Journal of Family Medicine and Primary Care

: 2020  |  Volume : 9  |  Issue : 4  |  Page : 1825--1833

A review of genetics of nasal development and morphological variation

Prateek Gupta, Tulika Tripathi, Navneet Singh, Neha Bhutiani, Priyank Rai, Ram Gopal 
 Department of Orthodontics and Dentofacial Orthopaedics, Maulana Azad Institute of Dental Sciences, Bahadur Shah ZafarMarg, New Delhi, India

Correspondence Address:
Prof. Tulika Tripathi
Department of Orthodontics and Dentofacial Orthopaedics, Maulana Azad Institute of Dental Sciences, Bahadur Shah ZafarMarg, New Delhi - 110 002


The nose is central in the determination of facial esthetics. The variations in its structural characteristics greatly influence the ultimate dentoskeletal positioning at the end of an orthodontic therapy. A careful insight into its developmental etiology will greatly aid the health care professional in identifying patient's real concern about the facial appearance. This in turn will aid in the fabrication of a better treatment plan regarding the end placement goals for the teeth and jaws in all the three dimensions of space. However, this important structure is often missed as a part of the diagnostic and treatment planning regime owing to the lack of meticulous understanding of its developmental etiology by the orthodontists. The development of the nose in the embryo occurs in pre skeletal and skeletal phases by a well-coordinated and regulated interaction of multiple signaling cascades with the crucial importance of each factor in the entire mechanism. The five key factors, which control frontonasal development are sonic hedgehog (SHH), fibroblast growth factors (FGF), transforming growth factor β (TGFβ), wingless (WNT) proteins, and bone morphogenetic protein (BMP). The recent evidence suggests the association of various nasal dimensions and their related syndromes with multiple genes. The revelation of nasal genetic makeup in totality will aid in ascertaining the direction of growth, which will govern our orthodontic treatment results and will also act as a harbinger for potential genetic editing and tissue engineering. This article describes at length the morphological and genetic aspect of nasal growth and development in light of the gender and racial variability along with the emphasis on the importance of knowing these nasal features with regard to diagnosis and treatment planning in orthodontics.

How to cite this article:
Gupta P, Tripathi T, Singh N, Bhutiani N, Rai P, Gopal R. A review of genetics of nasal development and morphological variation.J Family Med Prim Care 2020;9:1825-1833

How to cite this URL:
Gupta P, Tripathi T, Singh N, Bhutiani N, Rai P, Gopal R. A review of genetics of nasal development and morphological variation. J Family Med Prim Care [serial online] 2020 [cited 2021 May 18 ];9:1825-1833
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Full Text


Nasal morphology has a great bearing on the facial appearance of an individual. An eye-tracking analysis of observers asked to identify a male or female face has shown gaze concentration around the nasal base.[1] The importance of the nose in facial esthetics was first emphasized by Jones,[2] whereas Meerdink et al. found a high correlation between nasal attractiveness and facial esthetics.[3] Further, its importance can be elucidated from the fact that rhinoplasty is a commonly performed procedure to improve facial esthetics.[4] Moreover, the nasal region was found to be more reliable in the detection of asymmetry as compared to mouth or eyes.[5] The orientation of the nasal ridge greatly affects the perception of symmetry owing to its location at the facial center of gravity.[6] Thus off-centered nose tip may lead to disparity in the size of either side of the face and may be mistaken for facial asymmetry. The nose is proximal to tissues affected by the orthodontic treatment, and hence nasal dimensions, growth, and development should be considered while making the treatment plan. Therefore, when studying facial esthetics, it is essential to understand growth, form, and function of the nose and the role of genes in defining nasal morphology. This is highly important in the cases of craniofacial syndromes where nasal form may show significant deviations and may limit the scope of orthodontic treatment unless surgical corrections are planned. The primary care physicians must have a thorough understanding of these facts concerning the facial appearance of the patients to direct appropriate treatment measures. Thus, the current paper describes the genetic basis affecting the various aspects of nasal morphology at length along with the clinical relevance of various anatomical variations in nasal morphology.

Data selection

We retrieved pertinent literature on the genetics of the development of the nose and its morphological variation, selected references and internet services using PubMed and Google scholar databases. We conducted comprehensive literature search using keywords, "craniofacial development;" "frontonasal development", "nose and genetic variation" and "facial morphology and genes."

 Clinical and Research Consequences

A. Morphological aspects of nasal development

i). Nasal growth, form, and function

• 1. Nasal Growth- The nasal growth is central to the growth and development of the entire face. The nasal septum acts as a growth site producing maxillary pull, which directs facial growth in forward and downward direction causing sevenfold increase in vertical length between 10th and 40th weeks post conception. The nasal cavity and nasal septum continue to be the prime determinant of facial growth pattern even post natally by acting as functional matrices.

