Genetics for Nurses in Pediatric Disciplines

1. Genetics for Nurses in Pediatric Disciplines A guide to recognition and referral of congenital and genetic disorders AUTHORS: Golder N. Wilson MD PhD,1 Vijay Tonk PhD,2 REVIEWERS Shirley Karr BSN RN,3 Joanna K. Spahis BSN CNS,4 Shirley Myers,5 RNC, MSN, FNP, and Sherry Letalian RN6 1Clinical Professor of Pediatrics, Texas Tech University Health Science Center at Lubbock and Private Practitioner, KinderGenome Genetics, Dallas Texas; 2Professor of Pediatrics and Obstetrics-Gynecology; Director, Cytogenetics Laboratory, Texas Tech University Health Science Center at Lubbock;3Genetics Coordinator, Maternal-Fetal Medicine and Genetics, Texas Tech University Health Sciences Center at Amarillo;4Pediatric Clinical Nurse Specialist in Genetics and Coordinator of the Down Syndrome Clinic, Department of Genetics, Children’s Medical Center of Dallas5Women’s Health Nurse Practitioner, Maternal-Fetal Medicine and Genetics, Texas Tech University Health Sciences Center at Amarillo;6Pediatric Clinic Coordinator, Department of Pediatrics, Texas Tech University Health Sciences Center, Lubbock Acknowledgement: This presentation was designed as part of the GEN-ARM (Genetics Education Network for Nursing Assessment, Recognition, and Management) for the Mountain States Region Genetics Collaborative (MSRGCC); contact www.mostgene.org or Ms. Joyce Hooker at joycehooker@mostgene.org

2. Genetic Disorders are Common Genetic diseases affect 5-10% of children Nurses can recognize and refer genetic disorders without need for esoteric genetic knowledge We will now present cases where your nursing skills and alertness (REYDAR=Recognize, EYDentify, Assess, Refer) can greatly benefit children with genetic diseases. These cases will introduce you to simple principles of genetics that will give you confidence in recognizing these patients and foster a medical home These cases and principles are geared to the nursing genetics primer and resources on the GENARM CD

3. Think genetics when something is unusual or extreme • Case A: A term AGA newborn product of a pregnancy with little prenatal care has an enlarged and distorted head, blue-gray sclerae (whites of the eyes), and deformed limbs. X-rays show multiple fractures, and the mother blames this on an auto accident at 7 months gestation. Do you agree? Newborn with large head and deformed bones with fractures by x-ray

4. This unusual presentation should prompt REYDAR for a genetic disease • More detailed family history would be useful, although many genetic disorders occur as new changes (new mutations) • The symptoms of blue sclerae and multiple fractures could be searched on the website Online Mendelian Inheritance in Man (go to http://www.ncbi.nlm.nih.gov/entrez/ or enter OMIM in search engine). They point to a disorder called osteogenesis imperfecta (166210 • OMIM contains >6000 diseases that can be searched by symptom, name, or number; associated databases contain genetic education, medical literature (PubMed), and even the complete human genome sequence/gene map. • Also useful is the companion database www.genetests.org that lists testing (when available) for the particular genetic disease (go to the clinical laboratory section and search by disease name

5. The family history indicated that the mother and other relatives had mild features of osteogenesis imperfecta or brittle bone disease (see Chapter 2) Suspicion of genetic disease underlying this unusual infant led to referral and genetic counseling for this autosomal dominant disease—mother’s guilt about her accident was assuaged and she learned she had a 50% chance each of her future children would have OI Family history Pedigree

6. Note that simple recognition and assessment of possible genetic disease, not sophisticated knowledge, optimized nursing care of this family. • Nurses with additional interest in genetics can learn to construct pedigrees, interpret inheritance mechanisms, and provide recurrence risks for the parents (genetic counseling) • Nurses are ideally positioned to be genetic counselors with their hands-on contact, emphasis on education, and focus on prevention • Read chapters 2-4 in the primer to acquire the skills for genetic counseling

7. Genetic disease can be defined by abnormal genes, tissues, or chromosomes (genetic testing) Categories of genetic disease relate to the steps from gene to family (genetic hierarchy) • A family has people with unusual symptoms • A person has abnormal form or function (disease) • A tissue (cell to organ) has abnormal structure (metabolic disorders) • A chromosome is extra or missing (chromosome disorders) • Several genes (plus environment) are abnormal (multifactorial disorders or susceptibilities) • A gene (DNA to RNA to protein) is abnormal (Mendelian disorders

8. Categories of genetic or congenital disease

9. Mendelian diseases like osteogenesis imperfecta have distinctive family patterns • The pattern of affected relatives is caused by transmission of single genes, each with a unique position (locus) on the chromosome. • The paired chromosomes 1-22 and XX in females imply paired genes except for X and Y genes in the male • Dominant or recessive diseases result when one or both gene partners (alleles) are abnormal. • Abnormal alleles can be predicted (genetic risks) and sometimes diagnosed through their abnormal DNA sequence or RNA/protein expression.

