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Biomedical subjects

B R Korf

Publications and source records attributed to B R Korf.

At least 19 recordsLinked to original sources
PubMed2001

Connexin 26 studies in patients with sensorineural hearing loss.

OBJECTIVE: To determine the spectrum of connexin 26 (Cx26) mutations and their phenotypes in children with sensorineural hearing loss (SNHL) or mixed hearing loss (MHL). DESIGN: Children with SNHL or MHL were prospectively tested for mutations in the entire coding region of the Cx26 gene. PATIENTS: Children with SNHL or MHL with no obvious etiology for the hearing loss. RESULTS: Between December 1, 1998, and July 1, 2000, 107 patients with SNHL or MHL from 99 families underwent Cx26 testing. Most patients were aged 1 week to 16 years (61 boys and 46 girls). Thirty (30%) of 99 probands had Cx26 mutations: biallelic mutations were detected in 18 (9 homozygous and 9 compound heterozygous) and single mutations were detected in 12. Twelve previously reported mutations (35delG, 167delT, E47X, L90P, M34T, G12V, V37I, R143W, V84L, V153I, V27I, and 310del14) and 3 novel mutations (E129K, T8M, and N206S) were found. Hearing loss in patients with biallelic Cx26 mutations ranged from unilateral high frequency to bilateral profound. Four children, 2 with biallelic mutations, had temporal bone abnormalities. CONCLUSIONS: Connexin 26 mutations are common in children with SNHL, and it is likely that the homozygous and compound heterozygous mutations cause the SNHL. However, pathogenicity is less certain when only a single Cx26 mutation is present. Patients with biallelic Cx26 mutations had a slightly higher incidence of milder hearing loss than in previous studies. Children with SNHL or MHL should be tested for Cx26 mutations early in their evaluation.

Adolescent↗
PubMed2001

Diagnosis and management of neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder whose major feature is the occurrence of multiple neurofibromas, which are benign tumors of the nerve sheath. It affects an estimated one in 3000 to 4000 individuals. In addition to neurofibromas, there are many other clinical manifestations, including malignant tumors such as gliomas or malignant peripheral nerve sheath tumors, and nontumor effects such as skeletal dysplasia and learning disability. Diagnosis is established on the basis of clinical criteria. Molecular genetic testing is feasible, but the large size of the gene and wide range of pathogenic mutations have so far impeded the development of a clinical diagnostic test. Insights into pathogenesis have followed from identification of the NF1 gene and the development of animal models. The major function of the gene product appears to be regulation of the ras protein. Tumors are believed to arise by the loss of function of the NF1 protein, suggesting that NF1 behaves as a tumor suppressor gene. Heterozygous effects on some cell types are also likely, however. The role of ras in the pathogenesis of tumors in NF1 has suggested an approach to treatment using ras inhibitors, some of which are likely to begin in clinical trials in NF1 patients in the near future.

Animals↗
PubMed2000

Cardiovascular malformations and other cardiovascular abnormalities in neurofibromatosis 1.

Although it is well recognized that a peripheral vasculopathy may occur in patients with neurofibromatosis 1 (NF1), it is unclear whether cardiovascular abnormalities are more common. We reviewed the frequency of cardiovascular abnormalities, in particular, cardiovascular malformations (CVMs), among 2322 patients with definite NF1 in the National Neurofibromatosis Foundation International Database from 1991-98. Cardiovascular malformations were reported in 54/2322 (2.3%) of the NF1 patients, only 4 of whom had Watson syndrome or NF1-Noonan syndrome. There was a predominance of Class II "flow" defects [Clark, 1995: Moss and Adams' Heart Disease in Infants, Children, and Adolescents Including the Fetus and Young Adult. p 60-70] (43/54, 80%) among the NF1 patients with CVMs. Pulmonic stenosis, that was present in 25 NF1 patients, and aortic coarctation, that occurred in 5, constitute much larger proportions of all CVMs than expected. Of interest was the paucity of Class I conotruncal defects (2 patients with tetralogy of Fallot), and the absence of atrioventricular canal, anomalous pulmonary venous return, complex single ventricle and laterality defects. Besides the 54 patients with CVMs, there were 27 patients with other cardiac abnormalities (16 with murmur, 5 with mitral valve prolapse, 1 with intracardiac tumor, and 5 with electrocardiogram abnormalities). No patient in this study had hypertrophic cardiomyopathy. There were 16 patients who had a peripheral vascular abnormality without an intracardiac CVM, plus an additional 4 patients among those with a CVM who also had a peripheral vascular abnormality.

