The natural history of hereditary multiple exostoses

We established a database of hereditary multiple exostoses for the state of Washington, on the basis of a retrospective review of the medical records and a clinical evaluation of family members, to determine the prevalence, clinical range of expression, and rate of malignant degeneration. The database comprised forty-six kindreds with 113 affected members; all kindreds had at least one member living in the state of Washington. The over-all prevalence was at least one in 50,000. Approximately 10 per cent of the subjects had no family history of multiple exostoses. With the use of twenty-three pedigrees that demonstrated an adequate multigenerational history for determination of penetrance of the gene, we identified one unaffected individual among twenty-six obligate heterozygotes, a rate of penetrance of 96 per cent. There was no evidence for a substantial reduction of penetrance in female subjects. The median age at the time of the diagnosis in the 113 affected individuals was three years (range, birth to twelve years). In a cohort of eighty-four subjects for whom we had complete information, the clinical range of expression was wide: thirty-three (39 per cent) had an obvious deformity of the forearm, eight (10 per cent) had an inequality in the lengths of the limbs, seven (8 per cent) had an angular deformity of the knee, and two (2 per cent) had a deformity of the ankle. The average number of operations for the patients for whom the operative history was known was two.(ABSTRACT TRUNCATED AT 250 WORDS)     

Identification of novel mutations in the human EXT1 tumor suppressor gene

Hereditary multiple exostoses (EXT) is a genetically heterogeneous bone disorder caused by genes segregating on human chromosomes 8, 11, and 19 and designated EXT1, EXT2 and EXT3, respectively. Recently, the EXT1 gene has been isolated and partially characterized and appears to encode a tumor suppressor gene. We have identified six mutations in the human EXT1 gene from six unrelated multiple exostoses families segregating for the EXT gene on chromosome 8. One of the mutations we detected is the same 1-bp deletion in exon 6 that was previously reported in two independent EXT families. The other five mutations, in exons 1, 6, 9, and the splice junction at the 3' end of exon 2, are novel. In each case, the mutation is likely to result in a truncated or nonfunctional EXT1 protein. These results corroborate and extend the previous report of mutations in this gene in two EXT families, and provide additional support for the EXT1 gene as the cause of hereditary multiple exostoses in families showing linkage to chromosome 8.     

The diagnosis of allergy to rifampicin confirmed by skin test

Multiple exostoses syndrome is a rare autosomal dominant disorder that affects the enchondral skeleton during growth. The formation of numerous exostoses causes deformities of bones and joints. Degenerative malignant changes are described. A careful follow up during paediatric age is required. Three new cases in the same family are reported in this paper.     

Tout-velu is a Drosophila homologue of the putative tumour suppressor EXT-1 and is needed for Hh diffusion

Hedgehog (Hh) proteins act through both short-range and long-range signalling to pattern tissues during invertebrate and vertebrate development. The mechanisms allowing Hedgehog to diffuse over a long distance and to exert its long-range effects are not understood. Here we identify a new Drosophila gene, named tout-velu, that is required for diffusion of Hedgehog. Characterization of tout-velu shows that it encodes an integral membrane protein that belongs to the EXT gene family. Members of this family are involved in the human multiple exostoses syndrome, which affects bone morphogenesis. Our results, together with the previous characterization of the role of Indian Hedgehog in bone morphogenesis, lead us to propose that the multiple exostoses syndrome is associated with abnormal diffusion of Hedgehog proteins. These results show the existence of a new conserved mechanism required for diffusion of Hedgehog.     

One-bone forearm as a salvage procedure for recalcitrant forearm deformity in hereditary multiple exostoses

Hereditary multiple exostoses commonly affect the forearm and cause significant deformity. The response of this disease to operative intervention is usually gratifying, but in recalcitrant cases salvage procedures may be necessary. We report two patients treated with radial-ulnar fusion, review the technical aspects of the creation of the so-called "one-bone forearm," and discuss the classification and treatment alternatives available to surgeons treating patients with forearm exostoses. Treatment of both forearms resulted in functional, painless extremities at 3- and 14-year follow-up.     

