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M H Breuning

Publications and source records attributed to M H Breuning.

At least 19 recordsLinked to original sources
PubMed2006

Tall stature and duplication of the insulin-like growth factor I receptor gene.

Trisomy of 15q26-qter is frequently associated with tall stature and mental retardation. Here we describe a patient with such trisomy, without a partial monosomy of another chromosome. The tall stature in this patient is most probably caused by duplication of the IGF1R gene. A duplication of the IGF1R gene is not a frequent finding in patients with tall stature. In 38 patients with features of Sotos syndrome without NSD1 alterations, a duplication was found only once. This patient was already known to have an unbalanced 2;15 translocation. Looking for a duplication of the 15qter region is still worth consideration in patients with tall stature and features of Sotos syndrome without an NSD1 alteration, especially when there is craniosynostosis or marked speech delay.

Body Height↗
PubMed2006

A variable degree of intrauterine and postnatal growth retardation in a family with a missense mutation in the insulin-like growth factor I receptor.

CONTEXT: The type 1 IGF-I receptor (IGF1R) mediates the biological functions of IGF-I. Binding of IGF-I to the IGF1R results in autophosphorylation of the intracellular beta-subunit and activation of intracellular signaling. OBJECTIVE: The objective of this study was to evaluate the functional characteristics of a novel IGF1R mutation and describe the phenotypic features of two patients with this mutation. DESIGN: The study was performed in a university hospital. PATIENTS: We describe a 35-yr-old female with mild intrauterine growth failure, progressive postnatal growth retardation, severe failure to thrive, and microcephaly. Her daughter was born with severe intrauterine growth retardation and also showed postnatal failure to thrive and microcephaly. RESULTS: We found a heterozygous G3148-->A nucleotide substitution in the IGF1R gene, changing a negatively charged glutamic acid at position 1050 into a positively charged lysine residue (E1050K). E1050 is a conserved residue in the intracellular kinase domain. Dermal fibroblasts of the mother showed normal binding of iodinated IGF-I, but autophosphorylation and activation of downstream signaling cascades upon challenging with IGF-I was markedly reduced. Consequently, the maximal [(3)H]thymidine incorporation upon challenge with a dose range of IGF-I was reduced compared with a panel of control cells (3.65 +/- 1.79-fold vs. 6.75 +/- 4.7-fold stimulation; P < 0.01). These data suggest that the mutation results in the inactivation of one copy of the IGF1R gene. CONCLUSIONS: These two patients support the key role for IGF-I in intrauterine and postnatal growth. The different phenotypes of these and earlier described patients may be associated with variability in IGF-I signaling. The degree of intrauterine growth retardation may be partially determined by the presence or absence of maternal IGF-I resistance.

Adult↗
PubMed2006

Duplications in the DMD gene.

The detection of duplications in Duchenne (DMD)/Becker Muscular Dystrophy (BMD) has long been a neglected issue. However, recent technological advancements have significantly simplified screening for such rearrangements. We report here the detection and analysis of 118 duplications in the DMD gene of DMD/BMD patients. In an unselected patient series the duplication frequency was 7%. In patients already screened for deletions and point mutations, duplications were detected in 87% of cases. There were four complex, noncontiguous rearrangements, with two also involving a partial triplication. In one of the few cases where RNA was analyzed, a seemingly contiguous duplication turned out to be a duplication/deletion case generating a transcript with an unexpected single-exon deletion and an initially undetected duplication. These findings indicate that for clinical diagnosis, duplications should be treated with special care, and without further analysis the reading frame rule should not be applied. As with deletions, duplications occur nonrandomly but with a dramatically different distribution. Duplication frequency is highest near the 5' end of the gene, with a duplication of exon 2 being the single most common duplication identified. Analysis of the extent of 11 exon 2 duplications revealed two intron 2 recombination hotspots. Sequencing four of the breakpoints showed that they did not arise from unequal sister chromatid exchange, but more likely from synthesis-dependent nonhomologous end joining. There appear to be fundamental differences therefore in the origin of deletions and duplications in the DMD gene.

Cohort Studies↗
PubMed2005

Genetic analysis of tall stature.

Tall stature is less often experienced as an important problem than short stature. However, a correct diagnosis may be of eminent importance, especially when interventions are planned, or to know the natural history. Overgrowth can be caused by endocrine disorders and skeletal dysplasias, but also by several genetic syndromes. Despite a systematic diagnostic approach, there will be patients with tall stature who do not fit a known diagnosis. In this group of patients possibilities of genetic analysis do exist, but are not common practice. The FMR1 gene should be analyzed in patients with tall stature and mental retardation, and in these patients the NSD1 gene can be considered whenever some features of Sotos syndrome do exist. In tall patients without mental retardation and some features of Sotos or Beckwith-Wiedemann syndrome it may still be useful to look for mutations in the NSD1 gene, but also for changes in the 11p15 region. The various possibilities are discussed and placed in a flowchart.

