Heavy-chain amyloidosis in TGFBI-negative and gelsolin-negative atypical lattice corneal dystrophy.

PURPOSE: An atypical case of late-onset lattice corneal dystrophy is described in a 61-year-old man without a family history of eye disease. Mutational analysis of the TGFBI gene excluded any pathogenic sequence variants. However, 2 years later, renal impairment and nephrotic syndrome were diagnosed, resulting in a diagnosis of systemic heavy-chain amyloidosis. METHODS: Slit-lamp examination, corneal photography, and in vivo confocal microscopy were performed. General systemic evaluation included blood and urine assessment, bone marrow and renal biopsies, and cardiologic evaluation. A DNA sample underwent initial mutational analysis of TGFBI and, subsequently, gelsolin. The renal biopsy sample was subject to direct protein sequencing by mass spectrometry. RESULTS: A bilateral, atypical, fine, midperipheral lattice corneal dystrophy with minor central subepithelial scarring was clinically characterized. Subsequently, abnormal renal functions with proteinuria, IgG lambda paraproteinemia, extensive deposition of amyloid in renal glomeruli, and increased plasma cells in bone marrow were identified. No pathogenic sequence mutations were identified in TGFBI or the gelsolin genes. Direct protein sequencing by mass spectrometry showed amyloid to be heavy-chain deposition rather than the more usual light-chain deposition. CONCLUSIONS: Atypical midperipheral lattice corneal dystrophy presenting with adult onset and negative family history should arouse suspicion for an association with paraproteinemias or amyloidosis. Exclusion of TGFBI mutations should alert the clinician to the possibility of potentially life-threatening conditions, with referral for careful systemic evaluation.

Role of genetic testing in retinoblastoma management at a tertiary referral centre.

BACKGROUND: Retinoblastoma (MIM +180 200) is a malignant neoplasm affecting embryonal retina, associated with mutations in the RB1 gene. This paper investigates the results of RB1 testing in retinoblastoma management in a tertiary referral centre. METHODS: A retrospective audit of genetic testing for retinoblastoma from 2003 to 2008, to determine epidemiology, rate of mutation detection and spectrum was undertaken. Eligible probands were identified from the department database and hospital records examined. DNA extracted from tumour tissue and/or peripheral blood was analysed. All patients and families underwent genetic counselling. RESULTS: Twenty patients, including one family, were identified. Eight had bilateral tumours, of whom seven presented before 2 years of age, whereas 10 of 12 unilateral cases presented after 2 years of age. Ten patients (50%) were European, four Maori (20%), three Pacific (15%), two Asian (10%), and one of mixed ancestry (5%). Genetic analysis achieved mutation detection on all affected alleles of all the patients, with tumour tissue available for testing in 19 cases. Ten (40%) had germline mutations (eight bilateral and two unilateral), including one mosaic. 75% of affected Maori had germline mutations compared with 40% Europeans. A wide range of mutations was detected with one novel mutation identified in a familial case. CONCLUSION: Advances in gene testing have enabled a high rate of mutation detection, particularly when tumour tissue is genotyped. Genetic analysis is integral to the management of retinoblastoma patients allowing enhanced follow-up care, avoidance of unnecessary examinations, family screening, counselling and reproductive planning, with early tumour detection in predisposed individuals.