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REVERSIBLE CUTIS LAXA DUE TO MATERNAL D-PENICILLAMINE TREATMENT
43 was negative. On persistent questioning about possible medications taken before the onset of her illness, she revealed that she had for 3 weeks taken phenylpropanolamine in the appetite suppressant ’Fullstop’. Over this period she had also ingested two or three 325 mg aspirin tablets and 650 mg aceta-
minophen (paracetamol). When the patient was seen at follow-up 2 weeks after discharge, she had a blood-urea-nitrogen of 19 mg/dl, a creatinine of 1.8mg/dl, and normal liver-function studies. 3 months after her illness she was completely well. I agree with Lee et al. that phenylpropanolamine, a drug with little proven therapeutic benefit, should be withdrawn from pharmaceutical preparations in view of the possible adverse effects. Division of Nephrology,
Hemodialysis Unit, and Department of Medicine, Health Sciences Center,
University of Oregon, Portland, Oregon 97201, U.S.A.
WILLIAM M. BENNETT
REVERSIBLE CUTIS LAXA DUE TO MATERNAL D-PENICILLAMINE TREATMENT
SIR, The introduction of D-penicillamine (dimethylcysteine) therapy has improved the chance of successful pregnancy in women with Wilson’s disease. However, penicillamine, by removing copper stores, could inhibit collagen synthesis and maturation thus giving rise to developmental malformations.’ In rats, penicillamine may provoke both a defective collagen synthesis and a corresponding inhibition of wound healing and increased skin fragility.2 An infant with generalised cutis laxa, born to a cystinuric mother who took penicillamine throughout pregnancy has been reported.3 We have seen a similar case, but with a more encouraging outcome. This 24-year-old woman had had two miscarriages in 1976. Wilson’s disease was diagnosed in March, 1977. One of her sisters also had this disorder. Since April, 1977, she was treated with D-penicillamine, 250 mg six times daily. Treatment was uneventful. A 16-week pregnancy was diagnosed in May, 1978. n-penicillamine was continued. The pregnancy was uncomplicated. On Nov. 3, 1978, a boy was delivered at 40 weeks -of gestation by cxsarean section because of acute fetal distress. His general condition seemed normal except for generalised cutis laxa giving a senescent appearance: the baby seemed to have too much skin for his body. Neither hypotonia nor hyperflexibility of joints were evident. He was discharged on day 6. On day 20 he was admitted with a right inguinal hernia. In view of the previous case3 surgical repair was felt to be contraindicated and the hernia was reduced manually under sedation. His general appearance was as in the immediate neonatal period (figure, a). Urine analysis, routine blood tests, chest X-ray, ECG, and EEG were normal. Serum-copper was 112 p.gldl and casruloplasmin 56 mg/dl. X-rays of the gastrointestinal tract showed normal bowel distribution but with hypotonic loops and barium transit. Gross brain arterial involvement was excluded by carotid angiography; only moderate tortuosity in the medium arterial branches was seen. Pyelography was normal. Punch skin biopsy at the age of one month showed some minor decrease of elastic fibres. Wound healing was good. At the age of 2 months the infant looked strikingly different (figure, b), and when last seen, at age 4 months, he was normal in external appearance and in physical and neurological development. In man and in laboratory animals low serum-copper levels may induce generalised elastic-tissue defects, that could 1. Marsh 2. Nimni
L, Fraser FC. Chelating agents and teratogenesis Lancet 1973;ii:846. ME, Bavetta LA. Collagen defect induced by penicillamine. Science, 1965; 150: 905-907.
Skin appearance of
baby born to mother taking penicillamine during pregnancy. (a) 20 days of age: wrinkling and folding of skin gives appearance
ofsenescence. (b) 9 weeks of age: normal skin. account for the changes in the skin, arteries, and other tissues. Thus the fetus of a woman on D-penicillamine treatment might be expected to have periods of low blood copper content which could induce both elastic and collagen tissue anomalies. After birth, our patient had consistently normal copper and caeruloplasmin concentrations, suggesting that postnatally, elastic and connective tissues are formed under normal conditions. This may account for the reversibility of the skin changes observed. The case reported by M)0lner0d et al. ended fatally probably as a consequence of surgical complications and septicaemia. These workers concluded that D-penicillamine should hardly ever be used in pregnancy. Walshe4 reported 14 normal children born to 10 penicillamine-treated mothers with Wilson’s disease. He concluded that pregnancy is not contraindicated in well-treated Wilson’s disease and that penicillamine is not a grave threat to the fetus. Since there is no evidence that the elastic and collagen defect induced by D-penicillamine is by itself lethal, and since clinical reversibility seems possible, we
agree that pregnancy is not contraindicated. Pædiatric, Neurological
A. LINARES
and Dermatological Departments, School of Medicine, Ciudad Sanitaria de la Seguridad Social,
J. J. ZARRANZ J. RODRIGUEZ-ALARCON
Bilbao, Spain
J. L. DIAZ-PEREZ
CHOLESTEROL AND COLON CANCER
SIR,-We thank Professor Oliver (April 28, p. 931), Dr Thornton (May 5, p. 971), and Professor Lewis (May 26, p. 1136) for their interest in our hypothesis (April 7, p. 752). Thornton chides us for not including "all the known facts"-specifically, data relating to dietary fibre, colonic bacteria, and bile salts. This omission was intentional. The cur3. Mjølnerød OK, Rasmussen K, Dommerud SA, Gjeruldsen ST. Congenital connective-tissue defect probably due to D-penicillamine treatment in
pregnancy Lancet 1971; i: 673-675. JM. Pregnancy in Wilson’s disease. Q J
4. Walshe
Med
1977, 46: 73-83.
minophen (paracetamol). When the patient was seen at follow-up 2 weeks after discharge, she had a blood-urea-nitrogen of 19 mg/dl, a creatinine of 1.8mg/dl, and normal liver-function studies. 3 months after her illness she was completely well. I agree with Lee et al. that phenylpropanolamine, a drug with little proven therapeutic benefit, should be withdrawn from pharmaceutical preparations in view of the possible adverse effects. Division of Nephrology,
Hemodialysis Unit, and Department of Medicine, Health Sciences Center,
University of Oregon, Portland, Oregon 97201, U.S.A.
