Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_4533_Библиотеки_им_академика_М_И_Перельмана
.pdf
70
https://t.me/medicina_free
U. Meyer
tree-making methods, which infer taxonomies
from very large datasets using explicit stochastic models of diverging organism traits during
speciation [ 8].
6.3 Current Concepts ofDisease
Classication
Many diseases (e.g., cancer, chronic inammatory diseases) in the current disease taxonomies
have either high genetic heterogeneity [9, 10] or
manifestation diversity [11–13], which give little
basis for tailoring treatment to a patient’s pathophysiology. This is also the situation in most craniofacial malformations.
Therefore, a deep understanding of diseases
based on the advances in disease biology, bioinformatics, and multi-omics data may help in
the reclassication of disease taxonomy [14].
In the past decade, efforts to reclassify diseases
based on molecular insights have increased with
studies related to molecular-based disease subtyping in different disease conditions. Given
the molecular network mechanisms [15, 16],
genetic pleiotropy [17], as well as complicated
genotype-phenotype associations underlying
diseases, the establishment of a molecular-based
disease taxonomy with clear boundaries is essential but challenging.
In regard to the ICD classication, authors
like Zhou etal. [18] found that although general correlations exist between disease closeness in ICD taxonomy and underlying
molecular proles, ICD still displays signicant limitations with regard to the heterogeneity of molecular diversity and clear category
boundaries. Recent studies show that a disease
with a high molecular diversity tends to be
classied into multiple disease categories,
which indicates that there exist more disease
subtypes for that disease. Despite the efforts
made in data integration methods that utilized
multiple types of data (e.g., ontological and
omics data), the development of a molecular
based disease taxonomy that links molecular
networks and pathophenotypes still remains
challenging [19–21].
6.4 Genetic Access toNormal
andDisturbed Head
Formation
In order to gain access to a more genetically
based classication of craniofacial malformations, it is important to have insight into the
genetic principles of normal and abnormal tissue
development in the craniofacial region. Inborn or
acquired craniofacial malformations are based on
a disturbance or disbalance of the normal growth
process. Therefore, it is essential to elaborate the
classication on the kind of the disturbance.
Disturbances can generally be based on genetic
or non-genetic aspects. The size and growth of
each of the facial bones (Fig. 6.3) are in part
genetically predetermined, yet environmental
inuences play a role. The chromosomes and
hundreds of genes are controlling the coordinated
patterning, proliferation, and differentiation of
tissues having multiple embryological origins.
Malformations can be based on disturbances of a
chromosomal, genetic, epigenetic, or external
level (Fig.6.4). They can be also complex with
features from each level. The underlying cause of
some malformations is well known; others are
under investigation and not yet claried or even
not known at all [22].
Development of the craniofacial skeleton and
the subsequent outcome of the whole hard and
soft appearance is a highly orchestrated and complex three-dimensional morphogenetic process.
These dynamic events are on one hand spatiotemporal and on the other hand time and tissue
dependent (Fig.6.5). Malformations can occur in
all tissues. Complex ectodermal-mesodermal
interacted tissues like teeth can be present as
complex hyper-numerations of teeth.
The development of the face involves a coordinated complex series of embryonic events.
From the moment of conception, the parental
environment can inuence the development of
the fetus. Facial development occurs very early at
a time when the mother is not always aware that
she is pregnant. The developing fetus may be
subject to adverse genetic or environmental stimuli (smoking, alcohol and drug intake, allergens,
physical forces in the maternal body, others).
