Skin of Neonates as a Neurodevelopmental Interface

SKIN OF NEONATES AS A NEURODEVELOPMENTAL INTERFACE

Embryological background:
(1) Skin:
The skin and its associated structures, the hair, nails, and glands are
derived from surface ectoderm[1]. Melanocytes, which give the skin its color, are
derived from neural crest cells, which migrate into the epidermis[2]. The
production of new cells occurs in the germinative layer. After moving to the
surface, cells are sloughed off in the horny layer [2]. The dermis, the deep layer
of the skin, is of mesenchymal origin.
Hairs develop from down growth of epidermal cells in the underlying
[3]
dermis . By about 20 weeks, the fetus is covered by downy hair, lanugo hair,
which is shed at the time of birth[3]. Sebaceous glands, sweat glands and
mammary glands all develop from epidermal proliferations[4].

(2) Central nervous system(CNS):

The CNS is of ectodermal origin and appears as the neural plate at the
middle of the 3rd week. After the edges of the plate become folded, the neural
folds approach each other in the midline to fuse into the neural tube. The cranial
end closes approximately at day 35, and the caudal end closes at day 27. The
CNS then forms a tubular structure with a broad cephalic portion, the brain and
a long caudal portion, the spinal cord. Failure of the neural tube to close results
in defects such as spina bifida and anencephaly. The term dysraphia is defined as
incomplete fusion of a raphe[5].
Hence it is clear that the skin and the nervous system have a common
ectodermal origin. Separation of the neural and cutaneous ectoderm occurs
early in gestational life at about the same time that the neural tube is fusing i.e
(28-32 days after conception)[6].
This embryologic association may explain simultaneous malformations of
the skin and the nervous system.
So skin of neonates could help for early prediction and intervention of some
neurodevelopmental disdorders.
Skin of Neonates as a Neurodevelopmental Interface
2

I. Developmental Defects:
(A) Cutaneous manifestations of neural tube defects (Dysraphism)
1] Cranial Dysraphism :
a- Cephaloceles
Cephalocele is the general term for congenital herniation of intracranial
structures through a scalp defect. Meningoceles are congenital lesions in which
only the meninges and cerebrospinal fluid herniated through a calvarial defect.
Large encephaloceles and meningoceles pose no diagnostic problems and easily
diagnosed prenatally or at birth. Smaller or atretic encephaloceles and meningo-
celes may be mistaken for cutaneous lesions such as hematoma, hemangiomas,
aplasia cutis, dermoid cysts, or inclusion cysts. All congenital, exophytic scalp
nodules should be evaluated thoroughly as 20 % to 37% of congenital non
traumatic scalp nodules connect to the underlying CNS[7]. If congenital nodule
occurs in association with cutaneous abnormalities, the diagnosis of cranial
dysraphism is highly suspect. Cutaneous stigmata of cranial dysraphism include
hypertrichosis or the "hair collar sign", capillary malformations, hemangiomas,
and cutaneous dimples and sinuses [8]. The hair collar sign may be found in
association with encephaloceles, meningoceles, atretic encephaloceles, atretic
meningoceles an heterotopic brain tissue but it also may be found with some
lesions of aplasia cutis. So this sign is not entirely specific [9]. From a clinical
stand point encephaloceles, meningoceles, atretic cephaloceles, heterotopic
brain tissue are impossible to differentiate, and all should be imaged and
surgically corrected as soon as possible to prevent complications .
b- Cranial dermoid cyst and sinuses:
Dermoid cysts are congenital subcutaneous lesions that are distributed
along embryonic fusion lines. The cysts may occur within the fusion lines of
the facial processes or within the neural axis [10]. Midline or nasal dermoid cysts
are of greater concern because 25% of these have an intracranial connection.
A nasal pit or sinus is present approximately in 25% of cases [11].
If the dermoid cyst connects to CNS, cerebrospinal fluid may drain from
the sinus. Dermal sinuses are 1-5 mm tracts that connect a dermoid cyst to the
skin surface. These usually are midline, found on the nose, occipital scalp and
anywhere along the spinal axis. They become clinically apparent when they
become infected and drain purulent material. A small tuft of hair is often found
protruding from the orifice. If the sinus or cyst directly communicates with the
CNS, the patient is at risk for meningitis. The sinus serves as an occult portal of
entry for bacteria often causing a recurrent meningitis. A thorough search for
Skin of Neonates as a Neurodevelopmental Interface
3

cutaneous fistulas should be carried out and may necessitate shaving the scalp
hair[12].
2] Spinal Dysraphism
This term encompasses many congenital anomalies of the spine including [13,14].
• Meningocele.
• Myelomeningoceles (Fig. 1)
• Myeloschisis
• Occult spina bifida
• Diastematomyelia
• Diplomyelia
• Tethered conus
• Intraspinal lipoma
• Lipomyelomeningocele
• Dermoid cyst Fig. (1): Myelomeningocele
• Dermal sinus.

Overlying cutaneous markers are found in 50% to 90% of patients with

occult tethered spinal cord cutaneous abnormalities may be the only indication
of tethered cord especially in newborn infants. The cutaneous lesions that
should alert physicians to an underlying occult spinal dysraphic state include
[13,15,16,17]
.
* High index of suspicion:
- Hypertrichosis
- Dimples
- Acrochordons, pseudotails, or true tails.
- Lipomas
- Hemangiomas
- Aplasia cutis or scar
- Dermoid cyst or sinus.
* Low index of suspicion:
- Telangiectasia
- Capillary malformation (port-wine stain)
- Hyperpigmentation
- Melanocytic nevi
- Teratomas.
Most of these lesions are found on or near the midline in the lumbosacral
region, however similar markers in the cervical or thoracic regions also may be
Skin of Neonates as a Neurodevelopmental Interface
4

