PART I

CLASSIFICATION AND TERMINOLOGY

Understanding Craniofacial Anomalies: The Etiopathogenesis of Craniosynostoses and Facial Clefting, Edited
by Mark P. Mooney and Michael I. Siegel, ISBN 0-471-38724-X Copyright © 2002 by Wiley-Liss, Inc.
CHAPTER 1
OVERVIEW AND INTRODUCTION
MARK P. MOONEY, Ph.D., and MICHAEL I. SIEGEL, Ph.D.
1.1 INTRODUCTION
As your knowledge and experience in mor-
phology (i.e., shape) and dysmorphology
(i.e., abnormal shape) increase, you will
find yourself scrutinizing the craniofacial
and somatic morphology of the people
around you, noticing subtle and not-
so-subtle asymmetries, deviations, and
abnormalities in everyone. Are these
morphologies the result of normal genetic
and developmental processes or are they
due to pathological conditions that pro
duce morphologies outside the range of
normal phenotypic variability? To answer
these questions, you need to appreciate the
normal variability of human facial form.
1.2 NORMAL CRANIOFACIAL
MORPHOLOGY
Biological variation is a natural conse-
quence of sexually reproducing organisms.
Such variation has allowed populations
to genetically adapt to changing environ-
ments. Enlow and Gans (1996) suggest that
the human face probably has more basic,
divergent kinds of facial patterns than
most other species, save domesticated dogs
Understanding Craniofacial Anomalies: The Etiopathogenesis of Craniosynostoses and Facial Clefting, Edited
by Mark P. Mooney and Michael I. Siegel, ISBN 0-471-38724-X Copyright © 2002 by Wiley-Liss, Inc.
(Stockard, 1941). This may be related to a
number of factors including the unique
evolutionary changes in the primate brain
and dentition (see Chapters 11 and 15),
human biological adaptations and develop-
mental acclimatizations to extreme envi-
ronments (Steegman, 1970; Harrison et al.,
1988; Bogin, 1988), and the fact that
humans are essentially a “domesticated”
species (Brace and Montagu, 1977).
Humans possess culture or the ability to
alter their environment through technol-
ogy and behavior. This ability somewhat
reduces natural selection pressures and
morphological canalization and homo-
geneity, which may subsequently increase
phenotypic craniofacial and dental vari-
ability (Brace and Montagu, 1977; Chapter
18). One salient example of this process is
the problem of cephalopelvic dispropor-
tion (CPD) during parturition. Historically,
the mortality rate of mothers and/or fetuses
during parturition was extremely high,
and even today in some emerging coun-
tries infant mortality rates approach 30%
(Kusiako et al., 2000). Although not all
cases of infant morality can be attributed to
CPD, it is still thought to play a significant
role in birth complications (Kusiako et al.,
2000). In countries where populations have
3
4 OVERVIEW AND INTRODUCTION
increased access to medical technology
(e.g., cesarean sections, prenatal ultrasound
scans, and so on), infant mortality rates
are approximately 11% (Meirowitz et al.,
2001). These findings suggest that, in part,
more individuals with large heads (and,
conversely, mothers with small pelvises)
are surviving. Thus, a greater frequency of
large-headed phenotypes, which might
normally have died during the birthing
process, remain in the gene pool. This
increases the range of normal phenotypic
variability and heterogeneity in facial form
in these populations. It is also an example
of domestication or artificial selection,
which is a process that increases pheno-
typical variability in a population (Brace
and Montagu, 1977).
Normal human craniofacial shape
extremes range from (1) dolichocephaly
(long, narrow head form, cranial width-to-
length index less than 0.75) with a lepto-
prosopic (long, narrow, protrusive) face
shape; to (2) mesocephaly and a meso-
prosopic face shape (proportional width-
to-length head and facial forms with a
Figure 1.1 Extremes in human head form shape (brachycephaly, mesocephaly, and dolichocephaly).
cranial width-to-length index between 0.75
and 0.80); to (3) brachycephaly (wide, short
globular head forms, cranial width-to-
length index greater than 0.80) with a
euryprosopic (broad, flat, less protrusive
facial form) face shape (Krogman, 1978;
Enlow, 1990; Enlow and Gans, 1996) (Fig.
1.1).Traditionally, these morphologies were
associated with different human popula-
tions and geographic regions: Subsaharan
African–derived populations were on
average more dolichocephalic, European-
and Middle Eastern–derived populations
were on average more mesocephalic,
and Asian-derived populations were on
average more brachycephalic. However,
the greatly increased genetic admixture
among these populations has increased
phenotypic heterogeneity and created dis-
tribution ranges of these head forms within
populations (Enlow and Gans, 1996). Other
genetic factors that may also influence
normal craniofacial morphology include
gender- and age-dependent growth pro-
cesses (Bogin, 1988; Enlow, 1990; Enlow
and Gans, 1996; Sarnat, 2001).

