• Users Online: 15
  • Print this page
  • Email this page


 
 
Table of Contents
REVIEW ARTICLE
Year : 2020  |  Volume : 9  |  Issue : 1  |  Page : 1-9

Orodental abnormalities in limb malformation syndromes: A review article


1 Department of Orodental Genetics, Human Genetics and Genome Research Division, Cairo, Egypt
2 Department of Dental Basic Science, Dental and Oral Research Division, Center of Excellence for Human Genetics, Cairo, Egypt
3 Department of Fixed and Removable Prosthodontics, National Research Centre, Cairo, Egypt
4 Department of Clinical Genetics, Human Genetics and Genome Research Division, Cairo, Egypt

Date of Submission06-Aug-2020
Date of Decision01-Oct-2020
Date of Acceptance15-Oct-2020
Date of Web Publication31-Dec-2020

Correspondence Address:
Nehal F Hassib
P.O.Box 11231, 33 ElBohous Street, Dokki, Giza
Egypt
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/MXE.MXE_12_20

Rights and Permissions
  Abstract 


The regular synchronization during development of an embryo results in the normal formation of his/her structures. The deviation from this harmony produces malformations. The pleiotropic effects of similar genes that contribute in the growth of limb and oral structures produce concurrent abnormalities indeed. The present review gives a brief hint at the shared causative genes of both limb and orodental structures. The nosology either of skeletal and limb malformations or of orodental findings and the types of orodental anomalies were reported in these syndromes. Pathognomonic orodental features and Egyptian experiences are emphasized.

Keywords: gene mutations, limb malformations, oral anomalies


How to cite this article:
Hassib NF, AbulEzz EA, Ramzy M, El-Badry T, Aglan MS, Temtamy SA. Orodental abnormalities in limb malformation syndromes: A review article. Middle East J Med Genet 2020;9:1-9

How to cite this URL:
Hassib NF, AbulEzz EA, Ramzy M, El-Badry T, Aglan MS, Temtamy SA. Orodental abnormalities in limb malformation syndromes: A review article. Middle East J Med Genet [serial online] 2020 [cited 2024 Mar 28];9:1-9. Available from: http://www.mxe.eg.net/text.asp?2020/9/1/1/305863




  Background Top


Birth defects are malformations programmed by gene mutations or by environmental insults such as infections and teratogens. The definition of congenital defects is structural or functional disabling disorder having physical, social, and intellectual influences (Feldkamp et al., 2017). The WHO declared that the prevalence of birth defects among neonates is one in 33 (Kurdi and Majeed-Saidan, 2015). An Egyptian study found that prevalence of congenital defects was 3.17% (Temtamy et al., 1998a, b), whereas another Egyptian study stated that congenital defects was 20 in 1000 neonates (Shawky et al., 2010a, b).

Congenital limb malformations follow congenital heart diseases as most frequent anomalies occurring in new-borns. Limb defects are exhibited either as an isolated entity or as a part of syndrome. Upper/lower or both extremities, unilateral or bilateral, are the affected sites in limb disorders (Tayel et al., 2005). Congenital limb defects have a percentage of 3.52% in fetal records; however, Egyptian percentage is ∼8.8% (Shawky and Sadik, 2011; Shi et al., 2018). Increasingly, the high rate of positive consanguinity in Egypt as well as exposure to teratogenic environmental factors raises the limb malformations to ∼20% among neonates when compared with other birth defects (Temtamy et al., 1998a, b).

The detailed clinical data should be accomplished by orodental examination. The full picture of the anomaly or syndrome characterization is usually associated with certain pathognomonic orodental findings, apart from its clinical description. This aids in accurate diagnosis, precise genetic counseling, correct treatment planning, and appropriate dental management if available.

The present review gives a brief hint on the developmental background and the shared causative genes of both limb and orodental structures. The nosology either of skeletal and limb malformations or of orodental findings and the types of orodental anomalies were reported in these syndromes. Pathognomonic orodental features and Egyptian experiences are emphasized.


  Role of Molecular Genetics in the Development of Human Limb and Oral Structures Top


Certain genes and their regulators are the maestro in the development of human limb and oral structures in a normal shape and function. T-Box transcription factors (Tbx4- Tbx5), the fibroblast growth factor genes (FGFs), the wingless inhibitory factor genes (WNTs), the sonic hedgehog genes (SHH), and the homeobox genes (HOX) and their formal interrelation directly regulate the embryological development of limb (Zuniga et al., 2012; Jin et al., 2019; Sun et al., 2019). Shh is a specific enhancer to regulate epithelium-mesenchymal proliferation, which directly affects teeth, tongue, and palate. The sonic hedgehog signal coordinates WNT gene, which simultaneously influences tooth development (Sagai et al., 2017; Seo et al., 2018).

DLX genes have strategic influence on normal development of limbs (Kantaputra and Carlson, 2019). Moreover, distal-less genes (DLXs), FGFs, bone morphogenic protein (BMP), and homeobox are the principal genes involved in craniofacial growth and features' characterization (Richmond et al., 2018; Deshpande and Goudy, 2019). An informative review of molecular aspects of limb development is provided by Mundlos and Horn (2014). The identical timing in embryonic period which starts at fourth week of gestation and the similar shared genes involved in limb and oral structures formation make a possibility that the pathogenic gene variants could affect limbs, providing malformation as well as orodental anomalies.


  Nosology and Classification of Limb Malformation Syndromes Top


One of the first classifications of limb malformations was established by Temtamy (1966) and published by Temtamy and McKusick in 1969. The classification was based mainly on clinical, anatomical, and genetic criteria. They divided the limb abnormalities into ten main groups [Table 1].
Table 1: Classification of limb malformations according to Temtamy and McKusick (1969)

Click here to view


Each of the aforementioned 10 groups was classified anatomically as preaxial, mesoaxial, or postaxial; clinically as isolated or associated with other organ malformation; genetically as inherited or sporadic; and according to the pattern of inheritance (Temtamy 1966).

