Neonate With Hypotonia and Subtle Anomalies

Neonate With Hypotonia and Subtle Anomalies
Published on Physicians Practice (http://www.physicianspractice.com)
Neonate With Hypotonia and Subtle Anomalies
February 01, 2008
By Golder N. Wilson, MD, PhD [1]
On morning rounds in the well-baby nursery, a nurse brings your attention to a 1-day-old girl who is
having trouble latching onto the breast. You examine the child and note the subtle anomalies shown
in Figure 1 along with a pronounced head lag and a systolic heart murmur.
On morning rounds in the well-baby nursery, a nurse brings your attention to a 1-day-old girl who is
having trouble latching onto the breast. You examine the child and note the subtle anomalies shown
in Figure 1 along with a pronounced head lag and a systolic heart murmur.
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Figure 1- Examination of the infant's hands and feet reveal a single palmar crease, fifth finger
clinodactyly, broad space between the toes, and a deep plantar crease.
The child, who weighs 2800 g, is the product of an uncomplicated term gestation and repeat
cesarean section delivery to a healthy 28-year-old mother. Her family history includes a healthy
older brother and no birth defects or disabilities on either side of the family.
WHAT IS THE LIKELY DIAGNOSIS?
WHAT LABORATORY TESTS WOULD SUPPORT THIS DIAGNOSIS WITH RESULTS AVAILABLE IN
4 TO 8 HOURS AND/OR 5 TO 10 DAYS?
WHAT RISKS AND TESTING OPTIONS WOULD THIS DIAGNOSIS IMPLY FOR THE NEXT
PREGNANCY?
WHAT WOULD THIS DIAGNOSIS IMPLY FOR EARLY INFANT CARE?
ANSWERS:
Down syndrome.
Diagnostic confirmation is available by rapid FISH or routine blood karyotype.
Parental recurrence risks depend on trisomy (about 1%) versus translocation (5% to 100%).
Options include prenatal ultrasonography, maternal serum marker screening, and/or fetal
chromosome studies.
Preventive health care should include referrals to a cardiologist and ophthalmologist as well
as early intervention and yearly thyroid screening.
Syndrome recognition begins with the realization that a child has more than one problem-multiple
defects are implicit in the word "syndrome" or "running together." For the primary physician, the
challenge is to recognize the possibility of a syndrome-not to remember many rare disorders.
Physical examination is the key-interpreting subtle minor anomalies that comprise an altered
developmental pattern. Changes in the face (upslanting palpebral fissures, epicanthal folds, wrinkles
when crying [Figure 2]) and limbs (single palmar crease, fifth finger clinodactyly, broad space
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between the toes, deep plantar crease [see Figure 1]) suggest the syndrome described by Dr Down
in 1866.1-6
Figure 2 - Infant with Down syndrome showing upslanting palpebral fissures (A); crying infant
showing exaggerated wrinkles between eyebrows (arrow) and epicanthal folds (B).
Complex structures are most susceptible to developmental alteration. This explains the mental
disability and organ defects common to many syndromes. Poor breast-feeding from hypotonia is a
common indicator of genetic disease and is often accompanied by seizures, abnormal
feeding/swallowing, and motor/speech delays.
Clinicians should attend carefully to these harbingers of developmental problems rather than
assuming inadequate maternal technique. Suspicion of a syndrome allows timely referral and
intervention that promotes preventive health care and preconception counseling for parents who are
considering a subsequent pregnancy.
A syndrome is obvious when multiple major anomalies derange appearance and function. (An
example is the cleft lip/palate and facial changes of Patau syndrome from trisomy 13.) Syndromes
such as Edwards (trisomy 18) or Down (trisomy 21) may be less obvious: subtle minor anomalies
must be tallied before it becomes evident that an apparently isolated heart murmur is in fact part of
a developmentally abnormal pattern.
