CHAPTER 1INTRODUCTION

1.1 BackgroundAccording to Centers for Disease and Control and Preventions statistics data, about one in every 33 babies (about 3%) is born with a birth defect. Birth defects are structural or physiological abnormalities that are present at birth and may lead to health problems and even infant deaths. One type of birth defects includes orofacial defects; cleft palate and cleft lip. A newborn baby suffering orofacial defect may have only cleft lip, only cleft palate, or both cleft lip and cleft palate.

In Indonesia, cleft lip and cleft palate have been a major problem for many newborn babies; accounted for more or less 7500 cases per year. Special treatment and care are crucial to prevent health degradation and complications to these babies. Although many have seen these orofacial defects from scientific views, some still believe that cleft lip and cleft palate are caused by Gods curse.

In this report, writers will prove that cleft lip and cleft palate are not caused by Gods curse, but instead there are scientific reasons and explanationsons behind them. The discussion will be based on five-year-old boy case who suffers from both cleft lip and cleft palate, and is brought by his parents to a hospital since they are wondering whether their son is cursed by God or not. Through this written report, writers are going to answer the parents question.1.2 Statement of the Problem1. What are meant by Cleft Lip and Cleft Palate?

2. What are the factors that cause Cleft Lip and Cleft Palate?

3. How to care and treat Cleft Lip and Cleft Palate patients?

4. How Cleft Lip and Cleft Palate are related to Gods Curse?1.3 Objectives1. To understand the meaning of Cleft Lip and Cleft Palate, including the characteristics of both birth defects.2. To know the factors those cause Cleft Lip and Cleft Palate.

3. To understand the procedure to treat Cleft Lip and Cleft Palate patients.

4. To answer whether Gods Curse is related to Cleft Lip and Palate formation.

CHAPTER 2

LITERATURE REVIEW2.1 Definition and Characteristics of Cleft Lip and Cleft Palate

Cleft Lip and Cleft Palate are orofacial birth defects that characterized by the formation of cleft in the lip and palate structure. Cleft is a split or fissure which divides a structure (in this case; lip or palate) into two parts. Cleft Lip is also called labiochisis while cleft palate is called palatoschisis.Normal Lip and Palate

lip and palate structure are complete, without any slit or fissure

Cleft Lip

lip structure is divided by a slit into two parts - unilateral cleft lip

lip structure is divided by two slits into three parts bilateral cleft lip

Classification of cleft lip based on severity: Isolated cleft lip cleft doesnt continuous to alveolar process

Incomplete cleft lip and alveolus cleft is continuous to alveolar process

Complete cleft lip and alveolus cleft is continuous to alveolar process and further until incisive foramen

Cleft Palate

palate structure is incomplete, slit is present

Cleft Lip and Palate

slit is continuous from lip structure to palate, incomplete lip and palate structure

2.2 Embryonic Formation and Development of Lip and Palate StructureEmbryonic facial development begins in the early fourth week of gestation period or after fertilization occurs. At the start, there are five facial primordia (tissue in its earliest stage of development) which surround a stomodeum (an opening that will develop into mouth).The five primordia are:

single frontonasal prominence

paired maxillary prominences

paired mandibular prominences

(these prominences are formed by neural crest cell that migrates to the designated location and differentiates)

From day 33 onwards, maxillary prominences grow toward each other, pushing nasal prominences medially.

Medial nasal prominences then will merge with each other and with lateral nasal and maxillary prominences, thus give rise to philtrum and primary palate

Figure of human embryo face at the 7th week or approximately 48 days:

In final stage of embryonic facial development: frontonasal prominence develops into dorsum & apex of nose

lateral nasal prominence develops into sides of nose

medial nasal prominence develops into nasal septum, philtrum, premaxilla, primary palate

Maxillary prominence develops into upper cheek, most of the upper jaw and lip

Mandibular prominence develops into lower jaw, chin, lower lip, lower cheek

2.3 Statistics Data of Cleft Lip and Palate Cases

The following statistics data is taken within year 2011-2013 at RSUP Prof. Dr. R. D. Kandou in Manado; a total of 142 cases.Cleft cases based on the types:

Type of CleftNo. of Cases%

Cleft Lip2819.7

Cleft Lip and Cleft Alveolus1812.7

Cleft Lip, Cleft Alveolus, and Cleft Palate (soft and hard palate)9365.5

Cleft Lip, Cleft Alveolus and Cleft Palate ( soft palate)10.7

Cleft Lip, Cleft Palate (soft palate21.4

Total142100

This table shows that the highest percentage of cleft type is Cleft Lip, Cleft Alveolus, and Cleft Palate (soft and hard palate) with 65.5%. Thus, this supports a research done by Faculty of Medicine University of Tartu, Estonia in 2012 that found cleft lip with cleft palate is more frequent than cleft lip without cleft palate. Cleft cases based on gender:

GenderNo. of Cases%

Male9567

Female4733

Total142100

This table shows that cleft lip and cleft palate is more likely to be suffered by male rather than female, with a ratio 2:1. This supports a research done by Triin Jagomagi, Marianne Soots and Mare Saag in 2012 that concludes that male cases is higher than of female.

