Version May 2024
INTRODUCTION — A congenital anomaly is any structural anomaly present at birth. These anomalies can be caused by genetic abnormalities and/or environmental exposures, although the underlying etiology is often unknown. Congenital anomalies can be isolated or present in a characteristic combination or pattern that may affect one or more organ systems. This topic discusses the epidemiology, types, and patterns of congenital anomalies. Causes and evaluation of congenital anomalies are discussed in detail separately, as are specific congenital anomalies. (See "Congenital anomalies: Causes" and "Congenital anomalies: Approach to evaluation".)
EPIDEMIOLOGY — Major congenital malformations are abnormalities that have medical, surgical, or cosmetic significance (see 'Major' below). They occur in approximately 2 to 4 percent of livebirths [1-5] and are more common in stillborn spontaneous miscarriages. The overall prevalence of congenital anomalies has remained constant [4].
The overall prevalence of most major congenital anomalies does not vary much across ethnic groups [6,7]. However, the risk for different types of malformations is variable and may be related to genetic susceptibilities, as well as cultural and social differences that can influence exposures (eg, increased presence of neural tube defects in populations that have dietary deficiency of folic acid) [7-9]. The prevalence of most major congenital anomalies has remained constant, although some have shown a significant increase such as gastroschisis [10]. It is hypothesized that this increase is due to environmental causes, although there is evidence that gastroschisis may result from genetic variants that influence blood pressure changes leading to vascular disruptions [11]. Minor anomalies (see 'Minor' below) are seen more frequently than major malformations and are also very common among stillborn and second trimester miscarried fetuses [12].
A combination of genetic and dietary factors may lead to congenital malformations, as in the case of folic acid and neural tube defects. One report highlights other such examples that may account for common malformations. Disruption of the nicotinamide adenine dinucleotide (NAD) metabolism and synthesis pathway may lead to NAD deficiency resulting in congenital anomalies [13]. Different malformations involving heart, kidney, and vertebrae were found in patients with homozygous loss-of-function pathogenic variants in two genes that encode enzymes in the kynurenine pathway. NAD levels were reduced in affected persons, and furthermore the defects were rescued with niacin in null mice that have similar defects in the NAD pathway.
Disruptions are vascular defects that result from destruction of or interference with normal development. The prevalence of disruptions (see 'Disruptions' below) is dependent upon the type of anomaly but can range from 0.5 to 4 per 10,000 [14,15]. Deformations (see 'Deformations' below) are the result of modification of normal structures, are more common in the limbs and head, and are seen in approximately 3 percent of newborns [16].
TYPES AND PATTERNS OF DEFECTS — Specific terms are used to describe congenital abnormalities. These terms indicate the cause of the anomalies (table 1). Other terms are used to describe specific patterns of malformations.
Malformations — Malformations are defects of organs or body parts due to an intrinsically abnormal developmental process. In this process, a structure is not formed, is partially formed, or is formed in an abnormal fashion.
Malformations often result from a defect in embryonic development. Thus, most occur prior to the eighth week after conception. However, malformations can also occur in body structures that develop or continue to develop after this time, such as the central nervous system (CNS), external and internal genitalia, and teeth.
Malformations can result from genetic or teratogenic environmental factors. An example of a genetic cause is pathogenic variants in HOXD13, a homeobox gene, that result in a combination of syndactyly and polydactyly (synpolydactyly) [17]. An example of an environmental cause is exposure to retinoic acid, which can cause anomalies such as microtia (underdeveloped external ear [pinna]) and CNS defects including polymicrogyria and hydrocephalus [18]. Malformations of unknown etiology are probably due to monogenic conditions that have not yet been identified, somatic variants arising at an early stage in development, combinations of genetic factors, or multifactorial disorders that result from the interaction of multiple genes and environmental factors.
