Oculocutaneous Albinism, A Family Matter Summer Moon, DO,* Katherine Braunlich, DO,** Howard Lipkin, DO,*** Annette LaCasse, DO***

*Dermatology Resident, 3rd year, Botsford Hospital Dermatology Residency Program, Farmington Hills, MI **Traditional Rotating Intern, Largo Medical Center, Largo, FL ***Program Director, Botsford Hospital Dermatology Residency Program, Farmington Hills, MI

Disclosures: None Correspondence: Katherine Braunlich, DO; [email protected]

Abstract Oculocutaneous albinism (OCA) is a group of autosomal-recessive conditions characterized by mutations in melanin biosynthesis with resultant absence or reduction of melanin in the melanocytes. Herein, we present a rare case of two Caucasian sisters diagnosed with oculocutaneous albinism type 1 (OCA1). On physical exam, the sisters had nominal cutaneous evidence of OCA. This case highlights the difficulty of diagnosing oculocutaneous albinism in Caucasians. Additionally, we emphasize the uncommon underlying genetic mutations observed in individuals with oculocutaneous albinism.

2,5 Introduction people has one of the four types of albinism. of exon 4. Additionally, patient A was found to Oculocutaneous albinism (OCA) is a group of We present a rare case of sisters diagnosed with possess the c.21delC frameshift mutation in the autosomal-recessive conditions characterized by oculocutaneous albinism type 1, emphasizing the C10orf11 gene. Patient B was found to possess the mutations in melanin biosynthesis with resultant uncommon genetic mutations we observed in these same heterozygous mutation and deletion in the two individuals. absence or reduction of melanin in the melanocytes. Figure 1 Melanin-poor, pigment-poor melanocytes phenotypically present as hypopigmentation of the Case Report 1,2 Two Caucasian sisters were referred to our hair, skin, and eyes. dermatology clinic after receiving a diagnosis of There are four genes responsible for the four principal oculocutaneous albinism type 1. Patient A was a types of OCA. OCA type 1A (OCA1A) and OCA 2-year-old Caucasian female, and Patient B was type 1B (OCA1B) are caused by a mutation in the a 5-year-old Caucasian female. On physical exam, tyrosinase gene (TYR) on chromosome 11q14.3.2,3 the sisters had nominal cutaneous evidence of OCA type 2 is caused by a mutation in the OCA2 OCA (Figures 1, 2). gene.2,3 OCA type 3 is caused by a mutation in the Patients A and B were diagnosed with OCA after tyrosinase-related protein 1 gene (TYRP1), and a retinal specialist recommended genetic testing to OCA type 4 is caused by a mutation in SCL45A2 2,3 identify the cause of the sisters’ underlying optical (a.k.a. MATP). OCA1A is considered the most impediments. The mother initially identified severe type of OCA due to a complete absence of optical difficulties in her younger daughter, patient melanin production. OCA1B, OCA2, OCA3 and A, around 8 weeks of age. She noticed the infant OCA4 are considered less severe, as they often displaying nystagmus and an inability to track. At show small amounts of pigment accumulation over 4 seven months, patient A began crawling, and it time. Overall, there is significant clinical overlap quickly became evident the infant could not see between the variants of OCA. Thus, molecular more than a few feet in front of her. The mother diagnosis is often necessary to establish the specific became increasingly concerned when, at one year of OCA subtype. The clinical characteristics found age, her daughter had difficulty seeing beyond 20 in individuals afflicted with OCA type 1 include feet (6 m). At that time, the child was evaluated by hypopigmentation of the skin and hair and the an ophthalmologist, who told the mother nothing distinctive ocular changes characteristic of all forms Figure 1. Patient A, 2-year-old female. 4 was structurally wrong. The mother insisted on of albinism. Decreased melanin production does further workup. The mother’s primary clue to the not alter the development of skin, but it does alter underlying abnormality was her older daughter, Figure 2 the color. The absence of melanin in the eye, on the patient B, who did not display these apparent optical other hand, leads to anomalous development and 2 difficulties. Patient A was referred to a neuro- function. The ocular changes associated with OCA ophthalmologist at the University of Michigan. include severe nystagmus, prominent photophobia, An electroretinogram (ERG) and magnetic reduced pigmentation of the retinal epithelium and 4 resonance imaging (MRI) were conducted for the reduced visual acuity. A pathognomonic finding initial ruling out of Leber congenital amaurosis of albinism is misrouting of the optic nerve at the (LCA). The MRI displayed no abnormalities. The optic chiasm, resulting in strabismus and reduced 2,4 ERG identified normal cones but decreased rods. stereoscopic vision. Mutations in the TYR gene Patient A was referred to a retinal specialist, who may entirely abolish tyrosinase activity, resulting in recommended genetic testing. OCA1A, or decrease the activity of the tyrosinase enzyme, resulting in the development of OCA1B. Both children underwent molecular analysis for Clinically, the difference between OCA1A and underlying genetic anomalies. The genetic testing OCA1B is seen over time, as OCA1B individuals was performed using PCR amplification and DNA often accumulate minor quantities of melanin and 2 sequencing in two directions. Quantitative PCR begin to display small amounts of pigmentation. analysis was performed using the ABI TaqMan copy number assay and CopyCaller software. Ultimately, OCA is considered a clinical diagnosis. qPCR primers for the OCA1 gene were used for The diagnosis is made if the individual has amplification and detection, namely Hs03778472_ hypopigmentation of the skin or hair in conjunction cn (intron 4), whereas RNAse P was used as the with the aforementioned characteristic ocular reference. signs. Molecular genetic testing is often used in combination with the clinical diagnosis to establish Patient A was found to possess a herterozygous the specific genetic mutation and thus the OCA 2 mutation and a heterozygous deletion in the subtype. Approximately one out of every 17,000 OCA1 gene, namely c.1217C>T, and deletion Figure 2. Patient B, 5-year-old female.

