Down Syndrome With an Unusual Etiology: Case Report and Review

244 VOLUME 16, ISSUE 6, JUNE 2004 JOURNAL OF THE AMERICAN ACADEMY OF NURSE PRACTITIONERS 245

CLINICAL CASE STUDY

Down Syndrome With an Unusual Etiology: Case Report and Review

Mattie Pastva, RN, MS, FNP

Elizabeth J. Corwin, RN, PhD, CRNP

Karen Morin, RN, DSN

INTRODUCTION

Within the last 10 years, more precise information has been reported on the chromosome 21 gene that causes specific features of Down syndrome. As a result, health care providers can make more accurate predictions concerning an individual’s degree of Down phenotype, allowing the treatment plan to be set accordingly. Nurse practitioners (NPs) are integral parts of the team for patients with Down syndrome, helping to assess and diagnose the condition, educating families regarding transmission of the disorder, coordinating care, and identifying expected outcomes.

In light of increasing responsibilities of NPs in the diagnosis and care of patients with Down syndrome, the following case report provides infor-mation on the genetic transmission of Down syndrome, in particular the transmission of a less common, but still significant, cause of the syndrome: robertsonian translocation. This report presents important information on determining expected outcomes for patients with Down syndrome and describes implications and strategies for NPs.

CASE BACKGROUND

A 2-month-old male infant named Brian (not his real name) was brought to the clinic with a skin rash. Brian was born by cesarean section to a 27-year-old woman (gravida I, para I). Delivery was complicated by the mother’s testing positive for group B streptococci during pregnancy. The father, aged 28, was in good health. A review of the history revealed that this couple had difficulty conceiving throughout a 1-year time span. Neither parent reported a previous history of recurrent abortion, mental retardation, or congenital malformation; however, the father reported that he had a sister die from a “hole in the heart.” The mother’s alpha-fetoprotein was normal, as were standard prenatal ultrasound-screening examinations, which indicated typical development. The pregnancy was full term at 40 weeks, with an emergency cesarean section being performed consequent to persistent decreased fetal heart rate. The infant weighed 8 lb, 2 oz and was 20 in. long at birth. Brian experienced neonatal pneumonia attributed to the birth via cesarean section, and the length of postnatal stay was extended to 1 week. While Brian was hospitalized, breast-feeding attempts met with limited success, as his mother had difficulty getting him to latch on and to stay awake during feedings. As a result, bottle-feeding was implemented. Thereafter, parents and caregivers recognized that feedings were small and that Brian had some episodes of dif-ficulty swallowing. Brian’s parents expressed concerns about “noisy breathing”

PurposeTo present the genetic etiology of an unusual case of Down syndrome, arising from translo-cation of chromosome 21 to chromosome 9; to discuss advanced genetic diagnostic tech-niques, focusing on how pinpointing a specific genetic mistake can influence treatment and outcome; and to review the role of the nurse practitioner (NP) in caring for families of chil-dren with Down syndrome.

Data SourcesCase report, literature review, and advanced genetic techniques.

ConclusionsNPs often answer patient questions regard-ing genetic abnormalities and risk factors for transmission of genetic errors to offspring. Advanced genetic analysis allows for the diag-nosis of unusual causes of common genetic disorders. The ability to identify a specific genetic mistake and to predict the scope of its effect on an individual offers health care providers the opportunity to develop a case-by-case plan of care.

Implications for PracticeNPs have a responsibility to be informed about the processes involved in the transmission of genetic errors and about the subtleties of various expressions of a genetic disorder. The availability of new genetic-testing techniques allows NPs to individualize patient care and family teaching.

Key WordsDown syndrome, translocation, robertsonian translocation.


and “periods of apnea” to their pediatrician. Brian’s mother also observed that the infant’s head was “flat on one side,” which was attributed to continually laying the baby on his back. Three infant checkups proceeded without incident until the skin rash presented.

