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David L Rimoin

Publications and source records attributed to David L Rimoin.

At least 19 recordsLinked to original sources
PubMed2006

Osteocraniostenosis-hypomineralized skull with gracile long bones and splenic hypoplasia. Four new cases with distinctive chondro-osseous morphology.

Osteocraniostenosis is a severe skeletal dysplasia characterized by a hypomineralized skull that has been previously described as kleeblattschädel (cloverleaf skull) and overtubulated long bones. Dysmorphic facial features include a short nose, short philtrum, and a small, inverted V-shaped mouth. Splenic a/hypoplasia is a constant finding. We report four infants (two unrelated and two siblings) with osteocraniostenosis and describe the clinical, radiographic and chondro-osseous morphology findings. The two siblings lack the moderate long-bone shortening that is typically seen. The skull configuration is likely caused by severely hypoplastic cranial bones (parietal) rather than true craniosynostosis, making the term "osteocraniostenosis" misleading. Histological examination of bone in all cases showed an abnormal growth plate with short irregular columns. The resting cartilage showed pleomorphic chondrocytes with increased cellularity and unique pseudocolumn formation. There are some radiographic and chondro-osseous morphologic similarities between osteocraniostenosis and severe Hallermann-Streiff syndrome (HSS), suggesting the two disorders may be pathogenetically related.

Adult↗
PubMed2006

A molecular and clinical study of Larsen syndrome caused by mutations in FLNB.

BACKGROUND: Larsen syndrome is an autosomal dominant osteochondrodysplasia characterised by large-joint dislocations and craniofacial anomalies. Recently, Larsen syndrome was shown to be caused by missense mutations or small inframe deletions in FLNB, encoding the cytoskeletal protein filamin B. To further delineate the molecular causes of Larsen syndrome, 20 probands with Larsen syndrome together with their affected relatives were evaluated for mutations in FLNB and their phenotypes studied. METHODS: Probands were screened for mutations in FLNB using a combination of denaturing high-performance liquid chromatography, direct sequencing and restriction endonuclease digestion. Clinical and radiographical features of the patients were evaluated. RESULTS AND DISCUSSION: The clinical signs most frequently associated with a FLNB mutation are the presence of supernumerary carpal and tarsal bones and short, broad, spatulate distal phalanges, particularly of the thumb. All individuals with Larsen syndrome-associated FLNB mutations are heterozygous for either missense or small inframe deletions. Three mutations are recurrent, with one mutation, 5071G-->A, observed in 6 of 20 subjects. The distribution of mutations within the FLNB gene is non-random, with clusters of mutations leading to substitutions in the actin-binding domain and filamin repeats 13-17 being the most common cause of Larsen syndrome. These findings collectively define autosomal dominant Larsen syndrome and demonstrate clustering of causative mutations in FLNB.

Abnormalities, Multiple↗
PubMed2006

Mutations in two regions of FLNB result in atelosteogenesis I and III.

The filamins are a family of cytoplasmic proteins that bind to and organize actin filaments, link membrane proteins to the cytoskeleton, and provide a scaffold for signaling molecules. Mutations in the gene encoding filamin B (FLNB) cause a spectrum of osteochondrodysplasias, including atelosteogenesis type I (AOI) and atelosteogenesis type III (AOIII). AOI and AOIII are autosomal dominant lethal skeletal dysplasias characterized by overlapping clinical findings that include vertebral abnormalities, disharmonious skeletal maturation, hypoplastic long bones, and joint dislocations. Previous studies have shown that heterozygosity for missense mutations that alter the CH2 domain and repeat 6 region of filamin B produce AOI and AOIII. In this study, 14 novel missense mutations in FLNB were found in 15 unrelated patients with AOI and AOIII. The majority of the mutations resided in exon 2 and exon 3, which encode the CH2 domain of the actin-binding region of filamin B. The remaining mutations were found in exon 28 and exon 29, which encode repeats 14 and 15 of filamin B. These results show that clustering of mutations in two regions of FLNB produce AOI/AOIII, and highlight the important role of this cytoskeletal protein in normal skeletogenesis.

Amino Acid Sequence↗
PubMed2005

Spondylo-mega-epiphyseal dysplasia with prominent upper limb mesomelia, punctate calcifications, and deafness.

We report on a previously undescribed form of skeletal dysplasia with rhizomelic, acromelic, and prominent mesomelic shortening, distal ulnar epiphyseal and pubic punctate calcifications (stippling), mega-epiphyses, platyspondyly, anterior beaking of the vertebrae, and sensorineural hearing loss. We compare this case to the other reported forms of skeletal dysplasias, particularly the mesomelic, acromesomelic, and mega-epiphyseal disorders.

