Current Oral Health Reports

https://doi.org/10.1007/s40496-019-00223-8

ORAL DISEASE AND NUTRITION (F NISHIMURA, SECTION EDITOR)

Nutritional Status Influencing Orofacial Developmental Anomalies

Ashish Shrestha 1 & Chandramani B. More 2 & Shashi Keshwar 1 & Bijayata Shrestha 3 & Toniya Raut 1

# Springer Nature Switzerland AG 2019

Abstract
Purpose of Review Developmental anomalies affecting orofacial region are not that uncommon. Genetic factors play an impor-
tant role in developmental anomalies of the orofacial region. However, the role of other factors including nutrition cannot be
disregarded. This review focuses on the current literature regarding the role of nutrition in the normal development and various
developmental anomalies associated with nutritional deficiency.
Recent Findings Neural crest cells have an enigmatic role in the development of orofacial region, and there are evidences to
support the importance of nutrition in its differentiation. Studies have been conducted to document the role of some nutrients in
the development and growth; despite that there are many, the roles of which are not yet established. Most of the studies are
focused on orofacial clefts but very sparse in other orofacial anomalies.
Summary The impact of malnutrition can also be considered a key factor in developmental anomalies of orofacial region. There
is an increasing need of awareness regarding balanced nutrition for the mother and developing child. Although role of nutrition in
normal development is established the role of many nutrients are still not established which highlights the need for further
research.

Keywords Developmental anomalies . Malnutrition . Neural crest cell . Nutritional deficiency . Orofacial

Introduction insults during the organization of these events might result

Development of orofacial component is a complex mecha-
nism. Intricate series of events requiring well-synchronized
programs for cell migration, growth, differentiation, and apo-
ptosis are involved in its development. Migration of cranial
neural crest cells to first and second pharyngeal arch rein-
forces the development of cranial structures such as the man-
dible, palate, tongue, teeth, and most facial muscles. Any
This article is Part of the Topical Collection on Oral Disease and
Nutrition
* Ashish Shrestha
ashish.shrestha@bpkihs.edu
1
Department of Oral Pathology, College of Dental Surgery, BP
Koirala Institute of Health Sciences, Ghopa Camp, Dharan-
18, Sunsari, Nepal
2 birth defects of the neural tube, other neurological abnormal-
Department of Oral Medicine and Maxillofacial Radiology, K. M.
Shah Dental College and Hospital, Sumandeep Vidyapeeth,
Vadodara, Gujarat, India
3
Department of Oral Pathology, Gandaki Medical College,
Pokhara, Nepal
in orofacial anomaly [1, 2].
Nutrition is the intake of food, considered in relation to the
body’s dietary needs (https://www.who.int/topics/nutrition/
en/). It is a critical part of health and development. Better
nutrition is related to improved infant, child, and maternal
health, stronger immune systems, safer pregnancy and
childbirth, lower risk of non-communicable diseases, and lon-
gevity (https://www.who.int/features/factfiles/nutrition/en/).
Malnutrition, on the other hand, presents significant threats
to human health. Today, the world faces a double burden of
malnutrition that includes both undernutrition and overweight,
especially in low- and middle-income countries (https://www.
who.int/features/factfiles/nutrition/en/).
Maternal nutrition is one of the most extensively studied
environmental factors in congenital disorders. During preg-
nancy, the nutritional status of the embryo is fully dependent
on maternal food intake and metabolism. A nutritional excess
or deficiency, during the organogenesis period, can lead to
ities, congenital heart disease, intestinal malformation, and
orofacial cleft [3]. The normal orofacial development seems
to be dependent on adequate nutrition of the mother at the time
of conception and during the first trimester of pregnancy [4].

