Clinical Genetics 1976: 9: 71-76
Dominant ichthyosis vulgaris with an ultrastructurally normal granular layer NAOMIFJTCH',RICHARD SEGOOL2, A1 EX FERENCZY3, .4ND HOWARD COHENl Lady Davis Institute, Department of Pathology, and Division of Dermatology, Jewish General Hospital and * Montreal Children's Hospital, Montreal, P. Q., Canada It has been suggested that ultrastructural studies of keratohyalin granules in the granular layer of the skin can clearly distinguish the dominant type from the X-linked recessive type of ichthyosis vulgaris. The distinctive features are found in the granular layer and the keratohyalin granules. In the dominant form the granular layer is absent or reduced in size and the keratohyalin granules are minute and crumbly in appearance. In the recessive form the granular layer and keratohyalin granules are normal. A family which probably has dominant ichthyosis vulgaris is described. The stratum granulosum and keratohyalin granules as determined by both light and electron microscopy are normal. In view of the inconstant morphologic appearance of the stratum granulosum in ichthyosis vulgaris, it is suggested that distinction between the dominant and X-linked forms should not be based on the structural characteristics of the granular layer alone, but rather on a combined evaluation of the pedigree, clinical features and the appearance of the stratum granulosum. Received I April, accepted for publication 15 May 1975
Ichthyosis vulgaris can be inherited as an autosomal dominant or as an X-linked recessive (Wells & Kerr 1966a). There are both clinical and histological differences between the two types (Wells & Kerr 1966a,b). The sex-linked recessive type of ichthyosis may start in the newborn, and consists of large, dark scales which are often found on the neck and flexor surfaces. The dominant type has fine white scales which are rarely found on the neck or flexor surfaces and the onset has never been observed at birth. Histologically, the main difference between the two types (Wells & Kerr 196613, Wells & Jennings 1967, Feinstein et al. 1970) is based on the appearance of the
granular layer. In the autosomal dominant type it is usually reduced or absent, whereas in the X-linked recessive type it is normal or increased in thickness. Ultrastructural studies (Anton-Lamprecht & Hofbauer 1972a, b, Anton-Lamprecht 1973, 1974) have shown that whereas in dominant ichthyosis the keratohyalin granules are minute and crumbly or spongy in appearance, they are normal or large in the X-linked recessive type. On the basis of these findings, Anton-Lamprecht & Hofbauer (1972a, b) have suggested that ultrastructural analysis alone may provide a clear distinction between the dominant and recessive types of the disease. The purpose of this report is to present
This work was supported by a grant from the Medical Research Council of Canada.
72
F I T C H E T AL
ww
111
0
TWINS
c]
iCHTHYOStS ONLY
1-11 SEVERE ECZEMA
MURMUR ONLY ICHTHYOSIS 8 MURMUR Flg. 1. Pedigree of family with lchthyosis and cardlac murmur
a family (Fig. 1) with dominant ichthyosis and a normal granular layer as evidenced by both light and electron microscopy. Case Report
The propositus is a 15-year-old boy with ichthyosiform scales on his legs, arms, trunk and scalp. The face, neck and flexor surfaces were not affected. The scales were about 4 mm long and whitish in color. In the summer the ichthyosis was much improved. The scaling was first noticed late in the first year of life. He had a short, grade 2/6, early, harsh systolic ejection murmur heard maximally along the left sternal border radiating to both carotids. The murmur was thought to be functional because the electrocardiogram and an echocardiogram were normal, a phonocardiogram showed a normal carotid pulse tracing and there was a normal apex cardiogram. An exercise test showed good tolerance. He has three younger brothers (Fig. 1) with ichthyosis. The ichthyoses had the
Fig. 2. Skin from shin. Note hyperkeratosis and norma1 granular layer. A mild perlvascular inflammatory reaction is seen in the superficial dermis (H & E stain x 40).