Major — Malformations can be classified as major and minor. Major malformations are those that have medical and/or social implications. These often require surgical repair or are life threatening. The neural tube defects, such as meningomyelocele or orofacial clefting (cleft lip and palate), are examples of common major malformations, and others are listed in the table (table 2). (See "Myelomeningocele (spina bifida): Anatomy, clinical manifestations, and complications" and "Overview of craniofacial clefts and holoprosencephaly".)
The prevalence of major malformations ranges from 2 to 4 percent, depending upon the population surveyed (eg, newborns versus children since the prevalence increases after the newborn period) and the method of ascertainment [1-3,19]. In a report from the Mainz congenital anomalies monitoring system in Germany, standardized physical and sonographic examinations were performed in 30,940 liveborn infants, stillborn infants, spontaneous abortions greater than 15 weeks, and induced abortions from 1990 to 1998 [20]. Major malformations were identified in 2144 (6.9 percent), highlighting the higher incidence of major malformations in the prenatal setting and in stillbirths.
Diverse molecular mechanisms lead to major malformations. The defects may interfere with many normal processes, such as apoptosis (cell death), migration of neural cell crest derivatives, intracellular signaling, and chromatin remodeling.
The following are examples of genes and proteins involved in specific malformations:
●Homeobox genes – Synpolydactyly (combinations of syndactyly and polydactyly), microphthalmia, holoprosencephaly
●Transcription factors – Conotruncal heart defects in DiGeorge syndrome caused by deletions of T-box 1 (TBX1) (see "DiGeorge (22q11.2 deletion) syndrome: Epidemiology and pathogenesis"), campomelic dysplasia (a rare skeletal dysplasia caused by pathogenic variants in SRY-box 9 gene [SOX9])
●Fibroblast growth factor receptors – Craniosynostoses, such as Pfeiffer syndrome, Crouzon syndrome, and Apert syndrome (see "Craniosynostosis syndromes")
●Enzyme defects – Defects in cholesterol biosynthesis in Smith-Lemli-Opitz syndrome
Minor — Minor malformations have mostly cosmetic significance. They rarely are medically significant or require surgical intervention. They represent part of the normal variation in the general population. Examples of minor anomalies include ear tags, clinodactyly (incurving of the fifth finger) (picture 1), and single transverse palmar creases (table 3).
Minor anomalies are common, although estimates of their prevalence vary with the population studied and the method of ascertainment [21]. In the Mainz congenital anomaly monitoring survey cited above, mild errors of morphogenesis were diagnosed in 11,104 of 30,940 infants (35.8 percent) [20]. In a study from 1964 limited to examination of newborn infants, 14 percent had a single minor anomaly. Two and three or more minor malformations occurred in 0.8 and 0.5 percent, respectively [1]. Approximately 50 percent of minor anomalies involve the head and neck [2,22].
Infants with three or more minor anomalies are at increased risk of having a major anomaly or syndrome. In two reports, a major malformation was present in 26 and 19.6 percent of infants with three or more minor anomalies [2,23].
Patterns — Multiple malformations are often grouped in a recognizable pattern (table 4).
Syndrome — A syndrome is a pattern of anomalies that occur together and are associated with a set number of signs and symptoms.
An example of a syndrome with a known cause is Turner syndrome due to monosomy of the X chromosome. Patients with this disorder typically have short stature, neck webbing, shield-like chest, underdevelopment of the secondary sexual characteristics, and infertility. (See "Clinical manifestations and diagnosis of Turner syndrome".)
An example of a syndrome with no known genetic basis is Aicardi syndrome. This is an X-linked dominant disorder characterized by a classical triad that includes agenesis of the corpus callosum, chorioretinal lacunae, and seizures. It is seen in females and is lethal in males [24]. While this syndrome is known to be X linked, the exact genetic defect is still unknown.