indicative of an underlying malformation. The gluteal cleft should be examined

carefully for small acrochordons or sinuses; it should be straight and the buttocks
symmetric. A gluteal cleft that deviates is suggestive of an underlying mass
such as lipoma or meningocele[18].
Here it is clear that cutaneous markers have a crucial role in the detection
and diagnosis of occult neural tube dysraphism.
(B) Congenital absence of skin (Aplasia cutis congenita):
The term congenital absence of skin is preferred to aplasia cutis congenita
because this condition is in many cases not the result of a failure of development
of the skin but the result of trauma. There have been several reports of familial
cases of this types of congenital absence of skin with an autosomal dominant
pattern of inheritance [19].
Many of these cases have associated with specific neurological
manifestations.
(1) Congenital absence of skin on the scalp with epidermal nevi: there have been
reports of cases in which sebaceous nevi occurred in close proximity to areas of
congenital absence of skin in the scalp[20].
Multiple areas of bullous congenital absence of skin have also been
associated with ophthalmological or neurological abnormalities . These
abnormalities are spastic hemiparesis, mental retardation, epilepsy, cerebral
vascular malformations, cortical atrophy and hydrocephalus. These findings
could happen any time from birth till adulthood [21].
(2) Congenital absence of skin overlying developmental malformation :
In the occipital and parietal areas of the scalp, heterotopic neural and/or
meningeal tissue is most characteristically indicated by the presence of domed
hairless nodules with a collar of surrounding hypertrichosis (hair collar sign)[22].
The surface of the lesion is most typically translucent and membranous [23]. The
lesion may be flat or depressed rather than raised, and will not always be sited
in the midline. There may be associated area of port-wine staining [24].
Congenital absence of skin may overlie defects of the vertebrae and spinal
cord. The overlying skin is also characteristically either absent or hypoplastic
in a number of other developmental malformations, including omphalocele,
gastroschisis and sternal clefts[25].
(3) Congenital absence of skin occurring as a feature of malformation
syndromes.
a- Trisomy (13).
Skin of Neonates as a Neurodevelopmental Interface
5

Congenital absence of skin in the

parietal or occipital scalp (Fig. 2) is a regular
feature of this chromosomal abnormality
syndrome, in which other characteristic findings include holoprosencephaly,
microphthalmia, iris colobomas, cleft lip and/or palate, polydactyly, narrow
and excessively convex nails, and a port- wine stain on the fore head [26].

b- Deletion of the short arm of chromosome (4) (the 4p- syndrome):

Congenital absence of skin in the posterior midline scalp is also a regular
finding in this chromosomal abnormality syndrome. Other typical features
include ocular hypertelorism, a beaked or broad nose, microcephaly, low-set,
simple ears and pre-auricular tags or pits.
Affected individuals are profoundly mentally retarded and generally
experience severe convulsions [27].
c-Oculocerebro cutaneous syndrome:
It occurs sporadically and in both sexes. The cutaneous features comprise
a highly characteristic combination of area of aplasia cutis and skin tags. Skin
tags may be up to centimeter in diameter and predominately found on the face,
most commonly around the eyes and the nose. Well-defined areas of cutaneous
hypoplasia have been reported principally in the scalp, on the neck, and in the
Lumbosacral area. A ring of more profuse hair growth around scalp lesions has
been noted. Typical non cutaneous manifestations of the syndrome include skull
defects, cerebral malformations particularly cystic spaces (porencephaly),
agenesis of the corpus callosum, microphthalmia, eyelid colobomas and orbital
cysts [28].
d- Johansson- Blizzard syndrome:
This rare disorder is transmitted as an autosomal recessive trait. Growth
deficiency is apparent from birth. Congenital absence of skin in the posterior
midline scalp is a regular feature . The hair is generally sparse with a marked
frontal upsweep. Hypoplasia of the alae nasi is one of the most striking facial
features. It has several features of ectodermal dysplasia. Other important
component of the syndrome is sensorineural deafness and hypothyroidism [29].
(C) Nevi and Developmental defects :
The association of epidermal nevi with other developmental defects,
particularly of the CNS, eye and skeleton is well recognized [30]. While
significant developmental anomalies occur in approximately 1.7% of all
neonates, a figure closer to 10% probably applies in children with epidermal
nevi. While the risk of such abnormalities increases with increasingly
Skin of Neonates as a Neurodevelopmental Interface
6

widespread distribution of the skin lesions. Serious non cutaneous

developmental defects may be found in children with a single epidermal
nevus[31].
(1) Epidermal nevus syndrome: (Fig.3)
Wide variety of neurological abnormalities
have been identified in about 50% of
patients with this syndrome[32].

Neurological abnormalities are much more frequent in patients who have

sebaceous nevi on head and neck , but the location of the skin lesions does not
provide reliable prediction of the laterality of intracranial brain anomalies [33].
Seizures, specially infantile spasms, occur in 50% of cases, many of whom
have underlying structural abnormalities of the CNS. Mental retardation,
spastic hemiparesis, and spastic tetraparesis are also common findings from birth
till adolescence [34].
The commonest structural CNS abnormalities have been ipsilateral gyral
malformations and complete or partial hemimegalencephaly but other have
included vascular malformations, hemiatrophy, posterior fossa abnormalities,
lateral ventricles enlargement, porencephaly, agenesis of the corpus callosum
and hamartoma[34]. Cranial nerve palsies have also been described fairly
commonly [35]. Other cutaneous abnormalities in addition to epidermal nevi have
included infantile haemangiomas, nevi flammeus, hypochromic nevi, café au
lait macules (CALMs), congenital melanocytic nevi, spitz nevi, and
dermatomegaly[32].
Many other non cutaneous abnormalities have now been reported in
association with epidermal nevi, including bilateral sensorineural deafness,
endocrine disease precocious puberty and a variety of cardiac and genitourinary
abnormalities [36].
(2) Congenital melanocytic nevus: (Fig. 4)
At birth congenital nevi may be very
pale macular lesions which enlarge, darken and
develop terminal hair over a period of years.
Small and medium sized congenital nevi
usually grow less rapidly than the infant so that
their surface area becomes relatively less. The
rare giant, garment or bathing trunk nevus is
immediately obvious and frequently very
Fig. 4)Congenital melanocytic nevus)
Skin of Neonates as a Neurodevelopmental Interface
7

distressing to parents at birth there may also be

large numbers of smaller congenital nevi
present on the infant's skin. As the infant
grows the surface may become rugose or warty
and nodules can develop within a large nevus. There may be associated
abnormalities such as meningeal involvement, spinabifida or meningocele when
the nevus is over the vertebral column, or club foot and hypertrophy or atrophy
of the deeper structures of a limb[37].

