Biomedical subjects
Publications and source records attributed to V P Sybert.
A family with childhood onset of hypotrichosis and morphea with apparent autosomal dominant inheritance is reported. Careful literature review suggests that this is a previously undescribed disorder.
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Ichthyosis vulgaris is an autosomal dominant disorder of keratinization characterized histologically by absent or reduced keratohyaline granules in the epidermis and mild hyperkeratosis. The basic defect in ichthyosis vulgaris is unknown. We have tested for the presence of filaggrin and its precursor, profilaggrin, in the epidermis of affected and unaffected individuals from 2 families with ichthyosis vulgaris and correlated its presence and relative quantity with ultrastructure findings in the same individuals. Filaggrin was present on stained sodium dodecyl sulfate gels and immunoblots of epidermal proteins from controls and unaffected family members. It was absent from the more severely affected individuals in each family and reduced in intensity in the less severely affected family members. Immunohistology in controls showed localization of filaggrin-related protein in the stratum corneum and within the granular layer. In contrast, tissue from affected individuals showed little or no reaction. Electron microscopic studies showed that keratohyaline granules were absent in 3 severely affected individuals, and reduced in number in the others. The relative amount of keratohyalin by electron microscopy correlated with the amount of filaggrin detectable on immunoblots. The stratum corneum was thicker than in normals but showed the typical "keratin pattern" staining suggesting that filaggrin is not essential for keratin filament aggregation and may have another function in vivo. We have demonstrated that the structural proteins, profilaggrin and filaggrin, are reduced or absent in 5 patients from 2 pedigrees with ichthyosis vulgaris. This biochemical abnormality correlates with the morphologic reduction in the amount of keratohyalin, and with the clinical severity of the disorder.
Aplasia cutis congenita (ACC) is a heterogeneous group of disorders whose common characteristic is focal absence of skin. In the majority of instances this is limited to the scalp, although other areas of the body may also be involved. Other congenital malformations have been reported to occur with ACC; limb defects appear to be a specific association. Given our experience with ACC, we suggest a classification based on genetically distinct entities. Type I ACC is limited to the scalp. Type II involves body or scalp; IIA involves body or limb defects. Type III is limited to the scalp or limbs. Type IV is associated with epidermolysis bullosa; type IVA is Bart syndrome. Although most reported cases have been sporadic, there are many familial occurrences of all types of ACC. Most published pedigrees are consistent with autosomal dominant inheritance with reduced penetrance, or autosomal recessive inheritance. Careful examination of family members of affected individuals is warranted.
One of 170 patients with karyotype-proven Turner syndrome from our institution has had pseudotumour cerebri. This patient and one previous report suggest that patients with Turner syndrome may be predisposed to increased intracranial pressure. Fourteen patients with pseudotumour cerebri were ascertained from hospital records; karyotypes of four were obtained and were normal. Karyotyping may be appropriate in women with pseudotumour cerebri who also have infertility, short stature, multiple pregnancy losses, or other features suggestive of Turner syndrome.
Adult heights of 66 individuals with karyotype documentation of Turner syndrome were analyzed. The mean adult height of 29 individuals given growth-promoting hormones, oxandrolone or fluoxymesterone, did not differ significantly from that of 37 untreated subjects (148.1 +/- 4.7 vs 146.3 +/- 5.5 cm, respectively). The type of X chromosome abnormality did not influence the mean adult height. No significant deleterious effect on height was seen with earlier induction of puberty with estrogens. Parental heights did not appear to influence final adult height. Based on this study, the use of androgens to increase adult height in Turner syndrome cannot be recommended and there appears to be no benefit in delaying induction of puberty with exogenous hormones beyond the mid-teens (14 to 16 years).
A variety of procedures have been recommended for post-mortem examination of stillbirths to determine the cause of the loss of the pregnancy and to provide an estimate of the risk of recurrence. We studied the relative usefulness of several such techniques, including gross and microscopical autopsy, photography, radiography, bacterial cultures, and chromosome studies. In 44 (35 per cent) of 124 cases of stillbirth or early neonatal death, structural physical abnormalities were evident at autopsy. In 35 of the 44 cases the abnormalities were due to chromosomal, single-gene, or polygenic disorders. The single most useful examination was the gross autopsy. Analysis of the various procedures suggests that when resources are limited, gross autopsy, photography, radiography, and bacterial cultures should be performed in all cases of stillbirth and early neonatal death, but that karyotyping and histopathology may be used selectively. This approach should minimize the use of expensive, low-yield procedures without compromising the ability to provide information for purposes of genetic counseling.
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Skin biopsy samples and amniotic fluid cells obtained in utero from two fetuses at risk for epidermolytic hyperkeratosis were examined by light and electron microscopy. Both fetuses were affected; the second was carried to term. Epidermal extracts were prepared from blisters of the newborn for analysis of keratin and filaggrin proteins. Abnormal clumps of keratin filaments were present in all layers of the prekeratinized fetal epidermis except the periderm and stratum germinativum. A significant population of amniotic fluid cells also contained the filament aggregations. Prenatal diagnosis of the disease should be possible using cells obtained at amniocentesis, thus avoiding fetal skin biopsy. Biochemical studies showed abnormalities in keratin and filaggrin proteins. The structural alterations in the tissue might be a consequence of altered interaction between these two abnormal epidermal proteins.
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The inherited abnormalities of the skin are easily recognizable and readily accessible. They involve structures of different embryonic origins, are amenable to study in in vitro systems, are available for study in laboratory and domestic animal models, and are eminently suited to the type of interdisciplinary research presented at this workshop. Biochemists, geneticists, and clinicians in various disciplines all profit by this exchange of information. Ultimately, the gain is for the patient in the treatment and prevention of inherited dermatologic disorders.
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