Some syndromes are inherited, such as Marfan syndrome or achondroplasia. Other congenital malformation syndromes appear sporadic, despite having an underlying genetic etiology, because they are reproductively lethal, and so the condition is not passed on to offspring. These conditions often arise from a de novo pathogenic variant in a dominant gene and generally have a very low recurrence risk (approximately 1 percent). An example is Cornelia de Lange syndrome (or Brachman de Lange syndrome), which is characterized by severe growth retardation, microcephaly, limb anomalies, distinctive dysmorphic features, and profound intellectual disability. Cornelia de Lange syndrome is caused by pathogenic variants of the nipped-B-like (NIPBL) gene in approximately 50 percent of cases [25]. It is less commonly caused by pathogenic variants in other genes, including structural maintenance of chromosomes 1A (SMC1A), histone deacetylase 8 (HDAC8), RAD21 cohesin complex component (RAD21), and structural maintenance of chromosome 3 (SMC3). There are some reported familial cases of this syndrome.
Sequence — A sequence is a pattern of anomalies in which a single known defect in development causes a cascade of subsequent abnormalities [26].
Potter sequence is an example of this group of disorders [27,28]. This disorder is caused by oligohydramnios secondary to renal agenesis or other renal anomalies that reduce fetal urine output production. The decreased volume of amniotic fluid restricts fetal movements, resulting in characteristic anomalies. These include flat facies, depression of the nasal tip, abnormal ear folding, wrinkled skin, and malposition of the feet, including clubfoot deformities. Pulmonary hypoplasia is often associated with the external deformities. (See "Renal agenesis: Prenatal diagnosis".)
Another example is Prune-belly sequence, in which patients have severe abdominal defects due to lack of the major abdominal muscles. This disorder occurs in male fetuses when malformations or obstruction of the urethra lead to a distended bladder, which can interfere with timely closure of the abdominal wall.
Developmental field defect — A field defect is a pattern of anomalies caused by disturbance of a region of the embryo that develops in a contiguous physical space. This region is known as a developmental field [29].
Holoprosencephaly is a classic example of a developmental field defect. The clinical manifestations are variable. They range from very severe cases with almost absent forebrain to milder manifestations, such as a single central incisor. Although there are many etiologies for holoprosencephaly, the primary defect is the lack of normal induction by the prechordal mesoderm on the forebrain, resulting in abnormal cleavage of the embryonic forebrain [30]. Craniofacial structures also are affected because the embryonic forebrain in turn influences mesoderm developmental processes on the mid-face. (See "Overview of craniofacial clefts and holoprosencephaly".)
Bladder exstrophy and cloacal exstrophy represent another developmental field defect. These conditions include urinary, genital, gastrointestinal, and orthopedic abnormalities. (See "Clinical manifestations and initial management of infants with bladder exstrophy".)
Association — An association is defined as two or more anomalies that are not pathogenetically related and occur together more frequently than expected by chance. In general, the etiology of associations is not defined. It is possible that some represent developmental field defects [31].
Examples of this pattern include the VATER or VACTERL association. These are acronyms for a group of typical associated anomalies. VACTERL association includes Vertebral anomalies, Anal atresia, Cardiac defects, TE fistula (tracheoesophageal fistula), Renal defects, and Limb defects [32]. A few patients also have Fanconi anemia [33,34]. Because anomalies in these associations tend to occur together more frequently, the finding of one abnormality should prompt the clinician to look for related anomalies. As an example, a child born with an imperforate anus should be evaluated for vertebral and renal anomalies that occur together in VACTERL association. In addition, patients with VACTERL association that have radial ray defects should have chromosomal breakage studies to screen for Fanconi anemia since the presence of that disorder has management implications [35]. For a more precise diagnosis of Fanconi anemia, exome sequencing or specific panels are used as there are over a dozen of genes that can cause Fanconi anemia. (See "Clinical manifestations and diagnosis of Fanconi anemia", section on 'FA-associated genes'.)
