496
Journal of the Royal Society of Medicine Volume 85 August 1992
The therapeutic options are limited, and there is little experience of bone marrow transplantations in infants with myelodysplasia, but one study has reported cure in around 50%8. Another option is the use of intensive chemotherapy similar to that given for AML6. However, this produces prolonged periods of marrow hypoplasia, and although there was complete remission in 70% of patients in adult studies, most long-term remissions were obtained after subsequent bone marrow transplantation7. Maturational agents such as low dose cytarabine, retinoids and vitamin D3 have been studied, but found to be ineffective5. There has been some temporary improvement with the use of the cytokines granulocyte and granulocytemacrophage colony stimulating factors. However, there is concern that these might accelerate the progression to AML5. The remaining option is conservative treatment until there is evidence of progression to AML. In the absence of an HLA matched sibling donor and with a diagnosis of one of the milder forms of myelodysplasia we adopted this approach, and have seen slow but definite improvement in the number and maturity of all cells lines. There do not appear to be reports of apparent improvement in the haematological parameters as seen in this case, and though reversion to a completely normal state has not yet been achieved there has been improvement in all haematopoietic cell lines. This case illustrates a rare and serious condition which generally progresses to AML in which there is an apparent haematological improvement over a 3-year period with conservative treatment.
Acknowledgment We thank Mr N B Westwood for performing the cell cultures.
Tendon contractures in hypercholesterolaemia
of ischaemic heart disease, a Z-lengthening procedure was performed to the tendon. Following this, the patient again became mobile in callipers.
J F Nolan FRCS Department of Orthopaedics, St Bartholomew's Hospital; London Keywords: tendo achilles; hypercholesterolaemia
Achilles tendinitis is a well recognized complication of type IIa hypercholesterolaemia. Tendon contractures, however, are previously unreported. Case report In 1968, a 29-year-old Caucasian woman first presented with tendo-achilles pain, swelling and tenderness. She was treated by immobilization in plaster. In 1974, a diagnosis of tenosynovitis of the tendo-achilles led to treatment with anti-inflammatory medication, steroid injections, and stretching under anaesthesia. In 1982, stripping of the tendo-achilles was performed, when xanthoma-like nodules were found in the tendon. Histology, however, demonstrated non-specific degeneration only, with cleft-like spaces. Further surgery and stretches were performed for a fixed equino-varus deformity, confirmed under anaesthesia, despite which the patient became wheelchair-bound. In 1989, following the diagnosis of type Ha hypercholesterolaemia and exposure of a strong family history Correspondence to: Mr J F Nolan, Orthopaedic Department, Princess Alexandra Hospital, Hamatel Road, Harlow, Essex CM20 1QX
References 1 Tefferi A, Thibodeau SN, Solberg LA Jr. Clonal studies in the myelodysplastic syndrome using X-linked restriction fragment length polymorphisms. Blood 1990;75:1770-3 2 Bennett JM, Catovsky D, Daniel MT, et al Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 1982;51:189-99 3 Weber RFA, Geraedts JPM, et al The preleukaemia syndrome. I. Clinical and haematological findings. Acta Med Scand 1980;207:391-5 4 Joseph AS, Cinkotai KL. Natural history of smouldering leukaemia. Br J Cancer 1982;46:160-6 5 Chessels JM. Myelodysplasia. In: Hann IM, Gibson BES, eds. Bailliere's Clinical Haematology. London: Bailliere Tindall, 1991: 459-82 6 Cheson BD. The myelodysplastic syndromes: current approaches to therapy. Ann Intern Med 1990;112:932-41 7 De Witte T, Zwaan F, Hermans J, et aL Allogeneic bone marrow transplantation for secondary leukaemia and myelodysplastic syndrome: a survey by the Leukaemia Working Party of the European Bone Marrow Transplantation Group. Br J Haematol 1990;74:151-55 8 Guinan EC, Tantravahi R, Weinstein HJ. Bone marrow transplantation for children with myelodysplasia. Blood 1989;73: 619-22
(Accepted 5 February 1992)