Aortic Coarctation↗
PubMed2000

Discordant phenotype in monozygotic twins with Fryns syndrome.

We report on a pair of monozygotic twins with Fryns syndrome discordant for severity of diaphragmatic defect. Both twins had macrocephaly, "coarse" facial appearance, hypoplasia of distal phalanges, and an extra pair of ribs. Twin A lacked an apparent diaphragmatic defect, and at 1 year of age had mild developmental delay. Twin B had a left congenital diaphragmatic hernia and died neonatally. Absence of diaphragmatic defect in Fryns syndrome may represent a subpopulation of more mildly affected patients whose developmental outcome is currently undetermined.

Hernia, Diaphragmatic↗
PubMed2000

Medical education in the 'postgenomic era'.

The sequence of the human genome is very nearly in hand; the first draft has been completed, and the finished sequence will be available years ahead of schedule. Already, advances in medical genetics have affected the day-to-day practice of medicine by providing more powerful approaches to diagnosis of genetic disorders and cancer. But the full impact of the integration of genetics into medical practice lies before us.

Education, Medical↗
PubMed2000

NF1 microdeletion syndrome: refined FISH characterization of sporadic and familial deletions with locus-specific probes.

Two familial and seven sporadic patients with neurofibromatosis 1-who showed dysmorphism, learning disabilities/mental retardation, and additional signs and carried deletions of the NF1 gene-were investigated by use of a two-step FISH approach to characterize the deletions. With FISH of YAC clones belonging to a 7-Mb 17q11.2 contig, we estimated the extension of all of the deletions and identified the genomic regions harboring the breakpoints. Mosaicism accounted for the mild phenotype in two patients. In subsequent FISH experiments, performed with locus-specific probes generated from the same YACs by means of a novel procedure, we identified the smallest region of overlapping (SRO), mapped the deletion breakpoints, and identified the genes that map to each deletion interval. From centromere to telomere, the approximately 0.8-Mb SRO includes sequence-tagged site 64381, the SUPT6H gene (encoding a transcription factor involved in chromatin structure), and NF1. Extending telomerically from the SRO, two additional genes-BLMH, encoding a hydrolase involved in bleomycin resistance, and ACCN1, encoding an amiloride-sensitive cation channel expressed in the CNS-were located in the deleted intervals of seven and three patients, respectively. An apparently common centromeric deletion breakpoint was shared by all of the patients, whereas a different telomeric breakpoint defined a deletion interval of 0.8-3 Mb. There was no apparent correlation between the extent of the deletion and the phenotype. This characterization of gross NF1 deletions provides the premise for addressing correctly any genotype-phenotype correlation in the subset of patients with NF1 deletions.

Chromosome Deletion↗
PubMed2000

Malignancy in neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) represents a major risk factor for development of malignancy, particularly malignant peripheral nerve sheath tumors (MPNST), optic gliomas, other gliomas, and leukemias. The oncologist will see NF1 patients referred for treatment of malignancy, and should be alert to the possibility of undiagnosed NF1 among patients with cancer. Brain tumors tend to have a more indolent course in NF1 than in the general population, and hence are best managed conservatively. MPNST, in contrast, do not respond to standard chemotherapy or radiation therapy. The most effective treatment of MPNST appears to be early diagnosis and surgery, but early diagnosis is hampered by frequent occurrence within preexisting large tumors, making new growth or change difficult to detect. New insights into pathogenesis now offer hope of development of specific methods of treatment with reduced toxicity and more precise molecular targeting. There is an urgent need, however, to develop methods to measure tumor growth and monitor outcomes, develop preclinical drug screening systems, and further explore the pathogenesis of the disorder to determine whether mechanisms other than Ras regulation may be important in pathogenesis.

