The Cleft Palate–Craniofacial Journal 53(2) pp. e34–e44 March 2016 Ó Copyright 2016 American Cleft Palate–Craniofacial Association

ORIGINAL ARTICLE Analysis of the Relationship Between Micrognathia and Cleft Palate: A Systematic Review Katherine E. Price, B.S., Yasmine Haddad, D.D.S., Ph.D., Walid D. Fakhouri, Ph.D. Objective: To gather data from relevant experimental and observational studies to determine the relationship between micrognathia and cleft palate. The goal is to raise awareness and motivate clinicians to consider the cause and effect relationship when confronted with patients with cleft palate, even if there is no clearly noticeable mandibular abnormality. Design: Several electronic databases were systematically examined to find articles for this review, using search terms including ‘‘cleft palate,’’ ‘‘micrognathia,’’ ‘‘tongue,’’ and ‘‘airway obstruction.’’ PubMed was the source of all the articles chosen to be included. Exclusion criteria included case reports, articles focused on treatment options, and articles only tangentially related to cleft palate and/or micrognathia. Results: A total of 930 articles were screened for relevance, and 82 articles were chosen for further analysis. Evidence gathered in this review includes a variety of etiological factors that are causative or associated with both micrognathia and cleft palate. Observational studies relating the two abnormalities are also included. Much of the included literature recognizes a cause-andeffect relationship between micrognathia and cleft palate. Conclusion: On the basis of the published data, we suggest that micrognathia does induce cleft palate in humans and animals. With knowledge of this causative relationship, clinicians should consider the importance of gathering cephalometric data on the mandibles and tongues of patients presenting with isolated cleft palate to determine whether they have micrognathia as well. With more data, patterns may emerge that could give insight into the complex etiology of nonsyndromic cleft palate. KEY WORDS:

airway obstruction, glossoptosis, mandibular hypoplasia, Pierre Robin sequence

between these animal studies and associated human disorders, specifically the Pierre Robin sequence (Antoniades et al., 1995, Murray et al., 2007; Ghassibe-Sabbagh et al., 2011). An insightful study by Diewert (1986) found similar secondary palatal developmental patterns in humans and animals, concluding that experimental mechanisms seen to cause cleft palate in animal models were also relevant to clefts seen in humans. Nevertheless, the knowledge of this causative relationship seen so often in animals has not translated into standardized clinical practices when treating human patients with isolated cleft palate. The purpose of this systematic review was to gather all published data from relevant experimental and observational studies on micrognathia and cleft palate to analyze the relationship between both abnormalities. The goal was to determine whether the data support the idea of a causeand-effect relationship that would justify raising awareness and motivating clinicians to consider this relationship when confronted with patients affected with cleft palate only. Even if no obvious signs of jaw abnormalities have been observed, further cephalometric examination may reveal subtle abnormalities that were sufficient to cause clefting during development. With more cephalometric data, patterns may emerge that could result in a better

Many studies that analyze craniofacial abnormalities, particularly dealing with the cleft palate, identify some type of association between micrognathia and isolated cleft palate in animal models (Shah, 1977; Bienengraber et al., 2001; Savontaus et al., 2004). In fact, many researchers suggest that micrognathia is causative of cleft palate in developing animal fetuses, perhaps through a series of events beginning with a small or retrognathic mandible causing abnormal placement/development of the tongue, ultimately resulting in the inability of the palatal shelves to elevate and fuse (Johnston and Nash, 1982; Antoniades et al., 1995; Dudas et al., 2004). Many even make connections

Ms. Price is D.D.S. student, Center for Craniofacial Research; Dr. Haddad is Clinical Assistant Professor, Department of Diagnostic and Biomedical Sciences; Dr. Fakhouri is Assistant Professor, Center for Craniofacial Research, Department of Diagnostic and Biomedical Sciences, School of Dentistry, University of Texas Health Science Center, Houston, Texas. Submitted August 2014; Revised November 2014; Accepted December 2014. Address correspondence to: Dr. Walid D. Fakhouri, Center for Craniofacial Research, Department of Diagnostic and Biomedical Sciences, School of Dentistry, University of Texas Health Science Center, 1941 East Road, BBS 4212, Houston, TX 77054. E-mail [email protected]. DOI: 10.1597/14-238 e34