Body Height↗
PubMed2005

Bifurcation of the femur with tibial agenesis and additional anomalies.

Bifurcation of the femur and tibial agenesis are rare anomalies and have been described in both the Gollop-Wolfgang Complex and the tibial agenesis-ectrodactyly syndrome. We report on two patients with bifurcation of the femur and tibial agenesis. Hand ectrodactyly was seen in one of these patients. Both patients had unusual additional anomalies. The first patient had in addition proximal focal femoral deficiency, the other patient had a tracheo-esophageal fistula and pyloric stenosis. Clinical and genetic aspects are discussed.

Abnormalities, Multiple↗
PubMed2005

[From gene to disease; PKHD1 and recessive polycystic kidney disease].

Autosomal recessive polycystic kidney disease (ARPKD) is a severe form of polycystic kidney disease characterised by enlarged kidneys and congenital hepatic fibrosis. The disease has an incidence of 1:7000-:20,000 and is caused by mutations in the PKHD1 gene, which under normal conditions produces the protein fibrocystin, also named polyductin. This protein may be a transmembrane receptor or ligand that plays a role in collecting duct and biliary differentiation. The major site of expression is the primary cilium, and in particular the basal body of the cilium, underlining a link between aberrant cilial function and cystogenesis. Prenatal diagnostics is possible using DNA analysis or ultrasonography.

Humans↗
PubMed2005

[From gene to disease; from CLN1, CLN2 and CLN3 to neuronal ceroid lipofuscinosis].

The neuronal ceroid lipofuscinoses (NCL) are worldwide the most common lysosomal storage disorders of childhood. Clinical features often include progressive visual impairment, seizures, psychomotor deterioration, dementia, and premature death. Most NCL cases are caused by mutations in the CLN1, CLN2 and CLN3 genes, which play an essential role in lysosomal protein degradation. Laboratory diagnostics for a patient suspected of NCL should start with enzyme analysis in the case of INCL and LINCL and investigation of lymphocyte vacuolisation for JNCL. Diagnosis at the protein level is not available for JNCL, but CLN3 mutation analysis is possible. The carrier status of healthy relatives in families with known mutations in either CLN1, CLN2, CLN3 or CLN6 can be determined with certainty by mutation analysis.

Aminopeptidases↗
PubMed2005

[Molecular diagnosis on indication of maturity onset diabetes of the young; results from 184 patients].

OBJECTIVE: To describe the results of mutation analysis of the genes involved in maturity onset diabetes of the young (MODY) types 1-3. DESIGN: Descriptive. METHOD: In the period July 2000-October 2003 the DNA from 184 possible MODY patients was analysed for the presence of mutations of the genes involved in MODY types 1, 2 and 3. The patients fulfilled at least one of the following criteria: diabetes mellitus had been diagnosed before the age of 25, or at least before the age of 40, there was a family history of diabetes mellitus at an early age, there were no characteristics to indicate diabetes mellitus type 1 or 2. RESULTS: In the blood of 65 patients (35%) a pathogenic gene mutation was found. A total of 45 patients had a mutation in the HNF-1alpha-gene (which is linked to MODY3), 11 in the glucokinase gene (MODY2) and 9 in the HNF-4alpha-gene (MODY1). Of all the HNF-1alpha-gene mutations, the insertion of a C in codon 291 was the most frequently seen (in 11 families). A mutation in exon 9 of the HNF-1alpha-gene was also shown in 9 apparently non-related families, which probably was a founder mutation. CONCLUSION: The MODY subtype was found in one third of the selected patients. This diagnosis may have implications in the clinical management of the patient.

Adult↗
PubMed2005

Multiplicity in polyp count and extracolonic manifestations in 40 Dutch patients with MYH associated polyposis coli (MAP).

