Newborn Screening Fact Sheets

Committee on Genetics

These newborn screening fact sheets were devel- who underwent testing too early). Under such cir- oped by the Committee on Genetics of the American cumstances, follow-up testing may be required for Academy of Pediatrics (AAP) with considerable as- certain infants even if the newborn screening results sistance and consultation from many individuals. It are negative. Unfortunately, most states do not re- is hoped that the information contained in these fact port negative results directly to the pediatrician, par- sheets will assist the pediatrician in understanding ticularly if the pediatrician is not the physician of the individual tests, their characteristics, and their record during the infant’s neonatal stay. All reports strengths and weaknesses. Newborn screening is an are sent to the hospital of birth and not necessarily to individual function of each state; therefore, screening the physician, making transfer of such information programs are not uniform throughout the United highly variable from state to state and institution to States (Table). Because the test results can affect chil- institution. Some states have developed a direct elec- dren and parents in a variety of ways, there are tronic system whereby these results may be easily special concerns about how states make decisions to obtained by the pediatrician; however, in many in- adopt new tests and how they evaluate their current stances, a direct and easily accessible system is not screening panels. Currently, many states are exam- currently in place and may require time-consuming ining their practices. The information in the fact efforts on the part of the pediatrician and office staff sheets was not designed to advocate specific new- to obtain a hard copy of the newborn screening re- born screening tests but to assist pediatricians in sults. The Committee on Genetics supports the active evaluating policies and procedures and in develop- involvement of the local academy state chapters in ing appropriate positions based on the needs of their working with state newborn screening programs to patients and their geographic regions. facilitate the prompt and direct transfer of informa- Confirmation of positive newborn screening test tion to the pediatrician. Many of these issues are results is always necessary. Additionally, newborn addressed in greater detail in the AAP 1992 policy screening programs should not preclude the pedia- statement “Issues in Newborn Screening,” which trician’s assessment of clinical symptoms at any age. should serve as a reference for these newborn screen- Some disorders (eg, galactosemia and maple syrup ing fact sheets. urine disease) may become symptomatic before the Our knowledge base regarding newborn screening availability of the results of newborn screening and is expanding rapidly, and there are numerous areas may warrant specific testing when clinically sus- of controversy. Recently, the Committee on Assess- pected. Furthermore, although newborn screening ing Genetic Risks of the Institute of Medicine has tests are designed to detect infants with metabolic recommended that ongoing newborn screening pro- illnesses, certain tests may also identify carriers (ie, grams be reviewed periodically, preferably by an heterozygotes) or individuals with variants who may independent body that is authorized to add, elimi- be clinically asymptomatic. Such information is im- nate, or modify existing programs. Furthermore, the portant for the family because of the identification of committee recommended that states with newborn “carrier couples.” This can have an impact on future screening programs for treatable disorders also have pregnancies and other family members. Thus, the programs available to assure that necessary treat- pediatrician needs to be aware of this aspect of new- ment and follow-up services are provided to affected born screening and provide appropriate counseling children identified through newborn screening with- or referral of such families. out regard to the ability to pay. Although no clear False-negative test results may occur for a variety consensus of the committee was forthcoming regard- of reasons. Pediatricians should be knowledgeable ing informed consent for newborn screening, a about the procedures used in their state programs strong recommendation was made that informed and be aware of those groups of infants likely to be consent be an integral part of newborn screening, missed through screening (ie, those born prema- including disclosure of the benefits and risks of the turely, those who have received blood transfusions, tests and treatments, and that information unrelated those out-of-state or out-of-country births, and those to the health of the individual (eg, carrier status and paternity) may be disclosed. For established tests in which patients would clearly benefit from early di- The recommendations in this statement do not indicate an exclusive course agnosis and treatment (eg, phenylketonuria [PKUI of treatment or serve as a standard of medical care. Variations, taking into and congenital hypothyroidism), it was thought ap- account individual circumstances, may be appropriate. PEDIATRICS (ISSN 0031 4005). Copyright 0 1996 by the American Acad- propriate for state departments of health to mandate emy of Pediatrics. the offering of such testing. Strong sentiment, how-

PEDIATRICS Vol. 98 No. 3 September 1996 473

Downloaded from www.aappublications.org/news by guest on September 29, 2021 TABLE. Newborn Screening bv States and Jurisdictions* State Phenyl- HYPO- Galac- Maple Homo- Bio- Cystic Adrenal Tyro- Toxo- Hemo- ketonuria thy- tosemia Syrup cystin- tinidase Fibrosis Hyper- sinemia plas- globi- roidism Urine uria De- plasia mosis nooathv. , Disease ficiency Alabama X X X X Alaska X X X rt P x X P Arizona X X X X X X X Arkansas X X X California X X X Colorado X X X X X X X Connecticut X X X X Delaware X X X X X District of X X :: X P X Columbia Florida X X X X Georgia X X X X X X X Hawaii X X P Idaho X X X X X Illinois X X X X X Indiana X X X X Iowa X X X Kansas X X Kentucky X X Louisiana X X Maine X X X X X Maryland X X X X P Massachusetts X X z X X X X Michigan X X X X Minnesota X X X Mississippi X X Missouri X X Montana X X P Nebraska X X X Nevada X X X X X X X New Hampshire X X X X X X New Jersey X X X New Mexico X X X New York X X X X X X North Carolina X X X X North Dakota X X X X X Ohio X X X X Oklahoma X X X Oregon X X X X X X X Pennsylvania X X X Rhode Island X X X X X South Carolina X X X South Dakota X X Tennessee X X X Texas X X X X Utah X X Vermont X X X X r P Virginia X X X X X X Washington X X X X West Virginia X X X P Wisconsin X X X X P X P X Wyoming X X X X X X X X Puerto Rico X X X Virgin Islands X X X X P X Total count 53 53 46 25 21 4 11 7 2 45 * States as of December 1995. Note: the Uniformed Services Program may contract with any laboratory for the performance of newborn screening. Most hospitals use the newborn screening program in the state in which they are located. Pediatricians should inquire about the newborn screening testing performed on such infants transferring to their practice. t P indicates selected population, pilot program, or physician request. ever, was expressed by several committee members Newborn screening varies by state. Information is that such testing should be universally mandated. provided for the following 11 conditions: biotinidase Although we have attempted to provide a consen- deficiency, branched-chain ketoaciduria (maple sus viewpoint, experts in this field do not always syrup urine disease), congenital adrenal hyperplasia agree. Pediatricians who desire additional informa- (CAH), congenital hypothyroidism, cystic fibrosis tion should contact the specialists in their region or (CF), galactosemia, homocystinuria, PKU, sickle cell those involved at a national level. General references disease, toxoplasmosis, and tyrosinemia. have been provided to assist in clarifying some of These fact sheets will require revision in the future. these points. Your comments and suggestions are appreciated.

Downloaded from www.aappublications.org/news by guest on September 29, 2021 474 NEWBORN SCREENING FACT SHEETS Note on Early Hospital Discharge for an all-inclusive program including follow-up With collection of specimens for newborn screen- confirmatory testing. These cost figures may not in- ing when the newborn is younger than 24 hours, clude the total system’s cost for repeated and confir- concerns have arisen regarding reliability of the as- matory testing (additional in some states), education, say results in identifying all infants with these dis- patient and physician notification and contact, fol- orders. Many newborn screening tests rely on time- low-up of affected patients, and management (eg, the dependent changes in the concentration of an analyte cost of special dietary supplements) and are not nec- in the blood for identification of the congenital con- essarily related to the number of disorders included dition. These analytes include thyroxine (TJ and thy- in the program. Such costs must not be overlooked in rotropin (TSH) for congenital hypothyroidism, phe- the care of identified children. nylalanine for PKU, leucine for maple syrup urine disease, methionine for homocystinuria, galactose GENERAL REFERENCES for galactosemia, and 17-hydroxyprogesterone (17- American Academy of Pediatrics, Committee on Genetics. Issues in new- OHP) for CAH. The following consensus recommen- born screening. Pedinfrirs. 1992;89:345-349 dations of a conference, “Early Hospital Discharge: American Academy of Pediatrics, Committee on Genetics. Newborn screen- Impact of Newborn Screening,” sponsored by the ing fact sheets. Pediatrics. 1989;83:449-464 Maternal and Child Health Bureau, concluded that: American Academy of Pediatrics Section on Endocrinology and Committee (1) the initial newborn screening specimen be col- on Genetics, and American Thyroid Association Committee on Public Health. Newborn screening for congenital hypothyroidism: recom- lected from all infants as close as possible to the time mended guidelines. Pedinfrics. 1993;91:1203-1209 of discharge from the nursery and in no case later Andrews LB. I.qnl I.i&ility clud Q~mlity Ass~/muce ill Newborn Srr~wtirrg than 7 days of age; (2) if the initial specimen for Chicago, IL: American Bar Foundation; 1985 newborn screening is collected before 24 hours of Andrews LB. Sfate 1.~~11s and Re~ulntio,rs Gorunin~~ Neu$~~rn Scrcuutq Chi- age, a second specimen should be collected before 2 cago, IL: American Bar Foundation; 1985 weeks of age; and (3) all newborns should have Bickel H, Guthrie R, Hammersen G, eds. Neon&l Scre~niqfor Inbortr Errors primary care providers designated before discharge of Metnbolism. New York, NY: Springer-Verlag; 1980 to ensure prompt and appropriate follow-up of new- Britton JR, Britton HL, Beebe SA. Early discharge of the term newborn. a born screening results. Additional monitoring of the continued dilemma. Pediofrics. 1994;94:291--295 true incidence of false-positive and false-negative Carter TP, Willey AM, eds. Genefic Dismee. ScrcT!linX otld Mmqcpe,ne~~I New test results in samples obtained before 24 hours of York, NY: Alan R. Liss, Inc; 1986 age and the development and assessment of techni- Clayton EW. Issues in state newborn screening programs. Pcdintrics. 1992; cal strategies to increase sensitivity of testing were 90641-646 also recommended. Pediatricians should be aware of Committee on Assessing Genetic Risks, Division of Health Sciences Policy, current practices in their community and their state Institute of Medicine, Andrews LB, Fullarton JE, Holtzman NA, Motulsky with regard to discharge before 24 hours of age, AG, eds. Assasin,p Cmtic Risks. Zmplimtions for Hcnlfh md Socinl Policy. timeliness of obtaining second specimens, and fol- Washington, DC: National Academy Press; 1994 low-up of such test results. Council of Regional Networks for Genetic Services. Eflrl!l Hospital Disrhnrge: Impact 011 Newborn Screenintyg. Pass KA, I.evy HL, eds. Atlanta, GA: Emory University School of Medicine; 1995 Note on Cost Elias S, Annas GJ. Generic consent for genetic screening. N En~l \ Mrzf. Newborn screening entails substantial costs, some 1994;330:1611-1613 of which are inherent in the screening process. All Holtnman C, Slazyk WE, Corder0 JF, Hannon WH. Descriptive epidcmiol- abnormal test results trigger diagnostic and some- ogy of missed cases of phenylketonurin and congenital hypothyroidism times therapeutic cascades, with their associated eco- Pediatrics. 1986;78:533-558 nomic costs, parental anxiety, and potential for iat- Holtzman NA. What drives neonatal screening programs? N En~l / Mvd. rogenic side effects. As more conditions warrant 1991;325:802--804 consideration for universal newborn screening, even McCabe ERB. Principles of newborn screening for metabolic disease. Pcri~ given an acceptable 1% to 3% false-positive result for natal Neonalol. 1982;6:63-73 each screening test performed, psychologic and eco- McCabe ER, McCabe I., Masher GA, Allen RJ, Berman JL Newborn screcn- nomic costs loom large, particularly when the benefit ing for phenylketonuria: predictive validity as a function of age. Pcdint- of early detection of affected children may not be rics. 1983;72:390-398 clear. Nevertheless, the conclusion that newborn Newborn Screening Committee, The Council of Regional Networks for screening for a selected group of treatable devastat- Genetic Services. N~tionnl Newborn Screening Xrporf-7992. Atlanta, GA: Council of Regional Networks for Genetic Services; 1995 ing disorders costs less than long-term treatment of Osorio RV. Neonatal screening and early nursery discharge. Scrmiq. persons not identified and treated seems supported 1994;3:169-171 even when examined only in financial terms. On the Striver CR, Beaudet AL, Sly WS, Valle D, eds. The Mefnbolic oud Mofm~lnr other hand, such a cost-benefit analysis completely Rmis of Inherited Dismsc. 7th cd. New York, NY: McGraw-Hill; 1995 ignores the cost in human terms of not identifying Seashore MR. Neonatal screening for inborn errors of metabolism: update. and treating these conditions. Scmin Perinotol. 1990;14:431-43R The costs for newborn screening are variable and Therrell BI., ed. l.nborntory Metkorls for N~onotnl Screening. Washington, DC: are generally cited as initial fees for neonatal testing American Public Health Association; 1993 in a state or regionalized laboratory. Historically, Therrell BL. Advances in neonatal screening. Presented at the Sixth lntcr- program costs of $1 to $2 for specimen handling, national Neonatal Screening Symposium; November 16-19,1986; and the administration, and overhead have been ascribed to Fifth National Neonatal Screening Symposium; November 20, 1986; Aus- PKU. Currently, state costs range from no fee to $50 tin, TX

Downloaded from www.aappublications.org/news by guest on September 29, 2021 AMERICAN ACADEMY OF PEDIATRICS 475 Therrell BL, Fanny SR, Davidson A, et al. US newborn screening system tients have metabolic ketoacidosis and organic aci- guidelines: statement of the council of regional networks for genetic demia. Possibly 15% to 20% of cases will be missed services. Screening. 1992;1:135-147 unless a specific quantitative assay for biotinidase Tiwary CM. Proposed guidelines for screening of metabolic and endocrine activity is requested. Nonspecific features may result diseases of dependent neonates of the US Armed Forces: derived from a survey of state guidelines for neonatal screening of metabolic diseases. in a delayed or missed diagnosis. Clin Pediatr (Phila). 1987;26:349-354 Genotype-Phenotype Correlation. Currently being Congress of the United States, Office of Technology Assessment. Newborn evaluated. Clinical variability exists among affected screening for congenital disorders. In: Healthy Children: Investing in the individuals from different families and also in the Future. Washington, DC: US Government Printing Office; 1988:93-116. expression of this disorder among affected individ- Publication OTA-H-345 uals within a sibship. Essentially all the biotinidase- BIOTINIDASE DEFICIENCY deficient patients who had neurologic symptoms in addition to cutaneous symptoms have had less than State Newborn Screening Availability 5% activity. Currently available in 19 states, the District of Genetic Counseling. Parents of affected children Columbia, and the US Virgin Islands. have serum biotinidase activities intermediate be- tween those of healthy and biotinidase-deficient in- Brief Clinical Description dividuals. A quantitative biotinidase assay is avail- An autosomal recessive disorder of biotin recy- able for carrier detection; the carrier detection cling that leads to multiple carboxylase deficiency. accuracy rate is 90% to 95%. Although biotinidase Many affected individuals initially show combina- activity can be measured in extracts of amniotic fluid tions of neurologic and cutaneous findings, includ- cells, prenatal diagnosis of biotinidase deficiency has ing myoclonic seizures, hypotonia, seborrheic or not yet been reported. Prenatal treatment may be atopic dermatitis, partial or complete alopecia, and potentially possible but is probably unnecessary, be- conjunctivitis. Other common features include cause heterozygous mothers can supply developing ataxia, hearing loss, optic atrophy, developmental fetuses with adequate amounts of free biotin. abnormalities, and organic acidemia with acute met- abolic decompensation resulting in coma. Death may occur. Severity and Variability Without Screening Mortality. Death has occurred during acute meta- Genetics bolic decompensation, but the frequency is unknown Chromosomal Map Location. Undetermined. (4 deaths in 20 reported affected). This may be an Incidence. Approximately 1 in 72 000 to 1 in 126 000 underreported number, because affected siblings in the United States; 1992 Council of Regional Net- may not have been diagnosed. works for Genetic Services (CORN) data from the Developmental Disabilities. Based on data from 35 newborn screening programs of 17 states yielded 14 patients, the age at onset of neurologic signs and confirmed cases in 1 224 018 screened newborns for symptoms has varied from 2 weeks to 3 years. Con- both profound (hydrolase that Clinical Disability. Follow-up has been limited. All specifically cleaves biotin from biocytin and biotinyl positive patients have been asymptomatic after treat- peptides that are formed during the proteolytic turn- ment for more than 3 years, with the oldest patient over of the holocarboxylases (acetyl-coenzyme A being 8 years of age. No treated infant with partial [COAL P-methylcrotonyl-CoA, propionyl-CoA, and deficiency has become symptomatic, but little is pyruvate carboxylases). It is the primary defect in known about the natural history of partial defi- most individuals with late-onset multiple-carboxy- ciency. Hypotonia, rash, and acidosis developed in lase deficiency. one partially deficient untreated patient with gastro- Potential for Symptomatic Diagnosis. With severe en- enteritis at 6 months of age; these symptoms then zyme deficiency, approximately 80% to 85% of pa- resolved with biotin treatment.

