To the best of our knowledge only 15 reports of familial HMI have been described in the current literature (Table
1). HMI may present in both sexes and dominant, recessive and X-linked inheritances have been reported [
1‐
3] as chromosomal aberrations of this rare disorder. HMI may also be transmitted from parent to child with variable presentation and expressivity (Table
1). In the HMI family described by Sacrez
et al. and Grosshans
et al. [
7,
8], the mother and her three daughters were all affected. The daughters showed clinical and histopathological cutaneous changes typical of HMI, marked psychomotor retardation, strabismus, hypodontia and skeletal dysplasia. The mother had only non-specific hypopigmented areas. The inheritance in this family with four female individuals suggested an X-linked dominant trait. Cram and Fukuyama described HMI in a child, his mother and his maternal grandfather [
9]. Patrizi
et al. [
10] reported two siblings, a boy and a girl, with typical HMI and neurological symptoms. The mother had typical pigmentary abnormalities without neurological defects [
10]. Vormittag
et al. [
3] reported a family with an affected mother and daughter that was probably consistent with HMI. The mother showed hypopigmentation, eye anomalies, epileptic seizures and skeletal abnormalities. Her daughter displayed hypopigmentation following the lines of Blaschko and eye anomalies [
3]. A pair of monozygotic and a pair of dizygotic twins with a patchy and linear hypopigmentation and autism were reported by Zappella [
11]. He found that, in the family of the dizygotic twins, the father had three small depigmented spots and the mother had two depigmented streaks [
11]. Our familial case showed only skin involvement without systemic alterations. Regarding the association between HMI and systemic features, Nehal
et al. suggested that the incidence of associated abnormal features described in previous studies is overstated, and that pigmentary anomalies along the lines of Blaschko are associated with abnormal systemic features less often than previously reported [
12]. In their retrospective case series the authors detected that extra-cutaneous abnormal features were present in 16 (30%) of 54 children with aberrant pigmentation along the lines of Blaschko and in particular in only 9 (33%) of 27 with hypomelanosis of Ito. Notably, however, the systemic manifestations can be related to the level of mosaicism in the affected organs. Although we cannot provide evidence of a common origin of the HMI in the father and his daughter in our case report, we postulate that the HMI in the daughter can be due to a rescue of the trisomy 2 zygote. When this is considered, the normal neurologic and systemic development of the young proband allows us to clinically exclude the effects of uniparental disomy (UPD) [
13]. It is known that cases of HMI not only show considerable phenotypic variability, but also genotypic variability, with a wide spectrum of chromosomal mosaicisms. A trisomy 2 mosaicism as described in our case report has been reported only once in HMI to the best of our knowledge [
14]. The authors described a newborn girl with classic skin findings of HMI with true (postnatal confirmation) trisomy 2 mosaicism. Complete trisomy 2 usually results in first trimester pregnancy losses; trisomy 2 is not fatal only when present in a mosaic style
. Cases of infants born live with trisomy 2 mosaicism previously described are characterized by intrauterine growth retardation and multiple congenital systemic anomalies [
15]. Due to the finding of different chromosomal aberrations, it has been suggested that HMI does not represent a single condition, but rather a non-specific manifestation of chromosomal mosaicism [
4]. Our clinical observations suggest that HMI constitutes a general diagnostic definition that can include different sporadic and/or familial clinical phenotypes characterized by the distribution of hypopigmented streaks along the Blaschko lines.
Table 1
Reported case of familial hypomelanosis of Ito (HMI)
| 1963 | Masumizu | Parents | None | Not performed |
| 1969 | Piñol et al.
| Mother and her daughter | Myopia, chorioretinal and retinal pigment epithelium atrophy in the right eye | Not performed |
| 1970 | Sacrez et al.
| Mother and three daughters | Congenital encephalopathy | Normal (peripheral lymphocytes) |
| (performed only in one daughter) |
| 1971 | Grosshans et al.
| Mother and three daughters | Marked psychomotor retardation, strabismus, hypodontia and skeletal dysplasia | Not performed |
| 1972 | Rubin | Two brothers, sister, father and paternal uncle | None | Not performed |
| 1973 | Jelinek et al.
| Distant and deceased relatives, paternal great aunt | Epileptic seizures and strabismus | Not performed |
| 1974 | Cram and Fukuyama | Child, his mother and his maternal grandfather | Epileptic seizures | Not performed |
| 1975 | Hellgren | Mother, sister and brother | Macrocheilia, iris pigmented spots and hair anomalies | Not performed |
| 1975 | Griffiths and Payne | Mother and father (first cousins) | Ocular hypertelorism, nails and fingers anomalies | Not performed |
| 1977 | Schwartz et al.
| Nephew and maternal grandmother | Epileptic seizures, retardation, macrocephaly, delayed closure anterior fontanelle, leg length discrepancy, scoliosis and iridial heterochromia | Not performed |
| 1987 | Patrizi et al.
| Mother and two sibs | Neurological symptoms | Not performed |
| 1990 | Amon et al.
| Mother and daughter | Ocular symptomatology | Deletion of chromosome 15 |
| (peripheral lymphocytes and fibroblasts) |
| 1991 | Montagna et al.
| Mother and two sibs | Mental and cerebellar signs, organic psychosis | Normal (peripheral lymphocytes) |
| 1992 | Vormittag et al.
| Mother and daughter | Epileptic seizures, ophthalmologic abnormalities, scoliosis and lordosis | Normal (peripheral lymphocytes) |
| Tetraploidy in #2 (23%), #5 (11%), #11 and #14 (6%), #18 and #21 (2%) (fibroblasts) |
| 1993 | Zappella | A pair of monozygotic and a pair of dizygotic twins | Autism, delayed psychomotor development and microcephaly | Normal (peripheral lymphocytes) |
| 2014 | Ponti et al.
| Father and daughter | None | Normal (peripheral lymphocytes) |
| Paternal trisomy 2 (fibroblasts) |