When Brian was seen for the skin rash, the pediatrician assessed the following: brachycephaly, flattened occiput, epi-canthal folds, flat nasal bridge, protruding tongue, low-set ears, bilateral clinodactyly, low muscle tone, and simian crease. The pediatrician suggested a diagnosis of Down syndrome. Parents believed a diagnosis of Down syndrome based on phenotype to be unlikely because the infant had a striking resemblance to his father. Genetic analysis was performed on the infant, however, and the family was referred to a genetic pediatric specialist. Results of genetic analysis revealed that Brian did indeed suffer from a chromosomal abnormality believed to involve a trisomy of chromosome 9. Based on these results, additional genetic test-ing involving fluorescence in situ hybridization (FISH), a more sensitive screening method, was ordered.

Inspection of the FISH results revealed that the child had experienced a translocation of a duplicated portion of chromo-some 21 onto chromosome 9. Because there were also two nor-mal copies of chromosome 21, the diagnosis of Down syndrome resulted from partial trisomy 21 due to a translocation of the long arm of chromosome 21 and chromosome 9 (46, XY, der [9] t [9;21] [q34.3;q21.1]). As a result of this translocation, a piece of chromosome 9 was lost as well.

Although the mental and physical implications of classic Down syndrome are well reported, the specific outcome of having experienced a translocation of a piece of chromosome 21 is often unclear. Likewise, little research is available on con-sequences of missing part of chromosome 9 (C. Bay, personal communication, April 17, 2002). This uncertainty added to the anxiety that Brian’s family experienced. In addition, when a child is found to have a translocation of a piece of one chromosome onto another, a similar, although balanced, translocation in the parents must be excluded (Cunniff, 2001). Standard genetic analysis was then suggested for both parents. Results revealed 46 normal chromosomes with no balanced translocations for either parent; however, it was recommended that the parents undergo further analysis using the more sophisticated FISH method. In

some cases, this computerized analysis is needed in order to iden-tify a subtle genetic rearrangement (Levy et al., 1997). An invita-tion to undergo FISH analysis and to enroll in a research study was given to the parents. Brian’s parents chose not to pursue the invitation and, instead, arranged for themselves a consultation at a regional Down syndrome clinic to learn the basic genetics of the disorder.

GENETICS

Down syndrome is seen in 1 in 800 live births, resulting in approximately 350,000 individuals with Down syndrome in the United States (March of Dimes, 2003). In 95% of cases, Down syndrome, also called trisomy 21, occurs when there are three copies of chromosome 21 instead of the typical two copies per cell, causing the individual to have 47 chromosomes rather than the normal 46 (Cooley & Graham, 1991). Trisomy usually occurs as a result of nondisjunction. In this type of cell division error, the two chromosomes fail to separate after duplication. Instead, the chromosomes move as a pair to the forming egg or sperm. Maternal origin of nondisjunction is said to occur in 95% to 97% of Down cases, and paternal origin is less than 5% (Cooley & Graham). Trisomy 21 due to nondisjunction of chro-mosome 21 is clearly apparent on amniocentesis (see Figure 1).

A much less common cause of Down syndrome, making up the remaining 5% of all cases, is translocation, as described in the current case. Translocation refers to a rearrangement of genetic material (Nadal et al., 1996; Simpson & Bischoff, 2002). In the case of a translocation resulting in Down syndrome, all or part of one of the normally duplicated chromosome 21 must travel, or translocate, to a nearby chromosome and fuse with it. The most commonly targeted chromosomes are 13, 14, 15, 18, or 22, but other chromosomes, including chromosome 9, may be targeted. Translocation of chromosome 21 to another chromo-some, which can cause Down syndrome, is called a robertsonian translocation. Translocation of chromosomes may be either bal-anced or unbalanced, depending upon whether a reciprocal piece of the other chromosome (13,14,15, etc.) likewise translocates (leading to balanced) or not (leading to unbalanced).