WILLIAM M. BENNETT
REVERSIBLE CUTIS LAXA DUE TO MATERNAL D-PENICILLAMINE TREATMENT
SIR, The introduction of D-penicillamine (dimethylcysteine) therapy has improved the chance of successful pregnancy in women with Wilson’s disease. However, penicillamine, by removing copper stores, could inhibit collagen synthesis and maturation thus giving rise to developmental malformations.’ In rats, penicillamine may provoke both a defective collagen synthesis and a corresponding inhibition of wound healing and increased skin fragility.2 An infant with generalised cutis laxa, born to a cystinuric mother who took penicillamine throughout pregnancy has been reported.3 We have seen a similar case, but with a more encouraging outcome. This 24-year-old woman had had two miscarriages in 1976. Wilson’s disease was diagnosed in March, 1977. One of her sisters also had this disorder. Since April, 1977, she was treated with D-penicillamine, 250 mg six times daily. Treatment was uneventful. A 16-week pregnancy was diagnosed in May, 1978. n-penicillamine was continued. The pregnancy was uncomplicated. On Nov. 3, 1978, a boy was delivered at 40 weeks -of gestation by cxsarean section because of acute fetal distress. His general condition seemed normal except for generalised cutis laxa giving a senescent appearance: the baby seemed to have too much skin for his body. Neither hypotonia nor hyperflexibility of joints were evident. He was discharged on day 6. On day 20 he was admitted with a right inguinal hernia. In view of the previous case3 surgical repair was felt to be contraindicated and the hernia was reduced manually under sedation. His general appearance was as in the immediate neonatal period (figure, a). Urine analysis, routine blood tests, chest X-ray, ECG, and EEG were normal. Serum-copper was 112 p.gldl and casruloplasmin 56 mg/dl. X-rays of the gastrointestinal tract showed normal bowel distribution but with hypotonic loops and barium transit. Gross brain arterial involvement was excluded by carotid angiography; only moderate tortuosity in the medium arterial branches was seen. Pyelography was normal. Punch skin biopsy at the age of one month showed some minor decrease of elastic fibres. Wound healing was good. At the age of 2 months the infant looked strikingly different (figure, b), and when last seen, at age 4 months, he was normal in external appearance and in physical and neurological development. In man and in laboratory animals low serum-copper levels may induce generalised elastic-tissue defects, that could 1. Marsh 2. Nimni
L, Fraser FC. Chelating agents and teratogenesis Lancet 1973;ii:846. ME, Bavetta LA. Collagen defect induced by penicillamine. Science, 1965; 150: 905-907.
Skin appearance of
baby born to mother taking penicillamine during pregnancy. (a) 20 days of age: wrinkling and folding of skin gives appearance
ofsenescence. (b) 9 weeks of age: normal skin. account for the changes in the skin, arteries, and other tissues. Thus the fetus of a woman on D-penicillamine treatment might be expected to have periods of low blood copper content which could induce both elastic and collagen tissue anomalies. After birth, our patient had consistently normal copper and caeruloplasmin concentrations, suggesting that postnatally, elastic and connective tissues are formed under normal conditions. This may account for the reversibility of the skin changes observed. The case reported by M)0lner0d et al. ended fatally probably as a consequence of surgical complications and septicaemia. These workers concluded that D-penicillamine should hardly ever be used in pregnancy. Walshe4 reported 14 normal children born to 10 penicillamine-treated mothers with Wilson’s disease. He concluded that pregnancy is not contraindicated in well-treated Wilson’s disease and that penicillamine is not a grave threat to the fetus. Since there is no evidence that the elastic and collagen defect induced by D-penicillamine is by itself lethal, and since clinical reversibility seems possible, we
agree that pregnancy is not contraindicated. Pædiatric, Neurological
A. LINARES
and Dermatological Departments, School of Medicine, Ciudad Sanitaria de la Seguridad Social,
J. J. ZARRANZ J. RODRIGUEZ-ALARCON
Bilbao, Spain
J. L. DIAZ-PEREZ
CHOLESTEROL AND COLON CANCER
SIR,-We thank Professor Oliver (April 28, p. 931), Dr Thornton (May 5, p. 971), and Professor Lewis (May 26, p. 1136) for their interest in our hypothesis (April 7, p. 752). Thornton chides us for not including "all the known facts"-specifically, data relating to dietary fibre, colonic bacteria, and bile salts. This omission was intentional. The cur3. Mjølnerød OK, Rasmussen K, Dommerud SA, Gjeruldsen ST. Congenital connective-tissue defect probably due to D-penicillamine treatment in
pregnancy Lancet 1971; i: 673-675. JM. Pregnancy in Wilson’s disease. Q J
4. Walshe
Med
1977, 46: 73-83.