More than 100 minor anomalies (Figure 3) can be detected by surface examination. The presence of
3 or more such anomalies conveys a 90% chance that the child has an accompanying major birth
defect.1,7 Dysmorphology thus depends on the common history and physical rather than mystic
powers of facial recognition or esoteric recall.
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Figure 3
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BLOOD CHROMOSOME STUDIES-AN IMPORTANT STEP IN
SYNDROME DIAGNOSIS
Chromosome aberrations are present in 50% to 60% of spontaneously aborted fetuses and in 0.5%
of newborns with hallmark findings of multiple defects and mental disability. Routine blood
chromosome analysis requires arresting dividing white blood cells in metaphase so that the
condensed chromosomes form linear bands (analogous to the barcodes at supermarkets). Harvest of
white cells from anticoagulated blood (green-top tube stored at room temperature) is followed by the
addition of lectins to stimulate growth (phytohemagglutinin), ar-rest in metaphase (colchicine), slide
preparation, and photomicroscopy that yields a standard karyotype in 5 to 10 days.6
A preliminary diagnosis of common chromosome disorders can now be achieved with fluorescent in
situ hybridization (FISH) techniques. Cloned DNA segments labeled with fluorescent signals will
hybridize to their chromosome of origin, thereby providing an identifying tag or probe. Exposure of a
blood sample to a FISH probe will quantify the number of target chromosomes without the need for
growth or metaphase arrest.
The rapid FISH test uses a mixture (panel) of differently colored FISH probes for chromosomes 13,
18, 21, X, or Y such that a normal female will have 2 signals for all but the Y chromosome, a normal
male 2 signals for the autosomes and 1 signal for the sex chromosomes X and Y. Abnormal
karyotypes can be detected through extra FISH signals-trisomies of 13, 18, 21, or X; extra sex
chromosomes in 47,XXY or 47,XYY-or missing FISH signals, as in monosomy X or Turner syndrome.
Normal signals for 46,XX or 46,XY individuals provide rapid genetic sexing that simplifies the
approach to ambiguous genitalia (virilized female vs incomplete male).6
As dictated by parental anxiety or management decisions, coordination of rapid FISH testing with the
cytogenetics laboratory can provide answers within 4 to 8 hours. However, a definitive karyotype
must still be performed because extra fluorescent signals for chromosome 21 will be present in
patients with trisomy or translocation Down syndrome. The precise count and arrangement of
chromosomes provided in the routine banded karyotype is needed to distinguish between 3
free-standing chromosomes 21-trisomy 21-rather than 2 chromosomes 21 plus a translocation
chromosome- t(14;21) most commonly.
Rapid FISH testing is also helpful in defining mosaicism, because it allows the cytotechnologist to
scan hundreds of cells for extra or missing signals. Statistics suggest that analysis of 11 cells in the
standard karyotype is sufficient to detect substantial mosaicism, but detection of low levels is
important in some situations (eg, Turner mosaicism in women with infertility or with risks for
gonadoblastoma when a Y-chromosome cell line is found).6
INTERPRETATION AND IMPLICATIONS OF CHROMOSOME
STUDIES
The routine blood karyotype uses cytogenetic nomenclature that places the number first, then the
sex chromosomes, and then any abnormalities. Normal karyotypes of 46,XX and 46,XY are modified
to indicate trisomy by the augmented number and chromosome identity (eg, 47,XX,+21 in a female
with trisomy 21 or 47,XY,+13 in a male with trisomy 13. Mosaicism (eg, mixtures of cells with
different karyotypes) are indicated by a slash mark between cell lines (eg, 47,XX,+21/46,XX for
mosaic Down syndrome). Rearrangements including translocations are indicated by special symbols,
such as "t" for translocation, "dup" for duplication, "del" for deletion, "r" for ring, "i" for
isochromosome (2 short or long arms joined together). Bands are numbered from the central joining
point (centromere) of each chromosome: those of the short arm are prefaced by "p" and those of the
long arm by "q." Joined chromosome regions, as with translocations, are separated by semicolons
and end points of deletions by colons. The characteristic short arm deletion causing cri-du-chat
syndrome can be precisely defined as 46,XX,del(5p16:).