Price et al., MICROGNATHIA AND CLEFT PALATE: A SYSTEMATIC REVIEW

understanding of nonsyndromic cleft palate. This understanding could, in turn, inform better diagnostic categorizations for isolated cleft palate, perhaps eventually leading to the development of effective treatment procedures or even to preventive measures. Evidence gathered in this study includes a variety of teratogens that are experimentally seen to link micrognathia with cleft palate. Other evidence includes a number of studies of mutated genes that cause phenotypes including both micrognathia and cleft palate. Still other studies simply observe incidences of micrognathia coinciding with cleft palate in both animals and humans. METHODS

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Finally, we used a final set of search terms to look for papers that made a connection to the Pierre Robin sequence. The search term ‘‘cleft palate AND pierre robin’’ was combined with ‘‘lower jaw’’ or ‘‘mandibular hypoplasia’’ to return another set of articles. Next, Google Scholar, Ovid MEDLINE, and the Cochrane Reviews search engines were used with the same search terms to find any additional relevant articles. The Cochrane Reviews full-text search returned few results, all with a treatment focus. Google Scholar and the Ovid MEDLINE Basic Search (without inclusion of related terms) returned thousands of articles, but none of these results were further examined because the volume was too vast to feasibly review. The PubMed articles seemed broad and sufficient for the purpose of the review.

Information Sources Study Selection In order to find relevant articles to examine for evidence of a relationship between micrognathia and cleft palate, four electronic databases were queried. The databases used were Google Scholar (from June 1–30, 2014), Ovid Medline (from June 1–30, 2014), PubMed (from June 1–30, 2014), and Cochrane Reviews (from June 1–30, 2014). Search Strategy Several combinations of key words were used in the search strategy to filter results and obtain a variety of articles. Search terms such as ‘‘cleft palate,’’ ‘‘tongue,’’ ‘‘airway obstruction,’’ and ‘‘Pierre Robin,’’ were combined with terms used synonymously for micrognathia to obtain a final set of articles. PubMed was the first electronic database queried, using an ‘‘All Fields’’ search. To filter the results to create a more manageable set, search terms were grouped together. Because we wanted to find articles relating a cleft palate to the mandible, sometimes by way of a tongue obstruction, the search term ‘‘cleft palate AND mandible AND tongue’’ was used. Similarly, we also used the search term ‘‘cleft palate AND micrognathia AND airway obstruction.’’ In the case that articles did not make a connection to the tongue, we used more general search terms to filter the results. The search term ‘‘cleft palate AND craniofacial’’ was combined with ‘‘micrognathia’’ or common synonyms like ‘‘mandibular retrognathia,’’ ‘‘mandibular hypoplasia,’’ or ‘‘hypoplastic mandible’’ to return a set of articles. Because ‘‘brachygnathia’’ is another, less used synonym, ‘‘cleft palate AND brachygnathia’’ was used. We also included more general searches using the words ‘‘cleft palate AND short mandible’’ and ‘‘cleft palate AND mandible AND craniofacial AND cephalometric’’ to capture more studies that performed cephalometric measurements in patients with isolated cleft palate compared with other types of orofacial clefts.

The retrieved articles were then reviewed on the basis of inclusion and exclusion criteria to determine which were to be used in this systematic review. First, the article titles were analyzed to determine relevance. Any articles dealing with cleft lip or cleft lip and palate only were excluded, along with case reports and articles with a treatment focus. Next, abstracts and full text were reviewed and excluded if mention of micrognathia and cleft palate was only tangential. Included articles were written in English and detail experimental or observational studies noting simultaneous occurrence of micrognathia and cleft palate. Articles with a diagnostic focus were also included if they provided useful contextual information. Data Collection A final set of PubMed articles were included in this review and were analyzed to extract data to report. For articles involving teratogens, data about dosage level, application type, time of application, and observed phenotype was retrieved. For articles involving genes, information about gene mutations, gene function, and observed phenotype was collected. Finally, for observational and diagnostic studies, information about the study type, participants, observations, and implications was recorded. The articles included in this review studied both animal and human models and collected diverse sets of data; therefore, the synthesis of results was not feasible. RESULTS Articles Retrieved by Database Search Table 1 shows the abridged results of the electronic database searches. In total, the PubMed searches returned 930 articles that were analyzed according to