Unlike Down syndrome due to complete trisomy 21, Down syndrome due to a robertsonian translocation occurs equally in all maternal age groups (Benke, Carver, & Donahue, 1995). Translocation cases of Down syndrome either occur spontane-ously or are inherited from a parent who has a balanced trans-location.

A parent with a balanced translocation has a rearrangement of chromosome material from one chromosome to another, but no extra genetic material is added to or lost from either chromo-some. For example, a parent may have had a section of chromo-some 21 translocate to chromosome 15, with the corresponding section of chromosome 15 replacing the missing section on chromosome 21 (Nasr & Roy, 2000). This situation creates a carrier of translocation; such a person is normal and healthy and displays no manifestations of abnormalities. Balanced transloca-tions are relatively common, affecting 1 in 500 people (Nasr &

AuthorsMattie Pastva, MS, CRNP, Elizabeth J. Corwin, Ph.D., MSN, CRNP, and Karen Morin, DSN, are all Faculty Members at the Pennsylvania State University School of Nursing in University Park.

AcknowledgementsThe authors wish to thank Dr. David Corwin and the directors of Dynacare Laboratories Inc., for generously making public the karyotypes published on their Web site, www.dynagene.com. The authors also wish to extend a sincere thank-you to Brian and his parents.


Roy). An offspring of a carrier of a balanced translocation of chromosome 21 and, for example, chromosome 15 could be chromosomally normal, receiving from the affected parent a normal chromosome 21 and a normal chromosome 15, as well as a normal chromosome 21 from the other parent. Likewise, an offspring of a carrier of a balanced translocation of chromosomes 21 and 15 could also have a balanced translocation, receiving from the affected parent both translocated chromosomes (e.g., 21 and 15) and from the other parent a normal chromosome 21. Finally, however, an offspring of a carrier of a balanced translo-cation of chromosome 21 and 15 could have Down syndrome, receiving from the affected parent his or her normal chromo-some 21 plus the chromosome 15 carrying the translocated piece of chromosome 21 and receiving from the other parent a normal chromosome 21 (Simpson & Bischoff, 2002).

It is important to emphasize that the parent will have no trac-es of Down syndrome, as he or she is a balanced translocation carrier. However, parental carriers have a much higher risk of reoccurrence with subsequent pregnancies (Cooley & Graham, 1991). In addition, parents with balanced translocations may have fertility problems (Paoloni-Giacobino, Kern, Djielati, Morris, & Dahoun, 2000; Simpson & Bischoff, 2002).

TranslocationsInherited translocations are responsible for approximately

one third of the cases of Down syndrome due to translocations

(Cooley & Graham, 1991). In the remaining two thirds of indi-viduals with Down syndrome due to translocation, the translo-cation occurs as an isolated event during conception, termed a de novo translocation (Cooley & Graham). When chromosome 21 and another chromosome separate and then join together, the combined chromosome acts like a single chromosome in cell division. The baby will then have the extra chromosome 21 material causing Down syndrome. Figure 2 presents a karyotype of an infant with Down syndrome resulting from an unbalanced translocation of chromosomes 21 and 10.

Phenotypic Mapping of Chromosome 21Niebuhr (1974) first suggested the notion that only a specific

region on chromosome 21 contributes to the features of Down syndrome. Innovations in genetic analysis have made it possible to determine the region of chromosome 21 that, when over-expressed, causes the typical features of Down syndrome. This work was prompted by the clinical similarities of phenotypes in individuals with complete versus translocated, partial trisomy of chromosome 21 (Nadal et al., 1997). Clearly, when complete trisomy occurs, all Down syndrome features are present. In par-tial trisomy, on the other hand, the features of Down syndrome depend upon the location of the break point of chromosome 21 and the region that was overexpressed (Epstein et al., 1991; Nadal et al., 1996). Genetic discoveries resulting from the study of multiple cases of partial trisomy have made it clear that band

Figure 1 Trisomy 21

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�� Unbalanced translocation (robertsonian translocation).