Of Sphenoid Bone
Of Palatine Bone
6 Classication ofCraniofacial Malformations
https://t.me/medicina_free
Frontal Bone
Temporal Bone
Orbital Process
71
Parietal Bone
Lesser Wing
Greater Wing
Of Sphenoid Bone
Orbital Lamina
Of Ethmoid Bone
Fig. 6.3 The skull represents the most complex 3D bone conguration of the whole body. Source: Reprinted from sti-
hii/Shutterstock.com with permission
Recognizable features of the human face develop
around the fourth week of gestation (Fig.6.5) and
are closely related to cranial neural crest cells
[23]. The facial processes fuse at different times;
maxillary, 6weeks; upper lip, 8weeks; and palate, 12weeks [24, 25] (Fig.6.6). Molecular studies have shown that the growth, structure, and
patternation of the facial primordia are controlled
by a series of complex genetic interactions that
involve dened genes, producing various cytokines such as broblast growth factors, sonic
hedgehog proteins, bone morphogenetic proteins,
homeobox genes Barx1 and Msx1, the distal-less
Lacrimal Bone
Perpendicular Plate
Of Ethmoid Bone
Middle Nasal Concha
Of Ethmoid Bone
Inferior Nasal Concha
Vomer
Nasal Bone
Zygomatic Bone
Maxilla
Teeth
Mandible
homeobox (Dlx) genes, and local retinoic acid
gradients [26–32]. The fusion between the facial
processes depends on a series of events involving
cell migration, growth, adhesion, differentiation,
and apoptosis (Fig.6.7). Disruptions in the fusion
of the facial processes may result in complete or
partial clefts of the face, lip, and/or palate. All
events are closely interacting and therefore specically susceptible to dysregulation as evidenced by the high proportion of congenital
defects that involve the skull and face. Whereas
genetics play a pivotal role, most modiable
environmental factors have only subtle effects on
72
U. Meyer
https://t.me/medicina_free
Cromosome variance
Gene alteration
Epigenetic change
Environmental
Fig. 6.4 Biological basis of craniofacial diseases.
Source: Reprinted from top-top vchal/Shutterstock.com,
top-middle: ktsdesign/Shutterstock.com, middle-bottom:
MoleculeQuest/Shutterstock.com, bottom-botoom: Olga
Moonlight/Shutterstock.com with permission
the face, except for strong environmental inuences (fetal alcohol syndrome, virus infections).
Craniofacial malformations occur through the
abnormal development (including cleft lip and/or
palate, craniosynostosis, branchial arch diseases,
conjoined twins, head deformations, others) during the gestational process. The whole gestational
period is known to be very vulnerable. The resulting facial malformations comprise over one-third
of all congenital birth defects, demonstrating the
highest complexity of skull formation throughout
the body. Whereas high-throughput sequencing
has recently led to the identication of many new
causative disease genes and functional studies
have claried their mechanisms of action, some
dened chromosomal alterations or gene defectrelated craniofacial diseases are long known.
Genetic studies of craniofacial Mendelian traits
are well known to be involved in craniofacial development or genetic syndromes affecting the face.
Down syndrome, Cri du chat syndrome, van der
Woude syndrome, Prader-Willi syndrome, and
Treacher Collins syndrome mostly present with
facial abnormalities and have dened chromosomal
or gene alterations. The altered facial appearance
and the relation to normal facial development [33,
34] have been investigated intensely. In contrast to
such dened chromosomal or gene-based craniofacial diseases, most malformations cannot be denitively related to singular genetic alterations.
Genome-wide association studies (GWAS)
have therefore investigated the association
between normal facial variation and millions of
single nucleotide polymorphisms (SNPs). GWAS
studies coupled with high-resolution threedimensional imaging of the face (as a documentation system) have enabled the study of the
spatial relationship of facial landmarks in great
detail. Twin studies have historically been
employed to explore the relative genetic and
environment inuence on facial shape (Fig.6.8a)
exploiting the genetic differences between monozygotic and dizygotic twins [35]. Twin studies
suggest that 72–81% of the variation of height in
boys and 65–86% in girls are due to genetic differences with the environment explaining 5–23%
of the variation [36]. Similar levels of geneticenvironmental contributions have been reported
for some other facial features (Fig.6.8b).
