Genetic Disorders, Malformations, and Inborn Errors of Metabolism*

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27. Genetic Disorders, Malformations, and Inborn Errors of Metabolism*
Anne Matthews and Nathaniel H. Robin
Aneonate born with a malformation, a genetic syndrome, or an acute metabolic disorder presents a management challenge for the neonatal intensive care unit (NICU) staff. If these conditions are not suspected and diagnosed in a critically ill neonate, an appropriate course of action might not be taken. Thus a specific diagnosis becomes imperative. An accurate diagnosis provides the staff with information about the cause of the condition, points the way toward appropriate treatment, and indicates the prognosis so that the most appropriate care of the infant can be initiated. Moreover, the broader issues of providing supportive care and counseling for the affected infant’s family can be addressed.
Genetic evaluation is a complex process that requires expertise in differentiating normal variations from abnormal findings and knowledge of the principles of embryology and dysmorphology to provide an accurate diagnosis. Skills in obtaining detailed information of prenatal and family histories may be equally important.
The field of genomics and genetic medicine has witnessed an explosion of new knowledge, much of which has been generated by the efforts of the Human Genome Project. 13 Advances in understanding of the genetic basis of development and function, as well as the interaction of genes and the environment, continue to provide new insights into human health.
This chapter presents a concise overview of the major categories of genetic disorders and the appropriate techniques to establish specific diagnoses. For an excellent review and detailed explanation of concepts, terminology, and specific genetic mechanisms, refer to Thompson and Thompson Genetics in Medicine.37 See Box 27-1 for a comprehensive list of terms.
BOX 27-1

Aerocentric chromosome A chromosome with the centromere near the end of the chromosome.
Allele One of a pair or series of alternate forms of a gene at the same locus.
Aneuploid Any chromosome number that is not an exact multiple of the haploid set.
Autosome A chromosome that is not a sex chromosome.
Centromere The primary constriction of a chromosome in which the long and the short arms meet.
Chromatid After replication of a chromosome, two subunits attached by the centromere can be seen; each is called a chromatid, and after separation, each becomes a chromosome of a daughter cell.
Chromosomes The microscopic structures in the cell nucleus composed of DNA and proteins that contain the genes.
Congenital Present at birth.
Dermatoglyphics The dermal ridge patterns on the digits, palms, and soles.
Diploid Two copies of all chromosomes; the number of chromosomes normally present in somatic cells. In humans, this is 46 and is sometimes symbolized as 2N.
Dominant A gene (allele) that is expressed clinically in the heterozygous state. In a dominant disorder, the mutant allele overshadows the normal allele.
Dysmorphic Morphologic abnormality, often a minor physical finding that may or may not have any cosmetic or functional significance and is present in less than 4% of the newborn population.
Fluorescence in situ hybridization (FISH) Molecular cytogenetic method for detection of microdeletions of chromosomes.
Gamete Mature reproductive cell, the egg or the sperm, containing the haploid number of chromosomes.
Gene The functional unit of heredity.
Genotype A person’s genetic constitution.
Haploid One copy of all chromosomes; the number of chromosomes present in the gamete; in humans this is 23 and can be symbolized as N.
Hemizygous The condition in which only one copy of a gene is normally present, so its effect is expressed because there is no counterpart gene present (e.g., the genes on the X or Y chromosome of the male).
Heterozygote An individual who has two different alleles at a given locus of two homologous chromosomes.
Homologous chromosomes Members of the same chromosome pair; normally they have the same number and arrangement of genes.
Homozygote An individual who has two identical alleles at a given locus of two homologous chromosomes.
Karyotype The standard pictorial arrangement of chromosome pairs, numbered according to centromere position and length.
Locus The position or place that a gene occupies on a chromosome.
Malformation A primary structural defect that results from a localized error of morphogenesis; abnormal development.
Metacentric chromosome Chromosome with the centromere in the center of the chromosome.
Monosomy Absence of one chromosome of one pair.
Mosaicism Presence in the same individual of two or more different chromosomal constitutions.
Mutation A heritable alteration in the genetic material.
Nondisjunction Failure of two homologous chromosomes to separate equally during cell division into two daughter cells, resulting in abnormal chromosome numbers in gametes or somatic cells.
Phenotype The observable expression of traits either physically or biochemically.
Recessive A gene (allele) that is expressed clinically in the homozygous state. In a recessive disorder, both genes at a given locus must be abnormal to manifest the disorder.
Sex chromosomes The X and Y chromosomes.
Syndrome Recognizable pattern of multiple malformations that occur together and have the same cause.
Transcription The process by which complementary messenger RNA is synthesized from a DNA template.
Translation The process whereby the amino acids in a given polypeptide are synthesized from the messenger RNA template.
Translocation Transfer of all or part of a chromosome to another location (i.e., on the same or another chromosome) after chromosome breakage.
Trisomy The presence of three homologous chromosomes rather than the normal two.
X-linked A gene located on an X chromosome.
Zygote A fertilized egg that develops into an embryo.