Downloaded from www.aappublications.org/news by guest on September 29, 2021 476 NEWBORN SCREENING FACT SHEETS Vuviability. Interfamilial and intrafamilial clinical ing evaluation of older, previously asymptomatic variability is seen. No cases have been identified by patients), parameters for optimal treatment, and het- screening and have been left untreated to evaluate erogeneity of the disorder. natural history. No children with 10% to 30% en- zyme activity were symptomatic at the time of diag- Special Concerns and Issues nosis. It is unknown whether completely asymptom- Postsymptomatic treatment may be as effective as atic persons with variant forms exist. presymptomatic treatment in some cases. The risks Possible Interventions. Oral biotin has reversed of treatment are unknown, but no complications physical and some neurologic findings. Reversal have been reported to date. The oldest known patient and/or prevention of developmental delay is un- is 18 years; therefore, the long-term outcome of treat- clear. Postsymptomatic treatment may not reverse ment is unclear. Some biotin preparations available hearing loss and/or optic atrophy and has not im- at pharmacies or health food stores may not provide proved retardation in some cases. The optimal dos- adequate doses of biotin. age of biotin is unknown. Hazards of biotin treat- ment are unknown; treatment with 10 mg/d has Professional and Public Education been well tolerated to date. Biotin treatment is rela- Biotinidase deficiency is a recently described met- tively inexpensive (estimated cost, $25 to $100 per abolic disorder with limited professional and public year). awareness. Educational efforts are needed.

GENERAL REFERENCES Screening Test Characteristics and Confirmation Dove-Petit DA, Heard GS, Wolf B. Newborn screening for biotinidase Type of Test. Calorimetric assay (for biotinidase) on deficiency. In: Therrell BL, ed. Laboratory Mefhods for Neonatal Screening. a dried blood spot. Affected infants and children Washington, DC: American Public Health Association; 1993:133-138 have 0% to 10% of normal adult activity. Levels Hart PS, Hymes J, Wolf B. Biochemical and immunological characterization between 10% and 30% of mean normal activity levels of serum biotinidase in profound biotinidase deficiency. Am 1 Med Genrf. are considered partial biotinidase deficiency. 1992;50:126-136 Timing. Optimal timing for testing is unknown. Hart I’S, Hymes J, Wolf B. Biochemical and immunologic characterization of Enzyme deficiency has been demonstrated in cord serum biotinidase in partial biotinidase deficiency. Dediatr Res. 1992;31: blood; therefore, any specimen obtained after birth is 261-265 anticipated to be adequate. Symptoms have not de- McVoy JR, Levy HL, Lawler M, et al. Partial biotinidase deficiency: clinical veloped in most patients before 2 months of age, but and biochemical features. J Pediutr. 1990;116:78-83 one patient was symptomatic at 3 weeks. Thus, rapid Thibodeau DL, Andrews W, Meyer J, Mitchell P, Wolf 8. Comparison of the turnaround may be needed. The mean age at onset of effects of season and prematurity on the enzymatic newborn screening tests for galactosemia and biotinidase deficiency. Screening. 1993;2:19-27 symptoms is 5 to 6 months. Thibodeau DL, Wolf B. Biotinidase Dejiciency: A Booklet for Families and Stability of Specimen. Samples stored for longer Proffssionals. Richmond, VA: Virginia Commonwealth University; 1993 than 18 months at room temperature or higher had Weissbecker KA, Nance WE, Eaves LJ, Piussan C, Wolf B. Statistical ap- no detectable activity. Activity was detected in sam- proaches for the detection of heterozygotes for biotinidase deficiency. ples less than 18 months old. Samples analyzed 1,30, Am J Mcd &net. 1991;39:385-390 and 60 days after collection were stable. Specimens Wolf B. Disorders of biotin metabolism. In: Striver CR, Beaudet AL, Sly WS, are stable frozen at -70°C for 3 years; samples frozen Valle D, eds. The Metabolic and Molecular Basis of Inherited Disease. 7th ed. at higher temperatures (-20°C) may lose activity, New York, NY: McGraw-Hill; 1995:31513181 which may lead to inappropriate diagnosis of partial Wolf B. Worldwide survey of neonatal screening for biotinidase deficiency. deficiency (B. Wolf, written communication, October J Inherit Metab Dis. 1991;14:923-927 1994). Wolf 8, Crier RE, Allen RJ, Goodman SI, Kien CL. Biotinidase deficiency: Confirmation. Both a calorimetric and a more sen- the enzymatic defect in late-onset multiple carboxylase deficiency. Clin sitive radioassay of serum are available to confirm Chim Acta. 1983;131:273-281 screening results. On the basis of families studied to Wolf B, Grier RE, Allen RJ, et al. Phenotypic variation in biotinidase defi- ciency. J Pediatr. 1983;103:233-237 date, heterozygotes (carriers) can be differentiated from affected and normal individuals with 90% to Wolf B, Heard GS. Screening for biotinidase deficiency in newborns: world- 95% accuracy. wide experience. Pediatrics. 1990;85:512-517 Wolf B, Heard GS, Weissbecker KA, McVoy JR, Grier RE, Leshner RT. of Accuracy Screening Test Biotinidase deficiency: initial clinical features and rapid diagnosis. Ann False-Negative Rate. Unknown. Rare (cl%) false- Neural. 1985;18:614-617 negative test results may occur with the use of sul- fonamides. All samples tested after the newborn pe- BRANCHED-CHAIN KETOACIDURIA: riod should be checked for the presence of MAPLE SYRUP URINE DISEASE sulfonamides. State Newborn Screening Availability False-Positive Rate. Unknown. Currently part of newborn screening in 23 states, Ongoing Studies. A pilot screening program was the District of Columbia, and the US Virgin Islands. initiated at the Medical College of Virginia by Barry Wolf. Screening is also being conducted in 15 coun- Brief Clinical Description tries worldwide. Follow-up of screening cases is in An autosomal recessive disorder of branched- progress. Information is needed concerning inci- chain ketoacid decarboxylation resulting in high dence, natural history, efficacy of treatment (includ- body fluid (serum, urine, and spinal fluid) levels of

Downloaded from www.aappublications.org/news by guest on September 29, 2021 AMERICAN ACADEMY OF PEDIATRICS 477 leucine, isoleucine, valine, and their corresponding no ketoacidosis, and about 40% of normal substrate ketoacids. Lethargy, irritability, and vomiting pro- oxidation. gressing to coma and death occur in affected indi- Genetic Counseling. Carriers show no detectable el- viduals if untreated. evations in branched-chain amino acids or ketoacids under most circumstances. They can be distin- guished biochemically using cultured skin fibro- Genetics blasts to assessbranched-chain ketoacid dehydroge- Chromosomal Map Location. 19q13.1-q13.2 fbranched- nase activity or branched-chain amino acid chain ketoacid decarboxylase). oxidation. Heterozygotes usually show 50% activity Incidence. US mixed population, 1 in 250 000 to 1 in compared with control cells. Prenatal diagnosis is 400 000; New England Newborn Screening Program, available using cultured amniotic fluid or chorionic 1 in 290 000; Supplemental Newborn Screening Pro- villus cells. gram in Pennsylvania, 1 in 170 000 to 1 in 175 000; 1992 CORN data, 1 in 209 000 (6 confirmed cases in Severity and Variability Without Screening 1256 605 screened newborns); and 1 in 180 000 in Mortality. Lethal in classical form, usually in the Quebec. first month of life, if unrecognized and untreated. Inheritance. Autosomal recessive. Sex ratio: male = Developmental Disabilities. Symptomatic patients female. frequently have irreversible retardation. Racial and Ethnic Variability. Highest in Mennonite Physical Findings. Spastic quadriparesis, dystonic population (1 in 760). May be more common in Af- posturing, dysarthria, and poor physical growth are rican-American and Asian populations. common. Molecular Pathology. Branched-chain ketoacid de- carboxylase deficiency. Branched-chain ketoacid dis- Clinical Outcome With Screening and Treatment ease complex consists of four proteins: El, two pro- Mortality. All deaths cannot be prevented. At least teins (binding sites for thiamine phosphate and one infant died at 9 days of age, 1 day before new- ketoacid substrate); E2, which transfers acyl groups born screening results were reported. Death within to CoA; and E3, flavoprotein lipomide. Specific point the first 2 weeks is not uncommon, and about one mutations and base deletions in the genes for these third of the infants have died before dietary therapy proteins in the enzyme complex have been defined could be instituted. Some patients die suddenly at and correlate with affected status. older ages despite therapy. Potential for Symptomatic Diagnosis. High and Clinical Disability. Age and neurologic symptoms should be considered in any infant with severe aci- at the time therapy is instituted (as well as adequacy dosis in the first 10 days of life. Initial symptoms are of continued control) affect outcome. Treated pa- poor feeding and marked lethargy. The odor of the tients frequently have irreversible retardation. Al- urine is characteristic. Elevated levels of urine and though about 27% of more recently reported treated plasma branched-chain amino acids and ketoacids patients have IQs higher than 90, the outcome is are found; plasma leucine levels are extremely ele- related to the time between the onset of symptoms vated (1000 to 5000 pmol/L in classic form and 50 to and therapy. Best outcomes have been achieved in 4000 pmol/L in other variants). Levels of urine second affected newborns in identified families and branched-chain ketoacids are elevated during illness. when treatment is begun within 24 hours of symp- Confirmation is obtained by plasma leucine levels, toms. quantitative urine branched-chain ketoacids, and measurement of leucine-decarboxylating activity in Variability. The outcomes of treated patients are white cells. only available for the classic form. Additional data are needed to evaluate the outcome of genetic vari- Genotype-Phenotype Correlation. Several different ants detected by newborn screening programs. allelic variants have been described, which vary in severity, age at onset, clinical symptoms, and thia- Possible Interventions. Screening programs require mine responsiveness. The classic form presents with immediate retrieval, diagnosis, and treatment of af- severe early onset, constant branched-chain amino fected infants. Dietary restriction of branched-chain amino acids requires frequent monitoring that must acid excretion and 0% to 2% of normal substrate oxidation. Early neonatal symptoms include poor be continued indefinitely. Commercial formula is feeding, seizures, coma, and ketoacidosis. An inter- available, but intake of branched-chain amino acids must be individually titrated. A nutritionist and spe- mittent form is triggered by protein stress (high pro- cially trained physician must coordinate therapy. tein intake) with intermittent branched-chain amino acid excretion and 2% to 40% of normal substrate The cost is variable and based on long-term use of oxidation. The intermediate form is associated with the special formula. mental retardation and ataxia but no ketoacidosis, mild constant urinary branched-chain amino acid Screening Test Characteristics and Confirmation excretion, and 5% to 25% of normal substrate oxida- Type of Test. Bacterial inhibition assay (BIA) for tion. The thiamine-responsive form is usually milder, leucine using a dried blood spot. of later onset, and characterized by recurrent ataxia Timing. Because symptoms occur early, results and occasional developmental delay. Such patients must be available in less than 2 weeks, and the show constant branched-chain amino acid excretion, specimen must be obtained as early as possible. Af-

Downloaded from www.aappublications.org/news by guest on September 29, 2021 478 NEWBORN SCREENING FACT SHEETS fected infants have had elevated leucine levels by 4 Matsuda I, Indo Y, Endo F, et al. Clinical and biochemical observation of to 14 hours of age regardless of protein intake. The maple syrup urine disease (MSUD) patients found by neonatal screening. In: Therrell BL Jr, ed. Advances in Neonatal Screening. New York, NY: presence of alloisoleucine has been detected as early Elsevier Science Publishers; 1987~217-218. Excerpta Medical International as 14 hours of age. Leucine screening may not be Congress series 741. sensitive if obtained before 12 hours of age. Naughten ER, Jenkins J, Francis DE, et al. Outcome of maple syrup urine Stability of Specimen. Short-term stability is excel- disease. Arch Dis Child. 1982;57:918-921 lent; longer-term stability is presumed excellent at Naylor EW. Newborn screening for maple syrup urine disease. in: Therrell -7O”C, but limited information is available under BL, ed. Laboratory Methods for Neonatal Screening. Washington, DC: Amer- special or ambient conditions. ican Public Health Association; 1993:115-124 Confirmation. Quantitative measurement of Naylor EW, Guthrie R. Newborn screening for maple syrup urine disease leucine, isoleucine, and valine; presence of alloisole- (branched-chain ketoaciduria). Pediatrics. 1978;61:262-266 ucine in serum; and elevated levels of urine Shih VE. Maple-syrup-urine disease. N Engl J Med. 1984;310:596-597 branched-chain amino acid and ketoacids. Specific Snyderman SE, Sansaricq C. Newborn screening for maple syrup urine enzymatic assays are available in research laborato- disease. J Pediatr. 1985;107:259-261 ries. Van Doorninck WJ, Nord A, Greene C. Age of dietary initiation and outcome at middle childhood in maple syrup urine disease. Am J Hum of Test Accuvucy Screening Gent?. 1989;45(suppl4):AlZ False-Negative Rates. Extremely low, greater than 99.9% specificity. May be dependent on age at test- CONGENITAL ADRENAL HYPERPLASIA ing. State Newborn Screening Availability False-Positive Rates. Limited information. Currently performed in 11 states. Ongoing Studies. Programs continue to evaluate the effectiveness of screening and dietary manage- Brief Clinical Description ment. Additional information is needed concerning CAH consists of a family of disorders arising from ethnic variation in the incidence of classic and vari- specific defects in the enzymes of the adrenal cortex ant forms, long-term prognosis, management at dif- required for the biosynthesis of adrenal corticoste- ferent ages, possibilities for improving turnaround roids. The most common form results from 21-hy- times, and efficacy of screening at different ages (ie, droxylase deficiency, which accounts for more than 24 hours as opposed to later). 90% of all recognized cases. This form can be de- tected by neonatal screening and is the only condi- Special Concerns and Issues tion discussed in this section. The defect results in Infants often have irreversible damage by the time increased androgen production, which is responsible they are identified by newborn screening programs. for the somatic and sexual precocity seen in these Therefore, a rapid turnaround time and screening patients. In the female newborn, the fetal adrenal program coordination are necessary. Specialized androgens may masculinize the external genitalia to care, including nutritional assessmentand planning, the extent that an incorrect male sex assignment is the ability to monitor amino acids, and long-term made. In approximately 75% of affected newborn assessment, is necessary to achieve the best potential boys, a “salt-losing syndrome” may be the only clin- outcomes. ical finding leading to the correct diagnosis. Treat- ment suppresses the abnormal steroidal pattern and avoids the consequences of excess virilization, short Professional and Public Education stature, and cortisol deficiency. Awareness of this disorder is limited. Aggressive education of physicians with emphasis on early clin- Genetics ical suspicion, even in states with newborn screening Chromosomal Map Location. 21-Hydroxylase: 6~22. programs, remains paramount because of the sud- Closely linked to the HLA major histocompatibility den early onset of this disorder, with poor outcomes complex. when dietary intervention is begun later than 24 Incidence. One in 12 000. The 1992 CORN data hours after the onset of symptoms. yielded 51 confirmed casesof classic CAH (salt wast- ing and simple virilizing) in 1 224 018 screened new- GENERAL REFERENCES borns (1 in 20 000). Clow CL, Reade TM, Striver CR. Outcome of early and long-term manage- Inheritance. Autosomal recessive. In clinically de- ment of classical maple syrup urine disease. Pediatrics. 1981;68:856-862 tected cases, girls exceed boys because of masculin- Chuang DT, Shih VE. Disorders of branched-chain amino and keto acid ization of the female fetus and neonatal death in metabolism. In: Striver CR, Beaudet AL, Sly WS, Valle D, eds. The undetected salt-wasting boys. Metabolic and Molecular Basis of Inherited Disease. 7th ed. New York, NY: Racial and Ethnic Variability. White, 1 in 12 880; McGraw-Hill; 1995:1239-1279 Japanese, 1 in 15 000; Yupik Eskimo, 1 in 680; and DiGeorge AM, Rezvani I, Garibaldi LR, Schwartz M. Prospective study of maple-syrup-urine disease for the first four days of life. N Engl J Med. Italian, 1 in 5500 to 1 in 10 000. 1982;307:1492-1495 Molecular Pathology. The clinical consequences of Hilliges C, Awiszus D, Wendel LJ. Intellectual performance of children with 21-hydroxylase deficiency arise primarily from the maple syrup urine disease. Eur J Pediatr. 1993;152:144-147 overproduction and accumulation of precursors Kaplan I’, Mazur A, Field M, et al. Intellectual outcome in children with proximal to the blocked enzymatic step. These are maple syrup urine disease. J Pediutr. 1991;119:46-50 shunted into the androgen biosynthetic pathway.