6.5 Pathogenetic Access
toNormal andDisturbed
Head Formation
The head with the highly complex threedimensional structure of underlying bones is the
scaffold for the facial connective tissues, the
musculature, vasculature, and associated innervation. Collectively these tissues are derived
from endoderm, mesoderm, ectoderm, and cranial neural crest cells (CNCCs) and their derivatives (Fig.6.9). Signalling between these cellular
components and the craniofacial mesenchyme
(formed primarily by CNCCs with a mesodermal
contribution) provides positional cues and regulates growth and differentiation [37]. During
undisturbed embryogenesis, the rst and second
bc
6 Classication ofCraniofacial Malformations
https://t.me/medicina_free
a
73
Fig. 6.5 (a) OPT, (b) CBCT and cross-sectional radio-
graph of dental malformations. The high number of complex teeth-Anlagen represents a temporal, spatial, and
ectodermal-mesodermal tissue dys-development. (Source:
Ulrich Meyer, informed consent of patient exists). (c)
branchial arches form facial prominences that
develop into specic craniofacial and skeletal
structures [38, 39]. Portions of the rst branchial
(or mandibular) arch develop into the skeletal,
muscular, and neural elements of the mandible,
whereas the dorsal edge of the rst branchial (or
hyomandibular) cleft forms the auditory meatus.
Cross-sectional radiograph of dental malformations. The
high number of complex teeth-Anlagen represents a temporal, spatial, and ectodermal-mesodermal tissue dysdevelopment. (Source: Ulrich Meyer, informed consent of
patient exists)
type is Treacher Collins syndrome (Fig.6.11) [41].
Aberrant neural crest cell differentiation, on the
other hand, results in premature suture mesenchyme ossication, which fuses the calvarial bones
(craniosynostosis, Fig.6.10) consequently restricting skull growth and impacting upon facial and
brain growth, development, and maturation [42].
Manifestations of rst and second branchial
arch anomalies depend on which phase of neural
crest cell development is disrupted (formation vs.
differentiation, Fig.6.10) [40]. For example, if neu-
6.6 Aspects ofDisease-Related
Phenotype Documentation
ral crest cell formation is perturbed, such as few
neural crest cells are produced or they fail to
migrate to nal destinations, this can result in phenotypes like branchial arch diseases or cleft palate.
One of the characteristic disorders of this abnormal
Most craniofacial classication systems try to
elaborate a disease-appearance relationship.
Therefore, not only the investigation and standardization of the pathogenesis are important; a
74
1st Branchil Arche
,
https://t.me/medicina_free
U. Meyer
standardized documentation and morphological
nomenclature system is a pre-requisite for a good
classication system.
The facial surface is readily visible and identiable with a close relationship to the underlying
cartilaginous and skeletal structures [43–47].
Differences in relative size, shape, and spatial
arrangement (vertical, horizontal, and depth)
between the various facial features (e.g., eyes,
nose, lips, etc.) make each individual human face
unique, although closely related individuals such
as monozygotic twins have very similar facial
structures. Standardized information on an individual’s facial morphology (e.g., by the use of
dened investigation settings) is important for
classication systems (Fig.6.12).
There are many imaging systems available to
capture the external facial surface topography
Entoderm
Mesoderm
Ectoderm
2nd Branchil Arche
3rd Branchil Arche
Branchial Cleft
Branchial Pouch
4th Branchial Arche
Mandibular Arch
Hyoid Arch
Thyrohyoid Arch
Unnamed
such as photography, lasers, photogrammetry,
optical 3D scans, magnetic resonance imaging
(MRI), computerized tomography (CT), and
cone beam computerized tomography (CBCT).
Many of these techniques have been evaluated in
terms of facial coverage, speed of capture, processing time, accuracy, validity, and cost [47–50].
For an individual who can sit still with a neutral
facial posture in natural head position, the speed
of capture is not critical. Even with relatively
long acquisition times for some photogrammetric, MRI, CT, and CBCT systems, facial landmark reliability of less than 0.5 mm can be
achieved [51–53]. For infants and individuals
with unpredictable facial or bodily movements, a
faster acquisition time will be required although
reliability of achieving the same facial posture
will be signicantly reduced.
