articulo cientifico reporte de caso

1. Pediatric Dermatology. 2019;00:1–5. wileyonlinelibrary.com/journal/pde | 1
Pediatric
Dermatology
© 2019 Wiley Periodicals, Inc.
1 | INTRODUCTION
Neonates with Down syndrome (DS) have an increased risk of he‐
matologic abnormalities affecting megakaryoblastic differentiation.
This may occur either as acute myeloid leukemia (AML) or, less fre‐
quently, in the form of transient abnormal myelopoiesis (TAM) or
transient myeloproliferative disorder (TMD). Transient myeloprolif‐
erative disorder is a rare clonal myeloid proliferation characterized
by peripheral leukocytosis, mimicking at presentation AML, particu‐
larly of the megakaryoblastic subtype.1
However, TMD occurs exclu‐
sively in infants with DS or with trisomy 21 (T21) mosaicism, and in
the majority of cases, other than having a low potential of transition
to nontransient AML, it resolves spontaneously.2
The leukemogenic source of this disorder is a somatic mutation
of the X‐linked GATA1 gene. GATA1 encodes a transcription factor
that plays an essential role in the differentiation and proliferation of
megakaryocytes.3
Cutaneous manifestations of TMD are noted in only 5% of af‐
fected neonates and present as diffuse erythematous, crusted pap‐
ules, papulovesicles, and pustules, often with prominent and initial
facial involvement.4
We report the case of a DS newborn who presented a widespread
vesiculopustular eruption, in whom genetic analyses detected a so‐
matic mutation of GATA1, leading to a diagnosis of TMD. We also
review the previously published cases describing vesiculopustular
lesions associated with TMD and DS. We were able to find 23 re‐
ported English‐language cases on a search of the PubMed database.
2 | CASE REPORT
A male neonate with DS, born at 39 weeks gestation, was noted on
the first day of life (DOL) to have a very high white blood cell (WBC)
count (88,100/mm3
), with 78% megakaryoblasts with “blebby”
DOI: 10.1111/pde.13931
C A S E R E P O R T
Neonatal vesiculopustular eruption in Down syndrome and
transient myeloproliferative disorder: A case report and review
of the literature
Valeria Brazzelli MD1
| Aviad Segal BS1
| Carlotta Bernacca MD1
| Adi Tchich BS1
|
Vittorio Bolcato MD1
| Giorgio Croci MD2
| Tommaso Mina MD3
| Marco Zecca MD3
|
Simona Zanette MD4
| Mauro Stronati MD4
1
Institute of Dermatology, IRCCS Policlinico
San Matteo Foundation, University of Pavia,
Pavia, Italy
2
Unit of Anatomic Pathology,
IRCCS Policlinico San Matteo
Foundation, University of Pavia, Pavia, Italy
3
Pediatric Haematology/Oncology,
IRCCS Policlinico San Matteo
Foundation, University of Pavia, Pavia, Italy
4
Neonatal Intensive Care Unit,
IRCCS Policlinico San Matteo
Foundation, University of Pavia, Pavia, Italy
Correspondence
Valeria Brazzelli, MD, Institute of
Dermatology; IRCCS Policlinico San Matteo
Foundation, University of Pavia, Piazzale
Golgi, 2, 27100 Pavia, Italy.
Emails: vbrazzelli@libero.it; v.brazzelli@
smatteo.pv.it
Abstract
Transient myeloproliferative disorder (TMD) is a spontaneously resolving clonal my‐
eloid proliferation characterized by circulating megakaryoblasts in the peripheral
blood that is restricted to neonates with Down syndrome (DS) or those with trisomy
21 mosaicism. Cutaneous manifestations of TMD are observed in only 5% of affected
neonates and present as a diffuse eruption of erythematous, crusted papules, papu‐
lovesicles, and pustules, often with prominent and initial facial involvement. We de‐
scribe the case of a male infant with DS and TMD, associated with a vesiculopustular
eruption, which appeared on day 36 of life, and review previous cases.
K E Y W O R D S
Down syndrome, neonatal vesiculopustular eruption, transient myeloproliferative disorder,
trisomy 21

2. 2 | Pediatric
Dermatology
BRAZZELLI et al.
appearance and severe anemia, together suggesting a diagnosis of
TMD. A somatic mutation of GATA1 was found in peripheral blood
cells, thus confirming the clinical suspicion of TMD.5
On day 5 of
life, there was an increase in WBC and megakaryoblasts, associated
with progressive splenomegaly. Chemotherapy was started with
low‐dose intravenous cytarabine (3 mg/kg/day for 5 days; first cycle
on day 16 of life; second cycle on day 27 of life). After a second
course of chemotherapy, WBC declined to 5,010/mm3
and mega‐
karyoblasts to 26%. On day 45 of life, WBC count was within the
normal range, with further reduction of megakaryoblasts (2%).