10. Sickle cell anemia is recessive, requiring both β-globin alleles to be abnormal (SS versus AS trait or AA normal). Sickle cell anemia can be predicted (25% risk for next child) and tested (abnormal S protein or gene) Other inherited anemias can be related to different abnormal globin alleles (C, D, E, thassemias). A or S

11. OI is caused by one abnormal allele at a collagen gene (genotype Oo) • Different phenotypes of OI relate to different collagen alleles • The >6000 Mendelian diseases thus relate to a similar number of different genes and abnormal alleles. • Characterization of abnormal alleles provides DNA testing—few of the >1600 characterized disease genes are available to the clinic. • Simultaneous analysis of multiple genes (DNA chips, arrays) is not yet practical in the way that karyotypes define any abnormal chromosomes

12. Know categories, not rare diseases • Single genes altering development cause birth defects and syndromes • Single genes altering enzyme pathways cause inborn errors of metabolism • Single genes altering organ function(s) produce extreme or early–onset • examples of common disease (e.g., neonatal diabetes) Mendelian diseases reflect transmission of single genes (abnormal alleles) = DNA diagnosis Multifactorial diseases reflect multiple abnormal genes plus environment = DNA/HLA markers Many genes altering development cause isolated birth defects like cleft palate Many genes altering enzyme pathways cause common metabolic diseases (e.g., adult-onset diabetes, hyperlipidemia) Many genes altering organ function(s) produce adult diseases (e.g., schizophrenia) Chromosomal diseases imbalance multiple genes and cause multiple birth defects = Karyotype

13. REYDAR of common pediatric presentations Recognition → Category → Referral ↔ Medical home • Case 1N, 3N—newborns with poor feeding, unusual appearance • Case 4N—Newborn with deterioration and lethargy • Case 5K—Child with hypotonia and motor delays • Case 6K—First-grader with school problems • Case 7K—Boy with tall stature • Case 8K—Girl with intermittent acidosis and fatigue (see Chapter 1)

14. Case 1N. Newborn with feeding problems(see Chapter 1 of primer)A term female infant exhibited slow growth in the last trimester of pregnancy but had normal ultrasound studies. After normal delivery and borderline low birth weight (5 lbs), the mother reported difficulty breast-feeding. Lactation education and reassurance were given and the infant was discharged with mild jaundice and a weight loss of 5% from her birth weight. Was this management appropriate?What additional history might have been helpful? REYDAR of common pediatric presentations Recognition to category to referral and management

15. Poor breast-feeding may signal syndromes or congenital disorders Case 1N (cont): Important history was that this child was mother’s second--her child was the problem, not her breast-feeding. The child’s low muscle tone and subtle facial changes (down-slanting palpebral fissures, broad nasal bridge, down-turned corners of the mouth) led to evaluation after discharge with chromosome studies that showed deletion of the number 4 short arm (4P- or Wolf-Hirschhorn syndrome. Recognition of H&P signals was the key to REYDAR, not knowledge of a rare disease.

16. A birth defect (VSD) plus other signs • Case 3N: A term male infant with a heart murmur was found to have a ventricular septal defect without failure but had continuing lethargy, low muscle tone, poor latch for breast-feeding and difficulty stooling. What else should be considered?

17. The infant’s facial appearance was slightly unusual and raised the question of Down syndrome (OMIM #190685), which would explain the low muscle tone and poor feeding. Single palmar creases were noted on the hands as well as wide spaces between the first and second toes. What testing would be most useful in determining the child’s diagnosis?

18. Routine chromosome analysis (karyotype) will show the extra chromosome 21 that is characteristic of Down syndrome which normally requires at least 5-7 days for results.

