Genetic Disorders and Dysmorphic Conditions

1 Genetic Disorders and Dysmorphic Conditions

The field of pediatric genetics and dysmorphology is complex, interesting, and rapidly evolving. Our knowledge base is gleaned from the careful observations of master clinicians and scientists who recognized clinical characteristics and patterns of malformation in individuals with genetic, teratogenic, developmental, and metabolic problems. They have provided us with a framework for the investigation of patients from clinical and laboratory perspectives. In addition to classic cytogenetics, molecular cytogenetics methods have been increasingly incorporated in clinical settings and have greatly assisted evaluation, enabling far greater understanding of the molecular and physiologic basis of these disorders, and have greatly increased the rate of diagnosis of children with genetic and metabolic disorders. However, even with the availability of an ever-widening array of confirmatory tests, clinical evaluation of patients remains an essential component of the complete assessment of children and adults with genetic diseases and dysmorphic conditions. This stems from the fact that careful evaluation can substantially reduce the number of differential diagnostic possibilities and, thereby, the number of diagnostic tests and the total expense.

Visual identification of dysmorphic features, baseline anthropometrics combined with serial measurements with recognition of patterns of malformation and behavioral phenotypes, remains an integral part of the diagnostic algorithm. As in pediatrics in general, genetic disorders should be investigated on the basis of a careful history, with a family pedigree and a thorough physical examination including evaluation for the presence of major and minor anomalies, and thoughtful laboratory testing. This chapter is designed to present clinicians who care for children with background on the general principles of genetics and dysmorphology, as well as updated information about important advances in our field. Although not exhaustive, it provides a framework for the broad categories of genetic diseases and discusses an approach to the evaluation of the dysmorphic child. Definitions and examples of the types of disorders resulting in genetic and/or congenital anomalies in children are described, including malformations, deformations, disruptions, associations, and sequences. We include examples of disorders inherited through classic mendelian inheritance patterns, including single-gene mutations, such as Marfan syndrome, Rett syndrome, Smith-Lemli-Opitz syndrome, and Conradi-Hünermann syndrome as well as examples of nonmendelian disorders such as teratogenic exposures in utero and disruptions or deformations of previously normal fetal structures. New etiologic mechanisms of diseases such as imprinting abnormalities and expansions of trinucleotide repeats in nuclear deoxyribonucleic acid (DNA) are presented. Last, a newly evolving area of genetics, the investigation of disorders of mitochondrial DNA and/or mitochondrial function, is discussed.

Common Chromosomal Disorders

General Principles

The Nature of Chromosomes

Productive insights gleaned from the results of the completed Human Genome Project have dramatically changed some of our understanding of how the human genome functions. However, it is important to introduce to the reader our current understanding of the subject matter. Human hereditary factors are located in genes (the genome). Approximately 10% are genes that encode proteins that are assembled to form tissue structures or to form enzymes that catalyze chemical reactions within cells. The other 90% have functions that are currently not clear (see also The Nature of Genes and Single-gene Disorders, later). The genes are composed of DNA and are stored in intranuclear cell organelles called chromosomes. Each chromosome contains one linear DNA molecule folded over onto itself several times, as well as ribonucleic acid (RNA) and proteins. Because all genes exist in pairs, all chromosomes must likewise exist in pairs. The members of each pair of genes are called alleles, and the members of each pair of chromosomes are known as homologues. The conventional depiction of the constitution of homologues in the nucleus is called the cell’s karyotype (Fig. 1-1). If at any gene locus the alleles are identical, that gene locus is homozygous. If the alleles are not identical, the gene locus is heterozygous.

Except for gametes, normal human cells contain 23 pairs of chromosomes, 46 in all. One of these pairs is concerned in part with inducing the primary sex of the embryonic gonads. These sex chromosomes are called the X and Y chromosomes, and they are not genetically homologous except in a few areas. Women have two X chromosomes, whereas men have an X and a Y chromosome. The remaining 22 pairs are called autosomes and they determine non–sex-related (somatic) characteristics.

During most of a cell’s life cycle, chromosomes are diffusely spread throughout the nucleus and cannot be identified by morphologic means. Only when the cell divides does chromosome morphology become apparent (Fig. 1-2). The in vitro life cycle and the cellular division, or mitosis, of a somatic cell are illustrated in Figures 1-3 and 1-4, respectively. The life cycle and divisions, or meiosis, of a germ cell are much more complex and are not suitable for ordinary clinical evaluation.