Downloaded from www.aappublications.org/news by guest on September 29, 2021 AMERICAN ACADEMY OF PEDIATRICS 479 The 21-hydroxylase functional gene (CYP21B) is premature fusion of epiphyses and ultimate short closely linked to the HLA major histocompatibility stature. complex, specifically adjacent to the C4B gene encod- ing the fourth component of serum complement. Clinical Outcome With Screening and Treatment This cluster is located between the HLA-B and -DR Mortality. Reduced substantially, but the fre- regions on the short arm of chromosome 6. About quency is unknown because of early onset, salt-los- 25% of classic deficiency alleles are deletions of ing crises that may occur before the screening results CYP21B; many of the remaining mutant alleles result are available. A number of patients have been in from deleterious mutations in the adjacent pseudo- severe crises at the time newborn screening results gene, which then encodes a defective protein, a phe- became available. nomenon termed gene conversion. Clinical Disability. Should be reduced because of Potential for Symptomatic Diagnosis. Generally good early treatment. (some cases may be missed) for affected girls with Variability. Early diagnosis should lead to correct classic 21-hydroxylase deficiency who are born with sex identification; eliminate problems of precocious ambiguous genitalia due to prenatal exposure to el- puberty, masculinization, and accelerated growth; evated levels of androgens. Postnatally, both sexes and decrease fertility problems in affected girls. The manifest rapid somatic growth, with accelerated risk of adrenal crisis with stress is still present. skeletal maturation, early closure of the epiphyses, Possible Interventions. Endocrinologic consultation and short adult stature-a problem that may not be is recommended. Treatment with glucocorticoste- completely prevented by current therapy. Of major roids serves the dual purpose of replacing cortisol concern are those newborns who also have a defect and suppressing excessive corticotropin production. in their ability to synthesize aldosterone and may die Patients with loss of salt and elevated plasma renin in the newborn period from shock caused by salt activity should receive mineralocorticoid therapy wasting. Diagnosis is confirmed by the presence of and may need supplemental salt intake in addition to elevated plasma levels of 17-OHP. hydrocortisone. The dose of glucocorticosteroids Genotype-Phenotype Cowelation. There seem to be should be appropriately increased for stress or ill- specific associations between HLAs tie, haplotypes) ness. Resection of the enlarged clitoris should be and different forms of 21-hydroxylase deficiency. done as soon as feasible, with additional surgery Haplotypes HLA-A3, -Bw47, -DR7, and -Bw60 are (vaginoplasty) performed at puberty. associated with salt wasting; HLA-B5 is associated with simple virilizing disease; and HLA-B14 and Screening Test Characteristics and Confirmation -DRl are associated with the nonclassic disease. Type of Test. Enzyme immunoassay or radioimmu- HLA-Al, -BB, and -DR3 haplotypes are negatively noassay for measurement of 17-OHP in 21-hydroxy- associated with 21-hydroxylase deficiency. lase deficiency can be performed on dried blood Genetic Counseling. Autosomal recessive, with 25% spots. risk for siblings. Prenatal diagnosis is possible with Timing. Elevation of 17-OHP is present at birth, DNA linkage and/or direct analysis for identifica- although levels obtained before 24 hours of age may tion of 21-hydroxylase mutations by chorionic villus be physiologically high. Rapid turnaround time may sampling in the first trimester and hormonal mea- be needed to detect boys and those nonvirilized un- surement, HLA polymorphism, and additional spe- detected girls who may present with early onset cific DNA studies by amniocentesis in the second adrenal crises and salt losing. Premature infants may trimester. HLA typing and DNA studies may allow have false-positive test results. Screening in the first detection of carriers in families with affected chil- 48 hours may increase the false-positive rate, but dren. further study is needed. Screening at 1 to 2 weeks of age detects some additional cases of simple virilizing Severity and Variability Without Screening CAH and increased numbers of the nonclassic form of 21-hydroxylase deficiency. Mortality. Life-threatening adrenal crises in the newborn period (mortality, 9%). Stability of Specimen. No decomposition of 17-OHP has occurred after periods of as long as 30 days in Developmental Disabilities. Usually absent but may blood dried on filter paper stored at room tempera- occur from salt-losing crisis and shock. ture. Physical Findings. Masculinization of female geni- Confirmation. Quantitative measurement of talia may be present at birth and may result in incor- plasma 17-OHP, available from many commercial rect sex assignment. In severe forms, adrenocortical laboratories. A relatively small sample of blood is insufficiency, salt-losing crises, and ambiguous gen- required. italia are seen in female patients. Those infants with partial forms have adequate but limited synthesis of Accuracy of Screening Test cortisol and aldosterone. Such patients are able to False-Negative Rate. Low: detects most cases respond appropriately to all but severe stress, Viril- (95%) of 21-hydroxylase deficiency. With an initial ization and ambiguous genitalia occur in girls; early screen of more than 65 ng/mL, 3% of salt wasters postnatal virilization occurs in boys. Adult sexual may be missed if screened before 24 hours of age. dysfunction has been reported. Increased androgenic False-Positive Rate. Ranges from 0.2% to 0.5%, de- secretion also causes accelerated early growth with pending on the cutoff level chosen. The cross-reac-

Downloaded from www.aappublications.org/news by guest on September 29, 2021 480 NEWBORN SCREENING FACT SHEETS tion of steroid compounds related to 17-OHP de- CONGENITAL HYPOTHYROIDISM pends on the antiserum used in the immunoassays of State Newborn Screening Availability steroids and whether organic solvent extraction is Performed in all 50 states, the District of Columbia, included in the testing protocol. Puerto Rico, and the US Virgin Islands. Ongoing Studies. Pilot screening programs have been completed in Alaska and Washington and in Brief Clinical Description several countries (Japan, Italy, France, Scotland, Swe- Results from an inadequate production of thyroid den, and New Zealand). Further data are needed to hormone, which may be due to a number of causes: assess false-negative and false-positive rates and to agenesis or ectopic thyroid gland, genetic disorders determine the extent to which clinical outcome is of thyroid hormonogenesis, endemic cretinism, and improved by early diagnosis and treatment. hypopituitarism. Patients who are not identified and treated promptly have mental retardation and vari- Special Issuesand Concerns able degrees of growth failure, deafness, and neuro- Analogues of hydrocortisone or cortisone are ef- logic abnormalities, as well as classic hypometabolic fective at suppressing adrenal androgens, but a dose symptoms of hypothyroidism. of any glucocorticoid that is too high may result in growth suppression. Genetics ChvomosomaE Map Locution. Has multiple causes, Professional and Public Education most of which are nongenetic. Limited general knowledge. Simple, inexpensive Incidence. One in 3600 to 1 in 5000 in the United screening is available, but this is not well known. States from screening; 1 in 3000 in Europe; 1 in 6600 Education of health professionals regarding CAH in to 1 in 7300 in Sweden by clinical diagnosis; and 1 in testing female newborns with ambiguous genitalia is 5700 in Japan. of paramount importance in all populations. Without Inheritance. Usually sporadic. Disorders of thyroid screening, diagnosis is difficult in male newborns hormonogenesis may be inherited as autosomal re- unless they become symptomatic. cessive traits. Thyroid hormone transport defects may be X linked. Sex ratio: 3:1, female to male (New England states), 2:l female to male by clinical diag- GENERAL REFERENCES nosis. Cacciari E, Balsamo A, Cassio A, et al. Neonatal screening for congenital Racial and Ethnic Variability. Considerably less in adrenal hyperplasia. Arch Dis Child. 1983;58:803-806 African-American populations (1 in 17 000 in Geor- Hofman LF, Pang S. Screening newborns for congenital adrenal hyperpla- sia. In: Therrell BL, ed. Laboratory Methods for Neonatal Screening. Wash- gia and 1 in 10 000 in Texas); more prevalent in ington, DC: American Public Health Association; 1993:155-168 Hispanic populations (1 in 2700) and Native Ameri- Gonzalez J. Congenital adrenal hyperplasia. Presented at the conference on cans (1 in 700). Early Hospital Discharge: Impact on Newborn Screening; March 31,1995; Molecular Puthology. The fetal hypothalamic-pitu- Washington, DC itary-thyroid axis begins to function by midgestation Larsson A, Thilen A, Magenfeldt L, et al. Screening of half a million Swedish and is mature in the full-term infant. If fetal hypo- newborn infants for congenital adrenal hyperplasia. Screening. 1992;l: thyroidism develops, untoward effects may be dem- 159-166 onstrated in the central nervous system and skeleton. Lebovitz RM, Pauli RM, Laxova R. Delayed diagnosis in congenital adrenal However, most infants with congenital hypothyroid- hyperplasia: need for newborn screening. Am J Dis Child. 1984;138: ism appear normal at birth. The hypothyroid fetus is 571-573 partially protected by placental transfer of maternal Miller WL, Levine LS. Molecular and clinical advances in congenital adrenal thyroid hormone; T, levels in cord blood of athyroid hyperplasia. J Pediafr. 1987;111:1-17 fetuses approximate one third of maternal levels. New MI, Gertner JM, Speiser PW, Del Balzo P. Growth and final height in classical and nonclassical Zl-hydroxylase deficiency. J Endocrinol Invest. Potential for Symptomatic Diagnosis. Clinical signs 1989;12(suppl 3):91-95 of hypothyroidism (other than neonatal jaundice) Pang S, Clark A. Congenital adrenal hyperplasia due to 21-hydroxylase may not appear until the infant is several months of deficiency: newborn screening and its relationship to the diagnosis and age or older. Infants with early clinical findings seem treatment of the disorder. Screening. 1993;2:105-139 to have a higher incidence of developmental disabil- Pang S, Wallace MA, Hofman L, et al. Worldwide experience in newborn ities. The observation of a higher incidence from screening for classical congenital adrenal hyperplasia due to 21- screening programs than from clinical surveillance hydroxylase deficiency. Pediatrics. 1988;81:866-874 suggests that cases may be missed. Therrell BL, ed. Congenital adrenal hyperplasia. In: Advances in Neonatal Genotype-Phenotype Correlation. Embryogenic de- Screening. New York, NY: Elsevier Science Publishers; 1987~279-300 fects of the thyroid gland can lead to ectopy (50% to Thompson R, Seargeant L, Winter JSD. Screening for congenital adrenal 55%) or aplasia or hypoplasia (30% to 35%), account- hyperplasia: distribution of 17 alpha-hydroxyprogesterone concentra- ing for 85% of the cases of congenital hypothyroid- tions in neonatal blood spot specimens. ] Pediatr. 1989;114:400-404 ism. Inborn errors of metabolism of thyroid hormo- Wallace AM, Beastall GH, Cook B, et al. Neonatal screening for congenital nogenesis account for 10% to 15%, which are termed adrenal hyperplasia: a program based on a novel direct radioimmunoas- say for 17-hydroxyprogesterone in blood spots. J EndocrinoL 1986;108: primary hypothyroidism. Embryogenic defects or in- 299-308 born errors at the level of the pituitary or hypothal- White PC, New MI, DuPont 8. Congenital adrenal hyperplasia. N Engl amus (secondary and tertiary hypothyroidism) rep- J Med. 1987;316:1580-1586 resent less than 4% of cases.

Downloaded from www.aappublications.org/news by guest on September 29, 2021 AMERICAN ACADEMY OF PEDIATRICS 481 Genetic Counseling. Depends on the diagnosis or Possible Intervention. Oral levothyroxine should be cause of the hypothyroidism. Dyshormonogenesis given at a dosage to produce a T4 concentration in the occurs most commonly as a result of autosomal re- upper half of the normal range by 2 weeks after the cessive genetic conditions and may occur in siblings. initiation of therapy. Growth and development must Other causes may have a familial basis. Determina- be monitored at monthly intervals, including fre- tion of cause may require other hormonal studies, quent laboratory evaluations of thyroid hormone evaluation for other congenital defects (occurs in levels to prevent poor achievement associated with 10% of these infants), and radionucleotide scanning low levels (eg, inadequate dosage and noncompli- of the thyroid gland. ance) and behavior problems associated with high levels. Consultation with a pediatric endocrinologist is advisable. Severity and Variability Without Screening Mortality. May be underestimated because of fail- ure of diagnosis. The historical increase in mortality Screening Test Characteristics and Confirmation in retarded patients may be related to institutional- Type of Test. Radioimmunoassay for T,, TSH, or ization. both. North American programs generally screen us- Developmental Disabilities. Vary in different stud- ing T, values followed by TSH levels on the lowest ies. On the basis of approximately 800 untreated 5% to 10%. The use of primary TSH screening is patients in the literature, the mean IQ was 80. Of 250 routine in Europe and Japan. Simultaneous determi- patients with reported test results, 67% had IQs of nation of both T4 and TSH is optimal. Nonisotopic less than 85,40% had IQs of less than 70, and more enzyme immunoassays have been developed for than 19% had IQs of less than 55. Other neuropsy- both TSH and T,. The use of simultaneous enzyme chologic problems are common. The degree of devel- immunoassay methods should allow less expensive opmental disability is probably different for different T, and TSH testing. Each type of test has been types of hypothyroidism. adapted for use with dried filter paper blood spots. Physical Findings. May include poor growth, goi- The T,-screening approach can also identify infants ter, low metabolic rate, constipation, poor peripheral with T,-binding globulin deficiency (1 in 5000 to 1 in circulation, bradycardia, and myxedema. More than 10 000) or hypothalamic-pituitary hypothyroidism 1 95% of infants with sporadic hypothyroidism show in 50 000). such minimal signs at birth that the diagnosis is Timing. Newborns older than 12 hours for T, test- missed. ing. Specimens collected in the first 24 to 48 hours of life may lead to false-positive TSH elevations using any screening test approach. Retesting of a second Clinical Outcome With Screening and Treatment sample for T4 has led to identification of an addi- Mortality. Not expected. tional 6% to 12% of cases. Clinical Disability. Contradictory results from large Stability of Specimen. Stable for many months if studies. The New England Congenital Hypothyroid- refrigerated with a desiccant. ism Collaborative study showed normal IQ, visual Confirmation. Quantitative measurement of T, and motor integration, and neuropsychologic profiles TSH; the free T4 value is low, and the TSH level is when compared with control values. The Quebec elevated. A response to TSH-releasing hormone is study showed normal developmental quotients, but occasionally needed to investigate secondary or ter- the scores were significantly lower than control val- tiary hypothyroidism. Radioisotope scanning is nec- ues. No growth or physical abnormalities were noted essary to identify the cause of the hypothyroidism. with treatment. The Ontario study also showed in- Repeated testing may be necessary to identify tran- telligence within the normal range, but the children sient hypothyroidism. had cognitive and neuromuscular impairment that seemed to reflect the severity and time of onset of Accuracy of Screening Test thyroid hormone deficiency. Recent studies from En- False-Negative Rate. Depends on the cutoff used, gland and the Netherlands using screening T, levels the screening methods, and the age of the infant. less than 50 pmol/L were predictive of a decline in Approximately 10% of cases are detected only by a IQ. second screening at 2 to 6 weeks of age. True biolog- Variability. The New England Congenital Hypo- ical false-negative test results account for about 11% thyroidism Collaborative showed that the only cor- of missed cases, Primary TSH screening misses sec- relation with outcome and disease-related factors is ondary or tertiary hypothyroidism. adequacy of treatment and compliance. Other stud- False-Positive Rate. Depends on the tests and cut- ies indicated that low thyroid hormone levels, agen- offs used. T, testing alone has low specificity, with a esis, and evidence of fetal hypothyroidism are asso- false-positive rate as high as 0.3%. T4 testing followed ciated with poor outcome in some cognitive areas. by testing for TSH and, when indicated, T,-binding Attention deficit problems have been observed in globulin, reverse triiodothyronine, or free T,, pro- older children with elevated circulating levels of T4 duces high specificity. Recall rates vary from 0.04% due to thyroid hormone receptor defects. Treatment to 0.5%. should be undertaken within the first few weeks of Ongoing Studies. Studies include long-term out- life to prevent permanent retardation of intellectual come, correlation of severe disease with possible pre- function and/or skeletal growth. natal effects, incidence of transient disease, hypothy-