As can be seen, there is a wide spectrum
of human craniofacial morphologies that
are all within the range of normal human
variation. This diversity is produced by an
interaction of normal genetic and epige-
netic factors such as developmental
acclimatizations to extreme environments
(Enlow, 1990; Steegman, 1970; Harrison et
al., 1988; Bogin, 1988). It has also been sug-
gested that populations with certain mor-
phologies may be predisposed or at risk for
craniofacial anomalies based, in part, on
facial, palatal, or cranial vault growth rates
and morphologies (Burdi et al., 1972;
Juriloff and Trasler, 1976; Trasler and
Machado, 1979; Ross and Johnston, 1978;
Siegel and Mooney, 1986; Johnston and
Bronsky, 1995; Vergato et al., 1997). This
underlying phenotypic variability makes
the study and treatment of human cranio-
facial pathologies and dysmorphologies
difficult and problematic but very exciting
and challenging nonetheless.
1.3 CRANIOFACIAL
DYSMORPHOLOGY
An understanding of craniofacial anom-
alies involves an appreciation of both the
underlying, wide spectrum of normal cran-
iofacial morphology and the overlying or
interfering dysmorphology. Jones (1988)
and Cohen (1997) suggest that craniofacial
anomalies should be interpreted from the
viewpoint of developmental anatomy and
pathology (see also Chapters 4 and 5). It
is important to determine which of the
TABLE 1.1 Three Types of Dysmorphogenesis
Type of Anomaly Developmental Process
Malformation Abnormal development of tissue
Deformation Unusual forces on normal tissue
Disruption Breakdown of normal tissue
Source: Adapted from Cohen, 1997.
CRANIOFACIAL DYSMORPHOLOGY 5
multiple anomalies represent the earliest or
primary defect in morphogenesis and if all
of the anomalies can be traced to a single
problem in morphogenesis. Knowledge of
these relationships is instrumental in deter-
mining the etiology of craniofacial anom-
alies, understanding the pathogenesis of
these conditions, assessing recurrence risks,
and designing therapies and managements
for the prevention and treatment of these
cases (Ross and Johnston, 1978; Melnick
and Jorgenson, 1979; Melnick et al., 1980;
David et al., 1982; Marsh and Vannier, 1985;
Vig and Burdi, 1988; Jones, 1988; Persing et
al., 1989; Sperber, 1989, 2001; Morris and
Bardach, 1990; Gorlin et al., 1990; Montoya,
1992; Turvey et al., 1996; Cohen, 1997;
Cohen and MacLean, 2000; Posnick, 2000;
Malek, 2001; Wyszynski, 2001).
Craniofacial anomalies can be divided
into three categories: malformations, defor-
mations, and disruptions (Spranger et al.,
1982; Jones, 1988; Cohen, 1997) (Table 1.1;
Fig. 1.2). Malformations are morphological
defects of an organ, part of an organ, or a
larger region of the body resulting from
an intrinsically abnormal developmental
process. Deformations are abnormal for-
mations or positioning of a part of the body
caused by nondisruptive mechanical forces.
Disruptions are morphological defects of
an organ, part of an organ, or a larger
region of the body resulting from a break-
down of, or an interference with, an origi-
nally normal developmental process (Table
1.1).
Depending on the developmental timing
and severity of the primary craniofacial
Craniofacial Examples
Cleft lip and palate, microcephaly
Positional plagiocephaly, Robin sequence
Hemifacial microsomia, rare facial clefts
6 OVERVIEW AND INTRODUCTION
Figure 1.2 Different morphogenetic pathways producing normal and abnormal craniofacial morphologies.
anomaly, consistent patterns of multiple
anomalies may be observed. These are
referred to as syndromes or sequences (for
an excellent discussion of these two con-
cepts, see Cohen, 1997). A syndrome is
a pattern of multiple anomalies that are
pathogenetically related and not known to
represent a single sequence (e.g., Down,
Crouzon, or Apert syndrome) (Spranger et
al., 1982; Jones, 1988; Cohen, 1997). In con-
trast, a sequence is a pattern of multiple
anomalies derived from a single known or
presumed prior anomaly or mechanical
factor (e.g., Robin or amniotic band
sequence) (Spranger et al., 1982; Jones,
1988; Cohen, 1997).
While syndromes are usually related
to multiple localized malformations,
sequences can be associated with all three
types of structural defects (Table 1.2; Fig.
1.2). Malformation sequences may occur
following a single localized poor formation
of tissue that initiates a chain of subsequent
defects. Typically these defects can affect
various growth centers of the craniofacial
complex (i.e., brain, synchondroses, globes,
cranial nerves, and craniofacial muscula-
ture and vasculature) (Enlow, 1990) and
usually result in the most severe craniofa-
cial anomalies (Table 1.2; see Chapters 4
and 5).
Deformation sequences may occur fol-
lowing unusual mechanical forces (such
as intrauterine constraint from malposi-
tioning or amniotic bands) on previously
normal tissue, which may result in altered
morphogenesis, usually of the molding type
(Jones, 1988). These defects usually happen
during the fetal period, only affect growth
sites (sutures, cortical surfaces, and cra-
niofacial musculature and vasculature)
(Enlow, 1990), and result in less severe
anomalies than malformations (Table 1.2).
Disruption sequences may be related to a
disruption of normal tissue (from mechan-
ical, vascular, or infectious origin) and
subsequent dysmorphogenesis or degen-
eration of tissue. Disruptions may affect
 ACKNOWLEDGMENTS 7