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TABLE 1

Summary of Search Results Using Various Electronic Databases Search Terms

Google Scholar*

Ovid MEDLINE

PubMed

Cochrane Reviews

cleft palate þ mandible þ tongue cleft palate þ micrognathia þ airway obstruction

14,900 3,590

7,583 47

133 64

7 1

1,480 4,980 227 467 3,780

2,301 2,396 3,470 5,394 6,957

207 138 35 17 100

5 0 1 0 0

cleft palate þ brachygnathia cleft palate þ short mandible

304 170

10 4,541

10 52

0 0

cleft palate þ pierre robin þ lower jaw þ mandibular hypoplasia

427 720

2,109 2,121

100 74

1 0

31,045

36,929

930

15

cleft palate þ craniofacial þ mandibular hypoplasia þ micrognathia þ mandibular retrognathia þ hypoplastic mandible þ mandible þ cephalometric

Total * Values are approximate.

inclusion/exclusion criteria to decide if they were to be used in the review. Identification of Articles for Inclusion The flowchart in Figure 1 details the inclusion and exclusion of articles for this review. The final set of

searches returned a total of 930 articles. Some of these articles, however, were redundant and showed up in two or more search result sets. Once the redundant articles were removed, 634 articles remained. To reduce the number of articles to a more manageable and relevant set, the article titles were initially analyzed. Any titles that mentioned cleft lip or cleft lip and palate only were

FIGURE 1 Flow diagram of the included studies according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

Price et al., MICROGNATHIA AND CLEFT PALATE: A SYSTEMATIC REVIEW

TABLE 2

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Teratogen and Antiteratogen Studies Observing Both Micrognathia and Cleft Palate* Subject

Teratogen 6-aminonicotinamide 6-aminonicotinamide All-trans-retinoic acid All-trans-retinoic acid b-aminoproprionitrile Bromodeoxyuridine (BrdU) Cortisone acetate Diazo-oxo-norleucine (DON) Dopamine mimetic (BRL 16644) Hadacidin Lamotrigine Retinoic acid Vitamin A palmitate Anti-teratogen Biotin† Folic acid‡

CONC (mg/kg)

Application

Time of Application

Reference

Jelinek and Peterka (1977) Diewert (1979) Padmanabhan and Ahmed (1997), Chen et al. (2011) Emmanouil-Nikoloussi et al. (2000) Diewert (1981) Antoniades et al. (1995) Jelinek and Peterka (1977) Diewert and Pratt (1979) Ridings and Baldwin (1992) Shah (1977) Padmanabhan et al. (2003) Newell-Morris et al. (1980) Hayes et al. (1981)

Mouse Rat Mouse

0.5 8, 16 100–200

IM IP Oral

E14 GD15 GD8 to GD15

Rat Rat Mouse Mouse Rat Rat Hamster Mouse Monkey Rat

50, 100 600 500 7.5 2.0 10–40 100–250 25–200 – 3.2–128

Oral Oral IP IM IP Oral IP IP

GD10 to GD12 GD14 to GD15 E11 to E13 E12 GD15 6 to 15 PC GD8 to GD11 GD7 to GD8 GD20 to GD44 GD6 to GD15

Mouse Rat

108 to 106 mol/L 4 mg/kg

– Oral Culture medium SC

N/A 14 to 17 PC

Watanabe et al. (1995) Bienengraber et al. (2001)

* CONC ¼ concentration; IM ¼ intramuscular injection; E ¼ embryonic day; IP ¼ intraperitoneal injection; GD ¼ gestational day; PC ¼ days postconception or postcoitum; SC ¼ subcutaneous injection. † Application of biotin to biotin-deficient mouse palates saw a reduced incidence of clefting. ‡ Application of folic acid to rats with induced clefting saw a reduced frequency of micrognathia and cleft palate.

