Biomedical subjects

D O Sillence

Publications and source records attributed to D O Sillence.

At least 19 recordsLinked to original sources

PubMed2005

Cyclic bisphosphonate therapy in osteogenesis imperfecta type V.

The clinical and radiographic features and management of a young person with recently delineated Osteogenesis Imperfecta Type V is described. A female aged 9 years presented with a history of multiple fractures since 3 years of age and bilateral dislocation of the elbows from infancy. She was commenced on a low dose frequent regimen of cyclic intravenous pamidronate, which resulted in progressive improvement in bone density, reduced fracture frequency and remission of symptoms of osteoporosis.

Anti-Inflammatory Agents↗

PubMed2003

Desbuquois syndrome: clinical and radiological report of the first two Chinese cases from a consanguineous family.

Two siblings from China have been observed with severe short stature of prenatal onset and developmental delay. The radiographic features were characteristic of Desbuquois syndrome. The association of a genetic skeletal dysplasia and developmental delay is a relatively rare combination, although this syndrome is readily diagnosable from its distinctive radiographic features.

Abnormalities, Multiple↗

PubMed2001

Lethal prenatal onset infantile cortical hyperostosis (Caffey disease).

We describe a sporadic case of lethal prenatal onset infantile cortical hyperostosis (Caffey disease), which resulted in early postnatal death at 30 weeks gestation. The mother presented with antepartum haemorrhage and preterm labour. She was found to have polyhydramnios. The infant showed extensive symmetrical diaphyseal subperiosteal cortical thickening throughout the skeleton with short extremities. Hepatomegaly and lung hypoplasia were present. Currently, in the absence of a specific marker, diagnostic ultrasound offers the only prospect of prenatal diagnosis. This diagnosis should be considered in infants with short angulated long bones, where the diaphyses are irregular and echodense, and where there is no sign of fractures.

Fatal Outcome↗

PubMed2001

Opalescent dentine in two affected siblings.

This report describes the dental findings and management of siblings in a family in which three generations had been affected by osteogenesis imperfecta Type IV with opalescent dentine. Hereditary opalescent dentine, or opalescent teeth, is a pathologic dental condition characterised by a disturbance of dentine formation that occurs concurrently with osteogenesis imperfecta. Osteogenesis imperfecta is a genetically heterogenous group of systemic disorders of the connective tissue. The two siblings affected with opalescent dentine were treated under general anaesthesia, and included stainless steel crowns, extractions, and strip crowns on primary teeth. These reports highlight that appropriate treatment of the dentition of young patients with opalescent dentine should be carried out early in the primary dentition, and that this initial treatment can have long-term benefits in the mixed and permanent dentitions.

Child, Preschool↗

PubMed2000

Spondylometaphyseal dysplasia Sedaghatian type associated with lethal arrhythmia and normal intrauterine growth in three siblings.

Spondylometaphyseal dysplasia of the Sedaghatian type is a rare dysplasia, characterized by mild limb shortening, but lethal in the neonatal period. We describe three affected male siblings, the offspring of consanguineous parents. One was stillborn. Neonatal death was due to cardiac arrhythmia in two of the siblings. This report confirms the importance of cardiac pathology in this probably autosomal recessive disorder. This diagnosis should be excluded in any newborn with an arrhythmia as the clinical limb shortening may not be obvious.

Arrhythmias, Cardiac↗

PubMed1998

A nonsense mutation in the carboxyl-terminal domain of type X collagen causes haploinsufficiency in schmid metaphyseal chondrodysplasia.

Type X collagen is a short-chain homotrimeric collagen expressed in the hypertrophic zone of calcifying cartilage. The clustering of mutations in the carboxyl-terminal NC1 domain in Schmid metaphyseal chondrodysplasia (SMCD) suggested a critical role for this type X collagen domain, but since no direct analysis of cartilage has been conducted in SMCD patients, the mechanisms of type X collagen dysfunction remain controversial. To resolve this problem, we obtained SMCD growth plate cartilage, determined the type X collagen mutation, and analyzed the expression of mutant and normal type X collagen mRNA and protein. The mutation was a single nucleotide substitution that changed the Tyr632 codon (TAC) to a stop codon (TAA). However, analysis of the expression of the normal and mutant allele transcripts in growth plate cartilage by reverse transcription PCR, restriction enzyme mapping, and a single nucleotide primer extension assay, demonstrated that only normal mRNA was present. The lack of mutant mRNA is most likely the result of nonsense-mediated mRNA decay, a common fate for transcripts carrying premature termination mutations. Furthermore, no mutant protein was detected by immunoblotting cartilage extracts. Our data indicates that a functionally null allele leading to type X collagen haploinsufficiency is the molecular basis of SMCD in this patient.

