Biomedical subjects

U Moog

Publications and source records attributed to U Moog.

At least 19 recordsLinked to original sources

PubMed2005

Oculocerebrocutaneous syndrome: the brain malformation defines a core phenotype.

BACKGROUND: Oculocerebrocutaneous syndrome (OCCS) is characterised by orbital cysts and anophthalmia or microphthalmia, focal aplastic or hypoplastic skin defects, skin appendages, and brain malformations. The eye and skin abnormalities are well described but the neuropathological features less so. To date, 28 patients with an unequivocal diagnosis of OCCS have been reported, with a preponderance of males. OBJECTIVE: To evaluate the brain imaging studies, clinical records, photographs, and pathological material of two new and nine previously reported cases of OCCS. RESULTS: There was a consistent pattern of malformations in eight of the 11 cases, consisting of frontal predominant polymicrogyria and periventricular nodular heterotopia, enlarged lateral ventricles or hydrocephalus, agenesis of the corpus callosum sometimes associated with interhemispheric cysts, and a novel mid-hindbrain malformation. The latter consisted of a giant and dysplastic tectum, absent cerebellar vermis, small cerebellar hemispheres in most cases, and a large posterior fossa fluid collection. CONCLUSIONS: The mid-hindbrain malformation appears pathognomonic for OCCS. The eye and skin features of OCCS show considerable overlap with several other syndromes, such as encephalocraniocutaneous lipomatosis, oculo-auriculo-vertebral spectrum, and focal dermal hypoplasia, none of which has a comparable pattern of brain malformations. In particular the unique mid-hindbrain malformation also distinguishes OCCS from related syndromes with comparable forebrain anomalies. The pattern of malformation described thus helps in differentiating OCCS from other entities. The mid-hindbrain malformation points to a defect of the mid-hindbrain organiser as the underlying pathogenic mechanism.

Abnormalities, Multiple↗

PubMed2005

Rett syndrome in females with CTS hot spot deletions: a disorder profile.

From a series of 107 females with Rett syndrome (RTT), we describe the long-term history of ten females with a deletion in the C-terminus of the MECP2 gene. We observed that their disorder profile is clinically recognizable with time and different from other atypical and milder RTT phenotypes. In females with hot spot deletions in the C-terminus, dystonia is present from childhood and results in a serious spine deformation in spite of preventive measures. Their adaptive behavior is surprisingly better preserved and in contrast with the typical decline in motor functioning. The delineation of disorder profiles by long-term clinical observation can teach us about genotype/phenotype relationships and eventually about the effect of epigenetic phenomena on the final phenotype.

Adult↗

PubMed2005

Subtelomeric chromosome aberrations: still a lot to learn.

Subtelomeric chromosome aberrations: still a lot to learn.Cryptic subtelomeric chromosome aberrations are a significant cause of mental retardation (MR). More than 4000 patients have been investigated, and the mean overall prevalence of subtelomeric rearrangements has been found to be 5.2%. In order to contribute to knowledge on the clinical presentation of subtelomeric rearrangements, we retrospectively studied patients with unexplained MR who had been evaluated for subtelomeric abnormalities by different fluorescence in situ hybridization (FISH) techniques. Hundred and two patients had an unexplained combination of MR with dysmorphism, congenital anomalies, and/or a positive family history and were investigated by total subtelomeric (TS) FISH (89/102), or by total painting (TP) in an obligate carrier in the case of familial MR (13/102). In 59 additional patients, a sequence-specific FISH was performed on clinical indication. In the 102 patients studied by TS or TP, six pathogenic aberrations (5.9%) were found in addition to one polymorphism. In total, eight clinically significant subtelomeric aberrations were found in the 161 index patients; four of these eight aberrations were familial. We report on the clinical presentation of all patients with an aberration and review the relevant literature. Factors complicating the interpretation of subtelomeric rearrangements are discussed, such as the occurrence of variants, clinical variability, and limited knowledge of the phenotype.

Chromosome Aberrations↗

PubMed2004

Randomized trial of a shared decision-making intervention consisting of trade-offs and individualized treatment information for BRCA1/2 mutation carriers.

