Aquifer Pediatrics: Case 29 - 9 wk old male infant with hypotonia

Trisomy 13 (Patau syndrome)

1 in 10,000 births Microphthalmia Microcephaly Severe intellectual disability Polydactyly Cleft lip and palate Cardiac and renal defects Umbilical hernias Cutis aplasia

Trisomy 18 (Edwards syndrome)

1 in 6,000 births Severe intellectual disability Prominent occiput Micrognathia Low-set ears Short neck Overlapping fingers Heart defects Renal malformations Limited hip abduction Rocker-bottom feet

Trisomy 21

1 in 700 births Intellectual disability Epicanthic folds Flat facial profile Single palmar crease Redundant neck skin Heart defects Intestinal stenosis Umbilical hernia Predisposition to leukemia Hypotonia Gap between first and second toes

"What is the most appropriate diagnostic test at this time?" (4 days old) Choose the single best answer. The best option is indicated below. Your selections are indicated by the shaded boxes. A. Lymphocyte karyotype B. Skin biopsy for cytogenetic studies C. Buccal smear for fluorescence in-situ hybridization using a chromosome 21 probe

A Lymphocyte karyotype remains the standard for the laboratory diagnosis of Down syndrome. Fluorescence in-situ hybridization ("FISH") studies of uncultured cells have not replaced lymphocyte karyotype as the diagnostic study of choice. Although cytogenetic studies can be done on skin fibroblasts, it is much easier to obtain and study peripheral blood lymphocytes.

Which of the following are prenatal diagnostic testing for Down syndrome? Select all that apply. The best options are indicated below. Your selections are indicated by the shaded boxes. A. Amniocentesis and chromosome analysis of amniotic fluid cells B. Chorionic villus sampling (CVS) and chromosome analysis of CVS tissue C. Maternal serum screening D. Ultrasound exam of the fetus

A and B

Which of the following are common features of newborns with Down syndrome? Select all that apply. The best options are indicated below. Your selections are indicated by the shaded boxes. A. Upslanting palpebral fissures B. Cleft lip or palate C. Small ears D. Downslanting palpebral fissures E. Ocular hypotelorism F. Flattened midface G. Bulbous nose H. Epicanthal folds I. Redundant skin on the back of the neck J. Hypotonia

A, C, F, H, I, J Common features of more than 50% of infants with Down syndrome include: Upslanting palpebral fissures Small ears (usually less than 34 mm at maximum dimension in a term infant) Flattened midface Epicanthal folds Redundant skin on back of neck (nuchal skin) Hypotonia (most consistent finding in infants with Down syndrome) Additional common physical findings are small brachycephalic head, Brushfield spots, small shaped mouth, single transverse palmar crease, short fifth finger with clinodactyly, and wide spacing and a deep plantar groove between the first and second toes. The degree of cognitive impairment is variable and may be mild (IQ of 50-70), moderate (IQ of 35-50), or occasionally severe (IQ of 20-35).

Which of the following conditions are known to occur with increased frequency in children with Down Syndrome and may need medical attention in the immediate newborn period? Choose all that apply. There is no single best answer. A. Congenital hearing loss B. Congenital cataracts C. Congenital heart disease D. Gastrointestinal atresia E. Hip dysplasia

ALL OF THE ABOVE All of the above answers are correct. There is a significant risk of hearing loss (75%); obstructive sleep apnea (50%-79%); otitis media (50%-70%); eye disease (60%), including cataracts (15%) and severe refractive errors (50%); congenital heart defects (50%); neurologic dysfunction (1%-13%); gastrointestinal atresias (12%); hip dislocation (6%); thyroid disease (4%-18%) and, less commonly, transient myeloproliferative disorder (4%-10%) and later leukemia (1%) and Hirschsprung disease (<1%) .

A 4-day-old infant is evaluated in the nursery for dysmorphic features. He was born at 40 weeks gestation by vaginal delivery to a 35-year-old G1P1 mother. Pregnancy was uncomplicated and mother declined prenatal screening. Vital signs and pulse oximetry are normal. Physical examination reveals has mild hypotonia, epicanthal folds, upslanting palpebral fissures and a flat midface. Chromosomal studies are pending. Which of the following chromosomal abnormalities is most likely in this patient? The best option is indicated below. Your selections are indicated by the shaded boxes. A. Trisomy 18 B. 45 X0 karyotype C. Trisomy 13 D. Trisomy 21 E. 47 XXY karyotype

Answer D is correct because an extra chromosome 21 is indicative of Down syndrome. Patients with Down syndrome will present with the features described in the vignette as well as small ears, redundant nuchal skin, clinodactyly (the fifth digit is shorter and curved toward the radius). Additionally, cleft lip or palate, strabismus, and hypothyroidism may be seen.

