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Biomedical subjects

D L Rimoin

Publications and source records attributed to D L Rimoin.

At least 145 records · Page 8Linked to original sources
PubMed1985

Pathologic findings in adenosine deaminase-deficient severe combined immunodeficiency. I. Kidney, adrenal, and chondro-osseous tissue alterations.

The authors have reviewed the autopsies of 8 patients with adenosine-deaminase-deficient severe combined immunodeficiency disease (ADA-SCID). Several new findings in nonlymphoid organs, including kidney and adrenal gland, and chondro-osseous tissue indicate the multisystem nature of this disorder. Examination of renal tissue in 7 of 8 cases showed mesangial sclerosis. This was confirmed in 3 cases by electron microscopy. One case, treated with multiple erythrocyte partial exchange transfusions for several years, had no mesangial sclerosis. Six of 8 cases showed adrenal-gland cortical sclerosis. Chondro-osseous tissue from vertebrae and costochondral junctions of 4 cases examined showed typical alterations previously reported in ADA-SCID such as short growth plates with few proliferating and some hypertrophic chondrocytes. The authors report the new observations of necrotic chondrocytes, as well as large amounts of cellular debris. These changes were not observed in the 2 other patients examined, who received bone marrow or multiple partial exchange transfusions. The distribution and severity of these lesions, their relationship to ADA replacement therapy, and their homology to mice treated with a potent ADA inhibitor suggests that, in addition to lymphoid dysfunction, disordered nucleoside metabolism due to absent ADA activity in ADA-SCID may be the cause of diverse multi-system pathologic changes in tissues which continue to differentiate or mature after birth.

Adenosine Deaminase↗
PubMed1984

Osteogenesis imperfecta type II delineation of the phenotype with reference to genetic heterogeneity.

A group of fetuses with a perinatally lethal variety of osteogenesis imperfecta (O.I. type II) is characterized by short limbs, and clinical and roentgenological evidence of severe osseous fragility and defective ossification. Forty-eight cases were reviewed and can be subdivided into 3 groups on the basis of small but probably significant differences in clinical and radiographic findings. Group A (38 cases): short, broad, "crumpled" long bones, angulation of tibiae and continuously beaded ribs. Group B (6 cases): short, broad, crumpled femora, angulation of tibiae but normal ribs or ribs with incomplete beading. Group C (4 cases): long, thin, inadequately modelled, rectangular long bones with multiple fractures and thin beaded ribs. Consistency of findings within sibships suggests the groups reflect genetic heterogeneity. An increased frequency of parental consanguinity, sib occurrence with normal parents, and normal mean paternal age at birth, suggest that most cases of O.I. type II represent autosomal recessive traits. Some previously reported cases and the biochemical findings in one case suggest still further genetic heterogeneity.

Consanguinity↗
PubMed1984

Syndrome of multiple pterygia, camptodactyly, facial anomalies, hypoplastic lungs and heart, cystic hygroma, and skeletal anomalies: delineation of a new entity and review of lethal forms of multiple pterygium syndrome.

Three unrelated stillborn infants (cases 1-3) are presented here with a distinct constellation of multiple anomalies: namely, multiple pterygia involving chin-to-sternum, cervical, axillary, antecubital, crural and/or popliteal areas, flexion contractures of multiple joints, small chest, hydrops, characteristic abnormal facial appearance with hypertelorism, markedly flattened nasal bridge with hypoplastic nasal alae, cleft palate, micrognathia, apparently low-set malformed ears, short neck with a cystic hygroma at the back of the neck and head, and pulmonary and cardiac hypoplasia. Radiographic studies, in addition, showed scalp edema, microbrachycephaly, flattened mandibular angle, lack of normal curvature at the cervico-thoracic junction, marked bony fusion of posterior spinous processes of older fetuses (cases 1, 2), thin crowded ribs, markedly hypoplastic scapulae, hypoplastic iliac wings, ischia and pubic bones, undermodeling of tubular bones, and radio-ulnar synostosis. Histologic studies of the skeletal system showed cartilaginous and bony fusion of the spinous processes (cases 1, 2), fusion of epiphyseal cartilages of distal humerus and proximal ulna, a poorly developed joint space, an abnormal growth plate, and weak safranin staining of the resting cartilages (cases 1, 2). To the best of our knowledge, this pattern of anomalies constitutes a previously undescribed syndrome. Prenatal diagnosis of this entity is possible by ultrasonographic studies on the basis of nonimmune fetal hydrops, a cystic hygroma at the back of the head and neck, diminished fetal activity, short and fixed limbs, and/or maternal hydramnios. Three additional cases (cases 4-6) are also presented to show a possible heterogeneity of this syndrome.

Abnormalities, Multiple↗
PubMed1984

Fibrochondrogenesis: radiologic and histologic studies.