Malnutrition refers to deficiencies, excesses, or imbalances
in a person’s intake of energy and/or nutrients. Micronutrient
deficiencies have varied effects on the human body because of
the diverse roles they play. During the process of cell growth,
DNA is transcribed to RNA, which is then translated to pro-
teins, which provide the enzymes and structures of the cell. At
every stage in the process, micronutrients are essential, either
as signals (retinoic acid, for example), or structural (zinc in
transcription factors) or catalytic (e.g., copper) elements [5].
Numerous keywords (like cleft palate, nutrition, vitamin
deficiency, and micrognathia) related to the topic were
discussed among the authors and searched in PubMed.
There were very few articles directly relating to the topic of
concern, so the same keywords were applied in google search.
After collecting the articles, each was reviewed meticulously
and selected for further review. We aim to compile the role of
nutrition in the development of orofacial structure and its sig-
nificance in developmental anomalies.
Nutrition and Orofacial Anomalies
The orofacial region of the human body comprises of a com-
bination of numerous hard and soft tissues arranged in an
intricate manner giving a particular form and structure to ex-
ecute a specific function. The formation of these structures is
governed by numerous complex signaling pathways, depend-
ing on factors like genetic, environment, and nutrition.
Deficiency of nutrition could lead to numerous orofacial
anomalies like orofacial clefts and micrognathia.
Orofacial Clefts
Orofacial clefts (OFCs), which include cleft lip (CL) and cleft
palate (CP), are one of the most common congenital anoma-
lies among craniofacial malformations observed in newborns
[6]. The prevalence of OFC is 1 in 500 births of Asian or
Amerindian ancestry [7]. Genetic and environmental factors
are generally thought to be involved in the etiologies of non-
syndromic orofacial cleft. A variety of environmental factors
that could have a contributory role for OFC during pregnancy
include the following: maternal smoking, tobacco use, alcohol
drinking, exposure to teratogenic agents (e.g., anticonvulsant,
aminopterin, corticosteroids), vitamin and folate deficiency
[1, 8, 9•].
Among all the nutritional and environmental factors that
have a role in the development of non-syndromic OFC, folic
acid levels were observed to be the most important [10]. The
complex process of folate metabolism depends on a series of
enzymatic reactions involving numerous genes and pathways
which form the active form of folic acid (tetrahydrofolate).
The intermediates which are produced during this complex
reaction function in vital physiological processes such as
Curr Oral Health Rep
nucleotide synthesis, cell division, and tissue growth. Any
interference in these folate metabolism pathways could result
in a folate deficiency, which ultimately causes disruption of
important biological processes, such as craniofacial develop-
ment (Fig. 1) [2, 11–15].
Multivitamin and folic acid supplementations have been
focused on various researches conducted to see the association
of maternal nutritional status and risk of developing OFC.
Studies have shown a protective effect of folic acid from sup-
plements and folate from the diet. Studies conducted by
Mungar et al. and Tamura et al. showed lower maternal blood
zinc concentration in mother with OFC [16, 17].
Food rich in beta carotene has been seen to have a protec-
tive effect on OFC, maternal nutritional status, and the risk for
orofacial cleft offspring in humans [18]. Lower intake of nia-
cin; riboflavin; thiamin; vitamins B12, C, and E; zinc; mag-
nesium; calcium; and choline is seen to be associated to in-
creased risk of cleft lip and palate [19]. Maternal hyperglyce-
mia is also seen to interfere with palatogenesis [20]. Both the
deficiency and overdose of retinoic acid have been observed
to cause Cleft lip/palate in rodents and humans and are con-
sidered vital in palatogenesis [3, 21, 22].
Observational Studies of Nutritional Deficiency and OFC
In a meta-analysis conducted by Goh Yi et al., the consump-
tion of folic acid before and during pregnancy was found to be
associated with a decreased risk of several birth defects, in-
cluding cleft lip and cleft palate [23]. Similarly Wilcox et al.
observed that folic acid consumption during pregnancy re-
duced the risk of cleft lip up to 30% with 400 μg per day or
higher doses [24].
In a case-control epidemiological study conducted by
Figueiredo RF et al., a high incidence of OFC was observed
in mothers with dietary folate deficiency during the
periconceptional period and during the first trimester of preg-
nancy [25].
In a case-control study to analyze the relation between ma-
ternal zinc and copper and risk of infant being born with
orofacial cleft, an estimate of risk of CL/P associated with
low zinc and high copper concentration in maternal blood
was concluded [4]. Angulo-Castro E et al. found a strong
association of dietary deficiency of folic acid and multivita-
mins during pregnancy and development of cleft lip and cleft
palate in a Mexican population where women were habituated
to smoking, alcohol abuse, and not taking folic acid and mul-
tivitamins during pregnancy [26].
The role of maternal zinc nutrition in human oral clefts
(OC) is not clear. Munger et al. measured plasma zinc con-
centrations (PZn) of mothers of Utah to evaluate the associa-
tions between Zn and risk of OC with and without other mal-
formation and found no association between the risk of devel-
oping OC with and without other malformations and maternal
Curr Oral Health Rep

