Original Article

Clinical aspects associated with syndromic forms of Orofacial Clefts in a Colombian population

Aspectos Clínicos asociados a Fisuras Orofaciales en una población Colombiana

Liliana Arias Urueña¹, Ignacio Briceño Balcazar², Julio Martinez Lozano³, Andrew Collins⁴, Daniel Alfredo Uricoechea Patiño⁵

¹ Medical School. Universidad de La Sabana, Bogota, Colombia
² Pontificia Universidad Javeriana. Bogota, Colombia
³ Genetic Epidemiology and Bioinformatics. University of Southampton. Southampton, UK

Arias UL, Briceño BI, Martinez LJ, Collins A, Uricoechea PDA. Clinical Aspects associated with Syndromic forms of Orofacial Clefts in a Colombian population. Colomb Med (Cali). 2015; 46(4): 162-67.

© 2015. Universidad del Valle. This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Article history:

Received: 03 October 2015 - Revised: 10 November 2015 - Accepted:14 December 2015

Corresponding author:

Liliana Arias: Facultad de Medicina Universidad de La Sabana. Campus del Puente del Común, Km. 7, autopista Norte de Bogotá. Chía, Cundinamarca, Colombia. Phone: +5 71 8616666. Ext 23013 E-mail: liliana.arias2@unisabana.edu.co.

---

Abstract

Objectives: To present descriptive epidemiology of Orofacial Clefts and to determine the association of syndromic forms with antenatal high-risk conditions, preterm birth, and comorbidities among nested-series of cases.
Methods: A study of nested-series of cases was conducted. Frequencies of cleft type, associated congenital anomalies, syndromic, non-syndromic and multiple malformation forms, and distribution of Orofacial Clefts according to sex and affected-side were determined. Odds ratios were calculated as measures of association between syndromic forms and antenatal high-risk conditions, preterm birth and comorbidities. A total of three hundred and eleven patients with Orofacial Clefts were assessed in a 12-month period.
Results: The most frequent type of Orofacial Clefts was cleft lip and palate, this type of cleft was more frequent in males, whereas cleft palate occurred more often in females. The most common cases occurred as non-syndromic forms. Aarskog-Scott syndrome showed the highest frequency amongst syndromic forms. Hypertensive disorders in pregnancy, developmental dysplasia of the hip, central nervous diseases and respiratory failure showed significant statistical associations (p <0.05) with syndromic forms.
Conclusions: These data provide an epidemiological reference of Orofacial Clefts in Colombia. Novel associations between syndromic forms and clinical variables are determined. In order to investigate causality relationships between these variables further studies must be carried out.

Keywords:

Cleft lip and palate, pre-eclampsia, aarskog-scott syndrome, congenital hip dysplasia.

---

Resumen

Objetivos: Presentar la epidemiología descriptiva en torno a las Fisuras Orofaciales y determinar asociaciones entre Fisuras Orofaciales sindromica y antecedentes antenatales de alto riesgo, parto pretérmino, y comorbilidades en una población Colombiana.
Métodos: Se planteó un estudio de serie de casos anidado estratificado. Se calcularon frecuencias en relación al tipo de fisura desde el punto de vista anatómico, anomalías congénitas paralelas, morbilidades y forma clínica. Se analizó la distribución de las Fisuras Orofaciales de acuerdo al género y lateralidad. Se determinaron razones de disparidad entre la forma sindrómica y antecedentes antenatales de alto riesgo, parto pretérmino, y comorbilidades. Se evaluaron trecientos once pacientes que asistieron a la consulta de genética clinica durante un año.
Resultados: La Fisura Labio-palatina fue el tipo más frecuente en la muestra evaluada y la más frecuente en hombres. La Fisura Palatina fué la más frecuente en mujeres, la forma clínica más común fue la no sindrómica. En la población sindrómica el Síndrome de Aarskog-Scott mostró la frecuencia más alta. Los trastornos Hipertensivos de Embarazo, la Displasia del Desarrollo de la Cadera, las enfermedades respiratorias y del sistema nervioso central mostraron una asociación estadísticamente significativa con la forma sindrómica. (p <0.05).
Conclusiones: Estos datos ofrecen una referencia epidemiológica descriptiva de las Fisuras Orofaciales en Colombia. Las asociaciones encontradas entre los aspectos clínicos estudiados y la forma sindrómica, deben ser investigadas en próximos estudios con el fin de determinar relaciones de causalidad.