excluded because this current analysis is focused on isolated cleft palate. Articles detailing treatment options or case reports were also excluded. After this initial set of exclusions, 158 articles remained. The abstract or full text of each remaining article was analyzed to determine relevance to this systematic review. Articles were excluded if they were simply informational, providing descriptions of different syndromes or disorders. Articles were also excluded if, upon reading the text, it was clear that the study focused on some other topic, with cleft palates and mandibles being mentioned only TABLE 3 Gene

incidentally. On the other hand, special attention was given to articles that detailed specific teratogens or genes that impacted jaw and palatal development, and these articles were included in the review. Observational studies linking the two abnormalities in animal models and humans were also included. Finally, literature about diagnostic mechanisms used to identify micrognathia and associated craniofacial anomalies was also included. In total, 82 articles were selected for detailed review by the end of this process. Of those remaining, 71 articles were classified as teratogen, gene, or observational

Genetic Studies Observing Both Micrognathia and Cleft Palate Phenotypes Gene Function

Mutation*

Subject

Alk2 Bmp4 Cho Col2a1

Transmembrane receptor Growth factor Cartilage regulator Encodes collagen

CKO/Wnt1-Cre CKO/Wnt1-Cre KO KO

Mouse Mouse Mouse Mouse

Delta Ef1 Dlg Egfr Faf1 Fuz Hand2 Hox-2.2 Mnt Msx2 Ovca1/Dph1 Paddle Prdm16 Ptprs, Ptprf Rspo2 Sc5d Snail1, 2 Sox9 Tak1 Twist1

Transcription factor Trafficking protein Cell surface receptor Mediate apoptosis Ciliogenesis regulator Signaling molecule Transcription factor Transcription factor Transcription factor Diphthamide biosynthesis Unknown Transcription factor Signaling Signaling Cholesterol biosynthesis Transcription factor Transcription factor Transcription factor Transcription factor

KO KO KO KD/CNC KO KO GOF KO Transgenic CKO/CNC KO KO DKO KO/ectoderm and mesenchyme KO DKO/CNC CKO/Wnt1-Cre CKO/Wnt1-Cre CKO/mandibular cells

Mouse Mouse Mouse Human/zebrafish Mouse Mouse Mouse Mouse Mouse Mouse Mouse Mouse Mouse Mouse Mouse Mouse Mouse Mouse Mouse

Reference Dudas et al. (2004) He et al. (2014) Seegmiller and Fraser (1977); Clarke et al. (1988) Rintala et al. (1993); Ricks et al. (2002); Savontaus et al. (2004) Takagi et al. (1998) Caruana and Bernstein (2001) Miettinen et al. (1999) Ghassibe-Sabbagh et al. (2011) Zhang et al. (2011) Yanagisawa et al. (2003) Kaur et al. (1992) Toyo-oka et al. (2004) Winograd et al. (1997) Yu et al. (2014) Johnston and Nash (1982) Bjork et al. (2010) Stewart et al. (2013) Jin et al. (2011) Krakowiak et al. (2003) Murray et al. (2007) Lee and Saint-Jeannet (2011) Song et al. (2013); Yumoto et al. (2013) Zhang et al. (2012)

* CKO ¼ conditional knockout; KO ¼ knockout; KD ¼ knockdown; CNC ¼ cranial neural crest cells; GOF ¼ gain of function; DKO ¼ double knockout.

