Split hand foot malformation is associated with a reduced level of Dactylin gene expression.

Split hand foot malformation (SHFM) is a congenital limb malformation presenting with a median cleft of the hand and/or foot, syndactyly and polydactyly. SHFM is genetically heterogeneous with four loci mapped to date. Murine Dactylaplasia (Dac) is phenotypically similar, and it has been mapped to a syntenic region of 10q24, where SHFM3 has been localized. Structural alterations of the gene-encoding dactylin, a constituent of the ubiquitinization pathway, leading to reduced levels of transcript have been identified in Dac. Here, we report a significant decrease of Dactylin transcript in several individuals affected by SHFM. This observation supports a central role for dactylin in the pathogenesis of SHFM.

Acrogeria of the Gottron type in a mother and son.

We report a familial case of acrogeria in a mother and son, with characteristic cutaneous involvement and no clinical signs of vascular Ehlers-Danlos syndrome (former EDS type IV) in spite of some tendency to bruising. The biochemical and molecular studies did not disclose any abnormality of collagen type III, which favours the diagnosis of acrogeria. It appears that recognition of acrogeria as an entity is of clinical significance since these cases are not associated with systemic involvement, and specifically with rupture of vessels and internal organs, occasionnally occurring in EDS.

Two new recurrent nucleotide mutations in the COL1A1 gene in four patients with osteogenesis imperfecta: about one-fifth are recurrent.

Previous observations on mutations causing osteogenesis imperfecta (OI) suggested that unrelated patients had private mutations. Here preliminary studies on two patients with type I OI indicated that some mutations in the COL1A1 gene for type I procollagen cannot be detected by analyses of cDNAs. Therefore, we developed a protocol whereby 43 exon and exon flanking sequences of the COL1A1 gene can be amplified by PCR and scanned for mutations by denaturing gradient gel electrophoresis. Two new recurrent nucleotide mutations in the gene were found in four apparently unrelated patients with OI. Analysis of previous publications indicated that up to one-fifth of the mutations causing OI are recurrent in the sense that they were identical in apparently unrelated probands. About 80% of these identical mutations were in CpG dinucleotide sequences.

Abnormal morphology of fibrillin microfibrils in fibroblast cultures from patients with neonatal Marfan syndrome.

The Marfan syndrome (MFS) is a connective tissue disorder manifested by variable and pleiotropic features in the skeletal, ocular, and cardiovascular systems. The average life span in MFS is about 35 years. A group with much more severe cardiovascular disease and a mean life span of approximately 1 year also exists. We refer to this latter group as "neonatal Marfan syndrome" (nMFS). Fibrillin defects are now known to be the cause of MFS and nMFS. Immunofluorescence studies were the first to demonstrate this association. Here we describe immunofluorescence studies in a series of 10 neonates and summarize their salient clinical features. In vitro accumulation of fibrillin reactive fibers was assayed using monoclonal antibodies to fibrillin in hyperconfluent fibroblast cultures. As was previously observed in MFS, fibroblast cultures from nMFS patients showed an apparent decrease in accumulation of immunostainable fibrillin. Significantly, however, the morphology of the immunostained fibrils in the nMFS cultures were abnormal and differed not only from control cultures, but also from those seen in cultures of MFS fibroblasts. The nMFS fibrils appeared short, fragmented, and frayed, characteristics that are not seen in MFS. Both the clinical and fibrillin morphology data provide evidence to suggest a useful subclassification of nMFS in the spectrum of MFS.

Fibrillin immunofluorescence in pseudoxanthoma elasticum.

BACKGROUND: Pseudoxanthoma elasticum (PXE) is a rare heritable connective tissue disorder manifested by skin, ocular, and cardiovascular anomalies. The basic defect is unknown; however, the microscopic findings are indicative of defects in elastic fibers. Among the components of the elastic fibers are elastin and elastin-associated microfibrils. OBJECTIVE: We assessed the fidelity of this fibrillar system in PXE with the use of antibodies to fibrillin, a major component of elastin-associated microfibrils. METHODS: Using a well-established immunofluorescence assay, we studied fibrillin deposition in dermal fibroblast cultures from 16 patients with PXE. RESULTS: Six of the 16 patients (37%) showed some abnormality of fibrillin deposition in fibroblasts derived from lesional skin. Fibroblasts from nonlesional skin displayed normal fibrillin immunofluorescence. The only sibship studied, however, was discordant for fibrillin immunostaining. CONCLUSION: Unlike the findings in Marfan syndrome, these data are not suggestive of causal fibrillin defects in PXE.

Recurrent mis-splicing of fibrillin exon 32 in two patients with neonatal Marfan syndrome.