Masticatoey Muscles (Temporalis, Masseter,
Lateral Pterygoid, Medial Pterygold),
Mylohyold, Digastric (Anterior Belly),
Tensor Tympani, Tensor Veli Palatini
Cranial Nerve V
(Mandibular Nerve From The Trigeminal)
Malleus And Incus, Portions Of the Mandible,
Meckel’s artilage, Sphenomandibular
Ligament, Anterior Ligament Of Malleus
Migmetic Facial Muscle, Stylohyoid Muscle
Digastric Muscle (posterior Belly)
Cranial Nerve VII (Facial Nerve)
Stapes, Styloid Process Of The Temporal
Bone, Lessor Cirnu Of Hyoid Bone,
Upper Part Of Hyoid Body
Stylopharyngeus Muscle
Cranial Nerve IX
(Glossopharyngeal Nerve)
Greater Cornu Of Hyoid Bone
Lower Part Of Hyoid Body
Pharyngeal And Laryngeal Muscles
Cranial Nerve X
(superior And Recurrent Larygeal Nerve)
Laryngeal Skeleton (Thyroid Cartilage,
Oricoid Cartilage, Arytenoid Cartilage,
Corniculate And Cuneiform Cartilage)
Larygeal Orifice
Fig. 6.6 Initial phase of facial development on the basis of the branchial arch system. Source: Reprinted from top:
stihii/Shutterstock.com, bottom: stihii/Shutterstock.com with permission
Neural Tube
vical Depression
Branchial Arch IV
6 Classication ofCraniofacial Malformations
https://t.me/medicina_free
Branchial Groove III
Branchial Arch III
Branchial Groove II
Branchial Arch II
Branchial Groove I
Branchial Arch I
75
Cer
Mandibular
Process
Optic Placode
Maxillary Process
Nasal Placode
Frontonasal Prominence
Umbilical Cord
Lower Limb Bud
Fig. 6.6 (continued)
Standardized clinical facial charts/tables/measures are routinely used for newborns (e.g., head
circumference, body length). Various specialties
such as maxillofacial surgery and orthodontics
use published norms for different treatment decisions. Phenotype analysis is used to identify individuals who fall within the normal range and
identify any facial dysmorphologies, but these
clinical charts are one descriptions of an alteration. They are of limited value, when details of a
disease manifestation are important for
classications.
6.7 Craniofacial Classication
Models
Classication models should ideally be aimed to
disentangle parental biological contributions to
heritable traits from environmental factors.
Models should also try to incorporate the etiology
Dorsal
Flexure
Upper
Limb Bud
Heart
Liver
Primitives Segmaents
of the disease and give respect to the situation that
in a lot of craniofacial anomalies, affected and
unaffected family members are present. Even
nowadays, classication systems are often based
on the group of persons who have developed such
classication systems. For example, the geneticist
might focus on discernible phenotypic differences
and heritability, while the surgeon concentrates on
appearance and function, and the developmental
biologist centers on gene expression and tissue
morphogenesis. Many systems have been developed to classify craniofacial malformation patterns to facilitate diagnosis, management, surgical
treatment, and research. The use of imprecise terminology in facial appearance description as well
as the growing appreciation of the spectrum of
phenotypes that are encompassed by this term
adds to the confusion. Yet, pediatricians, surgeons,
speech pathologists, nutritionists, geneticists, and
developmental biologists often classify craniofacial malformations differently. Much of this
76
Trigeminal Nerve (V)
Styloid Process Of
Fr
Fr
https://t.me/medicina_free
Geniculate Nerve (VII)
Glossopharyngeal
Nerve (IX)
Vagus Nerve (X)
1st Pharyngeal Arch With
Pharyngeal Arch Nerve (Mandibular Arch)
2nd Pharyngeal Arch With
Pharyngeal Arch Nerve (Hyoid Arch)
3rd Pharyngeal Arch
With Pharyngeal Arch Nerve
4th Pharyngeal Arch
With Pharyngeal Arch Nerve
(Fifth Rudimentary Only)
U. Meyer
Malleus
Sphenomandibular
Ligament
Meckel’s Cartilage
Incus
Greater Horn
Of Hyoid Bone
Styloid Ligament
Lesser Horn
Of Hyoid Bone