Fibrochondrogenesis is a distinct, neonatally lethal, short-limb skeletal dysplasia which was first described in a single patient in 1978. We report the radiographic and morphologic studies of 2 additional unrelated stillborn infants with fibrochondrogenesis. This syndrome has distinct radiographic and chondro-osseous morphologic defects different from those seen in the other known skeletal dysplasias. The long bones are short and dumbbell-shaped with metaphyseal flare. The spine is platyspondylic with superior-inferior clefting defects, and the ribs are short and distally cupped. The growth-plate cartilage is grossly disorganized and has a densely fibrous collagenous matrix when examined by light and electron microscopy. Light, transmission, and scanning electron microscopy shows diaphyseal and metaphyseal trabecular bone to be normal.

Abnormalities, Multiple↗
PubMed1984

No evidence for linkage between an insulin-dependent diabetes mellitus-susceptibility locus and immunoglobulin loci KM or GM.

We studied 52 families having more than one member affected with insulin-dependent diabetes mellitus (IDDM) for linkage of an IDDM-susceptibility locus to the immunoglobulin loci KM and GM. Linkage was analyzed by the LOD score method using single-locus recessive and dominant models of IDDM inheritance, with penetrances of the disease-susceptible genotypes being dependent on age and reaching a maximum of 20% by age 40. We found no evidence for linkage of IDDM to KM or GM. Close linkage (recombination fraction less than 5%) was rejected for KM under the recessive model and for GM under both models. These results suggest either that there are no IDDM-susceptibility loci closely linked to KM or GM or that use of a single-locus model of IDDM (which ignores the effects of the susceptibility locus in the HLA region) is inadequate for their detection.

Adult↗
PubMed1984

Leber's congenital amaurosis associated with familial juvenile nephronophthisis and cone-shaped epiphyses of the hands (the Saldino-Mainzer syndrome).

Three affected children (a 13-year-old girl and her 7- and 8-year-old brothers) in a sibship of eight had findings consistent with the Saldino-Mainzer syndrome (skeletal dysplasia associated with Leber's congenital amaurosis, familial juvenile nephronophthisis, and cone-shaped epiphyses of the hands). Two also had pigmented midline nevi. Although tapetoretinal degeneration and familial juvenile nephronophthisis are associated in the inherited Senior-Loken syndrome, the rare association of these abnormalities with cone-shaped epiphyses of the hands suggested an autosomal recessive syndrome with variable expression remarkably similar to the Saldino-Mainzer syndrome, which may or may not be distinct from the Senior-Loken syndrome. The association of tapetoretinal degeneration with skeletal dysplasia may indicate asymptomatic renal or hepatic disease.

Adolescent↗
PubMed1983

Association studies between Type 1 (insulin-dependent) diabetes and 27 genetic markers: lack of association between Type 1 diabetes and Kidd blood group.

One hundred and three unrelated patients with Type 1 (insulin-dependent) diabetes were typed for HLA, properdin factor B (BF), glyoxalase 1 (GLO), Kidd blood group, and 24 other genetic markers. Observed distributions of marker phenotypes among these patients were compared with those expected according to population frequencies, in an attempt to detect associations between Type 1 diabetes and the markers. Strong associations between Type 1 diabetes and both HLA and properdin factor B were confirmed, as was a lack of association between Type 1 diabetes and glyoxalase (GLO). There was an apparent deviation from Hardy-Weinberg equilibrium at the GLO locus, and statistically significant distortions in the distributions of pancreatic amylase (AMY2), galactose-1-phosphate uridyl transferase (GALT), and group-specific component (GC) among Type 1 diabetes patients, but these results are not significant when corrected for performance of multiple tests. An increase in the Lewis-negative phenotype reported elsewhere was observed here but was not statistically significant. A distortion in the distribution of Kidd types reported elsewhere was not confirmed.

Blood Group Antigens↗
PubMed1983

A search for heterogeneity in insulin dependent diabetes mellitus (IDDM): HLA and autoimmune studies in simplex, multiplex and multigenerational families.

HLA antigens (A, B, C and DR loci), serum islet cell antibodies, thyrogastric antibodies, and insulin antibodies were studied in 77 families (25 simplex, 42 multiplex, and 10 multigenerational). In order to test for intrafamilial constancy and intergroup variation, we compared simplex with multiplex families, HLA identical and non identical siblings within families, as well as groups of families characterized by different DR alleles (DR3, DR4, and DR3/DR4) for various immunologic and clinical characteristics. These comparisons did not reveal all the distinct subgroups suggested by different cross-sectional population studies, but did provide evidence for a compound form having an aggregation of different high risk alleles. This study suggests that in many cases (and possibly especially in families with multiple affected individuals), there are several different genetic influences leading to IDDM.