Animals↗

PubMed1998

Segregation of mutations in arylsulphatase E and correlation with the clinical presentation of chondrodysplasia punctata.

Sixteen males and two females with symmetrical (mild) type of chondrodysplasia punctata were tested for mutations in the X chromosome located arylsulphatase D and E genes. We identified one nonsense and two missense mutations in the arylsulphatase E gene in three males. No mutations were detected in the arylsulphatase D gene. Family studies showed segregation of the mutant genes establishing X linked inheritance for these families. Asymptomatic females and males were found in these studies. The clinical presentation varies not only between unrelated affected males, but also between affected males within the same family. We also conclude that clinical diagnosis of chondrodysplasia punctata in adults can be difficult. Finally, our results indicate that brachytelephalangy is not necessarily a feature of X linked symmetrical chondrodysplasia punctata.

Amino Acid Sequence↗

PubMed1997

Abnormal compartmentalization of cartilage matrix components in mice lacking collagen X: implications for function.

There are conflicting views on whether collagen X is a purely structural molecule, or regulates bone mineralization during endochondral ossification. Mutations in the human collagen alpha1 (X) gene (COL10A1) in Schmid metaphyseal chondrodysplasia (SMCD) suggest a supportive role. But mouse collagen alpha1 (X) gene (Col10a1) null mutants were previously reported to show no obvious phenotypic change. We have generated collagen X deficient mice, which shows that deficiency does have phenotypic consequences which partly resemble SMCD, such as abnormal trabecular bone architecture. In particular, the mutant mice develop coxa vara, a phenotypic change common in human SMCD. Other consequences of the mutation are reduction in thickness of growth plate resting zone and articular cartilage, altered bone content, and atypical distribution of matrix components within growth plate cartilage. We propose that collagen X plays a role in the normal distribution of matrix vesicles and proteoglycans within the growth plate matrix. Collagen X deficiency impacts on the supporting properties of the growth plate and the mineralization process, resulting in abnormal trabecular bone. This hypothesis would accommodate the previously conflicting views of the function of collagen X and of the molecular pathogenesis of SMCD.

Animals↗

PubMed1996

The Wolf-Hirschhorn syndrome in adulthood: evaluation of a 24-year-old man with a rec(4) chromosome.

We described a profoundly intellectually disabled 24-year-old man with Wolf-Hirschhorn syndrome, left hemiplegia, epilepsy, atrophy of the right cerebral hemisphere, and dilatation of the right ventricle. The patient had a small ventricular septal defect, was wheelchair bound, and totally dependent. He had no speech, but vocalised to show his feelings. In this patient, the del(4)(p15) was subtle and arose due to the inheritance of a recombinant chromosome (4) from a maternal pericentric inversion-46,XX,inv(4) (p15.32q35). Fluorescence in situ hybridisation with probe D4S96 confirmed the deletion. This is the second case of Wolf-Hirschhorn syndrome resulting from a large pericentric inversion of chromosome 4.

Abnormalities, Multiple↗

PubMed1996

Multiexon deletions in the type I collagen COL1A2 gene in osteogenesis imperfecta type IB. Molecules containing the shortened alpha2(I) chains show differential incorporation into the bone and skin extracellular matrix.

Osteogenesis imperfecta (OI) type IB is a rare subset of the mildest form of OI, clinically characterized by moderate bone fragility, blue sclera, and dentinogenesis imperfecta. Cultured skin fibroblasts from two unrelated individuals (OI-197 and OI-165) with the typical features of OI type IB produced shortened alpha2(I) chains. Reverse transcription-polymerase chain reaction of the alpha2(I)-cDNA revealed deletions in the triple helical domain of 5 exons (exons 7-11) in OI-197, and 8 exons (exons 10-17) in OI-165. This exon skipping was caused by genomic deletions in one allele of COL1A2 with the breakpoints located in introns 6 and 11 in OI-197, and introns 9 and 17 in OI-165. The secretion and deposition of the mutant collagen into the matrix was measured in vitro in cultures of skin fibroblasts and bone osteoblasts, grown in the presence of ascorbic acid to induce collagen matrix formation and maturation, as well as in collagen extracts from skin and bone. The secretion of mutant collagen was impaired and long term cultures of fibroblasts showed that the mutant collagen was not incorporated into the mature collagenous matrix produced in vitro by skin fibroblasts from both patients. Likewise, the shortened alpha2(I) chain was not demonstrable in skin extracts. In contrast, bone extracts from OI-197 showed the presence of the mutant collagen. This incorporation of the abnormal collagen into the mature matrix was also demonstrated in long term cultures of the patient's osteoblasts. The deposition of the mutant collagen by bone osteoblasts but not by skin fibroblasts demonstrates a tissue specificity in the incorporation of mutant collagen into the matrix which may explain the primary involvement of bone and not skin in these patients.