DOMINANT ICHTHYOSIS VULGARIS
same time of onset, the same distribution and the same improvement in the summertime in all four brothers. The propositus' three brothers also had a functional systolic murmur, as did an uncle on the paternal side and the uncle's son. We were unable to examine personally the father, uncle or his son, due to lack of cooperation of the family. For the same reason slit-lamp examination for corneal opacities (Sever et al. 1968) was not done. A biopsy was taken from the anterior part of the left leg, in the area of maximal involvement (Feinstein et al. 1970). Histological examination of the epidermis (Figs. 2 and 3) revealed a mild to moderate degree of hyperkeratosis, with well-developed gran-
73
ular and Malpighian layers and normal rete ridges. The granular layer was three-cell stratified throughout and the stratum corneum was primarily of the compact type. There was minimal infiltration by chronic inflammatory cells around the subepidermal blood vessels. Ultrastructurally (Figs. 4 and 3, the number, size, architecture, intracytoplasmic distribution and epidermal localization of keratohyalin granules were indistinguishable from normal ones (Odland & Reed 1967, Matoltsy & Parakkal 1967). Similarly, no abnormalities of tonofilamentdesmosome complexes and keratinosomes in keratinocytes were noted. Discussion
Fig. 3. Skin from shin. Higher magnification illustrating the normal stratum granulosum and the compact iamellated nature of the thickened stratum corneum (H & E staln x 120).
This family corresponds both clinically and by pedigree analysis (Fig. 1) to the autosoma1 dominant type of ichthyosis vulgaris. The characteristic features of the dominant type (Table 1) include: lack of onset of disease at birth; fine, white scales; and sparing of the neck, face and flexor surfaces. Pedigree analysis is typical of a dominant gene with incomplete penetrance. It has been known for many years that the dominant gene for ichthyosis does not have full penetrance (Kuokkanen 1969, Schnyder 1970), i. e. an individual may have the gene but not manifest the skin condition. In this family the father and his brother probably carry the gene, without manifesting the skin condition. The presence of a cardiac murmur in so many individuals with ichthyosis is interesting but it is not possible from this pedigree to state whether it is part of the expression of a gene which produces ichthyosis or the occurrence together is accidental. Nevertheless, it does suggest an explanation for the presence of a normal granular layer. If ichthyosis and a cardiac murmur were a new syndrome, the morphologic character-
FlTCH ET A L .
74
Fig. 4. Electron micrograph of stratum granulosum in which well-developed keratohyalin granules (arrow) are abundant. The overlying keratin layer (SC) and subjacent keratinocytes (K) contain no evidence of ultrastructural abnormalities. Glutaraldehyde O,O,, Epon ( X 24,420).
Table 1 Inherited ichthyosis Autosomal Present report
Wells dominant Kerr (1961a, b)
onset at birth scales on scalp on neck on flexor surfaces stratum granufosum
Wells 8 Kerr (196la,b)
X-linked recessive Passarge et al. Vibrans 8 (1971) Altwein (1970)
0 fine white
17 % large dark
215
012
large
414 014 014
40 OIo
58 010 53 010 38 010
215 215 1I5
dark 2/5
normal
decreased or absent, occasionally normal
normal or increased
normal, increased or decreased
014 fine white
7 010
2 010
2/2 decreased
DOMINANT ICHTHYOSIS VULGARIS
istics could wzll be different from the classical dominant autosomal type. However, the authors think that the above hypothesis is unlikely and that the explanation is probably the well-known variation in expressivity of the gene (Kuokkanen 1969, Schnyder 3970). In this regard, Wells & Kerr (1966 a, b) noted in the most mildly affected patients that the biopsies were identical to those of normal skin. Another autosomal dominant ichthyosis is congenital ichthyosiform erythroderma, bullous type (Schnyder 1970). At birth the skin is moist, red and tender. After a few weeks it becomes thick and horny. Bullous lesions occur spontaneously or due to friction, The family described in this paper has none of these features. There have been three types of X-linked ichthyosis reported (Table 1): a large series studied by Wells & Kerr ( 1 966a, b), a family with five affected individuals reported by
75
Passarge et aI. (1971), and another large family studied by Vibrans & Altwein (1970). It is of interest to note that Vibrans & Altwein have reported a decreased granular layer in the skin biopsy. It is not yet clear whether the above sex-linked recessive varieties are different genes or different expressions of the same gene. In conclusion, the present and previous genetic and morphologic analyses of ichthyosis vulgaris suggest that the appearance of the granular layer alone cannot always distinguish between the dominant and sexlinked types. The dominant may have a normal granular layer, as in this report, and the sex-linked type may have a decreased granular layer, as shown by Vibrans & Altwein (1970). In view of these observations, we believe that the appearance of the stratum granulosum must be used in conjunction with the pedigree analysis and clinical features in order to distinguish the different types of ichthyosis.