PURPOSE: To evaluate a shared decision-making intervention (SDMI) for BRCA1/2 mutation carriers who have to make a choice between screening and prophylactic surgery for breasts and/or ovaries. PATIENTS AND METHODS: The SDMI consisted of two value assessment sessions, using the time trade-off method, followed by individualized treatment information based on (quality-adjusted) life expectancy. After the baseline assessment (2 weeks after a positive DNA test result), women were randomly assigned to the SDMI group (n = 44), receiving the SDMI 2 months after the test result, or to the control group (n = 44). The short- and long-term effects, 3 and 9 months after the test result, were assessed using questionnaires. Data were collected on well-being, treatment choice, and decision-related outcomes. RESULTS: In the short term, the SDMI had no effect. In the long term, with respect to well-being, patients in the SDMI group had less intrusive thoughts (P =.05) and better general health (P =.01) and tended to be less depressed (P =.07). With respect to decision-related outcomes for the breasts, the SDMI group held stronger preferences (P =.02) and agreed more strongly to having weighed the pros and cons (P =.01). No effect was found on treatment choice. In the long term, interaction effects between the SDMI and cancer history were found. The SDMI showed an overall beneficial effect for unaffected women, whereas affected women tended to experience detrimental effects. CONCLUSION: We conclude that the SDMI improved decision making in unaffected BRCA1/2 mutation carriers. Supporting decision making in a systematic way using trade-offs is beneficial for these women.

Adult↗

PubMed2004

Impact of BRCA1/2 testing and disclosure of a positive test result on women affected and unaffected with breast or ovarian cancer.

To evaluate the impact of BRCA1/2 testing and disclosure of a positive test result on women affected and unaffected with cancer. Longitudinal cohort study including women affected and unaffected with breast or ovarian cancer testing for a BRCA1/2 mutation. Data on well-being (anxiety, depression, cancer related distress, general health), treatment choice, and decision making about cancer prevention were collected at baseline (1 week after blood sampling; affected n = 192, unaffected n = 176) and at follow-up (2 weeks after disclosure of a positive test result; affected n = 23, unaffected n = 66). Women affected and unaffected with breast or ovarian cancer were compared using univariate statistics. Change over time was examined using repeated measures analysis of variance. With respect to well-being, affected women scored worse at baseline. At follow-up, both affected and unaffected women experienced a decline in well-being, which tended to be stronger in affected women. Women diagnosed with cancer less than 1 year previously tended to report a worse well-being than those diagnosed longer ago. With respect to treatment choice, more affected women intended to obtain prophylactic surgery and valued it higher at both time points. With respect to decision making, affected women had a lower preference for participation in decision making at baseline; no differences were found at follow-up. At follow-up, both affected and unaffected women showed an increase in strength of treatment preference and a decrease in decision uncertainty. Disclosure of a positive test result had a negative impact on well-being. Affected women, especially those who have been recently diagnosed with cancer, experienced the worst well-being and could benefit from psychosocial support.

Adult↗

PubMed2004

Randomised trial of a decision aid and its timing for women being tested for a BRCA1/2 mutation.

The aim of the study was to evaluate the impact of a decision aid (DA) and its timing in women being tested for a BRCA1/2 mutation. Women with and without a previous history of cancer were included after blood sampling for genetic testing. The DA consisted of a brochure and video providing information on screening and prophylactic surgery. To evaluate the impact of the DA, women were randomised to the DA group (n=184), receiving the DA 2 weeks after blood sampling, or to the control group (n=184). To evaluate the impact of timing, mutation carriers who had received the DA before the test result (n=47) were compared to mutation carriers who received the DA after the test result (n=42). Data were collected on well-being, treatment choice, decision and information related outcomes. The impact of the DA was measured 4 weeks after blood sampling. The impact of timing was measured 2 weeks after a positive test result. The DA had no impact on well-being. Regarding decision related outcomes, the DA group more frequently considered prophylactic surgery (P=0.02) corroborated with higher valuations (P=0.04). No differences were found for the other decision related outcomes. Regarding information related outcomes, the DA group felt better informed (P=0.00), was more satisfied with the information (P=0.00), and showed more accurate risk perceptions. Timing of the DA had no effect on any of the outcomes. No interactions were found between the DA and history of cancer. In conclusion, women being tested for a BRCA1/2 mutation benefit from the DA on information related outcomes. Because timing had no effect, the DA is considered useful either before or after the test result.

Adult↗

PubMed2004

Hereditary motor and sensory neuropathy (HMSN) IA, developmental delay and autism related disorder in a boy with duplication (17)(p11.2p12).

