chondroitin-sulfates and Abnormalities--Multiple

Topics: Abnormalities, Multiple; Chondroitin Sulfates; Craniofacial Abnormalities; Enzyme Inhibitors; Farnesyltranstransferase; Genes, ras; Genotype; Germ-Line Mutation; Heart Defects, Congenital; Human Growth Hormone; Humans; Neoplasms; Phenotype; Syndrome

Sirenomelia is an extremely complex and rare malformation with different degrees of lower-extremities fusion associated with gastrointestinal, musculoskeletal, vascular, cardiopulmonary, and central nervous system malformations. In the English literature, there are only 5 reports of infants surviving with this condition. In our case, a 2540-g female infant was born with normal vital signs, no facial dysmorphism, and a complete soft tissue fusion of the lower limbs, from perineum to ankles. Radiologic examinations revealed an intestinal atresia and a single pelvic kidney, with a unique ureter, 2 femurs, 2 tibias, 2 fibulas, and 2 feet (simpus dipus). At 7 months of age, a multidisciplinary surgical team achieved complete separation of the lower limbs, with independent vascular and nerve supplies. At the time of this writing, the infant was 28 months old and had a regular growth curve. Many future reconstructive surgeries have been planned to achieve an acceptable quality of life for this infant.

Topics: Abnormalities, Multiple; Anal Canal; Calcaneus; Chondroitin Sulfates; Collagen; Colon; Ectromelia; Female; Hip; Humans; Ileostomy; Infant, Newborn; Intestinal Atresia; Leg; Patient Care Team; Plastic Surgery Procedures; Skin Transplantation; Skin, Artificial; Spine; Tissue Expansion; Tomography, X-Ray Computed; Vagina

Costello syndrome is a distinctive multiple congenital anomaly syndrome, characterized by loose soft skin with deep palmar and plantar creases, loose joints, distinctive coarse facial features, skeletal abnormalities, cardiac abnormalities (cardiovascular malformation (CVM), hypertrophic cardiomyopathy, tachycardia), predisposition to malignancy, developmental delays, and mental retardation. Previous studies with cultured fibroblasts from individuals with Costello syndrome demonstrate excessive accumulation of chondroitin sulfate-bearing proteoglycans, associated with both impaired formation of elastic fibers and an unusually high rate of cellular proliferation. Despite multiple clinical reports of cardiac abnormalities, there has been only one previously published report describing post-mortem findings in hearts from Costello syndrome patients. Here we provide a detailed description of the post-mortem findings of the hearts of three children with Costello syndrome. Routine histological examination and results of targeted histochemical and immunohistochemical studies revealed that in addition to cardiomyocyte hypertrophy, these hearts also demonstrated massive pericellular and intracellular accumulation of chondroitin sulfate-bearing proteoglycans and a marked reduction of elastic fibers. Normal stroma was replaced by multifocal collagenous fibrosis. Most peculiar was the finding that the bulk of the chondroitin sulfate accumulated in these Costello syndrome hearts is a chondroitin-6-sulfate. In contrast, deposition of chondroitin-4 sulfate was below the level detected in normal hearts. We propose that an imbalance in sulfation of chondroitin sulfate molecules and subsequent accumulation of chondroitin-6-sulfate in cardiomyocytes contribute to the development of the hypertrophic cardiomyopathy of Costello syndrome.

Topics: Abnormalities, Multiple; Cardiomyopathy, Hypertrophic; Child; Child, Preschool; Chondroitin Sulfates; Developmental Disabilities; Face; Fatal Outcome; Humans; Infant; Intellectual Disability; Male; Myocardium; Skin Abnormalities; Syndrome

Costello syndrome is characterized by mental retardation, loose skin, coarse face, skeletal deformations, cardiomyopathy, and predisposition to numerous malignancies. The genetic origin of Costello syndrome has not yet been defined. Using immunohistochemistry and metabolic labeling with [3H]-valine, we have established that cultured skin fibroblasts obtained from patients with Costello syndrome did not assemble elastic fibers, despite an adequate synthesis of tropoelastin and normal deposition of the microfibrillar scaffold. We found that impaired production of elastic fibers by these fibroblasts is associated with a functional deficiency of the 67-kD elastin-binding protein (EBP), which is normally required to chaperone tropoelastin through the secretory pathways and to its extracellular assembly. Metabolic pulse labeling of the 67-kD EBP with radioactive serine and further chase of this tracer indicated that both normal fibroblasts and fibroblasts from patients with Costello syndrome initially synthesized comparable amounts of this protein; however, the fibroblasts from Costello syndrome patients quickly lost it into the conditioned media. Because the normal association between EBP and tropoelastin can be disrupted on contact with galactosugar-bearing moieties, and the fibroblasts from patients with Costello syndrome revealed an unusual accumulation of chondroitin sulfate-bearing proteoglycans (CD44 and biglycan), we postulate that a chondroitin sulfate may be responsible for shedding EBP from Costello cells and in turn for their impaired elastogenesis. This was further supported by the fact that exposure to chondroitinase ABC, an enzyme capable of chondroitin sulfate degradation, restored normal production of elastic fibers by fibroblasts from patients with Costello syndrome. We also present evidence that loss of EBP from fibroblasts of Costello syndrome patients is associated with an unusually high rate of cellular proliferation.