Palabras clave:

Labio hendido, fisura del paladar, preeclampsia, síndrome de Aarskog-scott, luxacion congénita de la cadera.

---

Introduction

Orofacial clefts (OFC) represent one of the most common birth defects, occurring frequently in Asians and Amerindians^1-3. Affected subjects tend to have language and hearing problems and difficulty in social integration, therefore multidisciplinary care is required in order to improve health status⁴.

Based on their association with specific malformative patterns or their presence as isolated defects, OFCs can be classified as syndromic (SF) and nonsyndromic form (NSF), respectively⁵. Approximately 30% of cases of Cleft Lip and Palate (CLP) occur as SF^6,7. Patients affected by SF tend to have higher morbidity and mortality throughout life due to their associated congenital anomalies⁴. Given the complex etiology and pathogenesis of these anomalies, patients need genetic assessment to establish an accurate diagnosis and appropriate risk management⁸.

The prevalence of OFCs depends largely on factors such as ethnicity and geographic region⁹. Frequently, facial clefts are associated with other congenital defects^4,10. The study of past medical and family history and associated anomalies is useful in understanding inheritance patterns, risk factors and in providing public health strategies⁸.

No research in Colombia has addressed a complete descriptive epidemiology of OFC or the relationship of OFC with some clinical aspects^11,12, therefore providing epidemiological information is a research priority area. The current study was designed to: 1) present the frequency of cleft type, associated congenital anomalies, syndromic, non-syndromic and multiple malformation forms; 2) determinate associations between syndromic forms and antenatal high- risk conditions, preterm birth and comorbidities.

Materials and Methods

Subjects

Three hundred and eleven individuals with Orofacial Clefts aged between 3 weeks and 52 yrs who attended at Operation Smile Colombia from April 2012 to July 2013 were assessed by Medical Genetics Team at Operation Smile Colombia. A recruiting was not performed. The whole population was included in this study. Sampling was not carried out. 168 (52%) were males, 149 (48%) were females. Distribution by age is shown in Table 1. Ethical principles for medical research involving human subjects, as outlined in the declaration of Helsinki were followed. Universidad de La Sabana ethical committee approved the study protocol.

Table 1. Sex, age and region of origin (N= 311).

Variable		n	%
Sex	Male	168	54
	Female	149	48
Age Range (yrs)	<1 m	7	2
	<1	105	34
	2-5	41	13
	6-11	50	16
	12-17	58	19
	≥18	50	16
Origin area	Rural	137	44
	Urban	174	56
m= month

Procedure

Information about sex, type of cleft, past medical and family history was recorded in children (<18 yrs) and adults (≥18 yrs). In children, maternal, and pediatric history were recorded focusing on antenatal high-risk conditions, the presence or absence of preterm birth, comorbidities and neonatal diseases. Pregnancy dietary supplements and /or folate intakes were not assessed. Preterm birth was defined as delivery at ≤37 weeks gestation. Two trained physicians in clinical genetics performed a physical examination focusing on identifying other congenital anomalies and establishing a clinical diagnosis.

Based on clinical features the patients were classified into 3 categories:

1. Non- syndromic form (NSF): patients affected by isolated OFCs.
2. Syndromic form (SF): patients affected by OFCs and a specific syndrome can be recognized (OMIM).
3. Multiple malformation form (MMF): patients affected by OFCs and other malformations but a specific syndrome cannot be recognized.
4. A whole-exome sequencing was used to resolve clinical diagnoses for some syndromic phenotypes.

Data analysis

Cross tabulation was used to analyze the frequency distribution of the variables (sex, age, region of origin, cleft type, affected-side, clinical form, associate anomalies, morbidities). In order to determinate a measure of association between the occurrences of interest (antenatal high-risk conditions, presence or absence of preterm birth, and comorbidities) and SF of OFC, two cases were defined. Case 1: cases with SF (224). Case 2: cases with NSF (59). Taking into account MMF does not have any specific pattern it was not included in any case group.

Chi-square statistics (x²), Fisher's exact test and odds ratio (OR) calculations were used to determine associations. The frequency of the ocurrences in SF group to NSF group was compared. Results were considered to be significant at p <0.05. All data were analyzed using Epi Info version 7®¹³.

