Neonate With Hypotonia and Subtle Anomalies

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.

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 between the toes, deep plantar crease [see Figure 1]) suggest the syndrome described by Dr Down in 1866.^1-6

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.

Blood Chromosome Studies--An Important Step in Syndrome DiagnosisChromosome 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), arrest 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 karyo- type 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 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 women have 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 disability--must 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.

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 publications^2,3 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 shelters the patient with a medical home.⁵ 

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.

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. *