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Biomedical subjects

R S Lachman

Publications and source records attributed to R S Lachman.

At least 37 records · Page 2Linked to original sources
PubMed2000

Report of five novel and one recurrent COL2A1 mutations with analysis of genotype-phenotype correlation in patients with a lethal type II collagen disorder.

Achondrogenesis II-hypochondrogenesis and severe spondyloepiphyseal dysplasia congenita (SEDC) are lethal forms of dwarfism caused by dominant mutations in the type II collagen gene (COL2A1). To identify the underlying defect in seven cases with this group of conditions, we used the combined strategy of cartilage protein analysis and COL2A1 mutation analysis. Overmodified type II collagen and the presence of type I collagen was found in the cartilage matrix of all seven cases. Five patients were heterozygous for a nucleotide change that predicted a glycine substitution in the triple helical domain (G313S, G517V, G571A, G910C, G943S). In all five cases, analysis of cartilage type II collagen suggested incorporation of the abnormal alpha1(II) chain in the extracellular collagen trimers. The G943S mutation has been reported previously in another unrelated patient with a strikingly similar phenotype, illustrating the possible specific effect of the mutation. The radiographically less severely affected patient was heterozygous for a 4 bp deletion in the splice donor site of intron 35, likely to result in aberrant splicing. One case was shown to be heterozygous for a single nucleotide change predicted to result in a T1191N substitution in the carboxy-propeptide of the proalpha1(II) collagen chain. Study of the clinical, radiographic, and morphological features of the seven cases supports evidence for a phenotypic continuum between achondrogenesis II-hypochondrogenesis and lethal SEDC and suggests a relationship between the amount of type I collagen in the cartilage and the severity of the phenotype.

Achondroplasia↗
PubMed1999

Small deletions in the type II collagen triple helix produce kniest dysplasia.

Kniest dysplasia is a moderately severe type II collagenopathy, characterized by short trunk and limbs, kyphoscoliosis, midface hypoplasia, severe myopia, and hearing loss. Mutations in the gene that encodes type II collagen (COL2A1), the predominant protein of cartilage, have been identified in a number of individuals with Kniest dysplasia. All but two of these previously described mutations cause in-frame deletions in type II collagen, either by small deletions in the gene or splice site alterations. Furthermore, all but one of these mutations is located between exons 12 and 24 in the COL2A1 gene. We used heteroduplex analysis to identify sequence anomalies in five individuals with Kniest dysplasia. Sequencing of the index patients' genomic DNA identified four new dominant mutations in COL2A1 that result in Kniest dysplasia: a 21-bp deletion in exon 16, an 18-bp deletion in exon 19, and 4-bp deletions in the splice donor sites of introns 14 and 20. A previously described 28-bp deletion at the COL2A1 exon 12-intron 12 junction, deleting the splice donor site, was identified in the fifth case. The latter three mutations are predicted to result in exon skipping in the mRNA encoded from the mutant allele. These data suggest that Kniest dysplasia results from shorter type II collagen monomers, and support the hypothesis that alteration of a specific COL2A1 domain, which may span from exons 12 to 24, leads to the Kniest dysplasia phenotype.

Base Sequence↗
PubMed1999

Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN): phenotypic analysis of a new skeletal dysplasia caused by a Lys650Met mutation in fibroblast growth factor receptor 3.

We previously discovered a novel missense mutation (Lys650Met) in the tyrosine kinase domain of the fibroblast growth factor receptor 3 (FGFR3) gene in four unrelated individuals with a condition we called "severe achondroplasia with developmental delay and acanthosis nigricans" (SADDAN) [Tavormina et al., 1999: Am. J. Hum. Genet. 64:722-731]. Here we present a more detailed clinical account of the SADDAN phenotype. The FGFR3 Lys650Met mutation results in severe disturbances in endochondral bone growth that approach and overlap those observed in thanatophoric dysplasia, type I. However, this mutation is most often compatible with survival into adulthood. Other unusual bone deformities, such as femoral bowing with reverse (i.e., posterior apex) tibial and fibular bowing and "ram's horn" bowing of the clavicle, are also seen in some patients. In addition to skeletal dysplasia, progressive acanthosis nigricans, and central nervous system structural anomalies, seizures and severe developmental delays are observed in surviving SADDAN patients. Despite its location within the same FGFR3 codon as the thanatophoric dysplasia type II mutation (Lys650Glu) and a similar effect on constitutive activation of the FGFR3 tyrosine kinase, the Lys650Met is not associated with cloverleaf skull or craniosynostosis.

Acanthosis Nigricans↗
PubMed1999

Platyspondylic lethal skeletal dysplasia, San Diego type, is caused by FGFR3 mutations.

