Hypomelanosis Of Ito

A number sign (#) is used with this entry because of convincing evidence that hypomelanosis of Ito does not represent a distinct entity but is rather a symptom of many different states of mosaicism (Donnai et al., 1988; Thomas et al., 1989; Ritter et al., 1990; Sybert et al., 1990; Pellegrino et al., 1995; Kuster et al., 1998). Incontinentia pigmenti type 1, which was subsequently shown to be hypomelanosis of Ito, is associated with an X/autosome translocation involving Xp11.

See also linear and whorled nevoid hypermelanosis (LWNH; 614323), a benign pigmentation disorder with some similarities.

Clinical Features

Although some features are similar to those of classic incontinentia pigmenti (308300), the differences are sufficient to establish it as a separate disorder. The disorder is characterized by unilateral or bilateral macular hypopigmented whorls, streaks, and patches which are described as the 'negative pattern' of the hyperpigmented lesions of incontinentia pigmenti. Abnormalities of the eyes and the musculoskeletal and central nervous systems occur in some (Jelinek et al., 1973). Neurologic impairment can be quite severe with hemimegalencephaly and/or migration disorders. Montagna et al. (1991) described a brother and sister in their twenties with typical skin changes of this disorder associated with mental and cerebellar signs. Their mother showed only the skin changes and no neurologic disturbances. Fujino et al. (1995) presented neuropathologic findings of a severely affected Japanese girl who succumbed at 13 months. There was brachycephaly and micropolygyria with disarrayed cortical lamination with nerve cells in the white matter demonstrable histologically, suggesting a migration defect during maturation. Ogino et al. (1994) presented neurophysiologic studies in 3 affected children that illustrated great variability of central nervous system involvement. One patient presented with the West syndrome and had an asymmetric hypsarrhythmia. The second patient had only mild mental retardation and minimal EEG abnormalities, whereas the third patient was neurologically normal.

In an affected child, Happle and Vakilzadeh (1982) described talon cusps, i.e., pointed extra cusps protruding from the palatal aspect of the crown of 3 maxillary incisors. Browne and Byrne (1976) described a patient who had conical anterior deciduous teeth with pitted, yellow-brown crowns; her other teeth were normal. On light microscopy of the deciduous teeth, a localized mass of irregularly formed coronal dentin was found.

Bartholomew et al. (1987) described IPA in a 16-month-old black female; she also showed iris coloboma and single central deciduous maxillary incisor.

Urgelles et al. (1996) reported a patient with typical cutaneous changes of hypomelanosis of Ito as well as a midfacial flat angioma and an intracranial arteriovenous malformation.

Incontinentia Pigmenti, Sporadic

Cases of X/autosome translocation suggested the existence of a form of incontinentia pigmenti due to chromosomal aberration in the vicinity of the centromere (IP1), whereas linkage studies with RFLPs suggested that IP is located in the Xq28 band (IP2; 308300). Happle (1987) suggested that the second case of Hodgson et al. (1985) and the case of Gilgenkrantz et al. (1985) in fact had hypomelanosis of Ito rather than IP. As in the case of Hodgson et al. (1985), inflammatory or bullous skin lesions were absent in the case of Gilgenkrantz et al. (1985). The borders between dark and light skin were sharper than usually seen in the postinflammatory hyperpigmentation of incontinentia pigmenti. Furthermore, the patient suffered from severe mental retardation and seizures, and the teeth, more often affected in IP, were normal.

Happle (1998) reviewed the evidence that hypomelanosis of Ito is not an entity but merely a symptom of many different states of mosaicism, and specifically suggested that the 'sporadic type of incontinentia pigmenti' or so-called IP1 is hypomelanosis of Ito. The absence of typical neonatal inflammatory signs of incontinentia pigmenti is characteristic of hypomelanosis of Ito.

Ruggieri (2000) expressed skepticism about the existence of familial HMI.

Population Genetics

Pascual-Castroviejo et al. (1988) studied 34 Spanish children with this disorder. The incidence was about 1 per 1,000 new patients consulting a pediatric neurologic service, or 1 in 8,000 to 10,000 unselected patients in a children's hospital. About 94% of patients showed noncutaneous abnormalities. Autosomal dominant inheritance was demonstrable in some.

Inheritance

Parent-child affection was reported by Grosshans et al. (1971) and by Rubin (1972).

Hauschild et al. (1982) presented a case and suggested autosomal dominant inheritance. Microscopic changes were typical. This condition is also confused with Naegeli syndrome (161000).

Sacrez et al. (1970) reported familial occurrence: a mother and 3 daughters were affected. Cytogenetic analysis performed in one of the daughters in 1969 showed no visible abnormality, but translocation of a small segment might have gone unnoticed.