A key point of nomenclature concerns Robertsonian translocations that arise between chromosomes
13, 14, 15, 21, and 22 with small short arms (the acrocentric chromosomes). These chromosomes
are frequently joined by crossovers in their satellite DNA, merging 2 separate chromosomes into a
single translocation chromosome. A karyotype of 45,XY,t(14:21) thus denotes a normal male who
"carries" translocation chromosome 14:21 with a corresponding reduction in chromosome number
from 46 to 45. The karyotype of his daughter with Down syndrome would be 46,XX,t(14;21)
indicating 2 free-standing chromosomes 21 plus a third 21 as part of the t(14:21) translocation
chromosome.
Generalists need remember only the "t" for translocation and the "/" for mosaicism plus a simple
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rule: trisomies do not need parental karyotyping and have low recurrence risks of about 1%;
translocations or other rearranged chromosomes require parental karyotyping because of higher
recurrence risks to translocation carriers-5% to 10% to t(14;21) carriers and almost 100% for
t(21;21) carriers.
Informed parents can choose among such options as triple/quad screening, chorionic villus sampling,
or amniocentesis to monitor future pregnancies.3-6 Rapid FISH can confirm clinical suspicion of Down
syndrome but must be followed by a standard karyotype to distinguish the approximately 96% of
children with trisomy 21 from the 2% to 3% with translocation 21. The other 1% have significant
mosaicism that looms large in the minds of parents because of its optimistic prognosis. In fact, most
patients with mosaicism have outcomes similar to those with full trisomy. This reflects the inaccurate
prediction of cell composition in key organs like the brain from analysis of blood leukocytes.
Studies of disorders such as Turner syndrome have indicated that all humans are mosaics. Normal
womenhave XO mosaicism in 2% to 4% of their cells; this percentage increases slightly as they age.
In the sperm of normal males, there is a surprisingly high frequency of aneuploid cells.
For children with Down syndrome, the prognosis- as for any child with a potential mental disabilitymust await development of speech-language ability. Individual placement within the 30 to 70 IQ
distribution (mean of 50) cannot be determined until the child is 4 to 5 years old.6
PREVENTIVE HEALTH CARE FOR DOWN SYNDROME-THE
CHECKLIST APPROACH
Pediatrician Mary Coleman effected a sea-change in the care and prognosis for children with Down
syndrome when she designed a checklist for preventive health care.This approach was promoted by
key publications2,3 and is now universally recommended.2-6 Attention to common complications
(Table) ensures good vision and hearing without refractory pulmonary hypertension from missed
cardiac disease. Coincident social changes provide early childhood intervention, preschool programs,
inclusive schooling, and extended graduation schedules for children with special needs. Pivotal to
this improved outcome is the primary physician who coordinates care among subspecialists and who
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Table
The foundation for the medical home is set by the initial physician contact. Suggestions for informing
parents include common sense directives; ie, that both parents are present, a private space for
discussion, time for questions, and specified follow-up.3-6 Most important is a positive attitude on the
part of staff and especially from the physician who will foster family adjustment and coordinate the
medical home. Parents should be told that their child will speak, laugh, read, love, grieve, and
worship as do other members of the family and that their early shock and sadness will be
transformed by unexpected insights and treasures that attend the development of any child. The
frightening word "retardation" may be mentioned to ensure understanding but should be replaced
with "disability." Negative terms such as "mongolism," "simian crease," or "Down's baby" should be
replaced by Down syndrome, single palmar crease, and people-first language.6
Early care should include a timely return visit to assess neonatal weight gain and consideration of
supplemental feedings. The high frequency of cardiac defects means that families may tread a
tightrope between cardiac function and achieving adequate weight in preparation for surgery.
