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Primary amenorrhoea and xanthomatosis
CASE REPORT
Case report
Primary amenorrhoea and xanthomatosis
A S Kashyap, K P Anand An 18-year-old woman with primary amenorrhoea was referred to us for investigation of hypercholesterolaemia in October, 2002. She had no complaints of constipation, or cold intolerance, and no family history of autoimmune diseases, hyperlipidaemia, or premature coronary artery disease. On examination, she had dry skin, short stature, delayed sexual maturation, thickened achilles tendons, and xanthomas on palms, finger creases (figure), elbows, and toes. She was 135 cm tall, while a 13-year-old sister was 160 cm and the average of her parents’ height was 158·5 cm. We did radiographs, and determined that she had a bone age of 13 years. Fasting cholesterol was high; 11 mmol/L (normal 4·3–5·2), as were triglycerides; 5·4 mmol/L (<1·8 mmol/L), and the VLDL cholesterol/ triglyceride ratio; >0·3 (0·2). Plasma lipoprotein electrophoresis showed type III hyperliproteinaemia, so we looked for an underlying condition. Thyrotropin was high, 48 mU/L (0·4–5·0 mU/L), thyroxine 51 nmol/L (64–154 nmol/L), tri-iodothyronine 0·5 nmol/L (1·1–2·9), and oestradiol were low 100 pmol/L (110–180 early follicular), while luteinising hormone, follicle stimulating hormone, prolactin, and glucose concentrations were normal. A fine needle aspiration of the thyroid showed Hashimoto’s thyroiditis, and anti-thyroid peroxidase antibodies were present at a titre of 20 IU/ml (<2·0). Plasma isoelectric focusing for apo-E2 homozygosity and apo-E genotyping showed an E2/E2 phenotype and genotype, respectively. We examined her immediate family members, but they were healthy, with normal lipid profiles. Her parents had an ApoE2/E3 genotype, and her sister was homozygous for ApoE3. We gave the patient L-thyroxine and oral oestrogen for 6 months. Her lipid profile improved, and menstruation started spontaneously after the 6-month course of oestrogens was finished. She had attained sexual maturation and gained 11 cm in height when last seen in July, 2003. Our patient had primary amenorrhoea, skeletal, and sexual immaturity, caused by hypothalamic-pituitary dysfunction due to primary hypothyroidism.1,2 Juvenile hypothyroidism may cause isosexual pseudoprecocity, galactorrhoea, menorrhagia, short stature, poor scholastic performance, macroorchidism, and hypertrophic myopathy. Type III hyperlipoproteinaemia has a prevalence of 0·01–0·4%. Although 1% of the population is homozygous for ApoE2, most homozygous individuals have normal lipid profiles, until compensatory mechanisms are compromised
Multiple xanthoma on palmar surfaces
by a second defect in lipid metabolism caused by conditions such as hypothyroidism, obesity, diabetes, or alcoholism.1 Inheritance is autosomal recessive, and peripheral vascular disease is a common feature. Pathognomonic xanthoma planum occurs in 50% of patients,3 while xanthoma tuberosum is non-specific. The increased concentrations of lipoproteins are mostly due to remnants such as -VLDL. Increased triglycerides and cholesterol contribute to the lipid fraction. Low oestrogen concentrations slow clearance of lipoprotein remnants. Virtually all women with type III hyperlipoproteinaemia are post-menopausal, and the lipid profile returns to normal with therapeutic oestrogen.3,5 Hypothyroidism also impairs clearance of lipoprotein remnants and modulates the phenotype of type III hyperlipoproteinaemia, which responds to L-thyroxine.1,4 LDL cholesterol increases in clinical and subclinical hypothyroidism and causes hypercholesterolaemia. Hypertriglyceridaemia occurs if obesity co-exists. Oestrogen is vital for bone maturation and proportions, but not for linear growth. Thyroid hormone is necessary for bone growth because of the indirect effect of stimulating GH release. Thyroid hormone replacement reversed the severe lipid abnormalities, growth retardation, and pubertal delay in this young woman. References 1
2
3
Lancet 2004; 363: 616 Department of Medicine (A S Kashyap MD, Prof K P Anand MD), Armed Forces Medical College, Pune 411 040, India
4
Correspondence to: Dr A S Kashyap (e-mail: [email protected])
5
616
Krsek M, Ceska A, Horinek A, et al. Type III hyperlipoproteinaemia and primary amenorrhoea associated with severe hypothyroidism. Acta Paediatr 2000; 89: 1023–24. Jameson JL, Weetman AP. Disorders of the thyroid gland. In: Braunwald E, Fauci AS, Kasper DL, et al, eds. Harrison's principles of internal medicine.15th edn. Vol 2 New York-McGraw-Hill. 2001: 2060–84. Mahley RW, Rall SC Jr. Type III hyperlipoproteinaemia (familial dysbetalipoproteinaemia) In: Wass JAH, Shalet SM, eds. Oxford textbook of endocrinology and diabetes. New York: Oxford University Press. 2002: 1555–61. Stone NJ. Secondary causes of hyperlipidemia. Med Clin North Am 1994; 78: 117–141. Davignon J, Genest J Jr. Genetics of lipoprotein disorders. Endocrinol Metab Clin North Am 1998; 27: 521–50.
