Aarskog-Scott syndrome: confirmation of linkage to the pericentromeric region of the X chromosome.

Aarskog-Scott syndrome was tentatively mapped to Xq13 on the basis of an X:8 translocation by Bawle et al. [Am J Med Genet 17:595-602, 1984]. A review of the cytogenetics and the use of molecular markers in that family have resulted in revision of the breakpoints of the translocation to Xp 11.2 and 8q11.21 [Glover et al., Hum Mol Genet 2:1717-1718, 1993]. Two families, including one of the two initial families with Aarskog-Scott syndrome [Scott, BD:OAS VII (6): 240-246, 1971], have participated in our study to evaluate the localization of the gene for Aarskog-Scott syndrome to the pericentromeric region of the X chromosome. Using a series of DNA probes, we have been able to confirm linkage to the X chromosome, with multipoint analysis indicating the most likely localization of the gene to be on the proximal short arm.

Further delineation of spondylo-meta-epiphyseal dysplasia, short limb-abnormal calcification type, with emphasis on diagnostic features.

Further delineation of a generalized bone dysplasia which we call spondylo-meta-epiphyseal dysplasia, short limb-abnormal calcification type is presented. This dwarfing condition has several serious complications, with the most common cause of death being spinal cord damage secondary to atlantoaxial instability. It is a heritable condition with an autosomal recessive mode of transmission. Radiologic diagnostic criteria are developed on the basis of studies in 8 patients with the oldest being between 4 and 5 years old. The condition is clinically and radiographically apparent neonatally or in early infancy, and it is probable that all or almost all affected individuals will come to medical attention in the age range screened by this study.

The effect of nebulized albuterol on the activity of the renin-angiotensin system in asthma.

STUDY OBJECTIVE: We have previously described activation of the renin-angiotensin system (RAS) in acute severe asthma and have also reported activation of the RAS in normal subjects by single doses of nebulized beta 2-agonists. In the present study, we have examined the effect of single and multiple doses of nebulized albuterol on the activity of the RAS in mild asthma. DESIGN: Eight patients with mild asthma were studied. The effect of single and multiple doses of nebulized albuterol (5 mg) on the activity of the RAS was compared with that of placebo using a randomized, double-blind crossover study design. Nebulized drugs were administered at time 0 and 30 min. MEASUREMENTS: Plasma renin, angiotensin II (Ang II), and serum potassium levels were measured at baseline following a short rest, and thereafter at intervals up to 150 min. RESULTS: Renin levels increased after both the single (S) and double (D) nebulized doses of albuterol and were significantly greater than placebo at 30 min after S, and at 45 and 120 min after D. Plasma Ang II level also increased after S and D and was significantly greater than placebo at 30 and 45 min after S, and at 30 min and all timepoints thereafter following D. In addition, the effect of D was significantly greater than S at 45 min. CONCLUSIONS: These results confirm that there is activation of the RAS in asthmatic subjects by single doses of nebulized beta 2-agonists and that repeated dosing with nebulized albuterol has further, additive effects on plasma Ang II levels. It therefore seems likely that these agents are contributing to activation of the RAS in acute asthma, although the exact clinical significance of these transient changes in plasma Ang II levels in asthma is at present unclear.

Effect of infused angiotensin II on the bronchoconstrictor activity of inhaled endothelin-1 in asthma.

