We have presented a patient with a phenotype of HJMD. The fact that no other alterations were observed, apart from retinal dystrophy and hypotrichosis, allowed us to discard EEM. Although no radiological examination of hand or feet was performed, which would completely rule out EEM, on clinical examination no abnormality was noted. Mild anomalies of hand and feet have been noted in EEM patients misdiagnosed with HJMD [6, 19], we believe that this is not the case in our patient. Mild changes (as subtle shortening of distal phalanges or mild toe syndactyly) were not observable on the thorough clinical examination, performed on our patient.
The presence of two compound heterozygous mutations in the CDH3 gene in our patient, supported our clinical suspicion.
The ABCA4 gene was studied because it is the most frequent gene responsible for macular dystrophy in the young [26] and the retinal phenotype stated in the available reports were suggestive of macular dystrophy. As previously mentioned, first suspected diagnosis, based on the referral information, was ABCA4–related maculopathy?+?Keratosis Follicularis Spinulosa Decalvans. Even if our patient presented a mutation on the ABCA4 gene, it was discarded as responsible for the patient’s maculopathy as no second mutation was found. We cannot rule out that the p.Val2050Leu mutation in ABCA4 is playing a role in the patient’s ophthalmological phenotype. However, there is no known functional interaction between ABCA4 and CDH3 at a genetic or protein level; and, the pathogenic effect of the p.Val2050Leu change in ABCA4 is nowadays discussed (http://www.ncbi.nlm.nih.gov/clinvar/?term=%22Retina%20International%22[submitter]+AND+%22ABCA4%22[gene], date of access 04/04/2016). Additionally, the prevalence of patients affected by retinal dystrophy carrying an ABCA4 mutation with another causative gene for their retinal dystrophy is not rare [27].
As it has previously been noted the main differential diagnostic of HJMD from an ophthalmological point of view is not only Stargardt’s disease, which is caused mainly by ABCA4 mutations [20], but any retinal dystrophy phenotype suggestive of CDH3, regardless of the hair phenotype [22]. However, when patients access a Clinical Genetics Department they have to be evaluated as a whole. The presence of two genetic disorders in a given patient, one being retinal dystrophy may occur [28]. Nevertheless, in these co-occurrence cases, it is more likely that the different signs and symptoms are due to the same genetic cause.
Nowadays, performing an accurate diagnosis is essential since cell and gene therapy are being evaluated in retinal dystrophies [29, 30], and phenotypic and genetic characteristics are to be considered when selecting patients for future treatments [23].
Besides, the suspected dermatological diagnosis (Siemens Syndrome, OMIM: 305100) is an X-linked trait and has additional skin changes, not present in our patient. Therefore, the patient’s pedigree and phenotype were unlikely to suggest this inheritance model and diagnosis.
Interestingly, our patient’s retinal alteration was first noticed when he was two years of age and he was diagnosed as presenting Retinitis Pigmentosa Inversa. This fact supports the idea of an early onset retinal dystrophy rather than a juvenile onset, and the existence of a major implication of the retina beyond the macula [7, 20–23].
Despite the fact that the missense change p.Val205Met in CDH3 has not been reported previously, we have presented evidence of its pathogenicity. Moreover, a missense change has been described in the same aminoacid position (p.Val205Leu) with a minor allele frequency of 2*10?5 in Asian and Latino populations (http://exac.broadinstitute.org/gene/ENSG00000062038, date of access 04/04/2016).
To date, the CDH3 gene is the only gene known to be responsible for HJMD.
HJMD is a very rare disease, fact that makes both its clinical and genetic diagnosis difficult. However, clinical aspects when taken together should guide us to a clinical diagnosis and lead to us to the specific genetic test to be performed.
The presence of two compound heterozygous mutations in this gene in our patient with a phenotype highly suggestive of HJMD and the absence of additional systemic anomalies led us to the diagnosis of the first Spanish case, and one of the very few Caucasian cases, of HJMD and to describe a new mutation in the CDH3 gene.
Moreover, not only we prove that an accurate clinical genetic diagnosis is of crucial relevance for leading directed genetic studies, but we have widened the number of both HJMD cases and CDH3 mutations.
Additionally, we also present the importance of differential diagnosis in retinal dystrophies (syndromic or not) as prognosis, follow up, chance of treatment and familiar implications are deeply linked to the responsible gene.