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432
Pressure ulcers have also been reported on the
toes, due to the use of oximetry sensors. On the
legs, they are often due to the premature use of
postural splints.
These ulcers usually improve in a few days
after removal of the pressure source and after
mechanical or chemical debridement.
66.4.3 The Scalp andBack
The two main causes of scalp NPUs are birth
trauma and excessive pressure on the occiput.
Scalp injuries are present in around 15% of
babies born using ventouse or forceps [7]. The
lesions are often deep and semicircular, leaving a
visible area of scarred alopecia.
Figure 66.5 shows a case of scalp lesion secondary to ventouse extraction, which affected a
¾-circular area. Wound healing was obtained
after 3 weeks of closely supervised healing by
secondary intention and involved additional surgical intervention.
Wound healing is usually attained in a few
weeks under such supervision. Dressings need to
be changed daily and use silver sulphadiazine or
hydrogel.
There are other rare locations, which are nevertheless worth mentioning. The use of EEG
monitoring equipment can cause pressure on the
forehead; this can be a source of ulcers, which are
sometimes deep. Figure66.6 shows an example
of lesions seen in intensive care which caused
visible scarring.
In a recent study [5], pressure ulcers on the
back of the head were found to represent 14% of
all NPUs.
Excessive pressure can cause occipital ulcers,
which are sometimes extensive. They affect children in intensive care or recovery. Catastrophic
situations can result from the combined risk factors of mechanical ventilation, sedation, a central
C. Herlin
Fig. 66.5 Circular lesion caused by ventouse extraction
Fig. 66.6 Pressure ulcers on the forehead caused by EEG
electrodes
venous line, humidity, the warmth of the incubator, and the baby’s state of shock (see Fig.66.7).
In the baby seen in Fig.66.7, the pressure ulcer
was due to prolonged excessive pressure in the
context of major cardiac surgery, with prolonged
low cardiac output. The child had not been turned
because of its haemodynamic instability. Healing
was obtained after surgical debridement in the
intensive care bed, dressings using negative pressure therapy, followed by skin graft on a thin onelayer articial dermis (Matriderm®). One part was
closed without tension.
66 Neonatal Pressure Ulcer
433
a
b
d
c
Fig. 66.7 (a) Extensive and deep pressure ulcer of the
occipital and upper cervical region. (b) Result obtained
after debridement and initiation of negative pressure therapy. The muscles and aponeurosis have been affected,
The result was not perfect (see Fig.66.7d), but
it enabled rapid coverage, without adhesion.
66.5 Conclusion
Neonatal pressure ulcers are specic entities
which require special attention from neonatal
care teams. The thinness of the stratum corneum
makes the skin of the premature and nursing baby
particularly vulnerable to pressure. During the
critical maturation phase, care teams must remain
with contact involving the cervical spine processes. (c)
Closure of the superior area and repeated debridement
(×5). (d) Results at 5months after placement of articial
dermis and thin skin graft taken from the adjacent scalp
alert to the possibility of pressure ulcer formation, especially in an environment which can
encourage such ulcer development.
References
1. Curley MA, Quigley SM, Lin M. Pressure ulcers in
pediatric intensive care: incidence and associated fac-
tors. Pediatr Crit Care Med. 2003;4(3):284–90.
2. Ligi I, Arnaud F, Jouve E, Tardieu S, Sambuc R, Simeoni
U.Iatrogenic events in admitted neonates: a prospec-
tive cohort study. Lancet. 2008;371(9610):404–10.
434
C. Herlin
3. Cartlidge PH, Fox PE, Rutter N.The scars of newborn
intensive care. Early Hum Dev. 1990;21(1):1–10.
4. Zollo MB, Gostisha ML, Berens RJ, Schmidt JE,
Weigle CG.Altered skin integrity in children admitted
to a pediatric intensive care unit. J Nurs Care Qual.
1996;11(2):62–7.
