Recessive Robinow syndrome, allelic to dominant brachydactyly type B, is caused by mutation of ROR2.

The autosomal recessive form of Robinow syndrome (RRS; MIM 268310) is a severe skeletal dysplasia with generalized limb bone shortening, segmental defects of the spine, brachydactyly and a dysmorphic facial appearance. We previously mapped the gene mutated in RRS to chromosome 9q22 (ref. 4), a region that overlaps the locus for autosomal dominant brachydactyly type B (refs 5,6). The recent identification of ROR2, encoding an orphan receptor tyrosine kinase, as the gene mutated in brachydactyly type B (BDB1; ref. 7) and the mesomelic dwarfing in mice homozygous for a lacZ and/or a neo insertion into Ror2 (refs 8,9) made this gene a candidate for RRS. Here we report homozygous missense mutations in both intracellular and extracellular domains of ROR2 in affected individuals from 3 unrelated consanguineous families, and a nonsense mutation that removes the tyrosine kinase domain and all subsequent 3' regions of the gene in 14 patients from 7 families from Oman. The nature of these mutations suggests that RRS is caused by loss of ROR2 activity. The identification of mutations in three distinct domains (containing Frizzled-like, kringle and tyrosine kinase motifs) indicates that these are all essential for ROR2 function.

Localization of the gene for Cowden disease to chromosome 10q22-23.

Cowden disease (CD) (MIM 158350), or multiple hamartoma syndrome, is a rare autosomal dominant familial cancer syndrome with a high risk of breast cancer. Its clinical features include a wide array of abnormalities but the main characteristics are hamartomas of the skin, breast, thyroid, oral mucosa and intestinal epithelium. The pathognomonic hamartomatous features of CD include multiple smooth facial papules, acral keratosis and multiple oral papillomas. The pathological hallmark of the facial papules are multiple trichilemmomas. Expression of the disease is variable and penetrance of the dermatological lesions is assumed to be virtually complete by the age of twenty. Central nervous system manifestations of CD were emphasized only recently and include megalencephaly, epilepsy and dysplastic gangliocytomas of the cerebellum (Lhermitte-Duclos disease, LDD). Early diagnosis is important since female patients with CD are at risk of developing breast cancer. Other lesions include benign and malignant disease of the thyroid, intestinal polyps and genitourinary abnormalities. To localize the gene for CD, an autosomal genome scan was performed. A total of 12 families were examined, resulting in a maximum lod score of 8.92 at theta = 0.02 with the marker D10S573 located on chromosome 10q22-23.

Impact of national guidelines on family history breast cancer surveillance.

The breast cancer risk of women already under family history surveillance was accurately assessed according to national guidelines in an attempt to rationalize the service. Women attending two breast units in Glasgow between November 2003 and February 2005 were included. One thousand and five women under annual surveillance were assessed and had their relatives diagnoses verified. Four hundred and ninety-seven women were at significantly increased risk and eligible for follow-up. Five hundred and eight (50%) women attending were not eligible for family history surveillance, and 498 (98%) of these women accepted discharge. In conclusion, national guidelines have helped to more clearly define women who should undergo surveillance. This avoids unnecessary and potentially harmful routine investigations, and the service has been improved.

Mutation update for the CSB/ERCC6 and CSA/ERCC8 genes involved in Cockayne syndrome.

Cockayne syndrome is an autosomal recessive multisystem disorder characterized principally by neurological and sensory impairment, cachectic dwarfism, and photosensitivity. This rare disease is linked to mutations in the CSB/ERCC6 and CSA/ERCC8 genes encoding proteins involved in the transcription-coupled DNA repair pathway. The clinical spectrum of Cockayne syndrome encompasses a wide range of severity from severe prenatal forms to mild and late-onset presentations. We have reviewed the 45 published mutations in CSA and CSB to date and we report 43 new mutations in these genes together with the corresponding clinical data. Among the 84 reported kindreds, 52 (62%) have mutations in the CSB gene. Many types of mutations are scattered along the whole coding sequence of both genes, but clusters of missense mutations can be recognized and highlight the role of particular motifs in the proteins. Genotype-phenotype correlation hypotheses are considered with regard to these new molecular and clinical data. Additional cases of molecular prenatal diagnosis are reported and the strategy for prenatal testing is discussed. Two web-based locus-specific databases have been created to list all identified variants and to allow the inclusion of future reports (www.umd.be/CSA/ and www.umd.be/CSB/).