A nosology for skeletal disorders including limb anomalies was set in 1992 by Beighton et al. (1992) and updated regularly. Under the latest nosology classification skeletal disorders were included under 42 groups according to phenotypic presentations and protein nomenclatures [Table 2] (Mortier et al., 2019).
Table 2: The latest nosology classification of skeletal malformation disorders (Mortier et al., 2019)

Click here to view



  Orodental Abnormalities Associated with Limb Malformation Syndromes Top


The known limb malformation syndromes associated with significant orodental findings are included in Online Mendelian In Man (OMIM) and London Dysmorphology Databases (Winter and Baraitser, 2014).

Certain orodental features are commonly observed in most disorders, whereas a pathognomonic phenotype should be highlighted for helping in accurate diagnosis.

Upon discussing the Filamin group in the latest Nosology (2019), otopalatodigital syndrome (OMIM# 304120) is considered a disorder of syndactyly in hands and toes, clinodactyly of fifth fingers, short first metacarpal, and absent fibula. Characteristic features in the ears are conductive deafness and poorly modeled pinnae (Winter and Baraitser, 2014) The ultimately oral characterization of the syndrome is cleft palate, as well as bifid uvula and marked micrognathia (Robertson, 2007). The ciliopathies group includes chondroectodermal dysplasia (Ellis-Van Creveld syndrome (OMIM#225500), orofaciodigital syndrome (OMIM#311200, 252100), and short-rib- polydactyly syndrome (OMIM#613091), which are described with polydactyly of fingers or toes; moreover, absent fibula and syndactyly was reported with short-rib syndrome. These disorders shared similar orodental features [Table 3].
Table 3: Main pathognomonic orodental abnormalities exhibited in the group of ciliopathies with limb malformations

Click here to view


When mentioning the acromelic group, trichorhinophalangeal syndrome (OMIM#190350, 150230), characterized by brachydactyly, short feet, and wide hallux disorders, has noticeable oral anomalies, including micrognathia, accentuated obtuse angle of the mandible, supernumerary teeth, and malocclusion (Candamourty et al., 2012; Trippella et al., 2018). Less significant facial abnormalities are long flat philtrum, thin upper lip, and cleft palate (Trippella et al., 2018; Cho et al., 2019).

Robinow syndrome (OMIM#180700, 268310) was placed under the mesomelic/rhizomelic dysplasia group; it is also considered one of the brachydactyly syndromes. The dominant type has tented upper lip, long philtrum, and retromicrognathia. Intraoral examination revealed remarkable findings of gingival overgrowth, bifid uvula or palatal cleft, tongue ankyloglossia that leads to bifid tip of the tongue, malpositioned crowding teeth, and congenital teeth agenesis (Temtamy et al., 2004a, 2004b; Beiraghi et al., 2011). Campomelic dysplasia (OMIM#114290) presents with short metacarpals, brachydactyly, and clinodactyly of fifth fingers. The distinctive intraoral structures of the syndrome are microstomia, long philtrum, cleft palate, and retromicrognathia (Corbani et al., 2011).

Desbuquois dysplasia (OMIM#251450) was listed under the dysplasia with multiple joint dislocations group. It is characterized by progressive ossification of second metacarpals, bifid distal phalanx of the thumb as well as, dislodgment of interphalangeal joints. Microstomia and small retruded mandible are the only reported oral abnormalities of the disorder (Laccone et al., 2011).

The group of other sclerosing bone disorders included oculodentoosseous dysplasia (OMIM#164200, 257850), also known as oculodentodigital. This dysplasia is characterized by syndactyly and clinodactyly. Dental abnormalities are very specific and diagnostic, including enamel hypoplasia, odontodysplasia, microdontia, delayed teeth eruption, and hypodontia (Aminabadi et al., 2010).

The osteolysis group includes Hajdu-Cheney syndrome (OMIM#102500) and multicentric carpal-tarsal osteolysis syndrome (OMIM#166300). Both disorders shared acroosteolysis phenomena of carpal and tarsal bones with deformities of digits. Micrognathia is the main oral anomaly observed in the osteolysis group (Samuel et al., 2016; Choochuen et al., 2018), as well as premature loss of teeth, which is diagnostic in Hajdu-Cheney syndrome (Samuel et al., 2016).

The overgrowth syndromes with skeletal involvement group contained five disorders; two of them are characterized by arachnodactyly and camptodactyly, namely, the congenital contractural arachnodactyly (OMIM#121050) and Marfan syndrome (OMIM#154700). They share similar oral manifestations except few features that are presented in [Table 4] (Marina et al., 2003; Bollero et al., 2017). Another disorder not included in the nosology owing to it is rarity is van den Ende-Gupta syndrome (OMIM#600920). It is one of the contractural and arachnodactyly disorders. The only two oral anomalies reported were maxillary hypoplasia and everted lower lip (Schweitzer et al., 2003).
Table 4: Oral manifestations associated with congenital contractural arachnodactyly and Marfan syndrome

Click here to view


The remaining two disorders under the overgrowth group that have macrodactyly according to Temtamy's classification are Proteus syndrome (OMIM#176920) characterized by facial asymmetry, premature eruption of teeth, and large jaws of the affected side, as well as malocclusion, and enamel hypoplasia (Canabarro et al., 2008). Sotos syndrome (OMIM# 117550) was also in the group of macrodactyly in the old nosology (Temtamy and McKusick, 1978). Oral examination includes premature eruption of teeth, high-arched palate, malocclusion, and hypodontia (Hirai et al., 2011).

Hyaline fibromatosis syndrome (OMIM#228600) is under the group of genetic inflammatory/rheumatoid-like osteoarthropathies. The joints and digits show contractures with deformities in knees and elbows, resulting in limbs' movement limitation. Orally, it presents by gingival fibromatosis which aids in the diagnosis (Olczak-Kowalczyk et al., 2011).

Two syndromes belonging to the craniosynostosis group are presented with syndactyly, Apert syndrome (OMIM#101200) and Saethre-Chotzen syndrome (OMIM#101400), whereas a third one has radial aplasia and absent thumbs, which is the Baller-Gerold syndrome (OMIM#218600). The first exhibited bifid uvula, Byzantine pseudocleft at the anterior area, and malocclusion (Şoancă et al., 2010). The second showed mainly high-arched palate, hypoplastic maxilla, and protruded mandible (Pelc and Mikulewicz, 2018). The last displayed palatal abnormalities bifid uvula, cleft or high-arched palate, and micrognathia (Murthy et al., 2008).