Topics: Abnormalities, Multiple; Adolescent; Biglycan; Biopolymers; Cell Division; Cells, Cultured; Child; Child, Preschool; Chondroitin ABC Lyase; Chondroitin Sulfates; Culture Media, Conditioned; Elastin; Extracellular Matrix Proteins; Fibroblasts; Humans; Hyaluronan Receptors; Infant; Infant, Newborn; Molecular Chaperones; Molecular Weight; Proteoglycans; Receptors, Cell Surface; Syndrome; Tropoelastin

We report an unusual case with mental retardation, short stature, sparse scalp hair, prominence of scalp veins, atrophy of subcutaneous fat, pterygia of the neck and loose skin. The patient excreted greater amounts of low-sulphated chondroitin sulphate (LSC) in the urine than age-matched controls. The pattern of glycosaminoglycan in serum and its synthesis by the patient fibroblasts were normal. Collagen, elastin and decorin mRNA levels in the patient fibroblasts were also unaltered. These results suggest that this patient seems to be different from Lowe's syndrome and decorin-deficient progeroid. An abnormal LSC metabolism may be partially responsible for the pathology of these syndromes.

Topics: Abnormalities, Multiple; Cells, Cultured; Child; Chondroitin Sulfates; Fibroblasts; Glycosaminoglycans; Humans; Male; Progeria

The patient is a north african female, fourth born child in a family with consanguinity. Facial dysmorphia, clubfeet, swollen extremities and heel borne ponctuate calcifications are observed soon after birth. beta glucuronidase activity is very low in serum, leukocytes and skin fibroblasts. At 18 months, gorwth and psychomotor development are normal. Flat facies and dorsolumbar cyphosis are striking. There is no clinical sign of storage disease, neither ocular or cytologic (blood, bone-marrow) abnormalities. Squeletal abnormalities are predominant on cervical and lumbar column and pelvis. Urinary excretion of chondroitin 4 sulfate and chondroitin 6 sulfate is increased. A 4 year old sister is affected. Facial dysmorphia, mild squeletal abnormalities are observed. Again, growth is normal and there is no symptom of storage disease. Enzymic expression of parent heterozygotism is marked in serum studies, but less marked in leukocytes and fibroblasts. The last two children are heterozygotes. At the time of a 5th pregnancy, enzymic activity studies of amniotic fluid and amniotic cells have shown that the foetus was an inaffected female. This child was normal at birth.

Topics: Abnormalities, Multiple; Child; Chondroitin Sulfates; Consanguinity; Female; Glucuronidase; Humans; Infant, Newborn; Mucopolysaccharidoses

Two male and two female sibs with an unusual form of spondyloepiphyseal dysplasia were reported. The main clinical features were low stature, moderate shortness of trunk and neck, abnormal span: height ratio, low-normal UBS: LBS ratio, and peripheral corneal punctate opacities only seen by the slitlamp. Normal mental status was present. Typical metachromatic granules were not seen either in bone-marrow cells or in peripheral blood cells. The X-ray picture showed spondylar and pelvic dysplasia. Qualitative rather than quantitative anomalies were shown in the urinary mucopolysaccharides, mostly involving chondroitin-6-sulfate. The genetic data are consistent with autosomal recessive inheritance.

Topics: Abnormalities, Multiple; Adolescent; Adult; Child; Child, Preschool; Chondroitin; Chondroitin Sulfates; Corneal Opacity; Female; Genes, Recessive; Humans; Male; Mucopolysaccharidosis IV; Pedigree; Time Factors

Topics: Abnormalities, Multiple; Bone and Bones; Child, Preschool; Chondrocytes; Chondroitin Sulfates; Consanguinity; Diagnosis, Differential; Glycosaminoglycans; Humans; Keratan Sulfate; Male; Mucopolysaccharidosis IV; Osteochondrodysplasias; Radiography; Research; Sulfatases

Urinary mucopolysaccharides from three patients with acheiropodia were qualitatively and quantitatively analysed by agar gel electrophoresis coupled with enzymatic degradation. Although no abnormal pattern was characterized, eventual metabolic dysfunction detected only in bone/cartilage tissues could not be ruled out.

Topics: Abnormalities, Multiple; Adolescent; Adult; Child; Chondroitin; Chondroitin Sulfates; Foot Deformities, Congenital; Hand Deformities, Congenital; Humans; Syndrome

Clinical, radiological, histochemical, ultrastructural, and biochemical studies were conducted on three cases of I-cell disease. I-cell disease can be readily distinguished from Hurler syndrome (mucopolysaccharidosis I) by the presence of hypertrophic gums, vacuolated lymphocytes in peripheral blood, and a normal level of urinary mucopolysaccharides. Accumulation of proteoglycans was more prominent in the inclusion bodies of I-cell chondrocytes in comparison to cultured fibroblasts, which contained a large amount of glycolipids and a small amount of proteoglycans. An autosomal recessive mode of inheritance was suggested in two of the cases.

Topics: Abnormalities, Multiple; Cartilage; Child, Preschool; Chondroitin Sulfates; Cytoplasmic Granules; Female; Fibroblasts; Growth Disorders; Humans; Infant; Lipidoses; Lymphocytes; Male; Psychomotor Disorders; Renal Aminoacidurias; Syndrome