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studies and are summarized in Tables 1, 2, and 3, respectively. The remaining 11 articles are referenced in the text to provide supplementary or contextual information. Teratogens Associated With Cleft Palate and Micrognathia There have been many experiments observing teratogenic interference with mandible and palatal development. The mandible is particularly sensitive to teratogens, possibly because it grows rapidly and independently from the cranial base during development. The migratory cells in the mandibular prominence experience considerable cell proliferation when compared with other facial structures during the same period. The mandibular abnormalities following teratogenic influence lead to inhibition of normal palatal shelf elevation (Diewert, 1980). Table 2 summarizes the findings of the 13 teratogen studies analyzed in this systematic review, each observing phenotypes including both micrognathia and cleft palate. Two antiteratogen studies are also included, each observing a decreased incidence of clefting in animal models affected with both cleft palate and micrognathia, after application of the antiteratogen. Information from each study summarizing the specific teratogen used, the concentration applied, the test subject used, the application type, and the time of application has been collected. Genes Associated With Cleft Palate and Micrognathia The majority of the reviewed literature describes mutated genes that have been shown experimentally to cause micrognathia and cleft palate, mostly in mice. Many of the genes are involved in development of the cranial neural crest–derived mesenchyme or craniofacial morphogenesis. In addition, some genes are expressed in collagen synthesis or are transcription factors or regulators in common genetic pathways. Table 3 summarizes the findings of the 27 genetic studies analyzed in this systematic review that report incidences of both cleft palate and micrognathia. The particular gene involved is listed, along with a brief summary of the gene’s function. The test subject is also given, along with the specific gene mutation. Observational Studies Associated With Cleft Palate and Micrognathia Several observational studies have noted an association or a causative relationship between micrognathia and cleft palate. Several of the morphological studies observe that people with isolated cleft palate have different mandibular morphology than others, whether

considering retrusion, rotation, or length. Many of the observational studies have also demonstrated that patients with Pierre Robin sequence have variable degrees of mandibular hypoplasia; whereas, patients with cleft palate have skeletal abnormalities of both the mandible and maxilla. The observational genetic analyses identify genes that are linked to these craniofacial abnormalities in humans, which are the same or closely related to the genes described in animal models in Table 3. The data in Table 4 summarizes the findings of the 29 observational studies analyzed in this systematic review. The study type is listed, along with study participants, a summary of the main observations, and any implications of those observations. Diagnosis and Classification of Micrognathia and Associated Anomalies Literature discussing current diagnostic techniques used to identify and classify micrognathia and associated anomalies are further analyzed in this review. These articles provide context for the current clinical landscape for craniofacial disorders. A few articles discuss the usefulness of different technologies to diagnose prenatal craniofacial defects. Screening for abnormalities with ultrasonography and subsequent confirmation with fetal MRI is suggested in several studies. These studies mention the usefulness of ultrasound in diagnosing only severe forms of micrognathia (Costello and Edwards, 2010). Another article realizes the difficulty in properly diagnosing cleft lip and palate in utero and suggests a ‘‘flipped face’’ technique using three-dimensional (3D) sonography to increase diagnostic accuracy (Platt et al., 2006). Other articles attempt to classify craniofacial anomalies based on degrees of severity. One article, noticing variations in the severity of Pierre Robin sequence, proposes a system of classification (grades 1 to 3) based on tongue behavior and the amount of respiratory distress while nursed (Cole et al., 2008). A second article found variations in the definition, diagnosis, and management of Pierre Robin sequence. This article suggests that the severity of Pierre Robin sequence be assessed using several techniques to evaluate the infant airway (Mackay, 2011). We propose instead that isolated cleft palate be classified along a spectrum based on measurable phenotypes, as seen in Figure 2. Overall, we found inconsistency in defining, classifying, and diagnosing micrognathia and its associated anomalies. Micrognathia has been used to indicate a short mandible, regardless of the severity of the mandibular disorder. In addition, other terms (e.g., short mandible, mandibular hypoplasia, hypoplastic mandible, and brachygnathia) have been alternatively used to describe a similar phenotype to micrognathia, which may suggest the need to develop better diagnostic

Price et al., MICROGNATHIA AND CLEFT PALATE: A SYSTEMATIC REVIEW

TABLE 4

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Observational Studies Reporting Micrognathia and Cleft Palate*