Discussion Classical xanthomata of the tendo-achilles are of cosmetic concern only, although type Ha hypercholesterolaemia may present with tendinitis or arthritis1'3. Pain is then exacerbated by tension in the tendon, which exhibits a tender swelling, sometimes nodular, and warmth'. The tendon collagen is infiltrated by xanthoma, which may involve adjacent soft tissues and skin, increasing the tendon thickness by two or three times. This is significantly greater than occurs in secondary hypercholesterolaemia and differentiates these disorders4. Bilateral involvement occurs in 90% of patients, 66% also suffering from deposits in the extensor tendons ofthe hands, and 26% with patellar tendon disease5. The number and size of the lesions show some correlation with the cholesterol level and the increasing age of the individual6. Microscopically, xanthoma may be seen, with degenerative connective tissue. Inflammation is caused by cholesterol crystal deposition, which is responsible for clefts seen ifthe lipid is dissolved out during specimen preparation7. Tendo-achilles xanthomata usually present in young adulthood; occurrence under the age of 10 years being indicative of a homozygous patient8. These patients have exceptionally high cholesterol levels, and coronary artery atherosclerosis is severe. Survival beyond 30 years is rare6. Type Ha familial hypercholesterolaemia is acquired as an autosomal dominant trait, and affects approximately 0.2% of the population. It is characterized by a discrete rise in the beta-lipoproteins, with a marked elevation of cholesterol, and little or no rise in triglycerides. Recognition of the disorder at the earliest possible age is highly desirable in order that dietary and drug therapy may begin. This may reduce serum cholesterol levels by 15-25%, and with bezafibrate reducing the size of tendon xanthomas,
Case presented to Clinical Section, 8 November 1991
0141-0768/92
080496-02/$02.00/0 © 1992 The Royal Society of Medicine
Journal of the Royal Society of Medicine Volume 85 August 1992 an objective criterion exists for the efficacy of hypolipidaemic agents7. Simultaneous regression of atheromatous lesions, particularly coronary, is possible6. In the normo-lipidaemic subject, adiposity in the tendoachilles increases with age, and correlates with serum cholesterol. A direct correlation exists between the intensity of lipid deposition in the tendo-achilles and the coronary arteries, though not with the aorta6. Localization of lipid in the tendon has been attributed to ageing, avascularity and wear and tear, and reflects the greater stresses the gastrocnemius experiences compared with the soleus component. Spontaneous rupture at the musculo-tendinous junction corresponds with the area of maximum lipid deposition, although rupture through xanthomatous lesions * is rare9. In mammals other than man, the paucity of moderate or severe lipid insudation matches the rarity of advanced atherosclerosis. In domestic animals, rupture follows trauma or infection, and usually occurs through the body of the muscle9. Xanthomatous lesions can appear on plain X-ray as a sharply defined thickening of the tendo-achilles, with occasional small areas of calcification. Quantifying deposition has been described using a modification of the mammographic technique, echography, xeroradiography, and CT scanning1o-14. a
References 1 Glueck CJ, Levy RI, Fredrickson DS. Acute tendinitis and arthritis. A presenting smptom in type Ha hyperlipoproteinemia. JAMA 1968;206:2895-7 2 Fahey JJ, Stark HH, Donovan WF, Drennan DB. Xanthomaofthe achilles tendon. 7 cases with familial hyperbetalipoproteinemia. J Bone Joint Surg [Am] 1973;55A:1197-211 3 Friedman MS. Xanthoma of the achilles tendon. J Bone Joint Surg 1947;29:760-6
Familial precocious puberty in girls
J J Rangasami DCH MRCP D B Grant MD FRCP Department of Paediatric Endocrinology, Hospital for Sick Children, Great Ormond Street, London WC1N3JH Keywords: puberty; precocious; familial; female
Familial precocious puberty is a rare condition. It has been more commonly reported in boys, but is very unusual in girls. There are few reports of its occurrence in sister's and to our knowledge only five families have been reported in the English literature since 1922. We wish to report the sixth family of two sisters with familial precocious puberty.
Case reports Case 1 was referred for evaluation of early puberty at the age of 6.9 years. Puberty? started at 4 years, with breast development. When first seen her height was 134.2 cm and weight 36.8 kg. She had breast development stage III and pubic hair stage II with vaginal secretion but no menstruation.