Adolescent↗

PubMed1996

A novel germ line mutation in SOX9 causes familial campomelic dysplasia and sex reversal.

Mutations in the gene SOX9 result in the syndrome of campomelic dysplasia (CD) which includes sex-reversal in 75% of 46,XY affected individuals. These mutations only affect a single allele of SOX9 suggesting a dominant mode of inheritance for this syndrome. Consequently, CD and autosomal sex reversal may result from haploinsufficiency of SOX9. The SOX9 gene maps to the long arm of human chromosome 17 and translocations in this region also result in CD. We report a family in which there were three affected patients, two of whom showed 46,XY sex-reversal. Interestingly, despite all three patients being heterozygous for a familial mutation in SOX9 (Insertion of a cytosine residue at nucleotide position 1096), their gonadal phenotypes varied widely. The proband was found to have 46,XY true hermaphroditism with ambiguous genitalia. The other two sibs were 46,XY and 46,XX, and both had bilateral ovaries with normal female genitalia. The somatic cells in both parents revealed wild-type SOX9 nucleotide sequences. However, mutational analysis of the SOX9 gene in the father's germ cells revealed they were mosaic for mutant and wild-type sequences. This family is particularly informative as it demonstrates that the same SOX9 mutation can produce very different 46,XY gonadal phenotypes. The range of gonadal morphologies observed may be explained by several possible mechanisms such as variable penetrance of the mutation, increased activity of the non-mutant SOX9 allele or stochastic environmental factors. These results also demonstrate that paternal germ cell mosaicism of a mutant SOX9 sequence can result in a CD phenotype amongst his offspring.

Disorders of Sex Development↗

PubMed1996

The phenotypic features of osteogenesis imperfecta resulting from a mutation of the carboxyl-terminal pro alpha 1 (I) propeptide that impairs the assembly of type I procollagen and formation of the extracellular matrix.

The features of a baby with lethal perinatal osteogenesis imperfecta (OI-II), resulting from the substitution of tryptophan 94 by cysteine in the carboxyl-terminal propeptide of pro alpha 1 (I) chains of type I procollagen, were studied. The limbs and torso were of normal length, shape, and proportion. Similarly, all bones were of relatively normal shape and the long bones showed normal metaphyseal modelling. These clinical and radiographic features were similar to those observed in another baby with OI-II resulting from a mutation of the carboxy-terminal propeptide of pro alpha 1 (I) chains but dissimilar from those reported in babies with OI-II resulting from helical mutations of type I collagen.

Bone and Bones↗

PubMed1996

Overnight growth hormone secretion in achondroplasia: deconvolution analysis, correlation with sleep state, and changes after treatment of obstructive sleep apnea.

The normal profile for overnight GH secretion in achondroplasia has not been previously studied. Factors that have been shown to influence GH secretion include age, obesity, sleep state, and the presence of obstructive sleep apnea (OSA). We assessed GH levels in a group of subjects with achondroplasia, during overnight polysomnography. Nineteen subjects with achondroplasia were studied at 11.3 y of age (median 6.7, range 1.8-30.9). Levels of GH were measured using time-resolved immunofluorometric assay (DELFIA, Pharmacia Biotech Inc.) and analyzed by a deconvolution method. Five subjects were restudied after treatment for OSA. Secretion rates of GH were greater in slow wave (SWS) and rapid eye movement (REM) sleep than in stage one and two (SI-II = light non-REM) sleep (p < 0.01). Total overnight GH secretion decreased with increasing age (r2 = 0.22 p < 0.04). Neither the frequency of arousals, frequency of sleep state transitions nor the severity of OSA correlated with measures of GH secretion. Levels of IGF-I correlated independently with age, body weight (percent ideal), and GH secretion rate (r2 = 0.76, p < 0.001). In a group of five subjects treated for OSA, improved respiratory distress index and reduced sleep state transitions were not associated with significant changes in GH secretion rate by sleep stage; SWS [from 0.62 +/- 0.28 mIU/L/min to 1.02 +/- 0.25 mIU/L/min (NS)] and SI-II sleep [from 0.26 +/- 0.07 mIU/L/min to 0.60 +/- 0.16 mIU/L/min (NS)]. However, in those five subjects, a GH secretion peak during the first 2 h of SWS was initially absent, appearing only after treatment of OSA (1.09 +/- 0.38 mIU/L/min) compared with (2.40 +/- 0.59 mIU/L/min (p = 0.01). A profile of overnight GH secretion is presented for subjects with achondroplasia.