Results

The most common sex, age range and region of origin were male, 1-23 months and urban area respectively (Table 1). The most frequent type of OFC was CLP (69%). Analysis of cleft type by sex showed that CLP was more frequent in males, whereas Cleft Palate (CP) occurred more often in females (Table 2). The majority of CLP cases were left-sided (55.3%). Seventy two percentage of cases occurred as NSF, and 20% had a recognized-syndrome (Table 3). The most frequently identified syndromes were Aarskog-Scott and Velocardiofacial (Table 4). Among the 288 (92.6%) of patients who had an additional congenital defect, musculoskeletal, cardiovascular, urogenital and nervous systems were the most common types (Table 3). Among children 79.0% showed at least 1 morbidity (Table 3).

Table 2. Cleft type distribution according to sex. Sex, age and region of origin (N= 311).

Variable	Female	Male	Total
CL	13	7	20
CL±A	4	4	8
CLP	91	125	216
CP±A	1	3	4
CP	41	22	63
TOTAL	150	161	311
CL= cleft lip; CL±A= cleft lip with or without cleft alveolus; CLP= cleft lip and palate; CP±A= cleft palate with or without cleft alveolus; CP= cleft palate

Table 3. Frequency of clinical forms, congenital anomalies with orofacial clefts and morbidities in children and adults.

Variables		n	%
Clinical forms	MMF	28	9.0
	NSF	224	72.0
	SF	59	19.0
	Total	311
Birth according to clinical form in children
Term birth	MMF	21	11.0
	NSF	137	70.0
	SF	37	19.0
	Total	195
Preterm birth
	MMF	3	4.0
	NSF	48	73.0
	SF	15	23.0
	Total	66
Morbidities
Children (<18 yrs)	0	40	80.0
	1	5	10.0
	2	5	10.0
	≥3	0
	Total	50
Adults (≥18 yrs)
	0	141	54.0
	1	65	25.0
	2	38	14.6
	≥3	17	6.4
	Total	261
Associated congenital anomalies with OFCs
System or organ
	Nervous	27	8.7
	Eye	10	3.2
	Cardiovascular	28	9.0
	Urogenital	27	8.7
	Musculoskeletal	160	51.4
	Oral Cavity	12	3.9
	Intergument	24	7.7
	No	23	7.4
	Total	311
*Birth history was asked among pediatric population. Birth history is not included within Adult Medical History. Adults were not included in this analysis. Multiple malformation form; NSF= Non-syndromic form; SF= Syndromic form

Table 4. Frequency of syndromes associated to orofacial clefts.

Code	Mendelian Inheritance in Man	n	%
305400	Aarskog-Scott	10	17.0
101200	Apert	1	1.7
601701	Arthrogryposis and Ectodermal Dysplasia	1	1.7
123500	Crouzon	1	1.7
305100	Ectodermal Dysplasia and Hypohidrotic 1	3	5.1
129900	Ectrodactily, Ectodermal Dysplasia and Cleft Lip Palate 1	1	1.7
129830	Ectrodactyly Cleft Palate	1	1.7
-	Fetal Alcohol	1	1.7
164210	Hemifacial Microsomia	1	1.7
601471	Heriditary Congenital Facial Paresis 1	1	1.7
142900	Holt-Oram	1	1.7
300337	Hypomelanosis of Ito	1	1.7
-	Klinefelter	1	1.7
154700	Marfan	2	3.4
163950	Noonan	1	1.7
6002510	Oblique Facial Clefting 1	1	1.7
311200	Orofaciodigital 1	3	5.1
133900	Orofaciodigital 5	1	1.7
304120	Otopalatodigital 2	2	3.4
261800	Pierre Robin	5	8.4
119500	Popliteal Pterygyum	2	3.4
106600	Selective Tooth Agenesis 1	1	1.7
117550	Sotos	2	3.4
-	Turner Syndrome	1	1.7
192350	VACTERL association	1	1.7
119300	Van der Woude 1	3	5.1
192430	Velocardiofacial	10	17.0
	Total	59
Code= from OMIM, Catalog of Human Genes and Genetic Disorders

The distribution of preterm birth was similar among MMF, SF and NSF populations (Table 5). The only antenatal high-risk condition that showed significant statistical association with SF was the spectrum of Hypertensive Disorders in Pregnancy (p= 0.05). Preterm birth did not show significant statistical association with SF (p= 0.67). Heart diseases, respiratory failure, seizures, and developmental dysplasia of the hip had significant statistical associations with SF (p= 0.000, p= 0.0005, p= 0.002, 0.0006, respectively) (Table 5).

