Clinical Phenocopies of Albinism

Alina V Dumitrescu MD, Wanda L Pfeifer OC(C), COMT, Arlene V Drack MD University of Iowa, Department of Ophthalmology and Visual Science – Pediatric Ophthalmology

BACKGROUND RESULTS

Oculocutaneous albinism (OCA) causes vision loss1and some forms are syndromic. Case 4 - 2 yo male with congenital nystagmus and decreased vision, sectoral iris Clinical diagnosis of OCA is based on the presence of congenital nystagmus, iris transillumination heterochromia, peripheral iris transillumination defects, blond fundus and anomalous fovea defects, decreased fundus pigmentation, foveal hypoplasia, optic nerve abnormalities and decreased (hypoplastic) and optic nerve. visual acuity. Every one of these features is variable and not all of them need to be present for the clinical diagnosis of OCA. Confirmation of clinical suspicion using genetic testing is recommended but not always performed.

Iris transillumination defects Abnormal fundus pigmentation and Foveal hypoplasia

PURPOSE AND HYPOTHESIS This paper will present a series of patients originally clinically diagnosed with OCA who were subsequently confirmed as having another diagnosis. Initial genetic testing was negative for albinism. Also developing sensorineural hearing loss The purpose is to highlight the importance of confirmatory genetic testing and close follow up when requiring cochlear implant at age 3, progressive high myopia and mild developmental delay. they are negative, inconclusive or unable to be performed. Expanded genetic testing – pigmentation panel - Waardenburg syndrome 1 mutation in the MITF gene. MATERIALS AND METHODS Group of genetic conditions inherited in AD pattern that can cause variable hearing loss and IRB approved - retrospective chart review of all patients with clinical diagnosis of albinism and changes in pigmentation of the hair, skin, and eyes. There are four recognized types genetic testing performed, seen in the pediatric genetic eye disease service at University of Iowa of Waardenburg syndrome, which are distinguished by their physical characteristics and between 1980-2015. sometimes by their genetic cause. Hearing loss occurs more often in people with type II than in those with type I. Type III (sometimes called Klein-Waardenburg syndrome) includes RESULTS abnormalities of the arms and hands in addition to hearing loss and changes in pigmentation. Type IV (also known as Waardenburg-Shah syndrome) has signs and symptoms of 6 patients were initially clinically diagnosed with OCA based on typical clinical findings. Further both Waardenburg syndrome and Hirschsprung disease. workup, augmented by molecular genetic testing, led to diagnoses of: BCVA 20/60, high myopia (-8.00 at age 17) • Knobloch syndrome2, • Jeune syndrome, Case 5 and 6 • Donnai-Barrow syndrome, 5 yo female and respectively 4 mo baby girl with congenital nystagmus and decreased vision, • Waardenburg syndrome3 fair skin pigmentation, iris transillumination defects, blond fundus and anomalous fovea • Hermansky Pudlak syndrome (HPS) – 2 patients. (hypoplastic). Also have strabismus. One has astigmatism the second has myopia. These diseases have unique clinical and electrophysiological features that were not noted at presentation and will be discussed here.

Genetic testing for Case 1 - 3 yo male with congenital nystagmus and decreased vision, fair skin pigmentation, iris albinism was transillumination defects, blond fundus and anomalous fovea (hypoplastic) and optic nerve. negative. Both patients were evaluated for possible strabismus and were recommended platelet studies which were abnormal. Genetic testing for HPS was positive Genetic testing negative for albinism. Also with age - developing progressive high myopia, posterior for 2 mutations in staphyloma, seizures. HPS5 respectively Expanded genetic testing – exome sequencing positive for Knobloch syndrome (2 heterozygous HPS3. sequence variations in the coding sequence of COL18A1 gene). None of the Collagen disorder inherited in AR pattern, vitreoretinal degeneration with progressive high myopia, patients had high risk of RD. Another characteristic feature of Knobloch syndrome is occipital encephalocele or Puerto Rican ancestry. other skull defects and may be associated with intellectual disability. BCVA 20/100, high myopia (-11.00 at age 17) Hermansky- Pudlak syndrome is a multisystem, Case 2 - 4 mo male with congenital nystagmus and decreased vision, fair skin pigmentation, iris disease inherited in transillumination defects, blond fundus and anomalous fovea (hypoplastic) and optic nerve and high AR pattern myopia (-16D). characterized by platelet dysfunction, OCA features, colitis, kidney failure, and pulmonary fibrosis. There are nine different types of HPS, which can be distinguished by genetic testing. CONCLUSIONS

He also developed hearing loss, posterior staphyloma, RD, proteinuria and kidney disease. MRI – • Although clinical exam is the most important first step in diagnosis of ocular hypoplastic corpus callosum. Clinically diagnosed with Donnai-Barrow syndrome. disease it should not be the only step as it can miss the correct/complete Inherited in AR pattern, unusual facial features, severe hearing loss, high myopia, iris defects or diagnosis coloboma, hypoplastic corpus callosum and other structural abnormalities of the brain, mild to • Up to 4% of patients with clinical diagnosis of OCA have HPS. moderate intellectual disability and developmental delay, congenital diaphragmatic hernia, • Patients with a clinical diagnosis of albinism, with incomplete or negative omphalocele. genetic testing should be counseled about the possibility of another diagnosis Case 3 – 4yo male with decreased vision, accomodative esotropia, foveal blunting and mildly fair masquerading as albinism. skin and fundus pigmentation. • Some cases require multiple visits and testing to establish the correct diagnosis. REFERENCES

1. Grønskov K, Ek J, Brondum-Nielsen K. Oculocutaneous albinism. Orphanet J Rare Dis. 2007;2:43. doi:10.1186/1750-1172-2-43. 2. Gradstein L, Hansen RM, Cox GF, Altschwager P, Fulton AB. Progressive retinal degeneration in a girl with Knobloch syndrome who presented with signs of ocular albinism. Doc Ophthalmol. 2017;134(2):135-140. doi:10.1007/s10633-017-9574-1 Later developed small, narrow thorax, other skeletal abnormalities. Photophobia. Myopia. ERG 3. Chiang PW, Spector E, McGregor TL. Evidence suggesting digenic inheritance of waardenburg syndrome type II suggestive of cone dysfunction. Clinically diagnosed with Jeune's Thoracic Dystrophy Syndrome with ocular albinism. Am J Med Genet Part A. 2009;149(12):2739-2744. doi:10.1002/ajmg.a.33128.