Attenuated familial adenomatous polyposis (AFAP). A phenotypically and genotypically distinctive variant of FAP.

BACKGROUND: The usual manifestation of familial adenomatous polyposis (FAP) is hundreds or thousands of colonic adenomas. The authors previously described a colon cancer-prone syndrome characterized by fewer adenomas (1-100), most located in the proximal colon, and upper gastrointestinal lesions, particularly fundic gland polyps and duodenal adenomas. The colonic adenomas are often flat rather than polypoid, a feature emphasized in earlier reports with the term "hereditary flat adenoma syndrome." The syndrome has an autosomal dominant pattern of inheritance and is linked to the adenomatous polyposis coli (APC) locus at 5q. METHODS: This is a descriptive study based on one family that was followed for more than a decade. Total cell RNA was isolated from cultured lymphoblasts, and an in vitro protein synthesis assay was used to detect APC mutations. Sixteen individuals whose APC mutation status was known had sequential endoscopic evaluations. Five patients were given one or more courses of sulindac. RESULTS: There was perfect concordance between clinical affected status and an APC mutation. All affected members generated a 16-kDa polypeptide from the mutant allele, consistent with a 2-base pair deletion at the extreme 5' end of the APC gene. Sixteen mutation-positive individuals underwent upper gastrointestinal endoscopy and colonoscopy; 13 had colonic adenomas, with the number visualized at any one examination ranging from 1 to greater than 50. Upper gastrointestinal examination revealed fundic gland polyps in 15, gastric or duodenal adenomas in 4, and periampullary carcinoma in 1. CONCLUSION: AFAP is a phenotypically distinctive syndrome, differing from classic FAP by having fewer colonic adenomas that tend to be proximally distributed and flat rather than polypoid. The position of the APC germline mutation appears to allow for the molecular differentiation between FAP and the attenuated variant in that the extreme 5' APC mutations are associated with the latter.

Linkage of Usher syndrome type I gene (USH1B) to the long arm of chromosome 11.

Usher syndrome is the most commonly recognized cause of combined visual and hearing loss in technologically developed countries. There are several different types and all are inherited in an autosomal recessive manner. There may be as many as five different genes responsible for at least two closely related phenotypes. The nature of the gene defects is unknown, and positional cloning strategies are being employed to identify the genes. This is a report of the localization of one gene for Usher syndrome type I to chromosome 11q, probably distal to marker D11S527. Another USH1 gene had been previously localized to chromosome 14q, and this second localization establishes the existence of a new and independent locus for Usher syndrome.

Phenotypic variation in colorectal adenoma/cancer expression in two families. Hereditary flat adenoma syndrome.

Clinical, pathologic, and genetic studies on two colorectal cancer-prone families have disclosed right-sided colonic flat adenomas and colorectal cancer. Adenomatous polyp counts exceeded those found in hereditary nonpolyposis colorectal cancer (HNPCC) but were fewer than in familial adenomatous polyposis (FAP). Colon cancer occurred at a later age than in HNPCC or FAP and showed right-sided predominance. The older age of patients with colonic cancer, the right-sided predominance of colon cancer, and the paucity of rectal adenomas make FAP unlikely. Vertical transmission of polyps and colon cancer fit the pattern of autosomal dominant inheritance. A characteristic feature of this phenotype is the predominance of flat adenomas. Molecular genetic studies, with careful description of phenotype, should help clarify classification.

Localization of Usher syndrome type II to chromosome 1q.

Usher syndrome is characterized by congenital hearing loss, progressive visual impairment due to retinitis pigmentosa, and variable vestibular problems. The two subtypes of Usher syndrome, types I and II, can be distinguished by the degree of hearing loss and by the presence or absence of vestibular dysfunction. Type I is characterized by a profound hearing loss and totally absent vestibular responses, while type II has a milder hearing loss and normal vestibular function. Fifty-five members of eight type II Usher syndrome families were typed for three DNA markers in the distal region of chromosome 1q: D1S65 (pEKH7.4), REN (pHRnES1.9), and D1S81 (pTHH33). Statistically significant linkage was observed for Usher syndrome type II with a maximum multipoint lod score of 6.37 at the position of the marker THH33, thus localizing the Usher type II (USH2) gene to 1q. Nine families with type I Usher syndrome failed to show linkage to the same three markers. The statistical test for heterogeneity of linkage between Usher syndrome types I and II was highly significant, thus demonstrating that they are due to mutations at different genetic loci.

Usher syndrome: clinical findings and gene localization studies.

The issue of genetic heterogeneity is a critical problem in the localization of the gene(s) for Usher syndrome. Based on the data obtained on families studied to date, the differences between type I and type II Usher syndrome appear quite distinct with regard to auditory and vestibular function. Although the majority of families can be confidently diagnosed as typical type I or type II, clinical investigations revealed four families with findings that did not fit into either of the two more common subtypes. These findings emphasize the critical importance of an in-depth clinical analysis concomitant with the linkage investigation to assure accurate subtyping of Usher syndrome. Based on an analysis of only those families with definite type I or type II Usher syndrome, approximately 17% of the genome can be excluded as a potential site of the gene for type I, and 14% can be excluded as the site for the type II gene. This study will continue until the Usher gene(s) is successfully localized.

Usher syndrome: an otoneurologic study.