STUDY OBJECTIVES: Endothelin (ET)-1 is a potent bronchoconstrictor, and asthmatics demonstrate bronchial hyperresponsiveness to ET-1 given by inhalation. Angiotensin II (Ang II) is increased in plasma in acute severe asthma, causes bronchoconstriction in asthmatics, and potentiates contractions induced by ET-1 in bovine bronchial smooth muscle in vitro, and contractions induced by methacholine both in vitro and in vivo. We wished to examine any potentiation of the bronchoconstrictor activity of inhaled ET-1 by infused Ang II at subbronchoconstrictor doses. DESIGN: Double-blind randomized placebo-controlled study. SETTING: Asthma research unit in university hospital. PATIENTS: Eight asthmatic subjects with baseline FEV1 88% predicted, bronchial hyperreactivity (geometric mean, concentration of methacholine producing 20% fall, methacholine PC20 2.5 mg/mL), and mean age 37.1 years. INTERVENTIONS: We examined the effect of subbronchoconstrictor doses of infused Ang II (1 ng/kg/min and 2 ng/kg/min) or placebo on bronchoconstrictor responses to inhaled ET-1 (dose range, 0.96 to 15.36 nmol). MEASUREMENTS: Oxygen saturation, noninvasive BP, and spirometric measurements were made throughout the study visits. Blood was sampled for plasma Ang II levels at baseline and before and after ET-1 inhalation. RESULTS: Ang II infusion did not produce bronchoconstriction per se at either dose prior to ET-1 challenge. Bronchial challenge with inhaled ET-1 produced dose-dependent bronchoconstriction, but there was no difference in bronchial responsiveness to ET-1 comparing infusion of placebo with Ang II at 1 ng/kg/min or 2 ng/kg/min (geometric mean, concentration of ET-1 producing 15% fall, 5.34 nmol, 4.95 nmol, and 4.96 nmol, respectively) (analysis of variance, p > 0.05). There was an increase in systolic and diastolic BP at the higher dose of Ang II compared to placebo (mean 136/86 vs 117/75 mm Hg, respectively). Plasma Ang II was elevated following infusion of both doses of Ang II compared to placebo. CONCLUSIONS: In contrast to the potentiating effect on methacholine-induced bronchoconstriction, Ang II at subbronchoconstrictor doses does not potentiate ET-1-induced bronchoconstriction in asthma.

Influence of age, sex and osteogenesis imperfecta on count, protein content, and monoamine oxidase activity of human thrombocytes.

We determined the effect of count, age (2 to 24 year), sex, and osteogenesis imperfecta (OI) on the protein content and monoamine oxidase activity in human platelets. The reaction rate in presence of paramethoxybenzylamine was assessed in a sensitive and continuously recording spectrophotometric system. Platelets harvested from control subjects and OI patients displayed significant inverse linear correlations between count and protein content; there was near-constancy of the products of the two variables. The effects of age, sex, and osteogenesis imperfecta on protein content, count, and MAO activity were assessed by multivariate analysis of variance. It was found that, with increasing age, the count increased linearly and the protein content decreased. In patients with OI the protein content was depressed and monoamine oxidase activity elevated regardless of whether the latter was calculated on the basis of pellet protein or of count. The data suggest that, in osteogenesis imperfecta, thrombocytic monoamine and protein metabolism deviate from that of controls.

The effect of cerebellar stimulation on focal seizure activity and spasticity in monkeys.

Experiments were carried out in awake, unmedicated monkeys to determine the effect of application of current to the cerebellar hemispheres on electrically induced focal motor seizures and surgically induced spasticity. Application of current at various frequencies and pulse amplitudes did not significantly alter focal motor seizures but did significantly reduce spasticity. Analysis of evoked potential recordings carried out during various experimental procedures suggests that application of current to the cerebellar hemispheres may reduce cortical neuronal responsiveness.

The Scottish multi-centre prospective study of bronchoscopy for bronchial carcinoma and suggested audit standards.

Fibre-optic bronchoscopy is widely used to diagnose bronchial carcinoma. There is considerable variation in techniques for patient sedation, methods of obtaining samples and histopathological yield. We wished to examine variations in practice in different centres throughout Scotland and derive realistic audit standards for best clinical practice from these results. Diagnostic bronchoscopies from five centres were included. Patient details, grade of individual performing the test, endobronchial abnormalities, specimens taken and the histocytological yield were recorded. A patient satisfaction questionnaire was completed. One thousand eight hundred and two bronchoscopies were performed to look for bronchial carcinoma. Sedation and anaesthesia techniques varied considerably between centres. There were marked differences in patient satisfaction between centres. Nearly twice as many females as males would prefer not to have bronchoscopy repeated. Six hundred and fifty-eight carcinomas were confirmed by histocytology. Yield was unaffected by the grade of doctor performing bronchoscopy. Improving yield may be achieved by increasing the number of sampling techniques employed and changing the order in which specimens are taken (biopsies first and washings last). Eighty-seven percent of endoscopically visible tumours were confirmed histocytologically. There was a considerable variation in histological spectra between centres that may relate to differences in pathological interpretation rather than actual differences in case mix. Suggested audit standards are discussed. This study demonstrates the variety of techniques and also the levels of histocytological yield and patient satisfaction that can be achieved. Provisional standards of practice for this procedure have been agreed with a view to auditing performance against these. It is hoped that centres will adopt the methods that are shown to achieve the highest standards.

The spine in osteogenesis imperfecta.

