A novel candidate gene in autosomal dominant facial pruritus.

In the clinical investigation of a family with debilitating centrofacial pruritus by exome sequencing, we have observed a clear segregation of the TRPM3 variant outlined, which is highly suggestive of a causal relationship.

Fertility after young-onset colorectal cancer: a study of subjects with Lynch syndrome.

AIM: Infertility is a concern for young survivors of colorectal cancer (CRC), but this risk is not well quantified. Carriers of mismatch repair (MMR) mutations are a useful cohort for studying fertility after CRC as they commonly develop CRC when young, and unaffected family members provide demographically similar controls. The aim of this study was to determine the effect of CRC on fertility in a large cohort of MMR mutation carriers. METHOD: Mismatch repair mutation carriers identified from the Australasian Colorectal Cancer Family Registry were included. For each year of life within the fertile age range (15-49), the number of living individuals and the number of children born to them were determined. Individuals were grouped by whether or not they had had a diagnosis of CRC by that age. Age-specific and total fertility rates were calculated. RESULTS: We identified 1068 subjects (611 women and 457 men), of whom 467 were diagnosed with CRC. There were 1192 births during 18 674 person-years of follow-up to the women and 814 births during 14 013 person-years of follow-up to the men. The total fertility rate was decreased in women after a diagnosis of CRC compared with those who did not have CRC (1.3 vs 2.2; P = 0.0011), but age-specific fertility was only reduced in the 20-24-year age group. In men the total fertility rate was similar for both groups (2.0 vs 1.8; P = 0.27). CONCLUSION: Age-specific fertility was decreased in female CRC survivors with Lynch syndrome aged 20-24, but not in older women or in men.

The future in clinical genetics: affective forecasting biases in patient and clinician decision making.

When clinicians facilitate and patients make decisions about predictive genetic testing, they often base their choices on the predicted emotional consequences of positive and negative test results. Research from psychology and decision making suggests that such predictions may often be biased. Work on affective forecasting-predicting one's future emotional states-shows that people tend to overestimate the impact of (especially negative) emotional events on their well-being; a phenomenon termed the impact bias. In this article, we review the causes and consequences of the impact bias in medical decision making, with a focus on applying such findings to predictive testing in clinical genetics. We also recommend strategies for reducing the impact bias and consider the ethical and practical implications of doing so.

Mutations in SUFU and PTCH1 genes may cause different cutaneous cancer predisposition syndromes: similar, but not the same.

Many cancer predisposition syndromes are preceded or accompanied by a range of typical skin signs. Gorlin syndrome is a rare multisystem inherited disorder which can predispose to basal cell carcinomas (BCCs), childhood medulloblastomas in addition to various developmental abnormalities; the majority of cases are due to mutations in the PTCH1 gene. Approximately 5% of cases have been attributed to a mutation in the SUFU gene. Certain phenotypic features have been identified as being more prevalent in individuals with a SUFU mutation such as childhood medulloblastoma, infundibulocystic BCCs and trichoepitheliomas. Recently hamartomatous skin lesions have also been noted in families with childhood medulloblastoma, a "Gorlin like" phenotype and a SUFU mutation. Here we describe a family previously diagnosed with Gorlin syndrome with a novel SUFU splice site deleterious genetic variant, who have several dermatological features including palmar sclerotic fibromas which has not been described in relation to a SUFU mutation before. We highlight the features more prominent in individuals with a SUFU mutation. It is important to note that emerging therapies for treatment of BCCs in patients with a PTCH1 mutation may not be effective in those with a SUFU mutation.

Colorectal neoplasms detected colonoscopically in at-risk members of colorectal cancer families stratified by the demonstration of DNA microsatellite instability.

This study compared colonoscopic findings in families meeting the Amsterdam criteria (A) for hereditary non-polyposis colorectal cancer (HNPCC) but stratified according to whether the familial cancers showed DNA microsatellite instability. DNA was extracted from paired samples of normal and cancer, and microsatellite instability was analysed at up to six loci. Families were termed replication error positive (RER+) when at least 50% of tumours tested per family were positive. Of 26 families studied 17 were RER+ and 9 were RER-. Cancers in the A/RER- families showed no right-sided predilection (P < 0.001). Colonoscopies have been performed on 182 at-risk members of A/RER+ families and 60 members of A/RER- families. More of the at-risk members of A/RER-families were found to have adenomas at colonoscopy (P = 0.095), but these were smaller than those of A/RER+ families (P = 0.19). The adenoma:carcinoma ratio was twice as high in A/RER- families (13:1) as in A/RER+ families (7:1). One of the A/RER- families had hyperplastic polyposis. The others do not appear to have attenuated familial adenomatous polyposis and are similar to the adenoma families or late-onset colorectal cancer families described by others. This study illustrates the importance of molecular technology in separating HNPCC from syndromes with overlapping phenotypes.

Mixed epithelial polyps in association with hereditary non-polyposis colorectal cancer providing an alternative pathway of cancer histogenesis.

A member of a hereditary non-polyposis colorectal cancer (HNPCC) family developed two colorectal cancers and multiple polyps within four years of a negative colonoscopic examination. One of the cancers was only 4 mm in diameter and showed the gross and endoscopic appearances of a de novo carcinoma. Microscopic examination of multiple levels revealed a mixed hyperplastic polyp/adenoma (mixed polyp) in contiguity with the cancer. The colon harboured additional polyps of which five were tubular adenomas, seven were hyperplastic polyps and seven were mixed polyps (architecturally compatible with hyperplastic polyps but with atypical cytology). Atypical features of the mixed polyps included tripolar mitoses, bizarre chromatin aggregations and multinucleation. One mixed polyp showed DNA microsatellite instability. Under the influence of the mutator defect, hyperplastic polyps may develop atypical or adenomatous features and show progression to carcinoma. Such an alternative morphogenetic pathway could explain the differing molecular and pathological profiles of cancers showing DNA microsatellite instability.