5. Fujii K, Sugama J, Okuwa M, Sanada H, Mizokami
Y.Incidence and risk factors of pressure ulcers in seven
neonatal intensive care units in Japan: a multisite prospective cohort study. Int Wound J. 2010;7(5):323–8.
6. Hufnes B, Logsdon MC. The Neonatal Skin
Risk Assessment Scale for predicting skin breakdown in neonates. Issues Compr Pediatr Nurs.
1997;20(2):103–14.
7. Sardesai SR, Kornacka MK, Walas W, Ramanathan
R. Iatrogenic skin injury in the neonatal intensive care unit. J Matern Fetal Neonatal Med.
2011;24(2):197–203.
8. Jatana KR, Oplatek A, Stein M, Phillips G, Kang DR,
Elmaraghy CA. Effects of nasal continuous positive
airway pressure and cannula use in the neonatal intensive care unit setting. Arch Otolaryngol Neck Head
Surg. 2010;136(3):287–91.
9. Shanmugananda K, Rawal J.Nasal trauma due to nasal
continuous positive airway pressure in newborns. Arch
Dis Child Fetal Neonatal Ed. 2007;92(1):F18.
Open Access This chapter is licensed under the terms of the Creative Commons Attribution-NonCommercialNoDerivatives 4.0 International License (http://creativecommons.org/licenses/by- nc- nd/4.0/), which permits any noncommercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit
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Skin Necrosis inChildren:
Genodermatosis
CristinaHas andAgnesSchwieger-Briel
67
67.1 Introduction
The term genodermatosis comprises a large
group of dermatoses caused by genetic defects,
including monogenic and mosaic disorders. From
the physiopathogenic point of view, various compartments of the skin can be disturbed, such as
intraepidermal or epidermal-dermal adhesion,
cornication, DNA repair, the vascular system,
etc. The onset of clinical symptoms is most commonly at birth or during early childhood, and the
clinical course is progressive, without spontaneous healing or remission.
Cutaneous necrosis is a primary manifestation
of several disorders reviewed in this chapter.
Even though more common in the context of
acquired inammatory conditions predisposing
to infectious or ischemic necrosis, it can also be a
characteristic sign of genetic diseases.
C. Has (*)
Department of Dermatology, Medical Center—
University of Freiburg, Freiburg, Germany
e-mail: cristina.has@uniklinik-freiburg.de
A. Schwieger-Briel
Department of Dermatology, Medical Center—
University of Freiburg, Freiburg, Germany
Pediatric Skin Center, Dermatology, University
Children’s Hospital Zurich, Zurich, Switzerland
67.2 Genodermatoses that
Manifest withCutaneous
Necrosis asaLead Symptom
67.2.1 Progeroid Syndromes
67.2.1.1 Hutchinson–Gilford Progeria
Syndrome
andMandibuloacral
Dysplasia
Hutchinson–Gilford progeria syndrome (HGPS,
OMIM#176670) and mandibuloacral dysplasia
with type A lipodystrophy (MADA,
OMIM#248370) are allelic disorders that belong
to the premature aging syndromes (syn. progeroid
syndromes, laminopathies). They are caused by
pathogenic variants in the gene for lamin A/C
(LMNA), an essential structural component of
the nuclear envelope. HGPS is extremely rare
occurring in one per 20million newborns due to
a de novo mutation. MADA is an autosomal
recessive condition.
1. Physiopathogeny and biology:
In HGPS, a recurrent de novo monoallelic
variant (c.1824C>T) leads to formation of a
truncated prelamin A protein, called progerin,
which cannot undergo normal processing to
mature lamin A [1]. Normal prelamin A processing comprises four posttranslational modication steps. Mature lamin A is an
intermediate lament protein that is incorporated into the nuclear lamina lament mesh-
© The Author(s) 2024
L. Téot et al. (eds.), Skin Necrosis, https://doi.org/10.1007/978-3-031-60954-1_67
435
436
C. Has and A. Schwieger-Briel
work, where it interacts with many proteins
important for nuclear structure integrity [1].