482 NEWBORN SCREENINGDownloaded FACT from SHEETS www.aappublications.org/news by guest on September 29, 2021 roidism in premature infants, optimal diagnostic hypothyroidism: a long-term evaluation of the effects of neonatal treat- studies, and clinical management protocols. ment. I Pdiatr. 1994;124:903-909 LaFranchi SH, Hanna CE, Krainz PL, Skeels MR, Miyahira RS, Sesser DE. Screening for congenital hypothyroidism with specimen collection at two Special Concerns and Issues time periods: results of the Northwest Regional Screening Program. Pe- Normal newborn thyroid test results may decrease diafrics. 1985;76:734-740 vigilance for clinically symptomatic patients. The Layde PM, Von Allmen SD, Oakley GP Jr. Congenital hypothyroidism most common neonatal signs are prolonged jaun- control programs: a cost-benefit analysis. JAMA. 1979;241:2290-2292 dice, constipation, and umbilical hernia. Prevention Muir A, Daneman D, Daneman A, Ehrlich R. Thyroid scanning, ultrasound, of overtreatment requires careful follow-up evalua- and serum thyroglobulin in determining the origin of congenital hypo- tions, including thyroid function tests, to minimize thyroidism. Am J Dis Child. 1988;142:214-216 the risks of increased intracranial pressure and/or New England Congenital Hypothyroidism Collaborative. Correlation of craniosynostosis. A subgroup of premature infants cognitive test scores and adequacy of treatment in adolescents with exists in which the infants are at increased risk of congenital hypothyroidism. I Pediatr. 1994;124:383-387 true transient hypothyroidism as well as low T, lev- Rovet JF, Ehrlich RM, Sorbara DL. The effect of thyroid hormone level on els with euthyroidism and low T,-binding globulin temperament in infants with congenital hypothyroidism detected by screening of neonates. 1 Pedintr. 1989;114:63-68 levels. Rovet JF, Ehrlich RM, Sorbara DL. Neurodevelopment in infants and pre- school children with congenital hypothyroidism: etiological and treat- Professional and Public Education ment factors affecting outcome. I Pediatr Psychol. 1992;17:187-213 Generally adequate. Brochures for parents are pro- Tillotson S, Fuggle PW, Smith I, Ades AE, Grant DB. Relation between vided by state newborn screening programs and are biochemical severity and intelligence in early treated congenital available before or after delivery. Educational infor- hypothyroidism: a threshold effect. Br Mrd J. 1994;309:440-445 mation also is provided with positive screening test results. Routine mandated screening may lead to a CYSTIC FIBROSIS less efficient diagnosis of missed symptomatic in- State Newborn Screening Availability fants, because the clinician may assume that the dis- order has been definitively ruled out. Currently available in two states with pilot or vol- untary programs in two additional states. GENERAL REFERENCES American Academy of Pediatrics, Section on Endocrinology and Committee Brief Clinical Description on Genetics, and American Thyroid Association Committee on Public An autosomal recessive disorder characterized by Health. Newborn screening for congenital hypothyroidism: recom- a generalized disturbance in exocrine function re- mended guidelines. Pediatrics. 1993;91:1203-1209 lated to an abnormal transmembrane regulator pro- National Committee for Clinical Laboratory Standards. Blood Collection on tein that has properties of a chloride channel. Filter Paper for Neonatal Screeniftg Programs: Approved Standard. Villanova, PA: National Committee for Clinical Laboratory Standards; 1992. NCCLS Publication LA4-A2 Genetics Dussault JH, Mitchell ML, LaFranchi S, et al. Regional screening for con- Chromosomal Map Location. Long arm of chromo- genital hypothyroidism: results of screening 1 million North American some 7: 7q31. infants with filter paper spot T, and TSH. In: Burrow GN, Dussault JH, eds. Neonatal Thyroid Screening. New York, NY: Raven Press; 1980:155-165 Incidence. Northern European, 1 in 2000 average Fisher DA. Euthyroid low thyroxine (T,) and triiodothyronine (T3) states in (heterozygote, 1 in 22); African-American, 1 in 17 000 premature and sick neonates. Pediatr Clin North Am. 1990;37:1297-1312 (heterozygote, 1 in 65); Hispanic, 1 in 9000 (hetero- Germak JA, Foley Tl’ Jr. Longitudinal assessment of L-thyroxine therapy for zygote, 1 in 45). congenital hypothyroidism. J Pcdiak 1990;117:211-219 Inheritance. Autosomal recessive disorder. Sex ra- Glorieux J, Desjardins M, Letarte J, Morissette J, Dussault JH. Useful pa- tio: male = female. rameters to predict the eventual mental outcome of hypothyroid children. Racial and Ethnic Variability. Seventy percent of the Pediatr Res. 1988;24:6-8 mutations found in northern Europeans have a 6F508 Grant DB, Fuggle PW, Smith I. Increased thyroid stimulating hormone in (phenylalanine) deletion. Current surveys indicate treated congenital hypothyroidism: relation to severity of hypothyroid- ism. Arch Dis Child. 1993;69:555-558 that 85% to 90% of CF carriers in the North American white population can be detected by testing for 12 to Hanna CE, Krainz PL, Skeels MR, Miyahira RS, Sesser DE, LaFranchi SH. Detection of congenital hypopituitary hypothyroidism: ten-year experi- 32 mutations; the carrier detection rate is greater than ence in the Northwest Regional Screening Program. J Pediatr. 1986;109: 95% in Ashkenazi Jews but substantially less in Af- 959-964 rican-Americans, Hispanics, and Asians. Hannon WH, Therrell BL. Laboratory methods for detecting congenital MoZecular Pathology. Defective CF transmembrane hypothyroidism. In: Therrell BL, ed. Laboratory Methods for Neonntal regulator protein results in thick mucus secretions, Screening. Washington, DC: American Public Health Association; 1993: chronic obstructive lung disease, recurrent pulmo- 139-154 nary infection, car pulmonale, and death. In the ma- Heyerdahl S, Kase BF, Lie SO. Intellectual development in children with congenital hypothyroidism in relation to recommended thyroxine treat- jority of cases, exocrine pancreatic dysfunction be- ment. J Pediatr. 1991;118:850-857 gins in utero and may cause meconium ileus at birth, postnatal steatorrhea, and failure to thrive. Other Holtzman C, Slazyk WE, Corder0 JF, Hannon WH. Descriptive epidemiol- ogy of missed cases of phenylketonuria and congenital hypothyroidism. manifestations include abnormally high levels of Pediatrics. 1986;78:553-558 sweat sodium and chloride, cirrhosis of the liver, Kooistra L, Laane C, Vulsma T, Schellekens JM, van der Meere JJ, Kalver- abnormal glucose tolerance, absence of the vas de- hoer AF. Motor and cognitive development in children with congenital ferens, and infertility in boys.

Downloaded from www.aappublications.org/news by guest on September 29, 2021 AMERICAN ACADEMY OF PEDIATRICS 483 Potential for Symptomatic Diagnosis. Good with and clinical outcome among screened and non- meconium ileus, which occurs in about 10% of af- screened infants with CF have been reported from fected newborns. It is generally good for a patient Italian, Dutch, and Australian studies. with malnutrition and recurrent pulmonary prob- Clinical Disability. The impact of newborn screen- lems, but considerable delay frequently occurs. At ing remains unknown. Early initiation of appropriate least half of patients with CF go undiagnosed during treatment may reduce nutritional and pulmonary the first year of life; 25% remain undiagnosed by the disability. end of the second year. Variability. There is no characteristic pattern re- Genotype-Phenotype Correlation. Several hundred garding the severity of the disease, which may vary different mutations have been identified. The most depending on the specific mutations involved, as common 6F508 homozygous deletion results in pan- well as other epigenetic factors. Different homozy- creatic insufficiency and severe disease in 99% of gote family members can have mild or severe dis- patients, whereas only 36% of patients with CF with ease, with a wide spectrum in the natural history of other mutations have pancreatic insufficiency. this disorder. Milder disease states and pancreatic sufficiency oc- Possible Interventions. Improved parenteral and cur with other less common mutations and com- oral nutrition, fat-soluble vitamin supplements, pre- pound heterozygotes (eg, two different mutations at digested formula, and pancreatic enzyme replace- the CF locus). The genotype-phenotype relationship, ment enable more normal growth. Improved patient however, is not simple, because there is more phe- outcome also has been seen with pulmonary treat- notypic variation within the 6F508 population than ment with bronchodilator therapy, bronchial drain- there is among groups with different mutations. age with chest physiotherapy, and major advances in Genetic Counseling. Prenatal diagnosis is possible anti-Pseudomonas drugs and synergistic combina- for most families, particularly with available pro- tions of aminoglycoside, semisynthetic penicillin de- bands. Carrier screening of the general population is rivatives and aerosolized antibiotics. Newer aerosol- possible using available DNA mutation analysis, ized DNase, amiloride, adenosine triphosphate, which currently detects 80% to 90% of the heterozy- uridine triphosphate (an extracellular nucleotide that gote population, depending on the ethnic back- augments chloride secretion by CF respiratory epi- ground. It is difficult to detect all carriers. Although thelial cells), and a Pseudomonasvaccine are currently the feasibility of carrier-screening programs is cur- being evaluated. Gene therapy using recombinant rently being evaluated, CF carrier testing is not rec- DNA in an appropriate viral vector is under inves- ommended at this time for most individuals or cou- tigation and evaluation. ples who do not have family histories of CF. The primary benefit of newborn screening lies in the potential prevention of malnutrition as well as pos- Screening Test Characteristics and Confirmation sible improved pulmonary status and avoidance of Type of Test. The immunoreactive trypsin (IRT) test protracted medical evaluations; this benefit has not of dried blood spots, which uses an immunoassay, is been noted in some studies. Families of affected in- the screening test in the neonatal period. The sharp dividuals should be counseled regarding carrier de- decline in plasma concentration during the first 6 tection for other family members. Gene therapy is months of life decreases further in older children. currently under investigation. Normal values are 70 to 140 pg/mL, depending on the test kit and antibody used. Severity and Variability Without Screening Timing. Neonatal period; although elevations of Mortality. Ten percent of neonates with CF have IRT decline after the first several months of life, small-bowel obstruction due to meconium ileus, timing is not critical. IRT assays are of little or no which may lead to death in some cases. Neonates value in older infants and children. and infants have 13% mortality from malabsorption Stability of Specimen. Long-term stability and opti- and malnutrition. In the second to fourth decades of mal storage conditions have not yet been reported. life, death results from obstructive pulmonary dis- Confirmation. The optimal approach is currently ease and infection. Mean survival is now in the mid under investigation. The Colorado program uses se- to late 20s. rial IRT testing of those infants having a value of Developmental Disabilities. Rare; normal intelli- greater than 140 pg/mL with a second dried blood gence. specimen at about 30 days of age. Persistent eleva- Physical Findings. Poor growth with chronic respi- tion of greater than 80 pg/mL requires confirmation ratory infections, malabsorption, and gastrointestinal by a sweat test and/or DNA analysis. The Wisconsin abnormalities. pilot program performs 6F508 DNA analysis on the same filter paper for all specimens greater than the Clinical Outcome With Screening and Treatment initial cutoff value, thereby permitting confirmation Mortality. Conflicting study results have been re- if the specimen is homozygous for 6F508. ported with early intervention, but reduced morbid- Accuracy of ScreeningTest ity and mortality from malnutrition in infancy has False-Negative Rate. Three percent to 5%; an in- been suggested (Colorado study). No difference in crease in false-negative test results as great as 11.5% height and weight was noted by 4 years of age in a occurs among infants with meconium ileus. The IRT study from Wales. Significant differences in survival test detects 95% of infants with CF who do not have

Downloaded from www.aappublications.org/news by guest on September 29, 2021 484 NEWBORN SCREENING FACT SHEETS meconium ileus. Mutations that allow for pancreatic Dankert-RoelseJE, te Meerman GJ,Martijn A, ten Kate LP, Knol K. Survival sufficiency may also be missed by IRT screening, and clinical outcome in patients with cystic fibrosis, with or without because the IRT level will be normal. neonatal screening. J Pediatr. 1989;114:362-367 Farrell PM, Mischler EH. Newborn screening for cystic fibrosis. Adv Pediatr. False-Positive Rate. Elevated IRT in the neonatal 1992;39:35-70 period should have a high degree of specificity, be- Fost N, Farrell PM. A prospective randomized trial of early diagnosis and cause pancreatitis is extremely rare in the newborn. treatment of cystic fibrosis: a unique ethical dilemma. Clin Res. 1989;37: The false-positive-true-positive ratio with an initial 495-500 cutoff of greater than 140 kg/mL was 12:l. Incorpo- Gregg RG, Wilfond BS, Farrell PM, Laxova A, Hassemer D, Mischler EH. rating 6F508 analysis in the presence of an elevated Application of DNA analysis in a population-screening program for IRT analysis as part of the initial screening program neonatal diagnosis of cystic fibrosis (CF): comparison of screening pro- adds to the specificity of screening. tocols. Am J Hum Genet. 1993;52:616-626 Ongoing Studies. More than 4 million newborn in- Hammond KB, Abman SH, Sokol RJ, Accurso FJ. Efficacy of statewide neonatal screening for cystic fibrosis by assay of trypsinogen concentra- fants have been screened worldwide. Wisconsin and tions. N Engl J Med. 1991;325:769-774 several commercial newborn screening laboratories Heeley AF, Heeley ME, King DN, Kuzemko JA, Walsh Ml’. Screening for are using a two-step approach involving an initial cystic fibrosis by dried blood spot trypsin assay. Arch Dis Child. 1982;57: IRT with 6F508 analysis on the same (or subsequent) 18-21 specimen for confirmation. Extensive research is Holtzman NA. What drives neonatal screening programs? N Engl J Med. needed to determine the value of early treatment, 1991;325:802-804 genotype-phenotype correlations for predicting dis- Kerem E, Corey M, Kerem BS, et al. The relationship between genotype and ease severity, reliability and validity of screening phenotype in cystic fibrosis: analysis of the most common mutation (delta methods, and benefits and/or risks of early detec- F,,). N En@ J Med. 1990;323:1517-1522 tion, including stress on the family because of large McKinna JD, Hammond KB. Screening for cystic fibrosis in newborns. In: numbers of false-positive test results. Therrell BL, ed. Laboratory Methods for Neonatnl Screening. Washington, DC: American Public Health Association; 1993:202-213 Special Concerns and Issues National Institutes of Health. Special report: statement from the National Institutes of Health workshop on population screening for the cystic The impact of a presymptomatic diagnosis on the fibrosis gene. N Engl J Med. 1990;323:70-71 child and in reproductive planning for the family is Orenstein DM. Cystic fibrosis. Curr Probl Pediatr. 1993;23:4-15 unknown. The value of the IRT test in reducing the Ranieri E, Ryall RG, Morris CP, et al. Neonatal screening strategy for cystic number of missed cases of CF is under investigation. fibrosis using immunoreactive trypsinogen and direct gene analysis. Br Research will be enhanced by the potential identifi- Med J. 1991;302:1237-1240 cation of a large population of presymptomatic pa- Rock MJ, Mischler EH, Farrell PM, et al. Newborn screening for cystic tients. There is concern that children and their fam- fibrosis is complicated by age-related decline in immunoreactive ilies with false-positive IRT test results may be trypsinogen levels. Pediatrics. 1990;85:1001-1007 psychologically harmed. Physicians may dismiss Sorenson JR, Levy HL, Mangione TW, Sepe SJ. Parental response to repeat consideration of CF based on normal screening re- testing of infants with “false-positive” results in a newborn screening sults and then may not respond appropriately to program. Pediatrics. 1984;73:183-187 symptomatic patients. Spence WC, Paulus-Thomas J, Orenstein DM, Naylor EW. Neonatal screen- ing for cystic fibrosis: addition of molecular diagnostics to increase spec- ificity. Biochem Med Metab Biol. 1993;49:200-211 Professional and Public Education Tluczek A, Mischler EH, Farrell PM, et al. Parents’ knowledge of neonatal Although CF has wide public awareness, the po- screening and response to false-positive cystic fibrosis testing. J Da, Behov tential for newborn screening has not been widely Pediatr. 1991;13:181-186 recognized. This may increase with the availability of Welsh MJ, Tsui LC, Boat TF, Beaudet AL. Cystic fibrosis. In: Striver CR, newer treatment modalities, including gene therapy. Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Basis of Inherited Disease. 7th ed. New York, NY: McGraw-Hill; 1995:37993879 Wilcken B, Chalmers G. Reduced morbidity in patients with cystic fibrosis GENERAL REFERENCES detected by neonatal screening. Lancet. 1985;2:1379-1321 Ad Hoc Committee Task Force on Neonatal Screening, Cystic Fibrosis Foundation. Neonatal screening for cystic fibrosis: position paper. Pedi- GALACTOSEMIA atrics. 1983;72:741-745 American Society of Human Genetics Ad Hoc Committee on Cystic Fibrosis State Newborn Screening Availability Carrier Screening. Statement of the American Society of Human Genetics Currently available in 44 states, the District of on cystic fibrosis carrier screening. Am J Hum Genet. 1992;51:1443-1444 Columbia, and the US Virgin Islands. Boland C, Thompson NL. Effects of newborn screening of cystic fibrosis on reported maternal behavior. Arch Dis Child. 1990;65:1240-1244 Brief Clinical Description Bowling F, Cleghorn G, Chester A, et al. Neonatal screening for cystic An inherited disorder of galactose metabolism fibrosis. Arch Dis Child. 1988;63:196-198 leading to failure to thrive, vomiting, liver disease, Cassio A, Bernardi F, Piazzi S, et al. Neonatal screening for cystic fibrosis by cataracts, and mental retardation in untreated survi- dried blood spot trypsin assay: results in 47 127 newborn infants from a vors; lethal in most cases. homogeneous population. Acta Puediatr Stand. 1984;73:554-558 Chatfield S, Owen G, Ryley HC, et al. Neonatal screening for cystic fibrosis Genetics in Wales and the west Midlands: clinical assessment after 5 years of screening. Arch Dis Child. 1991;66:29-33 ChromosomalMap Location. Galactose-l-phosphate Crossley JR, Elliott RB, Smith PA. Dried-blood spot screening for cystic uridyl transferase (GALT), short arm of chromosome fibrosis in the newborn. Lancet. 1979;1:472-474 9: 9p13.