A gene is a segment of a deoxyribonucleic acid (DNA) molecule that codes for the synthesis of a single polypeptide and contains the hereditary information needed for development or function. DNA, which allows the storing, duplicating, and processing of hereditary information, consists of two long strands twisted around each other to form a double helix. Each strand of DNA is composed of four nucleotides: guanine (G), adenine (A), thymine (T), and cytosine (C). The specific order of the nucleotides determines the precise information that will be encoded at that site. Genes can (1) regulate other genes by turning them “on” or “off,” (2) specify the exact structure of proteins, which then control the activities of the cells, and (3) specify ribonucleic acid (RNA), which is necessary for protein synthesis.


Genes are packed in linear order on chromosomes. Chromosomes are found in the nuclei of cells. In humans, normal somatic cells contain 46 chromosomes (diploid number), of which 44 are termed autosomes and 2 are sex chromosomes. Females have two X chromosomes (XX), and males have an X and a Y chromosome (XY). Gametes—eggs or sperm—contain 23 chromosomes (haploid number). In the zygote and somatic cells, chromosomes are paired (homologs). In each pair, one homolog is maternal and the other is paternal in origin. Each chromosomal pair has unique morphologic characteristics that allow it to be distinguished from other chromosomes, such as size, position of the centromere, and the unique banding pattern that is demonstrated by special staining techniques (Figure 27-1). 19 To pass on the genetic information to daughter cells, the chromosomes must replicate and then divide correctly. Somatic cells undergo mitosis, in which cells replicate and then divide chromosomal material into two genetically identical daughter cells with 46 chromosomes each. In gametes, the process is known as meiosis, which is different from mitotic division in that daughter cells contain the haploid number of chromosomes (23) and crossing over or recombination between two homologs occurs, thus facilitating genetic variation in offspring. 37
An individual’s chromosome constitution can be determined by examining dividing body cells under certain laboratory conditions from any accessible tissue such as blood lymphocytes or skin fibroblasts. The resulting karyotype (see Figure 27-1), or pictorial arrangement, demonstrates the number and structure of that individual’s chromosomes.


Malformations and genetic disorders caused wholly or partly by genetic factors can be categorized into four major areas: (1) chromosomal disorders caused by numeric or structural abnormalities of chromosomes; (2) single-gene or mendelian disorders, which are secondary to single-gene mutations; (3) complex or multifactorial disorders resulting from interaction of genes and environmental influences; and (4) abnormalities caused by environmental exposures of the fetus during development.
More recently, better understanding of molecular processes has allowed the identification of additional genetic mechanisms contributing to genetic disorders: germline mosaicism, genomic imprinting, and uniparental disomy.

Chromosomal Disorders

Chromosomal abnormalities are relatively common. Approximately 0.5% to 0.7% of all live newborns have a chromosomal abnormality, and 4% to 7% of perinatal deaths result from a chromosomal abnormality. Moreover, it is estimated that at least 50% of all recognized first-trimester miscarriages are caused by a chromosomal aberration. 18 Current cytogenetic techniques, such as high-resolution banding, fluorescence in situ hybridization (FISH), and microarray-based comparative genomic hybridization (array-CGH), have increased the detection rate of chromosomal aberrations. Submicroscopic deletions, duplications, or other abnormal rearrangements of chromosome material that may not have been identified a few years previously are now being detected in children with congenital malformations or mental retardation.
Chromosomal aberrations should be suspected in any of the following situations:
Small for gestational age for weight, length, or head circumference
• Presence of one or more congenital malformations
• Presence of dysmorphic features
Neurologic or neuromuscular dysfunction
Family history of multiple miscarriages or siblings with mental retardation or birth defects along with one or more of the above
Chromosomal abnormalities can be classified into two major categories: (1) abnormalities of chromosome number (aneuploidy), in which there is an extra or missing chromosome; and (2) abnormalities of chromosome structure that result in the loss or duplication of part of the chromosomal material. Abnormalities of autosomes usually have more significant deleterious effects on the development of the infant than those seen with sex chromosome abnormalities.


