NEW BORN SCREENING
PRENATAL TESTING
   • DNA based diagnostic tests
   • F >35 ↑ risk for development of genetic disease
1...
1.   Congenital Adrenal Hyperplasia (CAH)
     •   Synonym: adrogenital syndrome
     •   All variants are autosomal reces...
o 95% - are PRIMARY
         o 3-5% - are SECONDARY as a result of a pituitary disorder or a
            malfunction of th...
•   Typical (+) PKU patient:
         o ↑Phenylalanine = >15mg/100mg
         o ↓Trosine = <5mg/100mg
 •   Ideal time to c...
•    Other Lab Test to aid in Dx:
             o AST and ALT (included in LFT) – liver enzymes will be ↑
             o Hi...
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New Born Screening Notes 072109 Dr Galido

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New Born Screening Notes 072109 Dr Galido

  1. 1. NEW BORN SCREENING PRENATAL TESTING • DNA based diagnostic tests • F >35 ↑ risk for development of genetic disease 1. Ultra sound – easiest to perform 2. Chromosomal analysis (karyotyping) • i.e. suspected Trysomi 21 defect (Down’s syndrome) • Sample of choice: amniotic fluid, chorionic villi sample (CVS) NEONATAL SCREENING • Primarily to detect disorders in which immediate treatment can prevent catastrophic consequences. • Detects mostly inborn errors of metabolism • Routine neonatal tests chosen are based mainly on the epidemiology, depending what chromosomal abnormalites are present or prevalent in a given area. • In the Philippines, according to REPUBLIC ACT 9288 there are 5 GENETIC DISEASES or INBORN ERRORS of METABOLIS that every new born MUST be tested for: 1. Congenital Adrenal Hyperplasia (CAH) 2. Congenital Hypothyroidism (CHT) 3. Phenylketonuria (PKU 4. Galactosemia 5. G6PD Deficiency • If a child has family Hx of a specific chromosomal abnormality, the lab must be notified to include the specific test for that particular abnormality in the screening process. • Most of the neonatal screening tests are tests for metabolic disorders. • FALSE NEGATIVE RESULTS may occur for some screening tests for some diseases of the following diseases if specimen from newborn is taken LESS THAN 24 hrs after birth: congenital hypothyroidism, homocystinuria, tyrosemia, cystic firosis. • The following tests may be performed on infants who appear clinically well in the 1st 24 hrs but develop signs of illness on the 2nd or 3rd day: o CBC – to test for any red cell or other hematological abnormalities o Blood gases- to test for metabolic acidosis or alkalosis o Urinalysis- to test for ketonuria o Blood lactate level – to test for lactic acidosis o Blood ammonia level o Liver function test o PT, PTT 1
  2. 2. 1. Congenital Adrenal Hyperplasia (CAH) • Synonym: adrogenital syndrome • All variants are autosomal recessive. • Most common variants: Type I and Type II • Most common cause (95%): 21-hydroxylase deficiency • Types I, II, and III - block formation of corticosterone, and cortisol o Abnormally ↑ androgen hormone production Male ♂ Female ♀ In Utero enlargement of genetalia ambiguous female (pseudohermaphtoditism (macrogenitosomia genetalia ) praecox) Masculization of external gentalia After Birth precocious puberty virilization Atypical variants ambiguous female Unaffected Type IV, V , and VI gentalia • Type II, IV, and VI – o causes a salt losing crisis similar to that seen in Addison’s disease. o Blocks the mineralcorticoid pathway • Methods/tests used to detect 21 hydroxylase deficiency: o Measuring the level of 17-OHP (hydroxypregnenolone) o Genotyping the blood of the newborn • Tx: glucocorticoid or mineralcorticoid replacement • Goals of Tx: o Children: normal growth, normal height, and pubertal development o Adult:  lessen signs of virilization and resume fertility  ↓ ACTH to <100 ng/L  ↑ 17-OHP (hydroxypregnenalone) to100-1000 ng/dL 2. Congenital Hypothyroidism (CHT) • Most common preventable cause of mental retardation. • Early detection is critical for the prevention of the severity of mental retardation associated with hypothyroidism. • Untreated CHT leads to mental retardation. • Prevalence: 1 in 3000 – 5000 births. Sometimes higher depending on the ethnicity and/or deficiency of iodine. o 85% - due to agenesis (failure of development of thyroid gland) – most common cause. o 10% - due to defect in enzymes of thyroid hormone synthesis 2