A high incidence of spinal curvature, approaching 80 per cent in patients more than twelve years old, was found in a large series of patients with osteogenesis imperfecta. Curves showed early progression and a predictable pattern. In the age range between one and five years the incidence of scoliosis was 26 per cent; thereafter, it rose precipitously. The degree of curvature was greater in the older children. The Milwaukee brace was ineffective in the treatment of the scoliosis and the complications of its use were detrimental. In several patients it deformed the rib cage. It had little or no effect on the progression of the curve. The incidence and degree of curvature was related to the type of bone present. Patients with chest deformities and those who were not ambulatory seemed to have a predilection for scoliosis.

The Syme amputation in patients with congenital pseudarthrosis of the tibia.

Eight patients with congenital pseudarthrosis of the tibia had a Syme amputation and were followed for an average of 5.9 years. The average age at amputation was 8.2 years, and an average of 3.8 surgical procedures were performed prior to the amputation in each patient. None of the pseudarthroses healed, but in spite of that the Syme amputation can be recommended when amputation is necessary. With a simple orthosis, the child can then engage in normal activities. The operation provides a longer stump than do conventional amputations, as well as better skin coverage and more potential for further growth of the tibia from the distal epiphysis.

Chondro-osseous growth abnormalities after meningococcemia. A clinical and histopathological study.

The cases of nine children who survived the acute stage of meningococcal septicemia and secondary disseminated intravascular coagulation were reviewed. All of the children had major orthopaedic problems as a result of the acute disease. Detailed histological studies were performed on specimens of bone and cartilage, obtained when these patients had either acute amputation for gangrene or subsequent revision for a chondro-osseous deformity. In the specimens that were obtained from the children who had acute gangrene, the histological changes included small-vessel thrombi, osteonecrosis, subperiosteal new-bone formation, cortical disruption, cellular disorganization in the physis, and medullary inflammation. These findings were compatible with a combination of inflammation (acute osteomyelitis) and ischemia. In the specimens that were obtained during revision of the amputation, three years or more after the initial infectious or ischemic process, the clinically relevant findings involved the epiphyses and physes. The growth plates showed variable permanent ischemic damage. Bone bridges connecting the epiphysis and metaphysis were observed in various stages of formation, including several early bridges with involvement of only the physis and metaphysis. Endosteal and cortical bone, in contrast, showed complete recovery with no evidence of permanent ischemic damage. We concluded that children who survive meningococcal septicemia are at high risk for complex orthopaedic problems, both acute and chronic. The disseminated intravascular coagulation and focal infections of the acute phase are primarily responsible for the vascular injuries to the growing chondro-osseous tissues. Ischemic changes also selectively involve the physeal circulation, but may take several years to adversely affect longitudinal and transverse growth of bone.

Orthopaedic management of lumbosacral agenesis. Long-term follow-up.

Twenty-two patients with lumbosacral agenesis were treated at the Shriners Hospital for Crippled Children, Chicago Unit, from 1953 to 1979. At the time of this study, ten of the patients were skeletally mature after an average follow-up of 24.1 years. Two patients had died, twelve could be examined, and eight who were unable to return for examination responded to a questionnaire. Eleven of the patients had diabetic mothers. Of the orthopaedic problems in these patients, knee-flexion contractures with popliteal webbing were the most difficult to correct. These deformities varied in severity with the level of the agenesis and the resulting loss of motor power. Other problems were dislocations and flexions contractures of the hips, scoliosis, equinovarus deformities of the foot, and instability at the spinal-pelvic junction. When there was inadequate quadriceps function it was difficult to correct knee-flexion contractures and to prevent them from recurring. For severe knee deformity, knee disarticulation and prosthetic fitting were the most effective treatment. Spinal-pelvic instability was not a problem in eighteen of the twenty surviving patients. Unreduced dislocated hips also did not cause any problems.

Congenital longitudinal deficiency of the tibia.