References
Anton-Lamprecht, I. (1973). Zur Ultrastruktur hereditarer Verhonungsstorungen. 111. Autosomal-dominante Ichthyosis vulgaris. Arch. Dernz.-Forsch 248, 149-172.
Anton-Lamprecht, I. (1974). Zur Ultrastruktur hereditarer Verhoningsstorungen. IV X-chromosomal-recessive Ichthyosis. Arch Derm.Forsch. 248, 361-378.
Anton-Lamprecht, I. & M. Hofbauer (1972a). Ultrastrukturelle unterscheidungsmerkmale von autosomal dominanter Ichthyosis vulgaris und X-chromosomal rezessiver Ichthyosis. Dermutologica (Basel) 145, 60-64.
Anton-Lamprecht, I. & M. Hofbauer (1972b). Ultrastructural distinction of autosomal dominant ichthyosis vulgaris and X-linked recessive ichthyosis. Hurnnngenetik 15, 261-264. Feinstein, A., A. Ackerman & L. Siprkowski (1970). Histology of autosomal dominant ichthyosis vulgaris and X-linked ichthyosis. Arch. Derm. 101, 524-527. Fig. 5. Keratohyalin granules at higher magnification ( x 37,800).
Kuokkanen, K. (1969). Ichthyosis vulgaris. Acta derm.-venereol. (Stockh.) 49, Suppl. 62, 5-35. Matoltsy, A. & P. Parakkal (1967). Keratiniza-
76
FlTCH
tion. Ultrastructure of Normal and Abnormal Skin, ed. Zelickson. Lea and Febiger. pp. 76-104. Odland, G. & T.Reed (1967). Epidermis. Ultrastructure of Normal and Abnormal Skin. ed. Zelickson. Lea and Febiger. pp. 54-75. Passarge, E., B. Post & E. Schopt (1971). Possible genetic heterogeneity of X-linked ichthyosis. The Clinical Delineation of Birth Defects. Part XII, Vol. 7, No. 8, pp. 46-49. Schnyder, U. (1970). Inherited ichthyosis. Arch. Derrii. 102, 240-250. Sever, R., P. Frost & G. Weinstein (1968). Eye changes in ichthyosis. J. Amer. med. Ass. 206, 2283-2286. Vibrans, U. & J. Altwein (1970). An X-linked recessive variety of ichthyosis vulgaris different from the X-linked ichthyosis of Wells and Kerr. Clin. Genet. 1, 304-309.
ET A L Wells, R. & M. Jennings (1967). X-linked ichthyosis and ichthyosis vulgaris. J . Amer. rned. Ass. 202, 485488. Wells, R. & C. Kerr (1966a). Clinical features of autosomal dominant and sex-linked ichthyosis in a n English population. Brit. rned. J . 1, 947-950. Wells, R. & C. Kerr (1966b). The histology of ichthyosis. J . iiivest. Dernz. 46, 530-535.