19. 13 18 21 X Y Cloned DNA segment from target chromosome FISH probes Fluorescent label 13, X, Y No culture or need for metaphase spreads 18 21 Male with trisomy 13 Now a rapid FISH test is available that does not require stimulation of white blood cell division and gives results within 2-4 hours. Rapid FISH highlights chromosomes commonly involved in disorders—e.g., 13 (Patau syndrome), 18 (Edwards syndrome), or 21 (Down syndrome), showing three versus the normal two FISH signals in each cell nucleus (X and Y probes also show Turner syndrome or document sex in cases of ambiguous genitalia)

20. RULE: Do not blame neonatal feeding problems on inexperience/adjustment without considering a congenital/genetic disorder • RULE: Consider congenital/genetic disorders in children with several physical variations (minor anomalies) and/or unusual facial appearance

21. Case 6K. A first-grader with school problems A 6-year-old girl is having trouble keeping up in the first grade because of distractibility and poor comprehension. She had some problems breast-feeding and later needed speech therapy. Her school nurse noted a somewhat unusual facial appearance with narrow eyes, long face, and prominent nose; she also had long fingers and a faint heart murmur. The child’s teacher felt she was a discipline problem due to attention deficit or conduct disorder and suggested possible medication therapy. Do you agree?

22. The subtle facial changes, speech delay, and school problems suggest mild mental disability--such children may be labeled as unmotivated or hyperactive unless the underlying congenital problem is recognized. This child had the Shprintzen-DiGeorge spectrum (OMIM #192430), proven by FISH testing showing submicroscopic chromosome 22 deletion (her parents were normal). Referral to cardiology showed a small cardiac defect and arrythmia; medication was needed, but not for the learning problem.

23. RULE: Look for additional physical variations (minor anomalies like single palmar crease) in children with apparently isolated birth defects because syndromes imply multiple problems and higher genetic risks • RULE: School problems may reflect cognitive disabilities due to genetic conditions rather than behavior or psychosocial problems.

24. Chromosome disorders • Miscarriages (50-60%), liveborn children (0.5%), cancer tissue (many have diagnostic changes) • Over 200 pediatric diseases due to extra or missing chromosome or parts of chromosomes (p small or q long arms) • Hallmarks are multiple major or minor anomalies (unusual appearance) with mental disability • Most recognized by a routine karyotype, but FISH is required to detect submicroscopic deletions (e.g., DiGeorge) or the 3% of suspect children who have changes on subtelomere FISH after normal karyotypes • Individual submicroscopic deletions are found in Williams (7q), hereditary retinoblastoma (13q), Prader-Willi (15q), Shprintzen-DiGeorge spectrum (22q), and ~15 others. • Consider chromosomes in any child with unexplained mental disability and/or multiple birth defects, couples with >2 miscarriages, prenatal diagnosis for women over age 35 See Chapter 7 for more information

25. Case 4N: Sudden deterioration and unusual odor in a newborn after 24 hours of feeding. • A term newborn male with appropriate birth weight had an uncomplicated vaginal delivery with good Apgar scores. The child fed avidly for 24 hours but slowly become lethargic and less active. The nurse noted jaundice and documented a cutaneous bilirubin of 8.0 mg %, mostly indirect. Review of the family history showed that the couple had 3 living children with 2 prior infant deaths of unknown cause; they came from the same small town in Mexico. The nurse also detected an unusual sweet smell to the urine and notified the pediatrician when the child became jittery and would not feed. What is the most likely disease category?

26. Inborn errors of metabolism • Metabolic diseases in children can have acute, intermittent, or insidious presentations. Unlike diabetes mellitus or “metabolic syndromes” in older children with obesity, early onset metabolic disorders are often due to abnormal genes that encode defective enzymes—inborn errors of metabolism. Acute inborn errors involve derangements of small molecules and often manifest when a newborn is removed from the maternal metabolism (delivery) and required to break down foodstuffs on its own. Many acute metabolic disorders have similar symptoms of lethargy, low tone, and jitteriness progressing to coma due to low blood sugar, acidosis, inability to make energy, or high ammonia. What screening tests are indicated to investigate an acute metabolic disorder?