Need for supervision in the elderly receiving long-term prescribed medication

Medication for 127 randomly selected patients aged over 70 in a large group practice was examined in relation to the available supervision for this treatment. About half the patients were on long-term treatment, mainly drugs associated with heart disease, depression, or anxiety. Nineteen had had no recorded contact with the family doctor for six months or longer, and examination by nurse surveillance suggested that three might be suffering from drug toxicity. It was concluded that reliance on self-referral by elderly patients was unsafe.     

Cervical spinal cord compression in hereditary multiple exostoses. Report of a case and a review of the literature

Spinal cord compression is an extremely serious complication of hereditary multiple exostoses (HME). A case of HME with compression of the cervical spinal cord is reported. Complete recovery following surgery was achieved. A review of the relevant literature revealed 51 previous cases of HME with cord/cauda equina compression. Most patients were under 30 years of age with more men affected than women. The family history was positive in 60%. The cervical and thoracic areas were predominantly affected, with the symptoms usually developing slowly. Recovery following surgery is to be expected in the majority of cases. In patients with HME and suffering from neurological symptoms, the possibility of spinal cord compression should be considered. Prompt diagnosis and surgical excision provide the best prognosis.     

3D-spiral CT of multiple exostoses

We report pre- and post-operative three-dimensional (3D)-spiral CT images in a patient with multiple exostoses. Images of 3D-CT, which were performed using the integrated 3D software of the CT system, showed the exact shapes and locations of the individual tumors around the knee joint in comparison with the surgical findings and resected specimen. 3D-spiral CT images of multiple exostoses would be useful for the planning of surgical procedure.     

Multiple Carcinomas. Results of 2 813 autopsies (author's transl)

The presence of multiple primary malignant neoplasms has been proved pathologically in a total of 50 cases recorded during a 5 years period (1970-1974). The 50 patients represented an incidence of 5.4% among the 992 patients proved to have cancer during the same 5 years period. The multiple lesions were diagnosed simultaneously in half of the patients. Twenty six patients had consecutive neoplasms, the average interval between the first and the second cancer was 6.9 years.     

The femoral nerve traction test with lumbar disc protrusions

Ten patients with multiple sclerosis were found to have lived in close proximity in a Nova Scotia farming community of 150 people. All had drunk unpasteurized milk as children, were teetotallers, ate a high animal fat diet, and were well educated. Of greater interest was the observation that six of the ten cases were related in two family groups. The only time all patients lived in the community at the same time was in 1951 and 1952 during a polio outbreak. The relationship of polio to multiple sclerosis bears further study. The average age of the patients when they had measles was 11.8 years. Evidence suggests a link between risk of multiple sclerosis and both late onset of measles and pubertal age. Late onset of measles may be important in this cluster. Further epidemiological studies are needed to examine the age of onset of measles in M.S. cases.     

Bioavailability and pharmacokinetics of beta-methyldigoxin after multiple oral and intravenous doses

To obtain true half lives, glycoside elimination from six healthy subjects was studied for 14 days after multiple intravenous doses or oral administration of a daily maintenance dose of beta-methyldigoxin 0.3 mg. After oral or intravenous administration of beta-methyldigoxin ceased, the plasma concentrations declined from the 14th to the 16th days with a half life of 1.7 days. From the 16th to the 20th day a change from a shorter to a longer half life of 2.8 and 2.9 days was observed. Similar half lives were found in urine: after the last dose the initial slope from the 14th to the 16th day had a half life of 1.8 days, and the terminal slope had one of 3.2 days. The results indicate release of the glycoside from slowly equilibrating tissues.     

