Biomedical subjects
Publications and source records attributed to M A van Steensel.
Rombo syndrome is a rare entity characterized by the presence of atrophoderma vermiculatum of the face, multiple milia, telangiectases, acral erythema and a propensity to develop basal cell carcinomas. We describe a patient whose clinical and histopathological abnormalities are consistent with this diagnosis.
We describe a Dutch kindred with a possibly novel dominant syndrome of premature loss of curly, brittle hair, premature loss of teeth due to caries, nail dystrophy and acral keratoderma. We discuss the possibility that this ectodermal dysplasia of group 1-2-3-4 is a variant of known disorders such as pachyonychia congenita. We conclude that none of these diagnoses fits the symptoms we observe in our patients and propose the name curly hair-acral keratoderma-caries syndrome in view of the most obvious abnormalities.
Heterozygous individuals carrying a "paradominant" mutation, as a rule, are phenotypically normal. Therefore, the mutation can be transmitted unperceived through many generations. The trait becomes manifest when a somatic mutation occurs during embryogenesis giving rise to loss of heterozygosity and forming a mutant cell population, being either homozygous or hemizygous for the mutation. This concept explains the occasional familial occurrence of usually sporadic traits like the Klippel-Trenaunay syndrome and others.
We report on a strategy for the identification of candidate genes for multiple malformation syndromes using expression data available in public databases. The basis for this pilot study was the assumption that, for a multiple malformation syndrome, the expression pattern of the causative gene should at least cover the organs or tissues affected by the syndrome. Twenty malformation syndromes were selected from the OMIM and defined by three to five main symptoms. These key symptoms were translated into anatomical terms that were used to query the Gene eXpression Database (GXD). The searches covered 65% of the database and yielded an average of 16 candidate genes per syndrome. Of these, 23% were ubiquitously expressed or housekeeping genes. Further database evaluation of these potential candidate genes was based on positional information and on information from mouse knockouts. In a first experiment, the correct gene was identified as a candidate in four of seven syndromes for which the causative gene is already known. In addition, this strategy identified new candidate genes for disorders for which the genetic basis is unknown. We identified candidate genes for the Walker-Warburg, DOOR, C, scalp-ear-nipple and oculocerebral hypopigmentation syndromes. Our results suggest that it may ultimately be feasible to identify disease genes by probing gene expression databases with simple syndrome descriptions.
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In this paper, we provide an overview of databases that are of importance to clinical geneticists. Some suggestions for the fruitful use for both research and diagnosis are given. For beginning 'web-surfers' we also list some well-known search engines and give a short overview of how to use these and other services. In addition, the URLs of some of the most important databases, gateways and tutorials are listed.
We describe a syndrome of midface hypoplasia, non-progressive sensorineural deafness and epiphyseal dysplasia in 3 sibs born to consanguineous parents. Clinical and roentgenographic findings are compatible with a diagnosis of oto-spondylo-megaepiphyseal dysplasia (OSMED). Histologic study of cartilage shows severe osteoarthritis, which may necessitate joint replacements in early adulthood. Ultrastructurally, collagen fibrils are increased in diameter and show aggregation. These findings have not been reported previously and may be diagnostic of OSMED. The affected sibs are homozygous for a COL11A2 missense mutation. We compare the clinical findings in our patients with a group of patients who have a dominantly inherited, non-ocular form of Stickler syndrome due to a COL11A2 splice-site mutation. Both syndromes include midface hypoplasia, epiphyseal dysplasia, and deafness, more pronounced in OSMED. Since mutations affecting the collagen XI genes can obviously result in a spectrum of phenotypes, we performed a literature-search using POSSUM, OSSUM, and the LDDB to identify conditions that might also be caused by mutations in one of the collagen XI genes. A number of conditions matched the search terms in all databases. Of these, Marshall syndrome is very similar to OSMED. Considering these phenotypic similarities and the close association between the COL11A1 and COL11A2 gene products, we propose that Marshall syndrome may be caused by a mutation in COL11A1. We also identify a number of other conditions that could be caused by mutations in one of the collagen XI genes.
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Procedures are being developed which use isolated articular cartilage (AC) chondrocytes to restore damaged articular surfaces. The availability of isolated human chondrocytes for transplantation may be increased by low-temperature storage (banking). At present, no single method of freezing chondrocytes has been proven to be optimal. In this project, two different freezing protocols, I and II, were compared. Protocol I used freezing rates of -1 degrees C/min down to a temperature of -40 degrees C. Protocol II used a freezing rate of -1 degree C/min down to -10 degrees C and faster rates thereafter. Cells were stored for 2 weeks at -196 degrees C. Survival and function of the cells after thawing were evaluated by histological examination and determination of 35S- and 3H-thymidine incorporation after 1 and 2 weeks of high-density monolayer culture. Cells frozen with protocol I showed better function and survival (99.75%) than cells frozen with protocol II (85%). Both groups showed slowing of metabolism and replication after freezing when compared with controls. We conclude that controlled freezing of adult human chondrocytes at rates of -1 degrees C/min improves survival. Banking of human AC chondrocytes may be feasible using protocol I, although some questions regarding the long-term behaviour of human AC chondrocytes after cryopreservation remain to be answered.
We describe two patients with an apparently unique autosomal dominant ectodermal dysplasia. Symptoms consist of thickening of all nails as seen in pachyonychia congenita and severe generalized hypotrichosis. No other abnormalities were present. Histopathological examination of scalp skin showed a reduction in the number of hair follicles, but other abnormalities were not found. Direct sequencing of the keratins known to be associated with pachyonychia congenita, Krt 6a, 6b, 16 and 17, failed to detect mutations. This suggests that this may be a new type of pachyonychia caused by a mutation in a so-called hard keratin.
For a long time, hair follicle development could be studied on the morphological level only. Now that molecular genetics is coming of age, we are beginning to understand the molecular basis of hair follicle development. The study of inherited hair disorders and basic research have both contributed to our insights and exciting developments can be expected in the near future. Here, we present a compact overview of the essential players in hair development and propose a simple model of the genetic interactions in the hair follicle.
We describe a girl of Turkish descent suffering from a peculiar combination of symptoms. The presenting complaint was bilateral lymphedema of the legs; additional symptoms include hypotrichosis, telangiectasias and angiomata limited to acral regions. We discuss the possibility that this girl suffers from Noonan/cardio-facio-cutaneous syndrome. We conclude that the combination of symptoms listed here probably represents a new syndrome for which we propose the name hypotrichosis-lymphedema-telangiectasia syndrome.
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