Adverse effects of trichothiodystrophy DNA repair and transcription gene disorder on human fetal development.

The effects of DNA repair and transcription gene abnormalities in human pre-natal life have never been studied. Trichothiodystrophy (TTD) is a rare (affected frequency of 10(-6)) recessive disorder caused by mutations in genes involved in nucleotide excision repair (NER) pathway and in transcription. Based on our novel clinical observations, we conducted a genetic epidemiologic study to investigate gestational outcomes associated with TTD. We compared pregnancies resulting in TTD-affected offspring (n = 24) with respect to abnormalities during their antenatal and neonatal periods to pregnancies resulting in their unaffected siblings (n = 18), accounting for correlation, and to population reference values. Significantly higher incidence of several severe gestational complications was noted in TTD-affected pregnancies. Small for gestational age (SGA) <10th percentile [Relative risk (RR ) = 9.3, 95% CI = 1.4-60.5, p = 0.02], SGA <3rd percentile (RR = 7.2, 95% CI = 1.1-48.1, p = 0.04), and neonatal intensive care unit (NICU) hospitalization (RR = 6.4, 95% CI = 1.4-29.5, p = 0.02) occurred more frequently among TTD-affected neonates compared with their unaffected siblings. Compared with reference values from general obstetrical population, pregnancies that resulted in TTD-affected infants were significantly more likely to be complicated by hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome (RR = 35.7, 95% CI = 7.6-92.5, p = 0.0002), elevated mid-trimester maternal serum human chorionic gonadotropin (hCG) levels (RR = 14.3, 95% CI = 7.0-16.6, p < 0.0001), SGA <3rd percentile (RR = 13.9, 95% CI = 7.4-21.1, p < 0.0001), pre-term delivery (<32 weeks) (RR = 12.0, 95% CI = 4.9-21.6, p < 0.0001), pre-eclampsia (RR = 4.0, 95% CI = 1.6-7.4, p = 0.006), and decreased fetal movement (RR = 3.3, 95% CI = 1.6-5.2, p = 0.0018). Abnormal placental development is an underlying mechanism that may explain the constellation of observed complications in our study. Thus, we hypothesize that TTD DNA repair and transcription genes play an important role in normal human placental development.

Chemoprevention of skin cancer in xeroderma pigmentosum.

Xeroderma pigmentosum is a rare recessive disease with sun sensitivity, increased freckling and defective DNA repair. Xeroderma pigmentosum patients have more than a 1000-fold increased risk of developing skin cancer including basal cell carcinoma, squamous cell carcinoma and melanoma. We studied chemoprevention of new skin cancers with oral retinoids in xeroderma pigmentosum patients who had multiple skin cancers. Xeroderma pigmentosum patients were cleared of all pre-existing tumors surgically and then treated with high dose (2 mg/kg/day) oral isotretinoin (13-cis retinoic acid, Accutane) for two years and then for one year off treatment. Patients were examined at regular intervals for new tumor formation and for side effects. Five xeroderma pigmentosum patients had a total of 121 basal or squamous cell carcinomas in 2 years before treatment and only 25 tumors during 2 years of treatment. The tumor frequency increased 8.5-fold after the drug was discontinued (New Engl J Med 318: 1633-1637, 1988). Toxicity (cutaneous, triglyceride, liver-function or skeletal abnormalities) prompted subsequent use of a low dose protocol. Patients were treated initially with 0.5 mg/kg/day oral isotretinoin and the dose was increased sequentially to 1.0 or 1.5 mg/kg/day. We found that toxicity was less with the lower doses. The lowest effective, least toxic dose varied among the xeroderma pigmentosum patients.

Treatment and prevention of basal cell carcinoma with oral isotretinoin.

Twelve patients with multiple basal cell carcinomas resulting from varying causes were treated with high-dose oral isotretinoin (mean daily dosage: 3.1 mg/kg/day) for a mean of 8 months. Of the 270 tumors monitored in these patients, only 8% underwent complete clinical and histologic regression. All patients developed moderate to severe acute toxicities, leading five patients to withdraw from the study. Retinoid skeletal toxicity was identified in two patients who were examined after long-term therapy. Lower doses of isotretinoin (0.25 to 1.5 mg/kg/day) were ineffective for chemotherapy but demonstrated a chemopreventive effect in a subset of three patients who received these lower doses for 3 to 8 years. Two of these three patients have been observed after discontinuation of therapy. In one patient with a history of arsenic exposure, only one new tumor has appeared in a 27-month posttreatment observation period; in the other patient with the nevoid basal cell carcinoma syndrome, 29 new tumors have appeared within a 13-month period. This suggests that the need for long-term maintenance therapy with isotretinoin for chemoprevention of basal cell carcinoma may depend on the underlying cause of the skin cancers.

Prevention of skin cancer in xeroderma pigmentosum with the use of oral isotretinoin.

To confirm reports that skin cancer can be prevented with retinoids, we conducted a three-year controlled prospective study of oral isotretinoin (also called 13-cis retinoic acid) in five patients with xeroderma pigmentosum who had a history of multiple cutaneous basal-cell or squamous-cell carcinomas. Patients were treated with isotretinoin at a dosage of 2 mg per kilogram of body weight per day for two years and then followed for an additional year, without the drug. Before, during, and after treatment, biopsies of all suspicious lesions were performed, and skin cancers were surgically removed. The patients had a total of 121 tumors (mean, 24; range, 8 to 43) in the two-year interval before treatment. During two years of treatment with isotretinoin, there were 25 tumors (mean, 5; range, 3 to 9), with an average reduction in skin cancers of 63 percent (P = 0.019). After the drug was discontinued, the tumor frequency increased a mean of 8.5-fold (range, 2- to 19-fold) over the frequency during treatment (P = 0.007). Although all patients experienced mucocutaneous toxic effects, and triglyceride, liver-function, or skeletal abnormalities developed in some, high-dose oral isotretinoin was effective in the chemoprophylaxis of skin cancers in patients with xeroderma pigmentosum.