II. Geno-Dermatoses:
Skin is considered to be a "pressure value" for the rest of the body, with
cutaneous disorders simply reflecting derangement of the humors that governed
bodily function. Although skin is now thought to be distinct cutaneous marker,
commonly betray the presence of a genetic disorder. In many cases, skin
findings are the initial manifestations of genetic disease allowing early diagnosis
and intervention.
(1) Neurofibromatosis type 1 (NF-1):
Neurofibromatosis type 1 (NF-1) or Von Recklinghausen disease, is an
autosomal dominant inherited neurocutaneous syndrome that affects 1 in 3000
individuals world wide [38]. The primary cutaneous findings in patients with NF-
1 is café au lait macule (CALM). CALMs are tan macules and patches that are
often present at birth but may develop during the first 5 years of life. Isolated
CALMs are common in general populations however six or more lesions
measuring 0.5 cm or more is one diagnostic criterion for the diagnosis of
NF-1[39]. Other major features that aid in establishing a diagnosis of NF-1 include
axillary or inguinal frecklings, dermal or plexiform (deeper) neurofibroma,
bilateral lisch nodules (iris hamartomas), optic gliomas, pseudoarthrosis of tibia
and sphenoid wing dysplasia. Typically at birth it can present itself as CALMs,
plexifrorm neurofibromas and/or tibial dysplasia (Table 1) [40].
Table (1): Age dependent presentation of NF-1

Clinical feature Age at presentation

• Café' an lait macules Birth to adulthood
• Skin fold freckling Preschool years
• Neurofibromatosis Preadolescence to adulthood
• Plexiform neurofibromatosis Birth
• Lisch nodules Preschool years, increase with age
Preschool years.
• Optic gliomas
Preadolescence
Skin of Neonates as a Neurodevelopmental Interface
8

• Scoliosis Life long, greatest in adulthood

• Malignancy risk, wilms' tumor, non
lymphocytic leukemias and CNS Birth
tumors
• Tibial dysplasias
CNS manifestations of NF-1include oligophrenia ,general impairment of
physical development,speech impediments and headache. Intracranial tumors as
optic nerve glioma, astrocytoma and schwannomas may occur. These intracranial
tumors may cause epilepsy. [40].
(2) Tuberous sclerosis (TS):
Tuberous sclerosis (TS) is dominantly
inherited neurocutaneous disorder with a high
spontaneous mutation rate (66%) and marked
intrafamilial variability in expression. The hallmark
cutaneous lesion is the hypopigmented macule, the
ash-leaf macules. These areas of decreased
pigmentation also may take the shape of thumbprint,
confetti or even dermatomal distribution.
Hypopigmented lesions may continue to develop
during the first year of life. Although a single lesion Fig. (5): Shagreen-patches
occurs in 4% of general population, more than three
hypopigmented macules is extremely unusual and
warrants evaluation [41].
Fibrous forehead plaque may be frequent at birth and together with the
hypopigmented macules, allow for a definitive diagnosis. Other cutaneous
lesions most commony develop at school age and beyond (Table 2)[42].
Table (2): Age- related presentation of cutaneous features of tuberous
sclerosis
Cutaneous feature Age at presentation
Hypopigmented macules Birth to preschool
Shagreen patch (Fig. 5). Birth to adulthood
Forehead plaque (forms of collagenoma) Birth to adulthood
Facialangiofibromas (adenoma sebaceum) Preschool-adulthood
Periungual fibromas . Preschool-adulthood
Skin of Neonates as a Neurodevelopmental Interface
9

Patients with TS have significant CNS findings that often lead to

developmental delay and retardation. CNS manifestations of TS can be
summarized as [43].
• Subepindymal nodules (abnormal neuronal and glial elements) which is
the most common cerebral lesion.
• Cortical and white matter tubers (abnormal heterotopic giant cells).
• Giant cell astrocytoma which originates from subependymal nodule near
foramen of Monroe, typically within the first 2 decades of life.
• Other findings as cerebral atrophy, cerebral infarcts, cerebral aneurysm
and arachnoid cyst. CNS tumors may lead to early seizures.
(3) Ring chromosome syndromes:
Features of ring chromosomes 7, 11,12 and 15 syndromes include, micro-
cephaly, mental retardation, short stature and skeletal abnormalities. Multiple
CAMLs were reported in the affected newborns as well as in some of the healthy
family members[44]. The ring chromosome phenotype is similar regardless of
which specific chromosome is affected [45].
(4) Cockayne's syndrome (CS):
This inherited syndrome characterized by short stature, mental deficiency,
photosensitivity , disproportionately large hand, feet and ears, ocular defects and
extensive demyelination [46].
Very early onset of presentation in the neonatal period has been reported
but the child may appear normal for the first year, when facial erythema in the
butterfly distribution develops after exposure to sunlight. The sensitivity to light
is eventually lost, but it is followed by mottled pigmentation and atrophic scars.
This,together with the progressive loss of subcutaneous fat on the face and the
sunken eyes give a characteristic premature senile appearance. The skin else
where shows little change, but the long limbs and disproportionately large hands
and feet are often blue and cold. The association of these findings with large
protruding ears has suggested a fancy resemblancy to Mickey Mouse.
Physical and mental development are greatly retarded. There is diffuse
extensive demyelination of the peripheral nerves and the CNS[47].
(5) Sjogren- Larsson syndrome (SLS):
It is an autosomal recessive condition comprising congenital icthyosis,
spastic diplegia and mild to moderate mental retardation. In addition a
characteristic neuropathy has been noted. Collodion baby presentation has been
Skin of Neonates as a Neurodevelopmental Interface
10

reported [48], but usually the skin is dry and mildly erythrodermic at birth , and
scaling develops within the first 3 months of life.
Neurological dysfunction is obvious in early infancy, with delayed motor
milestones and evolution of upper motor neuron signs in the legs and rarely in
the arms also. The motor features are of a typical, non progressive spastic
paraparesis. Altered posture and movement may lead to skeletal defects . Mild
to moderate mental disability is the rule [49].
Skin of Neonates as a Neurodevelopmental Interface
11

