Döring et al. BMC Pediatrics 2014, 14:126
http://www.biomedcentral.com/1471-2431/14/126

CASE REPORT

Open Access

A newborn with grouped facial skin lesions and
subsequent seizures
Michaela Döring1*, Karin Melanie Rohrer1, Ilias Tsiflikas2, Wolfgang Buchenau3, Marko Wilke4,
Rupert Handgretinger1, Christian Friedrich Poets3 and Rangmar Goelz3

Abstract
Background: Congenital grouped skin lesions are alarming signs of a variety of threatening diagnoses of quite
different origin. The present case report shows an impressive clinical pattern of a neonate and illustrates the
difficulty in differential diagnosis of mixed connective tissue disease and neonatal lupus erythematosus in
newborns. This reported case is to our knowledge the first description of an unrecognized mixed connective tissue
disease in the mother with an unusual clinical manifestation in the newborn, comprising skin lesions, neurological
damage and non-typical antibody constellation.
Case presentation: We report on a Caucasian female neonate from a perinatally asymptomatic mother, who
presented with grouped facial pustular-like skin lesions, followed by focal clonic seizures caused by multiple ischemic
brain lesions. Herpes simplex virus infection was excluded and both the mother and her infant had the antibody
pattern of systemic lupus erythematosus and neonatal lupus erythematosus, respectively. However, clinical signs in
the mother showed overlapping features of mixed connective tissue disease.
Conclusion: This case report emphasizes congenital Lupus erythematosus and mixed connective tissue disease as
important differential diagnoses of grouped skin lesions in addition to Herpes simplex virus-infection. The coexistence
of different criteria for mixed connective tissue disease makes it difficult to allocate precisely maternal and congenital
infantile disease.
Keywords: Congenital grouped skin lesions, Mixed connective tissue disease, Neonatal lupus erythematosus, Seizure

Background
Congenital grouped skin lesions are alarming signs of a variety of threatening diagnoses of quite different origin [1].
The present case report shows the surprising resolution of
an impressive clinical pattern of a neonate and his prenatally
asymptomatic mother. Infectious diseases and typical neonatal patterns as well as auto-immunological entities have to
be considered; especially in the latter, diagnosis may be difficult due to overlapping definitions.
Case presentation
A term female infant was delivered by a 39 year old
woman in a peripheral hospital after an uncomplicated 3rd
pregnancy with 41 week of gestational age. Delivery was
* Correspondence: michaela.doering@med.uni-tuebingen.de
1
Department I – General Paediatrics, Hematology/Oncology, University
Hospital Tuebingen, Children’s Hospital, Hoppe-Seyler-Str.1, Tuebingen 72076,
Germany
Full list of author information is available at the end of the article

assisted by vacuum extraction. Apgar score was 8/9/10
after 1/5/10 minutes respectively, and the infant had a
birth weight of 2920 g (8th percentile), a length of 50 cm
(20th percentile), and a head circumference of 35 cm (50th
percentile). The postnatal physical examination showed
grouped pustular lesions and annular erythema, partly
with central lightening, yellowish crusted plaques or slight
scaling on the skin, exclusively in the face and on the forehead (Figure 1). The rest of the integument and the mucosa were inconspicuous. The child was transferred to a
neonatal tertiary care center under the tentative diagnosis
of a herpes simplex virus (HSV) infection, and antiviral
therapy with aciclovir was promptly initiated. About six
hours postnatal, the baby developed focal clonic seizures
of the right arm. An electroencephalogram showed focal
temporo-parieto-occipital changes over the left hemisphere with low amplitude, slight increase of slow waves
and a reduced basic activity. Further, intermittent shortterm focal rhythmic parietal theta activity on the left as

© 2014 Döring et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain
Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article,
unless otherwise stated.