Cytogenetics

Incontinentia pigmenti was mapped to Xp11 by observations in 2 cases of X/autosome translocation (Hodgson et al., 1985). In both, a de novo X-autosome translocation involved Xp11. Gilgenkrantz et al. (1985) found t(X;9)(p11;q34) in a girl with IP and suggested that the IP gene may be at Xp11. In the second case of Hodgson et al. (1985) and in the case of Gilgenkrantz et al. (1985), almost the same breakpoint on chromosome 9 was involved, namely, q34. Happle (1987) suggested that the gene in this case is an autosomal dominant lethal gene located at 9q33-qter. In most cases, which are almost always sporadic, the condition is present in mosaic form, manifesting itself in skin lesions that follow the lines of Blaschko and rising from an early somatic mutation or from a gametic half-chromatid mutation. In the 2 published cases discussed by Happle (1987), the mosaicism was functional rather than genomic and the consequence of the inactivation of the portion of chromosome 9 that was translocated to one X chromosome.

In a girl with IP, mental retardation, and short stature, de Grouchy et al. (1985) found 45,X/46,X,r(X) mosaicism. Since the ring was very small, the finding suggests that the IP locus is juxtacentromeric, e.g., at Xp11. Mules (1985) observed a balanced translocation, t(X;4)(q21;q28), in a girl with probable incontinentia pigmenti. Kajii et al. (1985) described incontinentia pigmenti in a 19-month-old girl who also had bilateral retinoblastoma and carried a de novo translocation t(X;13)(p11.21;q12.3). Q-banding analysis showed that the translocated chromosomes were of paternal origin. The derivative X chromosome was late-replicating in 9% of cultured peripheral blood lymphocytes and in 1% of skin fibroblasts. The red cell esterase D (133280) activity was normal. Kajii et al. (1985) raised the possibility that functional monosomy of 13q14 had occurred in a minority of retinoblasts due to spreading of inactivation from the translocated X chromosome segment.

Turleau et al. (1986) reported an infant with mosaicism for a microdeletion of the proximal region of 15q similar to that observed in the Prader-Willi syndrome (176270). They pointed to 3 earlier reports of chromosomal rearrangements in this disorder, all of different types. The diversity of chromosome rearrangements seemed to argue against a monogenic nature of this disorder, but the existence of deletion in 1 case and of supernumerary fragments in 2 other cases suggested to Turleau et al. (1986) that the hypothesis of a mendelian disorder mapped to chromosome 15 could not entirely be discarded. They mentioned another hypothesis, i.e., that this disorder is a nonspecific marker for mosaicism.

Moss and Burn (1988) described a 27-year-old man who had this disorder. He had 2 children, 1 of whom had a congenital postaxial ray defect of 1 leg which was considered coincidental. The man had a cataract on the right and right facial hemiatrophy as well as camptodactyly of the middle finger bilaterally. Donnai et al. (1988) described 3 unrelated patients, 2 female and 1 male. Two, with unusual abnormalities of their toes, had a mixture of diploid and triploid cells in cultured skin fibroblasts. Donnai et al. (1988) concluded from the study of these cases and a review of the literature that hypomelanosis of Ito is a manifestation of an etiologically heterogeneous group of disorders, the common factor being the presence of 2 genetically distinct cell lines.

In 8 patients with pigmentary anomalies reminiscent of this disorder, Thomas et al. (1989) demonstrated chromosomal mosaicism in lymphocytes and/or skin fibroblasts. In 7 patients, abnormal, dark pigmentation followed Blaschko lines. They found in the literature at least 36 similar examples of the association between pigmentary anomalies and chromosomal mosaicism, as well as 5 examples of associated chimerism. The pigmentary anomalies are pleomorphic, and the chromosomal anomalies involved autosomes and sex chromosomes. In commenting on the paper by Thomas et al. (1989), Hall (1989) pointed out that hypomelanosis of Ito is a highly heterogeneous disorder. They stated that nondermal involvement may help identify these individuals.

Thomas et al. (1989) provided a diagram of Blaschko lines, which were first described by Blaschko (1901). On the basis of studies of linear skin diseases, Jackson (1976) reviewed Blaschko's work and reproduced some of the original drawings. Moss et al. (1993) reported findings they interpreted as indicating that epidermal rather than dermal mosaicism determines Blaschko lines in hypomelanosis of Ito: chromosomal mosaicism was not detected in lymphocytes or dermal fibroblasts, but was clearly shown in epidermal keratinocytes. Furthermore, the abnormal cell line was confined to the hypopigmented epidermis, and the normal epidermis contained only normal cells.

