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The editors and current author would like to thank and acknowledge the significant contribution of the previous author of this chapter from the 2004 first edition, Dr. Greigh I. Hirata. This current second edition chapter is a revision and update of the original authorís work.
A newborn infant male was born to a 33 year old G1P0 mother at 39 weeks gestation via NSVD (normal spontaneous vaginal devliery) with Apgars scores of 8 and 9 at one and five minutes, respectively. Upon examination, microretrognathia and a complete cleft of the hard and soft palates were noted. The remainder of the physical examination was unremarkable. The infant had continued feeding difficulties, and a gastrostomy tube was placed. Pierre-Robin sequence was diagnosed and an ophthalmology consultation and chromosomal microarray (CMA) was ordered. The CMA was normal, but the ophthalmology examination revealed myopia. When questioned about family history, the mother of the baby disclosed a personal history of high myopia with retinal detachments as a child, and arthritis with onset at 20 years of age. Both baby and mother were subsequently diagnosed with Stickler syndrome.
The mechanisms for fetal maldevelopment may be divided into four different categories: 1) malformation, 2) deformation, 3) disruption, and 4) dysplasia. A malformation is commonly defined as a single, localized abnormal formation of tissue(s). Anencephaly, for example, is a result of a failure of closure of the anterior neural tube prior to 26 days of fetal life which ultimately results in the degeneration of the forebrain. In comparison, a deformation is a result of extrinsic mechanical forces on otherwise normal tissue. This is illustrated in the characteristic pattern of abnormalities including the abnormal facies and limb contractures that result from fetal compression due to prolonged severe oligohydramnios. A disruption results from some type of acquired insult, which destroys normal tissue altering the formation of a structure. An example of a disruption is the pattern of findings that occur due to amniotic bands and limb strangulation, a condition in which torn amniotic tissue strands surround a portion of the body resulting in deep grooves or amputations. Finally, if the primary defect is a lack of normal organization of cells into tissue, a dysplasia will result. This is best illustrated by the pattern of bony abnormalities found in achondroplasia in which a defect in the gene encoding fibroblast growth factor receptor 3 (FGFR3) results in abnormal cartilage formation.
It is also important to recognize the differences between a "syndrome" and an "association." Syndromes are typically a result of a single genetic abnormality or common/related genetic mechanism, whereas associations are nonrandom collections of birth defects, which may have resulted from a number of genetic and/or environmental factors. VACTERL (Vertebral, Anal, Cardiac, TE fistula, Renal and Limb) is the most common recognized association. The understanding of these pathophysiologic mechanisms and nomenclature is important in the study of congenital anomalies.
Congenital anomalies that are commonly seen in newborns include neural tube defects, gastroschisis, omphalocele, orofacial clefts, clubfoot, and the group of birth defects seen in VACTERL Association. Most of these common birth defects, when isolated and not associated with a syndrome, exhibit multifactorial inheritance.
Neural Tube Defects
Neural tube defects (NTDs) are common congenital malformations that occur in approximately 1 per 1,000 live births. Failure of neural tube closure results in an NTD, with the phenotype (e.g. anencephaly, spina bifida, encephalocele) dependent on the region of neural tube that remains open. Anencephaly is a lethal defect, and affected infants may be stillborn or die within hours. Infants with open spina bifida usually survive, but typically have neurologic impairment below the lesion leading to sensory and motor deficits. As a group, NTDs are a leading cause of stillbirth, death in early infancy, and handicap in surviving children.
About two-thirds of affected infants are female. Both genetic and non-genetic factors are involved in the etiology of NTDs, and NTDs are believed to follow a multifactorial inheritance pattern. A small proportion of NTDs have specific causes such as amniotic bands, some teratogens, and some chromosome disorders. However, most NTDs are isolated defects.
NTDs can be associated with low maternal serum folic acid levels during pregnancy. Although the exact mechanism of folate action remains unclear, folic acid supplementation is an effective way of preventing a proportion of NTDs. Dietary supplementation with 400-800 mcg of folic acid per day begun at least one month prior to conception has been shown to reduce the incidence of NTDs by more than 75% (1). In 1992, the United States Public Health Service made the recommendation that all women of child-bearing age consume 400 mcg of folic acid daily to prevent NTDs (2). For women who have had a previous pregnancy affected with an NTD, the Centers for Disease Control and Prevention (CDC) recommend increasing the intake of folic acid to 4000 mcg (4 mg) per day beginning at least one month before conception and continuing through the first trimester (2).
