BRCA1/2 testing: uptake, phenocopies, and strategies to improve detection rates in initially negative families.

In families with clustering of breast and ovarian cancer, molecular testing of the major susceptibility genes BRCA1/2 helps to identify patients with disease mutations and healthy persons at high risk who can participate in targeted intervention programs. We investigated 5559 families from the German Consortium for Hereditary Breast and Ovarian Cancer included between 1997 and 2008 and treated under clinical routine conditions. In each family an index patient/person had been screened for deleterious mutations in BRCA1/2. Healthy relatives agreed to predictive testing in 888 of 1520 BRCA1/2 mutation-positive families (58%). Of 2646 eligible unaffected first-degree relatives 1143 decided to be tested (43%). In 325 families with BRCA1/2-positive index patients one related BC/OC patient was tested and 39 (12.0%; 95% confidence interval: 8.7-16.0%) discrepant cases found. A second related individual was screened in 163 of 3388 (4.9%) families with BRCA1/2-negative index patient and in eight families a BRCA1/2 mutation was found. In BRCA1/2 mutation-positive families, BC/OC patients lacking the familial mutation have to be expected at a rather high rate. In families with BRCA1/2-negative index patient we recommend a second screening if another patient with a high probability of carrying a BRCA1/2 mutation is available.

A new subtype of brachydactyly type B caused by point mutations in the bone morphogenetic protein antagonist NOGGIN.

Brachydactyly type B (BDB) is characterized by terminal deficiency of fingers and toes, which is caused by heterozygous truncating mutations in the receptor tyrosine kinase-like orphan receptor 2 (ROR2) in the majority of patients. In a subset of ROR2-negative patients with BDB, clinically defined by the additional occurrence of proximal symphalangism and carpal synostosis, we identified six different point mutations (P35A, P35S, A36P, E48K, R167G, and P187S) in the bone morphogenetic protein (BMP) antagonist NOGGIN (NOG). In contrast to previously described loss-of-function mutations in NOG, which are known to cause a range of conditions associated with abnormal joint formation but without BDB, the newly identified BDB mutations do not indicate a major loss of function, as suggested by calculation of free-binding energy of the modeled NOG-GDF5 complex and functional analysis of the micromass culture system. Rather, they presumably alter NOG's ability to bind to BMPs and growth-differentiation factors (GDFs) in a subtle way, thus disturbing the intricate balance of BMP signaling. The combined features observed in this phenotypic subtype of BDB argue for a functional connection between BMP and ROR2 signaling and support previous findings of a modulating effect of ROR2 on the BMP-receptor pathway through the formation of a heteromeric complex of the receptors at the cell surface.

Use of intensified early cancer detection in high-risk patients with familial breast and ovarian cancer.

A prospective follow-up study was carried out to evaluate the influence of risk and genetic counselling on use of early cancer detection. Five hundred and fifty-six subjects who fulfilled inclusion criteria for a genetic analysis of the BRCA1/2 genes (the high-risk group A) and 205 who did not fulfil the inclusion criteria (the lower risk group B) attended primary consultation in the interdisciplinary cancer genetic clinic. Information about participation in the early cancer detection programme was documented. Information about changes in use after consultation could be evaluated from 349 women (94 group B and 255 group A). Methods such as monthly self-palpation, breast palpation by gynaecologist, ultrasound of the breast, transvaginal ultrasound and pelvic examination had all been commonly used. Consultees at higher risk used mammography less often than women at lower risk. Magnetic resonance imaging of the breast was used rarely. Most methods were used more often at the recommended interval by women at higher risk during the follow-up period. In conclusion, at present intensified early cancer detection programmes for women at risk provide a less invasive option than chemoprevention or prophylactic surgery. Although the methods are used at high frequency it seems feasible to motivate women at risk to participate. This can be done by providing information and counselling in the cancer genetic clinic.

Prevention and therapy for BRCA1/2 mutation carriers and women at high risk for breast and ovarian cancer.

