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SHORT COMMUNICATION
Skin Lesions Suggesting Type 2 Segmental Mosaicism in Noonan Syndrome
Rudolf HAPPLE
Department of Dermatology, Medical Center – University of Freiburg, DE-79104 Freiburg, Germany. E-mail: [email protected]
Accepted Oct 15, 2018; E-published Oct 15, 2018
In autosomal dominant disorders, 2 types of segmental
mosaicism can be distinguished. The well-known type
1 results from a postzygotic mutation in an otherwise
healthy embryo, whereas type 2 originates in a hetero-
zygous embryo due to early loss of the corresponding
wild-type allele, usually by somatic recombination (1).
This mechanism gives rise to pronounced segmental
involvement being superimposed on the non-segmental
lesions of a given phenotype. Molecular proof of type 2
segmental mosaicism (T2SM) has been provided in many
autosomal dominant skin disorders, including Hailey-
Hailey disease, Darier’s disease, neurofibromatosis 1,
Gorlin syndrome, and PTEN hamartoma syndrome (2).
Noonan syndrome (NS) is an autosomal dominant
trait characterized by short stature, dysmorphic facial
appearance, low-set, posteriorly rotated ears, and conge-
nital heart defects including pulmonic stenosis (3). The
disorder (OMIM #163950) is genetically heterogeneous
(4). Approximately 50% of cases are caused by a hete-
rozygous mutation in PTPN11. The remaining cases are
due to mutations in SOS1, KSRS, NRAS, BRAF, RIT1,
SOS2, or LZTR1 (4). The objective of this article is to
review some reports that document cutaneous features
suggesting T2SM in children with NS.
CASE REPORTS
Case 1
Lacombe et al. (5) described a newborn boy with re-
spiratory distress and typical features of NS, including
hypertelorism, ptosis, low-set posteriorly rotated ears,
micrognathia, cleft palate, bilateral cryptorchidism, and
redundant nuchal skin. X-ray examination revealed 13
ribs with a supernumerary vertebra. Echocardiography
revealed an aortic supravalvular stenosis with cardiomyo-
pathy. Moreover, a 6×8 cm large patch of “molluscoid”
tissue, covered with folded skin of normal colour, was
noted in the left frontoparietal area of the scalp. The
boy died from cardiac failure at the age of 3 weeks.
Histopathological examination of the unusual segmental
scalp lesion showed hyperplasia of normal skin with
proliferation of “radiating adipocytes”. The authors
categorized this lesion as “nevoid cutis verticis gyrata”.
The patient’s mother had typical features of NS. Later,
the same case was published in French by Masson et al.
(6). Histopathologically, they described “an organoid
aspect with thickened subcutis of which the lobules are
oriented in a radial pattern above the fascia.” The authors
doi: 10.2340/00015555-3071
Acta Derm Venereol 2019; 99: 240–241
noted that the “nevoid cutis verticis gyrata” was clinically
reminiscent of a large plexiform neurofibroma, although
the histopathological findings excluded this diagnosis.
Case 2
Fox et al. (7) documented a 2-day-old African-American
girl who had mild respiratory distress, a III/VI holosys-
tolic murmur at the left sternal border, hypertelorism,
epicanthal folds, mild proptosis, a depressed nasal bridge,
posteriorly rotated and low-set ears, a high-arched palate,
redundant nuchal folds, and wide-spaced nipples. More-
over, she had a 6×6 cm “plaque of thick furrows, folds
and relative alopecia in the left frontoparietal scalp.” The
authors felt that this skin lesion was most consistent with
“cutis verticis gyrata” in a patient with NS. The patient’s
mother had non-segmental features of NS. The authors
believed that “resolved intrauterine scalp lymphedema
may account for the clinical presentation of cutis verticis
gyrata in patients with Noonan and Turner syndrome.”
Case 3
Boente et al. (8) reported a 10-year-old girl with typical
features of NS, including triangular facial appearance,
small low-set, posteriorly rotated ears, micrognathia,
curly hair, low nuchal hairline, and webbed short neck.
Moreover, she had in the right dorsal area a large pla-
que consisting of thick folds and deep furrows (Fig. 1).
Microscopic examination of a biopsy obtained from
this segmental lesion showed a normal epidermis “with
disorganization of the dermal collagen”. The authors
concluded that the unilateral “cutis gyrata” on the girl’s
back “could also be considered a sign of the lymphatic
alteration within this syndrome.”
DISCUSSION
These 3 cases may best be explained at present as pos-
sible examples of T2SM in children with NS. The strict
unilaterality of the skin lesions can be taken as an argu-
ment against the supposition that they simply represent
sequelae of intrauterine lymphedema. Future molecular
research may show whether the hypothesis of T2SM
holds true.
In this context, it may be worth mentioning that the
term “cutis verticis gyrata” has also been used for the
large segmental cephalic hamartomas, as sometimes
noted in tuberous sclerosis (9), which are probably a
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