Parents of children with an NTD have a 2% to 5% chance of having another child with a similar defect. This same chance applies to an affected individual when he/she has children. However, less than 5% of all individuals with NTDs are born to women with previously affected children. These risks are reduced with maternal use of folic acid. Anencephaly and most cases of open spina bifida can be identified prenatally by detection of increased maternal serum alpha-fetoprotein (AFP) levels and by ultrasound.
Gastroschisis occurs in approximately 1 in 4,000 live births and, along with omphalocele, is one of the most common congenital abdominal wall defects. It is a structural defect of the abdominal wall that involves herniation of the abdominal organs, usually to the right of the normally inserted umbilical cord. It is distinguished from omphalocele by being off the midline and by lacking a covering of amnion. Although the exact etiology of gastroschisis is unknown, it is thought to be due to an in-utero disruptive vascular accident.
Infants with gastroschisis rarely have associated abnormalities except for an increased incidence of intestinal atresia. Preterm delivery is more frequent in infants with gastroschisis when compared to unaffected infants, with an incidence of 28% (3). Cryptorchidism is also associated with gastroschisis, and is seen in about 15-30% of cases. However, it is unclear whether this is secondary to in-utero extra-abdominal entrapment of the testis or simply a byproduct of prematurity.
The majority of pregnancies complicated by gastroschisis are diagnosed prenatally. An elevated maternal serum AFP level may be the earliest indicator of the defect. Ultrasound visualization of the gastroschisis at any point after the normal embryonic return of the intestine to the abdominal cavity at 10 weeks of gestation confirms the diagnosis.
Most cases of isolated gastroschisis are sporadic events, and recurrence is low. However, a number of specific factors have been identified that appear to increase risk. These include young maternal age, primigravidity or primiparity, low socioeconomic status, lower pre-pregnancy body mass index, poor maternal diet, and exposure to vasoactive medication (4).
Long-term outcomes for infants born with gastroschisis are generally excellent. The majority of children will achieve normal growth and development after an initial catch-up period in early childhood.
Like gastroschisis, an omphalocele is an abdominal wall defect that involves herniation of the bowel. However, an omphalocele differs from gastroschisis in that herniation occurs within the umbilical ring, and the bowel is covered by an omphalocele sac. An omphalocele occurs when the intestines fail to return to the abdominal cavity after normal embryonic herniation into the umbilical cord during weeks 6 to 10 of development. Other intra-abdominal organs, including the liver, bladder, stomach, ovary, and testis, can be found within the sac, and the umbilical cord is continuous with the omphalocele sac.
An important distinguishing feature between omphalocele and gastroschisis is the different rate of associated anomalies. Chromosomal abnormalities, most commonly trisomies 13, 18, and 21, occur in up to 49% of fetuses diagnosed with omphalocele. Of those with normal karyotypes, nearly 80% have multiple other anomalies. Cardiac defects are the most common of these and are seen in approximately 18% to 24% of neonates (3). Specific conditions associated with omphalocele include Beckwith-Weidemann syndrome, cloacal exstrophy, and pentalogy of Cantrell and others.
Omphalocele can be a cause of elevated maternal serum AFP, although elevated AFP levels are seen less frequently in omphalocele than in gastroschisis. Prenatal diagnosis can be made as early as the first trimester if 3-D ultrasonography is available, but omphalocele is more commonly diagnosed on routine mid-gestation 2-D ultrasound. The incidence of omphalocele seen on ultrasound at 14 to 18 weeks is as high as 1 in 1,100, but due to both spontaneous intrauterine fetal demise and pregnancy termination, the incidence in live births is about 1 in 4,000. A prenatal diagnosis of omphalocele should be followed by a comprehensive fetal ultrasound including fetal echocardiography due to the high incidence of accompanying cardiac defects and other anomalies.