An important group was classified in the latest nosology named dysostosis with predominant craniofacial involvement, which included four disorders: acrofacial dysostosis (Nager type) (OMIM#154400), which was first identified as a distinct syndrome by Temtamy and McKusick (1978); hemifacial microsomia (OMIM#164210), acromelic frontonasal dysostosis (OMIM#603671), and Weyers acrofacial dysostosis. The first 2 syndromes present with preaxial reduction defects, e.g., absent thumbs or radial aplasia, while the third one has tibial aplasia, talipes deformity, and polydactyly. The most characteristic facial feature is facial asymmetry, whereas oral anomalies comprise cleft palate, retromicrognathia, malocclusion, and temporomandibular joint ankylosis/abnormalities (Martelli et al., 2010; Ismail et al., 2017). Acromelic frontonasal dysostosis presents with clefting and teeth agenesis (Koçak and Ceylaner, 2009). Weyers acrofacial dysostosis (OMIM#193530) has remarkable polydactyly and acroosteolysis. It is phenotypically similar to Ellis-Van Creveld syndrome except for additional amelogenesis imperfecta, which could be a diagnostic finding, in addition to its autosomal dominant pattern of inheritance (Shetty et al., 2012).

Brachydactilies with extra-skeletal manifestations provisionally consist of Rubinstein-Taybi syndrome (OMIM#180849), Temtamy preaxial brachydactyly syndrome (OMIM#605282), Coffin-Siris syndrome (OMIM#135900), and pseudohypoparathyroidism (OMIM#103580). Talon cusp dental malformation is helpful in the diagnosis of Rubinstein-Taybi and Temtamy syndrome (Temtamy et al., 1998a, b; Gunashekhar, Hameed and Bokhari, 2012). Microdontia and retromicrognathia are cliché for Coffin-Siris (Hoyer et al., 2012), whereas enamel hypoplasia, microdontia, delayed eruption, and short roots are the obvious dental findings in pseudohypoparathyroidism (Hejlesen et al., 2018).

The many syndromes in limb hypoplasia/reduction defects group are Hanhart syndrome (OMIM#103300), Moebius syndrome (OMIM#157900), Thrombocytopenia- Absent radius (TAR) (OMIM#274000), de Lange syndrome (OMIM#122470), and Roberts syndrome (OMIM#268300). The main oral feature observed in the five syndromes is palatal cleft. Tongue abnormalities such as hypoglossia, tongue asymmetry, or glossoptosis are marked in all disorders except TAR and Roberts syndromes. Micrognathia is fundamentally detected except in TAR (Naseh et al., 2012; Leanza, Rubbino and Leanza, 2014; Ismail et al., 2016; Hassib et al., 2019; Varal and Dogan, 2019). The group of ectrodactyly with or without other manifestations contains ectrodactyly-ectodermal dysplasia-cleft lip/palate (EEC) (OMIM#604292), ankyloblepharon-cleft lip/palate (AEC, Hay-Wells, Rap-Hodgkin) (OMIM#106260), and limb-mammary syndrome (OMIM#603543). Split hand/foot malformations, a combination of central ray reduction defects and syndactyly, are the cardinal limb malformations. The lip/palate clefting is the principal oral anomaly found in the syndromes, whereas limb-mammary disorder has hypodontia as the main dental abnormality (Van Bokhoven et al., 1999; Koul et al., 2014).

The last group of the latest skeletal dysplasia nosology includes other limb malformations as polydactyly-syndactyly-triphalangism group, for example, Cenani-Lenz syndrome (OMIM#212780) and Lacrimo-auriculo-dento-digital syndrome (LADD) (OMIM# 149730). Both disorders have syndactyly, whereas triphalangism is only reported in LADD syndrome. Micrognathia is frequently observed in Cenani-Lenz syndrome (Hettiaracchchi et al., 2018). Prominent dental anomalies in LADD are hypodontia, microdontia, and enamel hypoplasia (Talebi et al., 2017).

It is worth noting that in the nosology of skeletal dysplasias list, many syndromes with limb malformations associated with orodental anomalies were not included, which gives a hint that this classification is still incomplete. The classification of limb malformations by Temtamy and McKusick (1978) included the contracture and camptodactyly group, for example, Bartoscas-Papas syndrome (OMIM#263650), which is a lethal condition associated with cleft of the lip/palate and synechia (Kalay et al., 2012); Freeman-Sheldon syndrome (OMIM#193700), which presents with markedly long philtrum, microstomia, microglossia, high narrow palate and limited movement of soft palate (Johns, 2013); Gordon syndrome (OMIM# 114300), which exhibits cleft palate and micrognathia (Alisch et al., 2016); and Trismus pseudocamptodactyly (OMIM#158300), described by limited mouth opening is the crucial finding (Sreenivasan et al., 2013).

Brachydactyly syndromes like Aarskog (OMIM#100050) shows maxillary hypoplasia, high-arched palate, and tooth agenesis (Ahmed et al., 2016). The preaxial reduction defect syndrome of Juberg-Hayward (cleft lip/palate-abnormal thumb and microcephaly) (OMIM#216100) is only associated with clefting (Silengo and Tornetta, 2000). Syndactyly and polydactyly group presented by focal dermal hypoplasia (OMIM#305600), which orally has gingival papillomas, hypodontia, microdontia, and enamel hypoplasia (Nathwani et al., 2018).


  Egyptian Experiences Concerning Orodental Abnormalities Associated with Limb Malformation Syndromes Top


Temtamy et al. (1989), studied orodental and ultrastructural changes of pulp and gingiva in Marfan syndrome. The results revealed gingivitis and periodontitis in Marfan patients as a consequence of the increase of elastic fibrous tissue and defective collagen fibers. Orodental findings exhibited high-arched palate, enamel hypoplasia, and malocclusion. The pulp showed pulp stone and obliterated root canals with abnormal root morphology.