27. Inborn errors of metabolism • The standard newborn screen in Texas detects the acute metabolic disorders phenylketonuria (PKU-- OMIM #261600) and galactosemia (OMIM #230400) as well as sickle cell anemia (OMIM #603903), congenital adrenal hyperplasia (OMIM #201910, others), and hypothyroidism (OMIM #218700, others). • The expanded or supplemental newborn screen (employing in part an acylcarnitine profile) uses mass spectrometry to detect up to 50 additional acute metabolic disorders and is being adopted by most states. • The supplemental screen along with blood sugar, electrolytes, pH, and ammonia was obtained in this infant, showing a low sugar (45 mg %), elevated anion gap (sodium plus potassium concentration minus chloride and bicarbonate  12-14), acidosis (pH < 7.2), and abnormal acylcarnitines. These findings plus certain elevated blood amino acids (leucine, isoleucine, valine) suggested a diagnosis of maple syrup urine disease and led to successful dietary treatment of the metabolic disorder

28. Inborn errors of metabolism • Over 300 disorders with overall frequency 1 in 600. • Nearly all are Mendelian autosomal or X-linked recessive—the abnormal alleles cause their encoded enzyme to be defective with build-up of chemicals before the block and deficiency of those after the block • Children with inborn errors usually have a normal appearance with abnormal blood chemistries (low glucose, anion gap, high ammonia, high lactic acid) • Early recognition is key before organ damage occurs from acidosis, seizures, or chemical build-up; dietary treatment is often available

29. RULE : Suspect acute metabolic disorders in normal-appearing infants who decompensate after feeding: look for hypoglycemia, acidosis, or high ammonia. • RULE : The lack of a family history does not exclude a genetic disorder—suspect new gene mutations or chromosome aberrations.

30. Case 7K—A boy with tall stature . A pediatric nurse conducts a school physical on a 6-year-old boy who is very tall for his age. He has a height beyond the 97th centile despite average weight and head circumference, and his parents are not tall. The nurse notes other findings including an aged facial appearance, lax joints, heart murmur, and concave chest. The nurse suspects a genetic condition, and documents a family history

31. Case 6A, cont The family history shows numerous relatives with heart problems on the father’s side. The father (individual III-2) is not unusually tall (5’ 10”) and has no eye or heart problems. However, the father’s brother (individual III-1) developed aortic dilation and insufficiency at age 39, was 6’ 5” tall, and had a lean build with flat feet and inguinal hernias.

32. Disorders with extreme tall stature (gigantism), short stature (dwarfism), or failure to thrive are often genetic • Diagnosis: Marfan syndrome (154700) • Suspicion of the disorder led to protection from collision or high-intensity sports and led to cardiac studies demonstrating aortic dilatation. The boy and affected family members have a 50% risk to transmit the disease with each child.

33. Case 9P. Adolescent female with unplanned pregnancy • A 16-year-old female was referred to obstetric clinic from the emergency room after a diagnosis of malnutrition and a positive pregnancy test. She had been brought in by the police for vagrancy and alcoholism, exhibiting poor hygiene and nutrition on examination. Fetal ultrasound revealed a fetus of about 3 months gestation with very small head circumference, abnormal head shape, and intrauterine growth retardation. Her obstetric RN recognized two likely diagnoses, and referred her to maternal-fetal medicine for evaluation including level II ultrasound.

34. The fetal growth changes would be consistent with fetal alcohol syndrome but the severe microcephaly suggested anencephaly (OMIM #206500, others). Of growing importance in pediatrics is preconception care, illustrated here by the fact that folic acid taken early in pregnancy lowers the incidence of neural tube defects like anencephaly or spina bifida by 2/3. As with maternal diabetes, prevention must begin before planning the pregnancy since a missed period may not be noticed until 3-4 weeks after conception (after the primitive streak stage)

35. RULE : Pregnancy planning and preconception counsel are important priorities because recognition of pregnancy by a missed period (3-4 weeks embryonic age) may be too late for preventive measures

36. Multifactorial Disorders Table 4.1. Multifactorial Disorders in the United States *Ranks first for neonatal causes of death; approximate scale: ++++ (100% of predisposition due to genetic factors as for Mendelian disorders) to + (20% of predisposition due to genetic factors)

37. Multifactorial Disorders • Most isolated birth defects like cleft palate, hypospadias, heart defects, spina bifida • Many common diseases like diabetes mellitus, hypertension, mental illness • Multiple genes involved, giving lower transmission risks (about 3% for offspring of affected parent, sibling to affected child) • Therapeutic goals are to manipulate environment (e.g., folic acid) either generally or for specific high-risk individuals identified by associated DNA markers (more diverse and sensitive than HLA haplotypes

38. Multifactorial disorders: For some (e.g., coronary artery disease), single genes of major effect (e.g., those regulating cholesterol) are good risk markers) Recognizing at-risk children or adolescent females provides important opportunities for nursing education and prevention (see chapter 4)