We present a 6-year-old boy with moderate developmental delay, gait disturbance, autism related disorder and mild dysmorphic features. He was seen for evaluation of his retardation since the age of 2.8 years. At first sight, a cytogenetic analysis showed a normal 46,XY karyotype. Neurological examination at the age of 5.5 years revealed a motor and sensory polyneuropathy. A quantitative Southern blot with probes PMP22 and VAW409 specific for Charcot-Marie-Tooth type 1 (CMT1) disclosed a duplication which confirmed the diagnosis HMSN Ia. Subsequently, GTG banded metaphases were re-evaluated and a small duplication 17p was seen on retrospect. Additional FISH with probe LSISMS (Vysis) specific for the Smith-Magenis region at 17p11.2 again showed a duplication. Both parents had a normal karyotype and the duplication test for CMT1 showed normal results for both of them. The boy had a de novo 46,XY,dup(17)(p11.2p12) karyotype. The present observation confirms previous findings of mild psychomotor delay, neurobehavioural features and minor craniofacial anomalies as the major phenotypic features of dup(17)(p11.2) and dup(17)(p11.2p12); in cases of duplications comprising the PMP22 locus HMSN1 is associated. A recognizable facial phenotype emerges characterized by a broad forehead, hypertelorism, downslant of palpebral fissures, smooth philtrum, thin upper lip and ear anomalies.

Autistic Disorder↗

PubMed2003

Rett syndrome in adolescent and adult females: clinical and molecular genetic findings.

Rett syndrome (RTT) is a neurodevelopmental disorder which is diagnosed clinically. We report on 30 adolescent and adult females with classical or atypical RTT of whom 24 have a MECP2 mutation. In these 24 females, the clinical manifestations, degree of severity, and disorder profiles are discussed as well as the genotype phenotype correlation. After X-chromosome inactivation (XCI) study in these cases, we found no correlation between skewing and milder phenotype. Three large deletions were found after additional Southern blot analysis in three classical RTT cases. We confirm that early truncating mutations in MECP2 are responsible for a more severe course of the disorder. Three disorder profiles related to the missense mutations R133C and R306C, and to deletions in the C terminal segment are described and are of interest for further clinical study on larger numbers of cases. The R133C genotype has a predominantly autistic presentation while the R306C genotype is associated with a slower disease progression. The phenotype of the "hotspot" deletions in the C terminal segment is predominantly characterized by rapid progressive neurogenic scoliosis. Older women with RTT are underdiagnosed: seven adults were first diagnosed as having RTT between 29 and 60 years of age, and confirmed on finding a MECP2 mutation. Knowledge of the clinical phenotype of RTT at an adult age is important for all involved in the care of these individuals. The involvement of the parent support group is very important in this matter.

Adolescent↗

PubMed2003

Deletion of chromosome region 18q21.1 --> 18q21.3 in a patient without clinical features of the 18q- phenotype.

In a 16-month-old boy referred because of developmental delay and asymmetric motor development, chromosome analysis showed an aberrant chromosome 18 in all 25 metaphases examined. The chromosome aberration was initially interpreted either as an interstitial deletion of chromosome region 18q21.1 --> 18q21.3 or an unbalanced translocation involving the distal part of the long arm of chromosome 18. Chromosome microdissection in combination with fluorescence in situ hybridization demonstrated that the aberrant chromosome 18 had an interstitial deletion, the karyotype being: 46,XY,del(18)(q21.1q21.3). At age 27 months, his development was moderately retarded. He showed craniofacial asymmetry but no other anomalies. The clinical and cytogenetic findings are compared with previously reported patients with a terminal or interstitial deletion in the long arm of chromosome 18.

Chromosome Banding↗

PubMed2002

Wolf-Hirschhorn (4p-)syndrome in a near adult with major depression; successful treatment with citalopram.

The Wolf-Hirschhorn Syndrome (WHS) or 4p-deletion syndrome is characterized by mental retardation, growth retardation, microcephaly and typical facial features. In addition, a wide spectrum of somatic abnormalities can be associated that may cause comorbidity. The syndrome has been extensively described in children, but less information is available about adult patienis. In this case report a near adult female WHS patient is described who developed a major depression with atypical symptoms that was successfully treated with citalopram. Treatment for one year in the effective dose prevented recurrence of depressive symptomatology.

Abnormalities, Multiple↗

PubMed2001

Acampomelic campomelic syndrome.

