Clinicopathologic and molecular analysis of a choroidal pigmented schwannoma in the context of a PTEN hamartoma tumor syndrome.

PURPOSE: To report the first case of choroidal schwannoma in a patient affected by PTEN hamartoma tumor syndrome (PHTS) and investigate the molecular involvement of the phosphatase and tensin homolog (PTEN) and neurofibromin 2 (NF2) genes in this rare intraocular tumor. DESIGN: Observational case report. PARTICIPANT: A 10-year-old girl diagnosed with PHTS. METHODS: The enucleated specimen underwent histologic, immunohistochemical, and transmission electronic microscopy. The expression of PTEN and NF2 and their protein products were evaluated by reverse transcription-polymerase chain reaction and immunohistochemistry. Somatic mutations of PTEN and NF2, as well as allelic loss, were investigated by direct sequencing of DNA extracted from the tumor. PTEN epigenetic silencing was investigated by pyrosequencing. MAIN OUTCOME MEASURES: Histopathologic and molecular characterization of a choroidal pigmented schwannoma. RESULTS: Histopathologic, immunohistochemical, and electron microscopic analysis demonstrated features consistent with a pigmented cellular schwannoma of the choroid. We found no loss of heterozygosity at the genomic level for the PTEN germline mutation and no promoter hypermethylation or other somatic intragenic mutations. However, we observed an approximate 40% reduction of PTEN expression at both the mRNA and the protein level, indicating that the tumor was nonetheless functionally deficient for PTEN. Although DNA sequencing of NF2 failed to identify any pathologic variants, its expression was abolished within the tumor. CONCLUSIONS: We report the first description of a pigmented choroidal schwannoma in the context of a PHTS. This rare tumor showed a unique combination of reduction of PTEN and absence of NF2 expression.

Chiasmatic infiltration secondary to late malignant transformation of retinoma.

PURPOSE: To report the lethal course of malignant transformation of retinoma in an adult. METHODS: Case report. A 40-year-old patient presented with retinoma in his right eye and retinoblastoma in his left eye. Enucleation was recommended but refused and the patient received whole eye radiotherapy elsewhere. Five years later he presented again, with temporal hemianopsia of the left eye secondary to chiasmatic invasion. RESULTS: Diagnosis of retinoblastoma infiltration was confirmed by stereotactic biopsy of the chiasmatic lesion. Treatment with intravenous and intrathecal chemotherapy led to partial remission, and was followed by stereotactic irradiation of the chiasmatic mass and right optic nerve. The left eye was enucleated. Death occurred one year later due to cerebrospinal fluid metastases. CONCLUSION: Extraocular extension of retinoblastoma diagnosed in adulthood has never, to our knowledge, been reported. This case stresses the importance of lifelong retinoma monitoring and the necessity for radical treatment in the event of malignant transformation.

Peripheral exudative hemorrhagic chorioretinopathy: a clinical, angiographic, and histologic study.

PURPOSE: To describe the clinical and angiographic characteristics of peripheral exudative hemorrhagic chorioretinopathy, an uncommon chorioretinal mass lesion, important for its differential diagnosis to choroidal melanoma, but only rarely described in the literature. DESIGN: Retrospective, institutional chart review. METHODS: Institutional chart review of 45 patients (56 eyes) diagnosed with peripheral exudative hemorrhagic chorioretinopathy to describe the clinical findings and those obtained by fluorescein angiography (FA) and indocyanine green angiography (ICGA), in addition to a review of the histologic findings of an enucleated eye. RESULTS: Peripheral exudative hemorrhagic chorioretinopathy typically was characterized by increased age of the patient (mean, 77 years; range, 60 to 91 years), female preponderance (69%), frequent pigment epithelium detachment, temporal equatorial location, and a highly hemorrhagic and exudative presentation, sometimes extending to the macula. Bilateral involvement (24%) was associated with multiples lesions in the same eye (P < .001) and with nasal extension (P < .001). A neovascular origin was suspected on FA, but was more evident on ICGA. Histologic examination of the enucleated eye did not reveal a neovascular network. CONCLUSIONS: Peripheral exudative hemorrhagic chorioretinopathy is a characteristic peripheral degenerative disorder, frequently with benign outcome, although it can be vision threatening because of hemorrhage or exudation. Clinical features are helpful for its diagnosis. FA and ICGA contribute valuable evidence to the hypothesis of a neovascular origin, but further histologic studies are needed to prove this hypothesis.