CHAPTER 3DISCUSSION3.1 Factors Affecting Cleft Lip and Cleft PalateCleft Lip and Cleft Palate are caused mostly by multifactor; the exact cause may not be specifically clear. In addition, cleft lip and palate are often features of more than 300 birth disorders and syndromes, which will be discussed further later.3.1.1 Major Factor; Genetics

Majority of cleft lip and cleft palate cases are caused by the interaction of gene that form ones genetic makeup. During this interaction, some disorders may occur:

Gene mutation; alters the template for the production of amino acids sequence Inheritance of disordered gene from one or both parents during fertilization

Unsuccessful meiosis division during spermatogenesis or oogenesis that results in the inheritance of multiple genes; give rise to trisomy disorder.3.1.1.1 Gene Mutation

Gene mutation will alter the DNA sequence for protein production. As a result, synthesized protein will have different shape and may become functionless; enzymes cannot catalyses metabolic reactions, centrioles are not able to facilitate adequate neural crest cell division, etc. In a larger scale, these defect proteins are not able to work properly, hence causes incomplete formation of lip and palate structure (slits are present at these structures).Mutation of IRF6 gene that causes a rare condition called van de Woude syndrome is also often featured by cleft lip and cleft palate. In patient of ectodermal dysplasia, similar features are also often observed.

(Cleft lip and cleft palate in an infant with van der Woude syndrome)

(Cleft lip in and palate in infant with ectodermal dysplasia)3.1.1.2 Inheritance of disordered gene

Palate development in fetus is controlled by a gene in X chromosome called TBX22. When TBX22 gene is mutated, this faulty gene may have dominant or recessive characteristic for cleft palate. Hence, when this gene is passed down to an offspring, the probability for the offspring to suffer cleft palate is based on the diagram below:1. A normal father and carrier mother in X-linked recessive

In X-linked recessive, trait (cleft palate) is passed to male with higher probability than to female (0% for female, 50% for male according to the diagram above )2. A normal father and affected mother in X-linked dominant

In X-linked dominant, trait (cleft palate) is passed with the same probability both to female and male, regardless of gender.For cleft lip cases, it is similar to cleft palate, although different X-chromosome gene is involved (not TBX22). Furthermore, a study by Schroder concluded that 75% of the cleft lip cases are due to recessive inheritance while 25% are due to dominant inheritance. Since in recessive trait inheritance, male has higher probability of getting the trait, this is why cleft lip is more often suffered by male than female (refer to 2.3 Statistics Data of Cleft Lip and Palate Cases) .3.1.1.3 Trisomy 13 and Trisomy 18Trisomy is an condition when a cell contains an extra copy of a particular chromosome. Most trisomy cases are caused by non-disjunction during gametogenesis (meiosis division); homologous chromosome nondisjuction at meiosis I or sister chromatids non disjuction at meioisis II.

Trisomy leads to developmental abnormalities in infants, which are known as Patau Syndrome and Edwards Syndrome for Trisomy 13 and Trisomy 18 respectively. Both syndromes may have clinical features of cleft lip and cleft palate as shown below:. (Patau Syndrome Features: Midline defect with cleft lip

and cleft palate, clenched hand with overlapping fingers, eqyuinovarus deformity, etc)3.1.2 Minor Factors; Environmental FactorsThe following external / environmental factors may also affect cleft formation, yet in a smaller proportion:1. Viral InfectionVirus such as Rubella2. Medicine and Drug Consumptiona. Corticosteroid and AnticonsulvantCorticostreoid and Anticonsulvant are steroid medications that can cause bone loss and osteophorosis (Yeap and Hosking, 2002). When pregnant mother consumes corticosteroid, this medication will affect fetal calcium and vitamin D metabolism, resulting in the break down of bone matrix of palatine bone, thus causes incomplete / cleft palate. b. SulfadimidineSulfadimidine causes anemia (Meechan and Seymor, 2002).When this medication is taken by fetus, number of fetal red blood cell will be reduced in a relatively high quantities. Thus, fetal blood oxygen level will be highly reduced and causes inadequate ATP production for metabolic processes in lip and palate formation.3. Jamu (Indonesias Herbal Tonic)Jamu is a traditional herbal medicine that has been known for centuries in Indonesia, yet researchs on this subject are still limited. Recent research done by DewI Purnamawati and Iwan Ariawan in 2012 with a title Consumption of Jamu in Pregnant Woman as A Risk Factor of Birth Asphyxia in Bekasi has proven that mothers who consume jamu during pregnancy are at higher risk (7 times greater) to give birth baby with asphyxia than those who didnot consume jamu.Asphyxisa is a condition when baby is born with deprived oxygen. At time of birth, baby may shows symptoms sucah as weak breathing, pale skin colour, slow heart rate, poormuscle tone, weak reflex movements, lethargy and seizures.