Numeric chromosomal abnormalities occur as a result of nondisjunction in which aberrant segregation leads to loss or gain of one or more chromosomes. Nondisjunction can occur during either meiosis or mitosis, resulting in an abnormal gamete (egg or sperm) or abnormal somatic cell, respectively (Figure 27-2). Fertilization of an aneuploid gamete by a normal gamete produces a zygote with an extra chromosome (trisomy) or missing chromosome (monosomy). Aneuploidy in somatic cells results in chromosomal mosaicism (i.e., the presence of some cells with the normal number of chromosomes and other cells with an abnormal number of chromosomes) (Figure 27-3). Although nondisjunction may affect any chromosomal pair, the most commonly recognized trisomies in liveborns are trisomy 21 (Down syndrome), trisomy 18 (Edward syndrome), and trisomy 13 (Patau syndrome). On the other hand, trisomy 16 has been found exclusively in spontaneous abortions. 18 The most common monosomy is 45,X, Turner syndrome. As a rule, numeric chromosomal abnormalities are associated with intrauterine growth restriction (IUGR), dysmorphic features, malformations, and mental retardation. Physical abnormalities may be milder or absent in the newborn with mosaicism.


Structural abnormalities have been described in all chromosomes. These include deletions, translocations, duplications, and inversions (Figure 27-4). A deletion is a loss of chromosome material and results in partial monosomy for the chromosome involved. Loss of material from the end of a chromosome is known as a terminal deletion, as seen in 5p−, or cri du chat syndrome. An interstitial deletion involves a loss of chromosomal material that does not include the ends of the chromosome. A terminal deletion of both arms of a chromosome may result in reattachment of the remaining arms, leading to a formation of a ring chromosome. The presence of additional chromosome material results in duplication or partial trisomy of a chromosome. Translocation is the detachment of a chromosome segment from its normal location and its attachment to another chromosome. The translocation is balanced if the cell contains two complete copies of all chromosomal material, although in different order. In an unbalanced translocation, the rearrangement results in partial trisomy or monosomy.
B9780323067157000271/gr4.jpg is missing

(From Hathaway WE, Groothius J, Hay W, editors: Current pediatric diagnosis and treatment, ed 10, Norwalk, Conn, 1991, Appleton & Lange.)
Translocations can be reciprocal or robertsonian. A reciprocal translocation involves exchange of segments between two chromosomes (e.g., part of the short arm of chromosome 4 trades a place with a part of chromosome 10). Robertsonian translocations involve two acrocentric chromosomes fused at their centromeres. The most common robertsonian translocation is formed between chromosomes 14 and 21. 22
Inversions are the result of a double break in a single chromosome and reinsertion of the chromosomal material that has been inverted. Inversions are either pericentric (including the centromere) or paracentric (without the centromere). The most common inversion is a small pericentric inversion of chromosome 9, which is considered to be a normal variant, found in approximately 1% of the general population. 37 All other inversions may produce gametes that result in an individual with an unbalanced rearrangement (i.e., having both a duplication and a deletion of some chromosome material, such as that seen in recombinant 8 syndrome).


