Reis-Bücklers corneal dystrophy (RBCD; Mendelian Inheritance in Man 602082) and Thiel-Behnke corneal dystrophy (TBCD; Mendelian Inheritance in Man 608470) are clinically similar corneal dystrophies affecting Bowman's layer, caused by the TGFBI variants p.(Arg124Leu) and p.(Arg555Gln), respectively. Yet their distinct clinical courses complicate therapeutic decisions. This study aimed to compare the clinical course and surgical outcomes of genetically confirmed RBCD and TBCD. Medical records from 2016 to 2024 were reviewed for age at first surgical intervention, surgical procedure type, and time to clinically significant recurrence (SR). TGFBI genotyping was performed, and phenotypic features were documented using slit-lamp biomicroscopy and anterior segment optical coherence tomography. We retrospectively analyzed clinical data of 2 large French families with 24 patients, 8 being genotyped with either the p.(Arg124Leu) or the p.(Arg555Gln) variants. Main Outcome Measures were the age at first phototherapeutic keratectomy (PTK), recurrence interval after surgery, and visual acuity recovery after PTK. Patients with the p.(Arg124Leu) variant underwent their first surgical procedure at a younger age (mean: 18.43 ± 4.47 years) than those with the p.(Arg555Gln) variant (mean: 28.8 ± 4.16 years; P <0.001). Furthermore, the interval to SR after PTK was shorter in the p.(Arg124Leu) group (48.3 ± 10.4 months) than in the p.(Arg555Gln) group (121.2 ± 20.4 months; P <0.001). Our findings further support that the p.(Arg124Leu) variant is associated with an earlier onset and a more aggressive clinical course than the p.(Arg555Gln) variant. Genetic testing is key to precise differential diagnosis of these CDs and provides clinical prognostication to guide the therapeutic options.

Thiel-Behnke corneal dystrophy is a rare inherited condition characterized by symmetrical subepithelial corneal opacities that gradually reduce vision. It is an autosomal dominant inherited epithelial stromal TGFB1 dystrophy that mainly causes visual impairment. This case report describes case of a woman in her early 50s with progressive vision loss in her left eye over the past 3 months with a history of recurrent corneal erosions in childhood. Examination on a slit lamp showed corneal dystrophy affecting both eyes, matching the features of Thiel-Behnke dystrophy. Diagnosis was confirmed with anterior segment-optical coherence tomography, revealing a distinctive sawtooth pattern in Bowman's layer. The patient was managed conservatively for her dystrophy and was also surgically treated for her cataract in the left eye, which showed a significant improvement in her vision. Despite its rarity, Thiel-Behnke dystrophy along with cataract can severely impair vision, making early diagnosis and continuous monitoring crucial for preventing further visual decline. Corneal dystrophy (CD) is most recently defined as a collection of rare hereditary non-inflammatory disorders of abnormal deposition of substances in the cornea. CD was coined in 1890 by Arthur Groenouw and Hugo Biber, and the efforts of Ernst Fuchs, Wilhelm Uhthoff, and Yoshiharu Yoshida solidified the foundation of the understanding of these diseases. As proposed in 2015 by the International Classification of Corneal Dystrophies (IC3D), CD is sub-classified by the anatomic location affected: epithelial/subepithelial, epithelial-stromal, stromal, and endothelial dystrophies. Discoveries and unique case studies continue to broaden our understanding and classification of these diseases; therefore, it is difficult to categorize every single dystrophy solely into these four major labels.   The objective of this article is to present an overview of the evaluation and management for the most prominent and understood variants of CD. Highlights of these dystrophies will be discussed. However, further in-depth discussion on these dystrophies will be in separate StatPearls articles.  