Which of the following statements is true? Choose the single best answer. The best option is indicated below. Your selections are indicated by the shaded boxes. A. Consanguinity among parents is a greater risk factor for Down syndrome than maternal age. B. Most babies with Down syndrome are born to mothers who are younger than 35 years of age. C. The maternal age effect is lower in multiparous women. D. Paternal age is as important as maternal age as a risk factor for Down syndrome.

B

A 4-year-old boy with Down syndrome is brought by his mother to the office for increasing fatigue, intermittent fever, and decreasing appetite for three weeks. He is previously healthy. Physical examination reveals pallor and hepatosplenomegaly. What is the best next step in the management of this child? A. Advise the mother to use acetaminophen as needed for fever B. Send CBC and peripheral smear C. Send patient for chest x-ray D. Send TSH E. Start the patient on a 7-day course of amoxicillin

B B. This choice is correct because fatigue, decreased appetite, anemia, and HSM are all clinical signs and symptoms that may be associated with acute leukemia, for which patients with Down syndrome are at increased risk. A CBC would be helpful both for assessing the white blood cell count as well as the degree of anemia. A peripheral smear would be indicated to further evaluate for leukemia.

You are on the nursery service when your team is called to evaluate a 1-day-old infant. The infant was born via NSVD at 40 weeks' gestation to a 38-year-old G1P1A0 mother who did not have access to prenatal care and did not receive prenatal testing. The infant weighed 7 lbs 12 oz at birth and had Apgar scores of 7 and 8. On exam the infant is sleeping comfortably. She is afebrile with normal vital signs but appears to have low tone on exam. You also notice her ears seem to be lower than her eyes and appreciate mild edema of the hands and feet. Additionally, you note a fluid-filled sac at the base of the neck that does not appear to interfere with breathing. A karyotype performed after birth reveals a chromosomal abnormality. Which of the following is the most likely cause of this infant's condition? A. Down syndrome B. Turner syndrome C. Fetal alcohol syndrome D. Benign neonatal hypotonia E. Cystic hygroma

B B. Turner syndrome is correct. Turner syndrome is defined by the karyotype 45 XO. Characteristics of females with Turner syndrome include renal abnormalities, lymphedema (causing edema of hands and feet), low-set ears, congenital heart defects, dental abnormalities-such as narrow or high-arched palates-and cystic hygromas. Other possible physical findings include a webbed neck, widely-spaced nipples, and shield-like chest. As this mother did not have prenatal testing or a karyotype performed previous to her daughter's birth, one should be performed to confirm the diagnosis.

Which of the following sex chromosome abnormalities is most likely associated with physical differences at birth? Choose the single best answer. The best option is indicated below. Your selections are indicated by the shaded boxes. A. Klinefelter syndrome (47, XXY) B. Triple X (47, XXX) C. Turner syndrome (45, X) D. 47, XYY

C

A 39-year-old woman comes to the clinic for information on prenatal genetic counseling. She is at 22 weeks gestation. Family history is significant for a 10-year-old boy with intellectual disability. A photograph of her son reveals large ears and long face but no other congenital malformations. The mother is worried that she will have a second child with similar problems. Her triple screen testing and fetal ultrasound were both normal. If she were to have a second male child with developmental impairment, what would be the most etiology? The best option is indicated below. Your selections are indicated by the shaded boxes. A. Down syndrome B. Trisomy 13 C. Fragile X syndrome D. Turner syndrome E. Klinefelter syndrome

C C. Fragile X syndrome is the most common familiar cause of developmental impairment and is due to an abnormal number of trinucleotide repeats. These children present with large ears, long face and mandible and, after puberty, large testicles.