III. Disorders of pigmentation :

Pigmentary lesions comprise most birth marks. Lesions range from
uncommon to very common, some being essentially normal variants. The natural
history of these lesions varies from being transient phenomena of no significance
to permanent cutaneous abnormalities that may be associated with significant
systemic complications or disorders.
(A) Disorders of Melanocytes:
1) Incontinentia pigmenti(IP):
IP usually presents during the first 6 weeks
of life as linear arrays of small blisters. The
cutaneous findings typically occur in ordered four
stages. The first stage is usually present or soon
develops after birth. This consists of inflammatory
lineary arranged vesicles on an erythematous base.
Fig. (6). These vesicles tend to affect the
extremities and less often the trunk, but tend to
spare the face. The lesions resolve spontaneously
in a few weeks with desquamation [50]. Flaring of
Fig. (6) First stage of IP
these inflammatory stage through out childhood
and adulthood have been rarely reported.
The second stage evolves after a few weeks of birth and consists of
verrucous hyperkeratotic papules and plaques occurring most commonly on the
distal extremities.
The third stage begins around 3 months of age, and is heralded by the
appearance of hyperpigmented whorls and streaks following the line of Blaschko.
This stage mainly affects the trunk especially the groin, axilla, nipples and
proximal extremities.
A variable fourth stage consists of atrophic hypopigmented, lineary
arranged whorls and streaks devoid of hair and sweat glands [51].
The various cutaneous stages of IP may occur simultaneously or overlap.
So a newborn infant could born with any of the four stages [52].
IP is a systemic disease affecting many ectodermal tissues. About 30% of
patients have CNS involvement, including seizures, low mentality and spastic
abnormalities [53].
Neonatal seizures have been reported as a bad prognostic factor for the
development of mental retardation [51]. About 35% of patients experience eye
defects, including strabismus, cataracts, optic atrophy and retinal damage [54].
Skin of Neonates as a Neurodevelopmental Interface
12

IP is an X-linked dominant disease, the affected males usually die in utero.

Rare male patients with klienfelter syndrome (XXY) have been reported [55].

2) Waardenburg syndrome (WS):

It is a primary autosomal dominant
disorder, presents at birth with white forelock
Fig.(7) and depigmented patches mostly around
the forehead, ventral chest, abdomen, upper
limbs and lower legs[56].
It also involves pigmentary abnormalities
of the iris (heterochromia irides), sensorineural
deafness and neural tube defect (spina bifida) Fig. (7): White forelock
[57]
.
Assessment of neonates with WS should include ophthalmologic and
hearing evaluations
3) Albinism:
Albinism describes a group of genetic disorders involving abnormal
melanin synthesis. Patient's skin color may vary from pink to light brown.
Oculocutaneous albinism is differentiated into 10 variants according to genetic
defect that has been revealed in many instances[58].
The classic clinical picture is white hair, milky white skin, and pale
translucent irides, which may appear pink or red. It is well documented that
there is association of albinism with:
[a] Prader- Willi syndrome which include, mental retardation, hypotonia,
hypopigmentation, hypogonadism and obesity [59].
[b] Angelman syndrome which comprise choreoathetotic movements, mental
retardation, seizures, macrostomia, tongue thrusting and hypopigmentation[60].
[c] Chediak-Higashi (CHS)
CHS is a complex condition that is inherited as an autosomal recessive
disease.
Dermatologic manifestations of CHS include hair color varying from
blond to dark but exhibiting a silvery tint particularly noticeable in strong light.
Neurologic manifestations develop in patients who survive childhood and
include seizures, mental deficiency, and peripheral neuropathy [61].
Skin of Neonates as a Neurodevelopmental Interface
13

[d] Griscell syndromes (GS).

Griscell syndrome is an autosomal recessive genetic disorder that is
clinically characterized by partial pigmentary dilution or albinism with silver
gray hair.
Neurologic abnormalities are frequent including hyperreflexia, seizures,
signs of intracranial hypertention, regression of developmental milestones ,
hypertonia, nystagmus and ataxia[62].
4) Hypomelanosis of Ito:
This term is used for a phenotype with
linear streaks lighter than the patient's
background skin color, Fig. (8) extending around
the trunk and down the long axis of the
extremities, roughly following the lines of
Blaschko.
The pigmentary changes become
noticeable at birth or during early infancy and
usually remain stable. They are significant
because of the prevalence of extracutaneous
Fig.(8): Hypopigmented linear
manifestations especially those involving the streaks
CNS and muscloskeletal systems.
CNS involvement usually manifests before age of 2 years. CNS
involvement includes seizures, low mentality and spastic abnormalities [63].

(B) Disorders of bilirubin deposition

Bilirubin encephalopathy:
It is an acquired metabolic encephalopathy of the
neonatal period. Its etiology and pathogenesis ovelap to
some extent with hypoxic ischemic encephalopathy.
Kernicterus is caused by unconjugated hyperbilirub-
inemia that develops either as a result of hemolytic
disease or because of inability of the liver to conjugate
bilirubin. Unconjugated bilirubin crosses the blood
brain barrier and, because it is lipid soluble, it
penetrates neuronal and glial membranes. Bilirubin has
a special affinity for the hippocampus, globus pallidus
and subthalamic nucleus . The striatum, thalamus, Fig.(9): Bright yellow colour of
the affected neurones
inferior olives and dentate nucleus of the cerebellum are
Skin of Neonates as a Neurodevelopmental Interface
14

less frequently involved. In severe kernicterus, affected

structures have a bright yellow color [64]. Fig. (9)
Microscopically, they show neuronal necrosis, and in burned out
cases,neuronal loss, gliosis and atrophy.
Bilirubin is thought to be toxic to nerve cells [64]. It causes mitochondrial
damage and inhibits oxidative phosphorylation in vitro. The mechanism of
neurotoxicity and the reason for topography of the lesions are not known [65].
Patients surviving kernicterus have severe permanent neurologic
symptoms including choreoathetosis , spasticity,muscular rigidity, ataxia and
mental retardation [66] .
Hyperbilirubinemia presents itself clinically as yellowish discoloration of
the skin and mucous membranes. The problem is that bilirubin levels that are
toxic to one infant may not be toxic to another, or even to the same infant in
different clinical circumstances[66].