Psychological impact of predictive testing for colonic cancer.

Advances in DNA technology have facilitated presymptomatic testing for an inherited predisposition to a number of autosomal dominant cancer syndromes. While testing is generally undertaken with informed consent and within a counselling protocol, there is still much to be learned about the psychological impact of DNA testing in a predictive setting. In this study, patients' experiences were recorded using in-depth interview techniques following earlier testing for hereditary non-polyposis colorectal cancer which was coordinated through an hereditary cancer registry. Thematic analysis of the transcripts revealed consistent issues pertaining to identity as well as emotional responses to previous preventative strategies and ongoing cancer screening options.

Clinical and molecular aspects of Gaucher disease in New Zealand.

AIM: To report on the clinical and molecular aspects of Gaucher disease in New Zealand. METHODS: Patients known to have Gaucher disease were contacted and clinical information was recorded by questionnaire. Blood samples from affected individuals and their families provided DNA material for mutation analysis of disease causing alleles. Patients were assayed for beta-glucocerebrosidase, the enzyme deficiency which causes Gaucher disease. RESULTS: Twelve of 14 patients and 10 carriers were confirmed by DNA analysis. One asymptomatic individual was diagnosed. Four known mutations (N370S, 1444p, R463c and RecNcIl) and one unknown mutation were found from the 34 disease producing alleles that were identified. Of these, the L444P and N370S alleles were the most common. Most patients exhibited a clinical disorder typical of type 1 Gaucher disease. Two recent patients with severe neuropathic Gaucher disease had died in childhood. All patients showed a deficiency in beta-glucocerebrosidase. CONCLUSION: Gaucher disease in New Zealand is represented in a small number of non Jewish individuals with varying severity. Identifiable mutations and clinical symptoms aid in expanding the Australasian picture of this well studied disease. Enzyme replacement therapy for these patients has recently commenced in New Zealand.

Ehlers-Danlos syndrome in the Western Cape.

The Ehlers-Danlos syndrome (EDS) is an uncommon heterogeneous inherited disorder in which articular hypermobility is associated with cutaneous extensibility and tissue fragility. A wide variety of complications may occur and although some forms of EDS are innocuous, others can cause serious disability. The condition has been reported from many parts of the world, but there is little information about it in Africa. To elucidate the local situation 12 affected people from the Western Cape have been investigated and information concerning 8 others has been analysed.

Sotos syndrome--autosomal dominant inheritance substantiated.

Sotos syndrome, or Cerebral Gigantism is recognised as the syndromic association of mental retardation, macrocephaly and prenatal onset of accelerated growth. A kindred has been investigated in which the father and 4 affected offspring all have the Sotos syndrome. Autosomal dominant inheritance has been postulated in the past, and the family conform to this genetic pattern.

Epidermolysis bullosa misdiagnosed as child abuse. A report of 3 cases.

Three cases of epidermolysis bullosa are reported; the typical skin lesions were misdiagnosed as non-accidental injury to the children. Awareness of the manifestations of this uncommon genodermatosis, as well as the wearing of identifying Medic Alert discs, should prevent this inappropriate diagnostic stigmatization.

Primary oxalosis--an unusual cause of livedo reticularis.

A young woman presented with renal failure and skin lesions of livedo reticularis (LR) due to primary oxalosis. Primary oxalosis is a rare autosomal-recessive error of metabolism characterized by accumulation of calcium-oxalate crystals in the kidneys, eyes, heart and skin. This unusual cause of intravascular obstruction resulting in livedo reticularis should be considered in patients with renal impairment. An approach to the diagnosis of LR is presented.

X-linked ocular albinism and sensorineural deafness: linkage to Xp22.3.

X-linked ocular albinism with late-onset sensorineural deafness (OASD) is an autonomous disorder that poses significant clinical problems, causing affected individuals to be blind and deaf by early middle age. Classical X-linked ocular albinism (without deafness; OA1) has recently been linked to markers in the Xp22.2-Xp22.3 region of the human genome. In the present report, a large South African family with OASD was investigated at the molecular level and tight linkage was found to the DXS452 locus at Xp22.3 using 25 informative meioses, with a maximum lod score of 7.1 at a recombination fraction of 0.00. These findings suggest that OA1 and OASD are allelic variants or that they may be due to contiguous gene defects.

Genetic heterogeneity in tuberous sclerosis: phenotypic correlations.

There is increasing evidence for genetic heterogeneity in tuberous sclerosis (TSC) on the basis of linkage analysis in affected kindreds. We have performed a detailed assessment of an affected South African family in which there is no evidence of linkage to chromosome 9 markers. The affected persons have atypical clinical features, namely prominent nuchal skin tags, a confetti pattern of hypopigmentation of the skin of the lower legs, and absence of ungual fibromata. Further investigation of these unusual phenotypic features is warranted in order to determine whether these lesions are consistently present in families in whom the gene for TSC is not on 9q34. We conclude that confetti depigmentation and nuchal skin tags may be clinical pointers to an alternative locus for TSC.