Clinicopathological features of eyelid skin tumors. A retrospective study of 5504 cases and review of literature.

Eyelid tumors are the most common neoplasm in daily ophthalmology practice and encompass a wide variety of benign and malignant tumors. In this retrospective study, we report the clinical and histological features of 5504 eyelid skin tumors diagnosed at the Laboratory of Ophthalmopathology of the Hôpital Ophtalmique Jules Gonin, Lausanne, Switzerland, between January 1989 and December 2007. Benign tumors largely predominated over malignant ones, representing 84% of cases in this series, and the 5 most frequent subtypes were squamous cell papilloma (26%), seborrheic keratosis (21%), melanocytic nevus (20%), hidrocystoma (8%), and xanthoma/xanthelasma (6%). Basal cell carcinoma was the most frequent malignant tumor (86%), followed by squamous cell carcinoma (7%) and sebaceous carcinoma (3%). For several tumor subtypes, there was a poor correlation between clinical and histological diagnosis, stressing the numerous pitfalls in the diagnosis of eyelid tumors. We further discuss our results with reference to previously published series.

Ultrastructural changes of the internal limiting membrane removed during indocyanine green assisted peeling versus conventional surgery for idiopathic macular epiretinal membrane.

PURPOSE: To evaluate the histologic features of cellular retinal fragments on the internal limiting membrane (ILM) removed during idiopathic macular epiretinal membrane (MEM) peeling surgery with and without the aid of indocyanine green (ICG) diluted in 5% glucose. METHODS: ILM specimens removed from 88 eyes during idiopathic MEM surgery between 1995 and 2003 were reviewed retrospectively. Histologic analysis focused on the presence and characteristics of retinal fragments on the retinal surface of the ILM. Statistical analysis compared the results between group I (conventional surgery) and group II (ICG-assisted peeling). RESULTS: Seventy-one eyes underwent MEM surgery without the aid of ICG (group I) and seventeen underwent MEM ICG-assisted surgery (group II). The amount of Müller cell debris on the retinal surface of the ILM was more significant in the group I than in the group II (40.8 vs. 11.8; P = 0.024). Large fragments of Müller cells were more frequently observed in the group I (no ICG) than in the group II (ICG) (63.4 vs. 23.5%; P = 0.003). CONCLUSIONS: The use of ICG diluted with 5% glucose in ILM removal during MEM surgery was associated with less retinal debris attached to the retinal face of the ILM compared with surgery in which ICG was not used.

Utility of a biopsy in suspicious pigmented iris tumors.

BACKGROUND: In the presence of pigmented iris lesions evocative of malignant melanoma and implying oncological treatment, a foregoing biopsy to exclude a benign lesion may seem a reasonable approach. After examining patient files, the utility of such a diagnostic approach was explored. MATERIAL AND METHODS: Retrospective, consecutive histopathologic case series of 10 pigmented iris tumor specimens excised since 1993. Histopathologic diagnosis was compared with final diagnosis and outcome in the patient's medical chart. RESULTS: Five biopsies had only nevus cells, whereas ulterior clinical data or histopathologic examinations were compatible with the diagnosis of malignant melanoma. One biopsy contained insufficient sample tissue. Four biopsies confirmed clinical suspicion of iris melanoma. CONCLUSION: In the current case series, 6 out of 10 biopsies provided a falsely reassuring negative or an inconclusive result. Modern management techniques such as ultrasound biomicroscopy and proton therapy of the whole anterior segment have equally diminished indications for a biopsy. In cases clinically evocative of iris melanoma, a biopsy has only a relative value.

Tearing and folding of the retinal internal limiting membrane associated with macular epiretinal membrane.