You are called to the delivery of an infant boy experiencing fetal distress. After a vaginal delivery with vacuum assist, the infant cries spontaneously but remains acrocyanotic, despite supplemental oxygen delivered by mask. The neonate is hypotonic and moves his extremities only in response to noxious stimuli. Physical exam reveals an open mouth with a protruding tongue, upslanting palpebral fissures, low-set ears, and a transverse crease across both palms. You immediately recognize this syndrome, and your attending asks you what is the most common cardiac defect in these patients? A. Aortic insufficiency B. Coarctation of the aorta C. Endocardial cushion defects D. Patent ductus arteriosus E. Conduction pathway defects

C C. Endocardial cushion defects. This patient has physical signs of Down syndrome. Approximately 50% of children with Down syndrome are born with endocardial cushion defects, such as ventricular septal defect, atrial septal defect, or complete atrioventricular canal defect. **Coarctation is seen in 35%

Which is the most common familial cause of intellectual disability? Choose the single best answer. The best option is indicated below. Your selections are indicated by the shaded boxes. A. PKU B. Translocation Down syndrome C. Velocardiofacial syndrome D. Fragile X syndrome

D

Which of the following newborn screening tests is most likely to be abnormal in an infant with Down syndrome? Choose the single best answer. The best option is indicated below. Your selections are indicated by the shaded boxes. A. PKU B. Galactosemia C. MCAD deficiency D. Congenital adrenal hyperplasia E. Hypothyroidism

E

Epidemiology and Risk fo Having a Child with Down Syndrome

Epidemiology Down syndrome occurs about 1 in 700 births in the U.S. Risk Factors Children with Down syndrome can be born to any couple, regardless of their age. The chance of having a child with Down syndrome increases as the mother's age increases (particularly beginning in the mid-30s). The reason for this is unknown. However, the majority of infants with Down syndrome are actually born to women younger than 35 years of age. This is because there are many more total pregnancies in these younger women. The likelihood of finding a translocation increases in infants born to younger mothers, but trisomy is still most likely, regardless of the parental age. Dr Oh asks you to consider serious complications associated with Down Syndrome.

Klinefelter Syndrome

Klinefelter Syndrome Boys with Klinefelter syndrome are typically normal appearing at birth, and may not be diagnosed until adulthood. Findings vary but usually include infertility due to testicular atrophy. There may be a eunuchoid body habitus and gynecomastia in adolescence. IQ varies, but is usually in the low-normal range. There is no specific phenotype for either 47, XXX or 47, XYY. Developmental delay and decreased IQ is more common in 47, XXX. Adults with 47, XYY may be taller than average. IQ tends to be in the low-normal range. There may be an increased incidence of behavior problems.

Fragile X Syndrome

Pathophysiology Fragile X syndrome is caused by the expansion of a trinucleotide repeat segment (involving CGG repeats) that is just outside the coding region of the FMR1 gene on the X chromosome. Affected males usually have more than 200 repeats, while normal individuals usually have fewer than 50. Individuals with 52-200 repeats have a premutation that has the potential of expanding to a larger size, perhaps to a full mutation, when that individual makes reproductive cells. This expansion is more likely to occur when the gene with the premutation is inherited from the mother, and the larger the size of the premutation, the greater the chance of expansion to a full mutation. Epidemiology Fragile X syndrome is important because it is common (about 1 in 4,000 males) and because virtually all mothers of affected sons are carriers of at least a premutation. Inheritance Fragile X syndrome is an X-linked trait, and most affected individuals are male. Presentation The findings in early childhood can be subtle. There is some correlation between the severity of the mental retardation and the size of the expansion in patients with the full mutation. Females: Females with a full mutation range from being asymptomatic to having mental retardation and/or psychiatric or behavioral problems. Males: Findings in males may include large testes (after puberty), large ears and evidence of a mild connective tissue abnormality (joint laxity, pectus excavatum, flat feet).

Prenatal screening vs diagnostic testing for Down Syndrome

Screening Prenatal screening tests estimate the chance that a fetus has Down syndrome. Maternal serum screening and fetal ultrasound can potentially screen for Down syndrome (and other chromosomal abnormalities); that is, they can provide information about the risk of having an affected fetus, but cannot definitively diagnose for a specific condition: Measurement of analytes in maternal serum offers an indirect screening method that can help refine the risk that a fetus is affected; the specific analytes measured vary, and may include alpha fetoprotein, human chorionic gonadotropin, estriol, PAPP-A, and/or inhibin. This is a rapidly developing area, and newer tests and combinations of tests may be available. These tests are not specific for Down syndrome, however. Detailed ultrasonography, looking at nuchal skin thickness, nasal bone ossification and other growth parameters, has been used to identify fetuses at increased risk for having Down syndrome. Ultrasound may be used in combination with maternal age and analyte measurement to better refine the risk that a fetus is affected with Down syndrome or another common chromosomal abnormality. Measuring fetal-specific DNA sequences in maternal blood in the first trimester can detect Down syndrome with 98.6% certainty. The test relies on the detection of cell-free DNA that circulates between the fetus and the expectant mother. This blood test can detect up to 98.6% of fetuses with trisomy 21. A "positive" result on the test means that there is a 98.6% chance that the fetus has trisomy 21; a "negative" result on the test means that there is a 99.8% chance that the fetus does not have trisomy 21. A "positive" result cannot distinguish between trisomy 21, translocation Down syndrome and high-percentage mosaic Down syndrome. https://www.ndss.org/resources/understanding-a-diagnosis-of-down-syndrome Diagnostic testing Chromosome analyses of amniotic fluid cells and chorionic villus sampling (CVS) are both direct diagnostic tests for Down syndrome, because the cells that are obtained and analyzed are of fetal origin. Both amniocentesis and CVS do have risks of complications, particularly a slight risk of causing a miscarriage.

