The University of Manchester Research
Rare syndromes of the head and face: mandibulofacial and
acrofacial dysostoses
DOI:
10.1002/wdev.263
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Citation for published version (APA):
Terrazas, K., Dixon, J., Trainor, P. A., & Dixon, M. (2017). Rare syndromes of the head and face: mandibulofacial
and acrofacial dysostoses. Wiley Interdisciplinary Reviews: Developmental Biology , 6(3), [e263].
https://doi.org/10.1002/wdev.263
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Download date:10. Aug. 2022
Focus Article
Rare syndromes of the head
and face: mandibulofacial
and acrofacial dysostoses
AQ1 Karla Terrazas,
1
Jill Dixon,
2
Paul A. Trainor
1,3
and Michael J. Dixon
2
*
Craniofacial anomalies account for approximately one-third of all congenital
birth defects reflecting the complexity of head and facial development. Craniofa-
cial development is dependent upon a multipotent, migratory population of neu-
ral crest cells, which generate most of the bone and cartilage of the head and
face. In this review, we discuss advances in our understanding of the pathogene-
sis of a specific array of craniofacial anomalies, termed facial dysostoses , which
can be subdivided into mandibulofacial dysostosis, which present with craniofa-
cial defects only, and acrofacial dysostosis, which encompasses both craniofacial
and limb anomalies. In particular, we focus on Treacher Collins syndrome, Acro-
facial Dysostosis-Cincinnati Type as well as Nager and Miller syndromes, and
animal models that provide new insights into the molecular and cellular basis of
these congenital syndromes. We emphasize the etiologic and pathogenic simila-
rities between these birth defects, specifically their unique deficiencies in global
processes including ribosome biogenesis, DNA damage repair, and pre-mRNA
splicing, all of which affect neural crest cell development and result in similar
tissue-specific defects.
© 2016 Wiley Periodicals, Inc.
How to cite this article:
WIREs Dev Biol 2016, e263. doi: 10.1002/wdev.263
INTRODUCTION
AQ3
T
AQ3 he craniofacial complex houses and protects the
brain and most of the body’s primary sense
organs and is essential for feeding and respiration.
Composed of nerves, muscles, cartilage, bone and
connective tissue, head and facial development begins
during early embryogenesis with formation of the
frontonasal prominence and the pharyngeal arches,
which are transient medial and lateral outgrowths of
cranial tissue (Figure 1). The frontonasal prominence
ultimately gives rise to the forehead and the nose,
while the reiterated pattern of paired pharyngeal
arches give rise to the jaws and parts of the neck.
2
The basic structure of each prominence and arch is
the same. Externally, they are composed of ectoderm,
which with respect to the pharyngeal arches, forms
the pharyngeal clefts or grooves. Internally, the fron-
tonasal prominence and pharyngeal arches are lined
with endoderm, which forms the pharyngeal
pouches. At the junctions that separate the pharyn-
geal arches, the end oderm contacts the ectoderm by
an active movement called out-pocketing.
2–4
Between
the ectoderm and endoderm epithelia is a mesenchy-
mal core. In the frontonasal prominence the core is
composed of neural crest cells (NCCs), while in the
pharyngeal arches the mesenchymal core is composed
of both NCC and mesoderm.
5,6
NCC are a multipo-
tent progenitor cell population that is derived from
the neuroepithelium, undergoes an epithelial to mes-
enchymal transformation, delaminates and then
migrates, colonizing the frontonasal prominence and
pharyngeal arches
2,3
(Figure 1(a)–(c)). Collectively,
these four tissues, ectoderm, endoderm, NCC, and
*Correspondence to: mike.dixon@manchester.ac.uk
1
Stowers Institute for Medical Research, Kansas City, MO, USA
2
Division of Dentistry, Faculty of Biology, Medicine & Health,
Michael Smith Building, University of Manchester, Manches-
ter, UK
3
Department of Anatomy and Cell Biology, University of Kansas
Medical Center, Kansas City, KS, USA
AQ2
Conflict of interest: The authors have declared no conflicts of inter-
est for this article.