Campomelic syndrome (or campomelic dysostosis, CD; MIM *114290) is an autosomal dominant skeletal malformation syndrome characterized by shortness and bowing of long bones, especially of the lower limbs. Additional radiological and clinical findings are 11 pairs of ribs and a bell-shaped thorax, hypoplastic scapulae, narrow iliac wings, non-mineralized thoracic pedicles, clubbed feet, Robin sequence, typical facial anomalies and tracheomalacia. The disorder is frequently lethal due to respiratory distress. Sex reversal occurs in most patients with an XY karyotype. CD is caused by heterozygous mutations in the SOX9 gene, an SRY-related gene at 17q24.3-q25.1 with pleiotropic effects on the skeletal and genital systems. In addition, cases with chromosomal rearrangements involving 17q have been described that are most likely caused by disturbing one or more cis-regulatory elements from an extended control region. Campomelia (bowed limbs) is seen in most but not all patients, defining a so-called acampomelic campomelic dysostosis (ACD). Half of the CD cases with 17q rearrangements have no or mild campomelia. Furthermore, campomelia is absent or only mildly present in a small subgroup of cases with a normal karyotype. We present a chromosomally normal boy with ACD and his clinical follow-up up to the age of 2 years, in whom a heterozygous SOX9 missense mutation (H165Y) was identified. A SOX9 missense mutation was published in two other patients with ACD. Although up to now a general genotype-phenotype correlation could not be established for CD, a correlation emerges for the ACD variant that needs further confirmation.

Bone Diseases, Developmental↗

PubMed2001

Recombination hotspot in NF1 microdeletion patients.

Neurofibromatosis type 1 (NF1) patients that are heterozygous for an NF1 microdeletion are remarkable for an early age at onset and an excessive burden of dermal neurofibromas. Microdeletions are predominantly maternal in origin and arise by unequal crossover between misaligned NF1REP paralogous sequence blocks which flank the NF1 gene. We mapped and sequenced the breakpoints in several patients and designed primers within each paralog to specifically amplify a 3.4 kb deletion junction fragment. This assay amplified a deletion junction fragment from 25 of the 54 unrelated NF1 microdeletion patients screened. Sequence analysis demonstrated that each of the 25 recombination events occurred in a discrete 2 kb recombination hotspot within each of the flanking NF1REPs. Two recombination events were accompanied by apparent gene conversion. A search for recombination-prone motifs revealed a chi-like sequence; however, it is unknown whether this element stimulates recombination to occur at the hotspot. The deletion-junction assay will facilitate the prospective identification of patients with NF1 microdeletion at this hotspot for genotype-phenotype correlation studies and diagnostic evaluation.

Alleles↗

PubMed2001

Chemotherapy resistant ovarian cancer in carriers of an hMSH2 mutation?

Hereditary Non-Polyposis Colorectal Cancer (HNPCC, Lynch syndrome) is an autosomal dominant condition of cancer susceptibility with high penetrance, characterised by early onset of colon tumours as well as a variety of extracolonic tumours including ovarian cancer and, in particular, cancer of the endometrium. Germline mutations in one of five DNA-mismatch repair (MMR) genes (hMLH1, hMSH2, hMSH6, PMS1, PMS2) are known to cause HNPCC. To date, mutations in two of these genes (hMSH2 and hMLH1) are found in the majority of mutation positive families. Recent literature suggests that especially hMSH2 mutations are associated with extracolonic tumours. We describe two women from an HNPCC family carrying an hMSH2 mutation (deletion of exon 6 of this gene) who developed ovarian cancer. In these patients (full cousins) the ovarian cancers were noted for their aggressive development and rapid recurrence after surgical debulking and during regular multichemotherapy including Cisplatin. This report strengthens recent in vitro studies suggesting an involvement of MMR-gene mutations in ovarian cancer cell biology with decreased susceptibility to Cisplatin therapy. The possible implications for the therapy of ovarian cancer, the screening and genetic counselling of family members are discussed.

Adenosine Triphosphatases↗

PubMed2001

Lateral facial clefts: a case report.

A female new-born with bilateral lateral facial clefts, resulting in macrostomia, is reported. In addition she had a diminished palpebral fissure length. She died suddenly at the age of 6 months, presumably due to respiratory insufficiency. The unique combination of facial anomalies, present in this patient, has not been reported before. We discuss the differential diagnosis and the classification of facial clefts.

Brain↗

PubMed2001

Holoprosencephaly: the Maastricht experience.

