Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition.

Background: Prostate-specific antigen (PSA) and PSA-velocity (PSAV) have been used to identify men at risk of prostate cancer (PrCa). The IMPACT study is evaluating PSA screening in men with a known genetic predisposition to PrCa due to BRCA1/2 mutations. This analysis evaluates the utility of PSA and PSAV for identifying PrCa and high-grade disease in this cohort.

Targeted prostate cancer screening in BRCA1 and BRCA2 mutation carriers: results from the initial screening round of the IMPACT study.

Background: Men with germline breast cancer 1, early onset (BRCA1) or breast cancer 2, early onset (BRCA2) gene mutations have a higher risk of developing prostate cancer (PCa) than noncarriers. IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls) is an international consortium of 62 centres in 20 countries evaluating the use of targeted PCa screening in men with BRCA1/2 mutations.

Objective: To report the first year's screening results for all men at enrollment in the study.

The clinical utility of an SCN1A genetic diagnosis in infantile-onset epilepsy.

Aim: Genetic testing in the epilepsies is becoming an increasingly accessible clinical tool. Mutations in the sodium channel alpha 1 subunit (SCN1A) gene are most notably associated with Dravet syndrome. This is the first study to assess the impact of SCN1A testing on patient management from both carer and physician perspectives.

Detection of F508del mutation in cystic fibrosis transmembrane conductance regulator gene mutation among Malays.

Introduction: Cystic fibrosis (CF) is one of the common genetic disorders in the western world. It has been reported to be very rare in Asian populations. According to the Cystic Fibrosis Genetic Analysis Consortium, more than 1,000 mutations of the CF gene have been identified.

CDKN2A mutations in Scottish families with cutaneous melanoma: results from 32 newly identified families.

Background: Up to 5% of patients with melanoma have a family history of a first-degree relative also being affected.

Objectives: To study such families for germline mutations, to help clarify the gene-environment interaction in melanoma aetiology.

Methods: Thirty-two families in Scotland with melanoma in two or more first-degree relatives are reported for the first time.

Prevalence of exon 15 BRAF mutations in primary melanoma of the superficial spreading, nodular, acral, and lentigo maligna subtypes.

DNA was extracted from 52 thick primary melanomas and mutations sought in exon 15 of the BRAF (v-raf murine sarcoma viral oncogene homolog B1) gene using denaturing high performance liquid chromatograph (dHPLC) fragment analysis, sequencing, and allele-specific PCR. Exon 15 BRAF mutations were found in 13 of 52 (25%) primary melanomas. These comprised five of 17 (29%) superficial spreading melanomas, three of 11 (27%) nodular melanomas, two of 13 (15%) acral lentiginous melanomas, one of one (100%) mucosal melanoma and two of 10 (20%) lentigo maligna melanomas.

Craniosynostosis associated with intracranial calcification: a novel recessive syndrome.

We report three siblings who were variably affected by craniosynostosis, calcification of the basal ganglia, and mild facial dysmorphism comprising prominent eyes and a prominent nasal bridge. The children are of normal intelligence and have no limb abnormalities. Their parents are first cousins and are phenotypically normal.

The Southwest of Scotland Structural Chromosomal Abnormalities Database: an assessment of its contribution to genetic counselling in affected families.

Aim: To assess the effect of establishing a genetic database on the provision of genetic counselling to individuals and families with structural chromosomal abnormalities.

Method: For the four year period 1997-2000, we compared all cytogenetics laboratory records with entries on the database to determine its completeness. We assessed the extent to which families had been followed up, compared these findings with a previous four year period (1977-1980) and sought to discover why some families were not followed up.

Cranial magnetic resonance imaging mistakenly suggests prenatal ischaemia in PEHO-like syndrome.

We describe two sisters with a PEHO-like syndrome. The first-born had early epileptic spasms with hypsarrhythmia, visual inattention with optic atrophy, progressive microcephaly and absence of development. Cranial magnetic resonance imaging revealed periventricular white matter changes.

Absence of exon 15 BRAF germline mutations in familial melanoma.

We have analyzed DNA from peripheral blood of 42 cases of familial melanoma for germline mutations in exon 15 of the BRAF gene. No evidence of mutation was found. We have also analyzed DNA extracted from secondary melanoma from two members of these families.

A Schinzel-Giedion-like syndrome--a milder version or a separate condition?

We report two 12-year-old monozygotic twins followed from birth. Their features include midface hypoplasia, a prominent forehead, coarse features, sensorineural deafness, short stature with thoracic kyphosis and lumbar lordosis and intellectual delay. As they have developed, their features have been reminiscent of a storage disorder but mucopolysaccharidoses, mucolipidoses and gangliosidoses have been excluded by biochemical testing.

Cleft palate, hypotelorism, and hypospadias: Schilbach-Rott syndrome.

A mother and two sons have cleft palate and facial appearance closely resembling cases described by Schilbach and Rott in 1988. One of the two males has hypospadias and learning disability and, like his mother, is of short stature. The family described by Schilbach and Rott also supports an autosomal dominant inheritance pattern.

Phenotype, ovarian function, and growth in patients with 45,X/47,XXX Turner mosaicism: implications for prenatal counseling and estrogen therapy at puberty.

Objective: Our objective was to determine whether girls with the rare Tur-ner 45,X/47,XXX mosaic karyotype are less severely affected than girls with 2 commoner karyotypes.

Study Design: We evaluated growth status, phenotype, and ovarian function in 7 girls with 45,X/47,XXX mosaicism, age-matching each with 2 girls with 45,X and 1 with 45,X/46,Xi(X)(q10) karyotypes.

Results: For the index, 45,X, and 45,X/46,Xi(X)(q10) groups, respectively, the median/mean height SD score at the start of growth hormone therapy/comparable age was -2.