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Figure 1 Skin lesions and annular erythema. Pustular lesions and annular erythema, partly with central lightening, yellowish, crusted plaques or
slight scaling on the skin, exclusively in the face and on the forehead on the second day (A and B), after one month (C), and after three months (D).

well as rhythmic occipital delta activity on the left could
be detected while no typical epileptic discharges occured.
A lumbar puncture showed no sign of infection, with a
normal protein and white blood count. In particular, HSVPCR was negative. Anticonvulsive therapy with phenobarbital was initiated but seizures could only be controlled
after adding phenytoin. A diffusion- weighted magnetic
resonance imaging was performed on the 3rd day of life,
revealing multiple ischemic brain areas in the distribution
of the middle and posterior cerebral artery on the left side
(Figure 2A-C).
No evidence of sinus venous thrombosis was found.
Thrombocytopenia (minimal 91000/μl) was present, and
coagulation blood test showed evidence of an increased fibrinolysis and normal plasmatic inhibitors of coagulation,
normal antithrombin III (56%) and protein S (58%) but low
protein C (22%). Therapy with low molecular weight heparin was started. Echocardiogram revealed no structural
abnormalities, and an inconspicuous electrocardiogram
with a normal PQ interval and QRS complex was analyzed.
Central and peripheral bleeding spots were found in the
ocular fundus, most likely caused by trauma during birth.
Renal function test, albumin, transaminases, bilirubin and
calcium were normal. A smear of the grouped pustular lesions in the face showed no infection with staphylococcus.
But a biopsy of the affected skin showed evidence of cytoid
bodies compatible with an interface dermatitis. Serological

studies of the infant detected maternal HSV and varicella zoster virus (VZV) specific IgG antibodies, IgM
and a HSV-PCR of a swab of a skin lesion were negative.
However, antinuclear antibodies (ANA), anti-U1-snRNP
antibodies and anti-Sm antibodies were present, while
antiphospholipid, anti-Scl 70, SSA/Ro, SSB/La, anti-Tm,
anti-Jo-1 and anti-ds DNA antibodies could not be detected. Test results of the asymptomatic mother revealed the same autoantibody pattern.
Four weeks postpartum, the mother developed bilateral
erythema on the face and both forearms, muscle weakness
of both arms, a Raynaud’s phenomenon, arthralgia in hands
and swollen fingers. She was subsequently diagnosed with
mixed connective tissue disease (MCTD), since she exhibited three typical clinical symptoms (swollen fingers, muscle
weakness, Raynaud’s phenomenon), and one of the possible
antibody constellations (ANA, anti-U1-snRNP and anti-Sm
antibodies), both characteristic signs and symptoms of the
disease [2,3]. There had been no occurrence of symptoms
of rheumatic diseases in the infant’s siblings, a seventeen
years old sister and a seven years old brother. Further
questioning of the mother revealed that about six weeks
after the second delivery, transient arthralgia occurred,
which responded to oral steroids. No diagnosis was made
at that time.
The newborn infant was discharged on his 16th postnatal day, the lesions were healing (in parts showing

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Figure 2 MRI of ischemic lesions. Abnormal signal changes in multiple brain areas due to ischemic lesions in the distribution of the middle
and posterior cerebral artery on the left side. A-C: MRI on the 4th postnatal day. A: High-signal intensity in T2w imaging corresponding to B:
high-signal intensity in diffusion weighted imaging (DWI) (b1000) and C: low-signal intensity in apparent diffusion coefficient maps (ADC-MAP).
D-F: MRI at 32 months. D: T2w imaging E: DWI.(b1000) and F: ADC-MAP showing now a scar formation on the left occipital lobe.

scars as residual lesions), and until reassessment at the age
of 10 weeks with phenobarbital and low molecular weight
heparin as medical therapy displayed no symptoms; he was
consequently carefully weaned off medication. A transcranial duplex ultrasound after 4 weeks of birth showed a normal cerebral artery blood flow in all areas of the brain. A
follow-up MRI of the brain (Figure 2D-F) at the age of
32 months showed postischemic defects with involvement
of the gyrus supramarginalis and the peripheral visual cortex. The rest of the brain showed age-appropriate myelinization and no further over lesions. At the age of 6 years
there were no signs of cerebral palsy, seizures or amblyopia
but language development was delayed and complicated by
a speech disorder. Other cognitive development as tested
by the Snijders-Oomen non-verbal intelligence test was in
the lower norm and a somatic retardation with dystrophy
and microcephaly was diagnosed.
In summary, we describe a newborn infant who had cutaneous manifestations and the antibody pattern of neonatal
lupus erythematosus (NLE), complicated by neurological
symptoms.

