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Ralph S Lachman

Publications and source records attributed to Ralph S Lachman.

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

Terminal phalangeal accessory ossification center of the thumb: an additional radiographic finding in Larsen syndrome.

Larsen syndrome is an autosomal-dominant disorder characterized by multiple joint dislocations, vertebral anomalies and dysmorphic facies. Both autosomal-dominant and autosomal-recessive forms of the disorder have been proposed. Individuals with autosomal-dominant Larsen syndrome have characteristic "cylindrical-shape" thumbs caused by broad, shortened phalanges. Autosomal-dominant Larsen syndrome results from heterozygosity for mutations in filamin B, a cytoskeletal protein involved in multicellular processes. We report here a patient with a duplicated or accessory distal thumb phalanx and multiple large joint dislocations who was shown to be heterozygous for a filamin B mutation predicting the amino acid substitution G1691S. This adds a new radiographic finding, duplicated or accessory distal phalanx, to the radiographic abnormalities seen in this rare dominant disorder.

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

Brachydactylic multiple delta phalanges plus syndrome.

Delta phalanges are unusual, shortened bones of the hands and feet with abnormal epiphyses and diaphyses. Here, we report on a patient with a unique multiple congenital anomaly syndrome that includes brachydactyly consisting of multiple delta phalanges in several digits of the hands and feet. The patient, who was born to consanguineous parents, had several other congenital anomalies, including butterfly vertebrae, craniofacial dysmorphism, and coarctation of the aorta. We have called this distinctive condition "brachydactylic multiple delta phalanges plus syndrome." Although no other member of the family had obvious hand or foot anomalies, several siblings had other malformations. Possible modes of inheritance in this family include variable expression of a recessive or de novo dominant condition.

Abnormalities, Multiple↗
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

Marked phenotypic variability in progressive diaphyseal dysplasia (Camurati-Engelmann disease): report of a four-generation pedigree, identification of a mutation in TGFB1, and review.

Progressive diaphyseal dysplasia (PDD) (Camurati-Engelmann disease) is an autosomal dominant craniotubular dysplasia characterized by hyperostosis and sclerosis of the diaphyses of the long bones and the skull. Mutations in transforming growth factor beta-1 (TGFB1) were recently found in patients with PDD. We report on a four-generation pedigree with seven individuals affected by PDD, linkage and mutational analysis results, and review the literature. This pedigree demonstrates the autosomal dominant inheritance pattern, remarkable variation in expressivity, and reduced penetrance. The most severely affected individual had progression of mild skull hyperostosis to severe skull thickening and cranial nerve compression over 30 years. His carrier father remained asymptomatic into his ninth decade and had no radiographic hyperostosis or sclerosis of the bones. Symptomatic relatives presented with lower limb pain and weakness. They were initially diagnosed with a variety of other conditions. Two of the symptomatic individuals were treated successfully with prednisone. We genotyped 7 markers from chromosome region 19q13.1-13.3 in 15 relatives and confirmed linkage to this region in this family. We screened the TGFB1 gene for mutations and identified a missense mutation resulting in an R218H substitution in the affected individuals, the asymptomatic obligate carrier, and another unaffected relative. We genotyped the family for seven known TGFB1 polymorphisms and a novel TAAA tetranucleotide repeat in intron 1. These polymorphisms did not appear to account for the variability in disease severity in this family. Our review illustrates how the disorder can significantly compromise health. Cranial involvement, which occurs in 61% of patients, can be severe, entrapping cranial nerves or causing increased intracranial pressure. Therapy with corticosteroids should be attempted in all symptomatic patients.

Adrenal Cortex Hormones↗
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

A distinctive type of metaphyseal chondrodysplasia with characteristic thickening of the distal ulna and radius: possible metaphyseal chondrodysplasia-Rosenberg.

We report an 8-year-old boy with a distinctive form of metaphyseal chondrodysplasia (MCD). He presented with moderate disproportionate short stature and bony swelling of his wrists, knees, and ankles. There were severe metaphyseal abnormalities with a honeycomb appearance affecting the distal tibiae and fibulae, proximal tibiae, distal femurs, distal ulnae and radii, and both hands. His thoracolumbar spine was normal. Radiological examination of the mother's forearms revealed widening of the distal radii and short ulnae with hypoplastic distal ends. Rosenberg and Löhr [1986: Eur J Pediatr 145:40-45] reported a four-generational kindred in which affected members had thickening of the wrist proximal to the styloid process of the ulna and thickening of the dorsum sellae. Although many of the radiographic features of this patient are those of MCD-Rosenberg, the skeletal features of our patient do not appear to represent any known classified forms of MCD.