Birth asphyxia happens because baby is not getting enough oxygen before, during, or right after birth. This condtion of not getting enough oxygen in fetus before birth (in the mothers womb) is reffered as hypoxia or hypoxemia. Limited oxygen supply results in anaerobic respiration to occur, producing small amount of ATP and acid as a side product, which will harm and damage neural crest cells for palate and lip development.Furthermore, the same research stated that there is a possibility that chemicals of jamu are deposited in the amniotic fluid and turn it to become cloudy. Amniotic fluid is very important in the first trisemester gestation period, as the baby swallows the fluid as 4. gjh3.2 Abnormalities in Lip and Palate Embryonic Development

Any factors discussed in 3.1 may cause abnormal formation of lip and palate during gestation period, thus cleft exists. Below shows how cleft lip is formed.

3.3 Ghjkj3.4 Cleft Lip and Cleft Palate Prevention and Treatment3.4.1 Prevention

Here are some preventive actions that a mother can do during the first trimester of gestation period, since at this time lip and palate are developing:1. Increase Folic Acid Intake

Folic Acid or Vitamin B9 is essential in fetal red blood cell production. Red blood cell helps in transporting oxygen to surrounding active tissues to support synthesis of ATP for cell division and metabolic processes, which are important in the fusing of maxillary prominence and medial nasal prominence. Consumption of high-folic-acid-content food such as dried beans, peas, oranges, wheat, asparagus and brocolli can help to increase floic acid intake in mothers. To support this explanation, AJ Willcok et al, alao stated that folic acid has been proven to reduce the possiibility of cleft lip and cleft palate by about a third (2006).2. Termination of Smoking Habit and Alcohol ConsumptionCigarrete contains carcinogenic substance, tar, which can cause gene mutation in IRF6 gene. This mutation leads to cleft lip and palate abnormalities (refer to 3.1.1.1). Alcohol consumption in high dosage can also damage neural crest cells (Research and Outcomes Department of Operation Smile Inc. 2009). Neural crest cells are needed in the formation of prominences (refer to 2.2) and the fusing of maxillary prominence and medial nasal prominence. Damage to these cells lead to cleft lip and palate. 3. Intake of Prenatal VitaminPrenatal vitamin is rich in Vitamin B6 and B12. Vitamin B6 is responsible in the production of amino acids and protein such as enzymes, while B12 is used in the production in DNA. In conclusion inadequate amount of B6 and B12 will result in the inhibition of cell division of neural crest cells, which results in the incomplete fusion of medial nasal prominences and maxillary prominances. 4. Do Genetic CounselingBefore planning in having a child, couples are suggested to go to a genetic counselor. Genetic counselor will help in determining different prenatal tests that couple must undergo such as blood test, urine test, screening test, family history tracking, and genetic testing. All of these test are aim to identify the likelihood of passing certain genetic diseases and disorders, including passing cleft lip and palate traits.3.4.2 Treatment

Below are treatments that must be done by the babys attending physician and parents in order to prevent any health complications and health degradation.

REFERENCES1. Before We Are Born: Essentials of Embryology and Birth Defects byKeith L. Moore et al. published byElsevier2. ANGKA KEJADIAN SUMBING BIBIR DI RSUP Prof. Dr. R. D. KANDOU MANADO PERIODE 2011-2013 by Andriani Supandi, Alwin Monoarfa, Mendy Hatibie Oley3. Cleft Palate Foundation second edition ( Genetics and You)CONGENITAL CLEFT LIP, CLEFT PALATE AND LIP FISTULAE (VAN DER WOUDE SYNDROME) IN TWO NIGERIAN FAMILIES Osagie Akpata, BDS, FWACS;* Mike A. Ojo, BDS, MS;** Bawa M. Eroje, BDS;*** Ogoni Ohre, BDS****

(Edwards Syndrome suffered by a baby named Jules)

Normally, maxillary prominences will fuse with medial nasal prominences at approximately 48 days. However, in cleft lip case, both prominences fail to fuse together; hence a labial groove or cleft is persistent until the fetus is born.

Cleft palate formation has similar mechanism. Right and left palatine bones fail to fuse properly, resulting in a cleft