MOON, BRAUNLICH, LIPKIN, LACASSE Page 38 OCA1 gene, but she did not possess the c.21delC individuals at greater risk for the harmful effects References frameshift mutation in the C10orf11 gene. Both to UV radiation. Patients with OCA type 1, due 1. Oetting W, Brilliant M, King R. The clinical girls were found to have clinical and molecular to a pigment reduction in hair and skin, often spectrum of albinism in humans. Mol Med findings consistent with OCA1. Both mother develop solar keratosis, basal cell carcinoma and Today.1996 Aug 2;2(8):330–5. and father underwent molecular genetic testing. squamous cell carcinoma.4 Additionally, and The mother was found to possess the c.1217C>T arguably most commonly, these patients may 2. Grønskov K, Ek J, Brondum-Nielsen K. mutation and the father the deletion of exon 4. develop numerous actinic keratoses, predisposing 12-14 Oculocutaneous Albinism. Orphanet J Rare Dis. them to squamous cell carcinoma. Morbidity 2007 Nov 2;2:43. To date, both patients are doing well and being is influenced by phenotype, education and resource monitored with close follow-up. availability. Dermatologic consultation is essential, 3. Kamaraj B, Rituraj P. Mutational Analysis of as patients (and in juvenile cases, their parents) Oculocutaneous Albinism: A Compact Review. Discussion must be made aware of the importance of sun- Biomed Res Int. 2014 (2014), Article ID 905472, To date, 12 genetic mutations have been identified 6 protection in patients with OCA1. Extensive solar 10 p. in the development of albinism. OCA type 1 is exposure without protection results in a cumulative caused by a mutation in the tyrosinase gene (TYR) 2,3,7,8 increase in the risk of cutaneous neoplasms. Five 4. Lewis R. Oculocutaneous Albinism Type 1. on chromosome 11q14.3. The TYR gene to 10 minutes of sun exposure in individuals with GeneReviews [Internet]. 2000 Jan 19 [updated consists of 529 amino acids and five exons that 4 8 OCA1A is considered substantial. 2013 May 16; cited 2016 Aug 15]. Available from: span 65 kb of genomic DNA. The gene encodes http://www.ncbi.nlm.nih.gov/books/NBK1166/. tyrosinase, an enzyme that catalyzes the first It is also important to emphasize that while 8,9 two steps in the melanin biosynthesis pathway. melanoma is rare in individuals with OCA, it does 5. Witkop C. Albinism: hematologic-storage Tyrosinase converts tyrosine to L-dihydroxy- occur. In one case, a patient with OCA was found disease, susceptibility to skin cancer, and phenylalanine (DOPA) and then to dopaquinone. to have malignant amelanotic melanoma that optic neuronal defects shared in all types of The TYR gene mutation causes a complete or developed from an intradermal nevus.15 8,10 oculocutaneous and ocular albinism. Ala J Med Sci. partial loss of the catalytic activity of tyrosinase. 1979 Oct;16(4):327-30. Patients with OCA need to be screened regularly The current case emphasizes a rare molecular for changes to their skin. Ongoing surveillance 6. Oetting W, Fryer J, Shriram S, et al. presentation of OCA type 1, increasing awareness is imperative, particularly in those whose visual Oculocutaneous Albinism Type 1: The Last 100 of the condition’s varied clinical manifestations. impairments make it difficult to appropriately Years. Pigment Cell Res. 2003 Jun;16(3):307-11. Current literature on albinism suggests 90% of assess and monitor their own skin. Finally, patients OCA1A patients have two mutations. Among and families should be assured that persons with 7. Tomita Y, Takeda A, Okinaga S, et al. Human OCA1B patients, 37% have two mutations, and OCA have normal intelligence, fertility and, with oculocutaneous albinism caused by single base 63% have only one. In both forms, less than 1% proper skin protection, natural lifespans.2 insertion in the tyrosinase gene. Biochem Biophys of patients have an exonic or whole-gene deletion Res Commun. 