Abnormalities, Multiple↗
PubMed2005

Hand involvement in Schmid metaphyseal chondrodysplasia.

Schmid metaphyseal chondrodysplasia (Schmid MCD, MIM 156500) is caused by mutations in the COL10A1 gene and is clinically characterized by short stature, bowed legs, and a waddling gait. Radiographic findings include anterior cupping, sclerosis and splaying of the ribs, diffuse metaphyseal flaring, and irregularity that is most pronounced at the knees, coxa vara, and femoral bowing. We reviewed the radiographs of Schmid MCD patients at the International Skeletal Dysplasia Registry in Los Angeles for evidence of hand involvement. We found hand involvement in 47% (7/15) of cases included in our analysis. These changes were subtle and consisted of shortening of the tubular bones and metaphyseal cupping of the proximal phalanges and metacarpals. Mild hand involvement is a common feature of Schmid MCD.

Collagen Type X↗
PubMed2004

MED, COMP, multilayered and NEIN: an overview of multiple epiphyseal dysplasia.

This overview covers the group of disorders that presents radiographically as multiple epiphyseal dysplasia (MED). The disorders include "classic MED" (Ribbing and Fairbank types): MED that is caused by mutations in the cartilage oligomeric matrix protein (COMP), type IX collagen, and matrilin 3 genes (MATN3); and MED with multilayered patella, brachydactyly, and clubbed feet resultant from mutations in gene defect diastrophic dysplasia (DTDST). The recently identified gene/molecular abnormalities in these disorders have made more exact identification possible in many cases, although clinical testing is not always available. However, there are specific radiographic findings that allow the accurate diagnosis to be made, thus potentially guiding which molecular defect(s) should be investigated. The modes of inheritance of these distinct MED conditions are not identical. When a specific diagnosis is made, proper genetic counseling as well as prognostication, management issues and complications can be delineated to the patient and family. This review will include the mechanics of diagnostic and molecular triage for these disorders.

Cartilage Oligomeric Matrix Protein↗
PubMed2004

A history of medical genetics in pediatrics.

Medical genetics emerged from a basic science only one half century ago. Scientists and physicians housed in a variety of basic science and clinical departments have accomplished many of the major advances in the study of genetic diseases in children. A scientific approach to human genetics emerged in 1948 with the establishment of the American Society of Human Genetics. Even before the use of modern laboratory techniques, Pediatric departments spearheaded the clinical description of simple genetic disorders, syndromes, and major malformations. The burgeoning of medical genetics as a specialty and its tremendous growth in departments of pediatrics was stimulated by major technological advances, such as the ability to visualize human chromosomes, the development of methods to study biochemical variations in blood and urine, cell culture, somatic cell hybridization, and molecular technology, all of which allowed for the diagnosis, treatment, and prevention of genetic disorders in children. Many pediatricians sought training in genetics, and training programs in medical genetics flourished in departments of pediatrics. The explosion of knowledge concerning the metabolic and molecular causes of genetic disease and understanding of their pathogenesis has led to a variety of specific diagnostic, preventive, and therapeutic approaches for alleviating the symptoms or preventing the complications of many of these disorders. Medical genetics is now recognized as a distinct medical specialty with its own American Board of Medical Specialties approved board (American Board of Medical Genetics) and clinical specialty college (American College of Medical Genetics).

Child↗
PubMed2004

Occipital projections in the skeletal dysplasias.

Occipital projections of the cranium have been reported in a number of skeletal dysplasias and syndromes. We observed two cases of atelosteogenesis type I with a bony occipital projection. This finding has neither been noted nor reported in any form of atelosteogenesis. This led us to search the International Skeletal Dysplasia Registry for occipital projections, and we found them in four other syndromes in which they had not been reported. Thus occipital spurs are a non-diagnostic feature that can be found in at least ten distinct disorders as well as a normal variant.

Craniofacial Abnormalities↗
PubMed2004

Mutations in the gene encoding filamin B disrupt vertebral segmentation, joint formation and skeletogenesis.

