William J. Kimberling

Autosomal dominant polycystic kidney disease: Localization of the second gene to chromosome 4q13–q23

At least two loci are known to exist for autosomal dominant polycystic kidney disease (ADPKD). One was localized to 16p, but the second less common locus has remained unlinked. Over 100 microsatellite markers, distributed across all chromosomes, have been typed on informative family members from the large Sicilian kindred in which the genetic heterogeneity was first discovered. Both the affected and the unaffected status of every family member used in the study were confirmed by renal ultrasonography. This search has resulted in the successful localization of a second ADPKD gene to chromosome 4q. It was found to be flanked by the markers D4S231 and D4S414, defining a segment that spans about 9 cM. The new locus has been designated PKD4. This second localization will allow researchers to target another ADPKD gene for isolation in an effort to understand the pathogenesis of this common disorder. Furthermore, when flanking markers for the second ADPKD gene are used in conjunction with flanking markers for PKD1, the accuracy of the diagnosis of the subtype of ADPKD present in any particular family will be enhanced. This will improve the accuracy of linkage-based presymptomatic diagnoses by reducing the error due to genetic heterogeneity.

Natural history of hereditary cancer of the breast and colon

The natural history of 106 patients from eighteen families manifesting hereditary breast cancer syndromes, and 117 affected patients from twenty families manifesting nonpolyposis hereditary colon cancer were evaluated. Findings were compared with the American College of Surgeons (ACS) long‐term audits for breast and colon cancer respectively. The cardinal features of hereditary cancer were observed within the study group, including: (1) a significant younger age of onset (49 years, breast; 46 years, colon); (2) an excess of proximal lesions in the hereditary colon series (49%); and (3) an excess of bilaterality in the hereditary breast cancer patients. The clinical stage at presentation was similar for the hereditary and ACS audit patients. Five‐year survival was significantly improved (P < .05) for both hereditary cancer populations as compared to the ACS audits (67% hereditary breast cancer and 52% nonpolyposis hereditary colon cancer). Improved survival in hereditary colon and breast cancer patients may have a bearing on the design of future clinical protocols.

Familial atypical multiple mole-melanoma (FAMMM) syndrome: Segregation analysis

Genetic analysis was performed on four kindreds with clinical and pathological verification of the FAMMM syndrome. There were 80 affected or at risk members in these families. A segregation ratio of 0.47 was observed, which is consistent with an autosomal dominant mode of inheritance. Three obligate gene carriers who lacked any FAMMM phenotypic manifestations were observed and the rate of penetrance for the FAMMM gene was calculated to be 0.93. Cancer at all anatomical sites (exclusive of cutaneous malignant melanoma and intraocular malignant melanoma) showed a five-fold increase (p less than 0.004) in risk for gene carriers when age corrected and compared to the population expectation. Although there was an apparent excess of carcinoma of the lung, pancreas, and breast, the number of family members studied with specific organ cancer was too small; therefore, a larger sample size will be needed to verify this apparent excess. Our findings warrant further investigation in additional FAMMM kindreds.

A New Clinical Classification for Usher's Syndrome Based on a New Subtype of Usher's Syndrome Type I

Objectives Ushers syndrome is an autosomal recessive disorder characterized by sensorineural hearing loss and progressive visual loss secondary to retinitis pigmentosa. Ushers syndrome is both clinically and genetically heterogeneous. Three clinical types are known today.

Familial colon cancer in the Tel‐Aviv area and the influence of ethnic origin

The family history of colon cancer was investigated in 38,823 individuals (2,129 families) who comprised a control and an oncology patient series from Tel‐Aviv and nearby areas. A significant increased risk for colon cancer was observed among first‐degree relatives of colon cancer patients when compared to controls. When the patient sample was divided into two groups based on country and continent of birth—European (Ashkenazim) and other (non Ashkenazim)—the relatives of the nonAshkenazi subjects showed a greater relative risk for colon cancer (P < 0.05). Colon cancer was found to be less frequent in nonAshkenazim than in Ashkenazim controls. These findings suggest that although the colon cancer frequency in the nonAshkenazi group is lower, the genetic component may be more important than for the Ashkenazi sample. The nonAshkenazi Jews may represent distinct subgroups that differ with respect to either primary genetic susceptibility to colorectal cancer and/or they may have been subjected to peculiar, environmental carcinogenic exposures when compared to their Ash‐kenazim brethren.

Presence of De Novo Mutations in Autosomal Dominant Polycystic Kidney Disease Patients Without Family History

BACKGROUND At the University of Colorado Health Sciences Center, on detailed questioning, approximately 10% of patients with autosomal dominant polycystic kidney disease (ADPKD) gave no family history of ADPKD. There are several explanations for this observation, including occurrence of a de novo pathogenic sequence variant or extreme phenotypic variability. To confirm de novo sequence variants, we have undertaken clinical and genetic screening of affected offspring and their parents. STUDY DESIGN Case series. SETTING & PARTICIPANTS 24 patients with a well-documented ADPKD phenotype and no family history of polycystic kidney disease (PKD) and both parents of each patient. OUTCOME Presence or absence of PKD1 or PKD2 pathogenic sequence variants in parents of affected offspring. MEASUREMENTS Abdominal ultrasound of affected offspring and their parents for ADPKD diagnosis. Parentage testing by genotyping. Complete screening of PKD1 and PKD2 genes by using genomic DNA from affected offspring; analysis of genomic DNA from both parents to confirm the absence or presence of all DNA variants found. RESULTS A positive diagnosis of ADPKD by means of ultrasound or genetic screening was made in 1 parent of 4 patients (17%). No PKD1 or PKD2 pathogenic sequence variants were identified in 10 patients (42%), whereas possible pathological DNA variants were identified in 4 patients (17%) and 1 of their respective parents. Parentage was confirmed in the remaining 6 patients (25%), and de novo sequence variants were documented. LIMITATIONS Size of patient group. No direct examination of RNA. CONCLUSION Causes other than de novo pathogenic sequence variants may explain the negative family history of ADPKD in certain families.