Non-progressive mental retardation and peripheral neuropathy in a mother and her son.

The association of facial dysmorphism, moderate mental retardation and peripheral neuropathy was observed in a mother and her son. The son also has pyramidal tract involvement in the lower limbs. Although exactly the same association has not been described previously, it seems probable that it results from variable expression of a dominant gene defect.

Detection of mutations in the RB1 gene by single strand conformation polymorphism (SSCP) analysis, amplification mismatch detection (AMD) analysis and polymerase chain reaction sequencing.

Mutations of the retinoblastoma gene are known to cause both nonhereditary and hereditary forms of retinoblastoma. Most patients with hereditary retinoblastoma have bilateral disease. Hereditary predisposition to retinoblastoma is caused by a germline mutation at the retinoblastoma gene locus (RB1) and transmitted as an autosomal dominant trait with 90% penetrance.

A new case of Myhre syndrome.

Myhre Syndrome is a rare condition associated with mental retardation, short stature, generalized muscle hypertrophy, cardiac defects and a distinct facial appearance. There have only been five reported cases and we now present a sixth, together with a review of the clinical features of this syndrome.

A case of Acro-renal-mandibular syndrome in an 18 week male fetus.

An 18 week male fetus is described with Acro-renal-mandibular syndrome. This third reported case of the syndrome is the first known male case and extends the phenotypic spectrum that characterizes the condition.

Towards earlier diagnosis of 22q11 deletions.

Over a 7 year period, 551 patients were investigated for the presence of a chromosome 22q11 deletion by fluorescence in situ hybridisation. Analysis of the presenting features of the 67 individuals with this chromosome deletion permitted us to devise guidelines to facilitate early diagnosis.

The distress associated with cranial irradiation: a comparison of patient and nurse perceptions.

Distress associated with attendance at a radiotherapy treatment center for cranial radiotherapy was assessed in 10 consecutive patients using a method first employed by Munro et al. (1). This involved using a series of cards, each with a potential side effect of radiotherapy printed on it.

Detection of t(12;21) in childhood acute lymphoblastic leukemia by fluorescence in situ hybridization.

Metaphase preparations from 36 patients with acute lymphoblastic leukemia (ALL) have been retrospectively screened by fluorescence in situ hybridization (FISH) to determine the incidence of translocation (12;21) and the potential usefulness of FISH as an adjunct to conventional cytogenetic analysis. With the use of specific chromosome paints, 4 of 31 patients with B-lineage childhood ALL (13%) demonstrated rearrangements of chromosomes 12 and 21, and therefore, were considered to harbor the translocation, which had not previously been detected by conventional karyotyping. However, none of these positive cases revealed the standard reciprocal t(12;21)(p12;q22) as the sole abnormality involving chromosomes 12 and 21.

Acute intermittent porphyria: alternative splicing of hydroxymethylbilane synthase mRNA excludes exons 3 and 12.

The hydroxymethylbilane synthase (HMBS) mRNAs from 44 control individuals and 30 patients suffering from acute intermittent porphyria (AIP), were screened for length differences by reverse transcriptase polymerase chain reaction (RT-PCR) and any abnormalities were characterized by direct sequencing. Examination of the mRNAs extracted from the peripheral blood lymphocytes of the samples revealed varying degrees of alternative splicing, involving the removal of exons 3 and 12. Approximately 10-50% of the mRNA molecules were affected, despite the absence of genomic splice site mutations or any major deviance from consensus splice sequence values.

Recurrence risks in mental retardation.

Despite improvements in diagnostic techniques and progress made in mapping genes associated with syndromal mental handicap, the estimation of recurrence risks in non-syndromal mental retardation is still dependent on empirical data. Unfortunately, few studies are available to guide the clinician and their results differ significantly. For example, recurrence risks to all sibs of a male index patient with severe mental retardation vary between 3.

Identification of two novel mutations in the hydroxymethylbilane synthase gene in three patients from two unrelated families with acute intermittent porphyria.

We have screened the hydroxymethylbilane synthase cDNAs of 3 patients from 2 families suffering from acute intermittent porphyria (AIP) from Scotland and South Africa using heteroduplex and chemical cleavage of mismatch analyses. Direct sequencing was used to characterise the mutations. The two novel mutations identified were a missense mutation at nucleotide position 64 in exon 3 (R22C) and a single base-pair deletion in exon 15.

Dominantly inherited cerebral dysplasia: arachnoid cyst associated with mild mental handicap in a mother and her son.

We report a mother and son who each presented in infancy with hypotonia and global developmental delay. Subsequently, in both subjects, mild mental handicap was diagnosed in association with temporal lobe arachnoid cysts. Mendelian inheritance of this phenotype seems likely and macroscopic cerebral dysplasia in general may be underdiagnosed in people with familial, mild mental handicap.

Biochemical markers of trisomy 21 and the pathophysiology of Down's syndrome pregnancies.

Using biochemical and immunocytochemical methods, we have investigated endogenous levels of various markers in tissues obtained from 67 Down's syndrome pregnancies after therapeutic abortion in the second trimester and in corresponding tissues from unaffected abortuses. Alpha-fetoprotein (AFP), intact and free beta human chorionic gonadotrophin (hCG), pregnancy-specific beta-1 glycoprotein (SP-1), placental alkaline phosphatase (PALP), pregnancy-associated plasma protein A (PAPP-A), and gamma glutamyl transferase (GGT) were investigated in placental tissue; AFP and GGT in fetal liver; and GGT in fetal intestine. The results indicate that maternal serum levels of placental products reflect those found in the placenta: intact hCG, free beta hCG, and SP-1 levels were elevated in Down's syndrome pregnancies, while PAPP-A and PALP levels were little changed.