Downloaded from www.aappublications.org/news by guest on September 29, 2021 AMERICAN ACADEMY OF PEDIATRICS 485 Incidence. One in 60 000 to 1 in 80 000; 1992 CORN Clinical Outcome With Screening and Treatment data, 1 in 70 000 for classic galactosemia and 1 in Mortality. None expected, but some infants may 16 000 for other variant forms of galactosemia. die before the results of the screening test are avail- Inheritance. Autosomal recessive. Sex ratio: male = able because of susceptibility to E coli septicemia. female. Clinical Disability. The mean IQ is in the low end of Racial and Ethnic Variability. None reported. the normal range, but the range is wide. The IQ Molecular Pathology. The genetic disturbance is ex- seems to be dependent on the time of treatment, with pressed as a cellular deficiency of GALT (the defect best results (normal IQ) obtained when treatment is in the severe form of galactosemia), galactokinase, or started before 10 days of age. Visual-perceptual, uridine diphosphate-galactose-4-epimerase-the en- speech, and other learning disabilities are common. zymes catalyzing the reactions in the unique path- Ovarian failure with hypergonadotropic hypogon- adism and primary or secondary amenorrhea has way by which galactose is converted to glucose. Only occurred in the majority of treated females. newborn screening for GALT deficiency will be ad- dressed in this section. Many missense mutations in Variability. Phenotype classification using red cell highly conserved regions of the GALT gene have enzyme assays and electrophoretic mobility is neces- been identified, the most common being missense sary to determine treatment and compare outcomes. mutation QZ88R, present in 90% of the Irish homozy- Possible Interventions. A galactose-free diet should gous G/G population. This mutation is found in begin as soon as possible and should continue about 50% of the African-American alleles. Genetic throughout life. Galactose, a product of lactose me- compounds and variants with less severe clinical tabolism, is the compound that cannot be metabo- symptoms and higher enzyme activity have been lized. Avoidance of lactose and lactose-containing described. products is essential. Galactose-l-phosphate levels are sometimes used to determine compliance. Eval- Potential for Symptomatic Diagnosis. Fair. Symp- uation for learning disabilities should be performed toms may occur before receiving the results of new- as needed, and appropriate intervention should be born screening and require a high index of suspicion. arranged. In one survey, two thirds of the infants were symp- tomatic and under care at the time of the report of the positive newborn screening result. Simple urine Screening Test Characteristics and Confirmation screening shows non-glucose-reducing substances Type of Test. Test for elevated blood galactose con- (galactose). A galactose-free diet and supportive care tent: microbiologic test using E coli or E coli in com- for Escherichia coli sepsis, hypoglycemia, liver failure, bination with a bacteriophage (Paigen test). Test for and coagulation problems should be instituted pend- deficient GALT enzyme activity: fluorescent spot- ing confirmation of the diagnosis. screening test (Beutler test). Most newborn screening Genotype-Phenotype Correlation. Genotype-pheno- laboratories use a combination of the Beutler test and type correlations are emerging with relation to the a fluorometric assay for galactose (Hill test). In the specific gene mutation and enzyme level. In a subset latter test, the assay conditions are adjusted so that of African-American patients, despite the absence of fluorescence is visible only when total galactose is GALT activity in red cells, 10% enzyme activity is increased, usually more than 8 to 10 mg/dL. present in the liver and intestine with milder disease. Timing. Screening by measurement of enzyme The Duarte variant has 50% erythrocyte transferase GALT is accurate at any time. Methods measuring activity and a faster starch gel electrophoretic pat- galactose accumulation require ingestion of milk. Pa- tern. A variety of other clinical variants show differ- tients who have had transfusions may have negative ing but measurable levels of red cell transferase ac- Beutler test findings for as long as 2 to 3 months. tivity and are characterized by their altered Rapid screening is necessary because of E coli sepsis electrophoretic mobility. and presence of neurologic residua in patients Genetic Counseling. All enzymatic defects are in- treated late. herited as autosomal recessive conditions. Prenatal Stability of Specimen. Satisfactory for screening, but diagnosis is possible. the stability of transferase decreases in hot, humid climates, and false-positive results become common. Confirmation. Quantitative measurement for galac- Severity and Variability Without Screening tose, galactose-l-phosphate, and starch gel electro- Mortality. Usually fatal. In classic galactosemia, phoresis for transferase enzyme. Family studies may symptoms occur within the first 2 weeks of life; be necessary to determine the genotype. jaundice, vomiting, lethargy, hepatosplenomegaly, Accwucy of Screening Test cataracts, and failure to thrive may proceed to death False-Negative Rate. Excellent for homozygous and severe morbidity from liver failure, sepsis, or classic transferase deficiency, but partial deficiencies bleeding if untreated. E coli sepsis may be a present- (especially Duarte or Duarte/galactosemic com- ing sign. pound heterozygotes) may be missed. Developmental Disabilities. Present in survivors. False-Positive Rate. Varies with test; false-positive Physical Findings. Cerebral palsy, ataxia, seizures, results are especially high during hot summer mental retardation, cataracts, and liver disease. months with the Beutler test.

Downloaded from www.aappublications.org/news by guest on September 29, 2021 486 NEWBORN SCREENING FACT SHEETS Ongoing Studies. Ovarian failure in affected fe- Seashore MR. Neonatal screening for inborn errors of metabolism: update. males, speech problems and learning disabilities in Semin Perinatal. 1990;14:431- 438 treated patients, rigidity of diet restrictions, and clin- Segal S, Berry GT. Disorders of galactose metabolism. In: Striver CR, ical manifestations of compound heterozygotes and Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Basis of other variants are currently being studied. Inherited Disease. 7th ed. New York, NY: McGraw Hill; 1995:967-1001 Waggoner DD, Buist NRM, Donnell GN. Long-term prognosis in galactosemia: results of a survey of 350 cases. J Inherit Metab Dis. 1990; Special Concerns and Issues 13:802-818 Rapid turnaround time is needed because of early Webster D, Allen D. Laboratory methods for galactose testing. In: Therrell onset of symptoms; physician awareness of this BL, ed. Laboratory Methods for Neonatal Screeniq. Washington, DC: Amer- disorder needs to be maintained. Follow-up care ican Public Health Association; 1993:77-114 requires specialized metabolic and genetic clinics providing nutritional, psychologic, nursing, bio- HOMOCYSTINURIA chemical, and pediatric care. There is a need for State Newborn Screening Availability further information concerning the clinical manifes- tations in genetic variants and the incidence of cata- Currently performed in 20 states, the District of racts and gonadal failure among carriers. Columbia, and the US Virgin Islands.

Professional and Public Education Brief Clinical Description The public is generally unaware of this disorder. An autosomal recessive defect in the catabolism of Information is provided during the neonatal period sulfur-containing amino acids. The most common in the form of brochures developed by state newborn cause of homocystinuria is a deficiency of the en- screening programs. zyme cystathionine P-synthase. Elevated levels of homocysteine, methionine, and metabolites of homo- GENERAL REFERENCES cysteine accumulate in the blood and urine of Beutler E. Galactosemia: screening and diagnosis. Chin Biochem. 1991;24: these patients. Clinical problems include thrombo- 293-300 embolism, optic lens dislocation, scoliosis, osteo- Beutler E, Baluda MC. A simple spot screening test for galactosemia. J Lab porosis, developmental and mental retardation, sei- Chin Med. 1966;68:137-141 zures, psychiatric disturbances, myopathy, and a Diepenbrock F, Heckler R, Schickling H, Engelhard T, Bock D, Sander J. marfanoid habitus. Calorimetric determination of galactose and galactose-l-phosphate from dried blood. Clin Biochem. 1992;25:37-39 Genetics Donnell GN, de la Cruz F, Koch R, Levy HL, eds. Galactosemia: New Frontiers ChromosomalMap Location. Long arm of chromo- in Research. Washington, DC: National Institute of Child Health and Human Development; 1993. US Dept of Health and Human Services, NIH some 21: 21q22. publication 93-3438 Incidence. One in 50 000 to 1 in 150 000; 1992 Elsas LJ, Langley S, Steele E, et al. Galactosemia: a strategy to identify new CORN data, 1 in 670 000, with only 2 confirmed cases biochemical phenotypes and molecular genotypes. Am J Hum Genet. in approximately 1.3 million screened newborns. 1995;56:630-639 Inheritance. Autosomal recessive. Sex ratio: male = Gitzelmann R, Steinmann B. Galactosemia: how does long-term treatment female. change the outcome? Enzyme. 1984;32:37-46 Racial and Ethnic Variability. Ireland, Australia, and Hill GN, O’Reilly D, Robertson E. A simple screening test for galactosaemia based on accumulation of galactose and galactose-l-phosphate. In: Na- Great Britain, 1 in 82 000. The lowest incidence is in ruse H, Irie M, eds. Neonatal Screening. Amsterdam: Excerpta Medica; Japan. 1983252-253 Molecular Pathology. At least nine specific genetic Holton JB. Galactose disorders: an overview. J Inherit Metab Dis. 1990;13: disorders have been recognized that affect one of the 476-486 transsulfuration pathways that convert the sulfur Inoue B, Hata M, Ichiba Y, Wada H, Misumi H, Mori T. Results of newborn atom of methionine into the sulfur atom of cysteine. screening for galactose metabolic disorders. J Znherit Metab Dis. 7990;13: This pathway is the chief route of disposal of methi- 93-101 onine. The most common defect, cystathionine Kaufman FR, Xu YK, Ng WG, Donnell GN. Correlation of ovarian function P-synthase deficiency, results in high levels of serum with galactose-l-phosphate uridyl transferase levels in galactosemia. J Pe- methionine that can be detected by newborn screen- diatr. 1988;112:754-756 ing. One deletion mutation and two point mutations Kelly S. Galactosemia identified in newborn screening program: clinical and biochemical characteristics. NY State 1 Med. 1980;80:1836-1839 have been described. Potential for Symptomatic Diagnosis. The potential Kirby LT, Norman MG, Applegarth DA, Hardwick DF. Screening of new- born infants for galactosemia in British Columbia. Can Med Assoc J. for early clinical diagnosis is limited. Ocular abnor- 1985;132:1033-1035 malities, because of their distinctive lens displace- Levy HL, Hammersen G. Newborn screening for galactosemia and other ment, may lead to the diagnosis. The diagnosis galactose metabolic defects. J Pediatr. 1978;92:871-877 should be considered in any child or young adult Levy HL, Sepe SJ, Shih VE, Vawter GF, Klein JO. Sepsis due to Escherichia with thromboembolism affecting both the large and coli in neonates with galactosemia. N Engl J Med. 1977;297:823-825 small arteries as well as the veins, particularly in Nelson CD, Waggoner DD, Donnell GN, Tuerck JM, Buist NRM. Verbal association with developmental disabilities, mental dyspraxia in treated galactosemia. Pediatrics. 1991;88:346-350 retardation, or skeletal findings. Most patients, how- Paigen K, Pacholec F, Levy HL. A new method of screening for inherited ever, have nonspecific features so that definitive test- disorders of galactose metabolism. J Lab Clin Med. 1982;99:895-897 ing involving the measurement of serum or urine

Downloaded from www.aappublications.org/news by guest on September 29, 2021 AMERICAN ACADEMY OF PEDIATRICS 487 amino acids is not accomplished before the expres- Bi2, not cyanocobalamin) may be beneficial. Aspirin sion of more severe clinical symptoms. and dipyridamole have also been used to prevent Genotype-Phenotype Correlation. Affected patients thromboembolic phenomena. vary widely in the extent to which they manifest clinical abnormalities suggesting considerable ge- Screening Test Characteristics and Confirmation netic heterogeneity. Absent to relatively low residual Type of Test. BIA to determine elevated levels of activity (up to 10%) of cystathione /3-synthase has blood methionine. Newer methods include direct been noted among different families. The presence of methionine assay by tandem mass spectrometry. some activity of the enzyme seems necessary for a Normal values are less than 2 mg/dL. clinical response to pyridoxine (vitamin BJ adminis- Timing. Elevation in levels of methionine may be tration. Individuals clinically responsive to pyridox- minimal during the first 3 days of life until there is ine generally have milder or more slowly progres- adequate protein intake (milk feedings), especially in sive disease. patients responsive to vitamin Bg, who usually have Genetic Counseling. The specific enzymatic defect some residual enzyme activity. This probably ac- must be ascertained. Obligate heterozygote carriers counts for the difference in screening frequencies have 22% to 47% cystathione P-synthase activity in between the United States and United Kingdom, cultured fibroblasts or long-term cultured lympho- where screening specimens are obtained at 5 to 7 cytes. Prenatal diagnosis is available for cystathi- days. It may be preferable to screen for this disorder onine P-synthase deficiency using cultured chorionic at 2 to 4 weeks of age. Early discharge at 24 or even villus cells or amniotic fluid cells to measure the 48 hours results in many missed cases and makes activity of this enzyme. screening ineffective at this age. Stability of Specimen. Unknown. Severity and Variability Without Screening Confirmlation. Quantitative serum or plasma amino Mortality. Death has been reported within the first acid determination. Plasma amino acids show in- year of life. Approximately 50% of untreated indi- creased levels of methionine and homocystine con- viduals die by 25 years of age; death is frequently centrations with reduced levels of cystine and absent due to thromboembolic events. levels of cystathionine. A urine organic acid profile Developmental Disabilities. Developmental delay is with gas chromatography and mass spectrometry reported in 65% to 80% of untreated individuals. may be used to determine the presence or absence of Physical Findings. Marfanoid habitus, ectopia len- methylmalonic acid. tis, glaucoma, cataracts, osteoporosis with bone de- Accuracy of Screening Test formities, high palatal arch, and muscle weakness False-Negative Rate. Only limited information is with a shuffling gait. Arterial or venous thromboses available. The false-negative rate seems to correlate may involve the cerebral, pulmonary, renal, and with the time that the specimen was obtained and myocardial circulation. the level of residual synthase activity present (ie, the B,-responsive form). The false-negative rate is in- Clinical Outcome With Screening and Treatment creasing with earlier newborn discharges. Mortality. Treatment seems to reduce the risk of False-Positive Rate. About 1 in 5000 infants is thromboembolic episodes. found to have elevated blood methionine levels Clinical Disability. The incidence of mental retarda- greater than 2 mg/dL (Mountain States Screening tion may be prevented or reduced. Ectopia lentis Program). In most instances, this is a benign tempo- seems to be delayed, and the incidence of seizures is rary abnormality resulting from immaturity of the reduced. liver with transiently reduced enzyme levels or a Variability. Clinical variability remains despite high protein intake. Methionine levels may also be therapy. However, the relationship between this elevated in newborns with liver disease and in pre- variability and the underlying metabolic processes or mature infants. The true-positive-false-positive ratio compliance has not been ascertained. Not all affected is approximately 1:20. individuals have elevated methionine levels. Other Ongoing Studies. Programs continue to evaluate metabolic variants of homocystinuria include vita- the efficacy of screening and early treatment. Im- min B,, uptake or activation defects and tetrahydro- provement in screening to decrease the numbers of folate reductase deficiency. missed cases is important. Ethnic variability, under- Possible Interventions. Treatment depends on the standing different genetic types, and optimal treat- underlying cause of homocystinuria. Pyridoxine re- ment strategies need to be defined. sponsiveness should be ascertained. Approximately 50% of patients respond to large doses of vitamin B,. Special Concerns and Issues Nonresponsive patients with cystathionine /3-syn- Specialized care is required that includes the abil- thase deficiency should be treated with a methi- ity to monitor amino acids and provide nutritional onine-restricted, cystine-supplemented diet. Folic assessment and planning. Doses of pyridoxine acid and betaine therapy may also be helpful. In the greater than 900 mg have been associated with neu- disorders of cobalamin metabolism and transport in ropathy; however, these higher doses are usually not which methylmalonic acid and homocystine appear required for adequate treatment. Thromboembolic in the urine, hydroxycobalamin treatment (vitamin phenomena are more prone to occur during anesthe-