The platyspondylic lethal skeletal dysplasias (PLSDs) are a heterogeneous group of short-limb dwarfing conditions. The most common form of PLSD is thanatophoric dysplasia (TD), which has been divided into two types (TD1 and TD2). Three other types of PLSD, or TD variants (San Diego, Torrance, and Luton), have been distinguished from TD. The most notable difference between TD and the variants is the presence of large rough endoplasmic reticulum (rER) inclusion bodies within chondrocytes of the variants. We examined 22 cases of TD variants for the presence of missense mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. All 17 cases of the San Diego type (PLSD-SD) were heterozygous for the same FGFR3 mutations found in TD1. No mutations were identified in the Torrance and Luton types. Large inclusion bodies were found in all 14 cases of PLSD-SD. Similar inclusion bodies were present in two of 72 TD1 cases, but not in 39 controls. The material retained within the rER stained only with antibody to the FGFR3 protein. The radiographic and morphologic differences between TD and PLSD-SD may be a consequence of other genetic factors, perhaps in the processing of mutant FGFR3 molecules within the rER. The presence of rER inclusion bodies cannot reliably discriminate between closely related skeletal dysplasias.

Chondrocytes↗
PubMed1999

Acrodysplasia, severe ossification abnormalities with short stature, and fibular hypoplasia.

We present a girl with short stature, growth hormone neurosecretory dysfunction, severe hypoplastic/aplastic changes of the bones of the hands and feet with dysharmonic ossification, severely delayed bone age, microcrania, and fibular hypoplasia. Parental consanguinity suggests autosomal recessive inheritance. An additional three cases [Eiken et al., 1984: Eur J Pediatr 141: 231-235] sharing some of the radiographic manifestations of this patient have been reported. However, distinctive findings in the present case seem to outline a separate entity.

Age Determination by Skeleton↗
PubMed1999

Lethal osteosclerotic skeletal dysplasia with intracellular inclusion bodies.

We report an apparently previously undescribed form of lethal osteosclerotic skeletal dysplasia in a 30-week male fetus with micromelic shortness of the limbs. Radiographic findings at necropsy included increased density in all bones, most marked in the skull, mandible, and pubis. The ribs were very short, abnormally modeled, and wide anteriorly. The vertebrae were posteriorly hypoplastic and wedged, particularly in the cervical and lumbar regions. The femora and tibiae were short with wide distal metaphyses, undermodeled diaphyses, and coxa vara. The humeri, radii, and ulnae were also short and undermodeled with proximal and distal flare. Chondro-osseous morphology showed short chondrocyte columns, extension of hypertrophic cells into the metaphysis, and overgrowth of perichondral bone. In the resting cartilage there were large chondrocytes containing a homogeneous material staining pink with von Kossa trichrome, gray with toluidine blue, and black with silver methenamine. The cortical bone was lacking and the trabecular bone was hypercellular, thick, and coarse. Ultrastructurally, the resting zone chondrocytes were large and round with condensed chromatin and dilated loops of rough endoplasmic reticulum. The radiographic and histopathologic findings in this case are unique and differ from those seen in other reported lethal osteosclerotic skeletal dysplasias.

Abnormalities, Multiple↗
PubMed1999

Intrachromosomal triplication of 2q11.2-q21 in a severely malformed infant: case report and review of triplications and their possible mechanism.

A female fetus with brain malformations, multicystic kidneys, absence of the right thumb, and a posterior cleft of palate was delivered at 32 weeks of gestation. Cytogenetic studies including FISH showed a novel intrachromosomal triplication of the proximal long arm of chromosome 2 (q11.2-q21), resulting in tetrasomy for this segment. The middle repeat was inverted. At least 11 patients with intrachromosomal triplications have been reported, mostly involving chromosome 15q. The mechanism involved in formation of these rearrangements is compatible with U-type exchange events among three chromatids.

Abnormalities, Multiple↗
PubMed1999

Prenatal diagnosis of rhizomelic chondrodysplasia punctata due to isolated alkyldihydroacetonephosphate acyltransferase synthase deficiency.

Current practices in prenatal diagnosis of rhizomelic chondrodysplasia punctata (RCDP) are reviewed. A case is presented with a family having one daughter affected with RCDP due to alkyldihydroacetonephosphate acyltransferase synthase (DHAPAT synthase) deficiency, and three subsequent pregnancies. Biochemical test values are presented for the pregnancies and daughter. Post-mortem tests of one fetus of a terminated pregnancy showed that radiologic examination could not make the diagnosis of RCDP. We conclude that biochemical or molecular testing is necessary to accurately diagnose this type of RCDP prenatally.

Adult↗
PubMed1998

Lethal osteosclerotic osteochondrodysplasia with platyspondyly, metaphyseal widening, and intracellular inclusions in sibs.

