congenital disorder

Structural abnormality (e.g., atresia, agenesis), functional problem (e.g., cystic fibrosis, phenylketonuria), or disease present at birth.

Almost all are due to genetic factors (inherited or spontaneous mutations, chromosomal disorders), environmental influences during pregnancy (rubella or other maternal factors, exposure to toxins or radiation), or both. The most sensitive period is the first eight weeks after conception, during which time the human embryo is essentially formed. Major congenital malformations form during this period. Some inherited disorders result from simple Mendelian dominance or recessiveness. Others may involve multiple genes. Chromosomal disorders are rare, because few affected fetuses survive to be born. Environmental influences may affect only one of a pair of identical twins. At least 30 significant defects probably occur per 1000 births. See also birth defect; Down syndrome.

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▪ pathology

Introduction

      abnormality of structure and, consequently, function of the human body arising during development. This large group of disorders affects almost 5 percent of infants and includes several major groups of conditions.

Malformations: abnormalities of the embryonic (embryo) stage

      Malformations are abnormalities of the human form that arise during embryogenesis (the first eight weeks of development). Conventionally, embryogenesis is divided into two stages, blastogenesis and organogenesis.

Blastogenesis (budding)

      Blastogenesis refers to the first 28 days of development, during which the basic body plan and domains of gene expression are established and the developmental fate of all parts of the embryo is determined. The small size of the early embryo, close proximity of organ rudiments, and strongly integrated and interdependent nature of early development help explain why defects that occur in this stage are usually severe—and frequently lethal—and may affect multiple parts of the body. Severe malformations may include gross brain anomalies, facial clefts, eye defects, gross heart defects, laterality (“sidedness”) defects, and absence of limbs, in addition to many others.

organogenesis

      The second half of embryogenesis, from day 29 to day 56 of development, is known as organogenesis, because it is during this time that organ development occurs. Defects acquired during organogenesis tend to be milder than those of blastogenesis and affect single rather than multiple parts of the body and generally allow for survival of the developing organism. Defects may include cleft palate, webbed fingers, hypospadias (incomplete closure of the male urethra), and development of an extra finger.

Minor anomalies: abnormalities of the fetal (fetus) stage

      Minor anomalies are subtle defects of appearance and structure evaluated subjectively or by measurement. While malformations arise during blastogenesis and organogenesis, minor anomalies are defined as arising during phenogenesis (“attainment of final form,” between days 57 and 266 of development). During this time, enormous growth of the fetus, maturation of function and cell types in every organ, and acquisition of individual attributes occur. The degree of heredity of a given physical trait is variable, with some traits being strongly genetic (genetic disease, human) and others being influenced largely by environmental (environment) factors. Genetically caused defects often involve several or many genes inherited from both parents. Such variability is sometimes referred to as multifactorially (polygenically) determined.

      The latest-developing, mildest of malformations are rather common in the population and many appear to be dominant (dominance)ly inherited. Some of these are internal anomalies and may not be discovered until an autopsy after death from noncongenital causes or following an injury, when physical examination may reveal, for example, a defect of the heart or brain.

growth defects

      Growth defects overwhelmingly represent deficient rather than excess growth, and dozens of genetic growth failure syndromes have been identified. Most are congenital defects, even in those who grew normally for some time after birth and then slowed and whose condition is frequently found to represent familial, hereditary states, such as a congenital defect of thyroid (thyroid gland) or pituitary (pituitary gland) development, or a genetic disorder, such as chromosome abnormality as seen in Down syndrome (trisomy 21). Tables and graphs of prenatal growth have been established and serve as standards whereby length, weight, head size, and chest circumference of the newborn infant can be plotted to assess size and growth patterns. Extremes at both ends are cause for concern. Large infants may be an indication of actual or incipient maternal diabetes mellitus. Very small infants without obvious defects of the skeleton are considered to have intrauterine growth retardation. This may be due to failure of the placenta to provide adequate nourishment (in which case postnatal catch-up growth is expected), environmental agents such as smoking or alcohol, or intrinsic genetic factors in the fetus that impose a limitation on growth. In cases of intrinsic genetic defect, such as Down syndrome, the placenta has the same genetic constitution as the fetus, and placental constraints affect growth. Conversely, the prenatal survival of a fetus with an otherwise lethal genetic disorder, such as trisomy 13 or 18 (trisomy 18), results from the clonal proliferation of cells with a normal genetic constitution in the placenta.

      Most complex congenital syndromes—that is, simultaneous occurrences of multiple anomalies and growth deficiency—should be considered the result of autosomal recessive (recessiveness) inheritance or of minute chromosomal changes until proved otherwise. Some complex syndromes are associated with mental retardation (intellectual disability), whereas others predispose the fetus to malignancies or immunodeficiencies. In several such disorders, causative gene mutations have been identified. Disorders such as congenital shortness with abnormal body proportions are frequently genetic, involving the skeleton, connective tissue, and cells. Defects of excessive growth of all or part of the body may indicate a predisposition to tumour formation in an organ or tissue.

dysplasia

       dysplasias are usually congenital abnormalities of tissue development or differentiation. They include tumours of single or mixed tissue types, potentially affecting any part of the body, with a risk of malignant transformation. Most are sporadic, but some are dominant (dominance)ly inherited. In many dysplasias the gene mutations are patchy and require loss of the normal partner gene ( allele, “loss-of-heterozygosity”) for malignant transformation.