Glioma↗
PubMed1999

Descriptive analysis of tibial pseudarthrosis in patients with neurofibromatosis 1.

Five percent of individuals with neurofibromatosis type 1 (NF1) present with congenital long bone pseudarthrosis (PA). In large series, 50-80% of patients with congenital long bone PA also have NF1. Very little information exists on the natural history and pathogenesis of PA in NF1. This report is a descriptive analysis of a large series of patients with NF1 and tibial bowing or PA. Study A is a case-control study using the National Neurofibromatosis Foundation International Database (NNFFID). Eighty-five patients with PA were compared to a control group from the same database. There was a statistically significant male predominance of NF1 cases with PA (54 males to 31 females), compared to controls (85 males to 87 females) (chi2 = 4.0, P = 0.046, using a two-tailed test with Yates' correction). There was no significant difference in the clinical presentation of NF1 manifestations in NF1 patients with PA than in NF1 patients without PA. Of the affected individuals with PA, there were 24 de novo cases and 21 familial cases (9 through maternal and 12 through paternal inheritance). Questions that could not be answered by Study A were addressed by a partially overlapping case-series report, Study B, in which data on 75 cases ascertained through questionnaires completed by NF center directors were collected. From Study B we determined that half of the patients who had a fracture sustained it before age 2, and approximately 16% of the pseudarthrosis patients had an amputation. Our data indicate a male predominance and no parent-of-origin effect. Male gender may be a susceptibility factor for pseudarthrosis in NF1.

Adolescent↗
PubMed1999

Plexiform neurofibromas.

Plexiform neurofibromas are among the most common and debilitating complications of neurofibromatosis type 1 (NF1). They account for substantial morbidity, including disfigurement, functional impairment, and may even be life threatening. Plexiform neurofibromas are also subject to transformation into malignant peripheral nerve sheath tumor (MPNST), a complication that is refractory to treatment both because of a paucity of effective therapies for malignant soft tissue sarcomas in general, and because of the delay in diagnosis that results from change of a small portion of a large pre-existing tumor. The current mainstay of treatment of plexiform neurofibromas, and of MPNST for that matter, is surgical resection. The major variables are the timing and means of identification of plexiform neurofibromas, methods of follow-up, and indications for surgery. There is no established means of medical treatment, but research into the molecular pathogenesis of NF1, as well as advances in tumor therapy in general, are opening the way towards clinical trials for plexiform neurofibroma. Am. J. Med. Genet. (Semin. Med. Genet.) 89:31-37, 1999.

Humans↗
PubMed1999

PTEN mutation spectrum and genotype-phenotype correlations in Bannayan-Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome.

Germline mutations in the tumour suppressor gene PTEN have been implicated in two hamartoma syndromes that exhibit some clinical overlap, Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRR). PTEN maps to 10q23 and encodes a dual specificity phosphatase, a substrate of which is phosphatidylinositol 3,4,5-triphosphate, a phospholipid in the phosphatidylinositol 3-kinase pathway. CS is characterized by multiple hamartomas and an increased risk of benign and malignant disease of the breast, thyroid and central nervous system, whilst the presence of cancer has not been formally documented in BRR. The partial clinical overlap in these two syndromes is exemplified by the hallmark features of BRR: macrocephaly and multiple lipomas, the latter of which occur in a minority of individuals with CS. Additional features observed in BRR, which may also occur in a minority of CS patients, include Hashimoto's thyroiditis, vascular malformations and mental retardation. Pigmented macules of the glans penis, delayed motor development and neonatal or infant onset are noted only in BRR. In this study, constitutive DNA samples from 43 BRR individuals comprising 16 sporadic and 27 familial cases, 11 of which were families with both CS and BRR, were screened for PTEN mutations. Mutations were identified in 26 of 43 (60%) BRR cases. Genotype-phenotype analyses within the BRR group suggested a number of correlations, including the association of PTEN mutation and cancer or breast fibroadenoma in any given CS, BRR or BRR/CS overlap family ( P = 0.014), and, in particular, truncating mutations were associated with the presence of cancer and breast fibroadenoma in a given family ( P = 0.024). Additionally, the presence of lipomas was correlated with the presence of PTEN mutation in BRR patients ( P = 0.028). In contrast to a prior report, no significant difference in mutation status was found in familial versus sporadic cases of BRR ( P = 0.113). Comparisons between BRR and a previously studied group of 37 CS families suggested an increased likelihood of identifying a germline PTEN mutation in families with either CS alone or both CS and BRR when compared with BRR alone ( P = 0.002). Among CS, BRR and BRR/CS overlap families that are PTEN mutation positive, the mutation spectra appear similar. Thus, PTEN mutation-positive CS and BRR may be different presentations of a single syndrome and, hence, both should receive equal attention with respect to cancer surveillance.