Rubinstein-Taybi syndrome was studied by Temtamy et al. (1990) and Shawky et al. (2012) who presented the clinical, facial, and orodental phenotype of the syndrome among Egyptians. Talon cusps were prominent findings of the conditions shown by Temtamy et al. (1990).

Ectrodactyly-ectodermal dysplasia-cleft lip/palate was studied by Meguid et al. (1995) and Ashour and El-Badry (2004) who presented the variability in phenotypic characterization of the syndrome. Hypodontia, microdontia, enamel hypoplasia as well as cleft palate were the predominating features.

Temtamy et al. (1998a, b) first described the Temtamy preaxial brachydactyly syndrome characterized by multiple congenital anomalies and preaxial brachydactyly. Oral examination showed micrognathia, high-arched palate, microdontia, and talon cusps. Temtamy et al. (2012) studied the largest series of Temtamy preaxial brachydactyly syndrome with main digital and orodental anomalies (Temtamy et al., 2012). Aglan et al. (2014) reported a novel gene mutation in an additional Egyptian case with the same disorder suffering of same facial and orodental involvement.

Temtamy et al. (2003a, b, c) reported two families with Cenani-Lenz syndrome emphasizing for the first time in the literature the associated facial dysmorphism and orodental features including short prominent philtrum and malar hypoplasia.

The phenotypic spectrum of Baller-Gerold syndrome was investigated in details by Temtamy et al. (2003a, b, c). Orodental malformations were bifid uvula, cleft or high-arched palate, and micrognathia.

Orofaciodigital syndrome one of the polydactyly group of disorders was reported by Temtamy et al. (2003a, b, c) and Shawky et al. (2013; 2014). All reported the phenotypic variability of the syndrome. Multiple frena, clefted alveolar ridge, and lobulated tongue nodules were vigorously observed.

A genetic study of 46 Egyptian patients with congenital limb contractures was performed by Temtamy et al. (2004a, b). The authors provided full clinical and orodental studies to different contracture syndromes

Gingival overgrowth, delayed tooth eruption, tie tongue, and bifid tip of the tongue were the main orodental anomalies reported in Robinow syndrome by Tematamy et al. (2004). Histopathological studies revealed storage material in the gingiva. Aglan et al. (2015) reported four novel gene mutations in Robinow syndrome without altering the oral phenotype. One patient received surgical management to correct lip, nose, and zygomatic bone hypoplasia (Mossaad et al., 2018).

Ellis-Van Creveld syndrome was very challenging in orodental description, as the mentioned features were primarily reported by Mostafa et al. (2005). Orodental anomalies in this disorder are similar to those in the oro-facio-digital syndrome group except for the tongue nodules. Shawky et al. (2010a, 2010b) found extrafacial dysmorphism in another Egyptian case that presented with corneal abnormality, upward slanting palpebral fissures, and frontal bossing. A doctorate thesis was provided applying overdenture to restore the tooth agenesis in the anterior area associated with this disorder (AbdelKader, 2015). The study concluded that the ball/socket-retained partial overdenture was better than bar/clip-retained overdenture in terms of stress distribution.

Roberts syndrome which is characterized by phocomelia and cleft lip/palate was first delineated by Temtamy (1966), and Temtamy et al., 2006. Afifi et al. (2016) found new hypopigmentation in Roberts cases with a novel mutation. Genotype/phenotype correlation was studied in eight patients by Ismail et al. (2016).

Mehrez et al. (2010) provided the first cephalometric measurements to assess craniofacial involvement in some reduction defect syndromes. They proved the existence of cranio-facial and orodental abnormalities related to such category of disorders.

Abdalla (2016) described the clinical and radiographic findings in a case of Nager acrofacial dysostosis. The clinical, radiographic, and orodental examination confirmed the diagnosis. Ismail et al. (2017) detected a novel mutation and classical clinical and orodental features in the form of temporomandibular joint ankylosis, facial asymmetry, and retromicrognathia in another patient.

One case of Moebius syndrome was presented by Shawky (2015) who observed orofacial and skeletal malformations. Four cases of Moebius syndrome were published by Hassib et al. (2019). The cases had tongue abnormalities, retromicrognathia, enamel hypoplasia, and malocclusion. Ridge asymmetry was a new finding not previously reported. A modified prosthetic management was provided to one affected patient.

Demographic studies among certain Egyptian governorates were performed to calculate the prevalence of limb malformations and orofacial clefts among the country. Shawky et al. (2010a, b) examined 140 patients in Cairo, and syndromic limb anomalies were 54.6% of the total affected individuals. A wider study done by Shawky and Sadik (2011) included ∼660 000 patients from all over Egypt. They concluded that limb malformations and clefting of palate/lip among congenital anomalies were 8.8 and 1.5%, respectively. On studying Assiut governorate patients, Mohammed et al. (2011) found that skeletal abnormalities were 37.9% and cleft lip/palate were 9.7. Abulezz et al. (2016) surveyed hand malformations in Upper Egypt. Syndactyly and polydactyly were of high percentages, with 36 and 27, respectively. In Menoufia Governorate, AbouEl-Ella et al. (2018) found that skeletal anomalies and cleft palate/lip were 48 and 6%, respectively, whereas in Alexandria, Abdou et al. (2019) reported that musculoskeletal abnormalities were 32.9% and other anomalies were 4.2%, which may include orofacial clefting.