In HGPS, progerin accumulates as a farnesylated and methylated intermediate in the
nuclear envelope where it is toxic and causes
nuclear shape abnormalities and senescence.
This is the molecular basis for the polymorphic disease manifestations in different organs
in HGPS.
2. Diagnosis
The diagnosis is based on clinical features
and genetic testing. Clinical manifestations
are present in early childhood. Life expectancy is limited to the second decade of life in
HGPS.
Medical context and semiology:
HGPS
(a) Cutaneous features include atrophic,
scleroderma-like skin with progressive
loss of subcutaneous fatty tissue, cigarette paper-like appearance, clearly visible venous network. Additional
manifestations:
(b) Sparse hair, nail anomalies, delayed and
abnormal dentition
(c) Progeroid features: ‘bird’ facies with
sharp, thin nose and micrognathia
(d) Absent sexual secondary characteristics,
high-pitched voice
(e) Growth failure, skeletal anomalies, asep-
tic necrosis of bones reported, acroosteolysis and osteoporosis
(f) Cardiovascular anomalies (rapidly pro-
gressive atherosclerosis, early myocardial
infarction and strokes, hypertension, congestive heart failure)
MADA
(a) Cutaneous features include pigmentary
skin changes and lipodystrophy, characterized by a marked acral loss of fatty tissue with normal or increased fatty tissue
in the neck and trunk.
(b) Inconstant progeroid features
(c) Growth retardation, mandibular hypopla-
sia, skeletal abnormalities with progres-
sive osteolysis of the distal phalanges and
clavicles
(d) Metabolic complications can arise due to
insulin resistance and diabetes.
On the background of tissue atrophy and
vascular changes, skin necrosis and ulcers can
occur in both conditions in particular on acral
and on bony surfaces.
3. Treatment:
There is no cure for these rare disorders,
although many experimental strategies are
under research [1]. They include genetic
approaches or targeting the level and the posttranslational modications of progerin. The
treatment of necrosis is symptomatic, aiming at
controlling infections, saving tissue, and managing wounds. Prevention measures should
include careful skin care with moisturizers and
avoidance of mechanical pressure and trauma.
67.2.2 Vascular Anomalies
67.2.2.1 Cutis Marmorata
Telangiectatica Congenita
(Syn. Congenital Generalized
Phlebectasia, Naevus
Vascularis Reticularis,
Congenital Phlebectasia,
Congenital Livedo
Reticularis andvan Lohuizen
Syndrome)
Cutis marmorata telangiectatica congenita
(CMTC) is an uncommon congenital vascular
anomaly with features including erythematousto- violaceous, reticulated, net-like or marbledappearing patches of skin phlebectasias, and
cutaneous and subcutaneous atrophy [2]. It can
mimic physiological cutis marmorata (CM) but
does not disappear with warming. CMTC may be
present in some disorders such as Adams–Oliver
syndrome, phakomatosis pigmentovascularis
type 5A, and neonatal lupus erythematosus [3].
CMTC is a slow-ow vascular lesion that affects
capillaries and venules.
1. Physiopathogeny and biology:
CMTC is a mosaic disorder caused by
GNA11 mutations found in skin biopsies from
67 Skin Necrosis inChildren: Genodermatosis
437
CMTC-affected skin areas. The mutation is
either not detectable or found at a low level of
0.3% in blood [4].
2. Diagnosis:
CMTC is a clinical diagnosis. When suspi-
cion of CMTC is raised, it is recommended to
perform a careful evaluation of the patient for
associated anomalies, in cases with extensive
ndings, ideally in a multidisciplinary team
with a pediatrician, dermatologist, ophthalmologist and, if needed, orthopedic surgeon [5].