39. Review Questions • 1. A term female infant to a 37-year-old mother with three prior children has a low birth weight and a poor latch for breast-feeding the first 24 hours of life. Mother had first trimester maternal serum screening (quad screen) that was normal. Your assessment of the baby reveals an unusual facial appearance with a broad nose and extra skin folds on the neck. Based on the history, which of the following is the most likely reason for poor breast-feeding in this child: • Maternal incompetence • Autosomal dominant disorder in mother • X-linked recessive disorder in child • Chromosomal disorder in child • Multifactorial disorder in child • 2. Prior to receiving test results, the most important aspect of care along with evaluating the feeding problem is: • Genetic counseling regarding recurrence risk • Genetic counseling regarding prenatal diagnosis • Supportive counseling for future mental retardation • Supportive counseling for probable birth defects • Supportive counseling explaining the management plan

40. 3. A female infant demonstrates inconsistent bottle feeding and exaggerated jaundice with a total bilirubin of 14 at day 2 of life. Your assessment reveals the infant is less responsive than early on your shift, and you note decreased muscle tone with a poor suck. The prenatal history is normal except that the mother and father are from Pakistan and are second cousins. Which of the following conditions would be most likely in this infant? • Chromosome disorder • Biliary atresia • Inborn error of metabolism • Lactose intolerance • Multifactorial disorder • 4. As the infant is being evaluated, a grandparent brings documentation from Pakistan showing a prior child of this couple died with a diagnosis of maple syrup urine disease. Which of the following would resources would provide information on the inheritance of this disorder? • Online Mendelian Inheritance in Man • GeneTests • Alliance of Genetic Support Groups • ISONG • ACOG

41. Questions 5-6 • 5-6. A 21-year-old female was referred to obstetric clinic from the emergency room after a diagnosis of malnutrition and a positive pregnancy test. She had been brought in by the police for vagrancy and alcoholism, exhibiting poor hygiene and nutrition on examination. She also was affected with cystic fibrosis, having a milder disease course, and a sister had a child with spina bifida. Fetal ultrasound revealed a fetus of about 3 months gestation with very small head circumference, abnormal head shape, and intrauterine growth retardation. • 5. The poor malnutrition and unplanned pregnancy caused the young woman to miss the following standards of care: • Amniocentesis because of higher risks for chromosome abnormalities and cystic fibrosis • Triple/Quad screening with ultrasound to screen for fetal chromosome abnormalities • Preconception counsel including provision of vitamins with folic acid • Prosecution because of suspected alcoholism causing damage to the fetus • Preimplantation genetic diagnosis of to avoid the high risk for fetal cystic fibrosis

42. 6. Which of the following birth defects would be most likely to occur in this situation? • Congenital heart defect • Omphalocele • Anencephaly • Tracheo-esophageal fistula • Anal atresia

43. Answers 1-D 2-E • Questions 1-2. • Difficulty breast feeding by an experienced mother should prompt concern about a congenital disorder. The history of “advanced” maternal age (> 35) together with an unusual appearance in the child warrants consideration of a chromosome disorder. (answer 1D). First trimester quad screen plus ultrasound will detect as many as 87% of fetuses with Down syndrome but sampling of fetal cells (e.g., chorionic villus sampling or amniocentesis) with karyotyping is required for definitive diagnosis of fetal chromosome disorders.

44. Answers 3-C 4-A • Questions 3-4 • The difficulty feeding with progressive lethargy and family history of parental consanguinity (relatedness) suggest a metabolic disorder (see Chapters 2 and 10). Information on genetic disorders such as maple syrup urine disease can be found in Online Mendelian Inheritance in Man (enter OMIM in browser).

45. Answers 5-C6-C • Questions 5-6 • The importance of preconception counsel is recognized by the American College of Obstetrics and Gynecology (ACOG). Provision of folic acid prior to conception (the embryo will be at least 3 weeks along when mother misses her menstrual period) lowers the risk of neural tube defects (spina bifida, anencephaly) by 2/3. Neural tube defects exhibit multifactorial determination (see Chapter 4) with increased risk (0.5-1%) to relatives. The woman is affected with cystic fibrosis (219700--autosomal recessive) and would be a homozygote (genotype cc—see Chapter 3) but the father would be unlikely to be a carrier (at least 19/20 chance) and thus there would be no indication for prenatal diagnosis. A planned pregnancy could have included carrier screening for cystic fibrosis in the father.