Aplasia cutis congenita: three cases with three different underlying etiologies.
ABSTRACT Aplasia cutis congenita (ACC) is an uncommon condition in which localized or widespread areas of skin are absent or scarred at birth. There is no single underlying cause of ACC, as it simply represents a physical finding that reflects a disruption of intrauterine skin development. Here we report three cases of ACC of the scalp with three different etiologies: congenital rubella syndrome, trisomy 13 and fetal valproate syndrome. The aim of the present report is to increase awareness of these skin defects and emphasize the importance of underlying etiologies.
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ABSTRACT: Epidemiologic and experimental data support the notion that Ljungan virus (LV), endemic in some rodent populations in Sweden, Denmark, and the United States, can cause morbidity and mortality in animals and humans. LV infection can cause type I diabetes mellitus, myocarditis, and encephalitis in bank voles and experimental mice, and lemmings. Mouse dams infected with LV experience high rates of stillbirth that may persist across generations, and their fetuses may develop cranial, brain, and limb malformations. In humans, epidemiologic and serologic data suggest that LV infection correlates with intrauterine fetal death, malformations, placental inflammation, myocarditis, encephalitis, and Guillain-Barré syndrome. The proposed role of LV infection in SIDS is unconvincing. Further research is necessary to clarify the role of LV infection in animal and human disease.Birth Defects Research Part A Clinical and Molecular Teratology 10/2010; 88(11):947-52. · 2.27 Impact Factor
The Turkish Journal of Pediatrics 2009; 51: 510-514 Case Report
Aplasia cutis congenita: three cases with three different
Ercan Mıhçı1, Seyhan Erişir2, Şükran Taçoy1, Güven Lüleci3
Erkan Alpsoy4, Nihal Oygür2
Divisions of 1Clinical Genetics and 2Neonatology, Department of Pediatrics, and Departments of 3Medical Biology and
Genetics, and 4Dermatology and Venereology, Akdeniz University Faculty of Medicine, Antalya, Turkey
SUMMARY: Mıhçı E, Erişir S, Taçoy Ş, Lüleci G, Alpsoy E, Oygür N. Aplasia
cutis congenita: three cases with three different underlying etiologies. Turk
J Pediatr 2009; 51: 510-514.
Aplasia cutis congenita (ACC) is an uncommon condition in which localized
or widespread areas of skin are absent or scarred at birth. There is no
single underlying cause of ACC, as it simply represents a physical finding
that reflects a disruption of intrauterine skin development. Here we report
three cases of ACC of the scalp with three different etiologies: congenital
rubella syndrome, trisomy 13 and fetal valproate syndrome. The aim of the
present report is to increase awareness of these skin defects and emphasize
the importance of underlying etiologies.
Key words: aplasia cutis congenita, trisomy 13, fetal valproate syndrome.
Aplasia cutis congenita (ACC) is a rare
congenital skin defect that may be localized or
may affect wide areas of the body1,2. ACC is a
developmental absence of skin characterized by
well-demarcated, oval or circular ulcers or scars,
and it may present with solitary or multiple
lesions1,2. ACC is primarily a clinical diagnosis,
with no specific histologic alterations. The scalp
vertex is the most commonly involved site
(nearly 90%); only about 10-15% of ACC occur
in other body areas3,4. At birth, most cases of
ACC have ulcerated lesions, which may show
total absence of all layers of skin, extending to
the bone or dura3. ACC is not only a physical
sign but may provide a clue to an underlying
disorder. Most individuals with ACC have no
associated abnormalities, but it can also be
associated with other congenital malformations,
intrauterine infections, chromosomal anomalies,
or other disorders such as ectodermal dysplasia
and epidermolysis bullosa5-9.
Here we report three cases of ACC of the
scalp with three different etiologies - congenital
rubella syndrome, trisomy 13 and fetal valproate
syndrome, and we review the differential
diagnosis for ACC.
A 13-day-old female was admitted to the
hospital with a cardiac murmur and scalp
defect. She was the second child of a 28-
year-old gravida 2, para 2 mother and a 35-
year-old father, who were nonconsanguineous.
The mother had a history of generalized
maculopapular rash in the third month of
her pregnancy. She was suspected of having
a viral infection but no serological tests were
On physical examination of the patient, weight,
length, and head circumference were all below
the 3rd centile (2400 g, 46 cm and 31 cm,
respectively). She had prominent epicanthic
folds, low-set ears, bilateral camptodactyly, and
absence of skin on two adjacent parts of the
scalp: a 0.5x0.5 cm annular, atrophic lesion and
a 1x1 cm oval well-demarcated, crusted ulcer
(Fig. 1). Echocardiography revealed secundum
atrial septal defect and patent ductus arteriosus.