At times, structural chromosomal abnormalities are submicroscopic and therefore cannot be detected by conventional cytogenetic techniques. FISH is a molecular cytogenetic method that facilitates the detection of microdeletions. FISH uses segments of fluorescently labeled DNA called probes, constructed so that each probe can attach only to a specific segment of a chromosome, which then will be fluorescent during a microscopic visualization. In the case of a deletion of that chromosome segment, the probe cannot attach to the chromosome; thus the fluorescent segment is missing from the deleted segment of that chromosome. 45
The most recent advance being used to detect very small submicroscopic deletions and duplications is comparative genomic hybridization (array-CGH). 15 This technology blends molecular techniques with cytogenetics and allows the genome to be scanned at a higher resolution than conventional techniques. DNA from a patient sample and DNA from a control sample are differentially labelled, mixed in equal proportions, and hybridized to DNA substrates fixed on an array platform (i.e., bacterial artificial chromosomes [BACs] or oligonucleotides [short segments of DNA usually 8-50 base pairs]). This technique can measure the difference between two different DNA samples in copy number (dosage) of a particular segment of DNA. Thus microscopic gains and losses from a patient sample can be quantified. 15
Microdeletions result in phenotypic abnormalities. A number of well-recognized microdeletion syndromes may be suspected in the NICU. Prader-Willi syndrome, caused by an interstitial deletion of chromosome 15 (q11q13), usually manifests in a newborn as severe hypotonia, feeding difficulties, and micropenis or hypoplastic labia. 9Williams syndrome is caused by an interstitial deletion or mutation of the elastin gene (ELN) on the long arm of chromosome 7 (7q11). 35 The condition is often first seen in an affected newborn in the postterm period; the infant is small for family size. There may be a congenital heart defect, in particular, supravalvular aortic stenosis or peripheral pulmonic stenosis; hypotonia; failure to thrive with gastroesophageal reflux; poor suck and swallow; and vomiting and irritability or colic. Infantile hypercalcemia is seen in approximately 20% of these infants. Subtle dysmorphic facial features may be noted in the newborn. 35
One of the most commonly seen microdeletion syndromes is velocardiofacial syndrome (VCFS), which is characterized by cleft palate or velopharyngeal insufficiency, hypernasal speech, learning disabilities, conotruncal heart defects, and characteristic facies. VCFS actually represents one of a spectrum of clinical disorders all known to be caused by a deletion in chromosome 22q11 (del22q11). These include DiGeorge syndrome (DGS) (conotruncal heart defect, hypocalcemia, and thymic hypoplasia) and conotruncal anomaly face syndrome (CTAF) (conotruncal heart defects and typical facies). In addition, del22q11 has been found in 11% to 16% of cases of nonsyndromic congenital conotruncal heart disease and has been reported to present as apparently isolated neonatal hypocalcemia or learning problems. 14 Overall, del22q11 has an estimated incidence of 1 in 2000 to 4000 newborns. The availability of molecular cytogenetic testing by FISH has led to appreciation of both the high incidence of the del22q11, as well as the increasing variety of clinical presentations that can be seen even within a single family. 32
In the newborn period, the characteristic facial features are seldom obvious. However, most affected individuals manifest some of these findings by early childhood. Most prominent is the nose, which is described as long, with a “built up nasal bridge, squared off nasal root, and bulbous nasal tip.”42 The eyes appear narrow and slitlike, the mala (cheeks) are flat, and the jaw is recessed. The ears usually are small and in some way abnormally formed. There may be an overt cleft of the secondary palate, a bifurcated uvula, a subtle submucosal cleft, or cleft lip with or without cleft palate. Other nonstructural palatal abnormalities can be seen, most commonly velopharyngeal insufficiency. In an older child or adult, this presents as hypernasal speech; in a newborn, one sees excessive nasal regurgitation. Congenital heart disease (CHD) is seen in 35% of del22q11 patients. The type of CHD is fairly specific and includes those lesions classified as “conotruncal heart defects” (truncus arteriosus, interrupted aortic arch, tetralogy of Fallot, left-sided aortic arch, vascular rings, and some types of ventricular septal defects [VSDs]). Perhaps the most consistent finding in patients of all age-groups is long, thin fingers and toes. Additional nonspecific findings include abundant scalp hair; hypospadias; renal abnormalities that can include renal agenesis; tortuous retinal vessels; ectopic/aberrant/unilateral absence of carotid and vertebral artery; microcephaly; and microdontia (there are 166 different findings to date). 42
Developmental delay, learning disabilities, or mental retardation is common and quite variable. Behavioral and psychiatric problems are common but underappreciated findings in VCFS. These individuals have a characteristic personality, marked by a flattened affect and abnormal social interaction, ranging from being intermittently withdrawn to socially precocious. A host of other psychiatric diagnoses have been seen in patients with VCFS.
Both DiGeorge syndrome and VCFS have been recognized as being caused by deletions in 22q11. More than 95% of cases of DGS and VCFS are deleted. In a small number of patients with DGS, point mutations in TBX1 have been found when no deletion was identified. 50 There are a few cases of VCFS in which no 22q11 deletion or TBX1 mutation has been found. Thus obtaining family histories and examining parents for subtle features of the syndrome are important. In many cases, the infant has inherited the abnormality from a parent.