488 NEWBORN SCREENINGDownloaded FACT from SHEETS www.aappublications.org/news by guest on September 29, 2021 sia, surgical procedures, and prolonged immobiliza- and 1 in 16 000 for classic and clinically significant tion. hyperphenylalaninemia. Inheritance. Autosomal recessive. Sex ratio: male = Professional and Public Education female. This extremely rare disorder has limited physician Racial and Ethnic Variability. Considerable. Whites: and public awareness. Even with increased aware- 1 in 6000 in Ireland and Scotland; 1 in 8000 to 1 in ness, an early clinical diagnosis is difficult to make. 10 000 in former West Germany; 1 in 16 000 Italy; 1 in However, the diagnosis should be considered in in- 6000 among Yemenite Jews; and 1 in 60 000 among dividuals with characteristic eye problems and early Ashkenazi Jews. Less common among African- thromboembolic episodes. American and Asian families: China and Japan, 1 in 60 000. Non-PKU hyperphenyIalaninemia was previ- GENERAL REFERENCES ously known as benign hyperphenylalaninemia: Hu FL, Gu 2, Kozich V, Kraus JP, Ramesh V, Shih VE. Molecular basis of panethnic, 1 in 65 000 (average). cystathionine beta-synthase deficiency in pyridoxine responsive and non- Molecular Pathology. Hyperphenylalaninemia is a responsive homocystinuria. Hum Mel Genet. 1993;2:1857-1860 generic phenotype distinguished by a persistently Lieberman ER, Gomperts ED, Shaw KN, Landing BH, Donnell GN. elevated phenylalanine concentration above the nor- Homocystinuria: clinical and pathologic review, with emphasis on mal distribution that impairs the development of the thrombotic features, including pulmonary artery thrombosis. Perspect central nervous system. Hyperphenylalaninemia can Pediatr Pathol. 1993;17:125-147 be caused by mutations at the locus encoding the Ludolph AC, Ullrich K, Bick U, Fahrendorf G, Przyrembel H. Functional enzyme PAH, at the loci for at least two enzymes in and morphological deficits in late-treated patients with homocystinuria: a clinical, electrophysiologic and MRI study. Acfa Neural Stand. 1991;83: the pathway for the synthesis of tetrahydrobiopterin 161-165 (BH,), the cofactor for the hydroxylation reaction, Millington DS, Norwood DL, Kodo N, Roe CR, Inoue F. Application of fast and at the locus for dihydropteridine reductase, the atom bombardment with tandem mass spectrometry and liquid enzyme that regenerates BH, from the oxidized chromatography/mass spectrometry to the analysis of acylcarnitines in product of the hydroxylation reaction. Mutations in- human urine, blood and tissue. Anal Biochem. 1989;180:331-339 volving the PAH gene have been described, includ- McGill JJ, Mettler G, Rosenblatt DS, Striver CR. Detection of heterozygotes ing missense mutations, deletions, and splice site for recessive alleles. Homocystfelinemia: paradigm of pitfalls in pheno- mutations. types. Am J Med Genet. 1990;36:45-52 Potential for Symptomatic Diagnosis. The disease is Mudd SH, Skovby F, Levy HL, et al. The natural history of homocystinuria rarely diagnosed before 6 months of age and usually due to cystathionine beta-synthase deficiency. Am J Hwn Genef. 1985;37: 1-31 only after mental retardation is obvious. Because of universal newborn screening, PKU may not be con- Pass KA, Amador I’S Homocystinuria screening in newborns. In: Therrell BL, ed. Laboratoty Methods for Neonatal Screening. Washington, DC: Amer- sidered in the differential diagnosis in an infant with ican Public Health Association; 1993:125-131 progressive developmental delay. Some cases are not Schaumburg H, Kaplan J, Windebank A, et al. Sensory neuropathy from diagnosed until the disease is discovered in a subse- pyridoxine abuse: a new megavitamin syndrome. iV Engl J Med. 1983;309: quent sibling by newborn screening. 445-448 Genotype-Phenotype Correlation. Both PKU and Smolin LA, Benevenga NJ, Berlow S. The use of betaine for the treatment of non-PKU hyperphenylalaninemia represent genetic homocystinuria. 1 Pediatr. 1981;99:467-472 defects at the PAZ3 locus; the severity of the disease is Wilcken DEL, Wilcken B, Dudman NPB, Tyrrell PA. Homocystinuria-the generally related to the level of phenylalanine. Be- effects of betaine in the treatment of patients not responsive to pyridox- cause there are numerous mutations, most patients ine. N Engl J Med. 1983;309:448-453 (with the exception of inbred populations) are dou- bly heterozygous (ie, so-called compound heterozy- PHENYLKETONURIA gates) for two different mutations at the PAH locus. State Newborn Screening Availability There are other mutant alleles at the PAH locus that Currently performed in all states, the District of cause a lesser degree of hyperphenylalaninemia (ie, Columbia, Puerto Rico, and the US Virgin Islands. non-PKU hyperphenylalaninemia) with a lower risk of mental retardation. Brief Clinical Description Genetic Counseling. Prenatal diagnosis and carrier An autosomal recessive disorder of phenylalanine testing are available by DNA analysis using direct hydroxylation leading to accumulation of this amino mutation analysis when identified in the proband or acid. Patients with undiagnosed PKU have progres- by linkage analysis. Infants of untreated affected sive developmental delay in the first year of life, mothers (maternal PKU) may have microcephaly, severe mental retardation, seizures, autistic-like be- retardation, and congenital heart disease even when havior, and a peculiar odor. they are not affected by PKU. The efficacy of treat- ment to prevent fetal effects is under study; prelim- inary data show that treatment beginning before con- Genetics ception and continuing throughout pregnancy could Ckromosomal Map Location. L-Phenylalanine hy- be beneficial. droxylase (PAH), long arm of chromosome 12: 12q22-q24. Severity and Variability Without Screening Incidence. One in 10 000 to 1 in 25 000 (United Mortality. Classic PKU is not lethal, but data con- States); 1992 CORN data, 1 in 20 000 for classic PKU cerning institutionalized patients showed that their

Downloaded from www.aappublications.org/news by guest on September 29, 2021 AMERICAN ACADEMY OF PEDIATRICS 489 life spans are reduced. Cofactor variants may lead to screening cutoff level to 2 mg/dL when specimens death in childhood. are taken before 24 hours of age, but this practice Developmental Disabilities. In 95%, IQ less than 50. results in a marked increase in the false-positive rate Some milder forms of hyperphenylalaninemia do not and is not currently used in most state newborn reduce intelligence. screening programs. All infants should be screened Physical Findings. Convulsions, hyperactivity, and at the time of nursery discharge or transfer regard- eczema are common. less of age. Antibiotic treatment can affect the results by inhibiting bacterial growth in the Guthrie assay. Sick infants and premature infants should be Clinical Outcome With Screening and Treatment screened by 7 days of age, regardless of feeding Mortality. Not expected. history or antibiotic treatment. Clinical Disability. Normal early growth and devel- Stability of Specimen. Short-term stability and when opment and normal range of intelligence with opti- frozen at -70°C is excellent. Stability under ambient mal dietary control, which needs to be maintained conditions for several years has remained reliable. throughout life. Emerging data have indicated that Confirmation. Quantitative measurement of serum some patients on less restrictive diets or taken off phenylalanine, tyrosine, urinary pteridines, and dietary control have manifested late neuropsychiat- blood dihydropteridine reductase (to exclude cofac- ric disturbances, agoraphobia, and memory deficits, tor variants that require additional specialized ther- and magnetic resonance imaging scans have showed apy). Quantitative phenylalanine and tyrosine are white matter changes and deficits in the frontal cor- available in many laboratories; pterin measurements tex. are available in a few centralized laboratories. Quan- Variability. Cofactor-deficient variants may cause titative serum phenylalanine of more than 10 mg/dL progressive neurologic deficits despite dietary re- (0.60 mmol/L) is most likely to be the classic variant; striction, and patients with these variants have a lower levels are more likely to reflect milder variants. poorer prognosis. Patients with such variants require All infants with levels above 6 mg/dL should be additional therapy. Hyperphenylalaninemia may not considered for dietary restriction of phenylalanine. require treatment if the serum phenylalanine concen- Accuracy of Screening Test tration remains less than 6 mg/dL. False-Negative Rate. Depends on the infant’s age Possible Interventions. Dietary restriction of phenyl- at testing and the cutoff used. With a cutoff of 4 alanine with regular monitoring of serum phenylal- mg/dL, approximately one third with PKU would anine levels is highly effective when begun before be missed by a sample taken in the first 12 hours of the infant is 4 weeks old (optimally as soon as pos- life; 10% would be theoretically missed at 24 hours, sible) and should be continued indefinitely. Treat- 2.4% at 24 to 48 hours, and 0.15% after 48 hours. With ment of adults is strongly recommended and is re- a cutoff of 2 mg/dL, 2.6% would be missed when quired for women of childbearing age. Treatment tested before 12 hours of age, but less than 1% would after central nervous system damage has been sus- be missed at 24 hours. tained will not reverse retardation but may lead to some improvement in behavior control. Treatment False-Positive Rate. The false-positive rate using a may be costly and requires a special formula and a 4-mg/dL cutoff is approximately 1 in 3300 samples. diet of low-protein foods. A nutritionist and a spe- Lowering the cutoff rate to 2 mg/dL would more than triple the false-positive rate to 1 in 1000 samples cially trained physician are necessary to coordinate for a true-positive-false-positive ratio of approxi- therapy. Compliance is a problem for many adoles- cents. Cofactor variants need to be identified early mately 1:13. and require combined therapy for dietary restriction Ongoing Studies. Current studies include assess- and restoration of neurotransmitter homeostasis (eg, ments of long-term neuropsychiatric complications, biopterin, L-dopa, 5-hydroxytryptophan, and folinic the optimal maintenance level of phenylalanine, al- acid). ternative dietary products, treatment of cofactor variants, and the effect of maternal preconceptional and postconceptional dietary management in the Screening Test Characteristics and Confirmation prevention of the maternal PKU syndrome. DNA Type of Test. Measurement of the blood phenylal- analysis for detection of carriers and possible use of anine level by BIA using a dried blood spot (the DNA technology on dried blood spots for newborn original Guthrie test). Measurement by automated screening are being studied. A number of commer- fluorometric assay is performed as the initial screen- cial companies are currently undergoing Food and ing test in 10 state screening laboratories. The initial Drug Administration studies of calorimetric screen- screening cutoff level is greater than 4 mg/dL in 40 ing kits for use with filter paper specimens. states and jurisdictions, 3.0 mg/dL in 6 states, and greater than 2 mg/dL in the remaining 7 states (1992 Special Concerns and Issues CORN data). Reduction of phenylalanine levels requires protein Timing. Screening should occur in newborns older restriction, costly specialized formulas and foods, than 24 hours and younger than 7 days. Infants and avoidance of aspartame (in diet drinks and non- screened before 24 hours of life should be rescreened glucose sweeteners). Follow-up requires specialized by 2 weeks of age to detect possible missed cases. clinics (state or regional) and monitoring of serum This situation may be avoided by reducing the levels of phenylalanine. There may be a lack of ade-

Downloaded from www.aappublications.org/news by guest on September 29, 2021 490 NEWBORN SCREENING FACT SHEETS quate public and third-party support for costs of SICKLE CELL DISEASES: SS, SC, AND S treatment. Registries of affected girls and women are /3-THALASSEMIA being developed to track those at risk for maternal State Newborn Screening Availability PKU. Missed patients may include those screened Currently performed in 42 states, the District of before 24 hours of age, those not born in hospitals, Columbia, Puerto Rico, and the US Virgin Islands. those born in countries other than the United States, and those born before routine screening. Brief Clinical Description Professional and Public Education A group of genetic disorders characterized by the Commonly provided by state programs, regula- production of abnormal hemoglobin p chains (eg, tions, and/or law. sickle cell disease HbSS). Affected individuals have lifelong hemolytic anemia with acute and chronic GENERAL REFERENCES tissue damage secondary to the blockage of blood Aldis B, Hoffman G, Therrell BL. Laboratory methods for phenylalanine flow produced by the abnormally shaped red cells. anilysis on newborn screening specimens. In: Therrell BL, ed. Lobomtory Additional clinical manifestations include episodic Methods for Neorlatal Screening. Washington, DC: American Public Health vaso-occlusive crises, functional asplenia, sepsis, in- Association; 1993:47-75 fections, splenic sequestration, and bone marrow American Academy of Pediatrics, Committee on Genetics. New issues in aplasia. Other hemoglobinopathies can also be de- newborn screening for phenylketonuria and congenital hypothyroidism. tected by current newborn hemoglobinopathy- Pediatrics. 1982;69:104-106 screening methods. American Academy of Pediatrics, Committee on Genetics. Maternal phe- nylketonuria. Pediatrics. 1985;76:313-314 Genetics Arnopp JJ, Lorey FW, Currier RJ, et al. Results of screening for phenylke- tonuria using a lower cutoff value in early collected specimens. Screening. Chvomosomal Map Location. @Globin gene family, 1995;3:193-201 short arm of chromosome 11: 11~14. Doherty LB, Rohr FJ, Levy HL. Detection of phenylketonuria in the very Incidence. United States African-American live early newborn blood specimen. Pediatrics. 1991;87:240-244 births: HbSS, 1 in 375; HbSC, 1 in 835; and HbS Fishler K, Azen CG, Henderson R, Friedman EG, Koch R. Psychoeduca- /3-thalassemia 1 in 1667; 1992 CORN data, 1 in 40 000 tional findings among children treated for phenylketonuria. Am J Mend to 1 in 60 000 HbSS in non-African-American new- Defic. 1987;92:65-73 borns in California, New York, and Texas. Jew K, Kan K, Koch K, Cunningham G. Validity of screening early collected Inheritance. Autosomal recessive. Sex ratio: male = newborn specimens for phenylketonuria using a fluorometric method. Screening. 1994;3:1-8 female. Kaufman S, Berlow S, Summer GK, et al. Hyperphenylalaninemia due to Racial and Ethnic Variability. Most commonly deficiency of biopterin: a variant form of phenylketonuria. N Engf J Med. found in persons of African ancestry, but it also 1978;299:673-679 affects persons of Mediterranean, Caribbean, South Koch R, Azen C, Friedman EG, Williamson ML. Paired comparisons be- and Central American, Arabian, and East Indian an- tween early treated PKU children and their matched sibling controls on cestry. Prevalence of sickle cell disease (SS, SC, S intelligence and school achievement test results at eight years of age. /3-thalassemia) in US populations: whites, 1 in 58 000; J Inherit Metab Dis. 1984;7:86-90 Hispanics from eastern states, 1 in 1100; Hispanics Levy HL, Waisbren SE. Effects of untreated maternal phenylketonuria and from western states, 1 in 32 000; Asians, 1 in 11 500; hyperphenylalaninemia on the fetus. N Engf J Med. 1983;309:1269-1274 and Native Americans, 1 in 2700. McCabe ERB, McCabe L, Masher GA, Allen RJ, Berman JL. Newborn Molectllar Pathology. The inherited disorders of he- screening for phenylketonuria: predictive validity as a function of age. Pediatrics. 1983;72:390-398 moglobin fall into three overlapping groups: (1) structural variants, such as HbS and HbC, related to Medical Research Council Working Party on Phenylketonuria. Phenylketo- nuria due to phenylalanine hydroxylase deficiency: an unfolding story. Br single-amino acid substitutions (ie, missense muta- Med J. 1993;306:115-119 tions); (2) thalassemias, all characterized by a re-