Study Type

Study Participants

Cephalometric

CL or iCP

Cephalometric Cephalometric Cephalometric Cephalometric Cephalometric Cephalometric

iCP iCP iCP iCP iCP iCP or CLP

Cephalometric

PRS, iCP, or control

Cephalometric Cephalometric

PRS, iCP, UCLP, BCLP PRS or iCP

Cephalometric Cephalometric

PRS or iCP PRS or iCP

Cephalometric

PRS or iCP

Cephalometric Cephalometric

PRS or iCP UICL or CP

Cephalometric Cephalometric

UICL or iCP UICP or control

Genetic

Auriculocondylar syndrome

Genetic Genetic

PRS SATB2 mutations

Genetic

Tolling Retrievers with cleft palate

Morphologic

A/WySn murine embryos

Morphologic

Humans and rodents

Morphologic

PRS, iCP, or UCCLP

Morphologic

PRS, iCP, or UICL

Morphologic

PRS or UICL

Morphologic

Stickler syndrome

Observational

PRS

Observational

Treacher Collins syndrome

Observation/Implication CP group: reduced dimensions of the mandible, especially mandibular length Deficient mandibular growth Maxilla and mandible are retrusive Maxilla and mandible are short and retrusive Maxilla and mandible are short and retrusive Short maxillary and mandibular corpus length Noncleft parents of iCP group: mandibular ramus length is longer compared with CLP group PRS group: smallest mandibular length iCP group: smaller mandibular length than control CP group: reduced mandibular arch PRS group: mandibular hypoplasia iCP group: no deviations PRS group: more receded mandible PRS group: proportionate retrusion of the maxilla and mandible iCP group: small maxilla PRS group: short mandible iCP group: slightly short mandible PRS group: smaller mandible; higher frequency of clefting CP group: smaller mandibular length. Risk of cleft palate increases 58% per mm decrease in mandibular length iCP group: smaller mandible UICP group: shortened mandibular length and height (but mandible displayed catch-up growth) PLCB4 and GNAI3 are involved in auriculocondylar syndrome; characteristics include variable micrognathia and cleft palate (these genes are part of the EDN1 pathway) Regulatory elements near SOX9 are associated with PRS Translocation breakpoints upstream of SATB2 and SATB2 LOF cause cleft palate and micrognathia DLX6 is involved in producing micrognathia and cleft palate in the dog model; DLX5 may be involved in PRS in humans All fetuses with severe mandibular retrognathia have cleft palate Due to similar facial growth patterns, a mouse model can be applied to humans PRS group: most significant micrognathia iCP group: shorter mandibles when compared with UCCLP group PRS group: most significant micrognathia iCP group: shorter mandibles when compared with UICL PRS group: micrognathia and different facial morphology than UICL group 79% of affected children showed mandibular hypoplasia; whereas, 57% showed cleft palate ¨-shaped palatal clefts suggest mechanical interference due to an abnormality in early mandibular growth 38% of affected fetuses were diagnosed with the PRS

Reference Dahl et al. (1982) Smahel (1984) Heliovaara et al. (2003) ¨ Fujita et al. (2005) Heliovaara & Rautio (2009) ¨ Cronin and Hunter (1980) Mossey et al. (1997) Figueroa et al. (1991) Casal et al. (1997) Lu et al. (2007) Laitinen and Ranta (1992) Shen et al. (2012)

Daskalogiannakis et al. (2001) Laitinen et al. (1997) Hermann et al. (2014) Hermann et al. (2002) Xu et al. (2013) Rieder et al. (2012)

Benko et al. (2009) Rainger et al. (2014) Wolf et al. (2014)

Schubert et al. (2005) Diewert (1986) Hermann et al. (2003a)

Eriksen et al. (2006) Hermann et al. (2003b) Lucarini et al. (1987) Hanson and Smith (1975) Konstantinidou et al. (2013)

* CL ¼ incomplete left-sided cleft lip; iCP ¼ isolated cleft palate; CLP ¼ cleft lip and palate; PRS ¼ Pierre Robin sequence; UCLP ¼ unilateral cleft lip and palate; BCLP ¼ bilateral cleft lip and palate; UICL ¼ unilateral incomplete cleft lip; UICP ¼ unrepaired isolated cleft palate; LOF ¼ loss of function; UCCLP ¼ unilateral complete cleft lip and palate.