Conclusions
This case report emphasizes NLE/MCTD as an important
differential diagnosis of grouped skin lesions in addition to
HSV-infection, which may ultimately be a sign of several
conditions (see Table 1 for an overview). However, the coexistence of several sets of classification criteria for MCTD

makes it difficult to allocate precisely maternal and congenital infantile disease.
Based on the initial clinical presentation, the first differential diagnosis focused first on neonatal HSV infection
and, less probable, congenital VZV infection. Thus, aciclovir therapy (3x20 mg/kg/d) was started immediately. Seizures just six hours after birth further supported this
hypothesis. HSV infection in neonates is rather uncommon and might be difficult to diagnose [4]. Vesicular eruptions and seizures can occur at any time from soon after
birth up to beyond the neonatal period [5]. Congenital infection is usually identified within the first 48 hours following birth, characterized by skin vesicles or scarring, eye
lesions, neurologic symptoms, and later growth retardation and psychomotor developmental retardation [6].
Therefore, therapy in the present case had to be continued
until acute HSV and VZV infection had been excluded
[7,8] by serologic and PCR investigations. At his point, the
less-common NLE, MCTD, erythema multiforme (EM),
antiphospholipid syndrome (APS) and incontinentia pigmenti (IP) were considered. In general, vesiculopustular
eruptions in neonates are common in bacterial infections
like staphylococcal infections, congenital lues or listeriosis,
fungal infections (candidiasis) or parasitic disorders (scabies) [1]. Transient pustular melanosis is characterized by
eosinophilic staining. EM is a short-lasting skin condition
that occurs as a reaction to a viral infection (especially
HSV) or medication. In the present case, these diagnoses
could be excluded clinically, due to the normal microbial

Clinical characteristics in newborn patients with skin and neurological lesions
Diagnosis

Skin

Neurological characteristics

Serological characteristics

vesiculopustular lesions

seizures, tremors, lethargy

HSV1-IgM antibodies positive

skin rashes, papules, vesiculopustular
lesions, crusts

seizures

VZV-IgM antibodies positive

skin rash, vesicles, crusts, limited to a dermatome

seizures

VZV-IgM antibodies positive

Neonatal Lupus Erythematosus (NLE)

malar rash or butterfly rash, scaly patches,
skin and mucosa lesion like ulcers

seizures

ANA, anti- Sm antibodies, SSA/Ro and SSB/La
antibodies, anti-U1-RNP antibodies

Mixed Connective Tissue Disease (MCTD)

rash, scaly patches, overlapping symptoms
of SLE, PSS, PM and RA

-

ANAs, anti-U1-RNP antibodies, (anti-Sm
antibodies)

Undifferentiated Connective Tissue Disease
(UCTD)

malar rash, oral ulcers purpura, urticaria

seizures, neuropathy

ANA, anti-Ro/SSA, anti-Sm-, anti-ds DNA-, anti
RNP-, anti-Ku antibodies, rheumatoid factor

skin ulcers

seizures, strokes, abnormal
movements

antiphospholipid antibodies, β2- glycoprotein- 1
antibodies, anticardiolipin antibodies

Incontinentia Pigmenti (IP)

blistering, a wart-like rash, hyper/hypopigmentation

cerebral atrophy, seizures, slow motor
development, muscle weakness

NEMO IKBKG gene (chromosomal locus Xq28),
females skewed X-Chromosome inactivation