Correspondence to: Dr J J Rangasami, Qieen Maryts Hospital for Children, Carshalton, Surrey SM5 4NR
497
4 Mabuchi H, Ito S, Haba T, et aL Discrimination of familial hypercholesterolaemia and secondary hypercholesterolaemia by achilles tendon thickness. Atherosclerosis 1977;28:61-8 5 Gagne C, Moorjani S, Brun D, Toussaint M, Lupien PJ. Heterozygous familial hypercholesterolemia. Atherosclerosis 1979;34:13-24 6. Adams CWM, Bayliss OB, Baker RWR, Abdulla YH, HunterCraig CJ. Lipid deposits in ageing human arteries, tendons and fascia. Atherosclerosis 1974;19:429-40 7 Schumacher HR, Miciaels R. Recurrent tendinitis and achilles tendon nodule with positively birefringent crystals in a patient with hyperlipoproteinemia. J Rheumatol 1989;16:1387-9 8 Mabuchi H, Tatami R, Habu T, et aL Achilles tendon thickness and ischaemic heart disease in familial hypercholesterolemia.
Metabolism 1978;27:1672-9 9 Finlayson R, Woods SJ. Lipid in the achilles tendon. A comparative study. Atherosclerosis 1975;211:371-89 10 Gattereau A, Davignon J, Langelier HP, Levesque H-P. An improved radiological method for the evaluation of achilles
tendon xanthomatosis. Can Med Assoc J 1973;108:39-42 11 Rouffy J, Chanu B, Bakir R, et aL 'Changes in lipid- and lipoprotein levels and achilles tendon diameters and indices in familial hypercholesterolaemic patients vith tendinous xanthomatosis treated by diet and bezafibrate for two years. Curr Mid Res Opin 1988;11:123-31 12 Gerster JC, Hauser H, Fallet GH. Xeroradiographic techniques applied to achilles tendon in inlmatory or metabolic diseases. Ann Rheum Dis 1975;34:479-88 13 Seidl 0, Keller C, Berger H', Wolfram G, Zollner N. Xeroradiographic determination of achilles tendon thickness in familial hypercholesterolemia confirmed by tissue culture. Atherosclerosis 1983;46:163-72 14 Durrington PN, Adamsi JE; Beastall MD. The assessment of 'achilles tendon size in prim hypercholesterolaemia by
computed tomography. Atheroclerosig 1982;4Z:345-58
(Accepted 5 February 1992)
Clinical features and investigations performed at presentation are shown in Table 1. Treatment was started with Cyproterone Acetate. Later a long acting luteinising hormone releasing hormone (LHRH) analogue (buserelin intranasal) was added and the-progression of puberty sJowe;L At 10.5 years she started menstruation. Case 2, the younger sister of Case 1, started puberty at 5.3 years, with breast development. When evaluated at 5.4 years -she. was found to -have acceleration of growth with breast development and oestrogenization of the vulva*,In the next 6-7 mboths there was rapid growth and, progress. into puberty,and at 6 years she had stage m breast development and pubic hair stage fl. Clinical features and investigations performed at presentation are-shown in Table 1. Long acting LHRH analogue, buserelin was started intranasally with no effect. Treatment was changed to subcutaneous goserelin and after two courses, LHRH stimulation test showed excellent suppression ofluteiniaing hormone (UH) butt 1O mofiths later when she was 1.1 years of age' she hiad a single menstrual period. Then long acting depot LHRH analog&C leuprorelin acetatb a-d this resulted in good was started mi place ofsg6sere1itid suppression of'LH in' response to'LHRH stimulation. She has remained"at breast'sfage m and-pubic-hair sAage-II ;with moderate vulval oestrogenisation and -no further
Case presented to Section of Paediatrics, 22 November 1991
menstruation. Discussiwn True precocious puberty is a relatively uncommon condition. Approximate esmates are, four girls each year and one boy every other -year in a population of 4.5. million1. Female to -male ratio is between 4: 1 and 8: 1V. Th1 incidenteeof true
0141-078/2 080497-02/$02.00JO © 1992 The Royal Society of Medicine
Journal of the Royal Society of Medicine Volume 85 August 1992