This review has shown that the pleiotropic effects of genes participating in limb and oral structure development may explain the simultaneous malformations occurring during the embryonic period. Despite the large number of publications concerning limb anomalies in association with orodental abnormalities, new findings are still noticed which could help in determining the stereotype of the syndrome and delineate its phenotypic spectrum. Genotype/phenotype correlation is not yet well defined in most of the mentioned syndromes, especially craniofacial descriptions, which need further studies. Some syndromes remain very rare worldwide; thus, reaching the correct diagnosis in combination with orodental descriptions is a scientific precedent. The conjunction of clinical and orodental examination is of ultimate importance for the diagnostic accuracy and the genetic counseling. Although, oro-dental anomalies are associated with many syndromes, the oro-dental geneticists are few in number, and this domain is still not well propagated worldwide. The pathogenesis of various oral and dental developmental abnormalities, as well as their causative genes remains mostly unknown.[95]

Acknowledgements

Nehal F. Hassib contributed in collection of data, writing of the manuscript, and manuscript submission; Eman A. AbulEzz contributed in revision of the orodental part; Magda Ramzy contributed in editing of the manuscript; Tarek El-Badry contributed in editing of the manuscript; Mona S. Aglan contributed in correcting the clinical part of the manuscript; and Samia A. Temtamy contributed in revision and editing of the whole manuscript and providing many of the reference list.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Abdalla E (2016). Nager syndrome: report of clinical and radiological findings in an Egyptian infant. J Genet Syndr uoJ Gene Ther 7:1-2.  Back to cited text no. 1
    
2.
AbdelKader M (2015). Evaluation of two different treatment modalities restoring missing anterior teeth in Ellis van Creveld syndrome [doctorate thesis]. Prosthodontic Department, Azhar University, Cairo, Egypt  Back to cited text no. 2
    
3.
Abdou MSM, Sherif AAR, Wahdan IMH, Ashour KSED (2019). Pattern and risk factors of congenital anomalies in a Pediatric University Hospital, Alexandria, Egypt. J Egypt Public Health Assoc 94:3.  Back to cited text no. 3
    
4.
AbouEl-Ella SS, Tawfik MA, Abo El-Fotoh WMM, Elbadawi MA (2018). Study of congenital malformations in infants and children in Menoufia governorate, Egypt. Egypt J Med Hum Genet 19:359-365.  Back to cited text no. 4
    
5.
Abulezz T, Talaat M, Elsani A, Allam K (2016). Congenital hand anomalies in Upper Egypt. Indian J Plast Surg 49:206-213.  Back to cited text no. 5
    
6.
Adyanthaya A, Adyanthaya S (2015). Oral-facial-digital syndrome type 1: a review. Bangladesh J Med Sci 14:130–134.  Back to cited text no. 6
    
7.
Afifi H, Abdel-Salam G, Eid M, Tosson A, Shousha W, Abdel Azeem A, et al. (2016). Expanding the mutation and clinical spectrum of Roberts syndrome. Congenit Anom (Kyoto) 56:154–162.  Back to cited text no. 7
    
8.
Aglan M, Abdel-Hamid M, Ismail S, Temtamy SA (2014). A report of another Egyptian patient with Temtamy preaxial brachydactyly syndrome associated with a novel nonsense CHSY1 mutation. Middle East J Med Genet 3:37-41.  Back to cited text no. 8
    
9.
Aglan M, Amr K, Ismail S, Ashour A, Otaify G, Mehrez M, et al. (2015). Clinical and molecular characterization of seven Egyptian families with autosomal recessive robinow syndrome: identification of four novel ROR2 gene mutations. Am J Med Genet Part A 167:3054-3061.  Back to cited text no. 9
    
10.
Ahmed A, Mufeed A, Ramachamparambathu A, Hasoon U (2016). Identifying Aarskog syndrome. J Clin Diagn Res 10:11–13.  Back to cited text no. 10
    
11.
Alisch F, Weichert A, Kalache K, Paradiso V, Longardt A, Dame C, et al. (2016). Familial Gordon syndrome associated with a PI E ZO2 mutation. Am J Med Genet Part A 173A: 254–259.  Back to cited text no. 11
    
12.
Aminabadi NA, Pourkazemi M, Oskouei SG, Jamali Z (2010). Dental management of oculodentodigital dysplasia: a case report. J Oral Sci 52:337-342.  Back to cited text no. 12
    
13.
Ashour A, El-Badry T (2004). Comparison between isolated ectrodactyly and split hand/foot as a part of syndromes: clinical and orodental studies. Egypt J Med Hum Genet 5:79-96.  Back to cited text no. 13
    
14.
Badiner N, Taylor SP, Forlenza K, Lachmand RS, Bamshade M, Nickersone D, et al. (2017). Mutations in DYNC2H1, the cytoplasmic dynein 2, heavy chain 1 motor protein gene, cause short-rib polydactyly type I, Saldino–Noonan type. Clin Genet 92:158-165.  Back to cited text no. 14
    
15.
Beighton P, Giedion A, Gorlin R, Hall J, Horton B, Kozlowski K, Spranger J (1992). International classification of Osteochondrodysplasias. Am J Med Genet 44:223–229.  Back to cited text no. 15
    
16.
Beiraghi S, Leon-Salazar V, Larson BE, John MT, Cunningham ML, Petryk A, Lohr JL (2011). Craniofacial and intraoral phenotype of Robinow syndrome forms. Clin Genet 80:15–24.  Back to cited text no. 16
    
17.
Bollero P, Arcuri L, Miranda M, Ottria L, Franco R, Barlattani JRA (2017). Marfan syndrome: oral implication and management. Oral Implantol 10:87.  Back to cited text no. 17
    
18.
Canabarro A, Galheigo TM, Galheigo de Oliveira e Silva D, Tinoco EMB (2008). Periodontal findings and other oral manifestations in Proteus syndrome: a case report. Quintessence Int (Berlin, Germany: 1985) 39:307–311.  Back to cited text no. 18
    
19.
Candamourty R, Venkatachalam S, Karthikeyan B, Ramesh Babu MR (2012). Trichorhinophalangeal syndrome type 1: a case report with literature review. J Nat Sci Biol Med 3:209-211.  Back to cited text no. 19
    
20.
Cho KY, Kelley BP, Monier D, Lee B, Szabo-Rogers H, Napierala D (2019). TRPS1 regulates development of craniofacial skeleton and is required for the initiation of palatal shelves fusion. Front Physiol 10(MAY):1-12.  Back to cited text no. 20
    
21.
Choochuen P, Rojneuangnit K, Khetkham T, Khositseth S (2018). The first report of multicentric carpotarsal osteolysis syndrome caused by MAFB mutation in Asian. Case Rep Med 2018(Article ID 6783957):1–4.  Back to cited text no. 21
    
22.
Corbani S, Chouery E, Eid B, Jalkh N, Abou Ghoch J, Mégarbané A (2011). Mild campomelic dysplasia: report on a case and review. Mol Syndromol 1:163-168.  Back to cited text no. 22
    