Confirmation of CHD7 as a cause of CHARGE association identified by mapping a balanced chromosome translocation in affected monozygotic twins.

BACKGROUND: CHARGE syndrome has an estimated prevalence of 1/10,000. Most cases are sporadic which led to hypotheses of a non-genetic aetiology. However, there was also evidence for a genetic cause with reports of multiplex families with presumed autosomal dominant, possible autosomal recessive inheritance and concordant twin pairs. We identified a monozygotic twin pair with CHARGE syndrome and a de novo balanced chromosome rearrangement t(8;13)(q11.2;q22). METHODS: Fluorescence in situ hybridisation was performed with BAC and PAC probes to characterise the translocation breakpoints. The breakpoint on chromosome 8 was further refined using 10 kb probes we designed and produced using sequence data for clone RP11 33I11, the Primer3 website, and a long range PCR kit. RESULTS: BAC and PAC probe hybridisation redefined the breakpoints to 8q12.2 and 13q31.1. Probe RP11 33I11 spanned the breakpoint on chromosome 8. Using our 10 kb probes we demonstrated that the chromodomain gene CHD7 was disrupted by the translocation between exons 3 and 8. DISCUSSION: Identifying that the translocation breakpoint in our patients occurred between exons 3 and 8 of CHD7 suggests that disruption of this gene is the cause of CHARGE syndrome in the twins and independently confirms the role of CHD7 in CHARGE syndrome.

Exonic STK11 deletions are not a rare cause of Peutz-Jeghers syndrome.

BACKGROUND: Peutz-Jeghers syndrome (PJS) is a rare, autosomal dominant cancer predisposition syndrome characterised by oro-facial pigmentation and hamartomatous polyposis of the gastrointestinal tract. A causal germline mutation in STK11 can be identified in 30% to 80% of PJS patients. METHODS: Here we report the comprehensive mutational analysis of STK11 in 38 PJS probands applying conventional PCR based mutation detection methods and the recently introduced MLPA (multiplex ligation dependent probe amplification) technique developed for the identification of exonic deletions/duplications. RESULTS: Nineteen of 38 probands (50%) had detectable point mutations or small scale deletions/insertions and six probands (16%) had genomic deletions encompassing one or more STK11 exons. CONCLUSIONS: These findings demonstrate that exonic STK11 deletions are a common cause of PJS and provide a strong rationale for conducting a primary screen for such mutations in patients.

Does genetic counseling have any impact on management of breast cancer risk?

Despite there being an increasing literature on the impact of cancer genetic counseling on risk perception and mental health, there is a lack of data describing impact on risk management. Genetic counseling and testing for cancer predisposition genes aims to improve the future health of those at high risk through appropriate surveillance and screening. However, management of breast cancer risk in women with a family history of this disease is an area of controversy. Counseling services may recommend specific risk management options to women, who then rely on their local screening service to make provision. This study investigated the impact of genetic counseling on management of breast cancer risk in women attending Cancer Family Clinics. A total of 293 women attending four genetic clinics were enrolled. Rates of breast self-examination, clinical breast examination, mammography, biopsy, detected cancers, and other screenings were documented. Participants' perceived benefits and barriers to mammography were assessed along with cancer worry. Results show that rates of mammography, clinical breast examination, and breast self-examination were increased following clinic attendance (p < 0.001). Women in the under 35 age-group had limited access to screening. Rates for biopsy and detected cancers were low. Women reported positive attitudes to mammography, with few reported barriers. Contrary to previous studies, there was no evidence that anxiety about breast cancer impedes uptake of health surveillance methods. Genetic counseling had a positive impact on management of breast cancer risk. Whether this translates into future health gains remains to be established.