The therapeutic options are limited, and there is little experience of bone marrow transplantations in infants with myelodysplasia, but one study has reported cure in around 50%8. Another option is the use of intensive chemotherapy similar to that given for AML6. However, this produces prolonged periods of marrow hypoplasia, and although there was complete remission in 70% of patients in adult studies, most long-term remissions were obtained after subsequent bone marrow transplantation7. Maturational agents such as low dose cytarabine, retinoids and vitamin D3 have been studied, but found to be ineffective5. There has been some temporary improvement with the use of the cytokines granulocyte and granulocytemacrophage colony stimulating factors. However, there is concern that these might accelerate the progression to AML5. The remaining option is conservative treatment until there is evidence of progression to AML. In the absence of an HLA matched sibling donor and with a diagnosis of one of the milder forms of myelodysplasia we adopted this approach, and have seen slow but definite improvement in the number and maturity of all cells lines. There do not appear to be reports of apparent improvement in the haematological parameters as seen in this case, and though reversion to a completely normal state has not yet been achieved there has been improvement in all haematopoietic cell lines. This case illustrates a rare and serious condition which generally progresses to AML in which there is an apparent haematological improvement over a 3-year period with conservative treatment.
Acknowledgment We thank Mr N B Westwood for performing the cell cultures.
Tendon contractures in hypercholesterolaemia
of ischaemic heart disease, a Z-lengthening procedure was performed to the tendon. Following this, the patient again became mobile in callipers.
J F Nolan FRCS Department of Orthopaedics, St Bartholomew's Hospital; London Keywords: tendo achilles; hypercholesterolaemia
Achilles tendinitis is a well recognized complication of type IIa hypercholesterolaemia. Tendon contractures, however, are previously unreported. Case report In 1968, a 29-year-old Caucasian woman first presented with tendo-achilles pain, swelling and tenderness. She was treated by immobilization in plaster. In 1974, a diagnosis of tenosynovitis of the tendo-achilles led to treatment with anti-inflammatory medication, steroid injections, and stretching under anaesthesia. In 1982, stripping of the tendo-achilles was performed, when xanthoma-like nodules were found in the tendon. Histology, however, demonstrated non-specific degeneration only, with cleft-like spaces. Further surgery and stretches were performed for a fixed equino-varus deformity, confirmed under anaesthesia, despite which the patient became wheelchair-bound. In 1989, following the diagnosis of type Ha hypercholesterolaemia and exposure of a strong family history Correspondence to: Mr J F Nolan, Orthopaedic Department, Princess Alexandra Hospital, Hamatel Road, Harlow, Essex CM20 1QX
References 1 Tefferi A, Thibodeau SN, Solberg LA Jr. Clonal studies in the myelodysplastic syndrome using X-linked restriction fragment length polymorphisms. Blood 1990;75:1770-3 2 Bennett JM, Catovsky D, Daniel MT, et al Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 1982;51:189-99 3 Weber RFA, Geraedts JPM, et al The preleukaemia syndrome. I. Clinical and haematological findings. Acta Med Scand 1980;207:391-5 4 Joseph AS, Cinkotai KL. Natural history of smouldering leukaemia. Br J Cancer 1982;46:160-6 5 Chessels JM. Myelodysplasia. In: Hann IM, Gibson BES, eds. Bailliere's Clinical Haematology. London: Bailliere Tindall, 1991: 459-82 6 Cheson BD. The myelodysplastic syndromes: current approaches to therapy. Ann Intern Med 1990;112:932-41 7 De Witte T, Zwaan F, Hermans J, et aL Allogeneic bone marrow transplantation for secondary leukaemia and myelodysplastic syndrome: a survey by the Leukaemia Working Party of the European Bone Marrow Transplantation Group. Br J Haematol 1990;74:151-55 8 Guinan EC, Tantravahi R, Weinstein HJ. Bone marrow transplantation for children with myelodysplasia. Blood 1989;73: 619-22
(Accepted 5 February 1992)