21q22 of chromosome 21 is the “critical region” involved in Down syndrome (see Figure 3; Korenberg, 1993; Korenberg et al., 1994). Thus, when only this piece of chromosome 21 is overexpressed—as in translocated, partial trisomy 21—all the typical phenotypic (i.e., outward) features of Down syndrome will present. If the short arm of chromosome 21 is overexpressed, symptoms are typically milder.

Now that the long arm of chromosome 21 has been identified as the region responsible for the typical features of Down syn-drome, further molecular studies have pinpointed which genes cause specific phenotypes. Figure 3 is an example of a phenotypic map of Down syndrome. The goal of phenotype mapping is to identify the chromosomal regions associated with the pheno-types of Down syndrome (Korenberg et al., 1994). This tool is useful in genetic counseling, as overexpression of specific genes on chromosome 21 results in specific disorders (Delabar et al., 1993; Korenberg et al.). By knowing which genes are overex-pressed, one can predict both the severity of Down syndrome and which traits are likely to manifest as the individual develops. This knowledge will help health care providers to anticipate, prevent, or delay the onset of certain conditions.

Identifying the overexpressed region makes a wealth of infor-mation available to health care providers and families. This is important information for those diagnosed with only partial tri-somy of chromosome 21. As one can see from Figure 3, the more distal the overexpressed region on the long arm of chromosome

21, the greater the severity of Down syndrome features.

EXPECTED OUTCOMES

A person with a complete trisomy of chromosome 21 is at increased risk of congenital heart defects (50%); leukemia (less than 1%); hearing loss (75%); otitis media (50% to 70%); Hirschsprung’s disease (less than 1%); gastrointestinal atresias (12%); eye disease (60%), including cataracts (15%) and severe refractive errors (50%); acquired hip dislocation (6%); obstruc-tive sleep apnea (50% to 75%); and thyroid disease (15%; Cunniff, 2001). The phenotype of an individual with partial trisomy will depend on what section is present in triplicate. Survival of all individuals with Down syndrome has increased considerably, with 61% of people with Down syndrome now surviving to 50 years and 50% of that cohort surviving beyond the age of 57 years (Baird & Sadovnick, 1987). This increase is in part due to the ability of medical personnel to correct congenital malformations at birth and to the development of national health care guidelines for parents of children with Down syndrome.

NURSING PRACTICE IMPLICATIONS

NPs need to be familiar with a variety of genetic disorders

Figure 2 Unbalanced Translocation (Robertsonian Translocation)

22

�� Unbalanced translocation (robertsonian translocation).


and their transmission. Although robertsonian translocations are responsible for only 5% of Down syndrome occurrences, because of the many infants born with Down syndrome each year, this number is significant. It is important that NPs be able to discuss with families usual and unusual aspects of common disorders. In addition, NPs and nurses need to be prepared to use their assessment skills and to question unusual findings. When confronted with a potential genetic disorder, the NP must make prompt referral to a specialist, coordinate these meetings, and be available to the family for follow-up questions. At each sub-sequent well visit, a thorough developmental assessment by the NP is essential in order to maximize the potential of each child (Bosch, 2003). NPs also must be knowledgeable about what community resources are available for patients and for families of children with genetic disorders. Using an engaging and inter-active approach when delivering information will ensure that patients and families understand. For parents who are computer literate, Internet resources are available: Table 1 provides a short list that would be appropriate for families who have a child with Down syndrome.

It is also important for NPs to listen to parents when they express concern about their infant. Parents spend more time with their child than does any health care provider. In Brian’s case, his parents had many concerns during his first 4 months of life.

