The family history was positive for WD with a 14-year-old younger brother also being diagnosed with it. Genetic analysis revealed the p. (Arg778Leu) mutation in 1 allele and the p. (Asn1270Ser) mutation in the other allele of ATP7B. He has normal yellow skin, black hair and eyes, and the genetic analysis also confirmed he was negative for OCA. Her parents were negative for both OCA and WD.
This is the first case report in the literature concerning 1 patient who had WD and OCA coexisting. Based on her neuropsychiatric symptoms, KF rings, metabolism tests, and MRI scans, WD was impressed. However, her light skin color, dark brown eyelashes, blond hair and eyebrows were not compatible with the clinical features of WD. The association of dermatologic signs with WD has rarely been reported in the literature. Copper accumulation in the liver might result in the itchiness and yellowish skin. Other skin changes in WD are minor, and cutaneous findings in WD include generalized hyperpigmentation, blue lunulae of the nails, anetoderma, xerosis, acatnosis nigricans, pyoderma gangrenosum, and rippled hyperpigmentation. As a result, genetic analysis was subsequently conducted.
As a WD-causative gene, ATP7B encodes copper-transporting P-type ATPase. Most of ATP7B mutations are missense mutations, small deletions or insertions in the coding region, or splice junction mutations. The point mutation 2333G→T leading to Arg778Leu substitution in exon 8 was the most common ATP7B mutation with an allele frequency of 14 to 49% in patients from eastern Asia (China, South Korea, and Japan).[1,3,8] Her genetic study revealed that the p. (Arg778Leu) mutation in 1 allele and the p. (Asn1270Ser) mutation in the other allele of the ATP7B gene, and this confirmed the diagnosis of WD.
According to her clinical findings, which included very light skin, blond hair and eyebrows, and dark brown eyelashes and irises, OCA1 was highly suspected. OCA is a disorder caused by lack of melanin biosynthesis resulting in hypopigmentation of the hair, skin, and eyes. Several subtypes of OCA were defined by their causative mutation(s), and clinical presentation can vary widely. OCA type 1 (OCA1) is caused by mutations in the TYR gene on chromosome 11, which encodes tyrosinase. The gene consists of 5 exons spanning approximately 65 kb of genomic DNA and encodes a protein of 529 amino acids. The diagnosis of OCA1 for the patient in this study was the p. (D456fs) mutation in 1 allele and the p. (R299H) mutation in the other allele of the TYR gene.
The color of mammalian skin and hair is determined by a number of factors. The most important factor is the degree and distribution of melanin pigmentation. Melanin is formed in specialized pigment-producing cells known as melanocytes. The major cause of OCA lies in the fact that melanin biosynthesis dysfunction. The most important enzyme in melanogenesis is tyrosinase which is expressed in epidermis, follicle and oocytes, catalyzing the first 2 rate-limiting steps of melanin biosynthesis. Interestingly enough, it is generally known that tyrosinase is a multifunctional copper-containing glycoenzyme. WD patients exhibit excessive copper accumulation in most organs but especially the liver and brain, but in this environment of excessive copper, tyrosinase can’t finish melanin biosynthesis as normal. The results of our study show that the spatial distribution of 299 amino acids changed obviously, and the Cu-binding of the tyrosinase domain disappeared.
Menkes syndrome could have been an important differential diagnosis for this patient. Menkes syndrome is an X-linked recessive disorder caused by mutations in genes coding for the copper-transport protein ATP7A (located on chromosome Xq21.1), leading to copper deficiency. Clinical findings of Menkes syndrome include nervous system deterioration, kinky hair, and developmental delay, which were not compatible for the patient.
Treatments for WD involve diet control with low copper-containing foods and chelation therapy (D-penicillamine and zinc sulfate). These treatments were effective for the patient in this study according to her history. If left untreated, WD tends to become progressively worse and is eventually fatal. Most patients can live relatively normal lives with early detection and treatment. Treatments for OCA include strict sun protection from infancy, a comprehensive eye examination early in life, and treatment of refraction error with glasses or contact lenses. Life expectancy is not reduced in nonsyndromic OCA, although mortality from skin cancer can be increased in certain populations. Patients with OCA should have skin examinations at 6- to 12-month intervals starting in adolescence because of the increased risk of skin cancer.
Both WD and OCA are rare autosomal recessive disorder caused by mutations on chromosome 13 and chromosome 11, respectively. We have herein reported on the first case of a patient who simultaneously presented WD and OCA, bringing up the possibility of a presumable link between these 2 rare diseases.
Conceptualization: Shan Shu.
Data curation: Rao Rao, Shan Shu, Yong Zhu Han, and Yu-Jen Chiu.
Formal analysis: Rao Rao and Shan Shu.
Funding acquisition: Yong Sheng Han.
Investigation: Rao Rao.
Resources: Yong Zhu Han and Yong Sheng Han.
Writing – original draft: Rao Rao and Yu-Jen Chiu.
Writing – review & editing: Yong Sheng Han.
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Keywords:Copyright © 2018 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.
copper; melanin synthesis; oculocutaneous albinism; Wilson disease