Patients with CD can be asymptomatic, but if symptoms occur, they typically experience bilateral visual acuity loss, typically in the form of irregular astigmatism. Depending on the corneal layer affected, patients may also manifest with photophobia, dry eyes, corneal edema, and recurrent corneal erosions, especially with epithelial-based CD, which causes considerable pain. Symptoms can begin at any age, depending on the diagnosis. Treatment can range from conservative measures to corneal transplantation.   CD is a significant but rare ocular disease. The genetic component of this disease is important for patients to understand, especially for affected patients involved with family planning. As we begin to understand genetics in greater detail, better evaluation and treatments for CD will come to fruition.  The objective of this article is to present an overview of the general evaluation and management for the most prominent and understood variants of CD. Highlights of these dystrophies will be covered, but the author intends to elaborate on these dystrophies separately in other StatPearls articles. The variants of CD based on their new anatomic classifications in IC3D are:  Epithelial and subepithelial dystrophies  : Epithelial basement membrane corneal dystrophy (EBMCD), also previously known as map-finger-dot dystrophy, Cogan microcystic dystrophy, and anterior basement membrane dystrophy. . Epithelial recurrent erosion dystrophies (EREDs) which includes Franceschetti corneal dystrophy, dystrophia smolandiensis, and dystrophia helsinglandica . Subepithelial mucinous corneal dystrophy (SMCD) . Meesmann corneal dystrophy (MECD) also known as juvenile epithelial corneal dystrophy . Lisch epithelial corneal dystrophy (LECD) . Gelatinous drop-like corneal dystrophy (GDLD) . Epithelial-Stromal Dystrophies (still included under epithelial and subepithelial dystrophies) : Lattice corneal dystrophy (LCD), with its subtypes: type I (TGFBI mutation) and type II (familial amyloidosis Finnish type), including LCD variants . Granular corneal dystrophy (GCD), types I and II (Avellino-type)  . Reis-Bückler’s corneal dystrophy (RBCD) . Thiel-Behnke corneal dystrophy (honeycomb dystrophy) (TBCD) . Stromal dystrophies: Macular corneal dystrophy (MCD)  . Schnyder corneal dystrophy (SCD)  . Congenital stromal corneal dystrophy (CSCD)  . Fleck corneal dystrophy (FCD)  . Posterior amorphous corneal dystrophy (PACD)  . Pre-Descemet corneal dystrophy (PDCD)  . Central cloudy dystrophy of francois (CCDF) . Endothelial Corneal Dystrophies: Fuchs endothelial corneal dystrophy (FECD)  . Posterior polymorphous corneal dystrophy (PPCD)  . Congenital hereditary endothelial dystrophy (CHED)  . X-linked endothelial corneal dystrophy (XECD) .

Thiel Behnke corneal dystrophy (TBCD) and Reis Buckler corneal dystrophy (RBCD) are Bowman's layer dystrophies with overlapping clinical features causing diagnostic confusion. However, each entity has typical histopathological features. We describe in this case the successful use of Femtosecond laser (FSL) in the treatment of TBCD-related corneal opacity. We present a 54-year-old male with bilateral superficial corneal opacities consistent with TBCD based on clinical appearance, anterior segment optical coherence tomography (AS-OCT), and In vivo confocal microscopy. Management options were discussed with the patient before proceeding with Femtosecond Laser Assisted Superficial Lamellar Keratectomy (FSLASLK). The histopathological findings of the excised left anterior lamellar corneal flap were typical of TBCD and the patient had a satisfactory outcome. TBCD typically affects Bowman's layer centrally with progressive opacities involving the deeper layer of the corneal stroma and the periphery with advancing age. Histopathology typically shows subepithelial fibrosis with interrupted basement membrane and totally replaced Bowman's layer by uneven fibrous tissue forming the characteristic saw tooth pattern. The treatment of such cases is challenging with variable success and recurrence rates. Our case was managed successfully using FSL. TBCD, even though a rare type of dystrophy, should be suspected based on the appearance of the corneal opacities clinically. It can be diagnosed by typical AS-OCT findings supported by histopathological confirmation and can be successfully treated by FSASLK.