Medical context and semiology:
The most important cutaneous manifesta-
tion of CMTC, the reticulate marbled vascular
presentation. CMTC can be localized, segmental or widespread. Atrophy or skin ulceration
and lipoatrophy at the sites of vascular discoloration, as well as prominent veins, telangiectasias and hyperkeratosis may be present.
Association with limb asymmetry, glaucoma,
intellectual disability, patent ductus arteriosus,
and arterial stenosis have been reported [2,
3]. A review of the literature found extracu-
taneous anomalies in 42.5% of patients, predominantly body asymmetry and neurological
defects like seizure and developmental delay.
Fewer patients (10.1%) had ophthalmological
defects, usually glaucoma [5].
3. Treatment:
Some reports described effective laser
therapy for erythema and ulceration, while
other reports stated no effect of laser treatment [5–7]. PDL therapy for this condition
shows a variable response, often disappointing. The skin lesions tend to fade with age.
The only exception is a capillary malformation of the upper lip, often a feature of this
condition, which can respond well to laser
treatment [3].
67.2.3 Metabolic Disorders
67.2.3.1 Prolidase Deciency
Prolidase deciency (OMIM#170100) is an
inborn metabolic multisystemic disease characterized by skin lesions, recurrent infections,
dysmorphic facial features, variable intellectual
disability, and organomegaly with elevated
liver enzymes. Skeletal anomalies, chronic pulmonary disease, anemia, thrombocytopenia,
hypergammaglobulinemia, and hypocomplementemia are inconstant features [8]. Prolidase
deciency is one of the rare causes of leg ulcers
in children [9].
1. Physiopathogeny and biology:
Biallelic pathogenic variants in the gene
encoding prolidase are found in affected individuals. Prolidase is an enzyme that cleaves
di- and tripeptides containing carboxylterminal proline or hydroxyproline [10]. It is a
homodimer, with each subunit binding two
manganese ions that are required for enzymatic activity. The enzyme is required in the
nal catabolic steps of endogenous and dietary
proteins, rich in proline and hydroxyproline,
such as collagen. The deciency of prolidase
leads to accumulation of imidodipeptides, or
peptides with two amino acids, with a
C-terminal proline or hydroxyproline [8].
2. Diagnosis:
The diagnosis can be established based on
characteristic clinical ndings and imidodipeptiduria or reduced prolidase enzyme activity. Genetic testing identies biallelic
pathogenic variants in PEPD, the gene coding
for prolidase.
Medical context and semiology:
(a) Typically severe, chronic, recalcitrant,
and painful skin ulcers of the lower
extremities (Fig.67.1) and telangiectasias
of the face and hands. A review of the literature identied skin ulcers in 61% of
the reviewed cases. The ulcerations may
appear on the dorsal part of the foot and
on the sole and extend all over the legs,
sometimes leading to tendon lesions and
severe skin infections. No underlying
vascular anomalies were described [11].
(b) Infections of the skin and respiratory tract
(c) Splenomegaly and inconstant
hepatomegaly
3. Treatment:
Skin ulcers require treatment by a wound
care specialist; topical proline (often 5%) or
438
Fig. 67.1 Prolidase deciency
topical 5% proline-5% glycerine ointment
applied with dressing changes has been successful in some affected individuals [12].
Standard treatment should be employed for
developmental delay/intellectual disability,
seizures, infections, reactive airways disease/
pulmonary hypertension, respectively. One
group reported improvement of skin ndings
with the use of anticoagulants [13].
C. Has and A. Schwieger-Briel
Fig. 67.2 Ecthyma gangrenosum in EBS (kindly provided by Dr. L.Weibel)
67.2.4 Genodermatosis
withCutaneous Necrosis
asaPossible Complication
67.2.4.1 Inherited Epidermolysis
Bullosa
Epidermolysis bullosa (EB) encompasses genetic
disorders characterized by skin fragility and blistering with a broad range of clinical severity. The
main EB types are EB simplex, junctional EB,
dystrophic EB, and Kindler EB.Skin necrosis is
not a typical feature of EB but may occur in
wounded areas in the context of infections
(Fig.67.2) [14].