As health care providers, we must remind parents that along with Down syndrome (or other genetic disorder), the child has a full set of healthy chromosomes that were inherited from each parent. This fact accounts for the child in the above case resembling his father to a great extent, despite having Down

syndrome. The inheritance factor and environmental influences help to shape the child’s potential, which partially explains the varying degrees of disability in patients with Down syndrome.

At each visit, nurses and NPs should provide families with anticipatory guidance related to the growth and development of the child with a genetic disorder. For instance, for a child with Down syndrome, the onset of walking may not occur until 14 months of age or later. Delays in speech are common and, without anticipatory guidance, may be especially frustrating for parents. Likewise, tasks such as self-feeding can be delayed. Encouraging good eating habits, a balanced diet, avoidance of high-calorie foods, and regular physical activities will help fami-lies prevent a child with Down syndrome from becoming obese. Nurses and other health care providers should be using growth charts specific to patients with Down syndrome in order to appropriately assess data. In addition, the nurse or NP must still provide families with the typical health promotion and teaching interventions concerning infant safety, car seats, immunizations, teething, and toilet training.

The help of early intervention specialists makes the period of adjustment easier for parents. These specialists include develop-mentalists, physical therapists, and occupational therapists that help track the progress of the infant. Evidence suggests that early intervention programs aid the development of the child with a genetic disorder and help parents cope with and adjust to the diagnosis. When couples are young, are experiencing the birth of their first child, and have a desire for future pregnancies, genetic counseling helps to determine the chance of transmitting the disorder to future offspring. Knowing that the genetic error

Figure 3 Phenotype Map (Adapted from Korenberg et al., 1994)


developed spontaneously, as it appears to have done in Brian’s case, would offer reassurance to the parents that neither was a carrier. Initially, parents may feel overwhelmed by the task of finding the resources available to them. The health care provider needs to be prepared to answer questions and must be familiar with the process of connecting families to available resources. Programs are federally funded, and monetary assistance is avail-able for families with low incomes.

CASE DISCUSSION

The etiology of Brian’s condition appears to be an unbalanced de novo translocation of a piece of chromosome 21 to chromo-some 9. The overexpressed region of chromosome 21 was identi-fied as q21.2 to 22.3, an area clearly within the critical region for phenotypic expression (see Figure 3). There is no clear reason why an unbalanced translocation occurs. Environmental factors have been investigated, but with the exception of exposure to radiation, these have been rejected (Cooley & Graham, 1991). In the case example, there was no known exposure to radiation during pregnancy.

For this couple, the chance of having another baby with Down syndrome is less than 1% because neither parent was identified as a translocation carrier; therefore, the transloca-tion was likely spontaneous (Cooley & Graham, 1991). This information is important to Brian’s family, as the parents have expressed a desire to provide him with siblings for support and guidance throughout the years to come. If one of Brian’s parents did carry the translocation in the balanced form, the chance of another child with Down syndrome could be up to 12%, with greater incidence of expression if the mother were the carrier rather than the father (Benke et al., 1995). When a balanced translocation is found in an individual, all family members should receive genetic counseling and testing, due to the familial tendency of the balanced translocation. In this case, the parents have chosen not to undergo more sophisticated testing to posi-tively rule out parental transmission.

As for Brian’s health, an echocardiogram at 4 months of age revealed that Brian had a small atrial septal defect (ASD) of the heart. As part of his 1-year examination, a repeat echocardiogram was performed to assess the severity of the defect, which was subsequently found to be normal: The ASD had spontaneously closed. Additional diagnostic testing at the examination was unremarkable for internal defects. Endocrine function, hear-ing, and eye examination were also normal. According to the Down syndrome growth charts, at 1 year of age, Brian was in the 95th percentile for weight, length, and head circumference. Evaluation using two developmental tools, the Early Learning Accomplishment Profile and the Early Intervention Profile, determined that Brian demonstrated cognitive functioning and small motor functioning at the 11-month level. Testing revealed a small degree of gross motor delay, with performance at the 10-month level, and a significant delay in self-help/adaptive functioning, with abilities rated at the 8-month level. This lat-ter deficiency rating was given due to the fact that Brian was not yet eating textured foods or feeding himself. His social and emotional functioning were on target. Brian has experienced fre-quent upper respiratory infections and otitis media, along with episodes of constipation.

