- Email: [email protected]
Fetal dystrophin to diagnose carrier status
258
Clustering of features and genetics of von Hippel-Lindau syndrome SiR,-In response to our report (May 4, p 1052) on the clustering of clinical features in von Hippel-Lindau syndrome (HLS), Dr Filling-Katz and Dr Choyke, Dr Maher, and Professor Langenbeck (June 15, pp 1477-79) raise several interesting issues. Maher reports a heterozygote prevalence of 1 in 53 000 for HLS in East Anglia.This figure is in good agreement with our prevalence of 1 in 38 951, indicating that the Freiburg kindreds do not represent an epidemiological cluster of HLS. Apparently, there are occasional families presenting with both renal cell carcinoma and phaeochromocytoma. However, the great majority of recorded HLS kindreds show only one of these manifestations. An especially striking example is reported by Glenn et al.2 They observed an HLS family with 47 affected members, 57% of whom had phaeochromocytomas. Renal and pancreatic lesions were not detectable in any of these patients. In the same study most families presenting with renal and pancreatic features did not exhibit
phaeochromocytomas. Maher points out that
Department of Pathology, University of Zurich Zurich, Switzerland 1. Maher
Germany
HARTMUT P. H. NEUMANN
OTMAR D. WIESTLER
ER, Iselius L, Yates JRW, et al. Von Hippel-Lindau disease: a genetic study.
J Med Genet (m press). GM, Daniel LN, Choyke P, et al. von Hippel-Lindau disease: distinct phenotypes suggest more than one mutant allele at the VHL locus. Hum Genet (in press). 3. Neumann HPH. Basic criteria for clinical diagnosis and genetic counselling in von Hippel-Lindau syndrome. J Vasc Dis 1987; 16: 220-26. 4. Neumann HPH, Eggert HR, Weigel MD, et al. Hemangioblastoma of the central nervous system: a 10-year study with special reference to von Hippel-Lindau syndrome. J Neurosurg 1989; 70: 24-30. 5. Neumann HPH, Dinkel E, Brambs H, et al. Pancreatic lesions in the von Hippel-Lindau syndrome. Gastroenterology (in press) 2. Glenn
Fetal
DMD
family.
Arrow indicates carrier at risk.
renal carcinomas are frequently not detectable before the age of 44 (mean age of diagnosis in his study) and may, therefore, be missed in younger HLS patients. This cannot account for our results, since 12/28 of our patients from kindreds without renal lesions have passed the age of 44. Maher expresses concern that our focus on clustered manifestation of HLS may distract the attention for other features of the syndrome. All patients and potential gene carriers underwent a broad screening examination. 3,4 Filling-Katz and Choyke describe families with additional islet cell tumours and pancreatic adenocarcinoma as yet another example of a cluster of HLS features. However, it remains to be determined if these manifestations, which are most unusual in our HLS patients,s really represent manifestations of the syndrome. Several genetic models could account for the distinct patterns of features in HLS. We agree that, besides a complex genetic locus with several transcriptional units or cooperating genes on different chromosomes, allelic heterogeneity of the HLS gene on chromosome 3p is another potential genetic mechanism. Only a detailed molecular analysis in representative kindreds of the still elusive HLS gene will allow us to identify the genetic basis of these heterogeneous features. Department of Medicine, Albert Ludwig’s University, 7800 Freiburg im Breisgau,
Fig 1-Pedigree of Dutch
recombination distal to the DMD gene betwee H and F. However, the woman seeking advice had inherited an X-chromosome with a
potentially intragenic recombination between the proximal intragenic probe L and the first informative distal probe F. Although she had normal creatine kinase values, her carrier risk was high, possibly 20%. First trimester prenatal diagnosis on chorionic villi of her male pregnancy (III-2) showed the at-risk haplotype and the parents opted for termination. Muscle tissue of the fetus was studied immunohistochemically for dystrophin expression. We used monoclonal antibodies against the 30 kDa segment of dystrophin2 (aminoacids 1181-1388),3a59 kDa segment (aminoacids 17502248),4or the carboxy-terminal 17 aminoacids. All three showed clear staining of dystrophin in parts of the plasma membrane and at the distal ends of the myotubes5 (fig 2), an immunohistochemical pattern indistinguishable from that routinely found in normal fetuses. In affected fetuses, dystrophin cannot be detected with antibodies reactive with the distal part of the protein and sometimes not with
central antibodies either.6 Thus, this fetus was not affected and the recombination event in 11-2 has not included the DMD mutation. Her carrier risk was reduced to the population risk. Bieber et aF demonstrated by negative western blot testing that a 23-week-old DMD at-risk fetus was affected, confirming the DNA diagnosis and raising the mother’s carrier risk to 100%. We show here that even in younger fetuses sensitive dystrophin immunohistology permits genetic counselling. This will be especially valuable in DMD families where no mutation is found and the DNA markers are uninformative or show intragenic recombinations.