The hereditary breast (BC) and ovarian (OC) cancer syndrome (HBOC) includes genetic alterations of various susceptibility genes such as TP53, ATM, PTEN or MSH2, MLH1, PMS1, PMS2, MSH3 and MSH6, BRCA1 and BRCA2. Germline mutations of the cancer-susceptibility genes BRCA1 and BRCA2 seem to be the major aetiology of the HBOC. Genetic counselling and identification of high-risk families may be essential (1) to provide the best method for genetic testing by explaining the sensitivity and specificity of the methods, (2) to offer the opportunity to participate in specific early cancer detection programmes (breast (self) palpation, ultrasound, mammography and magnetic resonance tomography for breast cancer; vaginal exploration and ultrasound for ovarian cancer), (3) to inform them about prophylactic medication (oral contraceptive pill (OCP), chemoprevention (tamoxifen, raloxifen, aromatase inhibitors)) or surgery (bilateral prophylactic mastectomy or oophorectomy) and (4) to provide individualized psychological support. To fulfil these broad demands, an inter-disciplinary counselling approach (gynaecological oncology, human genetics, molecular biology, psychotherapy) in the setting of a cancer genetic clinic seems the most appropriate. There, participation in predictive genetic testing or the use of preventive or therapeutic options may be discussed extensively with the subjects. In particular, preventive options are emotionally disturbing for the subjects, and in cases of previous cancer. BC chemoprevention for high-risk women does not seem to be as effective as expected. However, OCP reduces the risk for OC. For prophylactic surgery, various points have to be considered, including: (1) individual risk assessment and gain in life expectancy, (2) value of screening and early detection methods or medical prevention, (3) disease characteristics and prognosis, and (4) anxiety and quality of life. Decisions regarding these options have to be individualized and psychological support must be offered during the period of decision and follow-up.

Microcephalic osteodysplastic primordial dwarfism type II: report of three cases and review.

We report on three further patients with microcephalic osteodysplastic dwarfism type II. All children have marked intrauterine and postnatal growth failure, microcephaly, and mental and statomotor retardation. They are disproportionately short statured due to short limbs. Characteristic skeletal abnormalities are small iliac wings with flat acetabular angles, coxa vara, V-shaped distal femoral metaphyses, and triangular distal femoral epiphyses, as well as pseudoepiphyses of metacarpals, short first metacarpals, and brachymesophalangy V. At age 3 years, bilateral epiphyseolysis of the femoral heads occurred in case 1. Including our patients, 17 cases have been published so far. We review the clinical picture and the cause.

[Tumor risk consultation for predisposed women from high risk cancer families]. / Tumorrisikosprechstunde für prädisponierte Frauen aus Krebsrisikofamilien.

Germline mutations of the cancer susceptibility genes BRCA1 and BRCA2 seem to lead to a very high risk for breast and/or ovarian cancer. Therefore, genetic counselling and identification of high-risk families may be essential to offer the opportunity to participate in a specific early cancer detection program and to provide individualized psychological support. In a two year period (August 1994-August 1997) 304 consultees present for genetic counselling at the interdisciplinary cancer genetic clinic (Department of Obstetrics & Gynecology and Human Genetics, Heinrich-Heine-Universität, Düsseldorf). For genetic testing a BRCA1/2 mutation detection strategy including protein truncation test (PTT), single strand conformation polymorphism (SSCP), and direct DNA sequencing is used. 161 families fulfilled the inclusion criteria; at present, 72 families for whom complete analytical material is available are analyzed. Although genetic testing for BRCA1 and BRCA2 is technically challenging, women with a family history of multiple sporadic breast/ovarian cancers and those with a hereditary BRCA1 and BRCA2 gene defect may be distinguished. For the first group of consultees this may ease their concern, for the second group preventive measures including an early cancer detection or prevention program, psychological support or prophylactic surgery may be discussed.

Prenatal diagnosis of infantile neuronal ceroid-lipofuscinosis: a combined electron microscopic and molecular genetic approach.

Based on two unrelated index patients afflicted with INCL, fetal chorion tissues were studied from subsequent pregnancies of the two respective mothers resulting in the prenatal diagnosis of INCL in two of the three pregnancies. Documentation of INCL was based on electron microscopy and DNA studies of the biopsied chorion tissue, later confirmed in the two affected fetuses after termination of their pregnancies by demonstrating INCL-specific lipopigments in post-mortem tissues, in the liver of both aborted fetuses and, additionally, in spleen and skeletal muscle of one of the affected fetuses. The autolysis of the aborted tissues, however, precluded a systematic documentation of all affected cell types and tissues. Thus, prenatal diagnosis of INCL is feasible and reliable for both Finnish and non-Finnish families.

[The problem of "benign macrocephaly"]. / Untersuchungen zur Frage der "benignen Makrokephalie".

24 families of probands with a high head circumference/height ratio greater than the 97th percentile were investigated for head circumference and height. It is concluded that "benign macrocephaly" represents rather the upper extreme of the normal distribution of head circumference than--as has been suggested by some authors--a discrete and autosomal dominant entity.

[Anthropometric studies of a student sample of Düsseldorf University]. / Anthropometrische Untersuchungen an einem Studentenkollektiv der Universität Düsseldorf.

The means of cephalic measurements and body height of students from the Düsseldorf university are given and compared to previous studies.