Phenotypic variation in the familial atypical multiple mole-melanoma syndrome (FAMMM).

The familial atypical multiple mole-melanoma syndrome (FAMMM) is characterised by an autosomal dominantly inherited susceptibility to multiple atypical moles which show variable colouration ranging from black to brown, tan, red, or pink, with occasional variegation. These compound naevi may be macular or papular, with regular or irregular borders, and measure 1 cm or more in size. They may be few in number or absent or may exceed 100 in a given patient. They are located predominantly on areas not exposed to the sun. Dysplastic changes in melanocytes, fibroplasia, focal chronic inflammatory cell infiltrate, and new blood vessel formation of the papillary dermis characterise their histopathology. These findings are not uniformly present. Because of these distinctive features, coupled with their propensity for transformation to cutaneous malignant melanoma, little attention has been given to the possibility of either minimal or absent cutaneous expression of the phenotype or more diverse neoplastic involvement in this disease. These latter phenomena, which we ascribe to the pleiotropic effects of the cancer-prone FAMMM genotype, were observed in a single FAMMM kindred, the subject of this report.

Volumetric neuroimaging in Usher syndrome: Evidence of global involvement

Usher syndrome is a group of genetic disorders consisting of congenital sensorineural hearing loss and retinitis pigmentosa of variable onset and severity depending on the genetic type. It was suggested that the psychosis of Usher syndrome might be secondary to a metabolic degeneration involving the brain more diffusely. There have been reports of focal and diffuse atrophic changes in the supratentorial brain as well as atrophy of some of the structures of the posterior fossa. We previously performed quantitative analysis of magnetic resonance imaging studies of 19 Usher syndrome patients (12 with type I and 7 with type II) looking at the cerebellum and various cerebellar components. We found atrophy of the cerebellum in both types and sparing of cerebellar vermis lobules I-V in type II Usher syndrome patients only. We now have studied another group of 19 patients (with some overlap in the patients studied from the previous report) with Usher syndrome (8 with type I, 11 with type II). We performed quantitative volumetric measurements of various brain structures compared to age- and sex-matched controls. We found a significant decrease in intracranial volume and in size of the brain and cerebellum with a trend toward an increase in the size of the subarachnoid spaces. These data suggest that the disease process in Usher syndrome involves the entire brain and is not limited to the posterior fossa or auditory and visual systems.

Breast cancer, genetics, and age at first pregnancy.

Hereditary breast cancer shows a distinctive natural history characterised by an earlier age of onset, excess bilaterality, vertical transmission, heterogeneous tumour associations, and improved survival when compared to its sporadic counterpart. To date, very little attention has been given to interrelationships between breast cancer risk factors and genetics. In the general population, early age of first term pregnancy has been generally accepted as protective against breast cancer. In addition, recent findings suggest that an early age of first pregnancy may be associated with an earlier age of breast cancer diagnosis. We studied the age at first pregnancy and age at onset of breast cancer among 162 females at 50% genetic risk, 72 of whom had already developed the disease. We then compared them to 154 consecutively ascertained breast cancer patients from the Creighton Cancer Center. In the hereditary subset (1) early first term pregnancy did not alter the frequency of breast cancer; (2) early age at first term pregnancy was not associated with an earlier age at cancer diagnosis; and (3) age of breast cancer onset in nulliparous females was not significantly lower than that in females having at least one term pregnancy. We speculate, therefore, that in our hereditary population, pregnancy does not influence the natural history of breast cancer in the same way that it does in the population at large.

Familial heterogeneity of colon cancer risk

The authors have assembled detailed family histories of cancer on 857 cancer probands, of whom 180 manifested colorectal carcinoma. This study determines if some families had a greater risk for colorectal cancer than others, and if so, what factors were associated with an increase in risk. To test for the possibility of heterogeneity of risk, a parameter called the Z‐score, was calculated for each family. The Z‐score is a measure of the number of cancer cases in the family adjusted for the number of expected cases. A permutation test was employed to test whether or not the variance of Z‐scores from the sample was greater then expected by random chance. The variance for families ascertained through colon cancer probands, but not in any of the other groups, was significantly increased. Of the colon group, 10.6% fell into a high‐risk category, as did 5.56% of the rectal cancer families, but only 3.95% of the other groups combined were at high risk. Anatomic sites (in the proband) with the highest Z‐score variances were sigmoid and transverse colon, whereas lower variances were seen for cecum and descending colon. Risk status therefore may be partially dependent upon exact anatomic sites within the colon. The effect of probands age of diagnosis was not significant, but did show the possibility of an effect on heterogeneity of risk for both the younger and older groups.