Any somatic cell that can divide in tissue culture can be used for chromosomal (cytogenetic) analyses. The most convenient tissue source is peripheral blood, from which lymphocytes can be stimulated to divide during 2 or 3 days of incubation in tissue culture medium. Fibroblasts obtained from skin remain a frequently used alternative when peripheral blood lymphocytes are not clinically suitable, but fibroblasts require an incubation period of 4 to 6 weeks. After death, lung tissue is the best tissue to culture for chromosomal analyses, although the process also requires a 4- to 6-week incubation period. Alternatively, skin fibroblasts are frequently obtained postmortem for various enzymatic and cytogenetic analyses, which may be used to confirm a clinical diagnosis. When a treatment decision requires urgency, preliminary chromosomal evaluation can be made within 4 to 24 hours by using uncultured bone marrow aspirate. Oftentimes the karyotype is supplemented within 48 to 72 hours by a molecular cytogenetics technique, either interphase or metaphase fluorescence in situ hybridization (FISH), using rapid culturing and diagnostic techniques. More recently, conventional cytogenetics is being substituted by high-resolution molecular karyotyping using microarray-based comparative genomic hybridization (array-CGH). Array-CGH enables copy number changes at high resolution. This is implemented in the clinical setting and is being recommended as the first step in the investigation of patients with developmental delays, mental retardation, and multiple congenital anomalies. FISH and other molecular techniques are now used primarily to confirm the imbalances detected by array-CGH. This is an ever-evolving area, and pediatric clinicians are advised to discuss clinical and laboratory investigations with clinical geneticists and/or laboratory directors before the initiation of tissue sampling to ensure the most productive use of samples and rapid testing methods.


Aneuploidy refers to an abnormality in chromosome number, in humans a chromosome number different from an even multiple of 23 (the haploid number) (Fig. 1-5). In aneuploidy there are typically 45 or 47 chromosomes instead of the usual 46. Rarely, multiples of the X or Y chromosome result in individuals with 48 or 49 chromosomes. Double aneuploidy, the simultaneous occurrence of two nondisjunctional events, has been described in the literature. In the liveborn, it usually involves one autosome and one sex chromosome. Double autosomal trisomy has been found repeatedly in spontaneous abortion but has not been demonstrated in a liveborn infant.

If aneuploidy occurs in a gamete as a result of an error of chromosomal division (nondisjunction or anaphase lag) during meiosis, all cells are affected in the fertilized embryo. With subsequent pregnancies, the risk for another chromosomal abnormality in the offspring is increased approximately 1% to 2% overall, in addition to the general background risk of abnormalities. The couple would be at risk for aneuploidy states of many types, not just the particular aneuploidy in their affected child. We are not yet aware of the underlying mechanism for the increased risk; however, families may benefit from an understanding of the possibilities for prenatal diagnosis in their individual case and may want to be referred for genetic counseling before the conception of another child (Fig. 1-6, AC).

Mosaic Aneuploidy States

Mosaicism, the presence of two or more genetically different cell lines within an individual, can result from an error in division during either meiosis or mitosis. In one possible scenario aneuploidy originates during meiotic division (i.e., before conception). In such cases the fetus starts out with an aneuploid chromosomal number and, subsequently, a division error occurs, resulting in the formation of another cell line that is chromosomally normal. In other cases of mosaicism the one-celled embryo (zygote) is chromosomally normal and a division error occurs after fertilization, during mitosis of an embryonic somatic cell, resulting in aneuploidy. Most individuals with mosaicism have only two or three different lines of embryonic cells. It requires considerable laboratory investigation to distinguish the meiotic or mitotic types. Generally speaking, parents are given a 1% to 2% recurrence risk because of the possibility of mosaicism present in a parental gonad, which is not identifiable in usual tissue sample analyses (Fig. 1-7).

Hypomelanosis of Ito is characterized by marbleized or mottled areas of hypopigmented whorls of skin along the Blaschko lines and is of heterogeneous etiology. Individuals with hypomelanosis of Ito can have multiple congenital anomalies, dysmorphic features, variable mental retardation, and other neurologic findings. Karyotyping from skin lesions will reveal mosaic abnormality of chromosomes from normal or hypopigmented and hyperpigmented regions. Balanced and unbalanced chromosome aberrations and uniparental disomy may be encountered (Fig. 1-8).

Abnormalities of Chromosome Structure

Chromosomes can be normal in number (diploid) but still be abnormal in structure. Inversions (Fig. 1-9), deletions (Fig. 1-10), and translocations (Fig. 1-11) of genetic material are examples of structural chromosomal abnormalities. These can arise as new (sporadic) mutations in the egg or sperm from which the embryo was formed, in which case the parents’ recurrence risk for another child with a chromosomal abnormality is again 1% to 2%. However, the abnormality may also be inherited from a phenotypically normal parent who is a “carrier” of a structural chromosomal abnormality (Fig. 1-12). About 1 in 520 normal individuals carries a balanced but structurally abnormal set of chromosomes, called a chromosome translocation. The term balanced, for the purposes of this chapter, means that on cytogenetic analysis the structural abnormality does not appear to have resulted in any net loss or gain of genetic material. If the apparently balanced chromosomal abnormality has been transmitted by other members of the family who are apparently phenotypically normal, it is considered a familial balanced translocation. Data suggest that a small percentage of individuals with apparently “balanced” translocations are actually mildly affected clinically by variable degrees of cognitive and physical deficits (Warburton, 1991). Thus high-resolution chromosome analyses and molecular cytogenetics techniques, such as array-CGH, are warranted in these instances including, as needed, in situ hybridization techniques using DNA probes to completely characterize the location of the chromosome breakpoints and to determine on a molecular level whether any genetic material is missing. Molecular studies for imprinting effects may also be warranted.