Abnormalities, Multiple↗
PubMed1999

Genetic testing for patients with renal disease: procedures, pitfalls, and ethical considerations.

The Human Genome Project is rapidly producing insights into the molecular basis of human genetic disorders. The most immediate clinical benefit is the advent of new diagnostic methods. Molecular diagnostic tools are available for several genetic renal disorders and are in development for many more. Two general approaches to molecular diagnosis are linkage-based testing and direct mutation detection. The former is used when the gene has not been cloned but has been mapped in relation to polymorphic loci. Linkage-based testing is also helpful when a large diversity of mutations makes direct detection difficult. Limitations include the need to study multiple family members, the need for informative polymorphisms, and genetic heterogeneity. Direct mutation detection is limited by genetic heterogeneity and the need to distinguish nonpathogenic allelic variants from pathogenic mutations. Molecular testing raises a number of complex ethical issues, including those associated with prenatal or presymptomatic diagnosis. In addition, there are concerns about informed consent, privacy, genetic discrimination, and technology transfer for newly developed tests. Health professionals need to be aware of the technical and ethical implications of these new methods of testing, as well as the complexities in test interpretation, as molecular approaches are increasingly integrated into medical practice.

Ethics, Medical↗
PubMed1998

Complex familial rearrangement of chromosome 9p24.3 detected by FISH.

We describe a newborn male with minor facial anomalies, pyloric stenosis, and a chromosome rearrangement that involves deletion and addition of material at 9p24.3. Routine studies showed a 46, XY, add (9) (p24) karyotype. Fluorescence in situ hybridization (FISH) with two different whole chromosome probes for chromosome 9 failed to identify whether the additional material was derived from that chromosome. FISH with single copy YAC probes from 9p24 (D9S1858, D9S1813 and D9S54) showed a more complex rearrangement involving a deletion at D9S1858 but not at D9S1813 or D9S54. Parental chromosome studies demonstrated an apparently identical 9p abnormality in the patient's mother. This report describes a familial chromosome rearrangement in an abnormal child and his normal mother and demonstrates the use and limitations of FISH in characterizing chromosomal abnormalities.

Abnormalities, Multiple↗
PubMed1998

Genetic heterogeneity of Saethre-Chotzen syndrome, due to TWIST and FGFR mutations.

Thirty-two unrelated patients with features of Saethre-Chotzen syndrome, a common autosomal dominant condition of craniosynostosis and limb anomalies, were screened for mutations in TWIST, FGFR2, and FGFR3. Nine novel and three recurrent TWIST mutations were found in 12 families. Seven families were found to have the FGFR3 P250R mutation, and one individual was found to have an FGFR2 VV269-270 deletion. To date, our detection rate for TWIST or FGFR mutations is 68% in our Saethre-Chotzen syndrome patients, including our five patients elsewhere reported with TWIST mutations. More than 35 different TWIST mutations are now known in the literature. The most common phenotypic features, present in more than a third of our patients with TWIST mutations, are coronal synostosis, brachycephaly, low frontal hairline, facial asymmetry, ptosis, hypertelorism, broad great toes, and clinodactyly. Significant intra- and interfamilial phenotypic variability is present for either TWIST mutations or FGFR mutations. The overlap in clinical features and the presence, in the same genes, of mutations for more than one craniosynostotic condition-such as Saethre-Chotzen, Crouzon, and Pfeiffer syndromes-support the hypothesis that TWIST and FGFRs are components of the same molecular pathway involved in the modulation of craniofacial and limb development in humans.

Acrocephalosyndactylia↗