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mesoderm, interact to give rise to the skeletal, muscu-
lar, vascular, and nervous tissue elements of the head
and neck
2,7,8
(Figure 1(d)–(f )). The complexity of
craniofacial development renders it susceptible to
developmental anomalies. Approximately one third
of all congenital anomalies affect the head and face
and, to date, more than 700 distinct craniofacial syn-
dromes have been described.
The facial dysostoses describe a set of rare, clini-
cally and etiologically heterogeneous anomalies of the
craniofacial skeleton. Facial dysostoses arise as a con-
sequence of abnormal development of the first and sec-
ond pharyngeal arches and their derivatives, including
the upper and lower jaw and their hyoid support struc-
tures. Facial dysostoses can be subdivided into mandi-
bulofacial dysostosis and acrofacial dysostosis.
Mandibulofacial dysostosis (OMIM610536)
9
mani-
fests at birth as maxillary, zygomatic, and mandibular
hypoplasia (Figure 2), together with cleft palate, and/or
ear defects. Many distinct mandibulofacial dysostosis
syndromes have been described; however, clinically,
the best understood is Treacher Collins syndrome
(TCS; OMIM 154500).
10–13
In contrast, acrofacial
dysostoses present with craniofacial anomalies similar
to those observed in mandibulofacial dysostosis but
with the addition of limb defects. The acrofacial dysos-
toses include the well-characterized disorders of Miller
syndrome (OMIM263750)
14,15
and Nager syndrome
(OMIM154400)
16–18
as well as more recently identi-
fied conditions such as Acrofacial Dysostosis-
Cincinnati type (OMIM616462).
19
TREACHER COLLINS SYNDROME
TCS occurs with an incidence estimated at 1:50,000
live births.
9,20
TCS is defined clinically by bilaterally
symmetrical features that include hypoplasia (under-
development) of the facial bones, in particular the
mandible (lower jaw) and zygomatic complex (cheek
bones), coloboma (notching) of the lower eyelids;
downward slanting of the palpebral fissures (opening
E8.25LacZ
(a) (b) (c)
(d) (e) (f)
TUJ1
E10.5
Mouse
E18.5
Human
adult
Mandible
Mandible
Maxilla
Maxilla
Frontal bone
Frontal bone
Alizarin red
Alcian blue
E8.5
FNP
PA1
PA2
E9.5
FIGURE 1
|
Neural crest cells and craniofacial development. (a–c)
Mef2c-F10N
-Lacz
1
whole-mount expression marking migrating neural crest
cells as they migrate away from the dorsal neural tube to colonize the frontonasal prominence (FNP) and pharyngeal arches 1 and 2 (PA1,PA2).
(d–f ) NCC derivatives. (d) TUJ1 whole-mount immunostaining for NCC and placode-derived neurons. (e) Alizarin red and alcian blue staining for
bone and cartilage, respectively. Frontal bone derived from the FNP, and maxilla and mandible derived from PA1. (f ) Schematic of the NCC-
derived craniofacial bones of a healthy human adult. Frontal bone derived from the FNP, and maxilla and mandible derived from PA1.
Focus Article wires.wiley.com/devbio
2of17 © 2016 Wiley Periodicals, Inc.
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between the eyelids); microtia or atresia (under-
development or absence) of the external ears; nar-
rowing of the ear canal, often resulting in conductive
hearing loss (Figure 2); and micrognathia (small
lower jaw) with or without cleft and/or high-arched
palate.
9,20,21
A considerable degree of interfamilial
and, in multigeneration families, intrafamilial varia-
tion has been observed.
11,12
In severely affected
cases, TCS may result in perinatal death due to a
compromised airway.
13
In contrast, individuals may
be so mildly affected that it can be difficult to estab-
lish an unequivocal diagnosis solely by clinical exam-
ination. Indeed, some patients are only diagnosed
after the birth of a more severely affected child.
The Genetic Basis of TCS
A combination of genetic, physical, and transcript
mapping led to the identification of causative muta-
tions for TCS in the gene-designated TCOF1 on
chromosome 5q32 in humans.
10
The major TCOF1
transcript was found to comprise an open-reading
frame of 4233 bp encoded by 26 exons.
22,23
How-
ever, two alternatively spliced exons, exon 6A and
exon 16A, may also be present in the minor
transcripts.