Achondroplasia↗

PubMed1995

Treatment of obstructive sleep apnea in achondroplasia: evaluation of sleep, breathing, and somatosensory-evoked potentials.

The occurrence of obstructive sleep apnea (OSA) is achondroplasia has been linked to brain stem compression. Overnight sleep studies (11 subjects) and somatosensory-evoked potentials (SEP's, 10 subjects) were recorded before and after conventional treatment of OSA in achondroplasia. The two groups were derived from 30 subjects who underwent diagnostic sleep studies and SEPs, including 15 females and 15 males with a median age 6.6 years (range 1.0-47.6) at the time of the first study. In 30 initial studies there was no correlation between severity of OSA and abnormalities on SEP evaluation. Treatment of 17 subjects included adenotonsillectomy (n = 3), weight loss (n = 1), and nasal-mask continuous positive airway pressure (CPAP) (n = 13). Sleep studies in 11 subjects after a delay of 8.8 +/- 2.8 months showed a reduction in respiratory disturbance index (RDI) from 38.4 +/- 6.9 to 6.5 +/- 1.8 events hr(-1) (p < 0.001) and movements/arousals fell from 10.4 +/- 2.2 to 4.8 +/- 0.2 hr(-1) (p < 0.04). Obstructive events were reduced from 33.7 +/- 6.9 to 2.4 +/- 1.0 hr(-1) (p < 0.001). Improvement of respiratory indices was associated with an increased proportion of slow-wave sleep from 25.2 +/- 4.0% to 32.3 +/- 2.4% (p = 0.01), and decrease in stage 1-2 sleep from 59.3 +/- 5.8% to 46.6 +/- 1.9% (p = 0.03). There was no increase in the percentage of REM sleep (15.2 to 21.2%). Repeat SEP studies in 10 subjects, after clinically effective treatment of OSA, showed improvement of SEP score of at least 1 grade, in 5 of 7 (71%) with initially abnormal values. We conclude that treatment of relieve upper airway obstruction improves OSA in achondroplasia, accompanied by changes in sleep structure and, in some cases, improved studies of neurological function.

Achondroplasia↗

PubMed1995

Abnormal type III collagen produced by an exon-17-skipping mutation of the COL3A1 gene in Ehlers-Danlos syndrome type IV is not incorporated into the extracellular matrix.

A novel heterozygous mutation of the COL3A1 gene that encodes the alpha 1(III) chains of type III collagen was identified in a family with the acrogeric form of Ehlers-Danlos syndrome type IV (EDS-IV). Cultured dermal fibroblasts produced normal and shortened alpha 1(III) chains. The triple helix of the latter chain was shortened owing to a 33 amino acid deletion of Gly-184 to Pro-216. The corresponding region of cDNA lacked 99 base pairs from nucleotides 1051 to 1149. The deletions corresponded exactly to the normal sequence encoded by exon 17 of the COL3A1 gene. The proband was heterozygous for a T to G transversion at position +2 of intron 17, which resulted in skipping of exon 17. The splicing defect was not corrected by growing the fibroblasts at 33 degrees C and no other splicing variants were identified at 33 or 37 degrees C. The affected brother had the same mutation but his unaffected mother did not. Heterotrimeric type III collagen molecules containing normal and mutant chains were retained within the cell. The mutant homotrimeric molecules were modified and secreted normally and were thermally stable. These normal characteristics of the mutant homotrimers suggested that the loss of ten Gly-Xaa-Yaa triplets (where Gly-Xaa-Yaa is a repetitive amino acid triplet structure in which Xaa and Yaa are other amino acids, proline and hydroxyproline being more common in the Yaa position) did not adversely affect the formation and stability of the triple helix or the structural requirements for secretion. However, the mutant homotrimers were not incorporated into the extracellular matrix of an in vitro model of EDS-IV dermis. The EDS-IV phenotype in this family was probably due to a deficiency in the amount of normal type III collagen available for formation of the heterotypic collagen fibrils of the extracellular matrix. Intracellular and extracellular quality-control mechanisms prevented the incorporation of heterotrimeric and homotrimeric mutant type III collagen molecules into the cross-linked extracellular matrix.