PURPOSE: To describe the clinical and histologic features of a particular form of macular epiretinal membrane. METHODS: The charts of all patients operated for macular epiretinal membrane by a single surgeon (E.H.B.) between June 2001 and January 2005 were retrospectively reviewed. Patients with macular epiretinal membrane associated with tearing and folding of the internal limiting membrane (ILM) were identified and the following parameters were recorded when available: age, gender, best-corrected visual acuity before and after vitrectomy; optical coherence tomography; pre-, intra-, and postoperative macular status; intraoperative staining by indocyanine green; histology. RESULTS: Twenty-three of 268 eyes (8.6%) with macular epiretinal membrane were associated with tearing and folding of the ILM, forming a whitish prominent band on the surface of the retina. The mean age of the patients was 68.6 years with a significant female predominance (78.3%). The vitreous was completely detached in 21 eyes. After surgical peeling, the mean visual gain was 3.2 Early Treatment Diabetic Retinopathy Study lines. No recurrence was observed. CONCLUSION: Tearing and folding of the ILM was associated with macular epiretinal membranes in 8.6% of cases. The ILM was probably torn during posterior hyaloid detachment, but the pathogenesis has not been clearly elucidated. The surgeon should begin to peel the macular epiretinal membrane by grasping the folded ILM to ensure complete removal of the ILM together with the epiretinal membrane. The postoperative visual prognosis was good.

Conjunctival intraepithelial neoplasia in a patient treated with tacrolimus after liver transplantation.

PURPOSE: To report a case of conjunctival intraepithelial neoplasia in a patient treated with tacrolimus after liver transplantation for hepatic carcinoma. METHODS: Description of the initial clinical presentation of a patient, tumor management, and 15-month follow-up. RESULTS: A 70-year-old man presented with a conjunctival intraepithelial neoplasia that developed on the site of a preexisting pterygium. After total surgical removal and additional application of mitomycin, local tumor control was achieved. CONCLUSIONS: We describe a case of intraepithelial conjunctival neoplasia in a patient treated with systemic tacrolimus. Local tumor control was achieved at 15 months after appropriate surgical management.

Tumors of the caruncle: a clinicopathologic correlation.

PURPOSE: To determine the types and incidence of caruncular lesions and to investigate the correlation between clinical and histologic diagnosis. DESIGN: Retrospective, observational case series. METHODS: Records of patients with a lesion of the caruncle that was excised and submitted to our ocular pathology department between January 1979 and May 2005 were reviewed. Lesions were classified by histologic type and correlated with patient age, gender, and preoperative clinical diagnosis. RESULTS: A total of 195 consecutive caruncular lesions from 191 patients were identified. Twenty-four different types of lesions were identified; the most common were nevi (n = 92, 47%) and papillomas (n = 29, 15%). One keratoacanthoma was identified. One hundred eighty-three lesions (93.8%) were benign, six (3.1%) were premalignant, and five (2.6%) were malignant. Preoperative clinical diagnosis corresponded to postexcision histologic diagnosis in 73 cases (37.4%). Suspected malignancy was a common reason for excision (61 cases, 31.3%), but malignancy was confirmed in only three (4.9%) of 61 cases. Two of the five malignant lesions were clinically thought to be benign. CONCLUSIONS: We hereby report the first caruncular keratoacanthoma. The rarity and variety of caruncular lesions make clinical diagnosis difficult. Malignancy is clinically overestimated, and some malignant lesions can take a benign aspect, justifying close photographic follow-up of all lesions. Because caruncular malignant melanoma is associated with poor prognosis, pigmented lesions should be monitored carefully. In the absence of clear criteria for malignancy, any change in color, size, or vascularization of a caruncular lesion should hasten excision.

Systemic investigation of keratoepithelin deposits in TGFBI/BIGH3-related corneal dystrophy.

PURPOSE: To investigate the location and tissue-specificity of the pathologic keratoepithelin (KE) deposition in a patient with a keratoepithelinopathy (KEP), TGFBI/BIGH3-related corneal dystrophy. METHODS: An autopsy was performed in a patient with lattice type I corneal dystrophy (LCDI) after authorization was obtained from the family. Mutation screening in TGFBI/BIGH3 was done on the patient several years ago. Eighteen different tissues or organs, including brain, heart, lung, kidney, liver, lymph nodes, spleen, aorta, esophagus, bone marrow, urinary bladder (including a papillary urothelial carcinoma), samples of a metastatic squamous cell carcinoma, adrenal gland, parathyroid gland, muscle, prostate, and cornea were investigated, and sections from the tissues were labeled with KE2 rabbit TGFBI/BIGH3 antiserum. RESULTS: The patient, diagnosed with LCDI and Alzheimer's disease, died at 79 years of age from a complicated chronic obstructive lung disease. Mutation analysis showed the classical Arg124Cys mutation in exon 4 of TGFBI/BIGH3, associated with LCDI. Except for the cornea, immunostaining with KE2 antisera did not reveal any deposits in any of the 17 other organs analyzed. CONCLUSIONS: Pathologic deposits caused by KE accumulation were only observed in the cornea and in no other tissue or organ in this patient. These results suggest a cornea-specific mechanism in the aggregation of KE. Further studies need to be done to investigate whether the degradation of mutated KE generates cornea-specific fragments that aggregate or whether the clearing of normal fragments is different in affected corneas, which then leads to aggregation.