OBJECTIVE: To investigate the contribution of MYH associated polyposis coli (MAP) among polyposis families in the Netherlands, and the prevalence of colonic and extracolonic manifestations in MAP patients. METHODS: 170 patients with polyposis coli, who previously tested negative for APC mutations, were screened by denaturing gradient gel electrophoresis and direct sequencing to identify MYH germline mutations. RESULTS: Homozygous and compound heterozygous MYH mutations were identified in 40 patients (24%). No difference was found in the percentage of biallelic mutation carriers between patients with 10-99 polyps or 100-1000 polyps (29% in both groups). Colorectal cancer was found in 26 of the 40 patients with MAP (65%) within the age range 21 to 67 years (median 45). Complete endoscopic reports were available for 16 MAP patients and revealed five cases with gastro-duodenal polyps (31%), one of whom also presented with a duodenal carcinoma. Breast cancer occurred in 18% of female MAP patients, significantly more than expected from national statistics (standardised morbidity ratio = 3.75). CONCLUSIONS: Polyp numbers in MAP patients were equally associated with the attenuated and classical polyposis coli phenotypes. Two thirds of the MAP patients had colorectal cancer, 95% of whom were older than 35 years, and one third of a subset of patients had upper gastrointestinal lesions. Endoscopic screening of the whole intestine should be carried out every two years for all MAP patients, starting from age 25-30 years. The frequent occurrence of additional extraintestinal manifestations, such as breast cancer among female MAP patients, should be thoroughly investigated.

Adenomatous Polyposis Coli↗
PubMed2004

Genomic imbalances in mental retardation.

INTRODUCTION: It has been estimated that cytogenetically visible rearrangements are present in approximately 1% of newborns. These chromosomal changes can cause a wide range of deleterious developmental effects, including mental retardation (MR). It is assumed that many other cases exist where the cause is a submicroscopic deletion or duplication. To facilitate the detection of such cases, different techniques have been developed, which have differing efficiency as to the number of loci and patients that can be tested. METHODS: We implemented multiplex amplifiable probe hybridisation (MAPH) to test areas known to be rearranged in MR patients (for example, subtelomeric/pericentromeric regions and those affected in microdeletion syndromes) and to look for new regions that might be related to MR. RESULTS: In this study, over 30 000 screens for duplications and deletions were carried out; 162 different loci tested in each of 188 developmentally delayed patients. The analysis resulted in the detection of 19 rearrangements, of which approximately 65% would not have been detected by conventional cytogenetic analysis. A significant fraction (46%) of the rearrangements found were interstitial, despite the fact that only a limited number of these loci have so far been tested. DISCUSSION: Our results strengthen the arguments for whole genome screening within this population, as it can be assumed that many more interstitial rearrangements would be detected. The strengths of MAPH for this analysis are the simplicity, the high throughput potential, and the high resolution of analysis. This combination should help in the future identification of the specific genes that are responsible for MR.

Abnormalities, Multiple↗
PubMed2004

Risk estimation for healthy women from breast cancer families: new insights and new strategies.

Risk estimation in breast cancer families is often estimated by use of the Claus tables. We analyzed the family histories of 196 counselees; compared the Claus tables with the Claus, the BRCA1/2, the BRCA1/2/ models; and performed linear regression analysis to extend the Claus tables with characteristics of hereditary breast cancer. Finally, we compared the Claus extended method with the Claus, the BRCA1/2, and the BRCA1/2/u models. We found 47% agreement for Claus table versus Claus model; 39% agreement for Claus table versus BRCA1/2 model; 48% agreement for Claus table versus BRCA1/2/u model; 37% agreement for Claus extended method versus Claus model; 44% agreement for Claus extended model versus BRCA1/2 model; and 66% agreement for Claus extended method versus BRCA1/2/u model. The regression formula (Claus extended method) for the lifetime risk for breast cancer was 0.08 + 0.40 (*) Claus Table + 0.07 (*) ovarian cancer + 0.08 (*) bilateral breast cancer + 0.07 (*) multiple cases. This new method for risk estimation, which is an extension of the Claus tables, incorporates information on the presence of ovarian cancer, bilateral breast cancer, and whether there are more than two affected relatives with breast cancer. This extension might offer a good alternative for breast cancer risk estimation in clinical practice.

Breast Neoplasms↗
PubMed2003

Genetic counselling and the intention to undergo prophylactic mastectomy: effects of a breast cancer risk assessment.

Scientific reports suggest that women at risk for familial breast cancer may benefit from prophylactic mastectomy. However, few data are available about how women decide upon this clinical option, and in particular, what role an objective risk assessment plays in this. The purpose of the present study is to assess whether this objective risk information provided in genetic counselling affects the intention for prophylactic mastectomy. Additionally, the (mediating) effects of breast cancer worry and perceived risk are investigated. A total of 241 women completed a questionnaire before and after receiving information about their familial lifetime breast cancer risk in a genetic counselling session. Path analysis showed that the objective risk information had a corrective effect on perceived risk (beta=0.38; P=0.0001), whereas the amount of breast cancer worry was not influenced by the counselling session. The objective risk information did not directly affect the intention for prophylactic mastectomy. The intention was influenced by perceived risk after counselling (beta=0.23; P=0.002), and by the precounselling levels of perceived risk (beta=0.27; P=0.00025) and breast cancer worry (beta=0.32; P=0.0001), that is, higher levels of perceived risk and breast cancer worry imply a stronger intention for prophylactic mastectomy. A personal history of breast cancer did not directly influence the intention for prophylactic mastectomy, but affected women who had undergone a mastectomy as surgical treatment were more positively inclined to have a prophylactic mastectomy than women who had had breast-conserving therapy. The impact of objective risk information on the intention for prophylactic mastectomy is limited and is mediated by perceived risk. Important determinants of the intention for prophylactic mastectomy were precounselling levels of breast cancer worry and perceived risk, suggesting that genetic counselling is only one event in the entire process of decision making. Therefore, interventions aimed at improving decision making on prophylactic mastectomy should explicitly address precounselling factors, such as personal beliefs and the psychological impact of the family medical history.