dystrophin to diagnose carrier status
SIR,-In a Dutch family with Duchenne muscular dystrophy (DMD) we have excluded carriership for a woman at risk (11-2, fig 1) by immunohistochemical analysis of her 12-week-old fetus after abortion for increased DMD risk. In this family, DNA analysis was uninformative. Two relatives (11-3,11-5) were affected with DMD. cDNA and polymerase chain reaction studies failed to show a mutation in the DMD gene, so the at-risk chromosome had to be identified by haplotype analysis.The informative markers used (H, F, L, C, and T) are identified in fig 1. Two non-carrier daughters were identified; 11-4 had the unaffected haplotype and 11-6 had a
Fig 2-lmmunohistological studies of fetal muscle. Tissue fixed and stained" and sections
were
carboxy-terminal monoclonal antibody.
was
immunostained with
259
This research is partly supported by the Princess Beatrix Fund, the Netherlands Foundation of Medical Research (MEDIGON), and the Muscular Dystrophy Association of America and Great Britain.
Department of Anatomy and Embryology,
IEKE B.
GINJAAR
Academic Medical Centre, Amsterdam
SYLVIA SOFFERS ANTOON F.M. MOORMAN
Neurochemistry Department, Newcastle General Hospital, Newcastle upon Tyne, UK
LOUISE V. B. NICHOLSON
Research Division, NE Wales Institute,
GLENN E. MORRIS
Clwyd
PATIENT CHARACTERISTICS AT TIME OF SEIZURES
*Hypoglycaemia. Department of Human Genetics, Sylvius Laboratory, 2333 AL Leiden, Netherlands
EGBERT BAKKER
ARIE VAN HAERINGEN GERT-JAN B. VAN OMMEN
E, Bonten EJ, Veenema H, et al. Prenatal diagnosis of Duchenne muscular dystrophy: a three year experience in a rapidly evolving field. J Inher Metab Dis 1989; 12 (suppl I): 174-90. 2. Hoffman EP, Brown RH, Kunkel L. Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell 1987; 51: 919-28. 3. Nicholson LVB, Johnson MA, Gardner-Medwin D, Bhattacharya S, Harris JB. Heterogeneity of dystrophin expression in patients with Duchenne and Becker muscular dystrophy. Acta Neuropathol 1990; 80: 239-50. 4. Nguyen thi Man, Ellis JM, Ginjaar IB, et al. Monoclonal evidence for structural similarities between the central rod regions of actinin and dystrophin. FEBS Lett 1. Bakker
1990; 1272: 109-12. 5. Wessels A, Ginjaar IB, Moorman AFM, van Ommen GJB. Different localization of dystrophin in developing and adult human skeletal muscle. Muscle Nerve 1991; 14: 1-7. 6. Ginjaar IB, Bakker E, van Paassen MMB, et al. Immunohistochemical studies show truncated dystrophins in the myotubes of three fetuses at risk for Duchenne muscular dystrophy. J Med Genet (in press). 7. Bieber FR, Hoffman E, Amos JA. Dystrophin analysis in Duchenne Muscular Dystrophy: use in fetal diagnosis and in genetic counseling. Am J Hum Genet 1989; 45: 362-67. 8. Moorman AFM, de Boer PAJ, Linders MTh, Charles R. The histone H5 variant in Xenopus laevis. Cell Diff 1984; 14: 113-12.
alone,8 and furthermore concurrent administration of ciprofloxacin increases serum concentrations of theophylline.9 Because of delays in presentation, concurrent drug concentrations were not available, but our suspicions that drug therapy contributed to seizures were reinforced by the finding of a raised serum theophylline concentration of 20 mg/1 in patient 4, some four days after his seizure and one day after discontinuing ciprofloxacin. Doctors should be alert to the possible adverse effects of theophylline and quinolones used singly or in combination, and we now advocate frequent measurement of theophylline concentrations in CF patients. Department of Respiratory Medicine, St Vincent’s Hospital, Dublin 4, Ireland
MARCELLA S. O’MAHONY MUIRIS X. FITZGERALD
1. Ayres J, Kinsella H. Multiple cerebral abscesses in an adult with cystic fibrosis. Br J Dis Chest 1982; 76: 99-101. 2. Simmonds EJ, Mahony MJ, Littlewood JM. Convulsion and coma after intranasal desmopressin in cystic fibrosis. Br Med J 1988, 297: 1614. 3. Stern RC, Horwitz SJ, Doershuk CF. Neurologic symptoms during coughing paroxysms in cystic fibrosis. J Pediatr 1988; 112: 909-12. 4. McIntosh HD, Estes EH, Warren JV. The mechanism of cough syncope. Am Heart J
1956; 52: 70-82.