Antibodies↗
PubMed1983

A distinct chondrodysplasia resembling Kniest dysplasia: clinical, roentgenographic, histologic, and ultrastructural findings.

Two sibs, one girl and one boy, were observed in infancy with a severe lethal skeletal dysplasia syndrome that radiologically and histologically resembled Kniest dysplasia but clearly differed in clinical course and inheritance. Kniest dysplasia is a nonlethal syndrome, whereas both of these infants died in the neonatal period. Kniest dysplasia appears to be inherited as an autosomal dominant trait; the likely transmission in this family was autosomal recessive. Roentgenograms revealed dumbbell-shaped long bones superficially similar to Kniest dysplasia, but with markedly shortened diaphyses and metaphyseal irregularities. Chondro-osseous morphology demonstrated a superficially similar foamy "Swiss cheese" appearance to the cartilage matrix, as seen in Kniest dysplasia, but there were distinctly different changes in the growth plate and resting cartilage. Ultrastructurally, the chondrocytic endoplasmic reticulum was found to have an appearance different from that observed in either normal or Kniest cartilage. These cases likely represent a distinct chondrodysplasia.

Cartilage↗
PubMed1983

HLA genotypic study of insulin-dependent diabetes the excess of DR3/DR4 heterozygotes allows rejection of the recessive hypothesis.

The genetics of insulin-dependent diabetes mellitus (IDDM) is currently an area of controversy, with some investigators proposing heterogeneity within the HLA region and even the existence of non-HLA-linked susceptibility genes, and others maintaining that a simple autosomal recessive gene linked to HLA with reduced penetrance is an adequate explanation. To resolve this latter question, we report here a simple method of testing whether a single HLA-linked susceptibility gene is inherited in a recessive fashion when it is associated with two different HLA alleles, as is the case for IDDM. It is shown that if the number of DR3/DR4 heterozygotes in a diabetic population exceeds the combined sum of DR3/3 and DR4/4 homozygotes in that same diabetic population, then a recessive mode of inheritance can be rejected. The advantages of the method are that it does not depend on ratios, as do relative risk calculations, nor does it depend on control data, but is based only on studies of the diabetics themselves. With data on 193 genotyped IDDM patients, we can clearly reject the recessive mode of inheritance, since the number of heterozygotes is 68 compared with a maximum of 22 homozygotes (P less than 10(-4)). Eight other published studies are in concordance with these results. Therefore, a nonparametric test, independent of the significance of any individual study, rejects equality of heterozygotes and homozygotes (P less than 0.002) and rejects the simple recessive mode of inheritance as a direct consequence. We conclude that more complex modes of inheritance of HLA-linked IDDM susceptibility, such as two different diabetogenic alleles or multiple loci, must be entertained. DIABETES 32:169-174, February 1983.

Alleles↗
PubMed1983

The search for heterogeneity in insulin-dependent diabetes mellitus (IDDM): linkage studies, two-locus models, and genetic heterogeneity.

One hundred families with insulin-dependent diabetes mellitus (IDDM) were analyzed for linkage with 27 genetic markers, including HLA, properdin factor B (BF), and glyoxalase 1(GLO) on chromosome 6, and Kidd blood group (Jk) on chromosome 2. The linkage analyses were performed under several different genetic models. An approximate correction for two-locus linkage analysis was developed and applied to four markers. Two different heterogeneity tests were implemented and applied to all the markers. One, the Predivided-Sample Test, utilizes various criteria thought to be relevant to genetic heterogeneity in IDDM. The other, the Admixture Test, looks for heterogeneity without specifying a prior how the sample should be divided. Results continued to support linkage of IDDM with three chromosome 6 markers: HLA, BF, and GLO. The total lod score for Kidd blood group, under the recessive model with 20% penetrance, is 1.63--down 1.2 from the 2.83 reported by us earlier. The only other marker whose lod score exceeded 1.0 under any model was pancreatic amylase (AMY2). The two-locus correction, which involved lowering the penetrance values used in the analysis, affected estimates of theta (recombination fraction) but did not markedly change the lod scores themselves. There was little evidence for heterogeneity within any of the lod scores, under either the Predivided-Sample Test or the Admixture Test.

Adult↗
PubMed1982

Growth curves for height for diastrophic dysplasia, spondyloepiphyseal dysplasia congenita, and pseudoachondroplasia.

Analysis of retrospective growth data from 72 patients with diastrophic dysplasia, 62 patients with spondyloepiphyseal dysplasia congenita and 61 patients with pseudoachondroplasia permitted the establishment of preliminary reference growth standards for height for each disorder. In addition, a comparison of mean height curves for these three disorders and achondroplasia revealed dissimilarities in growth patterns.

Achondroplasia↗