The expression of congenital ichthyosiform erythroderma in second trimester fetuses of the same family: morphologic and biochemical studies.

The first born offspring of first-cousin parents was affected with a keratinization disorder thought to be nonbullous congenital ichthyosiform erythroderma (CIE). In each of three subsequent pregnancies, the parents elected to have prenatal diagnosis based on evaluation of fetal skin biopsies. The epidermis of fetus 1 was identical to normal 21-wk estimated gestation age (EGA) fetal epidermis, but because keratinization begins normally around 24 wk EGA, the procedure was repeated 4 wk later. A thin epidermis with a few layers of stratum corneum indicated a normal fetus and a healthy infant was born at term. Skin biopsy samples from fetus 2 gave conflicting results; the epidermis of one sample appeared normal but the second had 5-15 layers of incompletely keratinized cells superficial to basal and intermediate layers. The hair canals of both samples were hyperkeratotic. Pelleted amniotic fluid cells contained aggregates of incompletely keratinized epidermal cells and concentric rings of keratinized cells. The fetus was thought to be affected and the pregnancy terminated. Regional variation in epidermal thickness and keratinization was noted upon gross examination of the fetus and by histology of the skin. Marked hyperkeratinization of follicles was evident in all regions. No abnormal keratins were expressed in the affected epidermis but epidermal lipids analyzed from two body regions had a lower triglyceride content and a higher content of free sterols compared with age-matched, normal fetal epidermis. Immunolabeling for markers of differentiation revealed variable stages of epidermal differentiation according to region. Four structurally identical biopsy samples were obtained from a third fetus. The epidermis appeared normal for age and hair canals were keratinized to various extents. The pregnancy was continued and at 33 wk a male infant was born with a severe ichthyosis of the face and scalp and fine, white scaling on the body. The epidermis of both the severely and mildly affected regions of the newborn had a thick, compact stratum corneum and other features of CIE. Scars from all four fetal biopsies were identified on the trunk, in areas which appeared less affected clinically. This study reports, for the first time, the criteria for prenatal diagnosis of CIE and the variable expression of this disorder in the midtrimester fetus. More importantly, it demonstrates the risks and pitfalls of this in utero diagnosis based on epidermal morphology.

Follicular depletion during the menopausal transition: evidence for accelerated loss and ultimate exhaustion.

Although the menopause is generally considered to be the consequence of follicular exhaustion, the relationship between follicle number and the menopausal transition has not been explicity studied. We addressed this question in 17 women, aged 45-55 yr, who were undergoing elective total abdominal hysterectomy and salpingo-oophorectomy. The women were divided into 3 groups according to their menstrual history: 1) menstruating regularly (n = 6), 2) perimenopausal (irregular menses; n = 7), and 3) postmenopausal (greater than 1 yr since last menses; n = 4). The mean ages of the 3 groups were similar. Menstrual histories were confirmed by plasma hormone levels and endometrial histology. One ovary from each woman was serially sectioned for determination of follicle numbers. The mean number of primordial follicles in the ovaries of women who were still menstruating regularly was 10-fold higher than that in perimenopausal women [1392 +/- 355 (+/- SEM) vs. 142 +/- 72]. Follicles were virtually absent in the postmenopausal ovaries. Comparison of these data with those obtained by others in younger women suggests that follicular depletion accelerates dramatically in the last decade of menstrual life. These results support the view that declining follicular reserve is the immediate cause of both the perimenopausal and menopausal transitions, and indicate that the rate and, therefore, the regulation of follicular depletion change during the final phase of reproductive life.

Prenatal diagnosis of congenital non-bullous ichthyosiform erythroderma (lamellar ichthyosis).

We report the first positive prenatal diagnosis of congenital non-bullous ichthyosiform erythroderma or lamellar ichthyosis. Fetal skin samples were obtained by fetoscopy at 21 weeks' gestation and examined by light and electron microscopy. Light microscopy revealed a thickened interfollicular epidermis with multiple layers of flattened cells and excessive keratinization of the epidermal lining of the follicular infundibulum. Electron microscopy of the thickened epidermis revealed granular cells that contained larger-than-normal keratohyalin granules and multiple layers of parakeratotic cornified cells. Although there was regional variation in the degree of interfollicular keratinization, follicles from all regions showed greater and more complete keratinization, indicating that they express the abnormality early enough in development to permit prenatal diagnosis at about 20 weeks' gestation.

Biochemical examination of fetal skin biopsy specimens obtained by fetoscopy: use of the method for analysis of keratins and filaggrin.

This paper describes a method for biochemical analysis of proteins from fetal skin biopsy samples. The method has wide potential application for diagnosis of disorders with a known protein abnormality detectable by protein staining or a specific antibody. Analysis requires a single 1 mm biopsy, is rapid (2 days) and extremely sensitive. In the present study, fetal skin biopsies from normal fetuses and a fetus at risk for lamellar ichthyosis were obtained. The epidermis or hairs with attached follicular cells were dissected from the remaining skin. Proteins were extracted and separated by SDS-polyacrylamide gel electrophoresis. Proteins from duplicate gels were transferred to nitrocellulose and immunostained for the acidic and basic keratins and for the keratin filament associated protein, filaggrin, using monoclonal antibodies. All samples contained keratins typical of fetal epidermis at 20 weeks gestation. Presence of filaggrin is variable at this age and depends on the presence of keratinized cells of hair canals. No keratin abnormalities in the fetus at risk for lamellar ichthyosis were detected, however, in one presumably normal biopsy, an abnormally low proportion of the 67 kd keratin and the presence of follicular keratins were evident. These results demonstrate that biochemical analysis of fetal biopsies is possible, thus increasing the diagnostic potential of the fetal biopsy procedure for disorders in which a known protein or antigen is altered in utero.

Comparison of rosaramicin and erythromycin stearate for treatment of cervical infection with Chlamydia trachomatis.

The macrolide antibiotic rosaramicin inhibits in vitro growth of Chlamydia trachomatis. Rosaramicin (1 g daily given to 18 patients for seven days) and erythromycin stearate (2 g daily given to 19 patients for seven days) were compared in the treatment of chlamydial cervicitis. Cultures of cervical specimens obtained nine to 11 days and 24-32 days after commencement of therapy were negative for all rosaramicin-treated patients seen at follow-up. The first follow-up culture of one erythromycin recipient was positive. The extent of cervicitis decreased in all patients after treatment, but the only patients to achieve a completely normal cervical appearance were those with minimal-to-moderate lesions before treatment. Gastrointestinal side effects, including nausea, vomiting, and abdominal pain, occurred in ten of 19 patients given erythromycin and in 13 of 18 given rosaramicin. Minimally elevated levels of alanine aminotransferase in serum occurred in four (22.2%) of 18 rosaramicin recipients. It is concluded that rosaramicin and erythromycin stearate both eradicate C. trachomatis cervical infection but frequently cause adverse gastrointestinal effects.