At birth, the nasal cavity floor lies between orbits and gradually positions below them by the age of 6 years.[7] The nasal growth ceases by the age of 16 years in girls and 18 years in boys.[8] The nasal length increases at the rate of 1.5 mm per year.[9]

The deficient growth and development of the nose and associated maxillary hypoplasia is seen in Binder's syndrome [Table 1]. The maxillary development remains deficient in the absence of nasal septal cartilaginous growth.{Table 1}

• 2. Nasal form and function. The nasal profile varies with varying skeletal transverse, sagittal, and vertical facial dimensions. Orthodontic treatment involving expansion, facemask therapy, extraction, growth modification, and orthognathic surgery impact nasal appearance.[10]

One of the major functions of the nasal cavity is the conditioning of the upper respiratory tract before passing it to the lower respiratory tract.[11] Thus, variations in the shape of the nose across populations may be attributed to acclimatization to prevailing climatic conditions.[11] The nasal obstruction affects the development and further growth of dentofacial complex. The correlation of form and function of the nose is well reflected in mouth breathers where the inadequate use of the empty space of the nasal cavity by mouth breathing causes long narrow face and high palatal vault.[7]

ii). Racial and gender variation

Racial and gender differences were observed in the nasal index (width of the nasal aperture/height of the nasal aperture).[12],[13] The distance between nasal alare was found to be higher in West African, South and East Asian races as compared to European races.[12]

3-D observations have revealed the protuberance of the nose as the largest anatomical sexual dimorphism in the human face [14] with nasal dimensions being higher in males.[15] Ideal nasal form has a dorsum which is straight, along with the presence of supratip break formed by cartilages above the nasal tip.[16] Enlow et al. observed straight to convex nose in males and straight to concave nose in females.[17] Thus, racial and gender variations in nose are important considerations for plastic surgeons while planning for rhinoplasty and also for forensic investigations.[13]

B. The genetic basis of development of the nose

With the great advancements at the molecular level, the role of genes is evident in determining the embryonic plan of the craniofacial development. Unlike genetic mutations that are alterations in DNA sequence, epigenetic alterations are changes in gene expression while both are heritable.[18]

The development of the nose is a multistep process involving cross talk among multiple signaling cascades, epithelial mesenchymal interactions, which regulate neural crest development, frontonasal process outgrowth, patterning, and skeletal differentiation. Overall, 173 genes are expressed in frontonasal prominence. There is an upregulation of 64 genes in the 4th week, 26 genes in the 5th week in frontonasal prominence, 36 genes in the 6th week in medial nasal prominence, and 45 genes in lateral nasal prominence.[19]

The nasal cartilaginous capsule is derived from neural crest cells. The development of nose occurs in 2 phases:

The pre skeletal phase, which consists of the formation of mesenchymal swellings encompassing external nasal placodes,The skeletal phase comprising chondrocranial phase, which establishes cartilaginous scaffolding and ossification phase involving an ingression of cellular constituents followed by the coalescence of skeletal components.[20]

1. Pre skeletal phase

The five key factors, which control frontonasal development through cell proliferation and differentiation are sonic hedgehog (SHH), fibroblast growth factors (FGF), transforming growth factor β (TGFβ), wingless (WNT) proteins, and bone morphogenetic protein (BMP)[21] [Figure 1]. Neural crest cells contributing to frontonasal process originate from the caudal forebrain and the rostral midbrain neural plate under BMP signaling in the gastrula stage and migrate over prospective telencephalon to reach the most rostral aspect of the neural tube [22] [Figure 2]. The initiation of WNT1 expression causes epithelial to mesenchymal transition (EMT) of crest cells and the expansion of telencephalon restricts these neural crest cell population to the frontonasal region of developing face. WNT signaling triggers FGF8 expression in facial ectoderm, which aids in maintaining the survival of cells in facial ectoderm as well as mesenchyme in the course of establishment of facial primordia.[23]{Figure 1}{Figure 2}

Initially, FGF8 expression is present in cephalic ectoderm that will cover the frontonasal process. The expression of SHH is initiated with the migration of neural crest cells in cephalic ectoderm, which restricts FGF8 expression to nasal pits.[24] The FGF8 and SHH are expressed in neuroepithelium and ectoderm of the frontonasal process creating a frontonasal ectodermal zone (FEZ) with an expression boundary between them. FGF8 is essential for early FEZ activity [24] and later was down regulated for the growth of frontonasal process. Retinoic acid (RA) synthesized in the frontonasal process (FNP) ectoderm expresses in neural crest cells through RA receptors. RA dependent signal from neural crest mesenchyme maintains the expression of FGF8 and SHH. FGF8 and SHH, in turn, maintains neural crest mesenchyme to initiate FNP outgrowth [Figure 3].{Figure 3}