Analysis of the phenotypic abnormalities in lymphoedema-distichiasis syndrome in 74 patients with FOXC2 mutations or linkage to 16q24.

INTRODUCTION: Lymphoedema-distichiasis syndrome (LD) (OMIM 153400) is a rare, primary lymphoedema of pubertal onset, associated with distichiasis. Causative mutations have now been described in FOXC2, a forkhead transcription factor gene. Numerous clinical associations have been reported with this condition, including congenital heart disease, ptosis, varicose veins, cleft palate, and spinal extradural cysts. SUBJECTS: We report clinical findings in 74 affected subjects from 18 families and six isolated cases. All of them were shown to have mutations in FOXC2 with the exception of one family who had two affected subjects with lymphoedema and distichiasis and linkage consistent with the 16q24 locus. RESULTS: The presence of lymphoedema was highly penetrant. Males had an earlier onset of lymphoedema and a significantly increased risk of complications. Lymphatic imaging confirmed the earlier suggestion that LD is associated with a normal or increased number of lymphatic vessels rather than the hypoplasia or aplasia seen in other forms of primary lymphoedema. Distichiasis was 94.2% penetrant, but not always symptomatic. Associated findings included ptosis (31%), congenital heart disease (6.8%), and cleft palate (4%). Other than distichiasis, the most commonly occurring anomaly was varicose veins of early onset (49%). This has not been previously reported and suggests a possible developmental role for FOXC2 in both venous and lymphatic systems. This is the first gene that has been implicated in the aetiology of varicose veins. CONCLUSION: Unlike previous publications, the thorough clinical characterisation of our patients permits more accurate prediction of various phenotypic abnormalities likely to manifest in subjects with FOXC2 mutations.

Genetic predisposition to cancer: the consequences of a delayed diagnosis of Gorlin syndrome.

This report outlines a case of Gorlin syndrome, the diagnosis of which was delayed for many years, and raises a number of important issues. These are the spectrum of late radiotherapy effects, particularly after treatment for benign disease, and the importance of considering the possibility of the presence of a genetic syndrome predisposing to cancer in all individuals before starting any treatment. As our knowledge of genetic syndromes expands, this will become increasingly important. Finally, if a genetic predisposition to cancer is suspected, consideration should be given to obtaining a blood sample from the affected patient for DNA storage, particularly if their prognosis is limited. Currently, genetic testing can only be instituted in most families by first obtaining DNA from an individual affected by cancer, as most genetic mutations are unique to a family. If all relatives with cancer have died, then, at this time, genetic testing cannot usually be attempted, unless such samples have previously been stored.

Genetic linkage in Muir-Torre syndrome to the same chromosomal region as cancer family syndrome.

The Muir-Torre syndrome, in which sebaceous gland tumours occur in association with internal malignancy, is inherited as an autosomal dominant disorder. Many features of the syndrome are similar to those of the Lynch II cancer family syndrome, and thus the two disorders might share a common genetic basis. We typed two large families with DNA markers on chromosome 2p around D2S123, a site recently shown to be linked to the Lynch II syndrome. LOD scores at this locus demonstrated significant and tight linkage to D2S123, suggesting that defects in the same gene might give rise to both syndromes.

Analysis of Li-Fraumeni syndrome and Li-Fraumeni-like families for germline mutations in Bcl10.

The Li-Fraumeni syndrome (LFS) is a dominant disease whose hallmark is an increased risk of breast cancers, brain tumours, sarcomas, leukaemia and adrenal carcinoma. Some, but not all LFS and Li-Fraumeni-like (LFL) families are caused by TP53 mutations. Bcl10 is a recently identified tumour suppressor reported to be commonly mutated in a wide range of cancers. To investigate the possibility that Bcl10 is a susceptibility gene for LFS and LFL we have analysed 27 LFS/LFL families. No mutations were observed. This indicates that Bcl10 is unlikely to act as a susceptibility gene for LFS and LFL.

Incontinentia pigmenti in a surviving male is accompanied by hypohidrotic ectodermal dysplasia and recurrent infection.