Fig. 1 Role of folic acid in neural Folic acid Inhibit

crest cells differentiation Methionine S-adenosylmethionine (SAM)
Deficiency -CH3 donor / cofactor

Smulate
Gene specific Inhibit DNA
demethylaon Methylaon
Pdmr-16 DNA Human α-folate
mutaon demethylaon receptor (FR-α)
Cell Gene expression
Defense
proliferaon
Mechanism
TGF-β3 expression
(Acini of salivary gland)
Gene Regulatory
Network
Homocystein accumulaon Neuroectoderm
(Metabolic byproduct) Time specific FR-α receptor expression BMP SLUG
FGF STX11
Specificaon Wnt Wnt
Defecve submandibular FOXD3 FGF
gland duct formaon SNAIL
Pre-neural crest cells
aggregaon

Proliferaon
Smulate Differenaon
Acn expression

Inhibit differenaon, Neural Crest cells

polarity, mobility (Migratory potenal)

Decrease/ defecve neural crest

cell formaon

Defecve/ no migraon to
st nd
pharyngeal arch (1 and 2 )

Cle lip/palate
Syndrome
Pierre Robin syndrome
Defecve Growth Madibulofacial dysostosis
Agnathia

Others
Microglossia
Aglossia

PZn [16]. Previous studies have observed that poor maternal
zinc status was a risk factor for OCs in the Philippines, where
OC prevalence is high and maternal PZn is low [17].
In a meta-analysis by Millacura N et al., a beneficial effect
of folic acid fortification policy was observed only for non-
syndromic CL/P prevalence and neutral influences on the oth-
er classifications of clefts [27]. In another meta-analysis by
Jahanbin A et al., a multivitamin containing FA showed a
more pronounced protective effect on CL/P and cleft palate
only than folic acid alone. They showed the protective effect
of periconceptional multivitamin containing folic acid on oral
clefts. At present, the daily use of a multivitamin supplement
including 0.4 to 0.8 mg of folic acid with a healthy diet and
lifestyle for women at the reproductive age, who want to have
a baby without oral clefts, is recommended [9•].
In a case-control study in Indian population, supplementa-
tion with multivitamin or folic acid preparations in the
periconceptional period did not seem to have any protective
effect. The reverse finding may be due to supplementation
only after the first antenatal visit in Indian population, which
usually takes place after the missed period or approximately 3
to 4 weeks after conception. They observed a strong associa-
tion of OFC and vegetarian diet as compared with non-
vegetarian diet. Women having vegetarian diets have low fo-
late and vitamin B12 levels, and a diet deficient in folate and
vitamin B12 was shown to be related with OFC [28].
Tongue
Tongue development is a complex process. The development
of the tongue required coordinated series of molecular and
morphogenetic events [29••]. Tongue connective tissue and
vasculature are derived from cranial neural crest cells
(CNCC), whereas the skeletal muscles originate from myo-
blasts. Reciprocal interactions between CNCC and myogenic
cells play an important role in regulating tongue development
[30]. The role of neural crest cell is very important in tongue
development. The defect in NCC can lead to various congen-
ital craniofacial developmental disorders called collectively as
neurocristopathies, like Treacher Collins syndrome and
Hirschsprung’s disease [31].

