.