  3. 3. o 95% - are PRIMARY o 3-5% - are SECONDARY as a result of a pituitary disorder or a malfunction of the hypothalamus • Fetal Screening for CHT: o Specimen used: dry blood spot on fetal screening card or cord serum o Test for BOTH T4 and TSH. • Result: ↓T4 and ↑TSH = HYPOTHYROIDISM • If ONLY T4 tested - may miss compensated hypothyroidism. • 15% of infants with a PRIMARY thyroid disorder have a normal T4 (compensated) and an ↑TSH. • If ONLY TSH tested – may miss hypothyroidism due to pituary disorder or hypothalamic malfunction. • FALSE ↓T4 may occur due to: 1. Very low birth weight (VLBW) infants o T4 must be re-tested on 2nd and 4th-6th week for late onset of transient hypothyroidsm. 2. Congenital absence of thyroid binding globulin (TBG) • TSH is MORE sensitive than T4 in testing for hypothyroidism. o LAB RESULT INTERPRETATION • TSH = <10 meq/L – NO further action needed • TSH = 10-20 meq/L – must repeat test in 2-6 weeks • TSH = >20 meq/L – Dx with CHT 3. Phenylketonuria (PKU) • It is an autosomal recessive genetic disorder. • Characterized by a deficiency in hepatic enzyme phenylalanine hydroxylase. • Phenylalanine hydroxylase in needed to convert amino acid PHENYLALANINE to amino acid TYROSINE. • Phenylalanine hydroxylase DEFICIENCY leads to PHENYLALANINE ACCUMULATON in the body. • Excess PHENYLALANINE in the body is CONVERTED to PHENYLPYRUVATE (also known as PHENYLKETONE) • PHENYLKETONE is detected in the URINE. • ACCUMULATION of phenylalanine in the body leads to MENTAL RETARDATION. • At birth, infant serum phenylalanine level = <2mg/100mg due to maternal enzymes. TESTING FOR PKU 1. Urine Phenyl Ketonurina Test or Ferric chloride Test • Detected 3-6 weeks 2. Blood Test/s • HPLC • Guthrie Test • Detects > 4mg/100ml • Test for both phenylalanine and tyrosine levels 3
  4. 4. • Typical (+) PKU patient: o ↑Phenylalanine = >15mg/100mg o ↓Trosine = <5mg/100mg • Ideal time to collect PKU specimen = after 48hrs (24-48 hrs after infant started breastfeeding or formula feeding) • If specimen taken <24 hrs of birth – have baby brought back for retest • If PKU result within normal range – have baby come back 1 to 2 weeks for confirmatory recheck. • Tx: low protein (especially phenylalanine) diet and avoid foods that contain aspartame (it contains phenylalanine). 4. Galactosemia • Autosomal recessive genetic disorder • Unable to convert galactose to glucose • Found in 1 out or 62,000 born infants • Most common cause: Deficiency in galactose-1-phosphate uridyl transferase (GALT) – causes Classic Galactosemia o Deficiency in GALT enzyme leads to ↑ galactose accumulation in blood o Some symptoms: hypoglycemia, vomiting, diarrhea, irritability, feeding difficulty, failure to thrive, jaundice, hepatomegaly, easy bruisability, lethargy, cataract, premature ovarian failure, brain damage, cirrhosis. o Duarte galactosemia is a variant of classical galactosemia. Mostly asymptomatic. o Dx by demonstrating galactose in blood and urine  2/3 of patients with galactosemia - test (+) for galactose  Copper sulfate reducing test (Clinitest)  Glucose oxidase test • 2 Other Enzyme Deficiencies that cause Galactosemia o Galactokinase (GALK) Deficiency  May cause cataracts in infants o Galactose Epimerase (GALE) Deficiency  Also known as GALE deficiency, Galactosemia III and UDP- galactose-4-epimerase deficiency  There are 2 forms of epimerase deficiency: benign RBC deficiency and Severe liver deficiency. Severe form is similar to galactosemia • Screening Tests: o Pager (sp?) Assay  Milk or formula feeding necessary to perform. o Beutler’s Fluorometric Method  Milk or formula feeding NOT necessary to perform.  Does NOT detect galacto kinase deficiency but DOES detect the Duarte galactosemia variant. 4
  5. 5. • Other Lab Test to aid in Dx: o AST and ALT (included in LFT) – liver enzymes will be ↑ o Histologically: biopsy reveals fatty metamorphosis as early as 3 months of age. • Tx: Restriction of galactose in the diet. 5. G6PD Deficiency • Out of the 5 components of the NBST, this is the only disorder that is X- linked. • Affects males more than females. • Mostly among Caucasian with Kurdish Jewish people with the highest Incidence. • Also common in the Middle East, the Mediterranean, and Asia. • G6PD is seen in the pentose phosphate pathway of the RBCs. It’s plays a role of glucose metabolism in the RBC. • Abnormal hemolysis in G6PD deficiency can manifest in a number of Ways: o Prolonged neonatal jaundice possibly leading to kernicterus o Hemolytic crises in response to:  Illness (especially infections)  Certain drugs: antimalarial, sulfa drugs, nitrofurontoin, apirin, and analgesics similar to aspirin like phenacetin.  Certain foods: most notably fava beans (favism)  Certain chemicals  Diabetic ketoacidosis o Very acute crisis can cause acute renal failure • Dx Test: o Peripheral Blood Smear • Look for the following features: o Poikilocytosis, spherocytes, and Heinz bodies. o Heinz bodies – precipitate seen when hemoglobin is Denatured. Special stains are used like methyl violet and Crystal violet o Other screening tests: Methemoglobin Test, gluthathione stability test, dye reduction test, ascorbic acid test, fluorescent spot test, G6PD assay.  False normal result with African Americans: GTS and DRT.  G6PD assay - Invalid result if patient transfused:. 6. Trisomy 21 (Down’s Syndrome) 7. Cystic Fibrosis 8. Amino Aciduria 9. Lysosomal Storage Disorder 5
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