Mosaicism in Trisomy 21

The concept of definitively ruling out mosaicism involves issues of statistical sampling and confidence interval considerations. It is virtually impossible to absolutely exclude mosaicism, because only a small number of cells are actually examined as part of the chromosome analysis, and these are usually all from the same cell type. However, the results can imply that the baby is probably not mosaic. Unless there is a cytogenetic finding of mosaicism or the patient has atypical clinical findings, it is presumed that a patient with trisomy 21 in all cells examined is non-mosaic. Down syndrome patients who are "mosaic" can vary widely in terms of their physical findings and cognitive impairment, depending on the percentage of normal and abnormal cells in important tissues. (Remember that testing is usually done on lymphocytes, which may not necessarily reflect the cytogenetic makeup of the brain, heart, etc.) There are several mechanisms by which mosaicism can occur. One possibility is that there is initially a trisomy 21 in the zygote, with a subsequent non-disjunctional mitotic event resulting in two different cell lines as the embryo develops. Clinical findings in mosaic Down syndrome can range from those of "classic" Down syndrome to virtually normal.

Follow-up Evaluation for Children with Down Syndrome

The following referrals or evaluations are recommended during the first 10 years of life of a child with Down syndrome: Annual thyroid screening (due to an increased incidence of hypothyroidism, even if not present at birth) Vision screening (due to increased incidence of vision problems) Hearing screening (due to increased incidence of hearing problems) Complete blood count in first month to assess for leukemoid reactions, or transient myeloproliferative disorders (TMD) Referral to a pediatric cardiologist (due to the increased incidence [50%] of structural heart disease in patients with Down syndrome and the difficulty of auscultating some of these cardiac defects) Beginning at 1 year of age, and then annually, a hemoglobin and hematocrit should be obtained to screen for iron deficiency anemia (due to increased risk for iron deficiency due to lower dietary iron intake than their peers) Referral for evaluation by early intervention is key to a child with Down syndrome receiving any needed therapies as early as possible. Additionally, there is an increased incidence of atlantoaxial instability in individuals with Down syndrome, so careful history and physical examinations should be performed at every well-child visit or when symptoms possibly attributable to spinal cord impingement are reported. At least biennially, the importance of cervical spine-positioning precautions for protection of the cervical spine during any anesthetic, surgical, or radiographic procedure should be discussed with parents. The other tests and referrals mentioned are not generally indicated, but are used as needed for individ ual patients.

Genetics of Down Syndrome

There are several karyotypes involving extra material from chromosome 21 that can cause the Down syndrome phenotype, including: Trisomy 21 (47, XY,+21 in this boy) (the most common and most likely, regardless of the mother's age); An unbalanced chromosome translocation resulting in extra chromosome 21 material; and Mosaicism for a trisomy 21 cell line.

Common Trisomies

Trisomy 13 (Patau syndrome) Trisomy 18 (Edwards syndrome) Trisomy 21 (Down Syndrome)

Turner Syndrome

Turner Syndrome Turner syndrome is the sex chromosomal disorder most likely to be associated with physical differences at birth. Physical findings Turner syndrome is associated with lymphedema in utero, which is the cause of many of the physical findings such as: Webbed neck Low ear placement Edema of the hands and feet Hyperconvex nails, and "Shield" chest, with widely spaced nipples Additional findings in Turner syndrome: Coarctation of the aorta is found in about 20% of affected girls. Short stature is common, and some girls are not diagnosed until early adolescence when they present with short stature and delayed sexual maturation (due to gonadal dysgenesis). Most have a normal IQ. Incidence The incidence of Turner syndrome is about 1/2,000 female live births, but the incidence at conception is much higher. It is estimated that about 99% of conceptuses with Turner syndrome miscarry, most in the first trimester. Link to a photo of a girl with Turner syndrome.

Disorders of Sex Chromosomes

Turners Klinefelters