A frequent way in which families with apparently balanced chromosome translocations present for evaluation occurs when a child is born with structural malformations and on karyotyping is found to have an unbalanced chromosome translocation. This may have occurred de novo in the child’s chromosomes only or may be due to a previously undiagnosed familial balanced chromosomal translocation in a parent. Parental karyotypes are used to distinguish the etiology and are crucial in providing accurate genetic counseling regarding future pregnancies for that couple.

Incidence of Chromosomal Abnormalities

Data from Hook (1992) suggest that upward of 50% of human conceptions terminate in a spontaneous abortion. Most of these miscarriages occur so early during gestation that the pregnancy is never recognized. The earlier the abortion occurs, the more likely it is that the miscarried embryo had a chromosomal abnormality. Of recognized first-trimester abortuses, 50% are chromosomally abnormal, compared with 5% of later embryos. Among the chromosomally abnormal abortuses, the most frequent abnormalities are triploidy (69 chromosomes), trisomy 16, and 45,X (Turner syndrome) (Table 1-1). Generally speaking, triploidy and trisomy 16 are not compatible with life and are only occasionally seen among liveborn infants. Despite the fact that Turner syndrome is relatively common among liveborn infants, the majority of conceptuses with 45,X also abort spontaneously. The incidence of chromosomal abnormalities among liveborn infants in general is about 6 in 1000. Among a group including both stillborn infants and infants who die in the immediate perinatal period, the number is increased to approximately 50 in 1000.

Table 1-1 Occurrence of Chromosomal Abnormalities

Among Spontaneous Abortuses Incidence (%)
Overall incidence 32.0
First trimester 52.0
After first trimester 5.8
Type of abnormality seen in spontaneous abortions  
Trisomy 16  
Other trisomies  
Among Liveborns No. of Cases per 1000
Overall incidence 6.20
Abnormality of autosomes 4.19 (males and females)
Balanced rearrangements  
Unbalanced rearrangements  
Abnormality of sex chromosomes 2.03 (males and females)
In males: XXY, XYY, mosaics  
In females: 45,X (0.08), XXX, mosaics (1.43)  

About one quarter of all conceptuses are chromosomally abnormal. About 50 in 1000 stillborns have a chromosomal abnormality.

When to Suspect a Chromosomal Abnormality

Chromosomal abnormalities of either number or structure are likely to have a detrimental effect on the phenotype of an affected individual. Aneuploidy of an autosome, or nonsex chromosome, generally significantly impairs physical and cognitive development. However, aneuploidy of a sex chromosome may have little or no apparent effect on the phenotype. One should look for clustering of abnormalities in family members to suggest a problem, although their absence does not rule out a chromosomal abnormality.

Carriers of an inherited or a de novo reciprocal translocation are usually genetically balanced and are subsequently normal. However, their conceptuses are likely to be genetically unbalanced and may abort spontaneously or be born with major congenital anomalies. A history of unexplained infertility, multiple spontaneous abortions (three or more), and particularly of a previous birth to the couple or to a close relative of a child with dysmorphic findings and/or major anomalies may be an indication that one of the parents carries a balanced chromosomal translocation or rearrangement. A chromosome study on the couple is thus indicated, and if translocation is found, they should seek antenatal genetic counseling. This may also be advisable for extended family members.

A normal person who carries a balanced reciprocal translocation can commonly produce six chromosomal types of gamete. On fertilization, these gamete types can result in several possible fertilized embryos: a normal conceptus, a carrier conceptus like the normal carrier parent, two types of immediately lethal conceptus resulting from gross chromosomal imbalances (i.e., too much or too little DNA), or two types of abnormal conceptus caused by lesser chromosomal imbalances. Whether the latter two types abort spontaneously or come to term as liveborns cannot be predicted in advance solely on theoretical grounds. Therefore genetic counseling in such situations depends somewhat on analysis of what has occurred within the individual family and in other families with similar rearrangements. Rarely, other types of chromosomal imbalances are found in conceptuses of such carrier parents.

Experience suggests the following: If a carrier has already produced a chromosomally unbalanced liveborn child, then it is apparent that it is possible for this to occur again in future pregnancies, and the risk that the translocation carrier might have another chromosomally unbalanced liveborn infant can be as high as 20%. However, if the translocation carrier parent has produced either only healthy liveborn infants or spontaneous miscarriages, then it is less likely that the chromosomally unbalanced gametes are viable. Consequently, that person’s risk for producing a chromosomally unbalanced liveborn is only about 4%. Last, if a couple of whom one spouse is a carrier has not yet experienced any pregnancies, their risk for a chromosomally abnormal liveborn is estimated to be about 10%.

New Technologies

Fluorescence in Situ Hybridization

FISH is a laboratory technology that has revolutionized the diagnostic capabilities of clinical cytogenetic laboratories. In this technique a DNA probe is tagged with a label that fluoresces when viewed under a special microscope. A cocktail of many repetitive DNA probes blanketing a specific chromosome from end to end can be obtained. This is called a FISH “paint.” Using special microscope filters, a clinician can simultaneously FISH paint a slide with probes fluorescing in two or three different colors. FISH paints specific for all chromosomes are available.

Some of the well-recognized syndromes described initially by FISH probes for chromosome microdeletion syndromes include the following:

See Figures 1-13 and 1-14 for details on Prader-Willi/Angelman syndrome and Wolf-Hirschhorn syndrome.