TABLE 1.2 Comparative Features of the Three Types of Dysmorphogenesis

Features Malformations Deformations Disruptions

Time of occurrence Embryonic Fetal Embryonic
Level of disturbance Organ Region Area
Perinatal mortality + - +
Phenotypic variability Moderate Mild Extreme
Multiple etiologies Very frequent Less common Less common
Growth center disruption + - +
Growth site disruption + + +
Spontaneous correction - + -
Postural correction - + -
Surgical correction + ± +
Relative recurrence rate High Low Extremely low
Approximate frequency in newborns 2–3% 1–2% 1–2%
Source: Adapted from Cohen, 1997.

either growth centers or growth sites. The
resultant craniofacial dysmorphogenesis
and the ability to surgically correct it will
vary depending on location. A comparison
of the various features of these structural
defects is presented in Table 1.2 and Figure
1.2.
1.4 CONCLUSIONS
Normal human craniofacial morphology
develops as a complex consequence of
genetic and environmental interactions. In
contrast, craniofacial anomalies may occur
as a result of early embryonic problems in
tissue formation or later biomechanical or
disruptive problems with normally differ-
entiated fetal tissue. Subsequent, secondary
craniofacial anomalies are typically a con-
sequence as well. These dysmorphologies
occur over a normal developmental
substrate.
This chapter presents a short introduc-
tion into normal and abnormal craniofacial
morphology. It is not our intent to present
an exhaustive discussion of these topics,
since there are many excellent generalized
(Melnick and Jorgenson, 1979; Melnick et
al., 1980; Enlow, 1990; Enlow and Gans,
1996; Jones, 1988; Montoya, 1992; Cohen,
1997) and specialized (Ross and Johnston,
1978; Melnick et al., 1980; David et al., 1982;
Marsh and Vannier, 1985; Vig and Burdi,
1988; Sperber, 1989, 2001; Persing et al.,
1989; Gorlin et al., 1990; Morris and
Bardach, 1990; Turvey et al., 1996; Cohen
and MacLean, 2000; Malek, 2001; Posnick,
2000; Wyszynski, 2001) textbooks available.
Instead, our intent is to provide an appre-
ciation of the interaction of these processes
as an adjunct to understanding the etio-
pathogenesis and research paradigms of
craniofacial anomalies as presented in the
following chapters.
1.5 ACKNOWLEDGMENTS
This work was supported in part by a Com-
prehensive Oral Health Research Center
of Discovery (COHRCD) program/project
grant from NIH/NIDCR (P60 DE13078) to
the Center for Craniofacial Development
and Disorders, Johns Hopkins University,
Baltimore, and a publication assistance
award from the Richard D. and Mary Jane
Edwards Endowed Publication Fund,
Faculty of Arts and Sciences, University of
Pittsburgh.
8 OVERVIEW AND INTRODUCTION
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