Abstract Mutations in the type I collagen genes have been identified as the cause of all four types of osteogenesis imperfecta (OI). We now report a mutation that extends the phenotype associated with structural abnormalities in type I collagen. Two siblings presented with a history of back pain and were diagnosed with juvenile osteoporosis, based on clinical and radiological examination. Radiographs showed decreased lumbar bone density and multiple compression fractures throughout the thoracic and lumbar spines of both patients. One child has moderate short stature and mild neurosensory hearing loss. However, neither child has incurred the long bone fractures characteristic of OI. Protein studies demonstrated electrophoretically abnormal type I collagen in samples from both children. Enzymatic cleavage of RNA:RNA hybrids identified a mismatch in type I collagen α2 (COL1A2) mRNA. DNA sequencing of COL1A2 cDNA subclones defined the mismatch as a single-base mutation (1715G → A) in both children. This mutation predicts the substitution of arginine for glycine at position 436 (G436R) in the helical domain of the α2(I) chain. Analysis of genomic DNA identified the mutation in the asymptomatic father, who is presumably a germ-line mosaic carrier. The presence of the same heterozygous mutation in two siblings strongly suggests that the probands display the full phenotype. Taken together, the clinical, biochemical, and molecular findings of this study extend the phenotype associated with type I collagen mutations to cases with only spine manifestations and variable short stature into adolescence.
We reviewed the results of lymphocyte karyotypes from 232 couples who had had two or more pregnancy losses (spontaneous abortions or stillbirths). Despite the use of strict criteria to correct for possible bias of ascertainment, 8% of these couples (19 of 232) had a chromosome abnormality. Six of these abnormalities were low-percentage mosaicism for aneuploidy or a translocation. If these couples were excluded, 13 (6%) of the study couples had a chromosome abnormality. There was no significant difference in the incidence of chromosome abnormalities in those couples having two losses as compared with those having three or more losses. The study couples were referred from a wide range of sources, and most women had not had extensive gynecologic evaluation. These results confirm the importance of cytogenetic analysis of couples with recurrent pregnancy loss, and suggest that such studies be considered after two losses.
Abstract We have described a previously unrecognized chondrodystrophy characterized by short‐limbed dwarfism, blue sclera, severe cardiopulmonary problems, and failure of postnatal growth. The first of two siblings thus affected died at age 6 months following attempted correction of an atrial septal defect. Growth plate cartilage from multiple sites obtained at autopsy showed a marked abnormality of architecture on the light microscopic level. Biochemical studies demonstrated an absence of normal α 1(II) collagen in costochondral junction growth plate cartilage and an appearance of the major collagen in a band which comigrates on sodium dodecyl sulfate‐polyacrylamide gel electrophoresis with 3α collagen. Cartilage extracted from structural rib appeared to be normal.
Abstract Two adults with β‐galactosidase deficiency were studied. Differences in a number of β‐galactosidase parameters (pH optima, heat denaturation, NaCl kinetics) were noted between the patients. Differences were also noted in β‐galactosidase electrophoretic mobilities and urinary oligosaccharides; however, there was no complementation in cell fusion studies. It is suggested that these two patients have different primary mutations at the β‐galactosidase locus which are probably structural in nature.
Abstract The Ruvalcaba syndrome is a rare malformation syndrome characterized by skeletal dysplasia, facial anomalies, and mental retardation. We report on a 22‐year‐old woman with severe growth and mental retardation and numerous manifestations characteristic of the Ruvalcaba syndrome. In addition, she has several anomalies not previously described in the Ruvalcaba syndrome, including upslanting palpebral fissures, torus palatinus, hiatal hernia with gastroesophageal reflux, recurrent respiratory infections, pectus excavatum, equinovarous deformity, hypotonia, unilateral renal hypoplasia, an accessory ovary, and atretic fallopian tube. Review of published reports of Ruvalcaba syndrome confirms variability of the clinical and radiographic changes. Findings present in at least 50% of reported patients include mental retardation, short stature, pubertal delay, an abnormal nose (usually beaked) with hypoplastic nasal alae, microstomia with narrow maxilla, thin upper lip vermilion, broad hips, small hands, joint limitation, short fingers and toes, and vertebral abnormalities. Because 5 of the reported patients had renal abnormalities, a renal ultrasound or contrast study is indicated in the evaluation of these patients. Additional reports, particular from multiplex families, will be important to better characterize this syndrome.
Fetal ultrasonography during evaluation of a pregnancy complicated by acute polyhydramnios suggested the presence of a Dandy-Walker cyst. At autopsy, the classic posterior fossa anomalies associated with that syndrome were present. In addition, the right vagus nerve was deformed by the cyst wall, suggesting that fetal dysphagia led to the polyhydramnios.