Outflow mechanisms after deep sclerectomy with two different designs of collagen implant in an animal model.

BACKGROUND: To study experimentally two different shapes of collagen implants (CI) used in deep sclerectomy (DS). The ability to promote drainage vessels, outflow mechanisms, success rates, and biodegradability, were studied prospectively in an animal model. MATERIALS AND METHODS: DS was performed in 20 eyes of ten rabbits. Each rabbit randomly received a cylindrical CI in one eye, while the other eye received a flat CI. Intraocular pressure (IOP) measurement, ultrasound biomicroscopy (UBM) examination of DS site and simultaneous fluorescein and indocyanin green anterior-segment angiography were performed preoperatively, at 1 and 2 weeks, 1, 2, 3, 6 and 9 months for each eye. At the end of the follow-up period, outflow facility (OF) was measured and histological examinations of the filtration site were performed. RESULTS: In the cylindrical implant group, IOP significantly dropped from a mean pre-operative value of 14.8+/-2.2 mmHg to a mean postoperative values of 10.9+/-3.3, 12.5+/-2.2, 11.8+/-2.6, 11.2+/-2.3, 10.7+/-1.9, 14.0+/- 3.2, 12.6+/-2.4 mmHg at 1, 2 weeks, and 1, 2, 3, 6, and 9 months, respectively. In the flat CI group, IOP significantly dropped from a mean preoperative value of 14.1+/-1.8 mmHg to a mean postoperative values of 10.4+/-2.7, 12.7+/-1.9, 12.5+/-3.2, 11.2+/-1.6, 11.6+/-1.8, 11.5+/-2.3, 11.0+/-2.2 mmHg at 1, 2 weeks, and at 1, 2, 3, 6, and 9 months, respectively. UBM images showed a gradual resorption of both type of CI during the first 3 months, and angiographies showed progressive growth of drainage vessels around the filtration site in both groups. The mean OF 9 months postoperatively for the cylindrical CI was 0.53 (SD +/- 0.23) ml/ min per mmHg and was 0.56 (SD+/-0.17) ml/min per mmHg for the flat CI (P=0.6). Histological examination revealed excellent biocompatibilty and a high density of drainage vessels in the sclera around the operative site in both groups. CONCLUSION: Using IOP and OF measurements, UBM, angiography, and histology, we were able to compare two types of CI used as space maintainer in DS. Both CIs showed efficient IOP lowering effect and outflow facility increase, possibly explained by stimulation of drainage vessels growth. Both implants showed excellent biocompatibility. The flat CI showed a slight tendency towards better overall performances.

Peripapillary choroidal neovascularization associated with melanocytoma of the optic disc: a clinicopathologic case report.

BACKGROUND: Melanocytoma of the optic disc is a benign melanocytic tumor that rarely causes visual impairment. We report a case of a melanocytoma of the optic disc with a decreased vision related to a peripapillary choroidal neovascular membrane (PCNVM) that was successfully treated by submacular surgery. METHODS: A 45-year-old southern European patient had a melanocytoma of the optic disc in his left eye with vision of 20/100. Fluorescein angiography demonstrated a PCNVM impeding the fovea associated with a subretinal hemorrhage. RESULTS: The patient underwent a complete vitrectomy and removal of the PCNVM. Subsequently, the subretinal hemorrhage disappeared and visual acuity improved to 20/25. Visual acuity remained good for a period of 14 months' follow-up without any recurrence of neovascular membrane. CONCLUSIONS: Submacular surgery is a potentially effective treatment for large PCNVM associated with a melanocytoma of the optic disc.

Surgery for epimacular membrane: impact of retinal internal limiting membrane removal on functional outcome.

