Constitutive deficiency in DNA mismatch repair.

Mutations in the DNA mismatch repair (MMR) genes are associated with the inheritance of hereditary non-polyposis colorectal cancer, also known as Lynch syndrome, a cancer syndrome with an average age at onset of 44. Individuals presenting with colorectal cancer are diagnosed with Lynch I, whereas individuals who present with extra-colonic tumors (such as endometrial, stomach, etc.) are identified as patients with Lynch syndrome II. Recently, 30 families have been reported with inheritance of biallelic mutations in the MMR genes. Here we summarize the phenotype of individuals with inheritance of homozygous or compound heterozygous mutations in the MMR genes that result in a complete lack of protein or greatly compromised protein function. In contrast to individuals with Lynch syndrome I and II, individuals with no MMR function present with childhood onset of hematological and brain malignancies, whereas residual MMR function can also result in gastrointestinal cancers and an age of onset in the second to fourth decade. Individuals with biallelic MMR mutations often present with café-au-lait spots, regardless of the level of MMR function remaining. Thus, the inheritance of two MMR gene mutations is a separate entity from Lynch I or II or the subtypes Turcot and Muir-Torre.

Constitutive deficiency in DNA mismatch repair: is it time for Lynch III?

Hereditary non-polyposis colorectal cancer (HNPCC), also known as Lynch syndrome types I and II, and the related subtypes Turcot and Muir-Torre syndrome, have all been associated with inheritance of germ line mutations in the DNA mismatch repair (MMR) genes. Fifty individuals have recently been identified with an early onset of a different spectrum of cancers associated with inheritance of two MMR mutations--resulting either in a constitutive loss of MMR function, or greatly impaired MMR function. In contrast to Lynch I and II individuals, individuals with inheritance of homozygous or compound heterozygous mutations in the MMR genes that result in a complete lack of protein, present with hematological and brain malignancies in the first decade of life. Biallelic mutations with compromised but residual protein function present with a broader spectrum of cancers (brain, hematological or gastrointestinal) in the second to fourth decades of life. We propose that inheritance of two MMR mutations in an individual and the unique tumor spectrum that occurs with an early onset should be defined separately from Lynch syndrome I and II, or the subtypes Turcot and Muir-Torre. We suggest Lynch III as an appropriate name for identifying individuals with constitutively compromised MMR associated with biallelic mutations.

Cost analysis of DNA-based testing in a large Canadian family with multiple endocrine neoplasia type 2.

One of the major goals of genetic testing is the reduction of morbidity and mortality. Given the appropriate circumstances, this can result in reduction in health care costs. Such savings can be demonstrated most effectively in large families with mutations in well characterized, dominantly acting genes. In our large family, a point mutation TGC>CGC in exon 10 of the RET proto-oncogene, which results in a missense mutation (Cys620Arg), was identified in two individuals. The proband has medullary thyroid carcinoma (MTC), as did her deceased mother. One son has MTC and Hirschsprung's disease. The proband's mother had nine siblings; the proband has three siblings, another son, and 69 maternal cousins. Genetic testing has been performed on the closest relatives and has identified four individuals with, and 54 individuals without, a familial RET mutation. Significant cost savings have been realized in both genetic testing and clinical surveillance. In this family, for every at-risk individual identified as a true-negative, the minimum yearly savings in clinical surveillance is 508 dollars per person. As demonstrated by this case, economic costs of genetic diagnostics should take into account the potential saved monies in tests, both molecular and clinical.

Hereditary colon cancer.

Hereditary colon cancer comprises approximately 10% of total colon cancer, a disease that affects 6% of the North American population. Knowledge of molecular genetics of familial adenomatous polyposis and hereditary nonpolyposis colon cancer has improved our diagnostic abilities and management, as well as furthered our understanding of the mechanisms of tumour initiation and progression.

Cardiac compression and decompensation due to hiatus hernia.

A seventy-seven year old man with long standing hiatus hernia, coronary artery disease and pulmonary fibrosis developed left atrial compression from incarceration of a paraesophageal hernia.

Life-threatening status asthmaticus at 12.5 weeks' gestation. Report of a normal pregnancy outcome.

A 26-year-old woman had a life-threatening attack of status asthmaticus at 12.5 weeks of pregnancy. Subsequently, an apparently normal male infant was born at full-term.

Recurrent spontaneous pregnancy loss. Investigation and reproductive follow-up.

Between July 1, 1985, and Dec 31, 1988, 187 women referred to the University of British Columbia Medical Genetics Clinical Unit for two or more consecutive, unexplained, spontaneous pregnancy losses were evaluated for seven categories of possible etiology. Follow-up of the total subsequent reproductive experience was obtained in 171 cases. For those who became pregnant, achievement of a live birth was tabulated according to the number of previous pregnancy losses, age at the investigation and abnormalities found in the investigation. Overall, 81.8% of those who became pregnant after the evaluation and with a known outcome or outcomes at follow-up had a live birth-78% of primary aborters (no previous liveborn infant) and 86.3% of secondary aborters (previous liveborn infant).

Turner syndrome and its variants.

Turner syndrome is suspected in females with short stature, gonadal dysgenesis, and lymphedema; however, there are no pathognomonic features of Turner syndrome, and the disorder should be considered in any girl with short stature or delayed puberty. This article discusses the natural history of Turner syndrome and complications that occur in various organ systems; it reviews the physical features and complications seen with various karyotypic changes in Turner syndrome. Age-specific screening and therapies are covered.

Myelodysplasia and leukemia syndrome with monosomy 7: a genetic perspective.

Acquired monosomy 7 is a frequent finding in myelodysplastic syndromes, including acute myelogenous leukemia. A subset of these patients has been described with an apparently distinct condition: myelodysplasia and leukemia syndrome with monosomy 7 (MLSM7). We report 2 brothers, 3 and 5 years of age, with MLSM7 and review other reports of familial occurrence. Genetic factors appear to be important in the cause of MLSM7, but the reported families do not fit neatly into any monogenic pattern. Recognition of the frequently familial nature of this condition requires hematological evaluation and genetic counseling for the families of patients with MLSM7.

Ependymomas in two sisters and a maternal male cousin with mosaicism with monosomy 22 in tumour.

A family with two sisters and their mother's male cousin had ependymomas. Of note is the fact that chromosome analysis on the tumour of the younger sister showed two cell lines, one a normal female line, the other with monosomy of chromosome 22.