Folic acid is an essential nutrient for the development of
craniofacial structure. It has a major role in the development of
tongue. Maternal folic acid deficiency during pregnancy is a
risk factor for tongue abnormality such as aglossia and
microglossia. Congenital malformation has multifarious etiol-
ogy which includes complex interaction between gene and
environment like periconceptional malnutrition and unhealthy
lifestyle. In the tongue, various factors like Wnt gene signal-
ing, TGF- β, and BMPs help in regulating migration,
pattering, proliferation, determination, differentiation, and
maturation either in different subpopulations of cranial neural
crest cells or in migrating myogenic progenitors. Deficiency
of folic acid causes hypomethylation, hyperhomocysteinemia,
DNA synthesis error, and inhibition of the cell growth. These
effects lead to a defect in the components which are developed
from neural crest cells like lingual vessels and lingual septum
that can hamper the development of the tongue and lead to
aglossia or microglossia. In an orchestrated manner, neural
crest cells are also first to migrate towards future tongue and
help in the development of myoblast populations. According
to these findings, Maldonado et al. concluded that deficiency
of FA in maternal diet alter the harmony of the genetic cascade
responsible for normal tongue development. They also con-
cluded that responsible effect is at the level of neural crest cells
which leads to the formation of anomaly of the tongue like
aglossia and microglossia [29]. Lack of tongue development
has also led to defective craniofacial growth [32].
Folic acid deficiency reduces the expression of vascular
endothelial growth factor (VEGF) which could be one of the
risk factors for the development of vascular malformation
mainly in the lingual vessel of the tongue due to compromised
vasculogenesis and angiogenesis [33, 34].
Jaw Bone
Growth of craniofacial structure is a complex process of de-
velopment of multiple macro- and micro-skeletal unit con-
comitantly. One of such macro unit is the formation of man-
dible contributing to lower segment of craniofacial complex.
At around 6th week of intra-uterine life first pharyngeal arch
extension, mandibular process becomes the primordium for
growth and development of mandible and any sort of hin-
drance in availability of growth-related factors affect the nor-
mal formation of mandible [35].
CaV1.2 is a voltage-gated calcium channel, expressed in
the first and second pharyngeal arches that allow regulation of
size and hypertrophy of mandibular chondrocyte. Calcium-
dependent phosphatase calcineurin regulates the nuclear fac-
tor of activated T cell (NFAT) signaling pathway, regulating
downstream of CaV1.2. Molecular study based on Cav 1.2
channel on mice and zebrafish in the context of mandibular
development states that depending upon amount of calcium
influx through this channel result in either hypertrophy or
Curr Oral Health Rep
hypoplastic jaw size. In state of intra-uterine deficiency of
calcium, Cav1.2 calcium channel gets downregulated through
calcineurin altering the calcium influx through and resulting in
hypoplastic mandible [35].
Cartilaginous nasal septum is a primary factor for growth
of mid-face region and is considered a pacemaker which reg-
ulates mid-facial growth from the middle of fetal life until the
eruption of the deciduous dentition is completed [36]. Normal
growth of mid-face region is dependent on growth at different
sutures present in developing cranial region mainly on
spheno-occipital synchondrosis (SOS), intersphenoidal
synchondrosis (ISS), and cartilaginous nasal septum [37•].
In contrast to the other synchondrosis which closes before or
immediate after birth, SOS persist with active growth even
after birth and complete closer is seen only at around 11–
13 years of life endowing in the growth of mid-face and cra-
nial base [38]. Vitamin K is a coenzyme for glutamate carbox-
ylase, more precisely reduced form of vitamin K mediated by
vitamin K epoxide reductase complex subunit 1 (VKORC1)
that is vitamin K hydrochinon which mediates the conversion
of glutamate (Glu) to gamma-carboxyglutamate (Gla) [39].
This matrix Gla protein (MGP) is the only protein that has
anti-calcification property [40]. A study was conducted to
detect the change seen in MGP-deficient mice in context of
mid-face region which showed disorganized SOS along with
an aberrant pattern of ectopic mineralization in 5 weeks of
MGP-deficient mice which normally remain un-mineralized
throughout the life [37•]. This premature mineralization re-
sults in early loss of growth potential of nasal septum through
sutures with the anatomical structure like cranial base and
mid-face region lagging behind in their growth. As MGP is
primarily obtained from carboxylation of Glu in which vita-
min K is the rate-limiting co-enzyme, in deficiency of fetal
environment with vitamin K becomes an obvious cause for
state of MGP deficiency resulting in mid-face hypoplasia [37•,
39].
Congenital Micrognathia
Pierre Robin sequence (PRS), named after the French
stomatologist, is a congenital disorder in which intrauterine
mandibular growth impairment during the first trimester of
pregnancy leads to an abnormally posterior tongue position
(glossoptosis) and failure of palatal shelf closure (cleft palate).
These ultimately result in upper airway obstruction and feed-
ing difficulties with affected infants at risk of failure to thrive
secondary to feeding difficulties and increased calorie utiliza-
tion from work of breathing [41, 42].
Micrognathia can be detected during routine fetal scan and
is usually associated with over 100 types of chromosomal
aberrations, genetic syndromes, and skeletal dysplasia.