We report on a previously undescribed form of lethal osteosclerotic skeletal dysplasia in sibs from nonconsanguineous parents. Radiographic findings included increased density in the base of the skull, clavicles, vertebrae, ribs, and the metaphyseal regions of the long bones. There was midface hypoplasia, a large anterior fontanel, micrognathia, and hypoplastic, wafer-thin vertebrae. The clavicles, ribs, metacarpals, metatarsals, and phalanges were especially thickened and widened. The long bones were shortened with flared metaphyses. Chondroosseous morphology of resting cartilage and growth plate was relatively normal, but there was hypercellular cortical and trabecular bone, and marrow fibrosis. Ultrastructurally, the resting chondrocytes, osteoblasts, and nonhematopoietic marrow cells had dilated rough endoplasmic reticulum (inclusion bodies). The radiographic and morphologic characteristics in this case are unique and differ from those seen in other previously reported lethal osteosclerotic skeletal dysplasias.

Abortion, Induced↗
PubMed1998

Radiographic and morphologic findings in a previously undescribed type of mesomelic dysplasia resembling atelosteogenesis type II.

The mesomelic chondrodysplasias are a heterogeneous group of dwarfing disorders characterized by shortness of the middle segments of limbs. We report on a 25-week fetus with disproportionate shortness of limbs with an apparently distinct form of mesomelic dysplasia. Radiographic findings at necropsy included ulnar deviation of hands, talipes equinovarus, distal tapering of the humeri, and hypoplastic fibulae, radii, and ulnae. Chondro-osseous morphology showed mild shortness of the physeal columns, overgrowth of perichondral bone, peripheral ingrowth of mesenchymal cells into the physis, and numerous areas of fibrillar degeneration with rings of collagen surrounding the chondrocytes. Ultrastructural findings included a degenerated territorial matrix, pericellular halos of collagen, and dilated loops of rough endoplasmic reticulum in chondrocytes. The radiographic appearance of the long bones is distinct from that of previously described mesomelic dysplasias. The chondro-osseous morphologic findings and the distal tapering of the humerus are somewhat reminiscent of atelosteogenesis type II, but the pattern of matrix degeneration and the presence of inclusion bodies in the chondrocytes distinguish it from disorders of sulfate transport.

Aggrecans↗
PubMed1998

Distinct, autosomal recessive form of spondyloepimetaphyseal dysplasia segregating in an inbred Pakistani kindred.

We describe a large inbred kindred from a remote area of Pakistan, comprising eight generations, with a distinct form of spondyloepimetaphyseal dysplasia (SEMD). We evaluated 16 affected individuals: 11 males and 5 females. Analysis of the pedigree strongly suggests autosomal recessive inheritance, and consanguineous loops could account for all the affected individuals being homozygous for the abnormal allele. The clinical findings included short stature evident at birth, short bowed lower limbs, mild brachydactyly, kyphoscoliosis, an abnormal gait, enlarged knee joints, precocious osteoarthropathy, and normal intelligence. Radiographs demonstrated delayed epiphyseal ossification at the hips and knees, platyspondyly with irregular end plates and narrowed joint spaces, diffuse, early osteoarthritic changes, primarily in the spine and hands, and mild brachydactyly. Mild metaphyseal abnormalities were seen predominantly at hips and knees. This distinctive phenotype is distinct from other autosomal recessive forms of SEMD because of the mild degree of metaphyseal involvement, the type of brachydactyly, and the absence of loose joints or other clinical findings.

Abnormalities, Multiple↗
PubMed1998

Molecular, radiologic, and histopathologic correlations in thanatophoric dysplasia.

Various mutations in the fibroblast growth factor receptor 3 (FGFR3) gene have recently been reported in thanatophoric dysplasia (TD). We examined the clinical, radiographic, and histologic findings in 91 cases from the International Skeletal Dysplasia Registry and correlated them with the specific FGFR3 mutation. Every case of TD examined had an identifiable FGFR3 mutation. Radiographically, all of the cases with the Lys650Glu substitution demonstrated straight femora with craniosynostosis, and frequently a cloverleaf skull (CS) was demonstrated. In all other cases, the femora were curved, and CS was infrequently present but was occasionally as severe as TD with the Lys650Glu substitution. Histopathologically, all of the cases shared similar abnormalities, but cases with the Lys650Glu substitution had better preservation of the growth plate. Cases with the Tyr373Cys substitution tended to have more severe radiographic manifestations than the Arg248Cys cases, but there was overlap in the phenotypic spectrum between them. One common classification of TD distinguishes affected infants based on the presence or absence of CS. In contrast, and as originally proposed by Langer et al. [1987: Am J Med Genet 3: 167-179], our data suggest that TD can be divided into at least two groups (TD1 and TD2) based on the presence of straight or curved femora. The variable presence of CS and severity of the radiologic and histologic findings in the other substitutions may be due to other genetic, environmental, or stochastic factors.

Chondrocytes↗
PubMed1998

Pacman dysplasia: report of two affected sibs.

