Ultrastructural distinction of autosomal dominant ichthyosis vulgaris and X-linked recessive ichthyosis

Summary In autosomal dominant ichthyosis vularis ultrastructural studies have revealed a severe disturbance of keratohyalin synthesis by which this entity may clearly be distinguished from X-linked ichthyosis.

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Zusammenfassung Die autosomal dominante Ichthyosis vulgaris ist durch einen Defekt der Keratohyalinsynthese gekennzeichnet, der erstmals elektronenmikroskopisch nachgewiesen wurde und eine klare Unterscheidung von der klinisch ähnlichen X-chromosomal rezessiven Ichthyosis erlaubt.

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Supported by the Deutsche Forschungsgemeinschaft, Sonderforschungsbereich Klinische Genetik, SFB 35/5 and 7.     

Steroid-sulfatase deficiency in sex-linked ichthyosis.

Steroid-sulfatase activity was absent in the cultured fibroblasts of nine affected members of eight families with sex-linked ichthyosis. An intermediate value of enzyme activity was found in an obligate heterozygote and a normal value in a patient with ichthyosis vulgaris. Cultured epidermal cells of an affected individual also had no enzyme activity, while normal cultured epidermal cells did.     

Molecular analysis of X-linked ichthyosis in Japan

BACKGROUND: X-linked ichthyosis (XLI) is an inherited skin disorder caused by a deficiency of steroid sulfatase (STS). The gene and protein of STS were examined in 19 Japanese patients with XLI. RESULTS: In Western blotting analysis, no cross-reacting peptide was detected in the patients' placenta, although a single band (63 kD) corresponding to STS in a normal subject was observed. Southern blotting was performed using EcoRI digests of cellular DNA from 13 XLI patients and full-length human STS cDNA as a probe. Normal males had bands of 20, 15, 10, 9.0, 6.1, 4.2, 2.6, and 1.5 kb. Twelve of the 19 patients had only 20- and 1.5-kb bands. Only one patient had the same band pattern as that of normal males. The STS gene was analyzed by PCR in 6 of the 19 patients. PCR amplification products were sequenced to analyze the STS gene. Two cases with one-base change in the STS gene and variation in amino acids H444R and E560P were found. Mutant STS cDNA was transfected into COS-1 cells and the STS enzyme activity was assayed. The enzyme activities were less than the minimum detection value of the detection system. CONCLUSIONS: These results suggest that XLI is mainly caused by an extensive deletion of the STS gene and that the PCR method is useful for detection of STS point mutations.     

Problems in prenatal diagnosis of the ichthyosis congenita group

Summary The late onset of normal keratinization after week 24 menstrual age (MA) of fetal life is the cause of considerable problems with the prenatal diagnosis of congenital ichthyosis. This paper summarizes the experiences with prenatal diagnosis in nine pregnancies at risk of congenital ichthyosis and one at risk of chondrodysplasia punctata, rhizomelic type. An important prerequisite—and the main problem—is the manifestation of the mutant genes early enough in fetal life to allow a safe exclusion. Continuous precocious keratinization of the interfollicular epidermis, hyperkeratosis, and/or specific markers of congenital ichthyosis such as various types of lipid inclusions had been expected. With a normal ultrastructure and development of fetal epidermis no evidence of ichthyosis was present in eight cases; all eight children were born healthy. Regional variations of the onset of keratinization of the interfollicular epidermis, observed in one of these eight fetuses as well as in one fetus at risk (but normal for) recessive dystrophic epidermolysis bullosa, posed considerable problems and might lead to a false-positive diagnosis. Examination after birth allowed one to localize these regions to areas close to the mamillae. Regional variations in addition to the well-known cranio-caudal gradient thus are normal findings: both children have normal skin. One fetus at risk of nonbullous congenital ichthyosiform erythroderma (type II) was involved without prenatal manifestation of interfollicular keratinization, specific markers, or increased numbers of cornified cells in the pilosebaceous follicles at 20 weeks MA. A slightly more irregular pattern of the horn cell contents was not regarded as sufficient evidence alone to indicate congenital ichthyosis. A severely affected boy was born in week 34 MA. Similarly the fetus at risk of chondrodysplasia punctata showed no skin abnormalities, neither at fetoscopy (week 22 MA) nor after abortion (week 24 MA) although based on other clinical features it was clearly affected. Thus, this genodermatosis cannot be diagnosed prenatally by its keratinization disturbances. In future cases, precocious keratinization and hyperkeratosis cannot be expected to be expressed before week 24 MA, and minor signs, such as irregularities of horn cell contents, have to be taken as an indication of involvement. Multiple biopsies are required, and a safe exclusion may be impossible before week 22 MA.     

Genotype/phenotype correlation in autosomal recessive lamellar ichthyosis.

Autosomal recessive lamellar ichthyosis is a severe congenital disorder of keratinization, characterized by variable erythema of the whole body surface and by different scaling patterns. Recently, mutations have been identified in patients with lamellar ichthyosis in the TGM1 gene coding for keratinocyte transglutaminase, and a second locus has been mapped to chromosome 2. We have now analyzed the genotype/phenotype correlation in a total of 14 families with lamellar ichthyosis. Linkage analyses using microsatellites in the region of the TGM1 gene confirmed genetic heterogeneity. In patients not linked to the TGM1 gene, the second region identified on chromosome 2 and a further candidate region on chromosome 20 were excluded, confirming as well the existence of at least three loci for lamellar ichthyosis. Sequence analyses of the TGM1 gene in families compatible with linkage to this locus revealed seven different missense mutations, five of these unpublished so far, and one splice mutation. No genotype/phenotype correlation for mutations in the TGM1 gene was found in this group of patients, which included two unrelated patients homozygous for the same mutation. Similarly, no clear difference in the clinical picture was seen between patients with TGM1 mutations and those unlinked to the TGM1 locus. Comparison of genetic and clinical classifications for patients with lamellar ichthyosis shows no consistency and thus indicates that clinical criteria currently in use cannot discriminate between the molecularly different forms of the disease.     