Array-based Technology: Microarray for Evaluation of Copy Number Variation

In addition to classic cytogenetics, molecular cytogenetic methods are being incorporated in clinical settings at an increased rate. More recently, conventional cytogenetics is being substituted with high-resolution molecular karyotyping using microarray-based comparative genomic hybridization (array-CGH). Array-CGH analyses are proficient in detecting imbalances in the genome and enable detection of copy-number changes at high resolution. This technique has been implemented by the American College of Medical Genetics (ACMG) as the first step in the investigation of patients with developmental delays, mental retardation, multiple congenital abnormalities, and autism spectrum disorders and has the highest diagnostic yield, up to approximately 15% to 28%. This is much higher than the diagnostic yield of G-banded karyotypes (on the order of 3%), excluding Down syndrome and other recognizable chromosomal syndrome (Miller et al, 2010). In addition, molecular cytogenetic techniques, such as array-CGH, have demonstrated that approximately 20% of apparently balanced chromosome translocations, de novo or familial, have gain or loss of genetic material at the breakpoints. Therefore, molecular cytogenetic studies are warranted because they completely characterize the location of the chromosome breakpoints and potentially identify additional genetic material that may be duplicated or deleted that would not otherwise be detected by the traditional cytogenetic methods. FISH and other molecular techniques are now used primarily to confirm the imbalances detected by array-CGH. With microarray testing, many new microdeletion and microduplication syndromes have emerged (e.g., deletion 1p36, deletion 1q21.1, and deletion 16p13.11 syndromes) (Fig. 1-15; and see e-Figs. 1-1 through 1-3).

Single-nucleotide polymorphism (SNP) arrays are being used in clinical settings and allow genome-wide copy-number analysis. The copy-number changes may provide insight into abnormalities such as segmental and uniparental disomy by revealing “copy number-neutral” areas of continuous homozygosity that can give rise to disease, congenital anomalies, and/or cognitive impairment. SNP arrays may be helpful in identifying translocated segments in uniparental disomy and in looking for imprinting effects of the chromosomal regions.

Molecular karyotyping and single nucleotide polymorphism (SNP) arrays are ultimately more cost-effective tests and have been extremely useful to clinicians in identifying necessary medical surveillance and treatment options, and they provide information on recurrence risks and prenatal options for families.

The impact of these newer methodologies continues to emerge, but their usefulness in providing information key to clinical prognosis is clearly becoming evident.

Array-CGH has been increasingly used for genetic testing of individuals with idiopathic mental retardation, developmental delay, autism spectrum disorders, and multiple congenital anomalies. By combining the array-CGH technique with classic cytogenetic and confirmatory FISH and appropriate molecular analyses, we are also able not only to identify cryptic genomic alterations but also to further analyze gross genomic alterations including marker chromosome or other rearrangements identified by the classic cytogenetic analysis.

In cases of disorders with several etiologic mechanisms such as Angelman syndrome, the absence of a deletion does not mean the child does not have the condition. An alternative mechanism, such as an imprinting center defect or uniparental disomy, may be the cause and would require methylation studies for detection.

DiGeorge sequence is discussed in Chapter 4, Williams syndrome is discussed in Chapter 5, and Angelman and Prader-Willi syndromes are covered later in this chapter. The remaining syndromes are outlined briefly in Table 1-2 and in Figure 1-16, AD; Figure 1-17; and Figure 1-18.

Table 1-2 Some Syndromes Identifiable with Fluorescence in Situ Hybridization Probes

Syndrome Major Findings Comments
Cri du chat (deletion 5p15.2) Microcephaly, round face, down-slanting palpebral fissures, epicanthal folds, hypertelorism, catlike cry in infancy  
Isolated lissencephaly Lissencephaly (incomplete development of brain with smooth surface) Approximately 30% have deletion 17p13.3
Miller-Dieker phenotype with lissencephaly Microcephaly, lissencephaly, variable high forehead, vertical furrowing of central forehead, low-set ears, small nose with anteverted nostrils, congenital heart disease, poor feeding Deletion 17p13.3 in vast majority
Deletion 22q11.2 Phenotypes:

Appears to be a common deletion and should be considered in the differential diagnosis of children with multiple anomalies even if the features are not classic to any one phenotype
Wolf-Hirschhorn (deletion 4p16.3) Moderate to severe cognitive impairment, hypertelorism, preauricular pit or tag, broad nasal bridge, micrognathia, cleft palate, short philtrum, growth deficiency  
Smith-Magenis (deletion 17p11.2) Brachycephaly, flat facies, broad nasal bridge, short stature Self-hugging behaviors, sleep disturbances

Approach to the Evaluation of a Dysmorphic Child

Approximately 2% to 3% of liveborn infants have an observable structural abnormality. This number rises to about 4% to 5% by the time the child is old enough to attend school. Structural differences can be determined to be either major or minor in character (Table 1-3, and Figs. 1-19 and 1-20). Major structural anomalies have functional significance. Examples are polydactyly, colobomas of the iris (see Chapter 19, Fig. 19-69), meningomyelocele, and cleft lip. Minor anomalies are usually of cosmetic importance only. Examples are epicanthal folds of the eyes, single transverse palmar creases, and supernumerary nipples. The incidence of isolated major anomalies in the general newborn population is approximately 1%, and the incidence of minor anomalies is approximately 14%. Both are more common in premature newborns.