23.
Deshpande AS, Goudy SL (2019). Cellular and molecular mechanisms of cleft palate development. Laryngoscope Investig Otolaryngol 4:160–164.  Back to cited text no. 23
    
24.
Feldkamp ML, Carey JC, Byrne JLB, Krikov S, Botto LD (2017). Etiology and clinical presentation of birth defects: population based study. BMJ 357:1-8.  Back to cited text no. 24
    
25.
Gunashekhar M, Hameed MS, Bokhari SK (2012). Oral and dental manifestations in Rubinstein-Taybi syndrome: report of a rare case. Primary Dental Care J Facult General Dent Pract 19:35–38.  Back to cited text no. 25
    
26.
Hassib N, Abdel-Kader M, Abul-Ezz E, Aglan M, Temtamy SA (2019). A report of four patients with Moebius syndrome: new oral anomalies and challenges in dental management. Middle East JMed Genet 8:90-95.  Back to cited text no. 26
    
27.
Hejlesen J, Underbjerg L, Gjørup H, Bloch-Zupan A, Rejnmark L, Haubek D (2018). Dental findings in patients with non-surgical hypoparathyroidism and pseudohypoparathyroidism: a systematic review. Front Physiol 9:1–15.  Back to cited text no. 27
    
28.
Hettiaracchchi D, Bonnard C, Jayawardana S, Jin Ng A, Tohari S, Venkatesh B, et al. (2018). Cenani-Lenz syndactyly syndrome – a case report of a family with isolated syndactyly. BMC Med Genet 19:1–4.  Back to cited text no. 28
    
29.
Hirai N, Matsune K, Ohashi H (2011). Craniofacial and oral features of Sotos syndrome: differences in patients with submicroscopic deletion and mutation of NSD1 gene. Am J Med Genet Part A 155:2933–2939.  Back to cited text no. 29
    
30.
Hoyer J, Ekici A, Endele S, Popp B, Zweier C, Wiesener A, et al. (2012). Haploinsufficiency of ARID1B, a member of the SWI/SNF-A chromatin-remodeling complex, is a frequent cause of intellectual disability. Am J Hum Genet 90:565–572.  Back to cited text no. 30
    
31.
Ismail S, Essawi M, Sedky N, Hassan H, Fayez A, Helmy N (2016). Roberts syndrome: Clinical and cytogenetic studies in 8 Egyptian patients and molecular studies in 4 patients with genotype/phenotype correlation. Genet Couns 27:305–323.  Back to cited text no. 31
    
32.
Ismail S, Fayez A, Otaify G, Sayed I, El-Ruby M, Aglan M, Temtamy S (2017). Nager acrofacial dysostosis with a novel mutation in SF3B4 and developmental retardation in an Egyptian child. Middle East J Med Genet 6:82–87.  Back to cited text no. 32
    
33.
Jin L, Wu J, Bellusci S, Zhang JS (2019). Fibroblast growth factor 10 and vertebrate limb development. Front Genet 10(JAN):1-9.  Back to cited text no. 33
    
34.
Johns DA (2013). Case report Freeman-Sheldon syndrome: a dental perspective. J Indian Soc Pedodont Prev Dent 31:2–5.  Back to cited text no. 34
    
35.
Kalay E, Sezgin O, Chelappa V, Mutlu M, Morsy H, Kayser H, et al. (2012). Mutations in RIPK4 cause the autosomal-recessive form of popliteal pterygium syndrome. American J Hum Genet 90:76–85. doi: 10.1016/j.ajhg. 2011.11.014  Back to cited text no. 35
    
36.
Kantaputra PN, Carlson BM (2019). Genetic regulatory pathways of split-hand/foot malformation. Clin Genet 95:132–139.  Back to cited text no. 36
    
37.
Koçak H, Ceylaner G (2009). Frontonasal dysplasia: a family presenting autosomal dominant inheritance pattern. Genet Counseling (Geneva, Switzerland) 20:63–68.  Back to cited text no. 37
    
38.
Koul M, Dwivedi R, Upadhyay V (2014). Ectrodactyly-ectodermal dysplasia clefting syndrome (EEC syndrome). J Oral Biol Craniofac Res 4:135–139.  Back to cited text no. 38
    
39.
Kurdi AM, Majeed-Saidan MA (2015). World birth defects day: towards a national registry for birth defects in Saudi Arabia. Saudi Med J 36:143–145.  Back to cited text no. 39
    
40.
Laccone F, Schoner K, Krabichler B, Kluge B, Schwerdtfeger R, Schulze B, et al. (2011) Desbuquois dysplasia type i and fetal hydrops due to novel mutations in the CANT1 gene. Eur J Hum Genet 19:1133–1137.  Back to cited text no. 40
    
41.
Leanza V, Rubbino G, Leanza G (2014). Atypical Cornelia de Lange syndrome: a case report [v1, ref status: approved with reservations 2, http://f1000r.es/xo]. F1000Res 3:1–8.  Back to cited text no. 41
    
42.
Marina K, Ayers S, Drummond BK (2003). Contractural arachnodactyly: a case report. Pediatr Dent 25:501–504.  Back to cited text no. 42
    
43.
Martelli H, Martelli H, Miranda R, Fernandess C, Bonan P, Paranaiba L, et al. (2010). Goldenhar syndrome: clinical features with orofacial emphasis, J Appl Oral Sci 18:646–649.  Back to cited text no. 43
    
44.
Meguid NA, Temtamy SA, Afifi HH, Aboul-Ezz EHA (1995). Clinical Variability and Chromosomal aberrations in EEC syndrome. Egypt J Pediatr 12:315-324.  Back to cited text no. 44
    
45.
Mehrez MI, Temtamy SA, El Dessouky S, El-Badry T, Aglan M (2010). Radiographic evaluation of orodental and craniofacial anomalies associated with limb reduction defects. J Appl Sci Res 6:1340-1345.  Back to cited text no. 45
    
46.
Mohammed YA, Shawky RM, Soliman AAS, Ahmed MM (2011). Chromosomal study in newborn infants with congenital anomalies in Assiut University hospital: cross-sectional study. Egypt J Med Hum Genet 12:79-90.  Back to cited text no. 46
    