On day 36 of life, erythematous papules appeared on the face and
scalp, followed 2 days later by vesicles on the cheeks, close to the mu‐
cosa of the upper lip (Figure 1), and to a lesser extent on the base of
the neck and arms (Figure 2). Some of the vesicles were ruptured with
apparently serous content. Bacterial and fungal cultures and Tzanck
smear were negative, as were the serologic tests for herpes simplex 1
and 2, varicella zoster virus, and cytomegalovirus antigens. Screening for
autoantibodies against BP180 and BP230 was negative. Histopathology
of a biopsied vesicle (on day 37 of life) showed a pustular dermatitis with
subcorneal vesiculopustules, neutrophilic infiltration of epidermis, and
perivascular inflammation in the superficial dermis (Figure 3A,B, and C).
Atypical cells, blasts, or viral inclusions were not present (Figure 3D). The
hematologic findings, negative workup for autoimmune or infectious eti‐
ology, clinical presentation, and genotyping all supported a diagnosis of
vesiculopustular lesions associated with TMD. Topical therapy was ini‐
tiated with aqueous solution of eosin 2% and mupirocin ointment. The
patient was transferred to a local hospital, close to his home, and the
eruption reportedly resolved 7 weeks after its onset.
FI G U R E 1 Erythematous papules and vesicles on the face of the
baby on day 38
FI G U R E 2 Erythematous papules and vesicles on the left arm
FI G U R E 3 Histopathological findings depict the presence of a subcorneal pustule (A, 2x) with an underlying mild dermal (B, 10x),
perivascular and interstitial inflammatory infiltrate (C, 20x). The cellular composition of the latter consists of scant lymphocytes and
histiocytes within a predominant population of segmented neutrophils. No evidence of myeloid blasts nor of precursors were present, as
also ascertained by CD34 negativity on the infiltrate (D, CD34 stain, 20x)

3. | 3
Pediatric
Dermatology
BRAZZELLI et al.
TA
B
L
E
1
TMD
cases
associated
with
vesiculopustular
eruption
reported
in
the
literature
No
Sex
Phenotype
DOL
a
Sites
of
appearance
Typical
findings
on
lesional
biopsy
(B)
or
Wright‐stained
smear
(WSS)
Week
of
resolution
b
Ref
1
M
Normal
DS
mosaic
3
Face,
trunk,
and
limbs
c
c
9,13
2
M
Normal
DS
mosaic
1
Trunk
and
limbs
B:
Lymphoid
infiltrate
with
giant
cells
2
9,13
3
M
Normal
DS
mosaic
1
Face
and
then
to
all
the
body
B:
Lymphocytoid
leukemic
clusters
in
the
perivascular
and
perifollicular
regions
4
9,13
4
M
DS
1
Scalp,
forehead,
cheeks,
trunk,
and
limbs.
Areas
of
trauma
B:
Intraepidermal
spongiotic
vesiculopustules.
Dermal
perivascular
infiltrate
of
immature‐appearing
myeloid
cells.
2
7
5
M
DS
13
Face
B:
Subcorneal
spongiotic
vesicles
with
immature
myeloid
infiltrate
in
vesicles
and
perivascular
8
8
6
M
DS
1
Face,
trunk,
limbs,
palms,
and
soles
WSS:
Immature
leukocytes
2
8
7
F
DS
2
Face,
chin,
and
cheeks.
WSS:
Immature
myelocytes
and
promyelocytes
with
some
mature
neutrophils
2
8
8
M
DS
4
Face,
trunk,
and
limbs
B:
Intraepidermal
pustule
with
mixed
infiltrate,
including
immature‐appearing
mononuclear
cells
with
atypical
nuclei
12
9
9
F
DS
3
Face,
trunk,
and
arm
B:
Neutrophils,
with
surrounding
patchy
epidermal
spongiosis.
Marked
exocytosis
of
mixed
inflamma‐
tory
cells
was
noted.
