American Journal of Medical Genetics 40:447-448 (1991)
Brief Clinical Report Hypomelanosis of Ito Associated With Chromosomal Translocation Involving X p l l M. Serena Lungarotti, Cecilia Martello, Anna Calabro, Franc0 Baldari, and Giacomo Mariotti Istituto di Pediatria, Universita di Perugia, Policlinico Monteluce, Perugia, Ztaly
We report on a 3-year-old girl with hypomelanosis of Ito (HI). She has typical skin lesions and mild CNS involvement characterized by impaired walking and borderline mental retardation. Cytogenetic investigation showed a 18K translocation with breakpoint on Xpll. This is the sixth case of HI in which this breakpoint has been reported, underlining that this event cannot be considered coincidental. Further studies are needed to understand the etiologic and pathogenetic meaning of this finding.
KEY WORDS: incontinentia pigmenti achromians, skin, CNS involvement INTRODUCTION Hypomelanosis of Ito (HI) or incontinentia pigmenti achromians is a rare genodermatosis characterized by skin anomalies associated with neurologic, muscoloskeletal, and ocular involvement. The typical skin lesions are represented by hypopigmented linear areas distributed in whorls, streaks, and patches. The etiology of HI is still a matter of controversy. The majority of patients are sporadic cases, but on the basis of familial cases, the condition has been attributed either to an autosomal dominant or X-linked dominant pattern of inheritance [Schwartz et al., 1977; McKusick, 19881. Furthermore, on several occasions, various chromosome anomalies have been reported. These consisted mostly in mosaicism of cell lines obtained by biopsies of normal and hypomelanotic skin [Donnai et al., 1986; Flannery et al., 1986; Turleau et al., 19861. We report on a 3-year-old female patient who shows the typical skin lesions of HI and neurologic impairment consisting of mild mental retardation and an abnormal gait. Received for publication September 12, 1989; revision received December 17, 1990. Address reprint requests to M. Serena Lungarotti, Istituto di Pediatria, Policlinico Monteluce, 06100 Perugia, Italy.
0 1991 Wiley-Liss, Inc.
CLINICAL REPORT C.S. is the second daughter of a 29-year-old father and a 27-year-old mother. Parents are in good health and not related. Family history is positive for otosclerosison the mother’s side. Delivery was a t term and normal, after an uneventful pregnancy. Birth weight was 3,600 g, and no complicationswere reported in the perinatal period. She had normal psychomotor milestones. She was evaluated at age 3 years because of mild mental retardation and an abnormal gait present only at the beginning of walking and which regressed after a few steps. Walking was impaired mainly in the morning on awakening. The condition worsened in cold weather. Physical examination disclosed skin lesions consisting of areas of linear hypopigmentation more evident on the trunk, distributed in whorls and streaks, along metameric lines (Fig. 1).On the abdomen, two types of pigmentation were observed: darker on right and lighter on left side, divided by linea alba, while on the legs, the skin lesions had a patchy aspect. Blood potassium before and after physical activity was normal. Muscular enzymes, cupremia, ceruloplasminemia, phytanic acid, EEG, and EMG were normal. Chromosomal investigation performed on peripheral blood lymphocytes showed a translocation between chromosome X and 18 with breakpoint a t Xpll (46,X + t (X;18)(pll;q23) (Fig. 2). Cultured skin fibroblasts showed the same chromosome constitution. Chromosomes of the parents were normal. DISCUSSION Most cases of HI are sporadic. Recurrence has occurred in three families [Grosshans et al., 1971; Jelineck et al., 19731.The major hypothesis is that HI is a variant of incontinentia pigmenti (IP), the former being the postnatal manifestation of the latter, which is considered to be of very early prenatal onset. This would be supported by common clinical manifestations of the two disorders, namely, skin, neurologic, and muscoloskeletal involvement together with eye and teeth anomalies. This hypothesis is no longer acceptable since it seems that the genes of the two disorders are in two different sites. The IP gene has been assigned to Xq28 through linkage study [Sefiani et al., 19891.
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Lungarotti et al.
Fig. 2. Partial karyotype showing chromosome translocation involving chromosome X and 18 with breakpoint on X p l l . A Peripheral blood lymphocytes; B: skin fibroblasts. G-banding.
mosaicism observed in two cases reported by Donnai et al. [1986]. This observation together with other reports in which an abnormal karyotype was present only in the abnormal skin [Rott et al., 19861underline the possible role of chromosomal mosaicism in causing the characteristic patchy lesions of HI. Further studies are necessary to clarify the pathogenesis of this disease and its relationship with IP. Fig. 1. Thoracic skin of the proposita showing hypochromic linear areas with typical distribution in whorls.