1. Physiopathogeny and biology:
EB is caused by loss of function pathogenic variants in genes encoding structural
proteins assuring the mechanical stability of
the skin, such as keratins, integrins, collagens,
or laminins [15]. Consequently, keratin intermediate laments, hemidesmosomes, focal
adhesions, or anchoring brils are weakened.
Blistering can be intraepidermal, junctional,
dermal, or mixed and results in erosions,
ulcerations, or chronic wounds. Congenital
absence of the skin is relatively common on
lower legs and can be a feature of any type of
EB. There is an alteration in the cutaneous
microbiome in EB, with loss of species diversity and abundance of Staphylococcus [16].
2. Diagnosis:
The diagnosis of EB is clinically suspected
based on mechanically induced blistering of
the skin and additional cutaneous features as
described in detail before [17].
Immunouorescence mapping and genetic
testing determine the type and subtype of EB
[18].
Medical context and semiology:
(a) Blisters, erosions, ulcerations, and
wounds, depending on the type of EB
(b) Scarring is a main feature of dystrophic
and Kindler EB
67 Skin Necrosis inChildren: Genodermatosis
439
(c) Nail dystrophy is common in junctional
and dystrophic EB
(d) Mucosal membranes are fragile leading
to inammation and scarring, in particular, in dystrophic and Kindler EB
(e) Extracutaneous organ involvement may
occur primary in syndromic EB subtypes
or secondary as a complication of severe
EB
3. Treatment:
Blisters should be lanced; antiseptics
should be used as well as proper wound dressings in order to assure uncomplicated healing
of the wounds. Mechanical pressure should be
avoided in particular on bony body areas.
Various cell therapies (e.g., broblasts, mesenchymal stem cells) administered topically
to epidermolysis bullosa wounds in small
clinical trials, showed positive effect on
wound healing [19–23].
Recently, Oleogel-S10 (containing birch
triterpenes, Filsuvez®) [24] was approved by
EMA and FDA for the treatment of wounds in
junctional and dystrophic epidermolysis bullosa. Beremagene geperpavec (B-VEC,
Vyjuvek®) is the rst gene therapy approved
by the FDA for the treatment of cutaneous
wounds in patients with dystrophic epidermolysis bullosa. This represents a signicant
progress for the treatment of this devastating
disease. It is based on non-replicative (nr)
recombinant HSV-1 vector containing two
copies of the COL7A1 gene [25, 26].
67.2.5 Harlequin Ichthyosis
Harlequin ichthyosis (OMIM#242500) is one of
the most severe types of congenital ichthyosis
that manifests at birth with tight horny plaques
that cover the entire body (harlequin-baby).
There is no primary extracutaneous involvement,
but skin contractions lead to ectropion, eclabion,
ear deformities, and deformities of the hands and
feet. Complications occur frequently in infants
and include respiratory distress, dehydration,
electrolyte imbalance, temperature instability,
feeding problems, and bacterial infections, often
with fatal consequences. Constriction bands may
cause skin necrosis.
1. Physiopathogeny and biology:
Harlequin ichthyosis is caused by biallelic
loss of function pathogenic variants in
ABCA12, the gene that codes for ATP binding
cassette subfamily A Member 12, a glucosylceramide transporter.
2. Diagnosis:
Medical context and semiology:
(a) Harlequin-baby at birth
(b) Erythroderma and generalized large
lamellar scales
(c) Ectropion, eclabion, ear deformities
(d) Severe palmoplantar keratoderma
(e) Digital autoamputation [27]
(f) Respiratory distress, dehydration, elec-
trolyte imbalance, temperature instability,
feeding problems, and bacterial
infections
3. Treatment
Early administration of oral retinoids
(acitretin 1 mg/kg) is effective in shedding
and softening of the large scales, reducing the
risk of constrictive bands and skin necrosis. In
addition, the use of skin moisturizers is mandatory (such as petrolatum).