Familial Incontinentia pigmenti (IP) is a rare X-linked dominant condition. The affected cases have characteristic skin lesions, hair, eye, teeth and nail abnormalities and may also have neurological problems. The diagnosis has traditionally been made on clinical grounds. Segregation analysis has suggested that it is lethal in males. Only one liveborn male has been reported who died at one day of age. Female cases of IP survive because of the moderating effects of Lyonization. This child was the affected son of a female with IP. He had a novel phenotype consistent with hypohidrotic ectodermal dysplasia with immune deficiency (HED-ID) but with additional features: he had major problems with hematological disturbances, failure to thrive due to malabsorption, recurrent infections, generalized osteosclerosis and lymphedema of his lower limbs. He also demonstrated some typical features of IP with a generalized reticular skin hyperpigmentation, sparse hair and delayed eruption of teeth. The gene for NEMO (NF-kappa B Essential Modulator) has recently been shown to be mutated in cases of IP. Furthermore, most (80%) of patients possess a recurrent genomic rearrangement that deletes part of the gene resulting in an inactive NEMO protein. In the male case described here, a NEMO stop codon mutation has been identified that has arisen de novo in his affected mother. This mutation is likely to have a less severe effect on NEMO activity and may explain why this child survived for two years and 7 months.

Apparent Mendelian inheritance of breast and colorectal cancer: chance, genetic heterogeneity or a new gene?

It is not uncommon for cancer geneticists to be referred families with apparently Mendelian co-inheritance of breast and bowel cancer. Such families present a particular problem as regards the intensity of their screening for these diseases and the utility of genetic testing. Many 'breast-colon' cancer families probably result from chance clustering of two common cancers. Other 'breast-colon' cancer families may result from known cancer syndromes, such as hereditary breast-ovarian cancer or hereditary non-polyposis colon cancer, either by conferring a high risk of one cancer type and a slightly increased risk of the other, or through a predisposition to one of the two cancers and chance occurrence of the other. Anecdotally, however, many geneticists wonder about the existence of a distinct 'breast-colon cancer syndrome', since some families present good a priori evidence of genetic disease and yet cannot readily be accounted for by known genes or chance. The identification of unknown 'breast-colon cancer' genes is likely to be difficult, relying primarily on candidate gene analysis, including loci separately implicated in breast or colorectal cancer, or in other multiple cancer syndromes. Studies such as those on APC I1307K and CHEK2 1100delC may suggest the way forward for the identification of 'breast-colon cancer' genes.

A rapid PCR-based method to distinguish between fetal and maternal cells in chorionic biopsies using microsatellite polymorphisms.

In some chorionic villus biopsy (CVB) cases the fetal/maternal origin of the tissue obtained is uncertain. An approach which only requires small amounts of CVB tissue to establish its origin is described. Since it is only the samples typed as female that could be either fetal or maternal, a paternal X chromosome contribution is sought by using highly polymorphic X-linked microsatellites.

Colonoscopy in symptomatic patients with positive family history of colorectal cancer.

BACKGROUND: Most patients with colorectal cancer (CRC) develop clinical signs and symptoms which are not specific for CRC, and usually at a late stage of the disease, resulting in a considerable delay of the diagnosis. In our study we examined patients with bowel symptoms which were at increased risk for developing CRC, because of their family history. METHODS: Over the last 6 years, colonoscopy was performed in 203 patients with colorectal symptoms, who had at least one Ist degree relative with CRC, at the Colorectal Surgery Unit of St George's Hospital. Five hundred ninety two individuals without CRC family history and with either rectal bleeding (n = 479), or with change of bowel habits (n = 113) were used as control group. RESULTS: In the group of patients with family history of CRC 81 colonic lesions were found in 53 patients (53/203, 26%). Patients with family history of CRC were grouped in three categories according to their main symptom. In the subgroup of patients with bleeding (n = 129) there were found 46 colonic lesions in 33 patients. In the subgroup of patients with change of bowel habits (n = 45) we were able to detect 39 colonic lesions. In the group of patients with abdominal pain (n = 29) 4 patients had a metaplastic polyp and one patient had a neoplastic polyp. With regard to the number of 1st degree relatives with CRC, we found that 16/172 (9%) patients with one such relative and 4/31 (13%) of the patients with two relatives were diagnosed with neoplastic polyps. CONCLUSIONS: Total colonoscopy (TC) is an excellent diagnostic procedure for the examination of symptomatic patients with positive family history of colorectal cancer. TC has a diagnostic role detecting the cause of symptoms or excluding the presence of malignancy. Simultaneous resection of the neoplastic and metaplastic polyps, provides an additional, secondary prevention of CRC.