PURPOSE: To examine eyes that underwent vitrectomy and peeling of epimacular membrane and to correlate the functional results with the presence or absence of an internal limiting membrane (ILM) in the histologic specimens. METHODS: Seventy-one eyes underwent vitrectomy and peeling of an epimacular membrane. These membranes were examined with a transmission electron microscope. Best-corrected visual acuities were recorded before macular surgery, 1 month after surgery, and at the final examination and were compared between group 1 (ILM removed) and group 2 (ILM not removed). The age, gender, status of the lens preoperatively, type of epimacular membrane (idiopathic or secondary), intraoperative and postoperative complications, and elapsed time between vitrectomy and cataract operation were recorded. All 71 eyes were pseudophakic at the final examination. The mean follow-up was 21 months. RESULTS: Long segments of ILM were found in the specimens from 55 (77%) of the cases. Final visual acuities were better in group 1 (ILM removed) than in group 2 (ILM not removed, P = 0.004). The visual gain was 3.1 lines on the Early Treatment of Diabetic Retinopathy Study chart in group 1 and 0.9 lines in group 2. At the last examination, a recurrent epimacular membrane was observed in 5 (9%) eyes of group 1 and 9 (56%) eyes of group 2. CONCLUSION: ILM removal during surgery for epimacular membrane is associated with better final vision and a lower risk of recurrent epimacular membrane.

CRYBA3/A1 gene mutation associated with suture-sparing autosomal dominant congenital nuclear cataract: a novel phenotype.

PURPOSE: To identify the genetic defect leading to the congenital nuclear cataract affecting a large five-generation Swiss family. METHODS: Family history and clinical data were recorded. The phenotype was documented by both slit lamp and Scheimpflug photography. One cortical lens was evaluated by electron microscopy after cataract extraction. Lenticular phenotyping and genotyping were performed independently with short tandem repeat polymorphism. Linkage analysis was performed, and candidate genes were PCR amplified and screened for mutations on both strands using direct sequencing. RESULTS: Affected individuals had a congenital nuclear lactescent cataract in both eyes. Linkage was observed on chromosome 17 for DNA marker D17S1857 (lod score: 3.44 at theta = 0). Direct sequencing of CRYBA3/A1, which maps to the vicinity, revealed an in-frame 3-bp deletion in exon 4 (279delGAG). This mutation involved a deletion of glycine-91, cosegregated in all affected individuals, and was not observed in unaffected individuals or in 250 normal control subjects from the same ethnic background. Electron microscopy showed that cortical lens fiber morphology was normal. CONCLUSIONS: The DeltaG91 mutation in CRYBA3/A1 is associated with an autosomal dominant congenital nuclear lactescent cataract. A splice mutation (IVS3+1G/A) in this gene has been reported in a zonular cataract with sutural opacities. These results indicate phenotypic heterogeneity related to mutations in this gene.

Melanocytomas of the optic disk.

PURPOSE: To evaluate the various forms of clinical presentation, the potential of growth, the risk of functional loss and the possibility of malignant transformation of optic disk melanocytomas in European patients. DESIGN: Retrospective observational case control study. METHODS: Evaluation of 37 cases of optic disk melanocytomas identified in the computer files of the ocular oncology unit of Jules Gonin Hospital to determine the clinical presentation of these tumors and the risk of complications. RESULTS: The tumor was asymptomatic in 28 cases. Visual acuity was normal in 26 cases, subnormal in 10 cases, and in one case it was reduced to 0.1. Visual field defects were observed in 19 cases; the size and extent of the tumor and the degree of papilledema appeared to influence the severity of the visual field defect. Tumor growth was demonstrated in 6 of the 9 cases in which follow-up was for at least six years. In two cases there was presumed malignant transformation that was treated by accelerated proton beam radiotherapy. CONCLUSIONS: Melanocytomas in white Europeans and those of European derivation are rarely symptomatic, have only a moderate effect on visual function and show a low rate of progression over long observation. The risk of tumor progression, although sometimes occurring as much as several years after the initial diagnosis, justifies a cautious approach with long-term regular surveillance of these patients.

[Histopathological study of corneal lamella excised after complications of myopia treatment with LASIK]. / Etude histopathologique d'une lamelle de cornée excisée après complications de traitement de myopie par Lasik.