Cystic fibrosis and seizures SIR,-Seizures in cystic fibrosis (CF) are very rare, and have occasionally arisen in association with cerebral abscess1 and hyponatraemia. We report a striking cluster of seizures in five adult CF patients, at our unit, within the past fifteen months. The table outlines clinical features, type and frequency of seizures, and concurrent drugs in the five individuals. All were young adults, afebrile, and not known epileptics. Four patients had generalised tonic/clonic seizures followed by post-ictal drowsiness and additionally in two cases by transient limb paresis. Two patients with generalised seizures also had previous separate episodes of focal seizures without loss of consciousness. The fifth patient had focal seizures only. All five patients had normal computed tomographic brain scans and none had epilepsy on electroencephalography. Plasma electrolyte concentrations were also normal. In only one patient was there an obvious cause: patient 2 had insulin-requiring diabetes and was hypoglycaemic before his seizure. The cause of seizures in the other four remained unclear. Possibly some were cough-induced, since in three patients six seizure episodes happened during coughing paroxysms. Although seizures have not previously been reported during coughing in CF, neurological symptoms, including transient paresis of limbs, have been recorded.3 Proposed mechanisms include impaired intracranial circulation,4concussion effects of raised cerebrospinal fluid pressure,s and reduced cardiac output due to raised intrathoracic pressure.6 It is difficult, however, to believe that coughing alone is the causative factor, since up to 15 months ago we had not seen seizures in our CF population. A drug cause is much more probable, especially since the outbreak of seizures coincided with a period of intensified therapy in our practice-ie, with more liberal use of oral theophylline and ciprofloxacin: four patients were taking theophylline, four ciprofloxacin, and three both drugs. Seizures arise in association with theophylline aloneciprofloxacin
5. Kerr A, Eich RH. Cerebral concussion as a cause of cough syncope. Arch Intern Med 1961; 108: 248-52. 6. Sharpey-Schafer EP. The mechanism of syncope after coughing. Br Med J 1953; ii: 860-63. 7. Bukowskyj M, Nakatsu K, Munt PW. Theophylline reassessed. Ann Intern Med 1984; 101: 63-72. 8. Sanders WE Jr. Efficacy safety and potential economic benefits of oral ciprofloxacin in the treatment of infections. Rev Infect Dis 1988; 10: 528-43. 9. Raoof S, Wollschlager C, Khan FA. Ciprofloxacin increases serum levels of theophylline. Am J Med 1987; 82 (suppl 4A): 115-18.