IV. Disturbances of skin vasculature:

Vascular birthmarks are cutaneous anomalies of angiogenesis and
vasculogenesis, resulting in various different clinical presentations and often
heralding other disease states or anomalies.
(1) Sturge- Weber syndrome (SWS):
It occurs sporadically in the general population
and is also known as encephalotrigeminal
angiomatosis.
It's characterized by a facial port-wine stain
Fig. (10) in the ophthalmic distribution of the
trigeminal nerve, which may or may not involve
the maxillary or mandibular distributions. :(Port-wine stain Fig. (10

SWS is thought to be caused by a defect in the development of cephalic

neural crest vasculature resulting in CNS abnormalities [60]. Specifically those
patients may have cerebral atrophy, malformation of leptomeninges, and
calcifications in the temporal and occipital cortex resulting in seizures, mental
retardation and hemiparesis [67]. In most cases, neurological symptoms have
their onset during the first 2 years of life [60].
(2) Cobb's syndrome: (Cutaneous meningo-spinal angiomatosis):
Skin of Neonates as a Neurodevelopmental Interface
15

This disorder comprises a very rare association of a port-wine stain in a

segmental distribution, and a vascular malformation of the spinal cord at the
corresponding levels [68].
In practice about 40% of patients with spinal vascular malformations also
have a port-wine stain which is situated in the corresponding dermatome in about
half of these [69].
The port-wine stain may be rather faint or more rarely, may have a more
keratotic appearance in a segmental distribution on the trunk or limbs. This is
associated with a vascular malformations of the spinal cord, which generally
will become symptomatic in childhood or adolescence, with the onset of spastic
paralysis of one or both lower limbs and sensory loss below the level of the
spinal lesion [68].
(3) Hereditary neurocutaneous angiomas:
An apparently distinctive familial disorder was described under this
name in 1979.
All the affected neonates, have one or more port-wine stain, at almost any
site associated with localized vascular malformations within the CNS.
These CNS vascular lesions show a marked tendency to bleed resulting
in a variety of neurological manifestations [70].
(4) Phakomatosis pigmentovascularis:
This syndrome has much in common with the sturg-weber syndrome.
However it has been argued that it differs firstly in the presence of widespread
dermal and usually scleral melanocytosis, secondly in the generally more
extensive port-wine stains and thirdly in the presence of ultrastructural
distinctions in the endothelial cell appearance.
CNS manifestations such as seizures and hemiplegia are common
associates [71].
(5) Von Hippel –Lindau disease:
This condition is transmitted as an autosomal dominant trait. Its fully
expressed forms constitutes the association of bilateral retinal angiomatosis and
cerebellar or medullary hemangioblastoma. About 5% of affected individuals
have been noted to have macular telangiectatic nevi, most often in the facial or
occipitocervical areas. CALMs also appear to be a feature in at least some
cases.
Cerebellar or less often medullary or spinal hemangioblastoma is
recognized during life in about 40% of cases. The commonest cause of death is
cerebellar hemangioblastoma [73].
Skin of Neonates as a Neurodevelopmental Interface
16
Skin of Neonates as a Neurodevelopmental Interface
17

V. Inflammatory systemic diseases:

(1) Systemic lupus Erythematosus (SLE):
SLE is the prototypal autoimmune disease,
with variable clinical features affecting all organ
systems.
CNS involvement occurs in more than half
of children and adolescents with SLE, usually
early in the course of the disease and usually with
both neurologic and psychiatric symptoms.
Cutaneous findings in neonatal lupus could
Fig. (11): Facial telangiectasia
be in the form of telangiectasia Fig. (11) and a
well demarcated erythematous, mild scaly plaque
that is often annular and appears predominately
on the scalp, neck or face.
This plaque is typically periorbital in distribution. Similar plaques may
appear on the trunk or extremities. They are sometimes crusted; this finding is
observed more often in male babies than in female babies. At times, small
angioma-like papulonodules may be seen [73].
Overt CNS involvement can range from global cerebral dysfunction with
paralysis and seizures to mild or focal symptoms such as headache or memory
loss. Movement disorders are more common in pediatric patients and
specifically , chorea[74].
(2) Behcet's syndrome:
The etiology and pathogenesis of Behcet disease remain obscure.
Currenty it is considered as an autoimmune disease. Cases of Behcet disease
have been described among newborns born to mothers with the diseases usually
who flared during pregnancy.
Although Behcet's syndrome is rarely diagnosed in children it must be
considered in the differential diagnosis of multisystemic inflammatory
disorders[75].
Cutaneous manifestations ranged from erythema nodosum-like lesions
and pseudofolliculitis which are probably the most common to papulopustular
eruptions, erythema multiforme-like lesions, ulcers, bullous necrotizing
vasculitis and pyoderma gangrenosum. Lesions often occur in combination . A
peculiar feature of Behcet disease is cutaneous hypersensitivity which results in
small pustules that form on skin after it has been scratched, shaved or prickled
with a needle (pathergy test) [75].
Skin of Neonates as a Neurodevelopmental Interface
18

The incidence of neurologic involvement in Behcet disease varied from

3.2% up to 49% according to the reports of different populations with CNS
involvement up to 25% inchildren. The most severe pathologic manifestation of
the disease include vasculitis, perivascular white matter inflammation and
demyelinating lesions.
Neurologic involvement may include meningoencephalitis,
multiplesclerosis like illness, acute myelitis, stroke or pseudotumor cerebri.
Focal neurologic abnormalities also can be seen [76].
The categories of neurologic involvement are : [77].
(1) Brain stem syndrome.
(2) Meningomyelites syndrome
(3) Organic confusional syndrome.
Neurologic manifestations usually occur within 5 years of onset of the disease.