Disruptions

      Disruptions are a group of congenital disorders that result from environmental disturbances of the processes of blastogenesis and organogenesis. Several classes of disruption have been recognized, including those due to prenatal infections such as rubella, cytomegalovirus, and toxoplasmosis; chemicals such as mercury, alcohol, thalidomide, and cancer chemotherapeutic (chemotherapy) agents; immune phenomena such as fetal graft-versus-host disease; vascular defects; metabolic defects; hormones such as diethylstilbestrol; gestational disruptions, including defects of implantation; and twinning disruptions such as the acardia anomaly that results in reverse flow of blood from one twin into the other, with the donor twin undergoing any number of regressive or degenerative phenomena eventually resulting in death.

Deformities (malformation)

      Congenital disorders known as deformities are defined as a secondary bending or change of shape. Commonly, these involve a lack of amniotic fluid (oligohydramnios) buffering the fetus from the pressure of the uterine wall and may be due to leakage or failure to produce fluid. Characteristics include flattening of the nose and ears, fixation of the joints (leading to clubbed hands and feet), growth retardation, and underdevelopment of lungs and gut. Arthrogryposes (clawed fingers and contracted joints) may be caused by extrinsic pressure, resulting in joint or limb deformities; however, the majority of cases are caused by intrinsic problems such as weakness from congenital spinal cord, nerve, or muscle dysfunction or abnormal formation of joints. Many intrinsic arthrogryposes are genetic disorders.

Metabolic disorders (metabolic disease)

      A large class of congenital disorders includes inborn errors of metabolism. The causes are hereditary and usually biparental, but they may occasionally be due to mutations on the X- chromosome or in the mitochondrial DNA. Mitochondrial DNA and diseases due to mitochondrial mutations are inherited in a strictly matrilineal manner. The mother's generally normal metabolism could, via the placenta, compensate for her infant's impaired metabolism, in which case no prenatal effects would be expected in the infant at birth. This is true in many metabolic diseases involving relatively small molecules such as amino acids (amino acid), simple sugars, and some hormones. In these conditions, separation of mother and fetus at birth heralds the onset of symptoms. The biochemical aspects of human metabolic diseases are enormously complex and rely heavily on modern technical and chemical advances for detection. See metabolic disease.

Blood disorders (blood disease)

      Congenital metabolic defects of pigments ( porphyrins) derived from the oxygen-carrying molecule hemoglobin in red blood cells may occur. Faulty or deficient production of hemoglobin leads to anemia or red blood cell defects categorized as sickle-cell (sickle cell anemia) disease and thalassemias. Congenital bleeding disorders may involve blood vessels, connective tissues, or clotting factors. The best known is hemophilia, caused by mutations of an X-linked gene.

Other congenital disorders

      The most common congenital disorder affecting cell membrane transport is cystic fibrosis. In the United States, the condition occurs in 1 in every 2,500 births, meaning that 4 percent of all persons are carriers of cystic fibrosis. Of the muscular dystrophies (muscular dystrophy), the X-linked form named for French neurologist Guillaume Duchenne (Duchenne, Guillaume-Benjamin-Amand) (1806–75) is the most common, and, despite detailed knowledge of the causative gene and its effect, it remains a lethal condition. The best known of the many congenital disorders of connective tissue is Marfan syndrome, a rare cause of sudden death in young athletes. The rare class of genetic disorders called imprinting defects is due to abnormal parental expression of usually normal genes. Imprinting defects result in improper embryonic and fetal growth and metabolism and placental function. Less commonly, these genes are deleted or mutated.

      There are numerous congenital immunodeficiency syndromes, some of which may not become manifest until exposure to a specific group of infectious organisms occurs. Another large group of congenitally caused disorders involves hormone deficiency or insensitivity, such as lack of growth hormone production or resistance of receptors to estrogen or testosterone.

Causes

      Most congenital disorders, especially malformations, occur sporadically, as a single isolated case within a family. The same sporadic occurrence in hereditary disease is either because family size is too small or because the disorder represents a new mutation, occurring for the first time in the male or female germ cell and leading to the conception of the affected child. Most chromosome abnormalities represent sporadic occurrence, and in cases of trisomy of chromosomes 13 (trisomy 13), 18 (trisomy 18), or 21 (Down syndrome), there exists a strong correlation with advancing maternal age. Many inborn errors of metabolism are the result of mutations inherited in maternal mitochondrial DNA. Parental defects in the regulation of gene expression cause genomic imprinting defects that result in abnormal expression of maternal and paternal alleles and disruption of embryonic development. In autosomal recessive disorders—that is, disorders inherited from both parents—each parent carries one mutated copy ( allele) of the given gene. The same chance of disorder applies at each conception regardless of the outcome of preceding pregnancies. Environmentally caused disorders such as fetal alcohol syndrome are presumably preventable.

John M. Opitz

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