At the 5th week of intrauterine life (IU), FNP develops medial and lateral nasal prominences on the both sides from mesoderm bordering the nasal placodes arising from surface ectoderm.[25] In the 6th week, nasal placodes invaginate into paraxial mesoderm to form the nasal pits under signaling by WNT production from the facial epithelium.[26] The SHH is expressed in the ectoderm of early medial nasal process and later its expression extends to the base of the nasal pit.[27]

The internal nose develops by theexpansion of nasal cavity with the atrophy of existing tissues and the formation of mesenchymal structures. The nasal pits deepen and lead to the formation of nasal sac by posterior fusion at the end of the 6th week. The oronasal membrane separates the nasal sac from the oral cavity and ruptures in the 7th week forming an opening with the oral cavity. The primary palate lies as floor of the primary nasal fossa. The definitive choanae arise with the formation of the secondary palate, at the junction of definitive nasal cavity and pharynx.[26]

2. Skeletal Phase

The skeletal phase begins with the condensation of mesenchymal stem cells from neural crest mesoderm and sex-determining region Y (SRY)-box 9 (SOX9) and muscle segment homeobox (msh) homeobox 2 (MSX2) genes are upregulated.[28] The nasal cartilaginous frame is formed of ventral mesethmoid cartilage and dorsal ectethmoid cartilage. Mesethmoid comprises nasal septum and vomer, whereas ectethmoid forms olfactory system, lamina cribrosa, crista-galli apophysis, crura, and chonchae. Mesethmoid determines proximodistal nasal dimensions and ectethmoid decides nasal bridge location and size.[29] These cartilaginous structures either undergo endochondral ossification or get resorbed. SOX9 directly activates type-II collagen promoter and also upregulates BMP4, which induces chondrogenesis. SOX9 also activates the promoters of cartilage markers aggrecan and type X collagen, whereas MSX2 represses SOX9 mediated chondrogenesis.[28]

With the degeneration of oronasal membrane at the 6.5 weeks, cartilaginous nasal capsule becomes distinct. Nasal bridge forms by frontal prominence while the crest and nasal tip forms by coalescence of medial nasal prominences. The alae of the nose and the paired lateral crura of alar cartilages develop from lateral nasal prominences.[26],[29] Three paired chondrification centers form lateral nasal cartilages.

At the 5th week, nasal septum arises from frontal prominence and grows in an antero-posterior direction to join tectoseptal mesenchymal expansion and finally palatine processes resulting in two nasal chambers. The nasal septum comprises a plate of ethmovomerine cartilage having high BMP receptor type IB (BMPRIB) expression.[30] At the 8th week, bony nasal septum forms over cartilaginous capsule by two ossification centers, one on each side of the middle line. The postero-superior segment of this cartilage ossifies into the perpendicular plate of ethmoid; antero-inferior part remains as septal cartilage, while vomer ossifies in the membranus covering of its postero-inferior portion. Mesenchymal stem cells undergo osteogenic differentiation upon induction by BMP9 and these committed osteoprogenitors are subjected to further osteogenic differentiation by TGFβ.[31] BMP can also induce core binding factor alpha 1 (CBFA1)/runt-related transcription factor 2 (RUNX2) gene, which is a marker of osteogenesis. RUNX2 is prerequisite for osteoblastic differentiation and hence bone and cartilage formation.[32]

Orthodenticle homeobox 2 (OTX2) gene (14q21-22) is expressed in the neural crest cells of frontonasal region and its mutations affect the development of lateral nasal wall and nasal epithelium.[33] At 9-10 weeks, cartilages of superior, middle, and inferior conchae having high expression of BMPRIB and BMPRII [30] arise from cartilaginous nasal capsule. This is initiated by the appearance of furrows, six in number that are separated by ridges resembling ethmoturbinals. The uncinate process remains after the regression of first ethmoturbinal process. The second ethmoturbinal gives rise to middle turbinate, and the third forms the superior turbinate. The fourth and fifth processes fuse to form supreme turbinate. The middle meatus and hiatus semilunaris develop from first primary furrow, superior meatus from second, and supreme meatus from third. At 13-14 weeks, the bone of maxilla replaces the lateral cartilaginous capsule to form the lateral wall of the middle meatus. At 15-16 weeks, all the three nasal turbinates are completely formed. At 17-18 weeks, ossification of cartilaginous turbinates start.[34] Lateral nasal walls extend diverticula into maxillary, frontal, ethmoid, and sphenoid bones to form paranasal sinuses. Each nasal bone is ossified from a single center, which arises in the membrane covering the cartilaginous nasal capsule at the initiation of third fetal month.