24
Several hundred largely family-specific
deletions, insertions, splicing, and nonsense muta-
tions have subsequently been identified
22,25–31
with
partial gene deletions accounting for a small propor-
tion of all mutations.
32,33
The typical effect of the
mutations is the introduction of a premature termina-
tion codon and the induction of nonsense-mediated
mRNA degradation, leading to haploinsufficiency of
TCOF1. This hypothesis is supported by the observa-
tion that cells derived from TCS patients exhibit sig-
nificantly reduced levels of TCOF1, with the mutant
allele being less abu ndant than its wild-type counter-
part.
34
To date, only a very small number of mis-
sense mutations have been identified and these all
affect amino acid residues toward the N-terminus of
the protein either within, or close to, a putative
nuclear export signal.
26,29
While usually character-
ized by an autosomal dominant mode of transmis-
sion, approximately 60% of cases do not have a
previous family history and arise presumably as the
result of a de novo mutation.
35
It is important to
note, however, there is at least one reported case of
recessive inheritance in association with TCS.
36
In
this instance, a homozygous nonsense mutation in
TCOF1 was identified in an individual in which the
PA6
Healthy development
(a) (b)
(c) (d)
Zygomatic arch
Maxilla
Mandible
Zygomatic arch
Mandibulofacial
dysostosis
Maxilla
Mandible
PA4 PA3 PA2 PA1
PA6 PA4 PA3 PA2 PA1
FIGURE 2
|
Mandibulofacial dysostosis. (a) Schematic of the pharyngeal arches of a healthy human embryo. (b) Maxilla and mandible bone
structures derived from neural crest cells that colonize the first pharyngeal arch. (c) Schematic of the pharyngeal arches of a human embryo with
mandibulofacial dysostosis which arises as a consequence of hypoplastic first and second pharyngeal arches. (d) Hypoplastic maxilla and mandible
bone structures observed in mandibulofacial dysostoses.
WIREs Developmental Biology Mandibulofacial and acrofacial dysostoses
© 2016 Wiley Periodicals, Inc. 3of17
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carrier parents were completely normal clinically.
The mutation was likely previously missed by direct
Sanger sequencing, due to the expectation of a heter-
ozygous sequence chromatogram peak given the
characteristic autosomal dominant nature of the
disease.
Collectively, about 80% of TCS cases are
thought to be caused by mutations in TCOF1, which
encodes the nucleolar phosphoprotein, Treacle
(Figure 3). As all the large, multigeneration TCS
families analyzed exhibited linkage to polymorphic
markers within human chromosome 5q32, TCS was
originally considered to be genetically homogeneous.
However, despite extensive searches, the causative
mutation in a subset of patients exhibiting classic fea-
tures of TCS remained unidentified. The use of
genome-wide copy number analysis in a child with
TCS who was negative for a TCOF1 mutation, led
to the identification of a de novo 156-kb deletion
within human chromosome 13q12.2 that resulted in
deletion of the entire POLR1D gene.
37
POLR1D
encodes a subunit of RNA polymerase I and III
(Figure 3).
37
Subsequently, a further 242 individuals
with classic features of TCS, but who were negative
Treacle
(a)
(b)
UBF SL1
rRNA
Ribosome
proteins
Mature
ribosomes
1
3
2
p53
MDM2
Pol I
POLR1D
18S 5.8S 28S
Nucleolus Nucleus Cytoplasm
POLR1C
Pol III
POLR1D
POLR1C
Treacle
UBF SL1
rRNA
Ribosome
proteins
Mature
ribosomes
1
3
2
5S
p53
MDM2
Pol I
POLR1D
18S
5.8S 28S
Nucleolus Nucleus Cytoplasm
POLR1C
Pol III
POLR1D
POLR1C
FIGURE 3
|
Ribosome biogenesis. (a) Wild-type cell. 1, normal ribosome biogenesis; 2, normal MDM2 inhibition of p53; and 3, normal protein
synthesis, cell growth and cell proliferation. (b)
Tcof1
+/−
,
polr1c
−/−
,
polr1d
-/-
cell. 1, nucleolar stress and decreased ribosome biogenesis;
2, ribosomal proteins bound to MDM2 causing a conformational change leading to enhanced p53 expression; and 3, decreased protein synthesis,
cell cycle arrest and apoptosis.
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