Address: D r . Naoini Fitch Lady Davis Institute of the Jewish General Hospital 3755 Cote Saint-Catherine Road Montreal, P . Q . Canada
Dominant ichthyosis vulgaris with an ultrastructurally normal granular layer NAOMIFJTCH',RICHARD SEGOOL2, A1 EX FERENCZY3, .4ND HOWARD COHENl Lady Davis Institute, Department of Pathology, and Division of Dermatology, Jewish General Hospital and * Montreal Children's Hospital, Montreal, P. Q., Canada It has been suggested that ultrastructural studies of keratohyalin granules in the granular layer of the skin can clearly distinguish the dominant type from the X-linked recessive type of ichthyosis vulgaris. The distinctive features are found in the granular layer and the keratohyalin granules. In the dominant form the granular layer is absent or reduced in size and the keratohyalin granules are minute and crumbly in appearance. In the recessive form the granular layer and keratohyalin granules are normal. A family which probably has dominant ichthyosis vulgaris is described. The stratum granulosum and keratohyalin granules as determined by both light and electron microscopy are normal. In view of the inconstant morphologic appearance of the stratum granulosum in ichthyosis vulgaris, it is suggested that distinction between the dominant and X-linked forms should not be based on the structural characteristics of the granular layer alone, but rather on a combined evaluation of the pedigree, clinical features and the appearance of the stratum granulosum. Received I April, accepted for publication 15 May 1975
Ichthyosis vulgaris can be inherited as an autosomal dominant or as an X-linked recessive (Wells & Kerr 1966a). There are both clinical and histological differences between the two types (Wells & Kerr 1966a,b). The sex-linked recessive type of ichthyosis may start in the newborn, and consists of large, dark scales which are often found on the neck and flexor surfaces. The dominant type has fine white scales which are rarely found on the neck or flexor surfaces and the onset has never been observed at birth. Histologically, the main difference between the two types (Wells & Kerr 196613, Wells & Jennings 1967, Feinstein et al. 1970) is based on the appearance of the
granular layer. In the autosomal dominant type it is usually reduced or absent, whereas in the X-linked recessive type it is normal or increased in thickness. Ultrastructural studies (Anton-Lamprecht & Hofbauer 1972a, b, Anton-Lamprecht 1973, 1974) have shown that whereas in dominant ichthyosis the keratohyalin granules are minute and crumbly or spongy in appearance, they are normal or large in the X-linked recessive type. On the basis of these findings, Anton-Lamprecht & Hofbauer (1972a, b) have suggested that ultrastructural analysis alone may provide a clear distinction between the dominant and recessive types of the disease. The purpose of this report is to present
This work was supported by a grant from the Medical Research Council of Canada.
72
F I T C H E T AL
ww
111
0
TWINS
c]
iCHTHYOStS ONLY
1-11 SEVERE ECZEMA
MURMUR ONLY ICHTHYOSIS 8 MURMUR Flg. 1. Pedigree of family with lchthyosis and cardlac murmur
a family (Fig. 1) with dominant ichthyosis and a normal granular layer as evidenced by both light and electron microscopy. Case Report
The propositus is a 15-year-old boy with ichthyosiform scales on his legs, arms, trunk and scalp. The face, neck and flexor surfaces were not affected. The scales were about 4 mm long and whitish in color. In the summer the ichthyosis was much improved. The scaling was first noticed late in the first year of life. He had a short, grade 2/6, early, harsh systolic ejection murmur heard maximally along the left sternal border radiating to both carotids. The murmur was thought to be functional because the electrocardiogram and an echocardiogram were normal, a phonocardiogram showed a normal carotid pulse tracing and there was a normal apex cardiogram. An exercise test showed good tolerance. He has three younger brothers (Fig. 1) with ichthyosis. The ichthyoses had the
Fig. 2. Skin from shin. Note hyperkeratosis and norma1 granular layer. A mild perlvascular inflammatory reaction is seen in the superficial dermis (H & E stain x 40).