Erythema Multiforme (EM)

pink-red blotches, target lesions

seizures (caused by HSV)

viral, bacterial or fungal infection

Neonatal Acne (NA)

comedones, papules, pustules

-

Malassezia species

scaly erythematosus lesions, red papules, eruptions on the
scalp

-

Impetigo Contagiosa (IC)

honey yellow crusts, plaques or bullae

-

Staphylococcus aureus, beta-hemolysing
Streptococcus, group A

Congenital Syphilis(CS)

pemphigus syphiliticus

seizures, pseudoparalysis

Treponema pallidum

Neonatal Herpes Simplex Virus 1 (HSV1)
Congenital Varicella Syndrome (VZV)
Herpes Zoster (HZ)

Antiphospholipid Syndrome (APS)

Langerhans Cell Histiocytosis (LCH)

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Table 1 Differential diagnosis of immune mediated disorders presenting with neurological symptoms and skin lesions

Page 4 of 7

Döring et al. BMC Pediatrics 2014, 14:126
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flora of skin, and by a negative C-reactive protein, which is
highly sensitive to bacterial infection [9]. The analyzed
skin biopsy made EM and IP unlikely [10-12]. In contrast
to these more common causes, immune-mediated disorders manifesting with neurological symptoms (such as seizures) in newborns are extremely rare [13,14]. Several
cases of NLE-associated seizures are reported [15-20].
NLE is an acquired autoimmune disease caused by maternal antibodies to SSA /Ro and SSB/La, ANAs, anti-ds
DNA or anti-Sm antibodies and in rare cases anti-RNP
antibodies [21]. Maternal anti-Ro/SSA and anti-La/SSB
antibodies are known to be associated with NLE including
fetal cardiac conduction block [22]. All infants who were
affected with NLE and tested positive only for anti-U1snRNP antibodies were male, only developed cutaneous
lesions and were not commonly associated with congenital
heart block [13,23]. In about 99% of SLE-patients, antinuclear antibodies were detected [24,25]. In most cases, the
presence of anti-Sm antibodies occurs after the clinical
manifestation of SLE therefore they serve as a diagnostic
criterion for SLE, while a high anti-U1-snRNP antibody
titer is associated with a more active illness. Nevertheless,
mild progressive forms often occur without nephritis [3].
Ultrasound scans showed normal structure and perfusion
of both kidneys in the present case.
The cause of the multiple ischemic brain areas in the
distribution of the middle and posterior cerebral artery on
the left side remains unclear. The homeostasis system of
neonates is characterized by decreased concentration of
protein S, protein C and antithrombin, elevated levels of
factor VIII and von Willebrand factor, and less active fibrinolysis, which results in a prothrombotic state. Neonatal thrombosis is a multifactorial event including several
inherited and acquired risk factors such as hereditary deficiencies of the naturally occurring coagulation inhibitors,
maternal preeclampsia, traumatic delivery, infection, dehydration, hyperviscosity, complex heart disease and catheter
placement in the newborn [26,27]. The activation of protein C plays a central role in the prophylaxis of microthrombi. Activated protein C is able to form complexes
with its cofactor protein S which may then inactivate the
coagulation factors Va and VIIIa [28]. The importance of
the function of protein C is shown by the life threatening
thrombotic complications in newborn infants. In the
process, there are two different forms of protein C deficiencies: type I is accompanied by reduced synthesis of
protein C thus reduced plasma levels, while type II is characterized by reduced protein C activity but normal plasma
level. Newborns born with a proven homozygous type I
deficiency experience severe thrombosis and purpura fulminans shortly after birth. The prevalence of heterozygous
protein C-deficiency (activity 30-65%) ranges from 1:200
to 1:500 [29-31]. In the present case, the female infant had
a mild deficiency of protein C (22%) [32,33]. Ultimately, a