Cranial magnetic resonance imaging (MRI)
revealed partial corpus callosum agenesis.
According to her serological tests, rubella IgM
Fig. 1. Case 1 - ACC on the vertex of the scalp.
Fig. 2a. Case 2 - A site of ACC on the vertex of the
scalp. 2b. Clinical aspect of Case 2.
and IgG were positive, toxoplasmosis IgM and
IgG were negative, cytomegalovirus IgM was
negative and IgG was positive, and herpes
simplex type 2 IgM and IgG were negative.
Karyotype analysis of the patient was 46,XX.
Her mother’s serological tests showed positive
rubella IgG and negative rubella IgM. Her
auditory evoked potential revealed mild type
sensory neural deafness. Her ophthalmological
examination was normal. Serologic tests of
the infant for rubella were repeated in the
third month of life. IgM was found negative
and IgG positive, with a slightly higher titer
than at the first testing. These findings were
consistent with a diagnosis of intrauterine
infection with rubella virus.
A 17-day-old term male infant was referred
for evaluation of facial dysmorphism and
scalp defect. His parents were healthy and
non-consanguineous. The family history was
unremarkable. On physical examination, his
weight was 3300 g (3rd centile), length was
49 cm (50th centile) and head circumference
was 33 cm (<3rd centile). His anterior and
posterior fontanels were 2x2 cm. Dermatologic
examination revealed a wide, circular well-
demarcated non-inflammatory ulcerative
3 cm scalp defect (Fig. 2a). There was an
underlying bony defect. He had frontal bossing,
downslanting palpebral fissures, wide nasal root,
microphthalmic right eye, bilateral cataracts,
bilateral retinal dysplasia, submucous cleft of
the palate, low-set ears, bilateral external ear
abnormalities, and short neck (Fig. 2b). He
had a grade 3/6 systolic murmur over the
entire precordium, a micropenis and phimosis.
There were flexion contractures of both hands,
bilateral pes planus, and increased space
between the first and second toes, bilaterally.
Echocardiography revealed transposition of the
great arteries, double outlet right ventricle,
atrial and ventricle septal defects, and mitral
insufficiency. Cranial MRI revealed bilateral
symmetrical T2-FLAIR hyperintense lesions on
the nucleus caudatus and lentiformis. Splenium
and genu of corpus callosum were absent. A
scalp defect without skin and fat tissue was
noted on MRI and no skull was revealed
under the defect area. Mega cisterna magna
was noted. His chromosomal study showed
47, XY, +13.
A one-day-old female full-term newborn was
admitted to the hospital for evaluation of a
systolic murmur. She was born by cesarean
section to a 20-year-old gravida 1, para 1
epileptic mother who had used valproic acid
and carbamazepine throughout her pregnancy.
The parents were nonconsanguineous. On
physical examination, her weight was 2600 g
(3-10th centile), length 47 cm (3-10th centile)
and head circumference 32.5 cm (3rd centile).
She had a well-demarcated oval-shaped scalp
defect with an area of 0.5 x 0.5 cm (Fig. 3),
micrognathia, epicanthus inversus, bilateral
coloboma of the irides, clinodactyly, weak
femoral pulses, hepatomegaly, and a grade 3/6
systolic murmur over the entire precordium.
The two-dimensional echocardiography and
computerized tomography revealed hypoplastic
aortic arch, aortic coarctation, aberrant right
subclavian artery, ventricular septal defect,
secundum atrial septal defect and patent ductus
Volume 51 • Number 5 Different Etiologies in Aplasia Cutis Congenita 511
Fig. 3. Case 3 - Two areas of ACC.
On the 7th day of admittance, the baby
had hepatomegaly, respiratory distress and
metabolic acidosis. She was intubated and
put on mechanical ventilation. Her condition
deteriorated and she died on the 13th day of
life. She was diagnosed with probable fetal
Aplasia cutis congenita was first reported by
Campell in 18261. Since then, there have been
a number of cases reported in the literature.
The incidence of ACC in liveborns has been
reported as nearly 2.8 cases per 10,00010.
Frieden9 classified ACC into nine groups
based on the site of skin defect, presence or
absence of other malformations, and pattern
of inheritance. The etiology of ACC may be
genetic or non-genetic (Table I), as illustrated
by our patients. ACC is most often a benign
isolated skin defect, but it can occur with
other physical anomalies or malformation
syndromes (Table II). Recently, Zehnaly et al.11
showed that development of a skin defect of
the scalp in mice resulted from the loss of the
TGF-beta type II receptor. Thus, they implied
that this gene was a candidate gene for ACC.