47.
Mortier GR, Cohn DH, Cormier-Daire V, Hall C, Krakow D, Mundlos S, et al. (2019). Nosology and classification of genetic skeletal disorders: revision. Am J Med Genet Part A 179:2393-2419.  Back to cited text no. 47
    
48.
Mossaad AM, Abdelrahman MA, Ibrahim MA, Al Ahmady HH (2018). Surgical management of facial features of robinow syndrome: a case report. Open Access Maced J Med Sci 6:536-539.  Back to cited text no. 48
    
49.
Mostafa MI, Temtamy SA, El-Gammal MA, Mazen IM (2005). Unusual pattern of inheritance and orodental changes in the Ellis-Van Creveld syndrome. Genet Couns 16:75–83.  Back to cited text no. 49
    
50.
Mundlos S, Horn D (2014). Limb Malformations: An Atlas of Genetic Disorders of Limb Development. 4th ed.. Heidelberg; New York, NY; Dordrecht; London: Springer.  Back to cited text no. 50
    
51.
Murthy J, Babu R, Ramanan P (2008). Radial, renal and craniofacial anomalies: Baller-Gerold syndrome. Indian J Plast Surg 41:76–78.  Back to cited text no. 51
    
52.
Naseh A, Hafizi A, Malek F, Mozdarani H, Yassaee V (2012). TAR syndrome, a rare case report with cleft lip/palate. Internet J Pediatr Neonatol 14:1–7.  Back to cited text no. 52
    
53.
Nathwani S, Martin K, Bunyan R (2018). Focal dermal hypoplasia: a novel fi nding in disguise. J Oral Biol Craniofacial Res 8:143-146.  Back to cited text no. 53
    
54.
Olczak-Kowalczyk D, Krasuska-Slawińska E, Rokicki D, Pronicki M (2011). Case report: Infantile systemic hyalinosis: a dental perspective. Eur Arch Paediatr Dent 12:224–226.  Back to cited text no. 54
    
55.
Pelc A, Mikulewicz M (2018). Saethre-chotzen syndrome: case report and literature review. Dent Med Prob 55:217–225.  Back to cited text no. 55
    
56.
Richmond S, Howe LJ, Lewis S, Stergiakouli E, Zhurov A (2018). Facial genetics: a brief overview. Front Genet 9(OCT):1-21.  Back to cited text no. 56
    
57.
Robertson SP (2007). Otopalatodigital syndrome spectrum disorders: Otopalatodigital syndrome types 1 and 2, frontometaphyseal dysplasia and Melnick-Needles syndrome. Eur J Hum Genet 15:3–9.  Back to cited text no. 57
    
58.
Sagai T, Amano T, Maeno A, Kiyonari H, Seo H, Cho S, Shiroishi T (2017). SHH signaling directed by two oral epithelium-specific enhancers controls tooth and oral development. Sci Rep 7:1-11.  Back to cited text no. 58
    
59.
Samuel SS, Shetty S, Arunachal G, Koshy S, Paul TV (2016). Hajdu cheney syndrome. J Clin Diagn Res 10:OD07–OD09.  Back to cited text no. 59
    
60.
Schweitzer DN, Lachman RS, Pressman BD, Graham JM (2003). van den Ende–Gupta syndrome of blepharophimosis, arachnodactyly, and congenital contractures: Clinical delineation and recurrence in brothers. Am J Med Genet 118A: 267–273.  Back to cited text no. 60
    
61.
Seo H, Amano T, Sekia R, Sagai T, Kim J, Cho S, Shiroichi T (2018). Upstream enhancer elements of SHH regulate oral and dental patterning. J Dent Res 97:1055-1063.  Back to cited text no. 61
    
62.
Shawky RM (2015). Moebius syndrome with macular hyperpigmentation , skeletal anomalies, and hypoplasia of pectoralis major muscle in an Egyptian child. Egypt J Med Hum Genet 16:277-281.  Back to cited text no. 62
    
63.
Shawky R, Hala M, Salem M (2010a). Genetic study of congenital limb anomalies among Egyptian children. Egypt J Med Hum Genet 11:47–57.  Back to cited text no. 63
    
64.
Shawky RM, Sadik DI, Seifeldin NS (2010b). Ellis-van Creveld syndrome with facial dysmorphic features in an Egyptian child. Egypt J Med Hum Genet 11:181-185.  Back to cited text no. 64
    
65.
Shawky RM, Sadik DI (2011). Congenital malformations prevalent among Egyptian children and associated risk factors. Egypt J Med Hum Genet 12:69–78.  Back to cited text no. 65
    
66.
Shawky RM, Elsayed NS, Seifeldin NS (2012). Facial dysmorphism, skeletal anomalies, congenital glucoma, dysplastic nails: Mild Rubinstein-Taybi Syndrome. Egypt J Med Hum Genet 13:233–237.  Back to cited text no. 66
    
67.
Shawky RM, Elsayed SM, Abd-Elkhalek HS, Gad S (2013). Oral-facial-digital syndrome type II: Transitional type between Mohr and Varadi. Egypt J Med Hum Genet 14:311-315.  Back to cited text no. 67
    
68.
Shawky RM, Elabd HSAE, Gad S, Gamal R, Mohammad SA (2014). Oral-facial-digital syndrome type VI with self mutilations. Egypt J Med Hum Genet 15:399-403.  Back to cited text no. 68
    
69.
Shetty DC, Singh HP, Kumar P, Verma C (2012). Report of two siblings with overlapping features of Ellis-van Creveld and Weyers Acrodental Dysostosis. J Clin Imaging Sci 2:18.  Back to cited text no. 69
    
70.
Shi Y, Zhang B, Kong F, Li X (2018). Prenatal limb defects. Medicine (Baltimore) 97:e11471.  Back to cited text no. 70
    
71.
Silengo M, Tornetta L (2000). Juberg-Haywars syndrome: report of a case with cleft palate, distally placed thumbs and vertebral anomalies. Clin dys 9:127-129.  Back to cited text no. 71
    