Down Syndrome

Down syndrome has an incidence of approximately 1 in 600 live births. Approximately 95% of cases are caused by nondisjunction involving chromosome 21, 4% are caused by a translocation, and 1% are mosaic. Down syndrome may manifest with marked hypotonia; a number of major malformations, most commonly congenital heart defects, duodenal atresia, and tracheoesophageal fistula; and a characteristic pattern of dysmorphic features. The classic phenotype seen in Down syndrome includes a flattened occiput, midfacial hypoplasia, depressed nasal bridge, upward-slanting palpebral fissures, epicanthic folds, grayish speckling of the iris (Brushfield spots), micrognathia, excess nuchal skin, single palmar creases (simian creases), single flexion creases and in-curving of the fifth fingers (clinodactyly), and increased distance between the first and second toes (Figure 27-5).
B9780323067157000271/gr5.jpg is missing

( A from Cohen MM: The child with multiple birth defects, ed 2, New York, 1997, Raven Press. B courtesy Dr. Eva Sujansky, Genetic Services at The Children’s Hospital, Denver, Colo.)
In full-term infants with the classic phenotype of Down syndrome, the clinical diagnosis is not difficult. However, it is imperative that cytogenetic studies be done to confirm the diagnosis and to differentiate a nondisjunctional trisomy from a translocation. This distinction has important implications for recurrence risks (see discussion in “Prevention” section). In premature infants, the classic facial phenotype is frequently missing, making clinical diagnosis more difficult. The presence of an atrioventricular (AV) canal or duodenal atresia with minor malformations, such as abnormal dermatoglyphics, should alert the clinician to the possibility of Down syndrome.

Trisomy 18

Trisomy 18 has an incidence of 1 in 6000 live births. The major phenotypic features include prenatal growth restriction, complex cardiac malformations, abnormal muscle tone, microcephaly, prominent occiput, short sternum, low-set and malformed ears, corneal opacities, micrognathia, peculiar hand posturing with the second and fifth digits overlapping the third and fourth, hypoplasia of fingernails, abnormal dermatoglyphics, prominent calcanei, and deep plantar furrows between the first and second toes (Figure 27-6). The prognosis is poor, and the majority of infants with trisomy 18 die within the first few months of life. Infants who have survived into childhood are profoundly retarded.
B9780323067157000271/gr6.jpg is missing

(From Paerregaard P, Mikkelsen M, Froland A, et al: Trisomy no. 17-18: report of two cases, Acta Pathol Microbiol Scand 67:479, 1966.)

Trisomy 13

Trisomy 13 is seen in approximately 1 in 15,000 live births. Phenotypic features include prenatal and postnatal growth restriction, microcephaly, sloping forehead, coloboma of the iris, microphthalmia or anophthalmia, low-set or malformed ears, cleft lip and palate, postaxial polydactyly, and abnormal palmar creases and dermatoglyphics (Figure 27-7). Internal abnormalities may include a number of central nervous system (CNS) malformations, such as holoprosencephaly, cardiac malformations, omphalocele, renal malformations, and urogenital abnormalities such as cryptorchidism in males and uterine malformations in females. The prognosis is extremely poor for these infants, with most dying within the first few months of life.
B9780323067157000271/gr7.jpg is missing

(From Hathaway WE, Groothuis J, Hay W, editors: Current pediatric diagnoses and treatment, ed 10, Norwalk, Conn, 1991, Appleton & Lange.)