Focal dermal hypoplasia (FDH), also known as
Goltz syndrome, is an X-linked disorder with a
developmental skin malformation like ACC, but
can be distinguished from ACC by the presence
of patchy dermal hypoplasia with herniation of
subcutaneous tissues, and papillomas, which
often conform to a Blaschko-linear pattern.
Recently, investigators found FDH associated
with the mutations of the PORCN gene12,13.
Our first case illustrates an etiology of ACC
related to intrauterine infection, in this
case rubella. Other infections during the
intrauterine period that have also been reported
as underlying causes of ACC include herpes
simplex virus or varicella9,14. Congenital rubella
syndrome was the first virus demonstrated
to be a teratogen. The risk of congenital
anomalies in liveborn children with intrauterine
exposure to rubella virus varies with a number
of factors, the most important of which is
the stage of pregnancy. Exposure in the first
trimester is the highest risk period for teratogen
effect from fetal rubella infectious, causing
major anomalies in 38-100%15. Our patient’s
developmental manifestations as scalp defect and
cardiac/central nervous system malformations,
Table I. Disorders Associated with ACC
a) Autosomal Dominant
Trisomy 13, Del (4p) syndrome, Tetrasomy 12p
Adams-Oliver syndrome, Autosomal dominant ACC,
Ectrodactyly-ectodermal dysplasia-clefting syndrome,
Ectodermal dysplasia, Scalp-Ear-Nipple syndrome
Recessive Autosomal recessive ACC, Johanson-Blizzard syndrome, Setleis
syndrome, Ectodermal dysplasia-clefting syndrome,
Goltz-Gorlin syndrome (focal dermal hypoplasia), MIDAS
(Microphthalmia, Dermal Aplasia and Sclerocornea) syndrome
Alcohol, cocaine, marijuana, methimazole, misoprostol,
Congenital infections (herpes simplex, rubella, varicella),
Amniotic band disruption complex
* Simplex, junctional, or dystrophic types of epidermolysis bullosa. Adapted from Evers8.
512 Mıhçı E, et al The Turkish Journal of Pediatrics • September - October 2009
Table II. The Abnormalities Most Commonly Associated with ACC
1. Head and neck
Facial abnormalities (i.e. cleft lip/palate), wooly hair,
cranial arteriovenous malformation, hemangioma, skin
tags, microphthalmia, corneal opacities, eyelid colobomas,
cranial stenosis, leptomeningeal angiomatosis
Supernumerary nipples, absent breasts, heart defects, renal
Pyloric or duodenal atresia, ureteral stenosis, gastroschisis,
omphalocele, pancreatic insufficiency, double cervix and
Limb hypoplasia or amputation, hypoplastic or absent distal
phalanges, nail hypoplasia or dysplasia, polydactyly, limb
position defects (i.e. club foot), arthrogryposis, spastic
2. Abdomen and internal organ abnormalities
4. OtherPsychomotor retardation, seizures, spinal dysraphism,
persistent cutis marmorata
Adapted from Frieden.9
together with a maternal history of generalized
maculopapular rash in the third month of her
pregnancy, suggest a viral (rubella) exposure
in the early periods of pregnancy.
Our second case illustrates a chromosomal
anomaly as an etiology of ACC: trisomy 13
syndrome. Scalp ACC is found in 50% of
newborns with this disorder and the defects
are generally 0.5 cm in size; however, they
can be very large9,16. Chromosomal analysis is
indicated in any child with scalp ACC, especially
if associated with multiple congenital anomalies
when a specific syndrome is not identified.
A few cases of ACC have been reported
in newborns with in utero exposure to
antithyroids, methimazole, carbimazole, and
misoprostol. Hubert et al.7 also reported a
newborn with isolated ACC whose mother
had been treated with valproic acid during
her pregnancy. Although the mother in this
case had been treated with the combination
of valproate and carbamazepine, our patient’s
clinical findings were compatible with fetal
valproate syndrome. Children exposed to
polytherapy for epilepsy containing valproate
usually have dysmorphic features related to
the valproate exposure7. Therefore, the scalp
defect and dysmorphic findings observed in
the third case may have been a consequence
of intrauterine exposure to valproic acid.
In conclusion, we present three etiologies of
ACC and review the differential diagnosis. ACC
is generally an isolated skin defect; however,
intrauterine infectious, genetic, and other
teratogenic factors should be investigated,
especially when ACC is associated with
dysmorphic findings and cardiac defects.
The authors thank Dr. Noralane M. Lindor for
her helpful comments during the preparation
of this manuscript.
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