Adult↗

PubMed1995

Distinct skeletal abnormalities in four girls with Shprintzen-Goldberg syndrome.

We describe 4 girls with Shprintzen-Goldberg syndrome. Skeletal abnormalities common to 3 of them include bowing of long bones (with a variable degree of progression over time), flare of the metaphyses, a large anterior fontanel with persistent patency into the second to fourth years of life, 13 pairs of ribs, distinct vertebral abnormalities which were absent neonatally but evolved by the second year of life, and progressive osteopenia. These abnormalities were generalized and, in one case, progressive over the first few years of life. Communicating hydrocephalus was present in all 4 cases. The eldest, an 11-year-old girl, had additional anomalies not reported previously in this syndrome, including intestinal malrotation, an anteriorly placed anus, and mild cerebral atrophy. This is the first detailed report of skeletal manifestations in this rare disorder of unknown cause. These cases, in conjunction with a review of the literature, suggest that skeletal abnormalities are common in Shprintzen-Goldberg syndrome.

Abnormalities, Multiple↗

PubMed1995

Endoplasmic reticulum-mediated quality control of type I collagen production by cells from osteogenesis imperfecta patients with mutations in the pro alpha 1 (I) chain carboxyl-terminal propeptide which impair subunit assembly.

A heterozygous single base change in exon 49 of COL1A1, which converted the codon for pro alpha 1(I) carboxyl-terminal propeptide residue 94 from tryptophan (TGG) to cysteine (TGT) was identified in a baby with lethal osteogenesis imperfecta (OI64). The C-propeptide mutations in OI64 and in another lethal osteogenesis imperfecta cell strain (OI26), which has a frameshift mutation altering the sequence of the carboxyl-terminal half of the propeptide (Bateman, J. F., Lamande, S. R., Dahl, H.-H. M., Chan, D., Mascara, T. and Cole, W. G. (1989) J. Biol. Chem. 264, 10960-10964), disturbed procollagen folding and retarded the formation of disulfide-linked trimers. Although assembly was delayed, the presence of slowly migrating, overmodified alpha 1(I) and alpha 2(I) chains indicated that mutant pro alpha 1(I) could associate with normal pro alpha 1(I) and pro alpha 2(I) to form pepsin-resistant triple-helical molecules, a proportion of which were secreted. Further evidence of the aberrant folding of mutant procollagen in OI64 and OI26 was provided by experiments demonstrating that the endoplasmic reticulum resident molecular chaperone BiP, which binds to malfolded proteins, was specifically bound to type I procollagen and was coimmunoprecipitated in the osteogenesis imperfecta cells but not control cells. Experiments with brefeldin A, which inhibits protein export from the endoplasmic reticulum, demonstrated that unassembled mutant pro alpha 1(I) chains were selectively degraded within the endoplasmic reticulum resulting in reduced collagen production by the osteogenesis imperfecta cells. This biosynthetic deficiency was reflected in the inability of OI64 and OI26 cells to produce a substantial in vitro collagenous matrix when grown in the continuous presence of ascorbic acid to allow collagen matrix formation. Both these carboxyl-terminal propeptide mutants showed a marked reduction in collagen accumulation to 20% (or less) of control cultures, comparable to the reduced collagen content of tissues from OI26.

Base Sequence↗

PubMed1995

X linked fatal infantile cardiomyopathy maps to Xq28 and is possibly allelic to Barth syndrome.

A number of families with X linked dilated cardiomyopathy with onset in infancy or childhood have now been described, with varying clinical and biochemical features. Of these, one condition, Barth syndrome (BTHS), can be diagnosed clinically by the characteristic associated features of skeletal myopathy, short stature, and neutropenia, but not all of these features are always present. Molecular genetic studies have delineated the gene for BTHS, which maps to distal Xq28, from the gene for so called X linked dilated cardiomyopathy (XLCM), a teenage onset dilated cardiomyopathy, recently mapped to the 5' portion of the dystrophin locus at Xp21. We report a large family in which male infants have died with congenital dilated cardiomyopathy, and there is a strong family history of unexplained death in infant males over at least four generations. Death always occurred in early infancy, without development of the characteristic features associated with Barth syndrome. Molecular analysis localised the gene in this family to Xq28 with lod scores of 2.3 at theta = 0.0 with dinucleotide repeat markers, p26 and p39, near DXS15 and at F8C. The proximal limit to the localisation of the gene in this family is defined by a recombinant at DXS296, while the distal limit could not be differentiated from the telomere. This localisation is consistent with a hypothesis of allelic and clinical heterogeneity at the BTHS locus in Xq28.

Alleles↗