Biomedical subjects
Publications and source records attributed to K Kozlowski.
We report two patients with Robinow syndrome, review the published literature and stress the importance and limitations of radiographic examination in the diagnosis of this disorder, which shows extreme clinical and radiographic variability. The radiographic differential diagnosis of Robinow syndrome is discussed.
Familial expansile osteolysis (FEO, MIM174810) is a rare syndrome which was observed world-wide in only three kinships and in two unrelated American individuals. We report a patient with familial expansile osteolysis from the Czech Republic, not related to the previously reported cases. This patient's extraordinary clinical course does not conform to the ordinary. Her radiographic bone involvement was unusually extensive, involving most of the peripheral skeleton and the skull. This case documents that familial expansile osteolysis is not only a disease of adults but does occur in childhood.
The diagnosis of punctate epiphyseal dysplasia (PED) after disappearance of puncta is problematical. In some instances, however, the phenotypic and radiographic characteristics may persist and permit a retrospective diagnosis of PED in persons with unclassified bone dysplasia or bone changes of unknown origin. We report a boy aged 8 years who presented with unusual bony abnormalities that were consistent with a diagnosis of PED.
We report three members of an Armenian family with Hajdu-Cheney syndrome. The history suggested that five other members of the family were also probably affected. This disorder is important for the radiologist because distinctive radiographic findings make the diagnosis possible before clinical signs and symptoms are fully developed. Additionally, radiographic examination is essential in all patients suspected of Hajdu-Cheney syndrome for confirmation of the clinical diagnosis. Radiographic examination also detects complications of the syndrome not evident on clinical examination.
Du Pan syndrome is a rare acromesomelic dysplasia with characteristic clinical and radiographic findings. It is inherited as an autosomal recessive trait. Almost all the patients reported have been from Muslim countries. We report on a female and her child with Du Pan syndrome from a Caucasian, Polish family. Three new heterozygous mutations clustered on one allele of the CDMP1 gene were identified in the affected individuals resulting in the first familial case with dominant Du Pan syndrome. A possible synergistic effect of the cis-acting mutations located in the active domain of the mature CDMP1 protein is likely to be responsible for the clinical expression of the disorder.
We report on monozygotic twins with short stature and severe spondyloepimetaphyseal dysplasia congenita (SEMDC) from the Polish population. Phenotype of the twin girls resembles spondyloepiphyseal dysplasia congenita Spranger-Wiedemann (SEDC-SW), but shortening of the stature is more severe and the cranioface is normal. The distinctive radiographic features, in spite of similarity to SEDC-SW, indicate different spinal and, notably, severe metaphyseal involvement. Molecular analysis of the COL2A1 gene revealed an A to G transition at nucleotide +79 of exon 41 that converted the codon for arginine at amino acid 792 to a codon for glycine (Arg792Gly). The twins were heterozygous for the mutation and neither parent had this change. The Arg792Gly substitution is located at the Y-position of Gly-X-Y triplet, and it is likely that this substitution decreased the thermal stability of the triple helix and may affect fibril growth by replacement of an arginine residue, which is important for a conformation of the triple helix.
We report on three Tunisian siblings with a rare assortment of clinical and radiographic abnormalities closely resembling Desbuquois dysplasia. However, the siblings have had normal facies, normal hands, and were mentally normal. There were severe musculo-skeletal distinguishing features such as joint stiffness, severe kyphoscoliosis, and multiple large joint dislocations. Moreover, the patients had an additional remarkable radiographic feature not reported in Desbequois dysplasia-multiple carpal ossification centers. The diagnosis of Desbuquois dysplasia is more difficult in older children and adults as the characteristic facial features of early childhood may recede, and the metaphyseal growth plates obliterate. This condition of these patients represents a novel Desbuquois-like syndrome.
We report a boy with a unique, "new" form of spondyloepimetaphyseal dysplasia. The conspicuous features of the spinal changes were the delay in ossification of the cervical spine and posterior elements of the thoraco-lumbar spine. The vertebral bodies were of abnormal shape but of normal size and well ossified. The hallmark of epiphyseal changes was markedly delayed ossification (bone age). The severely disturbed metaphyseal ossification was similar to Jansen metaphyseal dysplasia. This pattern of changes has not yet been described in spondyloepimetaphyseal dysplasia.
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.
Spondylocarpotarsal synostosis syndrome (SSS) is characterised by malsegmentation of the thoracic spine and carpal/tarsal fusions. A unilateral or bilateral unsegmented bar may be present in the thoracic spine. Presenting clinical signs are congenital scoliosis early in life, and shortening of the trunk with scoliosis and/or lordosis in older children. We report a 13-year-old girl with SSS and a midline unsegmented bar running along the spinal processes of T3 to L2 and extending into the posterior vertebral elements.
We report three further patients of the recently described new bone dysplasia-dominantly inherited pseudorheumatoid arthritis. The patients of this report have a similar clinical history, the same distinctive phenotype and almost identical radiographic findings. The only major difference is absence of weather dependent articular pain which characterized the family of the previous study. This report expands the clinical data of this bone dysplasia. All patients are Caucasians and originate from different parts of the Czech Republic. It seems that this disorder is quite a common constitutional bone disorder in this country. We propose the name of Czech Dysplasia Metatarsal Type for this unique disease.
