Spheroidal degeneration in H626R TGFBI variant lattice dystrophy: a multimodality analysis.
OBJECTIVE
The aim of this study was to describe clinical, imaging, molecular genetic, histopathologic, immunohistochemical, and ultrastructural characteristics of coexistent amyloid and spheroidal degeneration-type deposits in a family with histidine-626-arginine transforming growth factor beta-induced (H626R TGFBI) variant lattice dystrophy.


METHODS
This is a retrospective clinical-pathological and genetic analysis of one family with H626R variant lattice dystrophy.


RESULTS
Pedigree analysis showed an autosomal dominant inheritance pattern of the disease. Examination of 3 affected family members revealed asymmetric, thick, branching lattice-like deposits associated with corneal haze. Sequencing of the TGFBI gene revealed a high-penetrance disease-causing sequence variation (H626R CAT>CGT heterozygous). Optical coherence tomography demonstrated fusiform, poorly demarcated hyperechoic stromal deposits with focal hypoechoic central regions. Histology of the corneal discs from 2 affected family members showed stromal deposits consistent with TGFBI amyloid. Some amyloid deposits contained a central nidus of spheroidal degeneration-type material that demonstrated autofluorescence, stained with elastic and Masson trichrome stains, did not stain with periodic acid-Schiff or Congo red stains, was nonbirefringent, and did not immunoreact with keratoepithelin antibodies. Transmission electron microscopy confirmed the presence of amyloid fibrils with central, electrodense, homogeneous, discrete, spheroidal degeneration-type deposits.


CONCLUSIONS
The presence of spheroidal deposits in a subset of affected patients, variability in presentation within an individual and between family members, predominant anterior corneal stromal location and nonimmunoreactivity of deposits for keratoepithelin suggest that these deposits are degenerative in nature. The deposits may arise from ultraviolet light-altered proteins diffused from the limbus, which form a nidus for keratoepithelin deposition.
*Department of Ophthalmology, The New York Eye and Ear Infirmary, New York, NY; †Department of Pathology, Electron Microscopy Laboratory, Beth Israel Medical Center, New York, NY; ‡Department of Ophthalmology, University of California, San Francisco, CA; and §Department of Pathology and Laboratory Medicine, The New York Eye and Ear Infirmary, New York, NY.
Kevin
K
Lai
Jason
J
Reidy
Benjamin
B
Bert
Tatyana
T
Milman
D000293:Adolescent; D000328:Adult; D000368:Aged; D000682:Amyloid / Q000648:ultrastructure; D028226:Amyloidosis, Familial / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D002648:Child; D002675:Child, Preschool; D003317:Corneal Dystrophies, Hereditary / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D003319:Corneal Stroma / Q000648:ultrastructure; D004252:DNA Mutational Analysis; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D015948:Keratoplasty, Penetrating; D008297:Male; D008875:Middle Aged; D064847:Multimodal Imaging; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D041623:Tomography, Optical Coherence; D016212:Transforming Growth Factor beta / Q000235:genetics*; D000099222:betaIG-H3 Protein
D000682:Amyloid; D016326:Extracellular Matrix Proteins; D016212:Transforming Growth Factor beta; D000099222:betaIG-H3 Protein