Recurrence risks in families of children with symmetrical spasticity

This study was undertaken to evaluate the recurrence risks for sibs of patients with symmetrical spasticity (either quadriplegia or diplegia) in the absence of factors known to cause spastic cerebral palsy (e.g. pre-term birth, perinatal hypoxia). Among 669 children in the West Midlands with spastic cerebral palsy, 24 had symmetrical spasticity and normal birth histories. This group was clinically and genetically heterogenous. Among their 55 sibs, six had a spastic disorder similar to that in the index patient, and one further sib, who had died young, had been mentally retarded. Of particular interest were two families with an autosomal recessive condition of post-natal microcephaly, myoclonic epilepsy and spastic quadriplegia; and one family, and possibly a sporadic case of X-linked athetoid cerebral palsy. The recurrence risk in this series of approximately 1 in 9 suggests that about half the children with symmetrical spastic cerebral palsy and a normal birth history may have a recessive condition.     

Hepatic manifestations of Wilson's disease: frequency and pattern in Saudi patients

Seven symptomatic patients with Wilson's disease have so far been diagnosed at King Khalid University Hospital (KKUH), Riyadh, over the last six years. On family screening, another three asymptomatic patients were found to be affected. Five of the symptomatic patients had clinical features of liver disease on initial presentation and was preceded by renal dysfunction in another patient. The remaining patient presented with neurological features. Six patients had Kayser-Fleisher ring. Abnormal liver function tests were found in half of the patients. Ceruloplasmin was reduced in 7 of 10 patients. Serum copper and urinary copper estimations were most useful diagnostic laboratory tests. Morphological alteration was found in all 9 patients who had a percutaneous liver biopsy. All patients were treated initially with D-penicillamine and clinical response was noted in seven, of whom one developed neurological manifestations while receiving the treatment. D-penicillamine was replaced by zinc sulfate in 3 patients who developed thrombocytopenia. The data suggest that Wilson's disease may not be rare in Saudi Arabia. For early detection and prompt treatment, the disease should be suspected under appropriate clinical circumstances especially in young patients with liver diseases. Close relatives of such index patients should be routinely screened.     

Mutations of the CD40 ligand gene in 13 Japanese patients with X-linked hyper-IgM syndrome

X-linked hyper-IgM syndrome (XHIM) is a rare primary immunodeficiency caused by a defective CD40 ligand. We identified mutations of the CD40 ligand gene in 13 unrelated Japanese XHIM patients. Of the four patients with missense mutations, one had a mutation within the transmembrane domain, and the three others had mutations affecting the TNF homology region of the extracellular domain. Two of the missense mutations resulted in the substitution of amino acids that are highly conserved in TNF family proteins. Three patients had nonsense mutations, all of which resulted in the truncation of the TNF homology domain of the CD40 ligand. Three patients had genomic DNA deletions of 2, 3 or 4 nucleotides, respectively. All of the deletions were flanked by direct repeat sequences, suggesting that these deletions were caused by slipped mispairing. Three patients had mutations within introns resulting in altered splicing, and multiple splicing products were found in one patient. Thus, each of the 13 Japanese patients had different mutations, 9 of them being novel mutations. These results indicate that mutations in XHIM are highly heterogeneous, although codon 140 seems to be a hot spot of the CD40 ligand gene since two additional point mutations were located at Trp 140, bringing the total numbers of mutations affecting codon 140 to six. In one XHIM family with a missense mutation, prenatal diagnosis was performed by single-strand conformation polymorphism analysis of genomic DNA of a male fetus.     

Surgical treatment of ankyloses of the temporomandibular joint in children

Ankylosis of the temporomandibular joint leads in children to serious disorders such as loss of dentition, growth retardation of the lower jaw, facial asymmetry etc. During the period from 1993 till 1997 we treated 12 children incl. eight who had unilateral and four bilateral ankylosis. In six patients, after elimination of the ankylosis, reconstruction of the head was made with a total of nine costochondral grafts. In entire all patients the temporal muscle or a silicone plate was interposed between the skull base and mandible. Postoperative complications were minimal. Surgical treatment, which is only half of the issue of treatment, must be followed by long-term careful rehabilitation. The results which were achieved contributed in a significant way to a more favourable further development of the children.     