Ossification increases until puberty with outer nasal cartilages and some vomeronasal organ associated structures remaining as cartilages thereafter. It may be due to non responsiveness of FNP to WNT signaling while lateral nasal prominence is WNT positive.[35]

C. Correlation of nasal morphology and genetic basis of nasal development

The genotype along with epigenetic and environmental factors determines the phenotype of the organism, but the genotype is established prior to the characterization of phenotype. The nasal features like nose width, height, and prominence have a strong genetic component.[36] Nasal morphological dimensions have been represented in [Figure 4]. Loss of Aristaless like homeobox genes (ALX1, ALX3, and ALX4) has been observed to cause frontonasal dysplasia in humans. ALX1 greatly affects the early phase of chondrocyte development.[37] Bifid nose and hypertelorism occurs due to disruption in the fusion of frontal and medial nasal prominences as seen in ALX3 and ALX4 loss-of-function mutant phenotypes. Hypertelorism is a prominent feature of frontonasal dysplasia and may be due to disruptions of the Hedgehog signaling pathway. ALX genes are expressed in frontonasal mesenchyme and are thought to increase SHH activity.[38]{Figure 4}

1. Nasal ala length

Nasal ala length has a strong association with rs4648379, an intronic variant in PR domain containing 16 (PRDM16) gene at 1p36.23-p33 and rs1982862 of calcium voltage-gated channel auxiliary subunit alpha2 delta3 (CACNA2D3) gene at 3p14.3.[39]PRDM16 is associated with orofacial development and its transcripts were found in the nasal septum.[40] Nasal ala length was also observed to be associated with rs8007643 at 14q11.2, a region containing many genes of craniofacial development.[39] Among these, zinc finger protein 219 (ZNF219) encodes a transcription factor, which along with SOX9 is essential for chondrogenesis,[41] and chromodomain helicase DNA binding protein 8 (CHD8) is associated with autism spectrum disorder including a broad nose. SOX9 ( 17q24.3) and cancer susceptibility 17 genes (CASC17), which are 1Mb from each other have both been observed to influence the nasal shape.[42] In mice, Bbfc (Babyface) mutation of Sox9 gene and Sofa ("short face") mutation of phosphoribosylformylglycinamidine synthase (Pfas) gene resulted in the short nose as it leads to decreased purine availability for the transcription of genetic expression.[43] Moreover, mutations in mice type 2 collagen (Col2a1), Src homology 3 (SH3), and PX domains 2B (Sh3pxd2b), (Fgfr3) and phosphate regulating endopeptidase homolog X-linked (Phex) genes have also been found to cause shortened nose.[44] The DEAD (Asp-Glu-Ala-Asp) box polypeptide 10 gene (Ddx 10) in mice which encodes a DEAD box containing ATP-dependent RNA/DNA helicase caused short/split nose and DEAD-box helicase 10 gene (DDX10) mutation in humans has been observed to cause pear-shaped nose.[45]

2. Intercanthal width

An intronic single nucleotide polymorphism (SNP) (rs17447439) of tumor protein p63 (TP63) on chromosome 3q28, is linked to distance between the eyeballs.[46] SNP rs619686 of glutathione S-transferase mu 2 (GSTM2) gene at 1p13.3 and rs11093404 at chromosome Xq13.2 near histone deacetylase 8 gene (HDAC8) were associated with intercanthal width.[39] SNPs (rs16863422, rs12694574, rs974448, and rs7559271) at paired box3 (PAX3) in chromosome 2q35 and SNP rs805722 in collagen alpha-1 (XVII) chain (COL17A1) on chromosome 10q24.3 were found to be associated with the position of nasion relative to the eyeballs.[46]PAX3 is expressed in neural tube portion, which forms neural crest and is also observed in migrating neural crest cells. Thus, PAX3 might have a role in epithelial mesenchymal transformation.[47] SNP rs2289266 in the intron of the PAX3 was found to be associated with the transverse nasal prominence angle. PAX3 gene mutations are linked to Waardenburg syndrome, which shows prominent, broad nasal root and a round or square nose tip. Variants rs12041465, rs12076700, rs74884233, rs6741412, rs10496971, and rs59037879 located in the introns of LIMHomeobox 8 (LHX8), LaminA gene (LMNA), and Rotatin gene (RTTN), Family with Sequence Similarity 49 Member A gene (FAM49A), Testis Expressed 41 gene (TEX41), and Zinc Finger E-Box Binding Homeobox 1 (ZEB1) respectively were associated with transverse nasal prominence angle. LHX8 is involved in patterning and differentiation of various types of tissues. Its mutations causes secondary palate clefts in mice. LMNA protein is a component of inner nuclear membrane, which forms framework for the nuclear envelope and also interacts with chromatin to disrupt mitosis and induces premature senescence of the cell. RTTN gene maintains normal ciliary structure and controls left-right organ specification, axial rotation, and notochord development. The FAM49A protein might interact with microRNA (miRNA) molecules during pre implantation. ZEB1 is a transcriptional repressor. SNPs rs892457 and rs892458 located in the long non coding RNA (lncRNA) gene AC073218.1, were associated with the transverse nasal prominence angle. SNP rs2357442, located in the Long Interspersed Nuclear Element 1 (LINE-1) retrotransposon sequence was also associated with the transverse nasal prominence angle. It comprises approximately 21% of the human genome and modulate the expression of neighbouring genes.[48] Mice with shortened COL11A2 mRNA (the second alpha chain of type XI fibrillar collagen) display shorter and dimpled nasal bones.[47]