Thyroid Cartilage
Cricoid Cartilage
Stapes
Temporal Bone
Ophthalmic Nerve
om Trigeminal Nerve
Maxillary Nerve
From Trigeminal Nerve
Mandibular Nerve
om Trigeminal Nerve
Trigeminal Nerve (V)
Facial Nerve
From Geniculate Nerve (VII)
Glossopharyngeal Nerve (IX)
Laryngeal Nerve
From Vagus Nerve (X)
Muscles Of Facial Expression
(Mimetic Muscles)
Masseter Muscle
Anterior Belly
Of Digastric Muscle
Pharyngeal Muscles
Temporalis Muscle
Auricularis Muscles
Occipitalis Muscle
Posterior Belly
Of Digastric Muscle
Stilopharyngeus Muscle
Fig. 6.7 Initial and late phase of facial development on the basis of the branchial arch system. Source: Reprinted from
stihii/Shutterstock.com with permission
undocumented confusion resides also in the differing level of granularity with which each person
considers the disorder. Craniofacial malformations are a “difcult-to-dene group” of congenital anomalies named after the anatomical location
of a given defect present at birth. According to
working denitions, it could include any etiologic
category (chromosomal, environmental,
Mendelian, multifactorial, etc.), as well as any
pathogenetic mechanism (malformation, deformation, disruption, dysplasia), or any clinical category (developmental eld complex, isolated
defect, sequence, syndrome, etc.) [54]
Orofacial clefting as the most common craniofacial malformation is a typical example of a
classication problem, because it is a birth defect
with wide different genetic and pathophysical
patterns and a broad range of phenotypic variability. Studies using population-level data have
detected signicant associations between subclasses of cleft types and specic genomic
regions. Such subclassication is also likely to be
critical for identifying and understanding environmental contributions to clefting and resolving
issues related to the optimal surgical approaches
for CL repair. The benets of describing cleft
phenotypes with detail, accuracy, and reproducibility have been well-described [55].
As craniofacial malformations are relatively
rare conditions that exist in a multitude of patterns and in varying degrees of severity, historically systems of classication either have been
arbitrary or could not be standardized because of
extreme or bizarre distortions. Additionally, there
has been no unanimity of terminology or satisfactory standardization of the classication of the
innumerable craniofacial syndromes. At present,
there are over 700 craniofacial syndromes, with
new syndromes being described and published at
the rate of 25–50 per year [56, 57]. From a historical perspective, several of the craniofacial
malformations are identied according to the
6 Classication ofCraniofacial Malformations
https://t.me/medicina_free
a
77
b1 b2 b3
Fig. 6.8 (a) Facial appearance of monozygotic twins is
representative of the strong inuence of chromosomes and
genes at conception. (b) Facial appearance of the racer family Schuhmacher. The resemblance of the faces is indicative
names of the authors who rst described them,
such as the Goldenhar, Pierre Robin, Treacher
Collins, and Pfeiffer syndromes [56–58]. Other
malformations are identied by their descriptive
appearance and have been given names such as
hemifacial microsomia, retromandibulism, and
hypertelorism, without regard to their various
for the strong genetic inuence. Source: Reprinted from
a: Milan/Shutterstock.com with permission, b: Top left:
emperornie/wikimedia.org, Bottom left: AngMoKio/wikimedia.org, Top right: SvenMandel/wikimedia.org
causes. Various classication systems are based
on anatomic topography, with some authors
dividing the face into various regions and others
grouping the defects around the brain, sensory
organs, or branchial arch system [58, 59]. Burian
is credited with the rst attempt to classify the
whole range of craniofacial anomalies [59].