However, isolated micrognathia is highly suggestive of
Robin sequence, and cleft palate is suspected to be associated
Curr Oral Health Rep
with it. Kimakhe J et al. noted an increasing number of refer-
rals of cases of antenatal scans of fetus showing micrognathia
and suspected an isolated cleft palate associated with Robin
sequence by Fetal Medicine teams [43].
The first population-based study of the incidence of
PRS in the UK found incidence of PRS of 1 case per
2685 live births, which remained stable across the 10-
year study [42]. PRS can appear in isolation or associated
with different syndromes [44]. The three most common
syndromes (accounting for 65% of the syndromic cases)
are Stickler (the most frequent), velocardiofacial, and
Treacher Collins [45].
Among major hypotheses explaining the sequence of
events in PRS, the hypoplastic mandible theory is the one
mostly retained in the literature and the one that has been
demonstrated in animal models (mostly murine). The primary
defect is thought to be in Meckel’s cartilage which is the
embryonic structure involved in the formation and growth of
the mandible [45].
The most reasonable explanation for resulting
micrognathia is nutritional deficiency occurring at a critical
period of growth of the mandible. The interruption of activity
of its major growth center, if it occurs before the end of fourth
month, could contribute to the failure of palate to close. If the
interruption occurs after the fourth fetal month, the palate will
presumably have closed and resultant malpositioning of the
tongue will have no effect upon it. This led to the assumption
that, in this syndrome, the palatal cleft is the result of a man-
dibular growth failure rather than a primary maxillary growth
defect [46].
Various studies showed that malnutrition of embryo usual-
ly results in antenatal deformities such as cleft palate, hare lip,
and agnathia. Gladstone and Wakeley conclude that antenatal
deformities, such as cleft palate, hare lip, agnathia, and cy-
clops, are usually the result of imperfect nutrition, or malnu-
trition of the embryo [46, 47].
Maldonado et al. observed craniofacial structure alter-
ations among folic acid–deficient mice. They observed the
heads of malformed fetuses were smaller to those of con-
trols, and different types o f m alfo rmations like
microglossia with micrognathia (some combined with cleft
palate), and aglossia with either micrognathia or agnathia
[2].
Temporomandibular Joint
Craniofacial complex is contended with the presence of a
unique joint that makes jaw movement possible that is
presence of temporomandibular joint (TMJ) articulating
condylar head with the glenoid fossa. Condylar head is
not only a member of TMJ but also an active site for the
growth of the entire mandible including the TMJ itself and
is also referred to as secondary cartilage [48]. The cartilage
present on condylar head is the center for expression of
complex gene like Indian Hedgehog (IHh), sonic Hh,
Sox9 in which IHH is responsible for chondrocyte prolif-
eration disc and joint cavity formation which is operated
by signal transduction to the cell through the transcription
factors called zinc-finger transcription factors Gli1, Gli2,
and Gli3 [49]. Gli is a zinc finger protein which functions
as nuclear transcription factor. It is a complex assembly of
convoluted peptides in which zinc ions complex with cys-
teine and histidine residues giving finger-like, three dimen-
sional configuration of the peptide sequence [50]. IHH ex-
pression in the condylar cartilage is mandatory for TMJ and
condylar growth; however, in state of deficiency of zinc, DNA
binding of zinc-finger transcription factor is downregulated
because of which signals are not carried to the cell for protein
synthesis resulting in absence of disc primordium, lack of both
disc, and joint cavities along with reduced expression of sox9
and PTHrP which together accounts for growth and endo-
chondral ossification of TMJ and condyle [50–52].
Tooth and Nutrition
Defective mineralization and anomalies in tooth structures
could be due to deficiency of nutrition like vitamins A, C,
and D, and trace elements like magnesium and calcium. A
study conducted on rat has shown that, in the case of
magnesium-deficient rat, the dentin growth is retarded with
presentation of peculiar striation due to growth variability.
They also concluded that pulp formed in magnesium-
deficient environment shows formation of numerous pulp
stone. Vitamin E which is one of the major antioxidant of
human body has its contribution in developing the tooth sys-
tem. The deficiency results in a tooth with depigmentation
[53].
Ascorbic acid which potentiates fibroblast, osteoblast, and
odontoblast in deposition of collagen, bone, and dentin is
equally important in maintaining the histological background
of the teeth. Deficiency of ascorbic acid which also presents as
scurvy has its adverse effect on odontoblast which results in
atrophy of odontoblast presenting as loss of polarity and the
tall columnar representation of odontoblast cell. This disorga-
nized cell appears as an undifferentiated pulp cell that loses its
dentin laying capacity. The formed dentin is irregularly ar-
ranged in a very slow rate altering the normal growth and
development of the tooth [53].
Vitamin C deficiency severely affects collagen forma-
tion because deficiency of vitamin C leads to
underhydroxylation of collagen chains, which is a signifi-
cant step during collagen formation and crosslinking.
Deficiency of vitamin C also causes the production of ab-
normal predentin matrix by odontoblast. This matrix min-
eralized aspecifically. Abnormal matrix causes failure of
differentiation of the ameloblast as a cell-matrix type of