BACKGROUND: Several complications may occur after Lasik surgery, some of which can lead to corneal scarring and irreversible visual loss. We report such a case, with a clinicopathologic correlation. HISTORY AND SIGNS: A forty-seven-year-old patient with a - 6 D myopia had a Lasik performed with a 160 micron Moria microkeratome. This was complicated by the occurrence of a free cap which was sutured 3 times and of an epithelial ingrowth which was scraped. THERAPY AND OUTCOME: A superficial lamellar graft was performed 1S year later because of persistent photophobia and discomfort. Three weeks later the patient had a clear graft and was symptom free. Light microscopy showed an epithelial ingrowth, peripheral breaks and folds of Bowman's membrane, peripheral folds of superficial stroma with fibrosis and compensatory corneal epithelium acanthosis. There is keratolysis of the central stroma. By electron microscopy, the disrupted stroma showed activated fibroblasts, and the superficial epithelium is immature. Pathogenesis of these complications is discussed. CONCLUSIONS: The patient's clinical symptoms are to a certain extent explained by the histopathological findings. Epithelial ingrowth must be treated in time to avoid keratolysis.

Massive vascular endothelium growth factor (VEGF) expression in Eales' disease.

BACKGROUND: Eales' disease is an idiopathic retinal vasculitic and vaso-occlusive process complicated by extensive retinal neovascularisation and vitreous hemorrhages. The great propensity to produce retinal neovessels is one of the particular aspects of the disease that deserves to be further investigated. We report a case of Eales' disease having evolved over more than three decades, with a typical clinical presentation in one eye, while the other eye had to be enucleated because of a terminal neovascular glaucoma, thus allowing pathological examination. METHODS: The functional right eye was treated by vitrectomy, cerclage, cryocoagulation and endolaser. The non-functional phthitic left eye was enucleated and submitted for histopathological and immunohistochemical examination using antibodies against vascular endothelial growth factor, T-cells, B-cells and Müller cells. RESULTS: Evolution was favourable in the operated right eye, following management of the inflammatory reaction. The histopathological examination of the left eye revealed an occlusion of the anterior chamber angle by rubeosis iridis, tractional retinal detachments, pre-, intra- and sub-retinal neovascular membranes, and vitrous hemorrhages. Diffuse positive anti-VEGF immunostaining was found at the level of the retinal neovascular membranes. The retina exhibited prominent Müller cell immunostaining, indicating extensive gliosis, and predominantly B cell infiltrates were found in the eye. CONCLUSION: The present study indicates a close relationship between the prominent neovascular proliferation in Eales' disease and the intense expression of VEGF. The increased expression of VEGF, when compared to other conditions inducing neovascularisation, might explain the severity of neovascular growth and the propensity of repeated vitrous hemorrhages in Eales' disease.

BIGH3 mutation spectrum in corneal dystrophies.

PURPOSE: To investigate the molecular pathology underlying BIGH3-related corneal dystrophies (CDs) and to further delineate genotype-phenotype specificity. METHODS: Sixty-one index patients with CDs were subjected to phenotypic and genotypic characterization. The corneal phenotypes of all patients were assessed by biomicroscopy and documented by slit lamp photography. The BIGH3 gene was amplified exon by exon from constitutional DNA to perform single-strand conformation polymorphism (SSCP) analysis, followed by direct bidirectional sequencing of abnormal conformers. RESULTS: The phenotypes of CDs were classified as lattice CD in 30 patients, Groenouw type I in 12 (CDGGI), Avellino in 7 (CDA), Reis-Bückler in 8 (CDRB), and Thiel-Behnke in 4 (CDTB). Fifty occurrences of 16 distinct mutations were identified, including 8 novel mutations responsible for lattice type IIIA in three patients (CDLIIA), intermediate type I/IIIA (CDLI/IIIA) in four patients, and atypical CDL with deep deposits in one patient (CDL-deep). CONCLUSIONS: Disease-causing mutations were identified in 80% of the patients (50/61). All mutations localize in two regions of kerato-epithelin: the amino acid R124 and BIGH3 fasc domain 4. This study also confirms the mutation hot spot at positions R124 and R555 with nearly 50% of the mutations targeting these two amino acids (24/50). In addition the corneal phenotypes induced by changes at R124 and R555 are amino acid specific: R124C in CDLI, R555W and R124S in CDGGI, R124H in CDA, R124L in CRRB, and R555Q in CDTB. In CDLIIIA, CDLI/IIIA, and CDL-deep the genotype-phenotype correlation is domain specific, with all changes occurring at the boundary or within the fasc4 domain.