THE LANCET • Vol 363 • February 21, 2004 • www.thelancet.com
Case report
Primary amenorrhoea and xanthomatosis
A S Kashyap, K P Anand An 18-year-old woman with primary amenorrhoea was referred to us for investigation of hypercholesterolaemia in October, 2002. She had no complaints of constipation, or cold intolerance, and no family history of autoimmune diseases, hyperlipidaemia, or premature coronary artery disease. On examination, she had dry skin, short stature, delayed sexual maturation, thickened achilles tendons, and xanthomas on palms, finger creases (figure), elbows, and toes. She was 135 cm tall, while a 13-year-old sister was 160 cm and the average of her parents’ height was 158·5 cm. We did radiographs, and determined that she had a bone age of 13 years. Fasting cholesterol was high; 11 mmol/L (normal 4·3–5·2), as were triglycerides; 5·4 mmol/L (<1·8 mmol/L), and the VLDL cholesterol/ triglyceride ratio; >0·3 (0·2). Plasma lipoprotein electrophoresis showed type III hyperliproteinaemia, so we looked for an underlying condition. Thyrotropin was high, 48 mU/L (0·4–5·0 mU/L), thyroxine 51 nmol/L (64–154 nmol/L), tri-iodothyronine 0·5 nmol/L (1·1–2·9), and oestradiol were low 100 pmol/L (110–180 early follicular), while luteinising hormone, follicle stimulating hormone, prolactin, and glucose concentrations were normal. A fine needle aspiration of the thyroid showed Hashimoto’s thyroiditis, and anti-thyroid peroxidase antibodies were present at a titre of 20 IU/ml (<2·0). Plasma isoelectric focusing for apo-E2 homozygosity and apo-E genotyping showed an E2/E2 phenotype and genotype, respectively. We examined her immediate family members, but they were healthy, with normal lipid profiles. Her parents had an ApoE2/E3 genotype, and her sister was homozygous for ApoE3. We gave the patient L-thyroxine and oral oestrogen for 6 months. Her lipid profile improved, and menstruation started spontaneously after the 6-month course of oestrogens was finished. She had attained sexual maturation and gained 11 cm in height when last seen in July, 2003. Our patient had primary amenorrhoea, skeletal, and sexual immaturity, caused by hypothalamic-pituitary dysfunction due to primary hypothyroidism.1,2 Juvenile hypothyroidism may cause isosexual pseudoprecocity, galactorrhoea, menorrhagia, short stature, poor scholastic performance, macroorchidism, and hypertrophic myopathy. Type III hyperlipoproteinaemia has a prevalence of 0·01–0·4%. Although 1% of the population is homozygous for ApoE2, most homozygous individuals have normal lipid profiles, until compensatory mechanisms are compromised
Multiple xanthoma on palmar surfaces
by a second defect in lipid metabolism caused by conditions such as hypothyroidism, obesity, diabetes, or alcoholism.1 Inheritance is autosomal recessive, and peripheral vascular disease is a common feature. Pathognomonic xanthoma planum occurs in 50% of patients,3 while xanthoma tuberosum is non-specific. The increased concentrations of lipoproteins are mostly due to remnants such as -VLDL. Increased triglycerides and cholesterol contribute to the lipid fraction. Low oestrogen concentrations slow clearance of lipoprotein remnants. Virtually all women with type III hyperlipoproteinaemia are post-menopausal, and the lipid profile returns to normal with therapeutic oestrogen.3,5 Hypothyroidism also impairs clearance of lipoprotein remnants and modulates the phenotype of type III hyperlipoproteinaemia, which responds to L-thyroxine.1,4 LDL cholesterol increases in clinical and subclinical hypothyroidism and causes hypercholesterolaemia. Hypertriglyceridaemia occurs if obesity co-exists. Oestrogen is vital for bone maturation and proportions, but not for linear growth. Thyroid hormone is necessary for bone growth because of the indirect effect of stimulating GH release. Thyroid hormone replacement reversed the severe lipid abnormalities, growth retardation, and pubertal delay in this young woman. References 1
2
3
Lancet 2004; 363: 616 Department of Medicine (A S Kashyap MD, Prof K P Anand MD), Armed Forces Medical College, Pune 411 040, India
4
Correspondence to: Dr A S Kashyap (e-mail: [email protected])
5
616
Krsek M, Ceska A, Horinek A, et al. Type III hyperlipoproteinaemia and primary amenorrhoea associated with severe hypothyroidism. Acta Paediatr 2000; 89: 1023–24. Jameson JL, Weetman AP. Disorders of the thyroid gland. In: Braunwald E, Fauci AS, Kasper DL, et al, eds. Harrison's principles of internal medicine.15th edn. Vol 2 New York-McGraw-Hill. 2001: 2060–84. Mahley RW, Rall SC Jr. Type III hyperlipoproteinaemia (familial dysbetalipoproteinaemia) In: Wass JAH, Shalet SM, eds. Oxford textbook of endocrinology and diabetes. New York: Oxford University Press. 2002: 1555–61. Stone NJ. Secondary causes of hyperlipidemia. Med Clin North Am 1994; 78: 117–141. Davignon J, Genest J Jr. Genetics of lipoprotein disorders. Endocrinol Metab Clin North Am 1998; 27: 521–50.
THE LANCET • Vol 363 • February 21, 2004 • www.thelancet.com