SNP rs6555969 near C5orf50 (chromosome 5 open reading frame 50) at 5q35.1 is associated with nasion position.[46]C5orf50 encodes a transmembrane protein, which affects FBXW11 (F-box and WD repeat domain containing 11) expression, a gene linked to SHH signaling [Figure 1]. C5orf50 mutations have been observed in holoprosencephaly involving defects in midface and forebrain.[49]

3. Columella and nasal bridge breadth

SNP rs12644248 at 4q31 in DCHS2 (Dachsous cadherin-related 2 gene) affects the columella inclination. rs2045323 is located at the evolutionary conserved zone in DCHS2-SFRP2 (Secreted Frizzled- related protein2) intergenic region, and it was found to have a strong association with nose protrusion and nose tip angle.[50] DCHS2 is a calcium dependent cell adhesion protein, which was found to be involved in regulatory network influencing cartilage differentiation in craniofacial development. This regulation also involves SOX9, mutations of which were linked to craniofacial defects.[50] The allele C of single nucleotide polymorphism (SNP) rs2193054 (SOX9) was associated with protrusion of the nose than the alternate allele. The T allele of SNP rs2206437 (DHX35) was associated with wider and lower nose than allele A.[51]SFRP2 is expressed in osteoblast and has WNT inhibiting effect because of structural homology to frizzled receptor.[52]SUPT3H affects nasal root and lateral parts of the nasal bridge but spares nasal tip.[42]SUPT3H promoter can modulate RUNX2-P1 activity via direct association.[53] RUNX2 mutation was also observed in cleidocranial dysplasia and has role in differentiation of osteoblasts, chondrocytes, mesenchymal stem cells, and bone development.[54]KCTD15 (potassium channel tetramerization domain containing 15) at 19q13.11 affects nasal tip and its mutation has been observed to cause reduced snout length in mice.[42]

4. Nasal wing breadth

Nose wing breadth is associated with SNP rs4648379 of PRDM16 gene, rs17640804 at 7p13 containing GLI3 (GLI family zinc finger 3) gene, rs927833 and rs2424399 at 20p11 containing PAX1 gene.[39],[50] GLI3 regulates SHH signaling, involved in chondrocyte differentiation.[55] PAX1 is expressed in facial primordial mesenchyme during late facial development, which may have a role in epithelial mesenchymal interaction and affects chondrocyte differentiation.[56] Variant rs79867447 and Intronic SNP rs58733120 of Eyes Absent Homolog 1 and 2 (EYA1 and EYA2) gene was associated with the nose width and nasal index. The EYA encoded protein acts as histone phosphatase, which controls transcription during organogenesis. Missense mutation rs37369 in the Alanine-Glyoxylate Aminotransferase 2 gene (AGXT2) was associated with nose width, nasal index, and transverse nasal prominence angle. SNP rs1482795, located in the RNA gene RP11-494M8.4 was associated with the nose width and nasal index. SNP rs7311798, located in the lncRNA gene RP11-408B11.2 was associated with the nasal index.[48]

D. Gene identification in syndromes associated with nasal deformities

Genes associated with various syndromes having nasal deformities has been elaborated in Table 1.

Future prospects

The understanding of these genetic associations has led to the emergence of two strategies as future solutions to craniofacial reconstructive challenges. Pre natally, bacterial based type II clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) system will serve as a genomic editing tool to target desired location of genes, resulting in the incorporation of novel DNA fragments into the target site. Post natally, gene therapy for tissue regeneration can transform cells at the site of injury into induced-pluripotent stem cells, which will enhance their ability to differentiate towards their tissue of origin and aid in craniofacial reconstruction.

The presence of morphological variations despite unaltered gene sequence on a large scale might be explained by the study of proteins as they change with the turning on or off of genes in response to environmental changes. Moreover, the science of proteomics will facilitate identification of new biomarkers, which will enhance an understanding into phenotypic variations.

Application of genetic screening in orthodontics

Future progress in identifying the role of genes in the development of face and nose would change the face of orthodontic practice. Decision to implement a particular orthodontic intervention will be guided by the alteration of the dentofacial region in concordance to the future nasal shape changes predicted through genetic screening. Instead of making an educated guess about patient's future growth, orthodontists might employ software to make genetic growth prediction based on variation in genome sequencing. Moreover, the spatial and temporal control of any gene expression in orthodontically relevant tissues can now be done.