Bone Diseases↗
PubMed2003

van den Ende-Gupta syndrome of blepharophimosis, arachnodactyly, and congenital contractures: clinical delineation and recurrence in brothers.

We describe two Hispanic brothers born to unrelated parents with van den Ende-Gupta syndrome (VDEGS), a distinctive combination of characteristic dysmorphic features, skeletal abnormalities, and cerebellar hyperplasia. This syndrome was previously delineated by van den Ende et al. [1992: Am J Med Genet 42:467-469] and Gupta et al. [1995: J Med Genet 32:809-812], with additional reports by Phadke et al. [1998: Am J Med Genet 77:16-18] and Bistritzer et al. [1993: Clin Genet 44:15-19]. This is the fifth report of VDEGS, which is characterized by blepharophimosis, narrow nose with hypoplastic alae nasi, hypoplastic maxilla, everted lower lip, slender and elongated hands and feet, arachnodactyly, self-limiting joint contractures, and distinctive skeletal findings. This report of affected siblings, and a previous report of double second cousins born to consanguineous parents [Bistritzer et al. [1993: Clin Genet 44:15-19]], suggests autosomal recessive inheritance. This brings to eight, the total number of reported cases, derived from six families, three of which are consanguineous. It is important to distinguish VDEGS from Marden-Walker syndrome (MWS) since both syndromes include blepharophimosis, arachnodactyly, and congenital contractures. Both syndromes are inherited in an autosomal recessive fashion, but VDEGS lacks severe mental retardation, serious brain malformations, microcephaly, failure to thrive, and severe joint limitation, which are consistently present in MWS. Of particular importance, MWS may be associated with cerebellar malformations such as Dandy-Walker malformation, while the brothers reported herein with VDEGS both demonstrated distinctive cerebellar enlargement, a new finding for this disorder. While, congenital contractures with arachnodactyly are features commonly seen in several other delineated syndromes, such as congenital contractural arachnodactyly (CCA) syndrome, characteristic facial features (blepharophimosis, narrow nose with ocular hypertelorism, prominent ears, and everted lower lip), distinguish VDEGS from other syndromes associated with CCA, including CCA.

Blepharophimosis↗
PubMed2003

A novel dysmorphic syndrome with open calvarial sutures and sutural cataracts maps to chromosome 14q13-q21.

We describe a new dysmorphic syndrome in an inbred Saudi Arabian family with 21 members. Five males and one female have similar craniofacial features including wide open calvarial sutures with large and late-closing anterior fontanels, frontal bossing, hyperpigmentation with capillary hemangioma of the forehead, significant hypertelorism, and a broad and prominent nose. In addition, these individuals have Y-shaped sutural cataracts diagnosed by 1-2 years of age. No chromosomal or biochemical abnormalities were identified. A genome-wide scan was performed, and two-point LOD score analysis, assuming autosomal recessive inheritance, detected linkage to chromosome 14q13-q21. The highest LOD scores were obtained for marker GATA136A04 (LOD=4.58 at theta=0.00) and for the adjacent telomeric marker D14S1048 (LOD=4.32 at theta=0.00). Multipoint linkage analysis resulted in a maximum LOD score of 5.44 between markers D14S1048 and GATA136A04. Model independent analysis by SIBPAL confirmed linkage to the same chromosomal region. Haplotype analysis indicated that all affected individuals were homozygous for the interval on chromosome 14q13-q21 with two recombinants for D14S1014 (centromeric) and one recombinant for D14S301 (telomeric). These recombinations limit the disease locus to a region of approximately 7.26 Mb. Candidate genes localized to this region were identified, and analysis of PAX9 did not identify mutations in these patients. The unique clinical phenotype and the mapping data suggest that this family represents a novel autosomal recessive syndrome.

Abnormalities, Multiple↗
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↗