interaction plays an important role in the differentiation of
the preameloblast into functional ameloblast that leads to
hypoplasia or defective enamel formation [54].
Vitamin A is essential for the differentiation of mesen-
chymal cell into odontoblast for the formation of dentin. In
deficiency of vitamin A, the differentiation process of
odontoblast gets retarded and becomes incompetent to
send the signal during epithelial mesenchymal interaction
for reciprocal induction to occur for ameloblast differenti-
ation. Hence, in spite of healthy preameloblast cell forma-
tion, due to the defect in odontoblastic differentiation, the
entire tooth development pathway gets checked in vitamin
A deficiency status [53].
Deficiency of vitamin A affects histo-differentiation of
pulpal mesenchymal cells to odontoblasts, as well as glycos-
aminoglycan distribution in pulp [55]. Vitamin A is required
by the odontogenic epithelium for normal differentiation, and
its deficiency causes chemical changes in dentin which re-
duces the extent of mineralization. The continued presence
of these macromolecules is thought to inhibit mineralization
[56]. Similarly, it is also said that nutritional deficiency of
vitamin D causes enamel hypoplasia as the primary effect of
vitamin D is the absorption of calcium from the intestine along
with secondary influence on the absorption of phosphate [53,
57].
Conclusion
Effect of nutrition is irreplaceable in the normal development
of human beings. The deficiency of nutrition might lead to
developmental defect of various extents. World Health
Organization has provided scientific advices and decision-
making tools that can help countries take action to address
all forms of malnutrition to support health and wellbeing for
all (https://www.who.int/features/factfiles/nutrition/en/.). The
information of which and action taken could lead to decline in
incidence of developmental abnormalities, which is of
important social and financial concern.
Future wisdom or improvement in the knowledge of cra-
niofacial developmental anomalies and nutritional factors
could come from finesse new technologies and capitalize on
the knowledge provided by scientists, researchers, nutrition-
ists, and other disciplines.
Compliance with Ethical Standards
Conflict of Interest The authors declare that they have no conflict of
interest.
Human and Animal Rights and Informed Consent This article does not
contain any studies with human or animal subjects performed by any of
the authors.
Curr Oral Health Rep
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