VI. Metabolic disorders:

Phenylketonuria (PKU):
PKU is a rare inherited disease in which a deficiency of enzyme
phenylalanine hydroxylase leads to accumulation of phenylalanine in the plasma [78].
Cutaneous manifestations of PKU patients are fair skin and hair due to
impairment of melanin synthesis. This fair and sensitive skin readily develops
eczema. Although clinical light sensitivity has been reported, the ability to tan
and erythematous response to ultraviolet radiation are normal.
The incidence of pyogenic infections is increased. Scleroderma- like
lesions with involvement of muscles have been reported [79].
If untreated in early life, there is nearly always mental retardation . About
50% have epilepsy and often extrapyramidal manifestations such as athetosis ,
and exaggerated tendon reflexes may be found [80].

VII. Congenital infections:

Babies with congenital infections may suffer
particular damage to the developing brain and
sensory organs. The subsequent effects of the
infections are quite diverse resulting in a broad
range of developmental outcomes [81] .
Hearing loss is the most common
developmental disability, especially from
cytomegalovirus (CMV) and rubella infections [81,82] .
Fig. (12):Herpes virus infection
Skin of Neonates as a Neurodevelopmental Interface
19

Visual impairments are common especially with

herpes Fig. (12) and rubella infections [81,83] .
Mild to severe brain damage may occur, resulting in various degrees of
mental retardation, learning and behavioral disorders and autism.
Cutaneous manifestations for these infections may alert for detection of
these future-coming developmental defects Table (3) [81].
Table (3): Clinical Manifestations of Neonatal infections aquired In Utero
or at delivery
Microorganism
Clinical sign Rubella CMV Herpes Toxoplasma Treponema Streptococcus
virus virus gondii pallidum agalactiae (Grp
B) or E. coli
Skin Lesions
Petechiae/purpura + + + + + +
Vesicles - + ++ - + -
Maculopapular - - + + ++ -
exanthems
CNS Lesions
Meningoencephalitis + + + + + +
Microcephaly - ++ + + - -
Hydrocephalus + + + ++ - -
Intracranial - ++ - ++ - -
calcifications
Paralysis - - - - - -
Hearing deficits + + - - + -
- = either not present or rare in infected infants; + = occurs in infants with infection ' ++=
special diagnostic significance for this infection.

VIII. Percutaneous absorption:

During routine care of newborn infants at home, skin care products
containing at least 48 different environmental chemicals are applied to the skin
during the first month of life [84] creating significant potential for percutaneous
absorption leading to systemic toxicity. Permeability of even intact premature
skin is many fold greater than that of adult skin and increases inversely with
gestational age [85].
Some of topical application of skin in neonatal period have well
documented untoward neurological manifestations Table (4 ) [86].
Skin of Neonates as a Neurodevelopmental Interface
20

Potential untoward neurological effects from topical application of skin

care products in neonates.
Associated compound (possible Neurological manifestations
untoward effect)
Hexachlorophene Vacuolar encephalopathy
Boric acid Seizures
Lindane Seizures
Silver sulfadiazine Kernicterus
Mercury Hypotonia
Propylene glycol Seizures
Glycerin Seizures
Neomycin Neural deafness
Camphor Seizures
Iodohydroxyquin and di-iodohydroxyquin Blindness and neurophathy

The increased permeability of neonatal skin, especially in infants born at

less than 33 weeks' gestational age and during the first 2-4 weeks of life
mandates a conservative approach to the use of topical preparations [86].
Skin of Neonates as a Neurodevelopmental Interface
21

REFERENCES
1. Holbrook KA, Hoff MS.: Structure of the developing human embryo and fetal
skin. Seminar Dermatol; 3:185-202, 1984.
2. Smith LT, Holbrook KA: Embryogenesis of the dermis in human skin . Pediatric
Dermatol; 3:271, 1986.
3. Holbrook KA, Odland GF: Structure of the human fetal hair canal and initial
hair eruption. J Invest Dermatol; 71:385-90, 1978.
4. Sato S, Hiraga K, Nishiyrma A, et al.: Neonatal sebaceous glands: Fine structure
of sebaceous and denderitic cells . Acta Derm Venereol (stockh), 57:279-87,
1977.
5. Muller F, O'Rahilly R: The development of the human brain from a closed neural
tube. Anat Embryol 177:203, 1986.
6. Muller F, O' Rahilly R: The development of the human brain and the closure of
the rostral neuropore. Anat Embryol 175:205, 1986.
7. Oakes W: Butterfly-shaped mark. Pediatrics 87:956-957, 1991.
8. Drolet B,Clowry Jr L, McTigue K, et al: The hair collar sign: A cutaneous marker
for neural tube dysraphism. Pediatrics 96:309-313, 1995.
9. Drolet B, prendiville J, Golden J, et al: Membranous aplasia cutis with hair
collars: Congenital absence of the skin or neuro ectodermal defect? Arch
Dermatol 131: 1427:1431, 1995.
10. Powell K, Cherry J, Hougen T, et al: A prospective search for congenital dermal
abnormalities of the craniospinal axis. J Pediatr. 87:744-750, 1975.
11. Peter J, Sinclair – Smith C Devilliers J: Midline dermal sinuses and cysts and
their relationship to the central nervous system. Eur J Pediatr Surg. 1:73-79,
1991.
12. Kriss VM, Desal NS: Occult spinal dysraphism in neonates: Assessment of high-
risk cutaneous stigmata on sonography. AJR Am J Roentgenol 171:1687-
1692-1998.
13. Burrows F: Some aspects of occult spinal dysraphism: A study of 90 cases. Br J
Radiol 41:487, 1968.
14. Raghavendra B, Epstein F, Pinto R, et al: The tethered cord: Diagnosis by high
resolution real time ultrasound. Radiology 149:123-128, 1983.
15. Albright A, Gartner J, Weiner E: Lumbar cutaneous hemangimas as indicators of
tethered spinal cords. Pediatrics 83:977-980, 1989.
16. Anderson F: Occult spinal dysraphism: A series of 73 cases. Pediatrics 55:826-
829, 1975.
Skin of Neonates as a Neurodevelopmental Interface
22