Nasal dimensions have not yet drawn attention and gained appropriate consideration by orthodontists. Ascertaining the genotype should be accompanied by appreciable association with phenotypic characteristics, which entail prospective research to predict the treatment outcomes. Patients having variations in genetic constitution respond differently to the same intervention. The complex interactions of genetic factors govern orthodontic and dentofacial orthopedic treatment outcome.[69]

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


1Saether L, Van Belle W, Laeng B, Brennen T, Øvervoll M. Anchoring gaze when categorizing faces' sex: Evidence from eye-tracking data. Vision Res 2009;49:2870-80.
2Jones D. Sexual selection, physical attractiveness, and facial neoteny: Cross-cultural evidence and implications. Curr Anthropol 1995;36:723-48.
3Meerdink JE, Garbin CP, Leger DW. Cross-gender perceptions of facial attributes and their relation to attractiveness: Do we see them differently than they see us? Percept Psychophys 1990;48:227-33.
4Babuccu O, Latifoglu O, Atabay K, Oral N, Cosan B. Sociological aspects of rhinoplasty. Aesthetic Plast Surg 2003;27:44-9.
5Neby M, Ivar F. Ranking fluctuating asymmetry in a dot figure and the significant impact of imagining a face. Perception 2013;42:321-9.
6Evans CS, Wenderoth P, Cheng K. Detection of bilateral symmetry in complex biological images. Perception 2000;29:31-42.
7Sperber GH. The facial skeleton. In: Craniofacial Development. 1st ed. Hamilton BC Decker 2001. p. 103-12.
8Prasad M, Chaitanya N, Reddy KVK, Talapaneni AK, Myla VB, Shetty SK. Evaluation of nasal morphology in predicting vertical and sagittal maxillary skeletal discrepancies. Eur J Dent 2014;8:197-204.
9Wisth PJ. Nose morphology in individuals with Angle Class I, Class II or Class III occlusions. Acta Odontol Scand 1975;33:53-7.
10Johnson BM, McNamara JA, Bandeen RL, Baccetti T. Changes in soft tissue nasal widths associated with rapid maxillary expansion in prepubertal and postpubertal subjects. Angle Orthod 2010;80:995-1001.
11Negus VE. Introduction to the comparative anatomy of the nose and paranasal sinuses. Ann R Coll Surg Engl 1954;15:141-71.
12Farkas LG, Kolar JC, Munro IR. Geography of the nose: A morphometric study. Aesthetic Plast Surg 1986;10:191-223.
13Jabeen N, Magotra R, Choudhary S, Sharma AK. Study of nasal index in different zones of Jammu and Kashmir. JK Sci 2019;22:72-5.
14Burton AM, Bruce V, Dench N. What's the difference between men and women? Evidence from facial measurement. Perception 1993;22:153-76.
15Enlow DH. Handbook of Facial Growth. Philadelphia Saunders; 1982.
16Meng HP, Goorhuis J, Kapila S, Nanda RS. Growth changes in the nasal profile from 7 to 18 years of age. Am J Orthod Dentofacial Orthop 1988;94:317-26.
17Enlow DH, Hans MG. Essentials of Facial Growth. Philadelphia Saunders; 1996.
18Hallgrímsson B, Hall BK. Introduction. In: Hallgrímsson and Hall, editors. Epigenetics: Linking Genotype and Phenotype in Development and Evolution. 1st ed. University of California Press; 2011. p. 1-6.
19Sperber GH. New insights in facial development. Semin Orthod 2006;12:4-10.
20Adil E, Huntley C, Choudhary A, Carr M. Congenital nasal obstruction: Clinical and radiologic review. Eur J Pediatr 2012;171:641-50.
21Schneider RA, Hu D, Rubenstein JL, Maden M, Helms JA. Local retinoid signaling coordinates forebrain and facial morphogenesis by maintaining FGF8 and SHH. Development 2001;128:2755-67.
22Farlie PG, Baker NL, Yap P, Tan TY. Frontonasal dysplasia: Towards an understanding of molecular and developmental aetiology. Mol Syndromol 2016;7:312-21.
23Wang Y, Song L, Zhou CJ. The canonical Wnt/ß catenin signaling pathway regulates Fgf signaling for early facial development. Dev Biol 2011;349:250-60.
24Hu D, Marcucio RS, Helms JA. A zone of frontonasal ectoderm regulates patterning and growth in the face. Development 2003;130:1749-58.