DOMINANT ICHTHYOSIS VULGARIS
same time of onset, the same distribution and the same improvement in the summertime in all four brothers. The propositus' three brothers also had a functional systolic murmur, as did an uncle on the paternal side and the uncle's son. We were unable to examine personally the father, uncle or his son, due to lack of cooperation of the family. For the same reason slit-lamp examination for corneal opacities (Sever et al. 1968) was not done. A biopsy was taken from the anterior part of the left leg, in the area of maximal involvement (Feinstein et al. 1970). Histological examination of the epidermis (Figs. 2 and 3) revealed a mild to moderate degree of hyperkeratosis, with well-developed gran-
73
ular and Malpighian layers and normal rete ridges. The granular layer was three-cell stratified throughout and the stratum corneum was primarily of the compact type. There was minimal infiltration by chronic inflammatory cells around the subepidermal blood vessels. Ultrastructurally (Figs. 4 and 3, the number, size, architecture, intracytoplasmic distribution and epidermal localization of keratohyalin granules were indistinguishable from normal ones (Odland & Reed 1967, Matoltsy & Parakkal 1967). Similarly, no abnormalities of tonofilamentdesmosome complexes and keratinosomes in keratinocytes were noted. Discussion
Fig. 3. Skin from shin. Higher magnification illustrating the normal stratum granulosum and the compact iamellated nature of the thickened stratum corneum (H & E staln x 120).
This family corresponds both clinically and by pedigree analysis (Fig. 1) to the autosoma1 dominant type of ichthyosis vulgaris. The characteristic features of the dominant type (Table 1) include: lack of onset of disease at birth; fine, white scales; and sparing of the neck, face and flexor surfaces. Pedigree analysis is typical of a dominant gene with incomplete penetrance. It has been known for many years that the dominant gene for ichthyosis does not have full penetrance (Kuokkanen 1969, Schnyder 1970), i. e. an individual may have the gene but not manifest the skin condition. In this family the father and his brother probably carry the gene, without manifesting the skin condition. The presence of a cardiac murmur in so many individuals with ichthyosis is interesting but it is not possible from this pedigree to state whether it is part of the expression of a gene which produces ichthyosis or the occurrence together is accidental. Nevertheless, it does suggest an explanation for the presence of a normal granular layer. If ichthyosis and a cardiac murmur were a new syndrome, the morphologic character-
FlTCH ET A L .
74
Fig. 4. Electron micrograph of stratum granulosum in which well-developed keratohyalin granules (arrow) are abundant. The overlying keratin layer (SC) and subjacent keratinocytes (K) contain no evidence of ultrastructural abnormalities. Glutaraldehyde O,O,, Epon ( X 24,420).
Table 1 Inherited ichthyosis Autosomal Present report
Wells dominant Kerr (1961a, b)
onset at birth scales on scalp on neck on flexor surfaces stratum granufosum
Wells 8 Kerr (196la,b)
X-linked recessive Passarge et al. Vibrans 8 (1971) Altwein (1970)
0 fine white
17 % large dark
215
012
large
414 014 014
40 OIo
58 010 53 010 38 010
215 215 1I5
dark 2/5
normal
decreased or absent, occasionally normal
normal or increased
normal, increased or decreased
014 fine white
7 010
2 010
2/2 decreased
DOMINANT ICHTHYOSIS VULGARIS
istics could wzll be different from the classical dominant autosomal type. However, the authors think that the above hypothesis is unlikely and that the explanation is probably the well-known variation in expressivity of the gene (Kuokkanen 1969, Schnyder 3970). In this regard, Wells & Kerr (1966 a, b) noted in the most mildly affected patients that the biopsies were identical to those of normal skin. Another autosomal dominant ichthyosis is congenital ichthyosiform erythroderma, bullous type (Schnyder 1970). At birth the skin is moist, red and tender. After a few weeks it becomes thick and horny. Bullous lesions occur spontaneously or due to friction, The family described in this paper has none of these features. There have been three types of X-linked ichthyosis reported (Table 1): a large series studied by Wells & Kerr ( 1 966a, b), a family with five affected individuals reported by
75
Passarge et aI. (1971), and another large family studied by Vibrans & Altwein (1970). It is of interest to note that Vibrans & Altwein have reported a decreased granular layer in the skin biopsy. It is not yet clear whether the above sex-linked recessive varieties are different genes or different expressions of the same gene. In conclusion, the present and previous genetic and morphologic analyses of ichthyosis vulgaris suggest that the appearance of the granular layer alone cannot always distinguish between the dominant and sexlinked types. The dominant may have a normal granular layer, as in this report, and the sex-linked type may have a decreased granular layer, as shown by Vibrans & Altwein (1970). In view of these observations, we believe that the appearance of the stratum granulosum must be used in conjunction with the pedigree analysis and clinical features in order to distinguish the different types of ichthyosis.