Ritter et al. (1990) tabulated the nondermal anomalies in 61 patients with HMI, and the karyotype in 26 patients with HMI, including one of their own. They concluded that most patients are chromosome mosaics and that HMI is a causally nonspecific marker for chromosome mosaicism in persons with sufficiently dark skin to show lighter patches. Flannery (1990) commented on pigmentary dysplasias and genetic mosaicism. Chitayat et al. (1990) reported a case of this disorder in association with trisomy 18 mosaicism as evidence that it is a nonspecific marker of somatic mosaicism. Lungarotti et al. (1991) described this disorder in a 3-year-old girl who had an t(X;18) translocation with the breakpoint at Xp11. They pointed out that this was the sixth reported case of this disorder in association with an X/autosome translocation involving Xp11. Donnai and Read (1992) emphasized the paramount importance of mosaicism either for a chromosomal abnormality or for a point mutation in this disorder. They pointed to the report by Flannery et al. (1985) as the first evidence of mosaicism in this disorder.

Vormittag et al. (1992) observed hypomelanosis of Ito in mother and daughter. Although normal chromosomal findings were found after culture of peripheral lymphocytes, a diploid/tetraploid mosaicism (46,XX/92,XXXX) was found in cultured skin fibroblasts derived from a hypopigmented skin area in the mother, with a slowly decreasing tetraploidy rate in the course of passaging. In cultures of normal cells, only occasional tetraploid cells were found. Biopsy was refused in the case of the daughter. Steichen-Gersdorf et al. (1993) described a de novo constitutional (X;17)(q13;p13) translocation in a girl with the clinical features of hypomelanosis of Ito and choroid plexus papilloma. Koiffmann et al. (1993) observed ITO in a 7-year-old white girl with an inherited X/autosome translocation 46,Xt(X;10)(p11;q11)mat. The mother, from whom she inherited the translocation, had no cutaneous abnormality but had had tonic-clonic seizures as a child with spontaneous remission. Koiffmann et al. (1993) reviewed other reports of ITO or incontinentia pigmenti associated with translocations involving Xp11. They suggested that IP1 and ITO represent allelic forms or a contiguous gene syndrome, with different genetic alterations in the Xp11 region giving rise to ITO or IP1 or borderline phenotypes. They also suggested that all patients with ITO due to Xp11 mutation have functional or genetic mosaicism.

Pellegrino et al. (1995) reported a patient with mental retardation, behavioral disturbances, and pigmentary anomalies consistent with hypomelanosis of Ito; cytogenetic analysis revealed mosaicism for an unbalanced translocation that resulted in monosomy for 7q34-qter and for 15pter-q13 in cells containing the translocation. The human homolog of the mouse 'pink-eyed dilution' locus maps to human 15q11-q13. By fluorescence in situ hybridization, Pellegrino et al. (1995) confirmed that their patient was deleted for one copy of a P gene in the cells with the unbalanced translocation, and for loci within the region critical for the Prader-Willi/Angelman syndromes. Although hypomelanosis of Ito is a heterogeneous condition, Pellegrino et al. (1995) postulated that, in their case and potentially in others, the phenotype may result directly from the loss of specific pigmentation genes.

Cannizzaro and Hecht (1987) observed a female with typical IP who displayed an X;10 translocation with breakpoints in Xp11.2 and 10q22. Thus, the breakpoint in the X chromosome in all 4 reported cases of X/autosome translocation in IP has been in band Xp11. Cannizzaro and Hecht (1987) suggested that the IP gene is most likely in subband Xp11.2.

Using nonisotopic in situ hybridization technique and an X centromere-specific probe, Crolla et al. (1989) confirmed the Xp11 breakpoint in 3 cases of X/autosome translocation and a ring-X case. However, results from a fifth case, t(X;17), previously reported by Hodgson et al. (1985), showed that the X breakpoint was within the centromeric alphoid repetitive sequences. The clinical presentation in all 5 patients was the same. Gorski et al. (1991) stated that these 5 unrelated patients with nonfamilial IP and a constitutional de novo reciprocal X/autosome translocation all showed a breakpoint involving Xp11.21. They concluded that the breakpoints in 3 of the 5 patients whom they studied was separated by a distance of at least 1,250 kb. In a case of ring X chromosome in a female with IP, Sefiani et al. (1989) found breakpoints in or distal to p11.22 and between q12.2 and q13.1. Bitoun et al. (1992) described incontinentia pigmenti in association with an apparently balanced translocation t(X;5)(p11.2;q35.2). They pointed out that the 7 previously reported cases of type I IP with translocations had the same Xp11 breakpoint. They noted that there was no history of bullous lesions in these cases. They expressed the view that lesions of this type occur only in the 'classical' type II, or familial form of IP, which maps to Xq28.