2
9
10
F
Normal
DS
mosaic
6
Face,
trunk,
and
perineum
WSS:
No
eosinophils,
but
numerous
blast
forms
4
2
11
F
DS
2
Sites
of
trauma
c
12
13
12
M
DS
NR
Cheeks,
trunk,
and
limbs
c
8
13
13
F
Normal
DS
mosaic
1
Face,
cheeks,
and
previ‐
ous
sites
of
trauma
B:
Prominent
infiltration
of
mononuclear
cells
with
slightly
atypical
nuclei
within
the
epidermis
and
upper
dermis.
Infiltrated
cells
were
myeloid
lineage
or
immature
myeloid
(myeloperoxidase
staining—
suggesting
immature
neutrophils)
8
6
14
M
DS
1
Face,
trunk,
and
limbs
B:
Subcorneal
pustules
containing
neutrophils
and
eosinophils.
Immunohistochemical
staining
showed
that
the
infiltrating
cells
were
positive
for
myeloperoxidase
but
negative
for
CD3
and
CD20.
Furthermore,
there
were
no
CD41‐positive
cells,
suggesting
that
TMD
cells
had
already
disappeared.
GATA1
positive
1.5
10
15
F
Normal
DS
mosaic
3
Face,
trunk,
and
limbs
B:
Necrosis
of
the
epidermis;
and
a
mixed
inflammatory
infiltrate
of
neutrophils,
lymphocytes,
histio‐
cytes,
and
eosinophils.
Immature
myeloid
cells
also
were
noted.
c
11
16
F
DS
8
Face,
cheeks,
and
limbs
B:
Large
mononuclear
cells
with
hyperchromatic
nuclei
and
abundant
eosinophilic
cytoplasm
consistent
with
immature
myeloid
cells
with
megakaryoblastic
origin.
c
12
17
M
DS
9
Face,
cheeks,
and
limbs
B:
Moderate
dermal
infiltrate
with
perivascular
arrangement,
spreading
to
fatty
tissue
composed
by
cells
with
irregular
nuclei,
granular
chromatin,
and
scattered
cytoplasm.
Stains
with
myeloperoxidase,
CD3,
and
CD69
were
positive
8
13
18
M
DS
16
Face,
trunk,
and
limbs
B:
Atrophic
epidermis,
focal
liquefaction
of
the
basal
layer,
and
dermal
perivascular
blast
cell
infiltrate
mixed
with
eosinophils
and
neutrophils,
as
well
as
leukocytoclastic
vasculitis.
16
13
(
C
o
n
t
i
n
u
e
s
)

4. 4 | Pediatric
Dermatology
BRAZZELLI et al.
3 | DISCUSSION
Transient myeloproliferative disorder is unique among clonal neo‐
plastic disorders because of its relation to DS in the neonatal period,
with a reported incidence ranging from 4% to 10% in DS neonates,1
and its natural history of spontaneous regression. Although most
cases of TMD undergo spontaneous remission, 20% of affected ne‐
onates ultimately develop acute leukemia later in life,6
usually with
the characteristics of megakaryoblastic leukemia. Transient myelo‐
proliferative disorder has been shown to be associated with GATA1
mutations in the blast cells.3
Morphologically, TMD cells are indis‐
tinguishable from myeloid blast cells and often harbor features of
megakaryoblasts, as was demonstrated in our case.
Cutaneous eruptions related to TMD are noted in only 5% of
affected neonates.4
To our knowledge, 23 cases have been pub‐
lished to date (Table 1). The clinical presentation is usually a diffuse
eruption of erythematous, crusted papules, papulovesicles, and pus‐
tules, often with prominent and initial facial involvement (usually the
cheeks) that can be distributed over any part of the body (usually the
trunk and limbs) and, in rare cases, palms and soles of feet, perineum,
and neck.2,6-16
In 25% of cases, the lesions are described in sites of
pressure or trauma. The skin manifestations usually appear in the
first days of life, between days 1 and 22, with a median of 3 days.
They spontaneously resolve, without scarring, concurrently with the
resolution of TMD, usually between 1 and 2 months of age (with an
average of 6.5 weeks). Our case is unusual because the cutaneous
eruption started at the 36th DOL, after the beginning of chemother‐
apy, when hematologic improvement had already been achieved.