Table 1-3 Examples of Congenital Anomalies

Category Major Minor
Craniofacial Choanal atresia Plagiocephaly
    Flat occiput
Eyes Coloboma of iris Epicanthal folds
Ears Microtia Preauricular pit
Hands Polydactyly
Absent thumbs
Single transverse palmar crease

The probability of an infant having a major anomaly increases with the number of minor anomalies found. Thus all children with multiple minor anomalies warrant a careful clinical assessment in order to find potentially significant occult major anomalies. Once an anomaly is identified, assessing its significance begins with a determination of whether the anomaly in question is a single localized error in morphogenesis or one component of a multiple malformation syndrome. An understanding of the pathophysiologic mechanisms that produce structural abnormalities or differences provides an opportunity to define the types of structural abnormalities seen. This also assists the process of identifying the etiology and arriving at a specific diagnosis, which then can be useful in determining the prognosis and estimating the risk of recurrence of a similar problem in future pregnancies.

Definitions of the classifications of structural anomalies aid in communication between clinicians and in the process of evaluation and are summarized from Jones (2006):

Malformation: A malformation is an abnormality of embryonic morphogenesis of tissue. It usually results from genetic, chromosomal, or teratogenic influences, but it can be of multifactorial etiology. Malformations are divided into two main categories: those that constitute a single primary defect in development and those that represent a single component of a multiple malformation syndrome. A multiple malformation syndrome can be defined as one having several observed structural defects in development involving multiple organ systems that share the same known or presumed etiology. Malformations often require surgical intervention.

Deformation: A deformation represents an alteration (often molding) of an intrinsically normal tissue caused by exposure to unusual extrinsic forces. A classic example is clubfoot, which may be the result of uterine constraint from crowding associated with a multiple gestation. A more severe example is the compressed facial features (“Potter facies”) of a child exposed to severe uterine constraint associated with oligohydramnios, due to renal agenesis (see Chapter 13, Fig. 13-38). The vast majority of deformations respond to medical therapy alone and have a relatively good prognosis in contrast to malformations, which frequently require surgical intervention.

Disruption: A disruption represents a breakdown of normally formed tissue; the breakdown may be the result of vascular accidents or exposure to adverse mechanical forces that are usually more severe than those that produce deformation. A classic example is the combination of clefting, constriction bands, and limb reduction defects associated with the presence of amniotic bands (see Chapter 2, Fig. 2-46). The earlier these vascular accidents or abnormal forces occur during embryogenesis, the more severe the resulting defects (Fig. 1-21).

Dysplasia: Dysplasia is characterized by abnormal organization of cells within tissue, which usually has a genetic basis. An example is achondroplasia, the most frequent form of skeletal dysplasia.

(Note: Each of the preceding categories can have a sequence [see below] associated with it.)

Sequence: The term sequence refers to a recognizable pattern of multiple anomalies that occurs when a single problem in morphogenesis cascades, resulting in secondary and tertiary errors in morphogenesis and a corresponding series of structural alterations. A classic example is the Robin malformation or Pierre Robin sequence, in which the single primary malformation is microretrognathia (see Chapter 23, Fig. 23-63). The resulting glossoptosis, or posterior placement of the tongue in the oropharynx, interferes with normal palatal closure if the lingual displacement occurs before 9 weeks’ gestation. The resulting cleft palate is U-shaped, rather than having the V shape that is usually seen in classic cleft palate, a finding that aids in recognition.

Association: An association is a pattern of malformations that occurs together too frequently to be due to random chance alone, but for which no specific etiology is yet recognized.

The approach to the evaluation of a child with a dysmorphologic abnormality is similar to a careful diagnostic evaluation of most pediatric problems, starting with a complete history and careful physical examination. In obtaining these it is helpful to remember that there are six broad etiologic categories to be considered in the differential diagnosis: a known syndrome, an unknown syndrome, a chromosomal abnormality, a teratogen, a congenital infection, and a maternal disease and/or placental abnormalities.

The history should include the following:

The physical examination entails the following:

In addition, focused examination of immediate family members for physical characteristics and growth parameters and review of family photo albums may be helpful.

Determining how the child fits into the norms for growth and development for the general population, for the family’s ethnic group(s), and for the extended family is important. One continuing challenge is to determine whether the norms for the family are truly in the normal range for the general population and ethnic background or, in fact, constitute variability of a genetic trait present in its severe expression in the child or family member seen for evaluation.

The identification of a recognizable pattern of both major and minor anomalies provides the clinical dysmorphologist with a diagnosis, or a short list of differential diagnostic possibilities. Thus the detection of major and minor anomalies is critical in the diagnostic process. Identification of specific and unusual malformations that are uncommon and occur in only a few syndromes can be especially helpful. For example, finding that a child has long palpebral fissure length and pronounced fingertip fat pad size in combination with the pattern of anomalies typical of the Kabuki syndrome makes it extremely likely that the diagnosis is the Kabuki syndrome. Training in dysmorphology emphasizes the recognition of key components in patterns of malformation, as well as the specific findings useful in distinguishing syndromes with similarities from one another. Texts that outline currently recognized patterns of malformations can be helpful in assisting the clinician in the identification of specific features that can rule a diagnosis in or out. Commercial computer-based programs exist for syndrome identification; however, these are often more effectively used by experts in the field because of the complexity of terminology and the need for exacting descriptions of the anomalies present in a given child.