Fifty-seven patients (seventy-one limbs) who had congenital longitudinal deficiency of the tibia (tibial hemimelia) were retrospectively categorized according to radiographic type (Types 1 through 4, as described by Jones et al.). At an average follow-up of nine years, fifty-six of fifty-seven patients walked independently. An ablative surgical procedure was performed on sixty-one of the seventy-one lower extremities. According to the classification of Jones et al., fifty-four limbs had a Type-1 (a or b) or Type-2 deficiency. In twenty-two of these extremities, disarticulation of the knee was performed; in twenty-five, a Syme amputation; and in one, a Chopart amputation. The ipsilateral foot was retained in six extremities that had a severe Type-1 or Type-2 deficiency. Medial transfer of the fibula (the Brown procedure) generally yielded less than satisfactory results; in ten of fourteen extremities, one or more additional operations were needed. Seventeen extremities were classified as having a Type-3 or Type-4 deficiency; Syme amputation was done in nine and Chopart amputation, in four. Despite satisfactory reconstruction of the ankle, a Syme amputation was necessary in most extremities that had a Type-4 deficiency because a major leg-length discrepancy was projected. In four limbs that had a Type-3 or Type-4 deficiency, the foot was retained.

Dysplasia of the knee associated with the syndrome of thrombocytopenia and absent radius.

We studied the cases of twenty-one patients with the syndrome of thrombocytopenia and absent radius. Patients with this syndrome usually have associated intra-articular dysplasia of the knee joint bilaterally, causing genu varum and a flexion and torsional deformity that become manifest in the first or second year of life. Usually there is progression of the deformities during growth and therefore treatment with braces or operations, or both, will frequently be needed. Despite correctional osteotomy, the varus angulation and internal tibial rotation have a natural tendency to recur, possibly because of the intra-articular deformity that involves the femoral and tibial condyles. After skeletal maturity has been reached, minimum progression of the deformity has been observed.

The malignant potential of enchondromatosis.

In a tri-institutional, retrospective study with long-term follow-up, forty-four patients who had multiple enchondromas were identified. Thirty-seven patients did not have hemangiomas (Ollier disease) and seven did (Maffucci syndrome). Of the thirty-seven patients who had Ollier disease, a low-grade chondrosarcoma developed in four; an astrocytoma, in one; and a granulosa-cell ovarian tumor, in one. In four of the seven patients who had Maffucci syndrome, there were six low-grade chondrosarcomas, one high-grade osteosarcoma, one pancreatic adenocarcinoma, one biliary adenocarcinoma, and one astrocytoma. None of the patients in either group died of the skeletal sarcoma, but four of five patients who had a non-skeletal malignant lesion died. From life-table analyses of these patients, we estimated that the incidence of secondary chondrosarcoma in patients who have Ollier disease is about 25 per cent at the age of forty years, and that malignant degeneration is almost a certainty in patients who have Maffucci syndrome. We concluded that periodic surveillance of the brain and abdomen for occult malignant lesions is indicated in patients who have enchondromatosis.

Comparison of segmental spinal instrumentation devices in the correction of scoliosis.

Harrington distraction rods with either sublaminar wires or convexity compression rods and transverse loading wires were used to treat idiopathic scoliotic patients. Laboratory measurement of transverse forces and orthographic projection of the apical vertebra enabled calculation of x- and y- plane forces in addition to torque. The construct utilizing sublaminar wires generated more favorable corrective vectors. Both devices tended to further rotate the scoliotic spine. Use of the compression apparatus should be limited to spines where reduction of kyphosis is desirable.

Sacral ribs. A case report.

Supernumerary ribs are a rare anatomic curiosity usually discovered as an incidental finding on routine radiographs. The occurrence of sacrococcygeal ribs are extremely rare. Sacral ribs develop as a consequence of the failure of the rib anlage to fuse with the vertebral centers. The present case is unique from previous reports because of the associated scoliosis and hypoplasia of the ipsilateral gluteal musculature and foramina within the accessory rib.

Assessment of the accuracy of three techniques to predict leg length discrepancy.

Three techniques to predict leg length discrepancy were applied to a series of 50 patients with leg length inequality. The methods of Green and Anderson, the Moseley Chart, and a program written by the authors, designed to be run on a relatively inexpensive programmable calculator, were used.The data processed on the calculator produced slightly more accurate results than the Moseley Chart, though not statistically significant. The Green and Anderson technique resulted in the largest errors.

Sta-Peg arthroereisis for treatment of the planovalgus foot in cerebral palsy.

The Sta-Peg procedure is most effective in the non-rigid foot in which reasonable muscle balance can be attained. Where such balance cannot be attained or where rigid deformity exists, this procedure will not solve the problem and should not be used. The authors want to emphasize that this study pertains to the use of Sta-Peg in the valgus foot caused by cerebral palsy. The procedure is rarely needed in the flexible flatfoot of a normal child.