An economic appraisal of screening for Down's syndrome in pregnancy using maternal age and serum alpha fetoprotein concentration.

The direct and indirect costs and benefits of expanding the existing screening programme for Down's syndrome by using maternal age and serum alpha fetoprotein concentrations have been calculated using an ascertainment of Down's syndrome pregnancies from the North East Thames Regions in 1982. In addition, a possible approach to evaluating the total costs and benefits to the families concerned is presented. If the uptake of the proposed screening programme is maximal, the replacement rate is zero and a discount rate of 5% is used, the benefit cost ratio is 23.6. If the uptake of the programme is 50%, the replacement rate is 100% and a discount rate of 7% is used, the benefit cost ratio is 12.2. The proposed screening programme, based upon a risk of Down's syndrome of at least 1 in 220 using maternal age and serum alpha fetoprotein is both equitable for families at risk and of economic benefit to both families and society.

Two families with blepharophimosis/ptosis/epicanthus inversus syndrome have mutations in the putative forkhead transcription factor FOXL2.

Blepharophimosis/ptosis/epicanthus inversus syndrome (BPES) is an autosomal dominant disorder that is characterized by distinctive eyelid abnormalities. Two clinical subtypes have been described in which type I, but not type II, is associated with premature ovarian failure. Both types of BPES are linked to 3q22-23, and the gene has recently been identified as the putative forkhead transcription factor FOXL2. We report mutation screening of FOXL2 in two families with this condition. The two mutations detected were frameshift mutations resulting from a small insertion or duplication within the gene. Both mutations would result in the production of novel carboxyl terminii, one terminating the predicted protein earlier than the wild type, and the other giving rise to a larger protein product, assuming these proteins or their mRNA were not degraded. Based on the present data, this would suggest that the first family should be type I and the second, type II. Although there is evidence of infertility in the first family, all 3 females in the youngest generation have normal pelvic ultrasound and hormone levels, suggesting that the divide between types I and II may not be as distinct as has been suggested.

Genetic testing for women previously diagnosed with breast/ovarian cancer: examining the impact of BRCA1 and BRCA2 mutation searching.

This study sought to investigate the impact of BRCA1 and BRCA2 mutation searching on women previously diagnosed with breast or ovarian cancer. In-depth interviews were undertaken with 30 women who had undergone a BRCA1 and BRCA2 mutation search within the clinical setting. The main reasons reported for undergoing mutation searching were: to provide genetic information for other family members, general altruism, curiosity about the aetiology of cancer, and to provide information to facilitate risk management decisions. In the main, the process of undergoing genetic testing was not experienced as anxiety provoking. The benefit of receiving a result confirming the presence of a genetic mutation was seen as an end to uncertainty, whereas the costs included difficulties in disclosing information to kin and potentially increased anxiety about one's own or others' cancer risks. Women receiving an inconclusive test result reported a range of emotional reactions. There was evidence that some women misunderstood the meaning of this result, interpreting it as definitive confirmation that a cancer-predisposing mutation was not present within the family. It is concluded that women with cancer who participate in BRCA1 and BRCA2 testing need to receive clear information about the meaning and implications of the different types of test results. Some recommendations for clinical practice are discussed.

Caudal appendage, short terminal phalanges, deafness, cryptorchidism and mental retardation: a new syndrome?

We present monozygotic twin boys of a triplet pregnancy with phalangeal abnormalities, deafness, a caudal appendage and the additional features of short stature, cryptorchidism, mental retardation and facial dysmorphism.