Chondrodysplasia punctata (CDP) was diagnosed clinically and radiographically in a male child born in Cape Town in 1991. His only sibling, a brother born in 2000 was similarly but more severely affected. The boys' mother had longstanding disseminated lupus erythematosus and epilepsy, for which she had been treated with chloraquine and other therapeutic agents during both pregnancies. The parents were non-consanguineous, and the family history was unremarkable. In addition to these affected brothers, seven previous instances of the association of CDP and maternal lupus erythematosus (MLE) have been reported. On this basis, MLE must be regarded as yet another causative factor in CDP.
We present a girl with achondroplasia and enchondromatosis. Coexistence of these two disorders has, to the best of our knowledge, not been reported previously.
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3-M syndrome is a rare, autosomal recessive dwarfing syndrome characterized by prenatal growth restriction, facial dysmorphism and absence of both microcephaly and mental retardation. The term 3-M syndrome originates from the common initial of the first three authors of the first report. The diagnosis is established by a combination of clinical history, clinical examination and radiographic findings. The present report shows two sisters whose facial features were slightly different from those usually reported. In addition, they presented with small nails and abnormal dermatoglyphics. The present report expands the phenotypic spectrum of 3-M syndrome.
We present the case of a 3-year-old boy with post-natal growth failure, microcephaly, developmental delay, facial dysmorphism, an evolving pigmentary retinopathy, pituitary hypoplasia, micropenis, and growth hormone (GH) deficiency. He has a microcephalic osteodysplastic slender-bone disorder with disharmonic delayed osseous maturation, most closely resembling patients with microcephalic osteodysplastic primordial dwarfism type II (MOPD II). Intrauterine growth retardation, a universal finding in the MOPD II, was absent in our patient.
Multiple epiphyseal dysplasia (MED) is an autosomal dominantly inherited chondrodysplasia. It is clinically highly heterogeneous, partially because of its complex genetic background. Mutations in four genes, COL9A2, COL9A3, COMP, and MATR3, all coding for cartilage extracellular matrix components (i.e., the alpha2 and alpha 3 chains of collagen IX, cartilage oligomeric matrix protein, and matrilin-3), have been identified in this disease so far, but no mutations have yet been reported in the third collagen IX gene, COL9A1, which codes for the alpha1(IX) chain. MED with apparently recessive inheritance has been reported in some families. A homozygous R279W mutation was recently found in the diastrophic dysplasia sulfate transporter gene, DTDST, in a patient with MED who had a club foot and double-layered patella. The series consisted of 41 probands with MED, 16 of whom were familial and on 4 of whom linkage analyses were performed. Recombination was observed between COL9A1, COL9A2, COL9A3, and COMP and the MED phenotype in two of the families, and between COL9A2, COL9A3, and COMP and the phenotype in the other two families. Screening of COL9A1 for mutations in the two probands from the families in which this gene was not involved in the recombinations failed to identify any disease-causing mutations. The remaining 37 probands were screened for mutations in all three collagen IX genes and in the COMP gene. The probands with talipes deformities or multipartite patella were also screened for the R279W mutation in DTDST. The analysis resulted in identification of three mutations in COMP and one in COL9A1, but none in the other two collagen IX genes. Two of the probands with a multipartite patella had the homozygous DTDST mutation. The results show that mutations in COL9A1 can cause MED, but they also suggest that mutations in COL9A1, COL9A2, COL9A3, COMP, and DTDST are not the major causes of MED and that there exists at least one additional locus.
The specific role of PITX2 in the pathogenesis of anterior segment dysgenesis has yet to be clearly defined. We provide here new insight into PITX2 pathogenesis through mutational and functional analyses. Three PITX2 mutations were found in a screen of 38 unrelated individuals affected with anterior segment anomalies (8%). All three mutations were found among the 21 individuals affected with Axenfeld-Rieger syndrome (ARS). We have identified two novel mutations, a valine-->leucine (V45L) missense mutation at position 45 within the PITX2 homeodomain, and a seven amino acid duplication (7aaDup) of residues 6-12 of the homeodomain. DNA-binding studies of the two mutant PITX2 proteins demonstrated a <10-fold reduction in the DNA-binding activity of the V45L mutant, and a >100-fold reduction in activity of the 7aaDup mutant. Luciferase reporter assays showed a >200% increase in PITX2 transactivation activity of the V45L mutant, while the 7aaDup mutant was unable to transactivate at detectable levels. Our analyses of the V45L PITX2 mutant reveal that the DNA-binding domain of PITX2 can influence transactivation activity independently of DNA binding. Furthermore, our findings expand the hypothesis that the amount of residual PITX2 activity underlies the variable severity of ocular phenotypes that result from PITX2 mutation. For the first time, we present evidence that increased PITX2 activity may underlie the severe ARS ocular phenotype. We conclude that increased activity of one PITX2 allele may be as physiologically disruptive as a mutation that nullifies a PITX2 allele, with either condition resulting in ARS.