Report of the Medical Research Council Working Party on I’henylketonuria. duced rate of synthesis of one or more of the globin Recommendations on the dietary management of phenylketonuria. Arch chains of hemoglobin related to a variety of different Dis Child. 1993;68:426-427 mutational events; and (3) conditions in which fetal Striver CR, Glow CL. Phenylketonuria: epitome of human biochemical hemoglobin synthesis persists beyond the neonatal genetics (first of two parts). N Errgl J Med. 1980;303:1336-1342 period, known collectively as hereditary persistence Striver CR, Glow CL. Phenylketonuria: epitome of human biochemical of fetal hemoglobin. The substitution of the amino genetics (second of two parts). N Engl J Med. 1980;303:1394-1400 acid valine for glutamic acid in HbS results in re- Striver CR, Kaufman S, Eisensmith RC, Woo SLC. The hyperphenylalanine- duced deformability of the red cell (enhanced by miss. In: Striver CR, Beaudet AL, Sly WS, Valle D, eds. TJle Metabolic Basis acidosis and conditions of low oxygen tension) and, of Inherited Disease. 7th ed. New York, NY: McGraw-Hill; 1995:1015-1077 thus, its defective passage through the microcircula- Striver CR. Phenylketonuria-genotypes and phenotypes. N Engf J Med. tion, which is the basis for the vaso-occlusive mani- 1991;324:1280-1281 festations of sickle cell disease. These structural Seashore MR, Friedman E, Novelly RA, Bapat V. Loss of intellectual func- changes of the red cell lead to shortened survival and tion in children with phenylketonuria after relaxation of dietary phenyl- chronic hemolytic anemia. alanine restriction. Pediatrics. 1985;75:226-232 Potential for Symptomatic Diagnosis. Hemoglobin Tiwary CM. Proposed guidelines for screening of metabolic and endocrine diseases of dependent neonates of the US Armed Forces: derived from a electrophoresis study of at-risk individuals is easily survey of state guidelines for neonatal screening of metabolic diseases. accessible. The clinical diagnosis is rarely made be- Chin Pediatr Phila). 1987;26:349-351 fore 1 year of age, when symptoms will prompt

Downloaded from www.aappublications.org/news by guest on September 29, 2021 AMERICAN ACADEMY OF PEDIATRICS 491 investigation. Dactylitis (hand-foot syndrome) is an Possible Interventions. Infants with HbSS or SB” early manifestation. Overwhelming sepsis with un- thalassemia should begin penicillin prophylaxis at toward outcome may occur before any other symp- the time of diagnosis and by no older than 2 months. toms, particularly within the first 2 years of life. Immunization against pneumococcal, Hemophihs in- Genotype-Phenotype Correlation. Most individuals @enzae, and meningococcal infection should be of western African ancestry show variable but sig- given. Parent and patient education with rapid ac- nificant clinical manifestations. A mild form of sickle cess to appropriate medical care for aggressive pain cell disease (HbSS) exists in Saudi Arabia and India management, prompt recognition and early treat- and is associated with unusually high fetal hemoglo- ment of infections, management of dehydration and bin levels of 15% to 25%, which seem protective. The acidosis, blood transfusion therapy for selected pa- presence of the homozygous deletion form of tients (with severe anemia and cerebrovascular c-w-thalassemiain association with HbSS (which oc- events), and judicious use of oxygen seem to reduce curs in 2% of African-American and Jamaican pa- morbidity and mortality. tients) also produces a milder clinical course. Other Screening Test Characteristics and Confirmation compound sickle diseases with severe features simi- lar to those found in homozygous HbSS include Type of Test. Isoelectric focusing, hemoglobin elec- HbSD Los Angeles and HbSO Arab. I-IbS/B“ thalas- trophoresis on cellulose acetate followed by citrate semia is similar to HbSS; the B+ thalassemia com- agar or high-performance liquid chromatography pounds and HbSC cause milder symptoms. (HPLC) on cord blood or a dried heel stick blood spot. Genetic Counseling. All are autosomal recessive disorders. Carrier testing is readily available by he- Timing. Timing is unimportant. Cord blood or heel moglobin electrophoresis and other techniques. Sol- stick blood can be obtained any time following birth. ubility tests should not be used for screening or Stability of Specimen. Filter paper specimens and carrier testing. Prenatal and confirmational newborn cord blood are stable for several weeks frozen. Sta- screening diagnoses also are available by DNA anal- bility problems are more prevalent with cellulose ysis. acetate electrophoresis. Confirmation. Hemoglobin electrophoresis using Severity and Variability Without Screening citrate agar at acid pH and isoelectric focusing or Mortality. Can be lethal especially in early infancy HPLC. The use of cellulose acetate alone is insuffi- or childhood (10% mortality) because of overwhelm- cient for differentiating HbS from hemoglobins D or ing sepsis or splenic sequestration. Previous indica- G. Family studies and/or DNA analysis may be nec- tions of reduced life span in adults are being reeval- essary to distinguish sickle cell trait from SB+ thalas- uated as a result of more aggressive and careful semia, which depends on estimating the relative pro- management; current predictions indicate an 85% portions of hemoglobins A and S and may be chance that infants with HbSS will survive to 20 difficult to assessby electrophoretic methods; HPLC is also helpful. years of age. Developmental Disabilities. Usually none. Cerebro- Accuracy of ScreeningTest vascular accidents or sequelae of meningitis may False-Negative Rate. Unknown, because negative lead to neurologic deficits. tests are usually not repeated unless the states have Physical Findings. Aseptic necrosis of bones, leg routine or discretionary second tests. Presumably, ulcers, neoproliferative retinopathy, serious infec- false-negative test results are quite low, with sensi- tions, cerebral thromboses, renal concentrating de- tivities of 93.2% on citrate agar gel electrophoresis fects, and delayed growth and sexual maturation. and approximately 100% on isoelectric focusing. False-Positive Rate. One in 3000; 97.9% of positive results were confirmed. One hundred percent speci- Clinical Outcome With Screening and Treatment ficity was noted in Massachusetts and Georgia new- Mortality. With screening, penicillin prophylaxis, born screening laboratories using isoelectric focusing and heightened vigilance, early death and morbidity on cord blood and additional filter paper specimen from overwhelming sepsis are significantly de- confirmations. creased. Death from acute splenic sequestration and Ongoing Studies. Prospective studies regarding the aplastic crisis may be prevented or reduced. impact of early diagnosis and vigorous treatment on Clinical Disability. Risks are lowered by aggressive prognosis; methods of treatment to prevent sickle treatment of infection, dehydration, and cerebral crises: optimal use of blood products, oxygen, and thromboses. Long-term clinical outcomes of patients vaccines; potential for gene therapy. Additional identified by newborn screening programs are un- methods for improved screening include efficacy of clear, because treatment remains prophylactic and HPLC, immunologic approaches, and DNA analysis. symptomatic. Variability. Marked clinical variability ranging Special Concerns and Issues from a few symptoms to more severe symptoms to Locating all infants with positive test results has death in early life. In part, clinical severity is also been a problem in some areas. Coordinated care by influenced by the presence of other mutations, ie, specialized clinics (state or regional) or private pri- combinations of other /3 chain mutations or thalasse- mary care practitioners is needed, especially for ad- mic mutations. olescents and adults. Other concerns have included

Downloaded from www.aappublications.org/news by guest on September 29, 2021 492 NEWBORN SCREENING FACT SHEETS stigmatization, confusion about the meaning of being Therrell BL, Pass KA. Hemoglobinopathy screening laboratory techniques a carrier, confidentiality, potential identification of for newborns. In: Therrell BL, ed. Laboratory Methods for Neonatal Screen- nonpaternity, discrimination in the work place, and ixg. Washington, DC: American Public Health Association; 1993:169-189 insurability. No uniformity exists in dealing with the Vichinsky E, Hurst D, Earles A, Kleman K, Lubin B. Newborn screening for sickle cell disease: effect on mortality. Pediatrics. 1988;81:749-755 high number of carrier infants detected by newborn screening programs. Thalassemia testing in Asian- Zarkowski HS, Gallagher D, Gill FM, et al. Bacteremia in sickle hemoglo- Americans is also a problem. Screening programs binopathies. 1 Pediatr. 1986;:109:579-586 identify and report all abnormal hemoglobin vari- ants. Reports listing AF indicate there is more hemo- TOXOPLASMOSIS globin A than F, which may occur from a transfusion State Newborn Screening Availability in a homozygous SS patient, and an absence of he- Currently performed as part of the routine new- moglobin A may reflect homozygous fi-thalassemia born screening profile in Massachusetts and New or a normal biological variation. Hampshire by the New England Regional Newborn Screening Program. Professional and Public Education Awareness is generally high, although many pop- Brief Clinical Description ular misconceptions exist. Excellent educational ma- Congenital toxoplasmosis is a protozoan infection terials are provided by the US Department of Health that can result in blindness and mental retardation. and Human Services, state programs, comprehensive Most infected newborn infants have no symptoms at sickle cell centers, and local sickle cell organizations. birth, but by 20 years of age, as many as 85% of Sickle cell support groups are available in most areas affected individuals have chorioretinitis, including and serve as a resource for families. many who were free of symptoms at birth. GENERAL REFERENCES Incidence. Estimated to range from 1 in 1000 to 1 in Charache S, Lubin 8, Reid CD, eds. Management and Therapy of Sickle Cell 8000 births in the United States; 1992 CORN and Disease. Bethesda, MD: US Department of Health and Human Services; New England Regional Toxoplasma Working Group 1992. NIH publication 92-2117 data, 1 in 8650 and 1 in 12 000 respectively. Gaston MH, Verter JI, Woods G, et al. Prophylaxis with oral penicillin in Epidemiology. Toxoplasmosis gondii is ubiquitous in children with sickle cell anemia: a randomized trial. N Engl J Med. warm-blooded animals. Members of the cat family 7986;314:1593-1599 are definitive hosts. It remains one of the most com- Jacobs S, Peterson L, Thompson L, et al. Newborn screening for hemoglobin mon latent infections of humans throughout the abnormalities: a comparison of methods. Am J Chin Pathol. 1986;85: 713-715 world. Humans become infected either by consump- tion of poorly cooked meat (cysts are destroyed by Kinney TR, Ware RE, Schultz WH, Filston HC. Long-term management of splenic sequestration in children with sickle cell disease. J Pediatr. 1990; boiling), or by accidental ingestion of sporulated oo- 117:194-199 cysts from cat feces, soil, or contaminated food. Leikin SL, Gallagher D, Kinney TR, Sloane D, Klug I’, Rida W. Mortality in Transmission by blood product contamination and children and adolescents with sickle cell disease: cooperative study of from infected organ donors (heart and bone marrow) sickle cell disease. Pediatrics. 1989;84:500-508 has been documented. Aside from transplacental in- Milner PF, Jones BR, Dobler J. Outcome of pregnancy in sickle cell anemia fection from mother to fetus, toxoplasmosis is not and sickle cell-hemoglobin C disease: an analysis of 181 pregnancies in 98 communicable from person to person. Significant an- patients and a review of the literature. Am J Obstet Gynecol. 1980;138: tibody titers have been detected in approximately 239-245 50% (United States) to 80% (France) of adults but National Institutes of Health. Consensus Development Conference Statement. varies considerably among people and animals in Newborn Screening for Sickle Cell Disease and Other Hemoglobinopathies. different geographic areas. Bethesda, MD: US Department of Health and Human Services, Public Health Service, National Institutes of Health, Office of Medical Applica- Pathgenesis. With the development of a normal tions of Research; 1987 immune response (humoral and cell mediated), in- Nussbaum RL, Powell C, Graham HL, Caskey CT, Fernbach DJ. Newborn fectious tachyzoites disappear from tissue. When a screening for sickling hemoglobinopathies. Houston, 1976 to 1980. Am J pregnant woman acquires the infection during ges- Dis Child. 1984;138:44-48 tation, the organism may be disseminated hematog- Pattison JR, Jones SE, Hodgson J, et al. Parvovirus infections and hypoplas- enously to the placenta. When this occurs, infection tic crises in sickle-cell anemia. Lancet. 1981;1:664-665 may be transmitted to the fetus transplacentally or Pearson HA. A neonatal program for sickle cell anemia. Adv Pediatr. 1986; during vaginal delivery. Approximately 50% of un- 33:381-400 treated women who acquire the infection during ges- Pearson HA. Sickle cell diseases: diagnosis and management in infancy and tation transmit the parasite to their fetuses. The inci- childhood. Pediatr Rev. 1987;9:121-130 dence of transmission is least in early gestation and Piomelli S, Seaman C, Ackerman K, Yu E, Blei F. Planning an exchange greatest in late gestation. The transmission rate is transfusion in patients with sickle cell syndromes. Am J Pediatr Hematol approximately 17% during the first trimester, and Oncol. 1990;12:268-276 disease in the infant is usually severe. If the infection Shapiro BS. The management of pain in sickle cell disease. Pediatr Cfin North is acquired by the mother in the third trimester and Am. 1989;36:1029-1045 is not treated, approximately 65% of fetuses are in- Sickle Cell Disease Guideline Panel. CIinicaZ Practice Guideline: Sickle Cell fected, and involvement may be mild or inapparent Disease: Screening,Diagnosis, Management, and Counseling in Newborns and at birth. Congenital infection also may be transmitted Infants. Rockville, MD: US Department of Health and Human Services, Public Health Service; 1993. Agency for Health Policy and Research by an asymptomatic immunosuppressed woman (eg, publication 93-0562 those treated with steroids and those with human

Downloaded from www.aappublications.org/news by guest on September 29, 2021 AMERICAN ACADEMY OF PEDIATRICS 493 immunodeficiency virus infection). These different Severity and Variability Without Screening rates of transmission are most likely related to pla- Mortality. Premature births, stillbirths, and neona- cental blood flow, the virulence and amount of T tal mortality have been observed; the incidence is ill go&ii acquired, and the immunologic ability of the defined. mother to restrict parasitemia. Developmental Disabilities. On the basis of 152 pa- Potential for Symptomatic Diagnosis. Extremely vari- tients with clinically apparent disease in the first year able. Data in the literature indicate that more than of life, the following data were found: 94% chori- half of congenitally infected infants are considered oretinitis, 50% convulsions, 50% intracranial calcifi- healthy in the perinatal period, but almost all have cations, and 28% hydrocephalus. At 4 years of age, ocular involvement later in life. The New England for 101 of these same patients: 85% mental retarda- Regional Toxoplasmosis Working Group reported tion, 80% convulsions, 60% neurologic impairment that only 2 (4%) of 52 confirmed congenital cases (spasticity and palsies), 50% impaired vision, 40% detected by newborn screening were identified by hydrocephalus or microcephalus, and 15% deafness. initial clinical examination in the newborn period. By age 20 years, 85% of patients had chorioretinitis, with severe visual impairment in about 50%. Symptoms in the newborn period range from rela- tively mild signs, such as prematurity, small size for Physical Findings. Additional physical findings in- gestational age, peripheral retinal scars, persistent clude hepatosplenomegaly, lymphadenopathy, jaun- jaundice, mild thrombocytopenia, and cerebrospinal dice, and thrombocytopenia. fluid pleocytosis, to the classic triad of chorioretinitis, Clinical Outcome With Screening and Treatment hydrocephalus, and cerebral calcifications. Neonatal Mortality. All deaths are not prevented. Prematu- neurologic findings such as convulsions and hydro- rity and stillbirths will not be prevented unless dis- cephalus may be associated with substantial cerebral easeis detected prenatally and maternal treatment is damage. initiated. Prenatal Testing and Counseling. In women with Clinical Disability. Severe intrauterine disease oc- normal immune systems, congenital toxoplasmosis curs in some infants, particularly those infected in generally does not recur. Fetal transmission essen- the first trimester. However, 50 of 52 infants (New tially only occurs with an acute infection in the preg- England Regional Toxoplasma Working Group) nant woman. The Sabin-Feldman dye test and the were asymptomatic at birth by clinical examination, immunglobulin G (IgG) immunofluorescent anti- although 19 (40%) of 48 infants had abnormalities of body (IFA) measure the same, primarily IgG, anti- the central nervous system or the retina, which were bodies, and the titers tend to be parallel. Such anti- found on more detailed initial examinations as the bodies appear 1 to 2 weeks after infection, reach high result of positive newborn screening results. After levels, generally more than 1:lOOO IU after 6 to 8 treatment, only 1 of 46 children had a neurologic weeks, and then decline over months to years. Low deficit. Thirty-nine children had follow-up ophthal- titers (1:4 to 1:64) usually persist for life. Approxi- mologic examinations from 1 to 6 years of age; 10% mately half of the commercially available IFA kits had eye lesions that may have developed postnatally tested have been found to be improperly standard- despite treatment. ized and may yield significant numbers of false- Variability. The outcome of neurologic and oph- positive and false-negative results. The IgM IFA is thalmologic sequelae following neonatal treatment useful for the diagnosis of acute infection, because requires further evaluation. IgM antibodies appear earlier (often by 5 days after PossibleInterventions. Treatment regimens include infection) and disappear sooner than IgG antibodies. combinations of pyrimethamine, sulfadiazine or tri- More sensitive tests for the determination of a recent ple sulfonamides, and spiramycin, with leucovorin infection in pregnant women include the double- prophylaxis for potential pyrimethamine toxicity. sandwich IgM enzyme-linked immunosorbent assay Treatment may be effective in interrupting acute dis- (ELISA). For newborns, the IgM-specific ELISA on ease that progresses to damage vital organs. The filter paper cards is the test used and detects approx- length of therapy and optimal therapy are under imately 75% of infants with congenital infection. investigation using several combination regimens. These tests are best performed in reference laborato- Screening Test Characteristics and Confirmation ries. Type of Test. IgM-specific ELISA using filter paper Pregnant women, particularly those who do not cards. have specific antibodies to T gondii before pregnancy, should be counseled to avoid eating meat that is not Timing. Timing is unimportant. cooked and contact with oocysts found in cat feces, Stability of Specimen. Not determined. kitty litter, and soil. Cats that are kept indoors and Confirmation. Screening test results are confirmed fed prepared diets rather than fresh uncooked meat by serologic testing of the mother and infant. Incon- should not contract encysted T go&ii and shed oo- clusive results may require tissue culture and peri- cysts. Serologic screening and treatment of newly toneal inoculation of mice with blood and/or spinal infected pregnant women during gestation can also fluid. reduce the incidence and perhaps the manifestations Accuracy of ScreeningTest of congenital toxoplasmosis. False-Negative Rate. Reported sensitivity is 75%.