1989;164:990-6. identified after molecular review.4 Both of our Conclusion patients possessed a deletion of exon 4. Additionally, As with any genetic condition, a patient’s 8. Kamaraj B, Purohit R. Mutational Analysis of patient A had a distinctive mutation in the morbidity and mortality can be vastly improved Oculocutaneous Albinism: A Compact Review. C1Oorf11 gene. A mutation in the gene C10orf11 with identification, education and support. In this Biomed Res Int. 2014 Jun 29;1-10. on chromosome 10q22.2-q22.3 is associated case report, we showcase a rare genetic mutation with a new form of OCA, known as OCA7.8 observed in individuals with oculocutaneous 9. Kwon B, Haq A, Pomerantz S, et al. Isolation and However, the specific structural and functional albinism, aiming to provide additional information sequence of a cDNA clone for human tyrosinase behaviors of C10orf11 remain an enigma. The on an uncommon clinical entity to assist with early that maps the mouse c-albino locus. Proc Natl C10orf11 gene encodes a protein containing three diagnosis and management. Acad Sci USA. 1988 Sep;85(17):6352. leucine-rich repeats (LRRs) that have a variety of functions including cell adhesion, extracellular- 10. Cooksey C, Garratt P, Land E, et al. Evidence matrix assembly, neuronal development and RNA of the indirect formation of the catecholic processing.11 The C10orf11 mutation was observed intermediate substrate responsible for the in patient A but is not sufficient for the diagnosis autoactivation kinetics of tyrosinase. J Bio Chem. of albinism. It is currently unknown what effect, if 1997 Nov;272(42):26226-35. any, this mutation will have on patient A’s clinical symptoms. It is our hope that case reports like 11. Bella J, Hindle K, McEwan P, et al. The leucine- this will inspire continued research to identify rich repeat structure. Cell Mol Life Sci. 2008 the relationships between genetic and phenotypic Aug;65(15):2307-33. variations in the development of OCA. Identifying the significance of unique genetic mutations 12. Ihn H, Nakamura K, Abe M, et al. Amelanotic causing OCA will be vital to the development of metastatic melanoma in a patient with personalized medicine for patients with albinism. oculocutaneous albinism. J Am Acad Dermatol. 1993 May 28;5(2): 895–900. An essential component of medical management for these individuals involves genetic counseling. 13. Okoro AN. Albinism in Nigeria. A clinical and As in all types of autosomal-recessive inheritance, social study. Br J Dermatol. 1975 May;92: 485–92. these sisters will pass on one non-working copy of the OCA1 gene to all of their offspring. At 14. Satoko M, Kaneko T, Matsuzaki Y, et al. Case minimum, their children will be carriers of the of Oculocutaneous Albinism Complicated with condition. Additional patient education and Squamous Cell Carcinoma, Bowen’s Disease and future partner genetic counseling should be Actinic Keratosis. J Dermatol. 2014;41(9):863-4. encouraged. The optimal time to determine genetic 15. Wu C, Gao H, Chiang C. Malignant amelanotic risk and clarification of carrier status is before 4 melanoma developing from an intradermal naevus pregnancy occurs. This case highlights the value in a patient with oculocutaneous albinism. Clin of a dermatology consultation in young patients Exp Dermatol. 2009;34: 590-9. with clinical features of hypopigmentation and/ or ocular findings. As in this case, the initial diagnosis of oculocutaneous albinism was delayed until confirmed by an ophthalmologist aware of the spectrum of its clinical features. Delays can result in years of unprotected solar exposure in

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