Recurrence risks for parents who have had a child with an omphalocele depend on the presence or absence of associated structural and chromosomal anomalies. Recurrence is low if the omphalocele is isolated. However, if the omphalocele occurs with other abnormalities or as part of a genetic syndrome, recurrence may be as high as 50%.
Oral clefting is one of the most frequent congenital malformations, with an incidence of 1 in 700 live births, although there is variability across racial and ethnic groups. Oral clefts are commonly divided into two phenotypically and etiologically distinct groups: cleft lip with or without cleft palate (CL/P) and cleft palate only (CP). Based on the extent of tissue involvement, CL/P and CP may be further subdivided into unilateral or bilateral clefts, and complete or incomplete clefts. The frequency of CL/P and CP differs by sex: there is a 2:1 male to female ratio for clefts involving the lip, and approximately a 1:2 male to female ratio for clefts of the palate only.
Approximately 70% of CL/P and 50% of CP are thought to be isolated (5). The remainder includes a wide range of single gene disorders, chromosome abnormalities or teratogenic effects. CL/P is listed as a feature of more than 200 specific genetic syndromes. CP only is recorded as a component of more than 400 disorders including Velocardiofacial syndrome, Treacher-Collins, Stickler syndrome, and Kabuki syndrome (6).
The etiology of isolated oral clefting is largely unknown, although it has been suggested that the interaction between genetic factors and environmental exposures is likely the cause. Potential environmental risk factors include maternal exposure to tobacco smoke, alcohol, poor nutrition, viral infection, and anti-seizure medication. Maternal diabetes is a potential teratogen contributing to cleft palate.
Empiric recurrence risks consistent with multifactorial inheritance are used in genetic counseling. Although recurrence increases with severity, from unilateral to bilateral and from cleft lip alone to cleft lip with cleft plate, in general, recurrence of isolated clefts in first degree relatives is about 3% to 5%. Some studies have suggested that folic acid supplementation may help to decrease the risk for CL/P; however the role of folic acid in orofacial clefts is still not completely clear (5).
Congenital talipes equinovarus, often known as "clubfoot" is a common congenital birth defect, with an estimated incidence of 1 per 1,000 live births. It is defined as fixation of the foot in adduction, in supination, and in varus positioning. In approximately 20% of cases, clubfoot is associated with other anomalies as part of a genetic syndrome (7). These "syndromic" forms of clubfoot can be seen in congenital myotonic dystrophy, spinal muscular atrophy, Trisomy 18, and chromosome 22q11.2 deletion syndrome, among others. In the remaining cases, clubfoot is isolated.
Isolated clubfoot may be unilateral or bilateral. There is a difference in isolated clubfoot incidence across ethnic populations, with the lowest in Chinese (0.39 cases per 1,000 live births) and the highest in the Hawaiian and Maori populations (7 per 1,000 live births) (6). The ratio of isolated clubfoot among males to females is 2:1 and is consistent across ethnic groups.
Although the exact cause of isolated clubfoot is unknown, several proposed mechanisms exist to explain the etiology of the condition. These include uterine restriction, abnormalities of joint and/or bone formation, connective tissue anomalies, problems with distal limb vasculature, neurological development abnormalities, and developmental arrest. Research findings do not clearly support any particular mechanism, but it is likely that both genetic and environmental factors contribute to the cause of isolated clubfoot as part of multifactorial inheritance (8). Empiric studies have shown recurrence risks for first degree relatives to be between 2% to 5%. Approximately 25% of all patients with isolated clubfoot report a positive family history.
VACTERL association is the non-random occurrence of a group of congenital malformations, with each letter in the acronym representing a feature. "V" stands for vertebral anomalies, typically including segmentation defects (such as hemivertebrae or "butterfly vertebrae"), vertebral fusions, supernumerary vertebrae, or absent vertebrae. Approximately 60% to 80% are reported to have vertebral anomalies, and these are often associated with rib anomalies (9). "A" stands for imperforate anus/anal atresia. In patients with imperforate anus, genitourinary anomalies are also common. "C" stands for cardiac malformations of which structural heart anomalies are common. The severity of cardiac defect can range from mild to severe. "TE" stands for tracheo-esophageal fistula, and may present with or without esophageal atresia. "R" stands for renal anomalies which can include unilateral or bilateral renal agenesis, horseshoe kidney, and cystic and/or dysplastic kidneys. "L" stands for limb malformations, classically defined as radial anomalies including thumb aplasia/hypoplasia. It is important to note that individuals with VACTERL association do not typically have neurocognitive impairments.