REFERENCES
Our patient is the sixth case reported in the literature who displays an X-autosome translocation involving Xpll, and this cannot be considered coincidental. In addition, these concordant observations help to shed light on the problem of inheritance which should be considered X-linked dominant. On the basis of a recent study which took into consideration chromosome heteromorphism, HLA types, and DNA fingerprints, Donnai et al. [1986]concluded that HI is a manifestation of a heterogeneous group of disorders, the common factor being the presence of two genetically different cell lines which could result from chromosomal mosaicism or chimerism, from a postzygotic mutation, or from X inactivation. This latter pathogenetic interpretation would explain the distribution of skin anomalies along Blaschko lines, as a result of functional mosaicism of X chromosomes by effect of lyonization. In several cases of HI, chromosomal anomalies have been observed both in peripheral blood and in skin fibroblasts. Of interest is the finding of diploidkriploid
Donnai D, McKeown C, Andrews T, Read AP (1986): Diploiditriploid mixoploidy and hypomelanosis of Ito. Lancet i:1443-1444. Flannery DB, Byrd JR, Freeman WE, Perlman SA (1986): Hypomelanosis of Ito: A cutaneous marker of chromosomal mosaicism (Abstr.) Am J Hum Genet 37:A93. Grosshans EM, Stoebner P, Bergoend H, Stoll C (1971): Incontinentia pigmenti achromians (Ito). Etude clinique histopathologique. Dermatology 142:65-78. Jelinek J E , Bart RS, Schiff SM (1973): Hypomelanosis of Ito (‘‘incontinentia pigmenti achromians”). Report of three cases and review of literature. Arch Dermatol 107:596-601. McKusick VA (1988): “Mendelian Inheritance in Man,” 8th Ed. Baltimore, London: The Johns Hopkins University Press. Rott H-D, Ulmer R, Haneke E (1986): Hypomelanosis of Ito and chromosomal mosaicism in fibroblasts. Lancet ii:343. Schwartz MF, Esterly NB, Fretzin DF, Pergament E, Rozenfeld IH (1977):Hypomelanosis of Ito (incontinentia pigmenti achromians): A neurocutaneous syndrome. J Pediatr 90:236-240. Sefiani A, Abel L, Heuertz S, Sinnett D, Lavergne L, Labuda D, HorsCayla MC (1989): The gene for incontinentiapigmenti is assigned to Xq28. Genomics 4:427-429. Turleau C, Taillard F, Doussau de Bazignan M, Delepine N, Desbois JC, de Grouchy J (1986): Hypomelanosis of Ito (incontinentia pigmenti achromians) and mosaicism for a microdeletion of 15ql. Hum Genet 74:185-187.
Brief Clinical Report Hypomelanosis of Ito Associated With Chromosomal Translocation Involving X p l l M. Serena Lungarotti, Cecilia Martello, Anna Calabro, Franc0 Baldari, and Giacomo Mariotti Istituto di Pediatria, Universita di Perugia, Policlinico Monteluce, Perugia, Ztaly
We report on a 3-year-old girl with hypomelanosis of Ito (HI). She has typical skin lesions and mild CNS involvement characterized by impaired walking and borderline mental retardation. Cytogenetic investigation showed a 18K translocation with breakpoint on Xpll. This is the sixth case of HI in which this breakpoint has been reported, underlining that this event cannot be considered coincidental. Further studies are needed to understand the etiologic and pathogenetic meaning of this finding.
KEY WORDS: incontinentia pigmenti achromians, skin, CNS involvement INTRODUCTION Hypomelanosis of Ito (HI) or incontinentia pigmenti achromians is a rare genodermatosis characterized by skin anomalies associated with neurologic, muscoloskeletal, and ocular involvement. The typical skin lesions are represented by hypopigmented linear areas distributed in whorls, streaks, and patches. The etiology of HI is still a matter of controversy. The majority of patients are sporadic cases, but on the basis of familial cases, the condition has been attributed either to an autosomal dominant or X-linked dominant pattern of inheritance [Schwartz et al., 1977; McKusick, 19881. Furthermore, on several occasions, various chromosome anomalies have been reported. These consisted mostly in mosaicism of cell lines obtained by biopsies of normal and hypomelanotic skin [Donnai et al., 1986; Flannery et al., 1986; Turleau et al., 19861. We report on a 3-year-old female patient who shows the typical skin lesions of HI and neurologic impairment consisting of mild mental retardation and an abnormal gait. Received for publication September 12, 1989; revision received December 17, 1990. Address reprint requests to M. Serena Lungarotti, Istituto di Pediatria, Policlinico Monteluce, 06100 Perugia, Italy.
0 1991 Wiley-Liss, Inc.