Table 5. Association of SF and NSF with antenatal high-risk conditions in Children and comorbidities among children and adults.

Variables		SF	NSF
		n	n	Total	OR	p
Antenatal risk
Preterm Labor	Yes	1	1	2
	No	48	184	232	3.8	0.3700
Oligohydramnios	Yes	1	6	7
	No	48	179	227	0.6	1.0000
HDP	Yes	7	11	18
	No	42	174	216	2.6	0.0500
Bleeding (unknown cause)	Yes	1	5	6
	No	48	180	228	0.7	1.0000
FGR	Yes	1	6	7
	No	48	179	227	0.6	1.0000
Fetal distress	Yes	1	1	2
	No	48	184	232	3.8	0.3700
PPRM	Yes	1	2	3
	No	48	183	231	1.9	0.5000
Comorbidities
Respiratory infectious	Yes	10	26	36
	No	39	159	198	1.6	0.3000
Gastrointestinal Tract diseases	Yes	7	13	30
	No	42	172	214	2.2	0.1000
Heart diseases	Yes	14	2	16
	No	35	183	218	36.7	0.0000
DDH	Yes	6	3	9
	No	43	182	225	8.5	0.0006
Respiratory Failure	Yes	7	7	14
	No	42	178	220	4.2	0.0005
Diseases of the Newborn	Yes	6	16	22
	No	43	169	212	1.5	0.4400
Ophthalmopathy	Yes	3	4	7
	No	46	181	227	2.95	0.1500
CMO	Yes	4	27	31
	No	45	158	203	0.5	0.2300
Seizures	Yes	8	5	13
	No	41	180	221	7.0	0.0020
Kidney and urinary tract diseases	Yes	2	2	4
	No	47	183	230	3.9	0.1500
SF= syndromic form; NSF= nonsyndromic form; HDP= Hypertensive Disorders in Pregnancy; FGR= Fetal growth restriction; PPRM= Preterm premature rupture of membrane; DDH= developmental dysplasia of the hip; OR= odds ratio

Discussion

The present work is the first complete epidemiological descriptive study about Orofacial Clefts in Colombia^11,12,14. Our results are consistent with previously published studies of the distribution of OFC according to sex, affected-side and cleft type^6,7,15-17.

Aarskog-Scott syndrome (AAS) shows the highest frequency among SF. This observation differs from previously published papers, which reported Van der Woude Syndrome (VDW) as the most common^6,7,18. Aarskog-Scott syndrome is an X-linked condition caused by mutations of the FGD1 gene. It is a clinically and genetically heterogeneous condition characterized by facial dysmorphic features, short stature, brachydactyly, and genital anomalies^19,20. Although clinical manifestations and diagnostic criteria are well established, diagnosis is not simple, due to the extremely variable spectrum of phenotypical features^21,22. It is probable that AAS is being underdiagnosed and for that reason the frequency according to previous studies appears lower. Further studies must be.

However, geographical and ethnic factors of our population should be considered, given that they might influence the distribution of the SF with respect NSF. Research into FGD1 founder mutations might be usefully conducted in future studies.

The musculoskeletal system is the most frequently affected among SF population according to this research. This result is consistent with reported findings by Calzolari²³. This may reflect the impact of a number of genes which play an essential role in the development of connective tissue^4,24.

According to Sekhon²⁵ facial anomalies are the most frequently detected, followed by ocular, central nervous system, lower and upper extremities and cardiovascular. Most of the facial, lower and upper extremities anomalies involve connective tissue. It is important to consider that the published prevalence of associated anomalies vary considerably depending on methodological factors²⁶.

The roles of antenatal high-risk conditions among the SF population have not been well studied. Our work provides the first evidence that there is an association between SF and hypertensive disorders in pregnancy in comparison with NSF (OR= 8.5).