The diagnosis of VACTERL association is made on clinical grounds based on the presence of at least three of the component features. It is a diagnosis of exclusion, with no clinical or laboratory-based evidence for other similar or overlapping conditions, and the list of differential diagnosis can be large, depending on which defects are identified. This includes, but is not limited to chromosome anomalies (trisomy 18 in particular), Fanconi anemia, and CHARGE syndrome (coloboma of the eye, heart defects, atresia of the nasal choanae, retardation of growth and/or development, genital and/or urinary abnormalities, and ear abnormalities and deafness). Maternal diabetes is the most common teratogenic cause of VACTERL.
The prevalence of VACTERL association is estimated to be between 1/10,000 to 1/40,000 infants. Approximately 90% of cases of the condition appear to be sporadic, and the recurrence risk is relatively low. The cause of VACTERL association is difficult to ascertain, and the etiology remains unknown, although it is likely a complex inheritance pattern involving multiple interacting genetic and environmental factors.
1. Folic acid has been shown to be most effective in or associated with a reduction in population wide and recurrence risk for:
. . . . a. Cleft lip and palate
. . . . b. Neural tube defects
. . . . c. Gastroschisis
. . . . d. Omphalocele
2. All of the following birth defects can be detected prenatally by an elevation in maternal serum alpha fetoprotein EXCEPT:
. . . . a. Cleft lip and palate
. . . . b. Neural tube defects
. . . . c. Gastroschisis
. . . . d. Omphalocele
3. In isolated clubfoot:
. . . . a. Prevalence varies across different ethnic groups.
. . . . b. A motherís second pregnancy is more likely to be affected than her first.
. . . . c. Females are affected more often than males.
. . . . d. Recurrence risk for first degree relatives is approximately 10%.
4. In VACTERL Association:
. . . . a. The "A" stands for atresia of the choanae.
. . . . b. At least four of the component features must be present to make a diagnosis.
. . . . c. The majority of cases are sporadic.
. . . . d. Most will have neurocognitive impairments.
5. When comparing omphalocele and gastroschisis, all of the following are true EXCEPT:
. . . . a. Omphalocele has a much higher rate of associated anomalies.
. . . . b. In gastroschisis, herniation of the bowel occurs within the umbilical cord.
. . . . c. The bowel in an omphalocele is covered by a sac.
. . . . d. Both defects occur at approximately the same rate in live births.
1. Wald N, Sneddon J, Densem J, Frost C, Stone R, MRC Vitamin Study Res Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet. 1991;338:131-137.
2. Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. MMWR Recomm Rep. 1992;41:1-7.
3. Christison-Lagay ER, Kelleher CM, Langer JC. Neonatal abdominal wall defects. Semin Fetal Neonatal Med. 2011;16(3):164-172.
4. Jones KL, Benirschke K, Chambers CD. Gastroschisis: etiology and developmental pathogenesis. Clin Genet. 2009;75:322-325.
5. Dixon MJ, Marazita ML, Beaty TH, Murray JC. Cleft lip and palate: synthesizing genetic and environmental influences. Nat Rev Genet. 2011;12(3):167-178.
6. Mossey PA, Little J, Munger RG, Dixon MJ, Shaw WC. Cleft lip and palate. Lancet. 2009;374(9703):1773-1785.
7. Dobbs MB, Gurnett CA. Genetics of clubfoot. J Pediatr Orthop B. 2012;21(1):7-9.
8. Miedzybrodzka A. Congenital talipes equinovarus (clubfoot): a disorder of the foot but not the hand. J Anat. 2003;202(1):37-42.
9. Solomon BD. VACTERL/VATER association. Orphanet J Rare Dis. 2011;6(56).
1. b. Neural tube defects
2. a. Cleft lip and palate
3. a. Prevalence varies across different ethnic groups.
4. c. The majority of cases are sporadic.
5. b. In gastroschisis, herniation of the bowel occurs within the umbilical cord.