17. Hall D, udvarhely , G, Altman J: Lumbosacral skin lesions as markers of occult

spinal dysraphism. JAMA 246:2606-2608, 1981.
18. Karrer F, Flannery A, Nelson M, et al: Anorectal malformations: Evaluation of
associated spinal dysraphic syndromes. J Pediatr Surg 23:45-48, 1988.
19. Cutlip BD, Cryan DM, Vineyrad WR: Congenital scalp defects in mother and
child. Am J Dis Child 113:597-599, 1967.
20. Lantis S, Leyden J, Thew M, et al: Nevus Sebaceous of Jadassohn: Part of a new
neurocutaneous syndrome? Arch Dermatol 98:117-123, 1968.
21. Holden KR,Dekaban AS.: Neurological involvement by nevus unius lateralis and
nevus linearis sebaceous. Neurology 22:879-887, 1972.
22. Commeus C, Rogers M, Kan A.: Heterotopic brain tissue presenting as bald cysts
with a collar of hypertrophic hair. Arch Dermatol 125:1253, 1256, 1989.
23. Dolet BA, Prendiville J, Golden J, et al: Membranous aplasia cutis with hair
collars: congenital absence of skin or neuroectodermal defect? Arch
Dematol 131:1427-1431, 1995.
24. Dolet BA, Clowry LA, Mc Tigue MK, et al: The hair collar sign: A marker of
cranial dysraphism Pediatrics 96:309-313, 1995.
25. hagginbottom MC, Jone KL, James HE, et al: Aplasia cutis congenita: A
cutaneous marker of occult spinal dysraphism. J Pediatr 96:987-989, 1980.
26. Abuelo D, Feingold M.: Scalp defects in trisomy 13. Clin Pediatr 8:416-417, 1969.
27. Guthrie RD, Aase JM, Asper AC, et al: The up-syndrome: A clinically
recognizable chromosomal deletion syndrome. Am J DS Child 22:421-425,
1971.
28. Bleeker- Wagemakers LM, H Mel BC, Hennekam RCM, et al.: Oculocerebro
cutaneous syndrome. J Med Genet 27:69-70, 1990.
29. Mardini MK, Ghandour M, Sakati NA et al.: Johanson Blizzard syndrome in
large in bred Kindred with three involved members. Clin-Genet 14:247-250,
1978.
30. Feuerstesn RC, Mims LC.: Linear nevus sebaceous with convulsions and mental
retardation. Am J Dis Child 104:675-679, 1962.
31. Marden PM, Smith DW, McDonald MI: Congenital anomalies in the newborn
infant, including minor varations. J Pediatr 64:357-371, 1964.
32. Solomor LM, Esterly NB.: Epidermal and other congenital organoid nevi. Curr
Probl Pediatr 6:1-55, 1975.
33. Baker RS, Ross PA, Baumann RJ.: Neurological complications of the epidermal
naevus syndrome. Arch Neurol 44:227-232, 1987.
Skin of Neonates as a Neurodevelopmental Interface
23

34. Dodge NN, Dobyns WB.: Agenesis of the corpus callosum and Dandy- Walker
malformation associated with hemimegalencephaly in the sebaceous naevus
syndrome. A M J Med Genet 56:147-150, 1995.
35. Moskwitz R,Honig PJ.: Naevus sebaceous in association with an intracranial
mass. J Am Acad Dermatol 6:1078-1080, 1982.
36. Rogress M, McCrossen L, Commens C: Epidermal nevi and the epidermal nevus
syndrome. J Am Acad Dermatol 20:476-488, 1989.
37. Zvulunov A, Esterely N: Neurocutaneous syndromes associated with pigmentary
skin lesions . J Am Acad Dermatol 32:915-935, 1995.
38. Friedman JM: Epidemiology of neurofibromatosis type 1. Am J Med Genet 1:89,
1999.
39. Landau M, Krafchik BR: The diagnostic value of café' au lait macules. J Am
Acad Dermatol 40:877, 1999.
40. Gutmann DH, Aylsworth A, Carey K, et al: The diagnostic evaluation and
multidisciplinary management of neurofibromatosis 1 and neurofibromatosis
2. JAMA 51:278, 1997.
41. Vanderhoof SL, Francis JS, Pagon RA, et al: Prevalence of hypopigmented
macules in a healthy population. J Pediatr 129:355, 1996.
42. Webb DW, Clarke A, Fryer A, et al.: Cutaneous features of tuberous sclerosis: A
population study. Br J Dermatol 135:1-5, 1996.
43. Kwiatkowski DJ, Short MP: Tabcrous sclerosis. Arch Dermatol 130:348-354,
1994.
44. Park JP, Graham JM, Andrews PA, et al.: Ring chromosome 12. Am J Med
Genet 29:437-440, 1988.
45. Fagan K, Suthers GK, Hardacre G.: Ring chromosome 11 and café' au lait spots.
Am J Med Genet 30:911-916, 1988.
46. McDonald WB, Fitch KD, Lewis JC: Cockayne's syndrome. A heredofamilial
disorder of growth and development. Pediatrics 25:997-1007, 1960.
47. Lieberman WJ, Schimek RA, Snyder CH: Cockayne's disease. A report of a
case. Am J Ophthalmol 52:116-118, 1961.
48. Larregue M, Ottavy N, Bressieux JM, et al: Be'Be' collodion; trente deux
nouvelles observations. Ann Dermatol Vene'reol 113:773-785, 1986.
49. Commori JM, Leibovici V, Ziotogorski A.: Compound tomography in Sjogren
Larsson syndrome. Neuroradiol 29:557-559, 1987.
50. Carney RG. Incontinentia pigment: A world statistical analysis. Arch Dermatol
112:535-542, 1976.
51. Francis JS, Sybert VP: Incontinentia pigment. Semin Cutan Med Surg 16:54,
1997.
Skin of Neonates as a Neurodevelopmental Interface
24