A chromosome study should be performed on each child with a syndrome of congenital anomalies. Such a study may establish or confirm the diagnosis of a chromosomal disorder and its hereditary potential and may possibly help map the chromosomal location of genes for those syndromes known to be simple mendelian disorders.

Abnormalities of Autosomes

Down Syndrome

The worldwide incidence of Down syndrome among liveborns is approximately 1 in 660, with 45% of affected individuals born to women older than 35 years of age. The incidence of Down syndrome among conceptuses is far greater than among liveborns because the majority of Down syndrome fetuses spontaneously abort.

No single physical stigma of Down syndrome exists; rather, the clinical diagnosis rests on finding a recognizable constellation of clinical characteristics including a combination of major and minor anomalies (Fig. 1-22).

The most frequent features are up-slanting palpebral fissures and small external ears (by length). Several major anomalies are commonly associated with Down syndrome. Congenital heart disease is found in 45% of cases, particularly atrioventricularis communis and ventricular septal defects. Hence all newborns with Down syndrome should undergo cardiac evaluation with echocardiogram. About 5% have a gastrointestinal anomaly, most commonly duodenal atresia or Hirschsprung’s disease. An increased incidence of thyroid disorders also exists, particularly of the autoimmune type. Thus regular testing of thyroid function is recommended. Acute and neonatal leukemias occur 15 to 20 times more frequently in people with Down syndrome than in the general population. In newborns, much of this is represented by transient leukemoid reactions, with complete remission being the most frequent outcome. Quantitative abnormalities are found in many enzyme systems. People with Down syndrome are shorter than family members and the general population and have premature graying of hair. As adults, most males are infertile, but females may reproduce and can have children who will also have Down syndrome approximately one third of the time.

Minor anomalies include brachycephaly; inner epicanthal folds; Brushfield spots; flat nasal bridge; a small mouth with protruding tongue that fissures with age; a short neck with redundant skin folds; single transverse palmar (simian) creases; clinodactyly of the fifth fingers, with single digital crease caused by hypoplasia of the middle phalanx; and wide spacing between the first and second toes. The number of such anomalies varies in any particular case.

With rare exceptions, individuals with Down syndrome are cognitively impaired. The degree of impairment varies, with intelligence quotients (IQs) ranging from 20 to 80. Most individuals function in the mild to moderate range of developmental delay. The advent of individualized programs of early intervention therapy, education, and sporting activities has resulted in much improved outcomes and individuals who are much more likely to function at the maximum of their developmental capabilities. Autopsy analyses of brains from individuals with Down syndrome have revealed the neuropathologic changes of Alzheimer’s disease in 100% of those older than 40 years. Nevertheless, only about 25% of older individuals with Down syndrome exhibit clinical manifestations of Alzheimer’s disease. The reason for the clinical–pathologic discordance is not known. However, there does tend to be a progressive loss of cognitive functioning after the fourth decade of life. Longevity, although less than that of the general population, has steadily increased over the years. Individuals with Down syndrome who do not have congenital heart disease may expect to live well into their 60s. The principal causes of death in children with Down syndrome are infection, congenital heart disease, and malignancy.

The etiology of Down syndrome is trisomy 21, the presence of an extra chromosome 21 either as a simple trisomy or as part of a chromosome 21 fused with another chromosome. These fused chromosomes are often robertsonian translocation chromosomes or isochromosomes. Cases of mosaicism, in which trisomy 21 cell lines coexist with cell lines with the standard 46 chromosomes, exist as well and may range in phenotype from normal to that typical of complete trisomy 21. An association between trisomy 21 and advanced maternal age is clear (Table 1-4).

Table 1-4 Maternal Age–Specific Risk for Trisomy 21 at Live Birth

Maternal Age (yr) Prevalence at Live Birth
25 1/1350
30 1/890
35 1/355
40 1/97
45 1/23

About 5% of Down syndrome cases represent a centric fusion translocation between the long arm of a chromosome 21 and those of a 13, 14, 15, 21, or 22 acrocentric chromosome. Of these, about one third are inherited from a clinically normal, balanced carrier parent; in the remaining two thirds the translocation is new in the affected child. Chromosome studies should therefore be performed on the parents and appropriate family members of an individual with translocation Down syndrome. If a parent carries a 21/21 translocation, all liveborns will have Down syndrome; for the remaining 21/centric fusion translocations, the empiric recurrence risk for a Down syndrome liveborn is less than 2% if the father is the carrier and roughly 15% if the mother is the carrier. The parents of children with trisomy 21 may benefit from genetic counseling to determine their individual risk of having another child with Down syndrome or with other chromosomal abnormalities in future pregnancies.