References
Anton-Lamprecht, I. (1973). Zur Ultrastruktur hereditarer Verhonungsstorungen. 111. Autosomal-dominante Ichthyosis vulgaris. Arch. Dernz.-Forsch 248, 149-172.
Anton-Lamprecht, I. (1974). Zur Ultrastruktur hereditarer Verhoningsstorungen. IV X-chromosomal-recessive Ichthyosis. Arch Derm.Forsch. 248, 361-378.
Anton-Lamprecht, I. & M. Hofbauer (1972a). Ultrastrukturelle unterscheidungsmerkmale von autosomal dominanter Ichthyosis vulgaris und X-chromosomal rezessiver Ichthyosis. Dermutologica (Basel) 145, 60-64.
Anton-Lamprecht, I. & M. Hofbauer (1972b). Ultrastructural distinction of autosomal dominant ichthyosis vulgaris and X-linked recessive ichthyosis. Hurnnngenetik 15, 261-264. Feinstein, A., A. Ackerman & L. Siprkowski (1970). Histology of autosomal dominant ichthyosis vulgaris and X-linked ichthyosis. Arch. Derm. 101, 524-527. Fig. 5. Keratohyalin granules at higher magnification ( x 37,800).
Kuokkanen, K. (1969). Ichthyosis vulgaris. Acta derm.-venereol. (Stockh.) 49, Suppl. 62, 5-35. Matoltsy, A. & P. Parakkal (1967). Keratiniza-
76
FlTCH
tion. Ultrastructure of Normal and Abnormal Skin, ed. Zelickson. Lea and Febiger. pp. 76-104. Odland, G. & T.Reed (1967). Epidermis. Ultrastructure of Normal and Abnormal Skin. ed. Zelickson. Lea and Febiger. pp. 54-75. Passarge, E., B. Post & E. Schopt (1971). Possible genetic heterogeneity of X-linked ichthyosis. The Clinical Delineation of Birth Defects. Part XII, Vol. 7, No. 8, pp. 46-49. Schnyder, U. (1970). Inherited ichthyosis. Arch. Derrii. 102, 240-250. Sever, R., P. Frost & G. Weinstein (1968). Eye changes in ichthyosis. J. Amer. med. Ass. 206, 2283-2286. Vibrans, U. & J. Altwein (1970). An X-linked recessive variety of ichthyosis vulgaris different from the X-linked ichthyosis of Wells and Kerr. Clin. Genet. 1, 304-309.
ET A L Wells, R. & M. Jennings (1967). X-linked ichthyosis and ichthyosis vulgaris. J . Amer. rned. Ass. 202, 485488. Wells, R. & C. Kerr (1966a). Clinical features of autosomal dominant and sex-linked ichthyosis in a n English population. Brit. rned. J . 1, 947-950. Wells, R. & C. Kerr (1966b). The histology of ichthyosis. J . iiivest. Dernz. 46, 530-535.
Address: D r . Naoini Fitch Lady Davis Institute of the Jewish General Hospital 3755 Cote Saint-Catherine Road Montreal, P . Q . Canada