Page 5 of 7

combination of an autoimmune phenomenon and a heterozygous protein C deficiency likely leads to the unusual
neurologic manifestations in our patient.
The clinical presentation of the patient’s mother four
weeks postpartum was typical for MCTD but her antibody constellation was typical for SLE [34]. MCTD was
originally described by Sharp et al. in 1972 and is classically considered as an overlap syndrome presenting with
features of SLE, progressive systemic sclerosis, polymyositis, and rheumatoid arthritis. Anti-U1-RNP antibodies
are detectable in the blood of all MCTD patients, typically showing high titres of ANAs but without additional
antibodies like DNA antibodies of SLE and the Scl-70
antibodies typical for scleroderma [3,35]. Giving a precise definition of MCTD is difficult since there are four
different sets of criteria which are generally used in
international publications: the Sharp criteria, the AlarconSegovia criteria, the Kasukawa criteria, and the Kahn
criteria [36]. The basis of all these sets of criteria is the
presence of anti-U1-RNP autoantibodies. Comparing
the four sets of classification criteria, Amigues et al.
concluded that the criteria with the best performance
are those proposed by Alarcon-Segovia [35]. These criteria are widely used and do not consider the positivity
to Sm antigen as an exclusion criterion like the Sharp
criteria do [3,37]. They include five clinical symptoms
(swollen hands, synovitis, biologically proven myositis,
Raynaud’s phenomenon, and acrosclerosis with or
without proximal systemic sclerosis) in addition to
anti-RNP positivity. At least three out of five clinical
symptoms and the presence of anti-RNP antibodies are
necessary for diagnosis of MCTD [2,35]. This allows
the diagnosis of MCTD in the mother of the patient.
In conclusion, the diagnosis in the present case was difficult not only due to the exceedingly rare presentation of
such diseases in the neonatal period but also because the
mother’s autoimmune disease had not been diagnosed at
the time of delivery. This reported case is to our knowledge the first description of an unrecognized MCTD in
the mother with an unusual clinical manifestation in the
newborn, comprising skin lesions, neurological damage
and non-typical antibody constellation. It illustrates the
diagnostic difficulties in a symptomatic child born to an
asymptomatic mother, and underlines that the neonatal
manifestations of an autoimmune disease may differ dramatically from those observable in the mother.

Consent
Written informed consent was obtained from the patient’s parents for publication of this Case Report and
any accompanying images. A copy of the written consent
is available for review by the Editor-in-Chief of this journal. The present case report was performed in accordance with the institutional ethics regulations.

Döring et al. BMC Pediatrics 2014, 14:126
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Abbreviations
ANA: Antinuclear antibodies; APS: Antiphospholipid syndrome; EM: Erythema
multiforme; HSV: Herpes simplex virus; IP: Incontinentia pigmenti;
MCTD: Mixed connective tissue disease; NLE: Neonatal lupus erythematosus;
SLE: Systemic lupus erythematosus; VZV: Varicella zoster virus.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
All authors have participated in case report design, interpretation, and
writing of the report. MD collected the data of the case report, review of
literature, and drafted the first version of the manuscript. KMR, IT and WB
collected the data of the case report and wrote a part of the manuscript.
MW, RH and CFP reviewed the manuscript. RG primarily participated in case
report design and helped to draft the manuscript. All authors read and
approved the final manuscript.
Acknowledgements
We acknowledge support by Open Access Publishing Fund of Tuebingen
University.
Author details
1
Department I – General Paediatrics, Hematology/Oncology, University
Hospital Tuebingen, Children’s Hospital, Hoppe-Seyler-Str.1, Tuebingen 72076,
Germany. 2Department of Radiology, Diagnostic and Interventional
Radiology, University Hospital Tuebingen, Hoppe-Seyler-Str. 3, Tuebingen
72076, Germany. 3Department IV – Neonatology, University Hospital
Tuebingen, Children’s Hospital, Calwerstr. 7, Tuebingen 72076, Germany.
4
Department III – Neuropaediatrics, Developmental Neurology, Social
Paediatrics, University Hospital Tuebingen, Children’s Hospital,
Hoppe-Seyler-Str.1, Tuebingen 72076, Germany.
Received: 12 February 2014 Accepted: 19 May 2014
Published: 22 May 2014
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doi:10.1186/1471-2431-14-126
Cite this article as: Döring et al.: A newborn with grouped facial skin
lesions and subsequent seizures. BMC Pediatrics 2014 14:126.

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