Adult↗
PubMed2003

[From gene to disease; SLC3A1, SLC7A9 and cystinuria].

In total, 1-2% of adults and 6-8% of children suffering from kidney stones have cystinuria, a defect in the transport of amino acids, which leads to high concentrations of cystine in the urine. Two genes have been implicated, solute carrier family 3 (cystine, basic and) neutral amino acid transporter, member 1 (SLC3A1) coding for the protein related to the system bo,+ amino-acid transporter, and solute carrier family 7, member 9 (SLC7A9), coding for the protein bo,+AT. There are three clinically defined types of cystinuria. Type I (autosomal recessive) is characterised by mutations in the SLC3A1 gene; carriers have normal cystine levels in urine. In total 80% of non-type-I patients have a detectable mutation in the SLC7A9 gene. First-degree relatives of a patient with type 2 (dominant) or type 3 (incomplete recessive) cystinuria may have slightly elevated cystine levels in the urine. The early recognition and treatment of cystinuria is important because recurrent stone formation may lead to urinary tract infection and, eventually, renal failure.

Amino Acid Transport Systems, Basic↗
PubMed2003

Bannayan-Riley-Ruvalcaba syndrome: further delineation of the phenotype and management of PTEN mutation-positive cases.

Bannayan-Riley-Ruvalcaba syndrome (BRRS) is characterised by macrocephaly, intestinal hamartomatous polyps, lipomas, pigmented maculae of the glans penis, developmental delay and mental retardation. The syndrome follows an autosomal dominant pattern of inheritance. In 1997 reports on two BRRS patients with a deletion at 10q23.2-q24.1 were published. In the same year, the first two families with BRRS and a mutation of the PTEN gene were reported. Mutations in the PTEN gene have also been demonstrated in patients with Cowden syndrome (CS), which shows partial clinical overlap with BRRS, and in families with cases both of BRRS and CS. PTEN mutation positive BRRS and CS are likely to be different phenotypic presentations of the same syndrome. If BRRS and CS are one single condition, the question arises whether patients with BRRS should be screened for malignant tumours, since patients with Cowden syndrome have an increased risk of breast, endometrial, thyroid and renal cancer. We present two isolated cases and one family and confirm that BRRS and CS are allelic. Furthermore, we review the PTEN mutation positive BRRS cases, to further delineate the phenotype and to compare the cases with a genomic deletion with the cases with a point mutation. We recommend offering BRRS cases with a mutation in PTEN the same surveillance protocol for (malignant) tumours as is currently recommended for CS. In addition, we propose a yearly haemoglobin test from early infancy for the early detection of intestinal hamartomas, which are likely to give severe complications, especially in BRRS cases.

Adult↗
PubMed2003

Genetic analysis of short stature.

Short stature is a major concern for patients and their parents, and represents a diagnostic challenge to the clinician. A correct diagnosis is of particular importance in view of the availability of effective, but costly, therapy in a small subset of cases. Many different genetic etiologies of short stature are known. Therefore, chromosome as well as molecular analysis are requisite diagnostic investigations in children with short stature. Particularly in the group of children with idiopathic short stature, possibilities of molecular analysis are often underestimated. Important options are UPD7 and the FGFR3, SHOX, GH1 and GHR genes. Furthermore, analysis of the IGF and IGF1R genes should be considered. We propose a flow chart for molecular analysis in short stature.

Body Height↗
PubMed2002

[Phenotypic variability: genetics and chance--deletion 22q11 and schizophrenia].

Haploinsufficiency syndromes, such as the deletion 22q11, the velo-cardio-facial or DiGeorge/Shprintzen syndrome characterised by chromosome 22q11 deletion, show marked variability in the clinical features. This variability may be due to chance fluctuations in expression of genes in the deleted segment, which tend to have more impact if only one copy of the gene is present. The apparent association between deletion 22q11 and schizophrenia indicates a role for a gene within the deletion in signal transduction in the brain.

Abnormalities, Multiple↗