72.
Şoancă A, Dudea D, Gocan H, Roman A, Culic B (2010). Oral manifestations in Apert syndrome: Case presentation and a brief review of the literature. Rom J Morphol Embryol 51:581–584.  Back to cited text no. 72
    
73.
Sreenivasan P, Peedikayil FC, Raj SV, Meundi MA, Report C (2013). Case report trismus pseudocamptodactyly syndrome: a sporadic cause of trismus. Case Rep Dent 2013:3–6.  Back to cited text no. 73
    
74.
Sun L, Huang Y, Zhao S, Zhong W, Lin M, Guo Y, et al. (2019). Advances in understanding the genetics of syndromes involving congenital upper limb anomalies. Ann Jt 4:30-30.  Back to cited text no. 74
    
75.
Talebi F, Mardasi FG, Asl JM, Bavarsad AH, Tizno S (2017). Identification of a novel missence mutation in FGFR3 gene in an Iranian family with LADD syndrome by Next-Generation Sequencing. Int J Pediatr Otorhinolaryngol 97:192–197.  Back to cited text no. 75
    
76.
Tayel SM, Fawzia MM, Niran AAN, Said G, Al Awadi SA, Naguib KK (2005). A morpho-etiological description of congenital limb anomalies. Ann Saudi Med 25:219-227.  Back to cited text no. 76
    
77.
Temtamy SA (1966), Genetic factors in hand malformations [PhD thesis]. Johns Hopkins University, Baltimore  Back to cited text no. 77
    
78.
Temtamy SA, McKusick VA (1969). Synopsis of hand malformation with particular emphasis on genetic factors. Birth Defects Orig Art Ser 5:125-184.  Back to cited text no. 78
    
79.
Temtamy SA, McKusick VA (1978). The genetics of hand malformations. Birth Defects Orig Artic Ser 14:i–xviii.  Back to cited text no. 79
    
80.
Temtamy SA, Nassar AM, Ismail SR, Aboul-Ezz EH (1989) Orodental & ultrasturctural studies of pulp & gingiva in the Marfan syndrome. Bull NRC Egypt 13:264–273.  Back to cited text no. 80
    
81.
Temtamy SA, Salam SA, A M, Zaki M, Meguid NA, Aboul-Ezz E (1990). Rubinstein-Taybi syndrome in Egyptians. J Med Res Inst 11:55-72.  Back to cited text no. 81
    
82.
Temtamy SA, Abdel Meguid N, Mazen I, Ismail SR, Kassem NS, Bassiouni RA (1998a). genetic epidemiological study of malformations at birth in Egypt. Eastern Mediterranean Health J 4:252-259.  Back to cited text no. 82
    
83.
Temtamy SA, Meguid NA, Ismail S, Ramzy MI (1998b) a new multiple congenital anomaly, MR, preaxial brachidactyly, hyperphalangism, deafness and orodental.pdf. Clin Dysmorphol 7:249–255.  Back to cited text no. 83
    
84.
Temtamy SA, El-Ruby MO, Nemat AH (2003a). Phenotypic variations versus genetic differences in the oral-facial-digital syndromes Egypt. J Med Hum Genet 4:79-96.  Back to cited text no. 84
    
85.
Temtamy SA, Ismail S, Neamat A (2003b) Mild facial dyspmorphism and qausidominant in heritance in Cenani-Lenz Syndrome. Clin Dysmorphol 12:77–85.  Back to cited text no. 85
    
86.
Temtamy SA, Aglan MS, Neamat AH, Eid M (2003c). Expanding the phenotypic spectrum of the Baller-Gerold syndrome. Genet Couns 14:299-312.  Back to cited text no. 86
    
87.
Temtamy S, Aglan M, Ashour A, El Badry T, Helmy N (2004a). Genetic studies of congenital contractures of limbs. Egypt J Med Hum Genet 5:1-58.  Back to cited text no. 87
    
88.
Temtamy SA, El-Badry T, Abul-Ezz E (2004b) Clinical, Orodental and electron microscopic changes of gingival biopsy in autosomal recessive Robinow syndrome suggest a storage disorder and a midline developmental field defect. Egypt Med J Nat Res Centre 5:149–163.  Back to cited text no. 88
    
89.
Temtamy SA, Ismail S, Shelmy NA (2006). Roberts syndrome: study of 4 new Rgyptian cases with comparison of clinical and cytogenetic findings. Genet Couns 17:1-13.  Back to cited text no. 89
    
90.
Temtamy S, Aglan M, Topaluglu AK, Wollnik B, Amr K, El Badry TH, et al. (2012) Definition of the phenotypic spectrum of Temtamy preaxial brachydactyly syndrome associated with autosomal recessive CHYS1 mutations. Middle East J Med Genet :64-70.  Back to cited text no. 90
    
91.
Trippella G, Lionetti P, Naldini S, Peluso F, Monica M Della, Stagi S (2018) An early diagnosis of trichorhinophalangeal syndrome type 1: a case report and a review of literature. Ital J Pediatr 44:138.  Back to cited text no. 91
    
92.
Van Bokhoven H, Jung M, Smits A, van Beersum S, Schendorf F, van Steense M, et al. (1999). Limb mammary syndrome: a new genetic disorder with mammary hypoplasia, ectrodactyly, and other hand/foot anomalies maps to human chromosome 3q27. Am J Hum Genet 64:538–546.  Back to cited text no. 92
    
93.
Varal IG, Dogan P (2019) Hanhart syndrome: hypoglossia-hypodactylia syndrome, Pan Afr Med J 32:213.  Back to cited text no. 93
    
94.
Winter R, Baraitser M (2014). London Medical DataBase, Oxford University Press, UK  Back to cited text no. 94
    
95.
Zuniga A, Zeller R, Probst S (2012) The molecular basis of human congenital limb malformations. Wiley Interdiscipl Rev 1:803–822.  Back to cited text no. 95
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

Top
 
  Search
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
Abstract
Background
Role of Molecula...
Nosology and Cla...
Orodental Abnorm...
Egyptian Experie...
References
Article Tables

 Article Access Statistics
    Viewed1177    
    Printed106    
    Emailed0    
    PDF Downloaded103    
    Comments [Add]    

Recommend this journal