52. O'Brien JE, Feingold M: Incontinentia pigmenti a longitudinal study. Am J Dis

Child 139:711-712, 1985.
53. Lee AG, Goldberg MF, Gillard JH, et al: Intracranial assessment of incontinentia
pigmentosa in magnetic resonance imaging, angiography and spectroscopic
imaging. Arch Pediatr Adolesc Med 149:573, 1995.
54. Wald KJ, Mehta MC, Katsumi O, et al: Retinal detachments in incontinentia
pigmenti; arch Ophthalmol 111:614,1993.
55. Sefiani A, Abell L, Heuretz S, et al: The gene for incontinentia pegmenti is
assigned to Xq 28.Genomics 4:427, 1989.
56. Sheffer R, Zlotogora J: Autosomal dominant inheritance of klein- waardenburg
syndrome. Am J Genet 42:320, 1992.
57. Dourmishev AL, Dourmishev AL, Schwartz RA, et al: Waardenburg syndrome.
Int J Dermatol 38:656-663, 1999.
58. Orlow SJ: Albinism: An update. Semin Cutan Med Surg 16:24-29, 1997.
59. Butle MG: Hypopigmentation: A common feature of Prader- Willi syndrome. Am
J Hum Genet 45:140-146,1989
60. Magdalen AD, William PB, Lawrence FE: Vascular and pigmented birthmarks.
. Pediatr Clinic North Am. 47:783-812, 2000.
61. Ramirez Duque P, Arends T, Merino F.: Chediak- Higashi syndrome:
Description of a cluster in a venezuelan- Andean isolated region. J Med
13:431-451, 1982.
62. Chan L, Lapiere J, Chen M, et al: Partial albinism with immunodeficiency
Griscelli syndrome Report of a case and review of the literature. J Am Acad
Dermatol 38:295-300, 1998.
63. Glover MT, Brett EM, Atherton DJ: Hypomelanosis of Ito: Spectrum of the
disease. J Paediatr 115:75-80, 1989.
64. Newman T.B.: Neonatal hyperbilirubinemia and long term outcome. Another look
at the collaborative perinatal project. Pediatrics 92:651, 1993.
65. Newman T.B.: Does hyperbilirubinemia damage the brain of healthy fullterm
newborns? Clin Perinatol 17:331, 1990.
66. Ahfors CE, Herbsman O: Unbound bilirubin in a term newborn with kernicterus.
Pediatrics, 111:1110-1112, 2003.
67. Sujansky E, Conradi S: Sturge Weber syndrome: Age of onset of seizures and
glaucoma and the prognosis for affected children. J Child Neurol 10:49-58,
1995.
68. Jessen RT, Thompson S, Smith EB: Cobb syndrome. Arch Dermatol 133:1587-
1590, 1977.
Skin of Neonates as a Neurodevelopmental Interface
25

69. Doppman JL, Wirth FP, Dichiro G, et al.: Value of cutaneous angiomas in the
angiographic localization of spinal cord arteriovenous malformations. N
Engl J Med 281:1440-1444, 1969.
70. Zaremba I, Stepien M, Jelowicka M, et al: Hereditary neurocutaneous angioma: A
new genetic entity? J Med Genet 16:443-447, 1979.
71. Libow LF.: Phakomatosis pigmentovascularis type IIIB. J Am Acad Dermatol
29:305-307, 1993.
72. Christoferson LA, Gustafson MB, Peterson AG.: Von Hippel – Lindau's disease.
JAMA 178:280-282, 1991.
73. Grigor R, Edmonds J, Lewkonia R, et al: Systemic lupus erythematosus: A
prospective analysis. Ann Rheum Dis 37:121-128, 1978.
74. Feinglass EJ, Amett FC, Dorsch CA, et al: Neuropsychiatric manifestations of
systemic lupus erythematosus: diagnosis, clinical spectrum and
relationship to other features of the disease. Medicine 55:323-339, 1976.
76. Akman – Demic G, Serdaroglu P, Tasci B: Clinical patterns of neurological
involvement in Behcet's disease: Evaluation of 200 patients. Brain
122:2171-2182, 1999.
75. Sakane T, Takeno M, Suzuki N, et al.: Behcet's disease. N Engl J Med
342:1284-1291, 1999.
77. Akman Demir G, Baykan- Kurt B, Sendaroglu P, et al: Seven- year follow-up of
neurologic involvement in Behcet syndrome. Arch Neurol 53:691-694,
1996.
78. Guttler F, Guldberg P: Mutations in the phenyl alanine hydroxylase gene: genetic
determinants locus in the human genome. Acta Paediatr Suppl 407:49-56,
1994.
79. Jablonska S, Stachow A, Suffezynska M.: Skin and muscle indurations in
phenylketonuria. Arch Dermatol 95:443-450, 1967.
80. Walter TH: Late effects of phenyketonuria . Arch Dis Child 73:485-486, 1995.
81. Remington SJ, Klein OJ,: Infectious Diseases of the fetus and newborn infant. N
Engl J Med 333:531-532, 1995, (book review).
82. Williamson WD, Percy AK, Yow MD, et al: Asymptomatic congenital
cytomegalovirus infection audiologic, neuroradiologic and
neurodevelopmental abnormalities during the first year. Am J Dis Child
144:1365-1368, 1990.
83. Lazzarotto T, Varani S, Guerra B, et al: Prenatal indicators of congenital
cytomegalovirus infection. J Paediatr 137:4-6, 2000.
84. Cetta F,Lambert GH,Ros SP: Newborn chemical exposure from over the counter
skin care products. Clin Pediatr 30:286-289, 1991.
Skin of Neonates as a Neurodevelopmental Interface
26

85. Haprpin VA, Rutter N: Barrier properties of the newborn infant's skin. J Pediatr
102:419-425, 1983.
86. Darmstadt GL, Dinulos JG: Neonatal skin care. Pediatr Clinc North Am 47:757-
782, 2000.