Usher syndrome is an autosomal recessive disorder characterized by severe hearing loss or deafness and retinitis pigmentosa. Eleven families with 25 affected members were studied. The test battery included genetic studies, clinical examination, audiological, ophthalmologic, and otoneurological tests, and magnetic resonance imaging. Sixteen affected persons had profound hearing loss or were considered anacusic, with absent bilateral vestibular responses. These patients had varying degrees of retinitis pigmentosa. These 16 patients were considered to have type I Usher syndrome. Nine persons were diagnosed as Usher type II with a moderate to profound hearing loss, normal vestibular function, and retinitis pigmentosa of varying degree. Magnetic resonance imaging was normal in all cases. Otoneurological tests indicated no central nervous system disturbances. The conclusion is that hearing loss and balance problems in Usher syndrome are due to inner ear damage with no evidence of central nervous system disturbances. Furthermore, the ataxia seen in Usher type I is due to a combination of retinitis pigmentosa and bilateral peripheral vestibular deficiency.

Long-term follow-up of occlusion of the central retinal vein in young adults.

We did a long-term follow-up study of 42 patients aged 40 years and younger who had occlusion of the central retinal vein in order to learn its course and determine the frequency of related systemic disorders. Two groups of venous occlusion (complete and incomplete) were delineated by initial ocular findings. Final visual prognosis could not be predicted by the severity of the venous occlusion at the time of diagnosis. The presence of anomalous disk vessels closely correlated with a favorable prognosis in patients who had complete occlusion of the central retinal vein. None of the patients with incomplete central vein occlusion developed neovascular glucoma; three (14%) of the 21 patients with complete venous occlusion developed neovascular glucoma, which resulted in enucleation. Significant associated systemic maladies included cardiovascular disease and diabetes mellitus. An apparent correlation exists between occlusion of the central retinal vein and early death.

360 degrees prophylactic cryoretinopexy. A clinical and experimental study.

Complications occurred after 360 degrees prophylactic cryoretinopexy in three of six eyes in which fellow eyes had previously developed aphakic retinal detachment. Two of the six prophylactically treated eyes developed retinal detachment in advance of anticipated cataract surgery, and a third developed vitreitis and progressive preretinal membrane formation after uncomplicated cataract extraction. In an experiment study with rhesus monkeys, preretinal membrane formation was produced by administering heavy freezes with 360 degrees cryoretinopexy. Although the quantities of cold were considered excessive for clinical use, the cryoretinopexy used clinically in this series must also be considered excessive. The use of 360 degrees cryoretinopexy in the management of eyes at high risk for retinal detachment must be considered judiciously. Particular caution must be exercised in administering cryoretinopexy to nondetached retinas so as to avoid heavy freezes, which destroy the linear retinal layers.

What patients recall of the preoperative discussion after retinal detachment surgery.

We conducted a prospective study to determine the percentage of preoperative information that was retained by 100 patients undergoing a scleral buckling procedure. Each patient received a standardized preoperative discussion regarding the nature of retinal detachment and its management. During the immediate postoperative period, each patient was questioned about the informed consent discussion. Although 97% of the patients acknowledged a thorough preoperative discussion there was a definite disparity between the patients' concept of adequate physician disclosure and the actual retention of the preoperative explanation. Overall retention of preoperative disclosure based on correct answers to 12 questions was only 57%. Few patients, 23%, retained knowledge of surgical risks, and only 61% remembered that a foreign material would be permanently sutured to the eye. When a patient failed to remember the correct answer to a question, more than half of the time he or she denied that information relevant to the question had been discussed. The results of this study indicate that patients retain primarily information that seems to be in favor of their decision to have surgery.

Immune responsiveness in patients with choroidal malignant melanoma.

We studied selective in vivo and in vitro immunologic factors of 25 patients with choroidal malignant melanoma. Immune profile factors did not show consistent differences between patients with melanoma and an age-matched control population. The studies were also non-contributory in delineating variations in immunocompetence with respect to melanoma cell types. Serial immune profiles failed to identify a change when clinical evidence of metastasis developed. When tested as a group, patients with melanoma in whom metastatic disease developed during the study showed significant depression of initial mitogen-induced lymphocyte blastogenesis. This depression was noted in advance of clinically recognized metastatic disease. This group had a wide range of responses that overlapped those of control patients, thus making the usefulness of these testing factors questionable for individual prognosis or for clinical monitoring.

Impending central retinal vein occlusion associated with increased platelet aggregability.

A case is presented of an impending central retinal vein occlusion, venous stasis retinopathy, seen in an otherwise healthy 57-year-old woman. The patient demonstrated hyperactive platelets when tested for primary and secondary aggregation. Coagulation tests and platelet count were normal. It is proposed that such an abnormality in platelet function, when present, can be an important factor in the pathogenesis of impending central retinal venous occlusion. Antiplatelet therapy may be used in the management of this hemodynamic alteration.

Acute macular neuroretinopathy.

A 17-year-old boy had minor visual impairment, paracentral scotomata, and parafoveal retinal lesions following a presumed viral infection. Contact lens biomicroscopy demonstrated the retinal defects to be located at the level of the deep sensory retina. Fluorescein angiography revealed subtle areas of hypofluorescence which corresponded to the visible disturbances of the sensory retina. Follow-up examination three months later revealed persistent complaints of paracentral scotomata and persistent, but less recognizable retinal lesions. We believe the primary site of involvement to be the deep sensory retina.