25Helms JA, Cordero D, Tapadia MD. New insights into craniofacial morphogenesis. Development 2005;132:851-861.
26Sadler TW. Head and neck. In: Langman's Medical Embryology. 12th ed. Philadelphia Lippincott Williams and Wilkins 2012. p. 260-86.
27Xavier GM, Seppala M, Barrell W, Birjandi AA, Geoghegan F, Cobourne MT. Hedgehog receptor function during craniofacial development. Dev Biol 2016;415:198-215.
28Semba I, Nonaka K, Takahashi I, Takahashi K, Dashner R, Shum L, et al. Positionally-dependent chondrogenesis induced by BMP4 is co-regulated by Sox9 and Msx2. Dev Dyn 2000;217:401-14.
29Kosins AM, Daniel RK, Sajjadian A, Helms J. Rhinoplasty: Congenital deficiencies of the alar cartilage. Aesthet Surg J 2013;33:799-808.
30Ashique AM, Fu K, Richman JM. Signalling via type IA and type IB Bone Morphogenetic Protein Receptors (BMPR) regulates intramembranous bone formation, chondrogenesis and feather formation in the chicken embryo. Int J Dev Biol 2002;46:243-53.
31Lamplot JD, Qin J, Nan G, Wang J, Liu X, Yin L, et al. BMP9 signaling in stem cell differentiation and osteogenesis. Am J Stem Cell 2013;2:1-21.
32Ducy P, Zhang R, Geoffroy V, Ridall AL, Karsenty G. Osf2/Cbfa1: A transcriptional activator of osteoblast differentiation. Cell 1997;89:747-54.
33Kuratani S, Matsuo I, Aizawa S. Developmental patterning and evolution of the mammalian viscerocranium: Genetic insights into comparative morphology. Dev Dyn 1997;209:139-55.
34Bingham B, Wang RG, Hawke M, Kwok P. The embryonic development of lateral nasal wall from 8-24 weeks. Laryngoscope 1991;101:992-7.
35Brugmann SA, Goodnough LH, Gregorieff A, Leucht P, ten Berge D, Fuerer C, et al. Wnt signaling mediates regional specification in the vertebrate face. Development 2007;134:3283-95.
36Djordjevic J, Zhurov AI, Richmond S; Visigen Consortium. Genetic and environmental contributions to facial morphological variation: A 3D population-based twin study. PLoS One 2016;11:e0162250.
37Zhao GQ, Zhou X, Eberspaecher H, Solursh M, de Crombrugghe B. Cartilage homeoprotein1, a homeoprotein selectively expressed in chondrocytes. Proc Natl Acad Sci USA 1993;90:8633-7.
38Twigg SRF, Versnel SL, Nurnberg G, Lees MM, Bhat M, Hammond P, et al. Frontorhiny, a distinctive presentation of frontonasal dysplasia caused by recessive mutations in the ALX3 homeobox gene. Am J Hum Genet 2009;84:698-705.
39Shaffer JR, Orlova E, Lee MK, Leslie EJ, Raffensperger ZD, Heike CL, et al. Genome-Wide association study reveals multiple loci influencing normal human facial morphology. PLoS Genet 2016;12:e1006149.
40Warner DR, Horn KH, Mudd L, Webb CL, Greene RM, Pisano MM. PRDM16/MEL1: A novel Smad binding protein expressed in murine embryonic orofacial tissue. Biochim Biophys Acta 2007;1773:814-20.
41Takigawa Y, Hata K, Muramatsu S, Amano K, Ono K, Wakabayashi M, et al. The transcription factor Znf219 regulates chondrocyte differentiation by assembling a transcription factory with So×9. J Cell Sci 2010;123:3780-8.
42Claes P, Roosenboom J, White JD, Swigut T, Sero D, Li J, et al. Genome-wide mapping of global-to-local genetic effects on human facial shape. Nat Genet 2018;50:414-23.
43Palmer K, Fairfield H, Borgeia S, Curtain M, Hassan MG, Dionne L, et al. Discovery and characterization of spontaneous mouse models of craniofacial dysmorphology. Dev Biol 2016;415:216-27.
44Lee YC, Song IW, Pai YJ, Chen SD, Chen YT. Knock-in human FGFR3 achondroplasia mutation as a mouse model for human skeletal dysplasia. Sci Rep 2017;7:43220.
45Kashevarova AA, Nazarenko LP, Skryabin NA, Salyukova OA, Chechetkina NN, Tolmacheva EN, et al. Array CGH analysis of a cohort of Russian patients with intellectual disability. Gene 2014;536:145-50.
46Liu F, van der Lijn F, Schurmann C, Zhu G, Chakravarty MM, Hysi PG, et al. Agenome-wide association study identifies five loci influencing facial morphology in Europeans. PLoS Genet 2012;8:e1002932.
47Site MMRW. The Jackson Laboratory, Bar Harbor, Maine. World Wide Web ( Bar Harbor, Maine. 2010. Available from: 1053