Turner Syndrome

The only monosomy to be seen in live births is that of Turner syndrome—females with a 45,X karyotype. In addition, it is the only numeric abnormality of the sex chromosome that may be identifiable at birth. Turner syndrome has an incidence of 1 in 5000 female births. 40 Clinical features that may be evident in the newborn period are a short, webbed neck or redundant skin on the back of the neck and marked lymphedema of the dorsum of the hands and feet (Figure 27-8). Congenital heart defects are seen in approximately half of the patients, with 30% having a coarctation of the aorta. Renal anomalies may also be present. 23 Prognosis is usually excellent but depends on the presence and severity of the congenital heart defect. Intelligence is normal; however, some females with Turner syndrome have been noted to have problems with spatial perception or fine motor abilities. 40
B9780323067157000271/gr8.jpg is missing

(From Knuppel R, Drukker JD, editors: High risk pregnancy: a team approach, Philadelphia, 1988, Saunders.)

Cri du Chat

Cri du chat, or “cat cry” syndrome, is the result of loss of the terminal end of the short arm of chromosome 5 (5p−). The name of the syndrome reflects the unusual catlike, weak cry these infants have in the neonatal period. These infants are usually small for gestational age, hypotonic, and microcephalic and may have ocular hypertelorism, epicanthic folds, downward slant of the palpebral fissures, low-set ears, and micrognathia. They are significantly mentally retarded.

San Luis Valley Syndrome

Recombinant 8 or the San Luis Valley syndrome, named for the area in which many of these individuals were first identified, is an example of an unbalanced pericentric inversion with both a duplication and a deletion of chromosome 8 material. The pericentric inversion of chromosome 8 found in a parent and other relatives of a child with recombinant 8 syndrome has no phenotypic consequence because it is a balanced rearrangement. However, a carrier is at risk for producing unbalanced gametes during meiosis. In recombinant 8 syndrome, there is a deletion of chromosomal material of the short arm of chromosome 8 and a duplication of chromosome material of the long arm of 8. The phenotype is characterized by unusual facial features, including a wide face, depressed nasal bridge, hypertelorism, down-slanting palpebral fissures, upturned nose, long philtrum, low-set and malformed ears, cleft lip or cleft palate, congenital heart disease, and renal abnormalities. 43


The identification of chromosomal abnormalities in the newborn is important, not only for management issues about the infant but also because of the recurrence risks the abnormality carries for the family. In general, numeric chromosomal abnormalities carry low recurrence risks (approximately 1% to 2%). 18 In the presence of structural abnormalities, recurrence risks depend on whether one of the parents carries a balanced rearrangement. If parental chromosomes are normal, the recurrence risk is minimal. However, if a parent carries a balanced chromosomal rearrangement, the recurrence risk is significantly increased. The exact risk figure varies with the nature of the specific chromosomal rearrangement and, in some cases, the sex of the carrier parent. In either situation, prenatal diagnosis for chromosome analysis is available for parents and families concerned about recurrence risk.

Single-Gene Disorders

McKusick’s online catalog of mendelian inherited disorders currently lists more than 19,000 entries with approximately 6000 single-gene disorders with known patterns of inheritance. 38 Many of these disorders are singularly rare; however, collectively, they affect about 1% of the population. Single-gene disorders are the result of either a single or double dose of an abnormal gene. Single-gene disorders are classified as autosomal dominant, autosomal recessive, X-linked dominant, and X-linked recessive. Humans have two copies of each gene located at identical places (gene loci) on homologous chromosomes. In a single-gene disorder, an abnormal or mutated allele (an alternate form of a gene) is found on one or both members of a pair of chromosomes. 37 Individuals with identical alleles at a particular locus are homozygous for the gene. Individuals with different alleles are heterozygous for the gene. Because males have only one X chromosome and most genes located on the Y chromosome do not correspond to those located on the X, males are hemizygous for the genes on the X chromosome. Abnormal genes located on one of the 44 autosomes are the cause of autosomal disorders: disease-causing genes located on the X chromosome are the cause of X-linked disorders. Disorders are dominant when the phenotype is expressed in the presence of only one copy of the mutated gene. In recessive disorders, the phenotype is expressed only when both chromosomes carry the mutated gene.


Autosomal dominant disorders are ones in which the disorder is expressed in the heterozygous state. Major characteristics include the following: (1) multiple generations are affected (i.e., an infant would have an affected parent); (2) both males and females are affected, and both sexes can transmit the disorder to their offspring (i.e., male-to-male transmission can occur); (3) there is a 50% risk for each offspring to inherit the gene from an affected parent; and (4) individuals who do not have the gene cannot transmit the disorder to their offspring.
A negative family history does not rule out the presence of an autosomal dominant disorder.

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