Mobility of tibial tuberosity in Osgood-Schlatter’s disease SiR,—Iwould draw attention to a physical sign of OsgoodSchlatter’s disease (OSD) that might be unknown. In my experience OSD is often accompanied by a clear lateral mobility of the tibial tuberosity. This mobility is best looked for bimanually, with the patient supine, outstretched knees, and relaxed quadriceps muscles. One thumb is used to apply pressure on the tibial tuberosity in the medial or lateral direction. The thumb or the index finger of the other hand is placed on the other side of the tibial tuberosity and in this way the displacement of the tibial tuberosity relative to the tibia itself can be felt. This movement is often painful and ranges from slight to about 0-5 cm in severe cases. Slight lateral mobility is sometimes also found in youngsters without symptoms or signs of OSD. I have noted that colleagues find the idea of a mobile tibial tuberosity difficult to accept. Nevertheless, in an attempt to explain this sign, I would refer to Ogden and Southwick’s report.1 They described "the unique histological structure of the late-developing tuberosity growth plate" as being composed offibrocartilage and fibrous tissue. They felt that "these structural features would be an adaptation to the strong tensile forces exerted in this region". It is conveivable that these fibrous structures allow a slight lateral movement. I can only speculate about the relation between OSD and increased mobility in the epiphysis. The classic loss of function concomitant to the inflammation of OSD (primary OSD) could account for this
Clustering of features and genetics of von Hippel-Lindau syndrome SiR,-In response to our report (May 4, p 1052) on the clustering of clinical features in von Hippel-Lindau syndrome (HLS), Dr Filling-Katz and Dr Choyke, Dr Maher, and Professor Langenbeck (June 15, pp 1477-79) raise several interesting issues. Maher reports a heterozygote prevalence of 1 in 53 000 for HLS in East Anglia.This figure is in good agreement with our prevalence of 1 in 38 951, indicating that the Freiburg kindreds do not represent an epidemiological cluster of HLS. Apparently, there are occasional families presenting with both renal cell carcinoma and phaeochromocytoma. However, the great majority of recorded HLS kindreds show only one of these manifestations. An especially striking example is reported by Glenn et al.2 They observed an HLS family with 47 affected members, 57% of whom had phaeochromocytomas. Renal and pancreatic lesions were not detectable in any of these patients. In the same study most families presenting with renal and pancreatic features did not exhibit
phaeochromocytomas. Maher points out that
Department of Pathology, University of Zurich Zurich, Switzerland 1. Maher
Germany
HARTMUT P. H. NEUMANN
OTMAR D. WIESTLER
ER, Iselius L, Yates JRW, et al. Von Hippel-Lindau disease: a genetic study.
J Med Genet (m press). GM, Daniel LN, Choyke P, et al. von Hippel-Lindau disease: distinct phenotypes suggest more than one mutant allele at the VHL locus. Hum Genet (in press). 3. Neumann HPH. Basic criteria for clinical diagnosis and genetic counselling in von Hippel-Lindau syndrome. J Vasc Dis 1987; 16: 220-26. 4. Neumann HPH, Eggert HR, Weigel MD, et al. Hemangioblastoma of the central nervous system: a 10-year study with special reference to von Hippel-Lindau syndrome. J Neurosurg 1989; 70: 24-30. 5. Neumann HPH, Dinkel E, Brambs H, et al. Pancreatic lesions in the von Hippel-Lindau syndrome. Gastroenterology (in press) 2. Glenn
Fetal
DMD
family.
Arrow indicates carrier at risk.
renal carcinomas are frequently not detectable before the age of 44 (mean age of diagnosis in his study) and may, therefore, be missed in younger HLS patients. This cannot account for our results, since 12/28 of our patients from kindreds without renal lesions have passed the age of 44. Maher expresses concern that our focus on clustered manifestation of HLS may distract the attention for other features of the syndrome. All patients and potential gene carriers underwent a broad screening examination. 3,4 Filling-Katz and Choyke describe families with additional islet cell tumours and pancreatic adenocarcinoma as yet another example of a cluster of HLS features. However, it remains to be determined if these manifestations, which are most unusual in our HLS patients,s really represent manifestations of the syndrome. Several genetic models could account for the distinct patterns of features in HLS. We agree that, besides a complex genetic locus with several transcriptional units or cooperating genes on different chromosomes, allelic heterogeneity of the HLS gene on chromosome 3p is another potential genetic mechanism. Only a detailed molecular analysis in representative kindreds of the still elusive HLS gene will allow us to identify the genetic basis of these heterogeneous features. Department of Medicine, Albert Ludwig’s University, 7800 Freiburg im Breisgau,
Fig 1-Pedigree of Dutch
recombination distal to the DMD gene betwee H and F. However, the woman seeking advice had inherited an X-chromosome with a
potentially intragenic recombination between the proximal intragenic probe L and the first informative distal probe F. Although she had normal creatine kinase values, her carrier risk was high, possibly 20%. First trimester prenatal diagnosis on chorionic villi of her male pregnancy (III-2) showed the at-risk haplotype and the parents opted for termination. Muscle tissue of the fetus was studied immunohistochemically for dystrophin expression. We used monoclonal antibodies against the 30 kDa segment of dystrophin2 (aminoacids 1181-1388),3a59 kDa segment (aminoacids 17502248),4or the carboxy-terminal 17 aminoacids. All three showed clear staining of dystrophin in parts of the plasma membrane and at the distal ends of the myotubes5 (fig 2), an immunohistochemical pattern indistinguishable from that routinely found in normal fetuses. In affected fetuses, dystrophin cannot be detected with antibodies reactive with the distal part of the protein and sometimes not with
central antibodies either.6 Thus, this fetus was not affected and the recombination event in 11-2 has not included the DMD mutation. Her carrier risk was reduced to the population risk. Bieber et aF demonstrated by negative western blot testing that a 23-week-old DMD at-risk fetus was affected, confirming the DNA diagnosis and raising the mother’s carrier risk to 100%. We show here that even in younger fetuses sensitive dystrophin immunohistology permits genetic counselling. This will be especially valuable in DMD families where no mutation is found and the DNA markers are uninformative or show intragenic recombinations.