The ratio between males and females is 2:1, and from 24 cases,
6 cases were newborns with DS mosaicism. Although there are not
many explanations on the different incidence of the disease be‐
tween the two genders, the presence of somatic mutations of GATA1
on the X chromosome may contribute to the trend toward a higher
incidence in boys (single GATA1 mutation) as compared to girls (one
GATA1 mutation and a possibly “protective” normal gene).3,17
Upon literature review, we found no strong correlation be‐
tween WBC counts and the phase of skin eruption, with a wide
range of WBC counts observed at presentation (see Table 1). In
one case, there was an increase in the WBC count after onset of
the cutaneous eruption (see Table 1, and case no. 16). No correla‐
tion was found between the number of blasts circulating in the
peripheral blood and the presence of the skin eruption, either. In
2 cases, the number of myeloblasts/megakaryoblasts was much
lower than the peak (see Table 1, and cases no. 16 and 24). In re‐
viewing published lesional histopathology and Tzanck smears, in
5 cases, the authors were able to demonstrate the presence of
immature myeloid cells of megakaryoblastic origin (see Table 1,
and cases no. 4, 5, 7, 10, and 16), whereas 5 cases, 9-11,15
including
ours, showed a pustular dermatitis with subcorneal, vesiculopus‐
tular, neutrophilic infiltration, and perivascular inflammation in the
superficial dermis, with no atypical cells or megakaryoblasts. The
timing of biopsy during the evolution of TMD, with the presence
No
Sex
Phenotype
DOL
a
Sites
of
appearance
Typical
findings
on
lesional
biopsy
(B)
or
Wright‐stained
smear
(WSS)
Week
of
resolution
b
Ref
19
M
DS
20
Face
and
cheeks
c
12
13
20
M
DS
1
Face,
cheeks,
trunk,
and
limbs
c
8
13
21
M
DS
1
Face,
cheeks,
and
trunk
c
5
14
22
F
DS
1
Face,
trunk,
and
limbs
WSS:
Polymorphonuclear
leukocytes
and
myelocytic
cells
B:
Pustular
dermatitis
with
subcorneal
vesiculopustule,
neutrophilic
infiltration
of
epidermis
and
perivas‐
cular
inflammation
in
superficial
dermis.
Atypical
cells,
blasts,
or
viral
inclusions
were
not
present.
c
15
23
M
DS
2
c
B:
Nonspecific
epidermal
erosion
and
perivascular
dermatitis
4
16
24
M
DS
36
Face,
cheeks,
neck,
and
limbs
B:
Pustular
dermatitis
with
subcorneal
vesiculopustules,
neutrophilic
infiltration
of
epidermis,
and
perivascular
inflammation
in
superficial
dermis.
Atypical
cells,
blasts,
or
viral
inclusions
were
not
present.
8
Our
case
a
DOL—Day
of
life:
This
number
corresponds
to
the
age
at
time
of
cutaneous
findings.
b
Week
of
resolution
is
the
number
of
weeks
from
onset
that
the
vesiculopustular
eruptions
took
to
resolve
and
disappear.
c
Information
not
available.
TA
B
L
E
1
(Continued)

5. | 5
Pediatric
Dermatology
BRAZZELLI et al.
of a proliferative phase with megakaryoblasts or regression phase
without atypical cells, probably contributes to the described vari‐
able presentation incidences.3
Further studies are warranted to
understand the associated biologic factors that contribute to the
cutaneous eruption of TMD, given that TMD presents in only a
fraction of children with trisomy 21, and only a fraction of these
patients develop a cutaneous eruption, the appearance of which is
unrelated to the number of circulating blast cells.
4 | CONCLUSION
In conclusion, we highlight that the typical cutaneous findings of
TMD appear unrelated to either age at disease onset or to the num‐
ber of circulating WBC/blasts in the peripheral blood. Moreover, our
case is unique in that our patient demonstrated onset of the cutane‐
ous manifestations of his TMD even after chemotherapy had been
initiated, with hematologic response. Transient myeloproliferative
disorders should be included in the differential diagnosis for pustules
presenting in the newborn period in children with Down syndrome.
Reasoning conversely, unexplained pustules in phenotypically nor‐
mal children with increased WBC counts should prompt the clinician
to look for blasts in the peripheral smear and consider DS or trisomy
21 mosaicism.
ACKNOWLEDGMENTS
We wish to acknowledge the contribution provided by Einat Segal
for reviewing the English in this article.
ETHICAL APPROVAL
The study was conducted according to the Declaration of Helsinki.
ORCID
Valeria Brazzelli https://orcid.org/0000-0001-5898-6448
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How to cite this article: Brazzelli V, Segal A, Bernacca C, et al.
Neonatal vesiculopustular eruption in Down syndrome and
transient myeloproliferative disorder: A case report and
review of the literature. Pediatr Dermatol. 2019;00:1–5. https​
://doi.org/10.1111/pde.13931​