Discussion Classical xanthomata of the tendo-achilles are of cosmetic concern only, although type Ha hypercholesterolaemia may present with tendinitis or arthritis1'3. Pain is then exacerbated by tension in the tendon, which exhibits a tender swelling, sometimes nodular, and warmth'. The tendon collagen is infiltrated by xanthoma, which may involve adjacent soft tissues and skin, increasing the tendon thickness by two or three times. This is significantly greater than occurs in secondary hypercholesterolaemia and differentiates these disorders4. Bilateral involvement occurs in 90% of patients, 66% also suffering from deposits in the extensor tendons ofthe hands, and 26% with patellar tendon disease5. The number and size of the lesions show some correlation with the cholesterol level and the increasing age of the individual6. Microscopically, xanthoma may be seen, with degenerative connective tissue. Inflammation is caused by cholesterol crystal deposition, which is responsible for clefts seen ifthe lipid is dissolved out during specimen preparation7. Tendo-achilles xanthomata usually present in young adulthood; occurrence under the age of 10 years being indicative of a homozygous patient8. These patients have exceptionally high cholesterol levels, and coronary artery atherosclerosis is severe. Survival beyond 30 years is rare6. Type Ha familial hypercholesterolaemia is acquired as an autosomal dominant trait, and affects approximately 0.2% of the population. It is characterized by a discrete rise in the beta-lipoproteins, with a marked elevation of cholesterol, and little or no rise in triglycerides. Recognition of the disorder at the earliest possible age is highly desirable in order that dietary and drug therapy may begin. This may reduce serum cholesterol levels by 15-25%, and with bezafibrate reducing the size of tendon xanthomas,
Case presented to Clinical Section, 8 November 1991
0141-0768/92
080496-02/$02.00/0 © 1992 The Royal Society of Medicine
Journal of the Royal Society of Medicine Volume 85 August 1992 an objective criterion exists for the efficacy of hypolipidaemic agents7. Simultaneous regression of atheromatous lesions, particularly coronary, is possible6. In the normo-lipidaemic subject, adiposity in the tendoachilles increases with age, and correlates with serum cholesterol. A direct correlation exists between the intensity of lipid deposition in the tendo-achilles and the coronary arteries, though not with the aorta6. Localization of lipid in the tendon has been attributed to ageing, avascularity and wear and tear, and reflects the greater stresses the gastrocnemius experiences compared with the soleus component. Spontaneous rupture at the musculo-tendinous junction corresponds with the area of maximum lipid deposition, although rupture through xanthomatous lesions * is rare9. In mammals other than man, the paucity of moderate or severe lipid insudation matches the rarity of advanced atherosclerosis. In domestic animals, rupture follows trauma or infection, and usually occurs through the body of the muscle9. Xanthomatous lesions can appear on plain X-ray as a sharply defined thickening of the tendo-achilles, with occasional small areas of calcification. Quantifying deposition has been described using a modification of the mammographic technique, echography, xeroradiography, and CT scanning1o-14. a
References 1 Glueck CJ, Levy RI, Fredrickson DS. Acute tendinitis and arthritis. A presenting smptom in type Ha hyperlipoproteinemia. JAMA 1968;206:2895-7 2 Fahey JJ, Stark HH, Donovan WF, Drennan DB. Xanthomaofthe achilles tendon. 7 cases with familial hyperbetalipoproteinemia. J Bone Joint Surg [Am] 1973;55A:1197-211 3 Friedman MS. Xanthoma of the achilles tendon. J Bone Joint Surg 1947;29:760-6
Familial precocious puberty in girls
J J Rangasami DCH MRCP D B Grant MD FRCP Department of Paediatric Endocrinology, Hospital for Sick Children, Great Ormond Street, London WC1N3JH Keywords: puberty; precocious; familial; female
Familial precocious puberty is a rare condition. It has been more commonly reported in boys, but is very unusual in girls. There are few reports of its occurrence in sister's and to our knowledge only five families have been reported in the English literature since 1922. We wish to report the sixth family of two sisters with familial precocious puberty.
Case reports Case 1 was referred for evaluation of early puberty at the age of 6.9 years. Puberty? started at 4 years, with breast development. When first seen her height was 134.2 cm and weight 36.8 kg. She had breast development stage III and pubic hair stage II with vaginal secretion but no menstruation.