dystrophin to diagnose carrier status
SIR,-In a Dutch family with Duchenne muscular dystrophy (DMD) we have excluded carriership for a woman at risk (11-2, fig 1) by immunohistochemical analysis of her 12-week-old fetus after abortion for increased DMD risk. In this family, DNA analysis was uninformative. Two relatives (11-3,11-5) were affected with DMD. cDNA and polymerase chain reaction studies failed to show a mutation in the DMD gene, so the at-risk chromosome had to be identified by haplotype analysis.The informative markers used (H, F, L, C, and T) are identified in fig 1. Two non-carrier daughters were identified; 11-4 had the unaffected haplotype and 11-6 had a
Fig 2-lmmunohistological studies of fetal muscle. Tissue fixed and stained" and sections
were
carboxy-terminal monoclonal antibody.
was
immunostained with
259
This research is partly supported by the Princess Beatrix Fund, the Netherlands Foundation of Medical Research (MEDIGON), and the Muscular Dystrophy Association of America and Great Britain.
Department of Anatomy and Embryology,
IEKE B.
GINJAAR
Academic Medical Centre, Amsterdam
SYLVIA SOFFERS ANTOON F.M. MOORMAN
Neurochemistry Department, Newcastle General Hospital, Newcastle upon Tyne, UK
LOUISE V. B. NICHOLSON
Research Division, NE Wales Institute,
GLENN E. MORRIS
Clwyd
PATIENT CHARACTERISTICS AT TIME OF SEIZURES
*Hypoglycaemia. Department of Human Genetics, Sylvius Laboratory, 2333 AL Leiden, Netherlands
EGBERT BAKKER
ARIE VAN HAERINGEN GERT-JAN B. VAN OMMEN
E, Bonten EJ, Veenema H, et al. Prenatal diagnosis of Duchenne muscular dystrophy: a three year experience in a rapidly evolving field. J Inher Metab Dis 1989; 12 (suppl I): 174-90. 2. Hoffman EP, Brown RH, Kunkel L. Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell 1987; 51: 919-28. 3. Nicholson LVB, Johnson MA, Gardner-Medwin D, Bhattacharya S, Harris JB. Heterogeneity of dystrophin expression in patients with Duchenne and Becker muscular dystrophy. Acta Neuropathol 1990; 80: 239-50. 4. Nguyen thi Man, Ellis JM, Ginjaar IB, et al. Monoclonal evidence for structural similarities between the central rod regions of actinin and dystrophin. FEBS Lett 1. Bakker
1990; 1272: 109-12. 5. Wessels A, Ginjaar IB, Moorman AFM, van Ommen GJB. Different localization of dystrophin in developing and adult human skeletal muscle. Muscle Nerve 1991; 14: 1-7. 6. Ginjaar IB, Bakker E, van Paassen MMB, et al. Immunohistochemical studies show truncated dystrophins in the myotubes of three fetuses at risk for Duchenne muscular dystrophy. J Med Genet (in press). 7. Bieber FR, Hoffman E, Amos JA. Dystrophin analysis in Duchenne Muscular Dystrophy: use in fetal diagnosis and in genetic counseling. Am J Hum Genet 1989; 45: 362-67. 8. Moorman AFM, de Boer PAJ, Linders MTh, Charles R. The histone H5 variant in Xenopus laevis. Cell Diff 1984; 14: 113-12.
alone,8 and furthermore concurrent administration of ciprofloxacin increases serum concentrations of theophylline.9 Because of delays in presentation, concurrent drug concentrations were not available, but our suspicions that drug therapy contributed to seizures were reinforced by the finding of a raised serum theophylline concentration of 20 mg/1 in patient 4, some four days after his seizure and one day after discontinuing ciprofloxacin. Doctors should be alert to the possible adverse effects of theophylline and quinolones used singly or in combination, and we now advocate frequent measurement of theophylline concentrations in CF patients. Department of Respiratory Medicine, St Vincent’s Hospital, Dublin 4, Ireland
MARCELLA S. O’MAHONY MUIRIS X. FITZGERALD
1. Ayres J, Kinsella H. Multiple cerebral abscesses in an adult with cystic fibrosis. Br J Dis Chest 1982; 76: 99-101. 2. Simmonds EJ, Mahony MJ, Littlewood JM. Convulsion and coma after intranasal desmopressin in cystic fibrosis. Br Med J 1988, 297: 1614. 3. Stern RC, Horwitz SJ, Doershuk CF. Neurologic symptoms during coughing paroxysms in cystic fibrosis. J Pediatr 1988; 112: 909-12. 4. McIntosh HD, Estes EH, Warren JV. The mechanism of cough syncope. Am Heart J
1956; 52: 70-82.