The etiology of SF is related to mutations within several genes involved in mesenchymal and epithelial proliferation, cell adhesion and migration and angiogenesis. All of these are essential for lip and palate development^7,27,28. The disturbance of decidua-trophoblast interactions during early human pregnancy is one of the events implicated into the pathogenesis of hypertensive disorders in pregnancy^29-31. These interactions depend largely on maternal uterine endothelial cells activated by expression of selectins that enable adherence of trophoblast to maternal endothelium^32,33, and epithelial-mesenchymal transition during trophoblast differentiation^34,35. Given the above we propose that common processes may be disrupted in both entities: 1) cell adhesion mechanisms, 2) epithelial-mesenchymal transition, and 3) angiogenesis.

Transforming growth factor-beta 3 (TGF-β3), plays an essential role in these processes, and is known to be involved in the pathogenesis of hypertensive disorders in pregnancy^36-39 and some forms of OFCs^36,40. Therefore, it might be a candidate gene for both disorders. In order to test this hypothesis this gene should be investigated in patients and their mothers affected by SF and preeclampsia respectively. Associations of SF and developmental dysplasia of the hip (DDH) have not been reported in previous papers. The etiology of DDH is multifactorial, but has a considerable genetic component^41,42. Although oligohydramnios is a risk condition associated with DDH, the relationship between SF and oligohydramnios does not show significant statistical association according to this work. The causality relationships underlying this finding must be investigated with regard to the possibility of earlier hip screening among this population.

Desalu⁴³ reported that anatomical abnormalities associated with cleft lip and palate increase the risk of airway complications and this is confirmed by comparing SF and NSF in the current study (OR= 4.2). Clinical features such as micrognathia⁴⁴ and congenital heart diseases are common in SF; these factors might be involved in this association.

Preterm birth and other antenatal high-risk conditions do not show significant statistical association with SF, probably due to limited power given the small set of observations.

The associations found in this study contribute to appropriate medical and risk management of the affected patients. Clinicians can be guided by this study in order to provide comprehensive care for the benefit of these patients and their families. Based on the findings of this work, we are performing molecular diagnosis of the SF cases. Establishing causality relationships between the studied variables is one of the central goals of our future studies.

Conclusions

These data provide an epidemiological reference of Orofacial Clefts in Colombia. Novel associations between syndromic forms and clinical variables are determined. In order to investigate causality relationships between these variables further studies must be carried out.

Acknowledgments:

We thank all patients involved in this study, Operation Smile Colombia for offering the set of research and epidemiologists for their input and advice throughout this review.

Conflict of interest:

We certify that there is no conflict of interest with any financial organization regarding the material discussed in the paper.

Funding:

This research was supported by Joven Investigador Colciencias Scholarship Call: 525-2011.

---

References

1. Vanderas AP. Incidence of cleft lip, cleft palate, and cleft lip and palate among races: a review. Cleft Palate J. 1987; 24(3): 216-25.         [ Links ]

2. Menegotto BG, Salzano FM. Epidemiology of oral clefts in a large South American sample. Cleft Palate Craniofac J. 1991; 28(4): 373-6.         [ Links ]

3. Harville EW, Wilcox AJ, Lie RT, Vindenes H, Abyholm F. Cleft lip and palate versus cleft lip only: are they distinct defects? Am J Epidemiol. 2005; 162(5): 448-53.         [ Links ]

4. Mossey PA, Modell B. Epidemiology of oral clefts 2012an international perspective. Front Oral Biol. 2012; 16: 1-18.         [ Links ]

5. Stuppia L, Capogreco M, Marzo G, La Rovere D, Antonucci I, Gatta V, et al . Genetics of syndromic and nonsyndromic cleft lip and palate. J Craniofac Surg. 2011; 22(5): 1722-6.         [ Links ]

6. Jugessur A, Murray JC. Orofacial clefting: recent insights into a complex trait. Curr Opin Genet Dev. 2005; 15(3): 270-8.         [ Links ]

7. Dixon MJ, Marazita ML, Beaty TH, Murray JC. Cleft lip and palate: understanding genetic and environmental influences. Nat Rev Genet. 2011; 12(3): 167-78.         [ Links ]

8. Mossey P. Epidemiology underpinning research in the aetiology of orofacial clefts. Orthod Craniofac Res. 2007; 10(3): 114-20.         [ Links ]