Study on the elimination of Angiostrongylus costaricensis first stage larvae in the experimental infection of Swiss mice

We report six of 16 U.K. melanoma families and two of 17 patients with multiple primary melanomas and a negative family history who have between them four different functionally damaging mutations of the CDKN2A (p16) gene: an Arg 24 Pro substitution in exon 1 in one family, a stop codon at codon 44 of exon 1 in one family, and a Met 53 Ile substitution in exon 2 in four families. One multiple primary melanoma patient also has the Met 53 Ile mutation and a second has a G-T substitution at the IVS2 + 1 splice donor site. Our data together with other recent publications from France and the U.S.A. indicate that screening melanoma kindreds with only two affected family members for CDKN2A mutations is justified.     

Multiple tarsal coalitions in the same foot

I reviewed 60 cases of tarsal coalition seen at Texas Scottish Rite Hospital for Children over the last 10 years. Twenty-nine patients had plain films only and were excluded from the study. One patient was diagnosed with synovitis at the time of surgery and was also excluded. Thirty patients with 53 coalitions had computed tomographic (CT) and, in many cases, surgical documentation of a tarsal coalition. Of these 30 patients, six had multiple coalitions in the same foot. This article briefly summarizes the six cases and reviews the literature of multiple tarsal coalitions, both before and after the use of CT. I suggest that multiple coalitions in the same foot are more common than once thought and recommend CT evaluation of both feet in transaxial and coronal planes in patients with suspected tarsal coalition.     

Psychiatric disturbances of aged patients in skilled nursing homes

The authors found that 85% of 74 patients supported by Medicaid in two skilled nursing facilities had significant psychiatric disorders in addition to serious multiple medical illnesses. Almost two-thirds of the psychiatric disturbances had not been diagnosed. Although staff were more concerned with the psychosocial than the physical aspects of patients' problems in more than half of the cases, they often had difficulty recognizing the legitimacy of psychological complaints and relating to patients with psychological disturbances. Staff were not clear about the orders for psychotropic medications that were prescribed for more than half of the patients. The authors point out that more psychiatric consultation is needed to ensure appropriate and effective care for psychiatric patients in such facilities.     

Exostosis of the external auditory meatus or ear canal nodes. A study of etiology and therapeutic results

In this study we evaluated the relation between exposure of the ear canal to cold water and development of exostosis. Furthermore we wanted to evaluate the clinical outcome of surgical removal of the exostosis. The material consisted of a group of 15 winter bathers who had been exposed to cold water over a period varying from three to 45 years. All but one subject who had exposed the ear canal to cold water had developed exostoses of the ear canals. Follow-up examinations of nine patients after surgical removal of the exostosis revealed normal, well calibrated ear canals. Three winter bathers who continued the exposure to cold water developed a new exostosis.     

Autosomal dominant progressive external ophthalmoplegia with multiple deletions of mtDNA: clinical, biochemical, and molecular genetic features of the 10q-linked disease

Autosomal dominant progressive external ophthalmoplegia (adPEO) is a mitochondrial disease characterized by accumulation of multiple large deletions of mtDNA in patients' tissues. We previously showed that the disease is genetically heterogeneous by assigning two nuclear loci predisposing to mtDNA deletions: one on chromosome 10q 23.3-24.3 in a Finnish family and one on 3p 14.1-21.2 in three Italian families. To reveal any locus-specific disease features, we report here the clinical, biochemical, and molecular genetic characteristics of the 10q-linked disease in the single family reported to date. All seven patients and four asymptomatic subjects had ragged-red fibers and multiple deletions of mtDNA in their muscle. Ptosis and external ophthalmoplegia were the major clinical findings, and depression or avoidant personality traits were frequently, but not consistently, present in the subjects carrying mutant mtDNA. In six of the subjects with mutant mtDNA, the activities of the respiratory chain complexes I or IV, or both, were below or within the low normal range. Two autopsy studies revealed the characteristic distribution of mutant mtDNA in these patients: highest proportion of mutant mtDNA is found in different parts of the brain, followed by the skeletal and ocular muscle, and the heart.