48Barash M, Bayer PE, van Daal A. Identification of the single nucleotide polymor- phisms affecting normal phenotypic variability in human craniofacial morphology using candidate gene approach. J Genet Genome Res 2018;5:041.
49Solomon BD, Mercier S, Velez JI, Pineda-Alvarez DE, Wyllie A, Zhou N, et al. Analysis of genotype-phenotype correlations in human holoprosencephaly. Am J Med Genet C Semin Med Genet 2010;154C: 133-41.
50Adhikari K, Fuentes-Guajardo M, Quinto-Sánchez M, Mendoza-Revilla J, Camilo Chacón-Duque J, Acuña-Alonzo V, et al. Agenome-wide association scan implicates DCHS2, RUNX2, GLI3, PAX1 and EDAR in human facial variation. Nat Commun 2016;7:11616.
51Cha S, Lim JE, Park AY, Do JH, Lee SW, Shin C, et al. Identification of five novel genetic loci related to facial morphology by genome-wide association studies. BMC Genomics 2018;19:481.
52Thysen S, Cailotto F, Lories R. Breast, Skin, Soft tissue and bone osteogenesis induced by frizzled-related protein (FRZB) is linked to the netrin-like domain. Lab Invest 2016;96:570-80.
53Barutcu AR, Tai PW, Wu H, Gordon JA, Whitfield TW, Dobson JR, et al. The bone-specific Runx2-P1 promoter displays conserved three-dimensional chromatin structure with the syntenic Supt3h promoter. Nucleic Acids Res 2014;42:10360-72.
54Fujita T, Azuma Y, Fukuyama R, Hattori Y, Yoshida C, Koida M, et al. Runx2 induces osteoblast and chondrocyte differentiation and enhances their migration by coupling with PI3K-Akt signaling. J Cell Biol 2004;166:85-95.
55Pan A, Chang L, Nguyen A, James AW. A review of hedgehog signaling in cranial bone development. Front Physiol 2013;4:61.
56Takimoto A, Mohri H, Kokubu C, Hiraki Y, Shukunami C. Pax1 acts as a negative regulator of chondrocyte maturation. Exp Cell Res 2013;319:3128-39.
57Pius S, Ibrahim HA, Bello M, Mbaya K, Ambe JP. Apert syndrome: A case report and review of literature. Open J Pediatr 2016;6:175-84.
58Szeremeta W, Parikh TD, Widelitz JS. Congenital nasal malformations. Otolaryngol Clin North Am 2007;40:97-112.
59Patil S, Rao RS, Majumdar B. Single gene disorders with craniofacial and oral manifestations. J Contemp Dent Pract 2014;15:659-71.
60Pingault V, Ente D, Dastot-Le Moal F, Goossens M, Marlin S, Bondurand N. Review and update of mutations causing Waardenburg syndrome. Hum Mutat 2010;31:391-406.
61Asher JH Jr, Sommer A, Morell R, Friedman TB. Missense mutation in the paired domain of PAX3 causes craniofacial deafness-hand syndrome. Hum Mutat 1996;7:30-5.
62Abdollahifakhim S, Mousaviagdas M. Association of nasal nostril stenosis with bilateral choanal atresia: A case report. Iran J Otorhinolaryngol 2014;26:43-6.
63Pohl E, Aykut A, Beleggia F, Karaca E, Durmaz B, Keupp K, et al. Ahypofunctional PAX1 mutation causes autosomal recessively inherited otofaciocervical syndrome. Hum Genet 2013;132:1311-20.
64Vortkamp A, Gessler M, Grzeschik KH. GLI3 zinc-finger gene interrupted by translocations in Greig syndrome families. Nature 1991;352:539-40.
65Roessler E, Belloni E, Gaudenz K, Jay P, Berta P, Scherer SW, et al. Mutations in the human Sonic Hedgehog gene cause holoprosencephaly. Nat Genet 1996;14:357-60.
66Kaiser FJ, Ansari M, Braunholz D, Gil-Rodriguez MC, Decroos C, Wilde JJ, et al. Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance. Hum Mol Genet 2014;23:2888-900.
67Turnpenny PD, Ellard S. Alagille syndrome: Pathogenesis, diagnosis and management. Eur J Hum Genet 2012;20:251-7.
68Kruszka P, Li D, Harr MH, Wilson NR, Swarr D, McCormick EM, et al. Mutations in SPECC1L, encoding sperm antigen with calponin homology and coiled-coil domains 1-like, are found in some cases of autosomal dominant Opitz G/BBB syndrome. J Med Genet 2015;52:104-10.
69Wieczorek D, Newman WG, Wieland T, Berulava T, Kaffe M, Falkenstein D, et al. Compound heterozygosity of low-frequency promoter deletions and rare loss-of-function mutations in TXNL4A causes Burn-McKeown syndrome. Am J Hum Genet 2014;95:698-707.