Mutations in the fasciclin 1 domain 4 (FAS1-4) of transforming growth factor β-induced protein (TGFBIp) are associated with insoluble extracellular deposits and corneal dystrophies (CDs). The decrease in solubility upon mutation has been implicated in CD; however, the exact molecular mechanisms are not well understood. Here, we performed molecular dynamics simulations followed by solvation thermodynamic analyses of the FAS1-4 domain and its three mutants-R555W, R555Q, and A546T-linked to granular corneal dystrophy type 1, Thiel-Behnke corneal dystrophy and lattice corneal dystrophy, respectively. We found that both R555W and R555Q mutants have less affinity toward solvent water relative to the wild-type protein. In the R555W mutant, a remarkable increase in solvation free energy was observed because of the structural changes near the mutation site. The mutation site W555 is buried in other hydrophobic residues, and R557 simultaneously forms salt bridges with E554 and D561. In the R555Q mutant, the increase in solvation free energy is caused by structural rearrangements far from the mutation site. R558 separately forms salt bridges with D575, E576, and E598. Thus, we thus identified the relationship between the decrease in solubility and conformational changes caused by mutations, which may be useful in designing potential therapeutics and in blocking FAS1 aggregation related to CD.

Thiel-Behnke corneal dystrophy (TBCD) is an epithelial-stromal TGFBI dystrophy caused by mutations in the TGFBI (transforming growth factor beta induced) gene, though the underlying mechanisms and pathogenesis of TBCD are still obscure. The study identifies a novel mutation in the TGFBI gene (p.Gly623_His626del) in a TBCD pedigree. Characteristics of the typical vacuole formation, irregular corneal epithelial thickening and thinning, deposition of eosinophilic substances beneath the epithelium, and involvement of the anterior stroma were observed in this pedigree via transmission electron microscopy (TEM) and histological staining. Tgfbi-p.Gly623_Tyr626del mouse models of TBCD were subsequently generated via CRISPR/Cas9 technology, and the above characteristics were further verified via TEM and histological staining. Lysosomal dysfunction and downregulation of differential expression protein CTSD (cathepsin D) were observed using LysoTracker Green DND-26 and proteomic analysis, respectively. Hence, lysosomal dysfunction probably leads to autophagic flux obstruction in TBCD; this was supported by enhanced LC3-II and SQSTM1 levels and decreased CTSD. TFEB (transcription factor EB) was prominently decreased in TBCD corneal fibroblasts and administration of ATP-competitive MTOR inhibitor torin 1 reversed this decline, resulting in the degradation of accumulated mut-TGFBI (mutant TGFBI protein) via the ameliorative lysosomal function and autophagic flux owing to elevated TFEB activity as measured by western blot, confocal microscopy, and flow cytometry. Transfected HEK 293 cells overexpressing human full-length WT-TGFBI and mut-TGFBI were generated to further verify the results obtained in human corneal fibroblasts. Amelioration of lysosome dysfunction may therefore have therapeutic efficacy in the treatment of TBCD.Abbreviations AS-OCT: anterior segment optical coherence tomography; ATP: adenosine triphosphate; Cas9: CRISPR-associated protein 9; CLEAR: coordinated lysosomal expression and regulation; CRISPR: clustered regularly interspaced short palindromic repeats; CTSB: cathepsin B; CTSD: cathepsin D; CTSF: cathepsin F; CTSL: cathepsin L; DNA: deoxyribonucleic acid; ECM: extracellular matrix; Fas1: fasciclin 1; FC: flow cytometry; GAPDH: glyceraldeyde-3-phosphate dehydrogenase; GCD2: granular corneal dystrophy type 2; HE: hematoxylin and eosin; LAMP2: lysosomal-associated membrane protein; MT: mutation type; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; mut-TGFBI: mutant TGFBI protein; SD: standard deviation; TBCD: Thiel-Behnke corneal dystrophy; TEM: transmission electron microscopy; TFEB: transcription factor EB; TGFBI: transforming growth factor beta induced; WT: wild type.