FUTURE RESEARCH

Analysis of chromosome 21 through state-of-the-art molecu-lar biology has greatly increased the understanding of Down syn-drome. Particularly, identification of the critical region involved in inducing phenotypic abnormality has shed light on the condi-tion of partial trisomy 21. It is important to continue to identify those individuals with partial trisomy 21 in order to continue research on the relationship between genotypes and phenotypes (Nadal et al., 1997). Stem cell research looks at the earliest stages of human development. Now that specific genes on chromosome 21 are identified, it may not be unreasonable to predict that the cellular processes that give rise to Down syndrome will also be revealed. Miller (2002) reported that scientists have undertaken

Table 1 Web Sites Available for Families With Children Who Have Down Syndrome

Web Addresses

General Information www.downsyndrome.comwww.ndss.orgwww.ds-health.com/recordsheet1.htm

Parent and Sibling Support www.nas.com/downsyn/parent.html

Links to Worldwide Resources www.nas.com/downsyn/org.html

The Genetics of Down Syndrome www.ds-health.com/trisomy.htmwww.dynagene.com


the task of identifying those gene expressions that are linked with the development of Down syndrome; if these scientists are suc-cessful, the possibility of altering the disease progression may not be so far out of reach. The National Down Syndrome Society is currently sponsoring research on the causes of Down syndrome (National Down Syndrome Society, 2002).

CONCLUSION

The genetic analysis of chromosome 21 has led to new per-spectives on Down syndrome. The ability to identify and predict the outcome of a particular individual given his or her genetic makeup offers health care providers the opportunity to develop a case-specific, appropriate plan of care. These advances provide valuable information about the biological processes associated with Down syndrome and have led to improvements in the lives of individuals with Down syndrome and other genetic disorders. Down syndrome is a common genetic disorder that all NPs will likely encounter in their practices. NPs need to be aware that genetic differences in the disorder exist. Such awareness will help to ensure that patients receive the appropriate care and that families with children who have Down syndrome can identify the risk to future offspring.

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Delabar, J. M., Theophile, D., Rahmani, Z., Chettouh, Z., Blouin, J. L., Prieur, M., et al. (1993). Molecular mapping of 24 features of Down syndrome on chromosome 21. European Journal of Human Genetics, 1(2), 114–124.

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Ercis, M., & Balci, S. (1999). Can a parent with balanced robertsonian transloca-tion t(21q;21q) have a non-Down’s offspring? Lancet, 353(9,154), 751.

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March of Dimes. (2003). Medical references: Down syndrome. Available from http://www.modimes.org/msmres.asp?query=down+sydrome

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Nadal, M., Mila, M., Pritchard, M., Mur, A., Pujals, J., Blouin, J. L., et al. (1996). YAC and cosmid FISH mapping of an unbalanced chromosomal transloca-tion causing partial trisomy 21 and Down syndrome. Human Genetics, 98, 460–466.

Nadal, M., Moreno, S., Pritchard, M., Preciado, M. A., Estivill, X., & Ramos-Arroyo, M. A. (1997). Down syndrome: Characterization of a case with par-tial trisomy of chromosome 21 owing to a paternal balanced translocation (15;21) (q26;q22.1) by FISH. Journal of Medical Genetics, 34(1), 5–54.

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Paoloni-Giacobino, A., Kern, I., Djielati, R., Morris, M. A., & Dahoun, S. P. (2000). Familial t(6;21)(p21.1;p13) translocation associated with male-only sterility. Clinical Genetics, 58(4), 324.

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Down Syndrome With an Unusual Etiology: Case Report and Review