Holoprosencephaly (HPE) is a developmental field defect with impaired cleavage of the embryonic forebrain as the cardinal feature. The prevalence is about 1 in 11.000-20.000 in live births and 1 in 250 during embryogenesis. In most cases, craniofacial abnormalities are associated and reflect in 80% of cases the degree of severity. The severity is of marked variability and ranges from cyclopia to minimal craniofacial dysmorphism, such as mild microcephaly with a single central incisor. The etiology of HPE is very heterogeneous and comprises environmental factors (e.g. maternal diabetes) and genetic causes. Approximately 50% of HPE cases are associated with a cytogenetic abnormality (the most common of which is trisomy 13) or a monogenic syndrome. Based on recurrent cytogenetic abnormalities, there are at least 12 genetic loci that likely contain genes implicated in the pathogenesis of HPE. Currently, four human HPE genes are known: SHH at 7q36, ZIC2 at 13q32, SIX3 at 2p21 and TGIF at 18p11.3. Over the past 13 years, 16 patients with HPE have been observed at the Department of Clinical Genetics at Maastricht. Some of them are briefly presented in order to emphasize the spectral nature of HPE and the etiological heterogeneity. One patient appeared to have a partial 18p deletion due to a maternal cryptic translocation t(1:18) and, in addition, a SHH mutation. The mildest affected patient presented with microcephaly and a single maxillary incisor; she had a submicroscopic 7q deletion. Finally, we propose a protocol of etiological work-up of HPE cases.

Brain↗

PubMed2000

Genotypic and phenotypic spectrum in tricho-rhino-phalangeal syndrome types I and III.

Tricho-rhino-phalangeal syndrome (TRPS) is characterized by craniofacial and skeletal abnormalities. Three subtypes have been described: TRPS I, caused by mutations in the TRPS1 gene on chromosome 8; TRPS II, a microdeletion syndrome affecting the TRPS1 and EXT1 genes; and TRPS III, a form with severe brachydactyly, due to short metacarpals, and severe short stature, but without exostoses. To investigate whether TRPS III is caused by TRPS1 mutations and to establish a genotype-phenotype correlation in TRPS, we performed extensive mutation analysis and evaluated the height and degree of brachydactyly in patients with TRPS I or TRPS III. We found 35 different mutations in 44 of 51 unrelated patients. The detection rate (86%) indicates that TRPS1 is the major locus for TRPS I and TRPS III. We did not find any mutation in the parents of sporadic patients or in apparently healthy relatives of familial patients, indicating complete penetrance of TRPS1 mutations. Evaluation of skeletal abnormalities of patients with TRPS1 mutations revealed a wide clinical spectrum. The phenotype was variable in unrelated, age- and sex-matched patients with identical mutations, as well as in families. Four of the five missense mutations alter the GATA DNA-binding zinc finger, and six of the seven unrelated patients with these mutations may be classified as having TRPS III. Our data indicate that TRPS III is at the severe end of the TRPS spectrum and that it is most often caused by a specific class of mutations in the TRPS1 gene.

Adolescent↗

PubMed2000

Familial dup(8)(p12p21.1): mild phenotypic effect and review of partial 8p duplications.

We describe a family with direct transmission of a duplication of 8p12-->8p21.1. The phenotype of affected relatives included mild mental retardation but no minor anomalies. The duplication was identified by means of GTG-banding and fluorescence in situ hybridization with a probe specific for 8p12 generated by microdissection and degenerate oligonucleotide primed-polymerase chain reaction. Assay of glutathione reductase, which has been localised to 8p21.1, was significantly increased when compared with controls with normal chromosomal constitution. To the best of our knowledge, a proximal direct duplication of 8p restricted to subbands p12-->p21.1 has not been reported so far. The reported aberration is compared with other partial duplications of 8p, in particular to inversion duplications 8p and to small direct distal duplications involving 8p23.1. Am. J. Med. Genet. 94:306-310, 2000.

Adult↗

PubMed2000

Duplication of chromosome region 8p23.1-->p23.3: a benign variant?

Chromosome analysis was performed in a 34-year-old man who was phenotypically normal except for oligoasthenozoospermia. In this patient, analysis of GTG-banded chromosomes showed in one chromosome 8 additional chromosomal material of unknown origin. To characterize the aberrant chromosome more precisely, a paint specific for chromosome region 8pter-->8p23.1 was generated by microdissection and degenerated oligonucleotide primed-polymerase chain reaction (DOP-PCR) and used as fluorescence in situ hybridization (FISH) paint. After reverse painting, hybridization signals were only found on the short arm of the two chromosomes 8, with an enlarged signal on the derivative chromosome 8. The duplication was characterized further with band-specific FISH probes. We concluded that (part of) chromosome region 8p23.1-->p23.3 was duplicated. Chromosome analysis of the parents showed that the dup(8) was of maternal origin and that the fertile brother of the index patient also was a carrier of the chromosome aberration. There was no history of miscarriages. We suggest that duplication of region 8p23.1-->p23.3 can be regarded as euchromatic variant or duplication with no phenotypic effect.

Adult↗