Deformations — Deformations are abnormalities of the position of body parts due to extrinsic intrauterine mechanical forces that modify a normally formed structure [36]. Intrauterine forces, such as decreased amniotic fluid, uterine tumors, and uterine malformations (eg, bicornuate or septated uterus) can lead to fetal compression. Deformations can also occur with fetal crowding due to multiple gestations. (See "Neonatal complications of multiple births".)
Examples of common deformations include some cases of clubfoot, congenital dysplasia of the hip, and positional plagiocephaly (lopsided or flattened skull due to compression). These often can be corrected by physical therapy, casting, or the use of a special helmet to remodel the skull while the fontanelles are still open. (See "Overview of craniosynostosis", section on 'Positional flattening (positional plagiocephaly)' and "Prenatal diagnosis of talipes equinovarus (clubfoot)", section on 'Treatment and prognosis'.)
Disruptions — Disruptions are defects of organs or body parts that result from destruction of or interference with normal development. Destruction can result from vascular or mechanical processes that lead to tissue compromise, such as compression, strangulation, hemorrhage, thrombosis, or processes that interfere with fetal blood flow [37]. Most cases of disruption are single events that are sporadic rather than inherited. Thus, their recurrence risk is very low.
One of the most common examples of intrauterine disruption is the amniotic band sequence (ABS). ABS is a group of structural abnormalities that involve mostly the limbs but also may affect the craniofacial region and trunk. ABS occurs in association with amniotic bands, but the mechanism of amniotic band formation and the pathogenesis of ABS are not firmly established. The specific malformations caused depend upon the time of the disruption. The typical appearance consists of amputations and malformations caused by the encircling constrictions of the limbs or other body structures, but the clinical spectrum is highly variable. (See "Amniotic band sequence".)
Dysplasias — Dysplasias refer to anomalies that result from the abnormal organization of cells into tissues. An example is abnormal growth of bone resulting in skeletal dysplasias, such as achondroplasia. This disorder is caused by pathogenic variants in the fibroblast growth factor receptor 3 gene, leading to abnormalities in endochondral ossification [38]. (See "Skeletal dysplasias: Approach to evaluation" and "Skeletal dysplasias: Specific disorders" and "Achondroplasia".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Newborn appearance (The Basics)")
SUMMARY
●Overview – A congenital anomaly is any structural anomaly present at birth. These anomalies can be caused by genetic abnormalities and/or environmental exposures, although the underlying etiology is often unknown. (See 'Introduction' above.)
●Types of congenital anomalies – Specific terms are used to describe congenital anomalies (table 1). (See 'Types and patterns of defects' above.)
•Malformations – Malformations are defects of organs or body parts due to an intrinsically abnormal developmental process. In this process, a structure is not formed, is partially formed, or is formed in an abnormal fashion. (See 'Malformations' above.)
•Deformations – Deformations are abnormalities of the position of body parts due to extrinsic intrauterine mechanical forces that modify a normally formed structure. (See 'Deformations' above.)
•Disruptions – Disruptions are defects of organs or body parts that result from destruction of or interference with normal development. (See 'Disruptions' above.)
•Dysplasias – Dysplasias refer to anomalies that result from the abnormal organization of cells into tissues. (See 'Dysplasias' above.)
●Malformation patterns – Multiple malformations are often grouped in a recognizable pattern (table 4). (See 'Patterns' above.)
•Syndrome – A syndrome is a pattern of anomalies that occur together and are associated with a set number of signs and symptoms. (See 'Syndrome' above.)
•Sequence – A sequence is a pattern of anomalies in which a single known defect in development causes a cascade of subsequent abnormalities. (See 'Sequence' above.)
•Field defect – A field defect is a pattern of anomalies caused by disturbance of a region of the embryo that develops in a contiguous physical space. This region is known as a developmental field. (See 'Developmental field defect' above.)
•Association – An association is defined as two or more anomalies that are not pathogenetically related and occur together more frequently than expected by chance. (See 'Association' above.)
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