Trisomy 13

Trisomy 13 is a relatively rare (1 in 5000) genetic condition caused by the presence of additional chromosome material from all or a large part of chromosome 13. The vast majority of embryos with classic trisomy for a complete 13th chromosome abort spontaneously, but approximately 5% survive to be liveborn. They have a severe, recognizable pattern of malformation that allows clinicians to suspect this etiology immediately (Fig. 1-23). The hallmark features are defects of forebrain development related to those seen in holoprosencephaly, aplasia cutis congenita, polydactyly (most frequently of the postaxial type), and narrow hyperconvex nails. A broader listing of features is outlined in Table 1-5, which can be useful in comparing the features frequently seen in infants with trisomy 13 with those seen in trisomy 18. As with many syndromes, trisomy 13 and trisomy 18 share structural abnormalities; however, they usually are distinguishable on the basis of the pattern of anomalies present. Liveborn infants with trisomy 13 represent those who have the least severe structural abnormalities of major organs. Of these, about 5% survive the first 6 months of life. Thus discussions with parents about surgical interventions must take into account the small possibility of long-term survival and require sensitivity to the needs of the child and family.

Table 1-5 Physical Abnormalities and Frequencies of Occurrence in Trisomy 13 and Trisomy 18 Syndromes

Abnormality Trisomy 13 Trisomy 18
Severe developmental retardation †††† ††††
Approximately 90% die within first year †††† ††††
Cryptorchidism in males †††† ††††
Low-set, malformed ears †††† ††††
Multiple major congenital anomalies †††† ††††
Prominent occiput ††††
Cleft lip and/or palate †††
Micrognathia †† †††
Microphthalmos ††† ††
Coloboma of iris †††
Short sternum †††
Rocker-bottom feet †† †††
Congenital heart disease †† ††††
Scalp defects †††
Flexion deformities of fingers †† ††††
Polydactyly †††
Hypoplasia of nails †† †††
Hypertonia in infancy †††
Apneic spells in infancy †††
Midline brain defects †††
Horseshoe kidneys †††

Symbols: Relative frequency of occurrence ranges from †††† (usual) to † (rare).

Milder chromosome abnormalities involving extra material determined to originate from chromosome 13 must be identified and distinguished from classic trisomy 13 because the clinical phenotype and prognosis may be different and, in some cases, less severe. Children with mosaicism, that is, with a normal cell line and a trisomy 13 cell line, as well as those with trisomy of part of chromosome 13, can be identified by chromosome analysis. Careful laboratory investigation must be carried out to identify the exact chromosomal abnormality. The advent of FISH technology has dramatically increased the ability of laboratory specialists to characterize chromosome rearrangements, with the goal being to identify the exact breakpoints of the chromosomes involved in the rearrangements. Molecular studies then may be possible to determine any potential impact of the rearrangement on individual genes and their products. This information is extremely helpful to clinicians in determining prognosis and in providing more realistic information when discussing treatment options. Rarely, children who have the recognizable pattern of clinical features of trisomy 13 have normal chromosomes. If a geneticist/dysmorphologist is not already involved, a consultation is warranted to aid in diagnosis and prognosis counseling and to determine any recurrence risks for the parents in future pregnancies.

Trisomy 18

The chromosomal disorder trisomy 18 occurs in approximately 3 in 10,000 newborns, and females are more likely to be liveborn. Affected infants are small for gestational age and have a frail appearance, and the face tends to appear petite relative to the rest of the craniofacial contour (Fig. 1-24, A). They also have a recognizable pattern of malformation, but in these infants hallmark features—clenched hands with overlapping fingers (see Fig. 1-24, B), short sternum, and “low arch” fingerprint patterns—are minor anomalies. Major anomalies, especially congenital heart disease, are generally present as well and are the source of significant morbidity and mortality. Other common findings include a prominent occiput, low-set and structurally abnormal ears, micrognathia, and rocker-bottom feet (see Fig. 1-24, C). See Table 1-5 for a broader listing of clinical features that can be useful in distinguishing trisomy 18 from trisomy 13, which shares many of the same structural abnormalities.

Trisomy 18 was previously thought to be almost invariably fatal in the neonatal period; however, more recent data suggest that a small percentage of children can live longer, and that between 5% and 10% will be alive at their first birthday. Survivors are more frequently female and have less severe structural abnormalities of major organs than most affected infants. Even with optimal neonatal, pediatric, and surgical management and excellent home-based care, children with classic trisomy 18 often “fail to thrive” and have significant developmental and cognitive impairments. Discussions with parents about interventions must take into account the slim possibility of long-term survival and require sensitivity to the needs of the child and family. Great care must be taken in providing a balanced picture to the family when discussing treatment options.

Chromosome analysis allows clinicians to evaluate the etiology of the trisomy and can help determine prognosis. Results can demonstrate classic trisomy 18 due to a complete extra chromosome 18, mosaicism for trisomy 18, or a complex chromosome abnormality involving one or more chromosomes. Children with chromosomal rearrangements that result in partial rather than complete trisomy 18 may have a milder clinical outcome. Trisomy limited to the short arm of chromosome 18 is associated with a significantly milder prognosis, whereas trisomy of the entire long arm of chromosome 18 may be indistinguishable from an individual with classic trisomy 18. An infant with smaller areas of trisomy for the long arm of chromosome 18 may show some, but not all, of the features of classic trisomy 18. Thus chromosomal study of each child is essential.