Correspondence to: Dr J J Rangasami, Qieen Maryts Hospital for Children, Carshalton, Surrey SM5 4NR
497
4 Mabuchi H, Ito S, Haba T, et aL Discrimination of familial hypercholesterolaemia and secondary hypercholesterolaemia by achilles tendon thickness. Atherosclerosis 1977;28:61-8 5 Gagne C, Moorjani S, Brun D, Toussaint M, Lupien PJ. Heterozygous familial hypercholesterolemia. Atherosclerosis 1979;34:13-24 6. Adams CWM, Bayliss OB, Baker RWR, Abdulla YH, HunterCraig CJ. Lipid deposits in ageing human arteries, tendons and fascia. Atherosclerosis 1974;19:429-40 7 Schumacher HR, Miciaels R. Recurrent tendinitis and achilles tendon nodule with positively birefringent crystals in a patient with hyperlipoproteinemia. J Rheumatol 1989;16:1387-9 8 Mabuchi H, Tatami R, Habu T, et aL Achilles tendon thickness and ischaemic heart disease in familial hypercholesterolemia.
Metabolism 1978;27:1672-9 9 Finlayson R, Woods SJ. Lipid in the achilles tendon. A comparative study. Atherosclerosis 1975;211:371-89 10 Gattereau A, Davignon J, Langelier HP, Levesque H-P. An improved radiological method for the evaluation of achilles
tendon xanthomatosis. Can Med Assoc J 1973;108:39-42 11 Rouffy J, Chanu B, Bakir R, et aL 'Changes in lipid- and lipoprotein levels and achilles tendon diameters and indices in familial hypercholesterolaemic patients vith tendinous xanthomatosis treated by diet and bezafibrate for two years. Curr Mid Res Opin 1988;11:123-31 12 Gerster JC, Hauser H, Fallet GH. Xeroradiographic techniques applied to achilles tendon in inlmatory or metabolic diseases. Ann Rheum Dis 1975;34:479-88 13 Seidl 0, Keller C, Berger H', Wolfram G, Zollner N. Xeroradiographic determination of achilles tendon thickness in familial hypercholesterolemia confirmed by tissue culture. Atherosclerosis 1983;46:163-72 14 Durrington PN, Adamsi JE; Beastall MD. The assessment of 'achilles tendon size in prim hypercholesterolaemia by
computed tomography. Atheroclerosig 1982;4Z:345-58
(Accepted 5 February 1992)
Clinical features and investigations performed at presentation are shown in Table 1. Treatment was started with Cyproterone Acetate. Later a long acting luteinising hormone releasing hormone (LHRH) analogue (buserelin intranasal) was added and the-progression of puberty sJowe;L At 10.5 years she started menstruation. Case 2, the younger sister of Case 1, started puberty at 5.3 years, with breast development. When evaluated at 5.4 years -she. was found to -have acceleration of growth with breast development and oestrogenization of the vulva*,In the next 6-7 mboths there was rapid growth and, progress. into puberty,and at 6 years she had stage m breast development and pubic hair stage fl. Clinical features and investigations performed at presentation are-shown in Table 1. Long acting LHRH analogue, buserelin was started intranasally with no effect. Treatment was changed to subcutaneous goserelin and after two courses, LHRH stimulation test showed excellent suppression ofluteiniaing hormone (UH) butt 1O mofiths later when she was 1.1 years of age' she hiad a single menstrual period. Then long acting depot LHRH analog&C leuprorelin acetatb a-d this resulted in good was started mi place ofsg6sere1itid suppression of'LH in' response to'LHRH stimulation. She has remained"at breast'sfage m and-pubic-hair sAage-II ;with moderate vulval oestrogenisation and -no further
Case presented to Section of Paediatrics, 22 November 1991
menstruation. Discussiwn True precocious puberty is a relatively uncommon condition. Approximate esmates are, four girls each year and one boy every other -year in a population of 4.5. million1. Female to -male ratio is between 4: 1 and 8: 1V. Th1 incidenteeof true
0141-078/2 080497-02/$02.00JO © 1992 The Royal Society of Medicine