Novel transglutaminase 1 mutations in patients affected by lamellar ichthyosis

Lamellar Ichthyosis (LI) is a form of congenital ichthyosis that is caused by mutations in the TGM1 gene that encodes for the transglutaminase 1 (TG1) enzyme. Functional inactivation of TG1 could be due to mutations, deletion or insertions. In this study, we have screened 16 patients affected by LI and found six new mutations: two transition/transversion (R37G, V112A), two nonsense mutations and two putative splice site both leading to a premature stop codon. The mutations are localized in exons 2 (N-terminal domain), 5, 11 (central catalytic domain), and none is located in the two beta-barrel C-terminal domains. In conclusion, this study expands the current knowledge on TGM1 mutation spectrum, increasing the characterization of mutations would provide more accurate prenatal genetic counselling for parents at-risk individuals.     

Linkage analysis in X-linked ichthyosis (steroid sulfatase deficiency)

Summary Linkage analysis has been carried out in nine unrelated families segregating for X-linked ichthyosis (steroid sulfatase deficiency) using seven polymorphic DNA markers from the distal Xp. Close linkage was found between the disease locus and the loci DXS16, DXS89, and DXS143. In all families except one, Southern hybridization with the human steroid sulfatase cDNA and GMGX9 probes showed a deletion of corresponding loci in affected males. Three patients belonging to the same family had no evident deletion with either of the two above-mentioned probes. None of the other six DNA loci included in the linkage analysis were found to be deleted.     

Does "ichthyosis uteri" have malignant potential? : A case report of squamous cell carcinoma of endometrium associated with extensive ichthyosis uteri

This short report discusses a case of solitary colonic polypoid ganglioneuroma associated with melanosis coli in a woman with no systemic manifestations. To our knowledge this is the first ganglioneuroma reported in the literature in association with melanosis coli. The nature and significance of this event remains unclear, although this may be coincidental due to the laxative intake. Further investigation is necessary to clarify this point. The interest of this case lies moreover in the rarity of this entity and its endoscopic and histologic resemblance to sessile polyps frequent in the clinical practice.     

Follow-up of a family group suffering from ichthyosis hystrix type Curth-Macklin

Summary A family examined by Curth and Macklin in 1952 and found to suffer from generalized or localized forms of ichthyosis, was reexamined in 1970. The concept that the disorder had been conditioned by a dominant gene which manifested itself with varying degrees of severity in the various family members, seemed proved again.Analysis for autosomal linkage was done with an IBM model 1130 computer. Linkage to the AB0 locus, as close as 10 recombination units was ruled out. Very close linkage was also excluded for P, Rh, Duffy, Kidd, Gm, haptoglobin, Ag, and phosphoglucomutase. Loose linkage was not ruled out with respect to any marker.Due to clinical, histopathological and ultrastructural findings, our cases are regarded as an independent nosological entity and are therefore to be separated from the other forms of hystrix-like ichthyosis.

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Zusammenfassung Die von Curth u. Macklin 1952 erstmals untersuchte Familie mit generalisierten oder lokalisierten Formen von Ichthyosis wurde 1970 erneut untersucht. Die Annahme eines autosomal dominanten Erbganges mit wechselnder Expressivität konnte erneut bestätigt werden.Mit einem IBM Computer Modell 1130 wurden marker-Analysen und Kopplungsstudien durchgeführt. Kopplung an den AB0-Locus in einer Entfernung von 10 Rekombinations-Einheiten konnte ausgeschlossen werden. Enge Kopplung wurde außerdem für die marker P, Rh, Duffy, Kidd, Gm, Haptoglobin, Ag und Phosphoglucomutase ausgeschlossen. Nicht für jeden der geprüften marker konnte Kopplung generell ausgeschlossen werden.Die beschriebenen Fälle werden auf Grund der klinischen, histopathologischen und elektronenoptischen Befunde als eigenständige nosologische Entität angesehen und von den übrigen hystrixartigen Ichthyosen abgetrennt.

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Supported by the Deutsche Forschungsgemeinschaft, Sonderforschungsbereich Klinische Genetik, SFB 35, programs 5 and 7.     

Linkage of autosomal recessive lamellar ichthyosis to chromosome 14q.

We have mapped the locus for lamellar ichthyosis (LI), an autosomal recessive skin disease characterized by abnormal cornification of the epidermis. Analysis using both inbred and outbred families manifesting severe LI showed complete linkage to several markers within a 9.3-cM region on chromosome 14q11. Affected individuals in inbred families were also found to have striking homozygosity for markers in this region. Linkage-based genetic counseling and prenatal diagnosis is now available for informative at-risk families. Several transcribed genes have been mapped to the chromosome 14 region containing the LI gene. The transglutaminase 1 gene (TGM1), which encodes one of the enzymes responsible for cross-linking epidermal proteins during formation of the stratum corneum, maps to this interval. The TGM1 locus was completely linked to LI (Z = 9.11), suggesting that TGM1 is a good candidate for further investigation of this disorder. The genes for four serine proteases also map to this region but are expressed only in hematopoietic or mast cells, making them less likely candidates.