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The Coffin-Lowry syndrome is an inherited syndrome of mental retardation, characteristic facies and skeletal anomalies. The occurrence of severe manifestations in males, with no instance of male-to-male transmission, suggests an X-linked inheritance. The paper describes seven families from five European Centers.
The Coffin-Lowry syndrome (CLS) is an X-linked inherited disease of unknown pathogenesis characterized by severe mental retardation, typical facial and digital anomalies, and progressive skeletal deformations. Our previous linkage analysis, based on four pedigrees with the disease, suggested a localization for the CLS locus in Xp22.1-p22.2, with the most likely position between the marker loci DXS41 and DXS43. We have now extended the study to 16 families by using seven RFLP marker loci spanning the Xp22.1-p22.2 region. Linkage has been established with five markers from this part of the X chromosome: DXS274 (lod score [Z] (theta) = 3.53 at theta = .08), DXS43 (Z(theta) = 3.16 at theta = .08), DXS197 (Z(theta) = 3.03 at theta = .05), DXS41 (Z(theta) = 2.89 at theta = .08), and DXS207 (Z(theta) = 2.73 at theta = .13). A multipoint linkage analysis further placed, with a maximum multipoint Z of 7.30, the mutation-causing CLS within a 7-cM interval defined by the cluster of tightly linked markers (DXS207-DXS43-DXS197) on the distal side and by DXS274 on the proximal side. Thus, these further linkage data confirm and refine the map location for the gene responsible for CLS in Xp22.1-p22.2. As no linkage heterogeneity was detected, this validates the use of the Xp22.1-p22.2 markers for carrier detection and prenatal diagnosis in CLS families.
Cultured skin fibroblasts were prepared from two unrelated adult patients with full expressions of Coffin-Lowry syndrome. Glycosaminoglycans (GAGs) were isolated either from the medium or from the cell layer of cultured skin fibroblasts. Two-dimensional electrophoresis of GAG preparations on cellulose acetate film revealed that hyaluronate was the major component both in the medium and in the cell layer. Quantitative analysis of GAGs was carried out by measuring optical density at 615 nm of Alcian blue-stained GAG spots on electrophoretograms. Increase in the hyaluronate content was found both in the culture medium and in the cell layer of Coffin-Lowry fibroblasts. In addition, the incorporation of [14C]glucosamine into hyaluronate was similarly activated in skin fibroblasts from patients, suggesting the active biosynthesis and or the suppressed degradation of hyaluronate by cultured skin fibroblasts from Coffin-Lowry syndrome. The abnormal metabolism of hyaluronate in Coffin-Lowry fibroblasts may be implicated in some of the clinical aspects of this genetic disorder.
Glycosaminoglycans in calcified cervical ligamenta flava from a male patient with Coffin-Lowry syndrome were analyzed biochemically. Hexuronate content based on the tissue dry weight was 8-fold and 5-fold concentrated in the calcified center as compared with the peripheral area and with age-matched, normal ligamenta flava, respectively. Two-dimensional electrophoresis of glycosaminoglycan preparations on cellulose acetate film revealed that, although dermatan sulfate was the major glycosaminoglycan in the normal ligamenta flava, chondroitin sulfate was the predominant glycosaminoglycan in the pathological tissue. Relative amounts of chondroitin sulfate disaccharide units were determined after digestion of glycosaminoglycans with chondroitinase, and the ratio of chondroitin 6-sulfate to chondroitin 4-sulfate tended to decrease with the distance from the calcified center to the peripheral area. These observations suggest that an alteration in glycosaminoglycan metabolism may be a contributing factor in calcification of ligamenta flava in Coffin-Lowry syndrome.
A case of Coffin-Lowry syndrome is reported. Severe mental retardation is associated with characteristic craniofacial anomalies, short stature and "soft hands". X-linked inheritance is supposed.
The Coffin-Lowry is characterized by mental retardation, characteristic facies and hands, and skeletal changes. Discovery of two others brothers presenting vertebral curvature and suffering from the same syndrome led to a familial investigation which allowed the making of an inventory of six members affected in this family. Only subjects with characteristic fingers were included because according to Lowry this anomaly is necessary to assert the Coffin-Lowry syndrome. The series is quite interesting because this is the greatest of Lowry with five cases. The authors emphasize the importance of a detailed preoperative cardiac exploration to search for cardiomyopathy the existence of which in Coffin-Lowry syndrome was never noted before.
Clinical and ultrastructural study of four cases of Coffin-Lowry syndrome (CLS), a heritable disorder with peculiar facies, stooped posture, vertebral changes, and mental retardation, is reported. Three of the four cases had myelopathy caused by calcification of the ligamenta flava in early adulthood. These patients demonstrated that CLS is a calcium pyrophosphate dihydrate crystal deposition disease, and it is postulated that a metabolic abnormality in collagen and in proteoglycans are responsible for some aspects of CLS.
We describe the major autopsy findings in two adult sibs of the original pedigree of Lowry et al [Am J Dis Child 121:496-500, 1971]. These results support the idea that Coffin-Lowry syndrome is a systemic connective tissue disorder. Visceral neuropathy was also noted as the basis of extensive intestinal diverticular disease.
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Eight patients in three families had mental retardation, characteristic facies and hands, and skeletal changes; the clinical features suggested to us that they had a syndrome previously thought to represent two entities described by Lowry and associates and by Coffin and associates, respectively. New findings include skeletal, orodental, and dermatoglyphic abnormalities and histopathologic changes suggesting that the syndrome is a heritable disorder of connective tissue. Severe expression in males and transmission through mildly affected females suggest X-linked or sex-influenced autosomal dominant inheritance.
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Explore the source record for details and available documents.
Explore the source record for details and available documents.
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We report on 4 generations in a family with 3 living males, 3 males who died in infancy, and 3 females with neurologic impairment and agenesis of the corpus callosum (ACC). Manifestations in the surviving males include severe acquired micrencephaly, mental retardation, limb contractures, scoliosis, tapered digits with hyperconvex nails, a characteristic face with large eyes, prominent supraorbital ridges, synophris, optic atrophy, broad alveolar ridges and seizures. Urologic anomalies include renal dysplasia, cryptorchidism, and hypospadias. Two affected females were less severely impaired and continued to be socially responsive as adults, but had spastic quadriplegia and seizures. One obligate heterozygote was retarded with emotional problems while another obligate carrier female and her daughter were clinically normal. Pedigree analysis suggested X-linked inheritance with variable expression in females. These findings are inconsistent with the well-described X-linked conditions with ACC including FG syndrome and Aicairdi syndrome. ACC has not been described in Coffin-Lowry syndrome, a condition with similar clinical findings, which also demonstrates marked variability of expression in carrier females. In order to assist in carrier determination, brain imaging studies and DNA linkage analysis of the affected relatives was performed. We found a spectrum of agenesis of the corpus callosum with the most severe manifestations in the most severely affected males. DNA analysis using a series of X-linked probes suggests linkage with a LOD score of 1.26 at theta = 0 to a region between p 11.3 and p 21.3.
We revisited a family with the Coffin-Lowry syndrome (CLS) first reported by Procopis and Turner in 1972. Twelve affected members are now known in 3 generations of which 9 were seen personally. DNA marker studies supported X-linkage with localization of CLS to Xp near DXS43 at p22.2-22.1 (theta = 0.001 Z = 2.71). Such linkage is reinforced by positive lod scores for DXS28 (theta = 0.00, Z = 0.90) and for DXS84 (theta = 0.09, Z = 1.56). Recombination with DXS84 and DXS164 places CLS distal to DMD in Xp21-pter.