terminology. A systematic review analyzing tonguebased airway obstruction in newborns, a condition often associated with Pierre Robin sequence, came to similar conclusions. The review found that there were no standardized diagnostic procedures among 59 analyzed studies. Most diagnoses were made based on subjective criteria involving clinicians observing some level of micrognathia or respiratory distress (Bookman et al., 2012). A few articles do describe techniques to objectively diagnose fetal defects. Using two-dimension-

al and 3D ultrasound, one study uses measurements to discriminate between fetal micrognathia and retrognathia (Rotten et al., 2002). Another study defines a ‘‘jaw index’’ calculation, based on the alveolar overjet and the maxillary and mandibular arch ratio, to diagnose the severity of micrognathia (van der Haven et al., 1997). But articles using objective data often base their studies on patients already diagnosed with Pierre Robin sequence, which is not particularly helpful when trying

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FIGURE 2 Spectrum of severity in micrognathia and associated phenotypes. We propose that isolated cleft palate is caused by alteration in mandibular development during pregnancy, with possible compensation in growth after birth.

to define criteria for prospective diagnosis (Bookman et al., 2012). DISCUSSION Summary of Evidence It is important to note that there is not a complete consensus among researchers on the causative role of the mandible and tongue in the development of isolated cleft palate. The Abramovich (1972) study of the teratogen Lathyrus odoratus found that a low percentage of mandibular abnormalities were not associated with cleft palate and concluded that there was no causal relationship between the two abnormalities. Also, Rintala et al. (1984) showed that tongue position did not seem to have a pathogenic role in most Pierre Robin sequence clefts, noting instead that Pierre Robin sequence may be the result of a genetic disturbance in maxillary and mandibular growth. Furthermore, Han et al. (1995) and Lu et al. (2007) did not detect a shorter mandible in patients with isolated cleft palate (compared with patients with unilateral cleft lip and alveolus or unilateral cleft lip and palate) but rather a slightly posteriorly positioned mandible. Regardless, in this review, substantial evidence was found supporting the causative relationship between micrognathia and cleft palate than disputing it. First, 71 reviewed articles found simultaneous occurrence of micrognathia and cleft palate. Observing both phenotypes together in diverse studies of 11 different teratogens and 23 unique genes lends credence to the idea that there may be some relationship between the two. Three of the articles only noted some kind of an

association between micrognathia and cleft palate (Shah, 1977; Bienengraber et al., 2001; Savontaus et al., 2004). Many more, however, suggested a cause-andeffect relationship to explain the results of their studies (e.g., Jelinek and Peterka, 1977; Diewert 1979; Antoniades et al., 1995). Several studies even continued on to compare their observations in the animal models with human birth defects, making note of the Pierre Robin sequence in particular (Schubert et al., 2005; Murray et al., 2007; Song et al., 2013). As mentioned in several comparative morphological studies, people diagnosed with isolated cleft palate had less significant mandibular abnormalities than those diagnosed with Pierre Robin sequence (Figueroa et al., 1991; Laitinen et al., 1997; Daskalogiannakis et al., 2001; Hermann et al., 2003a; Eriksen et al., 2006; Lu et al., 2007). In fact, Hermann hypothesizes that a distribution exists for isolated cleft palate, where the Pierre Robin sequence group appears at the farthest end and displays the most severe micrognathia (Hermann et al., 2003a). We continue with this hypothesis and suggest that nonsyndromic isolated cleft palate occurs along a spectrum (Fig. 2). At one extreme, cleft palate occurs with a variety of additional phenotypes including the rest of the Pierre Robin sequence (micrognathia and glossoptosis), along with airway obstruction and microstomia. But at the other end, isolated cleft palate probably has a different etiology, and patients with cleft palate may have some lesser degree of mandibular hypoplasia. Precise skeletal measurement using cephalometric radiographs would be helpful to properly diagnose the mild to moderate micrognathia to determine the exact relation of the mandible to the maxilla in terms of length, height, position, rotation and inclina-

