ARTICLE
Many skin disorders reflect genetic mosaicism. A mosaic is an organism
that is composed of two or more genetically distinct cell populations.
Many types of cutaneous mosaicism have been observed, Blaschko's lines
being the most well-known manifestation. It has been proposed that some
disorders are the result of mosaicism for a lethal autosomal trait. If
the trait were to exist in all cells of the organism (e.g. be holoblastic),
it would not survive. Examples include McCune-Albright syndrome and nevus
sebaceus or nevus sebaceus syndrome. Mosaicism has been demonstrated at
the molecular level for McCune-Albright syndrome [1]. Occasionally, disorders
that can exist only in a mosaic state are transmitted as dominant traits
or otherwise show familial occurrence. This is highly unusual and has
been described for a few disorders, notably Becker's hairy nevus [2],
Klippel-Trenaunay syndrome [3] and nevus sebaceus [4-7]. To explain this,
the concept of paradominant inheritance was put forward [8-10]. Heterozygous
carriers of a genetic defect are phenotypically normal and pass on the
trait to their children, who appear normal as well. When a mutation leads
to loss of the healthy allele during embryogenesis, a clone of mutant
cells will arise that is either homozygous or hemizygous for the mutant
allele. The phenotype is then expressed in a mosaic form, with the extent
of the abnormalities depending upon the stage of embryogenesis at which
the mutation took place.
Here, we present two sibs with a nevus
sebaceus of the scalp in the absence of other abnormalities. The parents
are not affected. Occurrence of a nevus sebaceus in sibs born from healthy
parents has not been previously described and may represent another example
of paradominant inheritance. The identical location in two sibs may be
coincidental or represent a clue to the underlying mutational mechanism.
Case reports
An 8-year-old boy and his 6-year-old sister presented to the outpatient
clinic with identical skin lesions on the scalp. Examination of the boy
showed a sharply demarcated lesion on the left parietal scalp. It had
a yellowish micronodular surface, was devoid of hair and had an elastic
consistency. It measured approximately 4.5 x 3 cm (Fig.
1). His sister had an identical though smaller lesion, located
slightly more toward the apex (Fig.
2). Other skin abnormalities could not be found. No overt neurological
abnormalities or eye lesions were present. Histological examination showed
hyperkeratosis and papillomatous change of the epidermis. Immature hair
follicles filled with keratin were seen as well as some mature sebaceous
glands (Fig. 3). These
findings are consistent with a diagnosis of nevus sebaceus.
Discussion
Nevus sebaceus of Jadassohn (12, MIM 163200) is defined as a hamartoma
with a predominantly sebaceous component. The development of the latter
is dependent upon the patient's age: it is inconspicuous during childhood
but develops strongly in puberty, accompanied by epidermal proliferation
with hyperkeratosis and papillomatosis. Hair follicles are absent. The
development of secondary tumors in the nevus is a well-known phenomenon.
The commonest secondary tumors are syringocystadenoma papilliferum and
trichoblastoma. Other types of tumor including malignancies have been
reported as well [12]. The lesions are found most commonly on the face
and scalp. If the nevus is accompanied by eye and brain abnormalities,
the denominator Schimmelpenning-Feuerstein-Mims syndrome is used. Although
some researchers believe that the different forms of epidermal nevi represent
mutations in different genes [13], we hypothesize that it is the extent
of the mosaicism that determines whether the phenotype is a nevus sebaceus
or a full-blown Schimmelpenning-Feuerstein-Mims syndrome. A mutation occurring
late in embryogenesis will give a phenotype of nevus sebaceus. If a mutation
occurs early in embryogenesis in an ectodermal cell whose progeny will
form part of the brain as well, the phenotype may be that of Schimmelpenning-Feuerstein-Mims
syndrome. It is difficult to explain all the gradual differences and overlap
in and between the different nevus sebaceus groups with a different gene
for each form, since all have the nevus sebaceus in common and one might
expect to see different types of nevi as well if different genes are involved.
The occurrence of nevus sebaceus in family members
has been previously described, though this is the first report of its
occurrence in siblings. We believe that paradominant inheritance is the
most plausible explanation for a familial occurrence such as the one described
here. The chance of a rare anomaly such as nevus sebaceus occurring twice
by coincidence, in sibs, is extremely remote, given the fact that the
incidence of nevus sebaceus must be estimated at less than 1 per 100,000
(extrapolated from the number of cases reported so far). Syndromes showing
paradominant inheritance are not amenable to classic genetic analysis.
Some newer molecular biology techniques, such as comparative genomic hybridization
and representational difference analysis [14, 15], might offer some hope
for the identification of the causative gene. The presence of two clonal
populations differing only in one gene makes such techniques useful.
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