9. Bell JC, Raynes-Greenow C, Bower C, Turner RM, Roberts CL, Nassar N. Descriptive epidemiology of cleft lip and cleft palate in Western Australia. Birth Defects Res A Clin Mol Teratol. 2013; 97(2): 101-8.         [ Links ]

10. Milerad J, Larson O, Ph DD, Hagberg C, Ideberg M. Associated malformations in infants with cleft lip and palate: a prospective, population-based study. Pediatrics. 1997; 100(2)Pt: 1180-6.         [ Links ]

11. Cerón Zapata AM, López Palacio AM, Aristizábal Puerta GM, Uribe Alvarez C. A retrospective characterization study on patients with oral clefts in Medellín, Colombia, South America. Rev Fac Odontol Univ Antioq. 2010; 22: 81-7.         [ Links ]

12. Bedón RM, Villota GLG. Labio y paladar hendido: tendencias actuales en el manejo exitoso. Arch Med. 2012;12:107-19.         [ Links ]

13. CDC. Epi.Info 7.1.5. 2013. Accessed: 2013 June 29. Available from: wwwn.cdc.gov/epiinfo/7/.         [ Links ]

14. Charry I, Aguirre M, Castaño Castrillón J, Gómez B, Higuera J, Mateus G, et al. Caracterización de los pacientes con labio y paladar hendido y de la atención brindada en el Hospital Infantil Universitario de Manizales (Colombia), 2010. Arc Med (Manizales). 2012; 12(2): 190-8.         [ Links ]

15. Fraser FC. The genetics of cleft lip and cleft palate. Am J Hum Genet. 1970; 22(3): 336-52.         [ Links ]

16. Wyszynski DF, Beaty TH, Maestri NE. Genetics of nonsyndromic oral clefts revisited. Cleft Palate Craniofac J. 1996; 33(5): 406-17.         [ Links ]

17. Rittler M, Cosentino V, Lopez-Camelo JS, Murray JC, Wehby G, Castilla EE. Associated anomalies among infants with oral clefts at birth and during a 1-year follow-up. Am J Med Genet A. 2011; 155A(7): 1588-96.         [ Links ]

18. Zucchero TM, Cooper ME, Maher BS, Daack-Hirsch S, Nepomuceno B, Ribeiro L, et al . Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate. N Engl J Med. 2004; 351(8): 769-80.         [ Links ]

19. Aarskog D. A familial syndrome of short stature associated with facial dysplasia and genital anomalies. J Pediatr. 1970; 77(5): 856-61.         [ Links ]

20. Hoffman JD, Irons M, Schwartz CE, Medne L, Zackai EH. A newly recognized craniosynostosis syndrome with features of Aarskog-Scott and Teebi syndromes. Am J Med Genet A. 2007; 15(12): 1282-6.         [ Links ]

21. Orrico A, Galli L, Obregon MG; de Castro Perez MF.Falciani M.Sorrentino V , . Unusually severe expression of craniofacial features in Aarskog-Scott syndrome due to a novel truncating mutation of the FGD1 gene. Am J Med Genet A. 2007; 143(1): 58-63.         [ Links ]

22. Zou W, Greenblatt MB, Shim JH, Kant S, Zhai B, Lotinun S, et al . MLK3 regulates bone development downstream of the faciogenital dysplasia protein FGD1 in mice. J Clin Invest. 2011; 121(11): 4383-92.         [ Links ]

23. Calzolari E, Pierini A, Astolfi G, Bianchi F, Neville AJ, Rivieri F. Associated anomalies in multi-malformed infants with cleft lip and palate: An epidemiologic study of nearly 6 million births in 23 EUROCAT registries. Am J Med Genet A. 2007; 143(6): 528-37.         [ Links ]

24. Hwang SJ, Beaty TH, McIntosh I, Hefferon T, Panny SR. Association between homeobox-containing gene MSX1 and the occurrence of limb deficiency. Am J Med Genet. 1998; 75(4): 419-23.         [ Links ]

25. Sekhon PS, Ethunandan M, Markus AF, Krishnan G, Rao CB. Congenital anomalies associated with cleft lip and palate-an analysis of 1623 consecutive patients. Cleft Palate Craniofac J. 2011; 48(4): 371-8.         [ Links ]

26. Wyszynski DF, Sarkozi A, Czeizel AE. Oral clefts with associated anomalies: methodological issues. Cleft Palate Craniofac J. 2006; 43(1): 1-6.         [ Links ]