67.2.6 Olmsted Syndrome
Olmsted syndrome (OS OMIM#614594,
#619208, #300918) is a rare genodermatosis
classically characterized by the combination of
bilateral mutilating transgradient palmoplantar
keratoderma (PPK) and perioricial keratotic
plaques, but which shows considerable clinical
heterogeneity. The disease starts usually at birth
or in early childhood. Less than 100 cases have
been reported worldwide [28].
1. Physiopathogeny and biology:
OS is genetically heterogeneous, being
caused by pathogenic variants in three distinct
genes TRPV3 (transient receptor potential cat-
440
C. Has and A. Schwieger-Briel
ion channel subfamily V member 3), PERP
(TP53 apoptosis effector), or MBTPS2 (membrane bound transcription factor peptidase,
Site 2). TRPV3 is a thermosensible cation non
selective channel, activated by temperature
and several chemical ligands, predominately
expressed in keratinocytes, and in sensory
neurons. MBTPS2 is a zinc metalloprotease
essential for cholesterol homeostasis and
endoplasmic reticulum stress response [28].
2. Diagnosis:
Medical context and semiology:
(a) Bilateral mutilating transgradient palmo-
plantar keratoderma. Progression of the
keratoderma may lead to exion deformities, constrictions of digital bands, and
even spontaneous digit amputations.
(b) Perioricial keratotic plaques (mouth,
nose, eyes, genital, anal, ears, navel)
(c) Other features may be nonperioricial
keratotic lesions involving the thighs,
arms, elbows, knees, and intertriginous
folds; hyperkeratotic linear streaks, follicular keratosis, pachyderma, cheilitis,
ichthyotic lesions, or chronic blepharitis.
(d) High clinical variability and a wide range
of inconsistent clinical manifestations
have been reported [28]
3. Treatment
(a) Symptomatic treatments of hyperkerato-
sis include emollients, keratolytics, retinoids, or corticosteroids, either topical or
systemic
(b) Recently, targeted inhibition of the epi-
dermal growth factor receptor and mammalian target of rapamycin signaling
pathways demonstrated signicant
improvement of clinical manifestations of
OS [29, 30].
1. Physiopathogeny and biology:
Patients are lacking the β2-integrin chain
CD18 (ITGB2) of the leukocyte cell adhesion
molecule, essential for cell–cell and cell–
extracellular matrix interactions.
Consequently, the function of granulocytes,
monocytes, and lymphocytes is impaired.
2. Diagnosis:
Medical context and semiology:
Newborns often suffer from navel infec-
tions with Pseudomonas aeruginosa, leading
to severe skin necrosis. Skin manifestations
consist of abscesses, mucosal ulcers, and
wound healing defects.
(a) Recurrent, life-threatening bacterial
infections of the skin, mouth, and respiratory tract
(b) Periodontitis and tooth loss
3. Treatment
(a) Control of infections with antibiotics.
(b) Hematopoietic cell transplantation repre-
sents the only cure for LAD-I.
67.2.8 Other Genetic Diseases
Skin necrosis may be a complication of various
disorders:
• Autoinammatory disorders who can have
vasculopathies
• Interferonopathies
• Hematologic diseases such as sickle cell ane-
mia cause severe ulcerations
• Genetic primary lymphedema
• Klinefelter syndrome
67.3 Conclusion/Take Home
Messages
67.2.7 Leucocyte Adhesion
Deciency Type I
Leukocyte adhesion deciency type 1 (LAD-I)
(OMIM#116920) includes three types, of which
type I is the most common.
Skin necrosis is rare in children and may be a manifestation of a serious genodermatosis. The diagnosis should be made based on clinical manifestations
and genetic testing. Although specic therapies are
lacking, intensive symptomatic management of
skin lesions should be the main focus.
67 Skin Necrosis inChildren: Genodermatosis
441
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