The filamins are cytoplasmic proteins that regulate the structure and activity of the cytoskeleton by cross-linking actin into three-dimensional networks, linking the cell membrane to the cytoskeleton and serving as scaffolds on which intracellular signaling and protein trafficking pathways are organized (reviewed in refs. 1,2). We identified mutations in the gene encoding filamin B in four human skeletal disorders. We found homozygosity or compound heterozygosity with respect to stop-codon mutations in autosomal recessive spondylocarpotarsal syndrome (SCT, OMIM 272460) and missense mutations in individuals with autosomal dominant Larsen syndrome (OMIM 150250) and the perinatal lethal atelosteogenesis I and III phenotypes (AOI, OMIM 108720; AOIII, OMIM 108721). We found that filamin B is expressed in human growth plate chondrocytes and in the developing vertebral bodies in the mouse. These data indicate an unexpected role in vertebral segmentation, joint formation and endochondral ossification for this ubiquitously expressed cytoskeletal protein.

Codon, Terminator↗
PubMed2003

Broad phenotypic spectrum caused by an identical heterozygous CDMP-1 mutation in three unrelated families.

CDMP-1, a cartilage-specific member of the TGFss superfamily of secreted signaling molecules, plays a key role in chondrogenesis, growth and patterning of the developing vertebrate skeleton. Homozygous CDMP-1 mutations cause Hunter-Thompson and Grebe types of acromesomelic chondrodysplasia and DuPan syndrome in humans, as well as brachypodism in mice, while heterozygous mutations cause brachydactyly type C (BDC). We present clinical and radiographic data from three unrelated families in which 12 members share the same heterozygous CDMP-1 mutation, an insertion (insG206), resulting in a frameshift predicted to cause functional haploinsufficiency. Although eight mutation carriers display BDC, four have normal hands and feet, confirming nonpenetrance of BDC with CDMP-1 mutations. In addition, several carriers have other skeletal abnormalities, including severe bilateral vertical talus (in two), developmental hip dysplasia (in one), and short stature (in two, who are otherwise unaffected). Premature vertebral end-plate disease was observed in four mutation carriers and was associated with spondylolysis and spondylolisthesis in three of these. Axial skeletal involvement has not been previously reported in association with CDMP-1 mutations. This finding is consistent with CDMP-1 expression in human hypertrophic chondrocytes, which are present in the ring epiphyses of vertebral end plates. Phenotypic variation in BDC has previously been attributed either to locus heterogeneity or to the varied functional effects of different CDMP-1 mutations. The remarkable range of phenotypes caused by this identical CDMP-1 mutation in these families emphasizes the crucial role of genetic background, stochastic variation and/or environmental factors in modifying the observed phenotype. Our findings illustrate that nonpenetrance for the typical features of BDC can be appreciable and that atypical skeletal features that have been reported in some patients with BDC (i.e., clubfoot, short stature, spondylolysis) may also result from CDMP-1 mutation.

Bone Diseases↗
PubMed2003

Pacman dysplasia: a lethal skeletal dysplasia with variable radiographic features.

BACKGROUND: Punctate or stippled cartilaginous calcifications are associated with many conditions, including chromosomal, infectious, endocrine, and teratogenic etiologies. Some of these conditions are clinically mild, while others are lethal. Accurate diagnosis can prove instrumental in clinical management and in genetic counseling. OBJECTIVE: To describe the diagnostic radiographic features seen in Pacman dysplasia, a distinct autosomal recessive, lethal skeletal dysplasia. MATERIALS AND METHODS: We present the fourth reported case of Pacman dysplasia and compare the findings seen in our patient with the three previously described patients. RESULTS: Invariable and variable radiographic findings were seen in all four cases of histologically proven Pacman dysplasia. CONCLUSION: Pacman dysplasia presents both constant and variable diagnostic radiographic features.

Bone and Bones↗
PubMed2002

Mental retardation and abnormal skeletal development (Dyggve-Melchior-Clausen dysplasia) due to mutations in a novel, evolutionarily conserved gene.

Dyggve-Melchior-Clausen dysplasia (DMC) and Smith-McCort dysplasia (SMC) are similar, rare autosomal recessive osteochondrodysplasias. The radiographic features and cartilage histology in DMC and SMC are identical. However, patients with DMC exhibit significant developmental delay and mental retardation, the major features that distinguish the two conditions. Linkage studies localized the SMC and DMC disease genes to chromosome 18q12-21.1, providing evidence suggesting that they are allelic disorders. Sequence analysis of the coding exons of the FLJ90130 gene, a highly evolutionarily conserved gene within the recombination interval defined in the linkage study, identified mutations in SMC and DMC patients. The affected individuals in two consanguinous DMC families were homozygous for a stop codon mutation and a frameshift mutation, respectively, demonstrating that DMC represents the FLJ90130-null phenotype. The data confirm the hypothesis that SMC and DMC are allelic disorders and identify a gene necessary for normal skeletal development and brain function.