We report on two sib fetuses with radiological and morphological findings similar to those of the recently described lethal skeletal dysplasia termed Pacman dysplasia (McKusick, 167220, Am J Med Genet 1993, 45:558-561). The first fetus, a male, was electively terminated after a routine ultrasound study at 20 weeks showed short-limb dwarfism. The second fetus, a female sib, was also electively terminated after similar, abnormal ultrasound findings were noted at 16 weeks of gestation. Similar to Pacman dysplasia, the radiographic appearance was characterized by under-mineralized bone, stippling, rhizomelic and mesomelic shortness, platyspondyly, and a short, broad pelvis. The metaphyses were dense, but the diaphyseal cortices were thin with undermodeled long bones, and there was a deficient trabecular pattern suggesting marrow replacement. Chondro-osseous structure was characterized by deficient trabecular bone formation, a fibrous marrow, and numerous, large, multinucleated osteoclasts lining the endosteal surfaces of the metaphyseal bone. The occurrence of this dysplasia in sibs of differing sex suggests autosomal recessive inheritance.

Female↗
PubMed1998

Structurally abnormal type II collagen in a severe form of Kniest dysplasia caused by an exon 24 skipping mutation.

Type II collagen mutations have been identified in a phenotypic continuum of chondrodysplasias that range widely in clinical severity. They include achondrogenesis type II, hypochondrogenesis, spondyloepiphyseal dysplasia congenita, spondyloepimetaphyseal dysplasia, Kniest dysplasia, and Stickler syndrome. We report here results that define the underlying genetic defect and consequent altered structure of assembled type II collagen in a neonatal lethal form of Kniest dysplasia. Electrophoresis of a cyanogen bromide (CNBr) (CB) digest of sternal cartilage revealed an alpha1(II)CB11 peptide doublet and a slightly retarded mobility for all major CB peptides, which implied post-translational overmodification. Further peptide mapping and sequence analysis of CB11 revealed equal amounts of a normal alpha1(II) sequence and a chain lacking the 18 residues (361-378 of the triple helical domain) corresponding to exon 24. Sequence analysis of an amplified genomic DNA fragment identified a G to A transition in the +5 position of the splice donor consensus sequence of intron 24 in one allele. Cartilage matrix analysis showed that the short alpha1(II) chain was present in collagen molecules that had become cross-linked into fibrils. Trypsin digestion of the pepsin-extracted native type II collagen selectively cleaved the normal length alpha1(II) chains within the exon 24 domain. These findings support a hypothesis that normal and short alpha-chains had combined to form heterotrimeric molecules in which the chains were in register in both directions from the deletion site, accommodated effectively by a loop out of the normal chain exon 24 domain. Such an accommodation, with potential overall shortening of the helical domain and hence misalignment of intermolecular relationships within fibrils, offers a common molecular mechanism by which a group of different mutations might act to produce the Kniest phenotype.

Amino Acid Sequence↗
PubMed1998

Omphalocele with absent radial ray (ORR): a case with diploid-triploid mixoploidy.

We observed omphalocele, absence of radii, hypoplasia of one humerus, a hemivertebra, and syndactyly in a stillborn male at 22 weeks of gestation. Craniofacial and genitourinary abnormalities were absent. DNA measurement by flow cytometry on a paraffin-embedded autopsy specimen showed 32% triploid cells. ORR (omphalocele-radial ray) complex appears to be a consistent combination, and diploid-triploid mixoploidy may be one of its causes.

Abnormalities, Multiple↗
PubMed1998

Anomalous inferior and superior venae cavae with oculoauriculovertebral defect: review of Goldenhar complex and malformations of left-right asymmetry.

We observed a girl with an interrupted, left inferior vena cava with hemiazygous continuation, bilateral superior venae cavae, heart defects, and sacral agenesis. She had macrostomia and bilateral ear tags and pits, as in oculoauriculovertebral defect. Maternal diabetes was present. The combination, which we call OAV-heterotaxia complex, supports the view that some cases of oculoauriculovertebral defect may be part of a midline field defect of blastogenesis.

Female↗
PubMed1998

Gracile bone dysplasia.

Gracile bones are a frequent abnormality associated with fetal hypokinesia of any cause. With the exception of thin, undermineralized bones, the chondro-osseous structure is usually normal in these cases. We present a lethal skeletal dysplasia comprising minor anomalies, central nervous system abnormalities, gracile long bones, and abnormal chondro-osseous morphology. In addition to a short, disordered growth plate, the chondrocytes contained dilated loops of rough endoplasmic reticulum, suggesting an abnormality of an extracellular matrix protein. This protein appears to have effects on chondro-osseous and on facial and central nervous system development. We suggest the term "gracile bone dysplasia" to describe this disorder.

Bone Diseases, Developmental↗