Price et al., MICROGNATHIA AND CLEFT PALATE: A SYSTEMATIC REVIEW

tion, and association with cleft palate with or without cleft lip. To advance our understanding of isolated cleft palate, further data of patients exhibiting the phenotype should be extensively analyzed, with focus extending beyond the palate itself. As the Diewert (1986) study notes, several different developmental events that do not directly involve the palate can contribute to palatal abnormalities. In particular, precise measurements of the length and position of the mandible and tongue should be gathered, given that many studies have shown the mandible playing an important role in palatal development. In this way, patterns may emerge that could provide insight into the complex etiology of isolated cleft palate (Joshi et al., 2014). This insight may then inform better diagnostic categorizations for cleft palate, perhaps distinguishing it from the orofacial cleft category. More accurate diagnosis could then lead to the eventual development of effective treatment protocols or even to preventive measures. A potential area of future research may focus on identifying maternal supplements that could reduce the incidence of orofacial clefting, as seen in the study of the antiteratogen folic acid, by enhancing cartilage formation using glucosamine and chondroitin (Bienengraber et al., 2001). With this in mind, we encourage clinicians to consider the role of the mandible when faced with cases of isolated cleft palate and not to rely only on the traditional classification of cleft palate as a type of orofacial clefting. Even if there is no obvious mandibular abnormality, the cleft palate may still be a result of very subtle mandibular irregularities that could be identified through precise cephalometric measurements. Limitations of the Review This systematic review attempts to identify and include all relevant literature in the study of micrognathia as it relates to cleft palate by querying electronic databases and collecting evidence from a variety of literature, including teratogenic, genetic, and observational studies. There are, however, several possible limitations to this systematic review. First, only articles written in English were used. The majority of articles returned from the various searches are in English, so we do not expect this limitation to impact the quality of the review. Second, the referenced animal studies use inconsistent parameters to define micrognathia and use inconsistent techniques to measure craniofacial features in humans. For example, tissues are sometimes measured rather than bone. One last limitation is that the results reported here are confined to articles found in the systematic search of the databases. To mitigate this limitation, many different words or phrases used often in literature to indicate micrognathia were used to query the database for

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articles. But inevitably, some relevant articles were overlooked. However, we are aware of several articles that were not found during our systematic approach. For example, one human cephalometric study noted the differences of mandibular shape between clefts that involve the palate and those that do not. Clefts involving the palate were associated with a backward rotation of the mandible (da Silva et al., 1993). One other study of craniofacial growth in mice determined that the growth of the Meckel cartilage was important for shelf elevation (Diewert, 1982). Finally, one of the earliest cephalometric studies on different types of orofacial clefting indicated that patients with isolated cleft palate had retrognathia and a small mandible base angle (Dahl, 1970). CONCLUSIONS A comprehensive examination of articles describing micrognathia and cleft palate has led to several conclusions. (1) Micrognathia is often seen occurring with isolated cleft palate in animal and human models (Lucarini et al., 1987; Kaur et al., 1992; Padmanabhan and Ahmed, 1997); (2) many researchers have identified an association or a causative relationship between micrognathia and cleft palate in animal models and humans (Hanson and Smith, 1975; Jelinek and Peterka, 1977; Johnston and Nash, 1982); (3) many agree that the observations made in animal studies have similar characteristics to the suggested pathogenesis of cleft palate in some human disorders (Clarke et al., 1988; Antoniades et al., 1995; Murray et al., 2007). Following this line of reasoning, we suggest that micrognathia is likely one cause of isolated cleft palate in humans as well as animals. With knowledge of this relationship, clinicians should consider the possibility that isolated cleft palate in their patients could be secondary to micrognathia. Gathering cephalometric data on the mandibles and tongues during fetal development and after birth in affected patients could identify patterns that may provide insight into the complex etiology of isolated cleft palate. Acknowledgements. We would like to thank Dr. Catherine Flaitz for providing helpful comments on the content of this review. This study was supported by startup funding to W.D.F. from School of Dentistry, University of Texas, and from the Research Office at School of Dentistry to K.P.

REFERENCES Abramovich A. Cleft palate in the fetuses of lathyric rats and its relation to other structures: nasal septum, tongue and mandible. Cleft Palate J. 1972;9:73–83. Antoniades K, Economou L, Sioga A, Vahtsevanos K, Manthos A. Pathogenesis of bromodeoxyuridine-induced cleft palate in mice. J Craniomaxillofac Surg. 1995;23:252–255.

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Analysis of the Relationship Between Micrognathia and Cleft Palate: A Systematic Review.

Objective To gather data from relevant experimental and observational studies to determine the relationship between micrognathia and cleft palate. The...
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