CLINICAL REPORT C.S. is the second daughter of a 29-year-old father and a 27-year-old mother. Parents are in good health and not related. Family history is positive for otosclerosison the mother’s side. Delivery was a t term and normal, after an uneventful pregnancy. Birth weight was 3,600 g, and no complicationswere reported in the perinatal period. She had normal psychomotor milestones. She was evaluated at age 3 years because of mild mental retardation and an abnormal gait present only at the beginning of walking and which regressed after a few steps. Walking was impaired mainly in the morning on awakening. The condition worsened in cold weather. Physical examination disclosed skin lesions consisting of areas of linear hypopigmentation more evident on the trunk, distributed in whorls and streaks, along metameric lines (Fig. 1).On the abdomen, two types of pigmentation were observed: darker on right and lighter on left side, divided by linea alba, while on the legs, the skin lesions had a patchy aspect. Blood potassium before and after physical activity was normal. Muscular enzymes, cupremia, ceruloplasminemia, phytanic acid, EEG, and EMG were normal. Chromosomal investigation performed on peripheral blood lymphocytes showed a translocation between chromosome X and 18 with breakpoint a t Xpll (46,X + t (X;18)(pll;q23) (Fig. 2). Cultured skin fibroblasts showed the same chromosome constitution. Chromosomes of the parents were normal. DISCUSSION Most cases of HI are sporadic. Recurrence has occurred in three families [Grosshans et al., 1971; Jelineck et al., 19731.The major hypothesis is that HI is a variant of incontinentia pigmenti (IP), the former being the postnatal manifestation of the latter, which is considered to be of very early prenatal onset. This would be supported by common clinical manifestations of the two disorders, namely, skin, neurologic, and muscoloskeletal involvement together with eye and teeth anomalies. This hypothesis is no longer acceptable since it seems that the genes of the two disorders are in two different sites. The IP gene has been assigned to Xq28 through linkage study [Sefiani et al., 19891.
448
Lungarotti et al.
Fig. 2. Partial karyotype showing chromosome translocation involving chromosome X and 18 with breakpoint on X p l l . A Peripheral blood lymphocytes; B: skin fibroblasts. G-banding.
mosaicism observed in two cases reported by Donnai et al. [1986]. This observation together with other reports in which an abnormal karyotype was present only in the abnormal skin [Rott et al., 19861underline the possible role of chromosomal mosaicism in causing the characteristic patchy lesions of HI. Further studies are necessary to clarify the pathogenesis of this disease and its relationship with IP. Fig. 1. Thoracic skin of the proposita showing hypochromic linear areas with typical distribution in whorls.
REFERENCES
Our patient is the sixth case reported in the literature who displays an X-autosome translocation involving Xpll, and this cannot be considered coincidental. In addition, these concordant observations help to shed light on the problem of inheritance which should be considered X-linked dominant. On the basis of a recent study which took into consideration chromosome heteromorphism, HLA types, and DNA fingerprints, Donnai et al. [1986]concluded that HI is a manifestation of a heterogeneous group of disorders, the common factor being the presence of two genetically different cell lines which could result from chromosomal mosaicism or chimerism, from a postzygotic mutation, or from X inactivation. This latter pathogenetic interpretation would explain the distribution of skin anomalies along Blaschko lines, as a result of functional mosaicism of X chromosomes by effect of lyonization. In several cases of HI, chromosomal anomalies have been observed both in peripheral blood and in skin fibroblasts. Of interest is the finding of diploidkriploid
Donnai D, McKeown C, Andrews T, Read AP (1986): Diploiditriploid mixoploidy and hypomelanosis of Ito. Lancet i:1443-1444. Flannery DB, Byrd JR, Freeman WE, Perlman SA (1986): Hypomelanosis of Ito: A cutaneous marker of chromosomal mosaicism (Abstr.) Am J Hum Genet 37:A93. Grosshans EM, Stoebner P, Bergoend H, Stoll C (1971): Incontinentia pigmenti achromians (Ito). Etude clinique histopathologique. Dermatology 142:65-78. Jelinek J E , Bart RS, Schiff SM (1973): Hypomelanosis of Ito (‘‘incontinentia pigmenti achromians”). Report of three cases and review of literature. Arch Dermatol 107:596-601. McKusick VA (1988): “Mendelian Inheritance in Man,” 8th Ed. Baltimore, London: The Johns Hopkins University Press. Rott H-D, Ulmer R, Haneke E (1986): Hypomelanosis of Ito and chromosomal mosaicism in fibroblasts. Lancet ii:343. Schwartz MF, Esterly NB, Fretzin DF, Pergament E, Rozenfeld IH (1977):Hypomelanosis of Ito (incontinentia pigmenti achromians): A neurocutaneous syndrome. J Pediatr 90:236-240. Sefiani A, Abel L, Heuertz S, Sinnett D, Lavergne L, Labuda D, HorsCayla MC (1989): The gene for incontinentiapigmenti is assigned to Xq28. Genomics 4:427-429. Turleau C, Taillard F, Doussau de Bazignan M, Delepine N, Desbois JC, de Grouchy J (1986): Hypomelanosis of Ito (incontinentia pigmenti achromians) and mosaicism for a microdeletion of 15ql. Hum Genet 74:185-187.