27. Bueno DF, Sunaga DY, Kobayashi GS, Aguena M, Raposo-Amaral CE, Masotti C, et al . Human stem cell cultures from cleft lip/palate patients show enrichment of transcripts involved in extracellular matrix modeling by comparison to controls. Stem Cell Rev. 2011; 7(2): 446-57.         [ Links ]

28. Leslie EJ, Marazita ML. Genetics of cleft lip and cleft palate. Am J Med Genet C Semin Med Genet. 2013; 4: 246-58.         [ Links ]

29. Higgins JR, Papayianni A, Brady HR, Darling MR, Walshe JJ. Circulating vascular cell adhesion molecule-1 in pre-eclampsia, gestational hypertension, and normal pregnancy: evidence of selective dysregulation of vascular cell adhesion molecule-1 homeostasis in pre-eclampsia. Am J Obstet Gynecol. 1998; 179(2): 464-9.         [ Links ]

30. Young BC, Levine RJ, Karumanchi SA. Pathogenesis of preeclampsia. Annu Rev Pathol. 2010; 5: 173-92.         [ Links ]

31. Ji L, Brkic J, Liu M, Fu G, Peng C, Wang YL. Placental trophoblast cell differentiation: physiological regulation and pathological relevance to preeclampsia. Mol Aspects Med. 2013; 34(5): 981-1023.         [ Links ]

32. Kaufmann P, Black S, Huppertz B. Endovascular trophoblast invasion: implications for the pathogenesis of intrauterine growth retardation and preeclampsia. Biol Reprod. 2003; 69(1): 1-7.         [ Links ]

33. Powe CE, Levine RJ, Karumanchi SA. Preeclampsia, a disease of the maternal endothelium: the role of antiangiogenic factors and implications for later cardiovascular disease. Circulation. 2011; 123(24): 2856-69.         [ Links ]

34. Vicovac L, Aplin JD. Epithelial-mesenchymal transition during trophoblast differentiation. Acta Anat. 1996; 156(3): 202-16.         [ Links ]

35. Goldman-Wohl D, Yagel S. Regulation of trophoblast invasion: from normal implantation to pre-eclampsia. Mol Cell Endocrinol. 2002; 187(1-2): 233-8.         [ Links ]

36. Degitz SJ, Morris D, Foley GL, Francis BM. Role of TGF-beta in RA-induced cleft palate in CD-1 mice. Teratology. 1998; 58(5): 197-204.         [ Links ]

37. Salonen Ros H, Lichtenstein P, Lipworth L, Cnattingius S. Genetic effects on the liability of developing pre-eclampsia and gestational hypertension. Am J Med Genet. 2000; 91(4): 256-60.         [ Links ]

38. Stanier P, Moore GE. Genetics of cleft lip and palatesyndromic genes contribute to the incidence of non-syndromic clefts. Hum Mol Genet. 2004; 13(Spec No 1): R73-81.         [ Links ]

39. Wilson ML, Desmond DH, Goodwin TM, Miller DA, Ingles SA. Maternal and fetal variants in the TGF-beta3 gene and risk of pregnancy-induced hypertension in a predominantly Latino population. Am J Obstet Gynecol. 2009; 201(3): 22.         [ Links ]

40. Osoegawa K, Vessere GM, Utami KH, Mansilla MA, Johnson MK, Riley BM, et al . Identification of novel candidate genes associated with cleft lip and palate using array comparative genomic hybridisation. J Med Genet. 2008; 45(2): 81-6.         [ Links ]

41. Cohen MM, Jr. The new bone biology: pathologic, molecular, and clinical correlates. Am J Med Genet A. 2006; 140(23): 2646-706.         [ Links ]

42. Shi D, Dai J, Ikegawa S, Jiang Q. Genetic study on developmental dysplasia of the hip. Eur J Clin Invest. 2012; 42(10): 1121-5.         [ Links ]

43. Desalu I, Adeyemo W, Akintimoye M, Adepoju A. Airway and respiratory complications in children undergoing cleft lip and palate repair. Ghana Med J. 2010; 44(1): 16-20.         [ Links ]

44. Paladini D. Fetal micrognathia: almost always an ominous finding. Ultrasound Obstet Gynecol. 2010; 35(4): 377-84.         [ Links ]