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.

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.

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.

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.

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.

Muir-Torre syndrome: a variant of the cancer family syndrome.

Muir-Torre syndrome is characterised by the association of sebaceous tumours of the skin with internal malignancy. In many instances there is a strong family history of cancer and the autosomal dominant mode of inheritance, tumour spectrum, and high incidence of synchronous and metachronous tumours show parallels with the cancer family syndrome or Lynch II syndrome. We report a five generation family with at least two persons displaying the Muir-Torre phenotype, while many other family members have had tumours consistent with cancer family syndrome. The majority of tumours are gastrointestinal, gynaecological, and urological, with several persons having multiple primaries. The prognosis appears to be better than would be expected. Sebaceous tumours are a marker for internal malignancy and should prompt a search for occult cancer in the individual person and family members. In documented Muir-Torre families, at risk persons should be entered into screening programmes similar to those used in the Lynch II syndrome.

Colonoscopy in asymptomatic individuals with a family history of colorectal cancer.

BACKGROUND: This study was performed to evaluate the use of total colonoscopy as the optimal screening test in asymptomatic individuals with a family history of colorectal cancer (CRC). METHODS: Colonoscopy was performed in 249 asymptomatic individuals who had one or two first-degree relatives (FDRs) with CRC; individuals with three or more FDRs with CRC were excluded. RESULTS: Eighty-six colonic lesions were found in 51 individuals (51 of 249; 20.5%). Among these 51 subjects, 27 had neoplastic polyps (n = 38) and 29 had metaplastic polyps (n = 44). Although no invasive cancer was detected, in 14 individuals the lesions had a high malignancy potential because of their size and histopathology. We did not confirm a statistically significant difference in the incidence of neoplastic polyps according to the number of affected FDRs. Finally, the presence of metaplastic polyps was a very strong indication for the concomitant presence of metaplastic polyps (P <.0001). CONCLUSIONS: Total colonoscopy is the optimal screening procedure for the examination of asymptomatic individuals with a family history of CRC.

Frequency of familial colorectal cancer.

Familial clustering of cancer is not uncommon. The frequency of familial colorectal cancer was estimated by taking family histories from 100 patients presenting with apparently sporadic colorectal cancer. Compared with controls, the relative risk of a positive family history for colorectal cancer was 4.6. Life-table methods were used to examine the observed to expected mortality from colorectal cancer. Overall there was a fourfold increase in mortality rate (P less than 0.0001), which was greatest in female relatives of patients with colonic cancer (P less than 0.001). Three families with dominant inheritance of colorectal cancer and one family with Lynch type II syndrome were identified. Nine per cent of patients had siblings who had developed colorectal cancer a median of 4 years before the diagnosis of the index patient (range 1-17 years). It is recommended that a careful family history should be obtained from all patients with colorectal cancer. Where a positive history is obtained a geneticist may determine empirical risks for the development of colorectal cancer and the appropriate method of surveillance may be selected.

Feasibility of family based screening for colorectal neoplasia: experience in one general surgical practice.

Relatives of patients with colorectal cancer have on average a two to threefold increased risk for developing bowel neoplasia although in some families the risk is much higher. This study examined the compliance for endoscopic screening and faecal occult blood testing among first degree relatives of patients with colorectal cancer to determine the feasibility of offering a screening service in a surgical practice. The endoscopic method (flexible sigmoidoscopy or colonoscopy) offered depended upon the extent of family history. Spouses of patients were offered flexible sigmoidoscopy as a group for comparison. Compliance in first degree relatives was significantly higher than in spouses (69% v 47%, p < 0.01) and among those relatives of patients who had died recently from colorectal cancer but time since diagnosis in the index case had no effect. Adenomas were found in 14 of 92 (15%) relatives and three of 30 (10%) spouses. It is estimated that, under our screening guidelines, every 100 patients with colorectal cancer would generate a list of 35-40 relatives who would be screened once by flexible sigmoidoscopy and perhaps 75, who because of their young age, might be screened twice in their lifetime. Also, from this same 100 patients, about 12-15 relatives would merit entry in a colonoscopic screening programme because of their more extensive family history. These results indicate that endoscopic screening of relatives of patients with colorectal cancer is feasible within a practice.

Linkage analysis of early-onset breast and ovarian cancer families, with markers on the long arm of chromosome 17.

We have conducted linkage analysis in 16 breast cancer families, 13 of which are classified as site-specific breast cancer families and 3 of which are classified as breast-ovary families. Linkage analysis has largely focused on a single extended breast-ovary family. Analysis of all families combined shows significant evidence for linkage to 17q (LOD = 3.63 at theta = .0, for linkage to NME1), confirming the observations of Hall et al. and Narod et al. Many families were consistent with linkage, but their limited size and informativeness precluded confirmation of linkage. A putative recombinant in a breast-ovary family suggests that BRCA1 is distal to D17S250.

Linkage of recessive Robinow syndrome to a 4 cM interval on chromosome 9q22.

Autosomal recessive Robinow syndrome is a form of mesomelic dwarfism with multiple rib and vertebral anomalies. Using autozygosity mapping we have identified a genetic locus (RBNW1) for this syndrome at chromosome 9q22 in seven consanguineous families from Oman. Our results indicate that the gene lies within a 4 cM region between markers D9S1836 and D9S1803 (maximum multipoint LOD score 12.3). In addition, we have analysed two non-Omani families with autosomal recessive Robinow and found no genetic heterogeneity.