78
Neural crest cells (green)
cleft lip palate craniosynostosis
U. Meyer
https://t.me/medicina_free
Fig. 6.9 Cranial neural
crest cells (CNCCs)
with their migration and
differentiation have a
great inuence of facial
development. Source:
Reprinted from
sciencepics/Shutterstock.
com
with permission
Ektoderm (blue)
Mesoderm (red)
Endoderm (yellow)
neural crest cell formation neural crest cell differentiation
Fig. 6.10 Typical diseases of neural crest cell failure. Soucre: Reprinted from left: malost/Shutterstock.com, right:
sciencepics/shutterstock.com with permission
Several subsequent classications were attempted
by such authors as Sanvenero-Rosselli [58],
Burian [59], and other authors. Tessier, in 1976,
was the rst to present an orderly classication
system for all the established craniofacial malformations [60, 61]. In order to simplify the nomenclature of the clefts, Tessier devised a system in
which a number is assigned to the site of each
malformation, based on its relationship to the
sagittal midline. The classication system is
purely descriptive, however, and not related to
the embryologic development of the malformation or the underlying pathology. Nevertheless,
this system has become widely accepted because
of the ease of recording and simplicity of communication of the various malformations. It also
has been found to correlate clinical appearance
with practical surgical anatomy. Van der Meulen
[62] introduced a more complete, general category of craniofacial malformations. He participated in a group of European plastic surgeons
who proposed a redenition of terms and a new
classication in order to facilitate communication and attempt to avoid confusion among the
craniofacial syndromes and embryologic pathophysiology. Their classication represented the
collective experience of ve craniofacial surgeons (van der Meulen, Mazzola, Vermey-Keers,
Stricker, and Raphael) working in three different
countries (Netherlands, France, and Italy). The
van der Meulen etal. schema proposes that the
“common denominator” for all the craniofacial
malformations is a form of “dysplasia.”
Regardless of the cause, an arrest in skin, muscle,
Treacher Collins syndrome
Phenotype documentation
6 Classication ofCraniofacial Malformations
https://t.me/medicina_free
Fig. 6.11 Facial
appearance of a patient
with Treacher Collins
syndrome
Fig. 6.12 STL surface representation enables a precise
documentation of facial landmarks. Source: Reprinted
from Ryger/Shutterstock.com with permission
or bone development manifests itself as a “focal
fetal dysplasia.” The ultimate appearance and
severity of the dysplasia depend on the localization of the area(s) involved and the time the disturbance or developmental arrest occurs [62].
At present, there is no one classication that
satisfactorily explains all of the various craniofacial malformations. Better classications have
evolved and are continuing to evolve through
79
communication, standardization of terminology,
and the advancement of the science of embryology. There is therefore the need for large clinical,
genetic, and etiologic studies especially those
that are multi-center or multi-national in nature.
Additionally, the use of standardized and detailed
phenotypic classication was recognized and
urged [
63–67]. At the moment, there is not an all-
inclusive classication system present for craniofacial malformations. An improved classication
systems should give correlation between the full
phenotypic variability encompassed by the diagnosis of craniofacial malformations on the basis
of morphological, developmental, and pathogenic properties and the genetic and pathogenetic
attributes responsible for the heterogeneity of
such diseases. Recent insights into the genetics of
craniofacial malformations (for review see
Richmond [
22] or Ahmed [40]) enable a good
insight between dened gene alterations and disease outcome. A new classication should enable
researchers and clinicians to better appreciate the
limitations and challenges associated with using
disparate classication systems, and in the longer
term, the resulting ontology should be of great
utility for inter-center studies and populationlevel genetic investigations.
Соседние файлы в папке Библиотека им академика М.И. Перельмана