Anal stenosis early and constipation later (from hypotonia) may cause difficulty with bowel
movements.8 Stenosis may be relieved with gentle dilation. Diet or milk of magnesia may ease
constipation. Daily nasal saline and shampoo rinses of the eyelids can prevent infections. Lotions are
helpful for dry skin.8 Regular hearing and vision screens, early intervention, ophthalmological
examination at 6 months, annual thyroid screening, cervical spine radiographs, and celiac disease
screening at 2 to 3 years should be considered.3-6
Numerous alternative therapies for Down syndrome with emphasis on vitamin supplements have not
been effective in controlled trials. (Visit the Web site maintained by Len Leshin, MD, parent and
pediatrician, for a current overview: http://www.ds-health.com/ds_sites.htm.) Equally misguided was
the idea of a "critical region" for Down syndrome that could be replicated in mice; that theory has
now been debunked by a definitive research study.9
These extremes of false science and scientism emphasize the need for clinical perspective on Down
syndrome with the primary physician as ideal purveyor. Rarely will physicians have better
opportunities to promote hope and well-being than with families of children with syndromes. Simple
recognition with humane management can yield surprising appreciation and gratitude- rewards often
missed in the bureaucracy of routine care.
Down Syndrome: Helpful Resources
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Books
Kumin L. Early Communication Skills in Children with Down Syndrome: A Guide for Parents
and Professionals. 2nd ed. Woodbine House: Bethesda, Md. Available at:
http://www.woodbinehouse.com/ main.asp_Q_product_id_E_1-890627-27-5_A_.asp. Accessed
November 5, 2007.
Stray-Gundersen K, ed. Babies With Down Syndrome: A New Parents' Guide. 2nd ed.
Woodbine House: Bethesda, Md; 1995.
Web sites
National Association for Down Syndrome http://www.nads.org
National Down Syndrome Congress http://www.ndsccenter.org
National Down Syndrome Society http://www.ndss.org
Down Syndrome: Health Issues (News and information for parents and professionals by Len
Leshin, MD) http://www.ds-health.com
References:
1. Jones KL, Smith DW, eds. Minor anomalies In: Smith's Recognizable Patterns of Human
Malformation. 6th ed. Philadelphia: WB Saunders; 2006:817-834.
2. Rogers PT, Coleman M, Buckley S. Medical Care in Down Syndrome: A Preventative Medicine
Approach. New York: Marcel Dekker, Inc; 1992.
3. Cooley WC, Graham JM Jr. Down syndrome-an update and review for the primary pediatrician.
Clin Pediatr (Phila). 1991;30:233-253.
4. Committee on Genetics. American Academy of Pediatrics. Health supervision for children with
Down syndrome. Pediatrics. 2001;107:442-449. Available at:
http://aappolicy.aappublications.org/cgi/content/abstract/pediatrics;107/2/442. Accessed
November 5, 2007.
5. Cooley WC, McAllister JW. Building medical homes: improvement strategies in primary care
for children with special health care needs. Pediatrics. 2004;113: 1499-1506.
6. Wilson GN, Cooley WC. Autosomal aneuploidy syndromes. In: Preventive Health Care for
Children with Genetic Conditions. Providing a Primary Care Medical Home. 2nd ed. New York:
Cambridge University Press; 2006:149-193.
7. Wilson GN, Tonk V, Spahis JK. GEN-ARM CD-ROM for Nursing Genetics. Available at:
http://www.dshs.state.tx.us/genetics/doc/ Dysmorphologychecklist.doc. Accessed December
6, 2007.
8. Spahis JK, Wilson GN. Down syndrome: perinatal complications and counseling experiences in
216 patients. Am J Med Genet. 1999;89:96-99.
9. Olson LE, Richtsmeier JT, Leszl J, Reeves RH. A chromosome 21 critical region does not cause
specific Down syndrome phenotypes. Science. 2004;306:687-690.
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