Cystic fibrosis and seizures SIR,-Seizures in cystic fibrosis (CF) are very rare, and have occasionally arisen in association with cerebral abscess1 and hyponatraemia. We report a striking cluster of seizures in five adult CF patients, at our unit, within the past fifteen months. The table outlines clinical features, type and frequency of seizures, and concurrent drugs in the five individuals. All were young adults, afebrile, and not known epileptics. Four patients had generalised tonic/clonic seizures followed by post-ictal drowsiness and additionally in two cases by transient limb paresis. Two patients with generalised seizures also had previous separate episodes of focal seizures without loss of consciousness. The fifth patient had focal seizures only. All five patients had normal computed tomographic brain scans and none had epilepsy on electroencephalography. Plasma electrolyte concentrations were also normal. In only one patient was there an obvious cause: patient 2 had insulin-requiring diabetes and was hypoglycaemic before his seizure. The cause of seizures in the other four remained unclear. Possibly some were cough-induced, since in three patients six seizure episodes happened during coughing paroxysms. Although seizures have not previously been reported during coughing in CF, neurological symptoms, including transient paresis of limbs, have been recorded.3 Proposed mechanisms include impaired intracranial circulation,4concussion effects of raised cerebrospinal fluid pressure,s and reduced cardiac output due to raised intrathoracic pressure.6 It is difficult, however, to believe that coughing alone is the causative factor, since up to 15 months ago we had not seen seizures in our CF population. A drug cause is much more probable, especially since the outbreak of seizures coincided with a period of intensified therapy in our practice-ie, with more liberal use of oral theophylline and ciprofloxacin: four patients were taking theophylline, four ciprofloxacin, and three both drugs. Seizures arise in association with theophylline aloneciprofloxacin
5. Kerr A, Eich RH. Cerebral concussion as a cause of cough syncope. Arch Intern Med 1961; 108: 248-52. 6. Sharpey-Schafer EP. The mechanism of syncope after coughing. Br Med J 1953; ii: 860-63. 7. Bukowskyj M, Nakatsu K, Munt PW. Theophylline reassessed. Ann Intern Med 1984; 101: 63-72. 8. Sanders WE Jr. Efficacy safety and potential economic benefits of oral ciprofloxacin in the treatment of infections. Rev Infect Dis 1988; 10: 528-43. 9. Raoof S, Wollschlager C, Khan FA. Ciprofloxacin increases serum levels of theophylline. Am J Med 1987; 82 (suppl 4A): 115-18.
Mobility of tibial tuberosity in Osgood-Schlatter’s disease SiR,—Iwould draw attention to a physical sign of OsgoodSchlatter’s disease (OSD) that might be unknown. In my experience OSD is often accompanied by a clear lateral mobility of the tibial tuberosity. This mobility is best looked for bimanually, with the patient supine, outstretched knees, and relaxed quadriceps muscles. One thumb is used to apply pressure on the tibial tuberosity in the medial or lateral direction. The thumb or the index finger of the other hand is placed on the other side of the tibial tuberosity and in this way the displacement of the tibial tuberosity relative to the tibia itself can be felt. This movement is often painful and ranges from slight to about 0-5 cm in severe cases. Slight lateral mobility is sometimes also found in youngsters without symptoms or signs of OSD. I have noted that colleagues find the idea of a mobile tibial tuberosity difficult to accept. Nevertheless, in an attempt to explain this sign, I would refer to Ogden and Southwick’s report.1 They described "the unique histological structure of the late-developing tuberosity growth plate" as being composed offibrocartilage and fibrous tissue. They felt that "these structural features would be an adaptation to the strong tensile forces exerted in this region". It is conveivable that these fibrous structures allow a slight lateral movement. I can only speculate about the relation between OSD and increased mobility in the epiphysis. The classic loss of function concomitant to the inflammation of OSD (primary OSD) could account for this