Amino Acid Sequence↗
PubMed2002

Spectrum of dolichospondylic dysplasia: two new patients with distinctive findings.

Dolichospondylic dysplasia (DD) is a rare skeletal dysplasia primarily characterized by tall vertebral bodies and disproportionate short stature. Radiographic manifestations include tall vertebral bodies and gracile bones of the hands. Patients usually have eye and ear findings in addition to borderline mental retardation; however, tall vertebral bodies and slender tubular bones are also seen in the 3-M syndrome. Patients with the 3-M syndrome have a characteristic face with a triangular shape, frontal bossing, a flattened malar region, full eyebrows, a short nose with a bulbous tip, upturned nares, and full lips. We present two unrelated patients who share a distinct phenotype and have tall vertebral bodies, overtubulation of long bones, and short tubular bones of the hands and feet. We discuss the overlapping and distinguishing features between DD and the 3-M syndrome. Patient 1 was a 13-year-old female, and patient 2 was an unrelated adult female. These patients had normocephaly and short stature. They shared a common phenotype consisting of mild malar hypoplasia, a narrowed nasal body with a fleshy tip, full lips, and normal intelligence. In addition, they showed mild hand and foot abnormalities. These two patients lack many of the typical clinical features of both DD and the 3-M syndrome. They share a common phenotype and likely represent a distinct disorder. The spectrum of disorders with tall vertebral bodies as a key feature may include different entities that may be further defined with the characterization of the molecular defect(s).

Abnormalities, Multiple↗
PubMed2002

Evidence that Smith-McCort dysplasia and Dyggve-Melchior-Clausen dysplasia are allelic disorders that result from mutations in a gene on chromosome 18q12.

Smith-McCort dysplasia is a rare autosomal recessive osteochondrodysplasia characterized by short limbs and a short trunk with a barrel-shaped chest. The radiographic phenotype includes platyspondyly, generalized abnormalities of the epiphyses and metaphyses, and a distinctive lacy appearance of the iliac crest. We performed a genomewide scan in a consanguineous family from Guam and found evidence of linkage to loci on chromosome 18q12. Analysis of a second, smaller family was also consistent with linkage to this region, producing a maximum combined two-point LOD score of 3.04 at a recombination fraction of 0 for the marker at locus D18S450. A 10.7-cM region containing the disease gene was defined by recombination events in two affected individuals in the larger family. Furthermore, all affected children in the larger family were homozygous for a subset of marker loci within this region, defining a 1.5-cM interval likely to contain the defective gene. Analysis of three small, unrelated families with Dyggve-Melchior-Clausen syndrome, a radiographically identical disorder with the additional clinical finding of mental retardation, provided evidence of linkage to the same region, a result consistent with the hypothesis that the two disorders are allelic.

Alleles↗
PubMed2002

Cerebro-osseous-digital syndrome: four new cases of a lethal skeletal dysplasia--distinct from Neu-Laxova Syndrome.

Neu-Laxova Syndrome (NLS) is a severe disorder with intrauterine growth retardation, edema, and characteristic face (including microcephaly with receding forehead, protuberant eyes, a flattened nose, deformed ears, cleft palate, and micrognathia). Ichthyosis is often present. Limb anomalies include hypoplastic fingers and syndactyly of fingers and toes. Patients are usually stillborn or die shortly after birth. We report five unrelated patients--four with atypical NLS and one with typical NLS. All five patients were stillbirths. Clinically, the atypical NLS patients showed a large skull; rhizo-, meso-, and acromelia; and hypoplasia of the metacarpals and phalanges. The feet were similarly affected. Radiographically, the atypical patients showed interpediculate narrowing and hypoplastic vertebral bodies. The long bones were stick-like, showing diaphyseal widening that spared the metaphyses and was more pronounced in the lower extremities. The ilia had a half-moon configuration with widening of the sacrosciatic notches. The ischia were vertical and the pubic bone was absent. The typical NLS patient showed microcephaly, normal vertebral body, and long bone ossification, but a pelvic configuration similar to that of the atypical NLS patients. The common and distinguishing clinical and radiographic features are reviewed. Scott et al. [1981: Am J Med Genet 9:165-175] described two patients with NLS with radiographic and clinical findings similar to patients 1-4 reported here. Patients 1-4 of this report lack the typical findings of NLS and likely represent a distinct lethal skeletal dysplasia.

Abnormalities, Multiple↗