The Marfan syndrome (MFS) is an autosomal dominant heritable disorder of connective tissue. Variable and pleiotropic clinical features are observed in the skeletal, ocular, and cardiovascular systems. The most severe end of the phenotypic spectrum of this disorder comprises a group of patients usually diagnosed at birth, who have a life expectancy of little more than a year. To distinguish this group of patients from those with classical MFS, we refer to them as neonatal Marfan syndrome (nMFS). These infants usually die of congestive heart failure rather than aortic aneurysmal disease, the most frequent cause of morbidity and mortality in classical MFS. Defects in fibrillin, an elastin-associated microfibrillar glycoprotein, are now known to cause both the classical and neonatal forms of MFS. Here we report the recurrent mis-splicing of fibrillin (FBN1) exon 32, a precursor EGF-like calcium binding domain, in two unrelated infants with nMFS. The mis-splicing, in one patient, was due to an A-->T transversion at the -2 position of the consensus acceptor splice site; while that in the second patient was caused by a G-->A transition at the +1 position of the donor splice site. Characterization of FBN1 mutations in individuals at the most severe end of the Marfan syndrome spectrum should provide greater understanding of the multiple domains and regions of fibrillin.

Lack of linkage of apparently dominant cleft lip (palate) to two candidate chromosomal regions.

Two regions were chosen for linkage studies to cleft lip with or without cleft palate (CL[P]) because they are break points of a balanced translocation in a patient with severe bilateral facial clefting. We used dinucleotide repeats to test chromosomal regions 1q21 and 22q11.2 for such linkage. We studied three families with apparently dominantly inherited CL(P). Families #1 and #2 are local Caucasian families that have not been previously reported; family #3 is a Belgian family that has been previously published [DePaepe, 1989]. Significant evidence against close linkage of the dinucleotide repeats (D1S104, D22S156, D22S264) with CL(P) using a dominant model was obtained. Three other candidate regions were tested (2q37,4q31, and 8p) with the dinucleotide repeats PAX3, D4S175, and LPL respectively. The LOD scores generated at these three loci are not statistically significant for demonstrating negative linkage at these regions. However, they may be used with other informative families in the future, since LOD scores for the same model of inheritance may be added together. Negative or neutral LOD scores were generated at all informative loci using an autosomal dominant model with decreased penetrance.

The epidemiology of tracheo-oesophageal fistula and oesophageal atresia in Europe. EUROCAT Working Group.

The total prevalence rate of tracheo-oesophageal fistula and oesophageal atresia in 15 EUROCAT registries covering 1,546,889 births during 1980-8 was 2.86 per 10,000. There was a decreasing prevalence rate over time (3.5 per 10,000 in 1980-2, 2.7 in 1983-5, 2.5 in 1986-8). Ten per cent of cases were associated with chromosomal anomalies and of the remaining cases, half were multiply malformed. Sixty two per cent of cases were males. There was a significantly increased risk for mothers of less than 20 years of age (odds ratio compared with mothers of 25-29 = 1.82, 95% confidence interval 1.23 to 2.67). There were no apparent epidemiological differences between isolated and multiply malformed cases in secular trend, sex ratio, or maternal age. Both isolated and multiply malformed cases tended to be premature and small for gestational age. There was variation between centres in survival of affected liveborn children up to 1 year of age.

The contribution of 99mTc-pyrophosphate tomoscintigraphy in the evaluation of necrotic myocardial lesions.

Diagnostic contribution of Conventional Planar Scintigraphy (CPSc) and Single Photon Emission Computed Tomoscintigraphy (SPECT), using 99mTc-Pyrophosphate (99mTc-PYP), have been compared in 49 patients with either transmural (T.I., N = 40), or non-transmural (N.T.I., N = 9) infarction. Sensitivity ratios were, respectively for CPSc and SPECT, 75% and 100% in T.I., 78% and 88% in N.T.I. CPSc was non-diagnostic in 6 out of 49 patients, SPECT in only 1. Extent of the necrotizing process was better delineated on SPECT studies than on CPSc. Specificity of 99mTc-PYP tomoscintigraphy evaluated in a group of 6 young (under 40 years old) normal patients was 6/6 (100%). In nine out of ten additional patients without proven infarction who had underwent contrast coronarography within two weeks after a positive 99mTc-PYP SPECT study, significant stenosis (greater than 50%) were found on arteries supplying blood to pathologic territories as demonstrated on tomoscans. It is concluded that 99mTc-PYP SPECT is a very sensitive and specific way--better than CPSc--in the diagnosis as well as in the evaluation of the extent of necrotic myocardial process.