If a complex chromosome rearrangement is identified in a child, further parental chromosome studies are indicated. Chromosome analysis of the parents will determine whether the rearrangement is new in the child (de novo) or is the result of a familial balanced translocation. Full characterization of the extent of a chromosome rearrangement also allows clinicians to provide more accurate information regarding prognosis, treatment options, and recurrence risk to the family. If a familial balanced translocation is present in one of the parents, other family members may benefit from genetic counseling to discuss recurrence risk and the availability of prenatal diagnosis for future pregnancies.

It has been our experience that parent support organizations can be extremely helpful to family members in the long process of adjustment to having a child with a chromosome problem. If the child dies, these groups can be helpful as a resource to the parents because of the similarity of their collective experience and can assist them in the grieving and healing process. They can also be a source of ongoing support and information to parents of a child with trisomy 13 or trisomy 18 who may live but who will face major medical and developmental challenges due to the chromosomal abnormality.

Abnormalities of Sex Chromosomes

Turner Syndrome

Turner syndrome is one of the three most common chromosomal abnormalities found in early spontaneous abortions. The phenotype is female. About 1 in 2000 liveborn females has Turner syndrome. Primary amenorrhea, sterility, sparse pubic and axillary hair, underdeveloped breasts, and short stature (image to 5 ft) are the usual manifestations. Other external physical features may include webbing of the neck; cubitus valgus; a low-set posterior hairline; a shield chest with widely spaced nipples; and malformed, often protruding, ears (Fig. 1-25, AE). Internally, renal anomalies may be present along with congenital heart disease, particularly bicuspid aortic valve (in 30% of cases) and coarctation of the aorta (in 10% of cases). Affected women have an infantile uterus, and their ovaries consist only of strands of fibrous connective tissue. Newborns often have lymphedema of the feet and/or hands (Fig. 1-25, D and E), which can reappear briefly during adolescence. Mental development is usually normal. Schooling and behavioral problems seem to be the same as in age-matched control subjects, although difficulty with spatial orientation such as map reading may be a problem. The classic physical findings of Turner syndrome may be absent, or the abnormalities may be so minimal in the newborn that the diagnosis is missed. The first indication may be unexplained short stature in later childhood or failure to develop secondary sex characteristics by late adolescence. Thus a chromosome study is indicated as part of the diagnostic workup of adolescent girls with these complaints.

The karyotype in the majority of individuals with Turner syndrome is 45,X. Most often, the missing sex chromosome is paternally derived, so the risk of Turner syndrome does not increase with maternal or paternal age. Another 15% of individuals with Turner syndrome are mosaics (XO/XX, XO/XX/XXX, or XO/XY). The physical stigmata may be less marked in mosaics, some of whom may be fertile. If an XY cell line is present, the intraabdominal gonads should be removed because they are prone to malignant change. The remaining cases of Turner syndrome have 46 chromosomes including one normal plus one structurally abnormal X. The latter may have a short (p) arm deletion or may be an isochromosome duplication of the long (q) arm of the X chromosome; usually it is paternally derived. Cases of Turner syndrome with one normal and one abnormal X chromosome are more likely to have other, more serious major anomalies including cognitive deficits. A structurally abnormal X chromosome may lead to abnormal X inactivation resulting in a deleterious dosage effect for X-linked genes. Karyotypes such as 46,XYp- or 46,Xi(Yq) result in a female with Turner syndrome.

Moreover, loss of the short arm of an X chromosome results in full-blown Turner syndrome; deletion of the long arm usually produces only streak (fibrous) gonads with consequent sterility, amenorrhea, and infantile secondary sex characteristics without the other somatic stigmata of Turner syndrome. If the diagnosis is clinically suspected, a chromosome study should be ordered. Should the affected child be 45,X or a mosaic, the parental risk for recurrence of a chromosomally abnormal liveborn is 1% to 2% but may be higher if a parent carries a structurally abnormal X chromosome.

Antenatal diagnosis of chromosomally abnormal fetuses should be discussed with the parents, and the relatively good prognosis for Turner syndrome liveborns should not be overlooked. Girls with Turner syndrome should receive appropriate hormone therapy during adolescence to enable development of secondary sex characteristics and stimulate menses. Rarely, 45,X women with Turner syndrome have been fertile for a limited number of years.

Klinefelter Syndrome

One in 500 newborn boys has Klinefelter syndrome. The physical stigmata are subtle and usually not obvious until puberty, at which time the normal onset of spermatogenesis is blocked by the presence of two X chromosomes. Consequently the germ cells die, the seminiferous tubules become hyalinized and scarred, and the testes become small. Testosterone levels are below normal adult male levels, although the level varies from case to case (the average being about half as much as normal). Hence there is a wide range in degree of virilization. At one extreme is the man with a small penis and gynecomastia (Fig. 1-26); at the opposite extreme is the virile mesomorph with a normal penis. Scoliosis may develop during adolescence. The average full-scale IQ of men with Klinefelter syndrome is 98, which is about the same as the general population. Behavioral problems may be more common than in the population at large, however.

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Jul 11, 2016 | Posted by in PEDIATRICS | Comments Off on Genetic Disorders and Dysmorphic Conditions
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