494 NEWBORN SCREENINGDownloaded FACT from SHEETS www.aappublications.org/news by guest on September 29, 2021 False-Positive Rate. New England Regional New- tures range from mild retardation and linguistic de- born Screening Program confirmed 52 of 100 cases lays (neonatal form) to acute failure to thrive, vom- that were positive on initial screening. The true-pos- iting, diarrhea, hepatomegaly, and ensuing liver itive-false-positive ratio was 1:2. disease with death from liver failure in acute tyrosi- Ongoing Studies. The New England Regional Tox- nosis; chronic liver disease, renal tubular dysfunc- oplasma Working Group continues to evaluate the tion (Fanconi syndrome), and hypophosphatemic efficacy of screening modalities, optimal treatment rickets in chronic tyrosinosis; and characteristic cor- regimens, and long-term neurologic and ophthalmo- neal lesions and hyperkeratosis in Richner-Hanhart logic sequelae after neonatal identification and initi- syndrome. ation of treatment. Genetics Special Issues and Concerns Chromosomal Map Location. Fumarylacetoacetase About 45% to 50% of infants have central nervous hydroxylase (FAH): 15q23-q25 (type I tyrosinemia); system and ophthalmologic findings at birth by de- and tyrosine aminotransferase (TAT): 16q22-q24 tailed study, although only a small percentage (4% in (type II tyrosinemia). the New England Study) had obvious clinical mani- Incidence. CORN data from 1991 indicate 2 con- festations that would have led to more in-depth ex- firmed diagnoses in 94 000 screened newborns; no aminations. Improvement of the reported low sensi- confirmed cases were identified in 232 000 screened tivity rate and long-term outcomes with neonatal cases in the 1992 CORN report. Neonatal tyrosinemia treatment is in progress. Early studies suggest a sig- has the highest prevalence in premature infants: 1 in nificant reduction in neurologic and ophthalmologic 250 infants weighing less than 2500 g and 1 in 500 deficits; data are needed concerning cognitive devel- infants weighing more than 2500 g (Belgian newborn opment. Serologic testing is not uniform in many screening program). The highest incidence is in Ca- commercial laboratories. nadian Inuits who do not breastfeed their infants (1 Professional and Public Education in 16). Tyrosinosis (type I tyrosinemia) has an inci- Awareness is generally limited. Screening of preg- dence of 1 in 120 000 in Sweden and 1 in 100 000 in nant women is controversial and not routinely per- Norway. The highest prevalence is in the French- formed. Canadian population of Quebec, with an overall in- cidence of 1 in 12 500, 1 in 685 in the Lac-St Jean GENERAL REFERENCES region of Quebec. The incidence for Richner-Hanhart Couvreur J, Desmonts G, Tournier G, Szusterkac M. A homogeneous series syndrome (type II tyrosinemia) has not been estab- of 210 cases of congenital toxoplasmosis in 0- to ll-month-old infants lished. detected prospectively. Ann Pediatr Paris). 1984;31:815-819 Inheritance. Autosomal recessive. Sex ratio: male = Daffos F, Forestier F, Capella-Pavlovsky M, et al. Prenatal management of 746 pregnancies at risk for congenital toxoplasmosis. N Engl J Med. female. 1988;318:271-275 Racial and Ethnic Variability. Mostly white. The Guerina NG, Hsu H-W, Meissner HC, et al. Neonatal serologic screening neonatal form is most prevalent in Canadian Inuits. and early treatment for congenital Toxoplasma gondii infection. N Engl Tyrosinosis is most prevalent in the French-Cana- J Med. 1994;330:1858-1863 dian population in Canada and Northern Europe Koppe JG, Loewer-Sieger DH, de Roever-Bonnet H. Results of 20-year (Scandinavia). Cases of Richner-Hanhart syndrome follow-up of congenital toxoplasmosis. Lancet. 1986;1:254-256 have been described in several countries including McCabe R, Remington JS. Toxoplasmosis: the time has come. N Engl J Med. the United States, Canada, Italy, countries of north- 1988;318:313-315 ern Europe, Turkey, United Arab Emirates, and Ja- Remington JS, Desmonts G. Toxoplasmosis. In: Remington JS, Klein JO, eds. pan. Infectious Diseases of the Fetus and Newborn Infant. 3rd ed. Philadelphia: WB Molecular Pathology. Neonatal tyrosinemia and in- Saunders Co; 1990:89-195 creased excretion of tyrosine and its metabolites are Sever JL, Ellenberg JH, Ley AC, et al. Toxoplasmosis: maternal and pediatric not uncommon, particularly in preterm infants. De- findings in 23 000 pregnancies. Pediatrics. 1988;82:181-192 creases in incidence have been noted with a diet of Weiblen BJ, Grady GF, Hoff R. Screening for toxoplasmosis in newborns. In: human and low-protein milk (“humanized” cow Therrell BL, ed. Laboratory Methods for Neonatal Screening. Washington, DC: American Public Health Association; 1993:191-202 milk). It is generally assumed that this disorder is caused by a relative deficiency of p-hydroxyphe- TYROSINEMIA nylpyruvate, stressed by high-protein diets with re- State Newborn Screening Availability sulting high tyrosine and phenylalanine levels. Oth- Currently part of the routine newborn screening ers have suggested a mild defect in TAT activity. program in two states; five other states with pro- Most cases of type I tyrosinemia (tyrosinosis) are grams reported in the 1992 CORN data report are caused by a deficiency of FAH. This disorder, al- considering discontinuing (or have discontinued) the though not a primary disorder of tyrosine metabo- program. lism, is accompanied by elevated levels of tyrosine and its metabolites, which inhibit many transport Brief Clinical Description functions and enzymatic activities. It has been pro- Neonatal tyrosinemia, type I tyrosinemia (tyrosi- posed that the degree of residual FAH activity de- nosis), and type II tyrosinemia (Richner-Hanhart termines whether the disease will be acute or chronic syndrome) all show elevated levels of tyrosine and in the affected patient; patients with the acute form can be detected by newborn screening. Clinical fea- show no immunologically cross-reactive protein in

Downloaded from www.aappublications.org/news by guest on September 29, 2021 AMERICAN ACADEMY OF PEDIATRICS 495 the liver, whereas those with the chronic form have rosine is the only amino acid that has increased levels variable amounts of enzyme activity. Highest levels in the urine. of FAH are found in liver cells but are also present in Genotype-Phenotype Correlation , Remains unclear. chorionic villi, amniocytes, fibroblasts, lymphocytes, The specific defect in neonatal tyrosinemia still needs and erythrocytes. to be determined. The acute form of type I tyrosine- Type II tyrosinemia (Richner-Hanhart syndrome) mia is associated with absent FAH activity; the is associated with a deficiency of hepatic TAT, the chronic form usually shows present but decreased rate-limiting enzyme of tyrosine catabolism. Ty- enzyme activity. Both acute and chronic forms of the rosinemia, tyrosinuria, and increases in urinary phe- disease may occur within the same family. Although nolic acids, N-acetyltyrosine, and tyramine persist the gene for hepatic TAT has been localized, and the for life. The metabolism of other amino acids and hepatic enzyme activity has been assayed in several renal and hepatic function are otherwise normal. patients, no correlation has been established. PotentiaE for Symptomatic Diagnosis. Extremely dif- Genetic Counseling. The inheritance of neonatal ty- ficult unless there is a high index of suspicion result- rosinemia is unclear. Type I and II tyrosinemias are ing in the detection of increased levels of tyrosine in autosomal recessive, with a 25% risk for siblings, The plasma or urine by quantitative amino acid analysis. heterozygotes for type I have approximately half- Clinical findings in neonatal tyrosinemia are nonspe- normal levels of FAH activity in fibroblasts and lym- cific. Infants with persistent neonatal tyrosinemia phocytes. Prenatal diagnosis requires at least three may be somewhat lethargic and have difficulty swal- different procedures using amniotic fluid and cul- lowing, impaired motor activity, prolonged jaundice, tured amniocytes or chorionic villus cells. These pro- and increased levels of galactose, phenylalanine, his- cedures involve the direct measurement of succiny- tidine, and cholesterol. Mild acidosis may be present lacetone by combined gas chromatography and mass in about half of the infants. Mild retardation and spectrometry in amniotic fluid and FAH enzymatic decreased psycholinguistic abilities have been noted activity and the ability of succinylacetone to inhibit in some studies. aminolevulinic dehydratase activity in cultured am- Type I tyrosinemia in the acute form is character- niotic fluid or chorionic villus cells. The carrier state ized by failure to thrive, vomiting, diarrhea, a cab- for type II tyrosinemia has not been detected bio- bage-like odor, hepatomegaly, fever, jaundice, chemically, and prenatal diagnosis is not currently edema, melena, and progressive liver disease. If un- available. treated, death from liver failure may occur in the first year of life. The chronic form is similar but with Severity and Variability Without Screening milder features characterized by chronic liver disease Mortality. Death from complicating liver failure and renal tubular dysfunction (Fanconi syndrome) occurs in untreated patients during the first year of with hypophosphatemic rickets. Other features have life in the acute form and during the first decade of included hypertrophic obstructive cardiomyopathy, life in the chronic form of type I tyrosinemia. abdominal crises, polyneuropathy, hypertension, Developmental Disabilities. Mild developmental and and hepatoma (a late complication in one third of language delays have been noted in all forms of patients). Death occurs during the first decade of life. tyrosinemia but are quite variable. Mental retarda- Increased levels of tyrosine are present in blood and tion is an inconstant feature. urine. Urinary tests for succinylacetone and tissue Physical Findings. Hepatomegaly is an inconstant analysis for FAH establish the diagnosis. feature of neonatal tyrosinemia, present in type I Type II tyrosinemia is a distinctive oculocutaneous disorders with associated jaundice and abnormal syndrome. Eye findings may be limited to lacrima- liver function and absent in type II disorders. Type II tion, photophobia, and redness. Signs may include tyrosinemia has characteristic ocular and cutaneous mild cornea1 herpetiform erosions, dendritic ulcers, findings that are not present in the neonatal period and, rarely, cornea1 and conjunctival plaques. Neo- but generally become apparent in infancy or early vascularization may be prominent. Long-term effects childhood. include cornea1 scarring, nystagmus, and glaucoma. The skin lesions usually begin with or after the eye Clinical Outcome With Screening and Treatment lesions. Skin findings may begin as painful, nonpru- Mortality. Insufficient data are available to evalu- ritic blisters or erosions that crust and become hy- ate the effects of early treatment in patients detected perkeratotic and are usually limited to the palms and by newborn screening. A decrease in early mortality soles, especially the tips of the digits, and to the from progressive liver failure has been noted in type thenar and hypothenar eminences. They may be lin- I tyrosinemia with diets low in tyrosine, phenylala- ear or subungual. A skin biopsy is not diagnostic and nine, and methionine. Long-term outcomes are less may show nonspecific hyperkeratosis, acanthosis, optimistic. and parakeratosis. The skin lesions may be difficult Clinical Disability. Most cases of neonatal tyrosine- to distinguish from any of the more common forms mia, especially those seen in small preterm infants, of keratosis. Mental retardation is an inconstant fea- may be transient and controlled by reducing the ture; mild to moderate retardation, self-mutilating protein intake to 2 to 3 g/kg per day or by breast- behavior, disturbances of fine-motor coordination, feeding. Occasional patients respond to ascorbic acid and language deficits have been reported. Tyrosine- supplementation. Palliation in type I disease has re- mia is the diagnostic feature of this disorder. Ty- lied on a diet low in tyrosine, phenylalanine, and

Downloaded from www.aappublications.org/news by guest on September 29, 2021 496 NEWBORN SCREENING FACT SHEETS methionine. Liver transplantation has been per- this group) should be of benefit. Other modes of formed in an effort to prevent hepatoma but is not therapy seem to be required to offset the other met- effective in treating all the metabolic abnormalities. abolic abnormalities seen in this disorder. Elevated levels of succinylacetone persist. Therapy with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclo- Special Concerns and Issues hexanedione decreases succinylacetone production The confirmation of the exact cause of elevated and has shown promise if started early in the course tyrosine levels requires referral and evaluation by an of the disease. Therapy with a diet low in tyrosine expert in the field. Outcome with treatment remains and phenylalanine is curative in type II tyrosinemia. variable. Variability. Early diagnosis should lead to the ini- tiation of dietary restriction, but long-term outcome Professional and Public Education in type I remains uncertain. An elevated newborn Physician and public awareness of these relatively screening test result for tyrosine requires confirma- uncommon disorders, outside the French-Canadian tion and additional testing, because it may be caused experience, is minimal. Educational efforts are re- by other metabolic disorders (eg, fructose and galac- quired. tose enzyme deficiencies), giant cell hepatitis, neona- GENERAL REFERENCES tal hemochromatosis, and neonatal infections. Bergeron P, Laberge C, Grenier A. Hereditary tyrosinemia in the province Possible Interventions. Dietary restriction has been of Quebec: prevalence at birth and geographic distribution. CIiri Genet. the mainstay of therapy. Liver transplantation has 1974;5:157-162 been beneficial in type I disease. Other forms of Fois A, Borgogni P, Cioni M, et al. Presentation of the data of the Italian therapy to reduce levels of succinylacetone are under registry for oculocutaneous tyrosinaemia. Jlnherif Mefab Dis. 1986;9(suppl investigation. Patient follow-up requires maintaining 2):262-264 adequate protein to support growth and repeated Halvorsen S. Screening for disorders of tyrosine metabolism. In: Bickel H, measurements of blood tyrosine, methionine, cy-feto- Guthrie R, Hammersen G, eds. Neonatal Screening for Newborn Errors of protein, and blood and urine succinylacetone. Metabolism. New York, NY: Springer-Verlag; 1980:45-57 Holme E, Lindblad B, Lindstedt S. Possibilities for treatment and for early Screening Test Characteristics and Confirmation prenatal diagnosis of hereditary tyrosinemia. Lnncef. 1985;1:527-529 Hostetter MK, Levy HL, Winter HS, Knight GH, Haddow JE. Evidence for Type of Test. BIA of tyrosine on dried blood spots. liver disease preceding amino acid abnormalities in hereditary tyrosine- Abnormal levels are reported as greater than 6 mg/ mia. N Engl J Med. 1983;308:1265-1267 dL; Georgia uses a level of greater than 12 mg/dL. Kvittingen EA. Hereditary tyrosinemia type I: an overview. Stand 1 Clin Lab Timing. Neonatal period, but the optimal time for Invest. 1986;184:27-34 study is unclear. Presumably, it is best if measure- Kvittingen EA, Steinmann 8, Gitzelmann R, et al. Prenatal diagnosis of ments are obtained 48 to 72 hours after milk feeding. hereditary tyrosinemia by determination of fumarylacetoacetase in cul- Stability of Specimen. Has not been determined spe- tured amniotic fluid cells. Pediafr Res. 1985;19:334-337 cifically for tyrosine but should be similar to that of Mitchell GA, Lambert M, Tanguay RM. Hypertyrosinemia. In: Striver CR, phenylalanine. Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Basis of fnherifed Disease. 7th ed. New York, NY: McGraw Hill; 1995:1077-1107 Confirmation. The optimal approach is complex Striver CR, Perry T, Lasley L, Glow CL, Coulter D, Laberge C. Neonatal and requires amino acid quantitation of blood and tyrosinemia (NT) in the Eskimo: result of a protein polymorphism? urine for tyrosine as well as other amino acids and Pcdinfr Res. 1977;11:411 metabolites. Confirmation of neonatal tyrosinemia Tuchman M, Frees DK, Sharp HL, Ramnaraine ML, Ascher N, Bloomer JR. depends on the presence of elevated levels of ty- Contribution of extrahepatic tissues to biochemical abnormalities in he- rosine and phenylalanine; type I tyrosinemia has reditary tyrosinemia type I: study of three patients after liver transplan- elevated levels of urine succinylacetone and nonspe- tation. J Pediafr. 1987;110:399-403 cific aminoaciduria and requires tissue analysis (fi- ADDITIONAL NEWBORN SCREENING broblasts, erythrocytes, lymphocytes, or liver) for FAH activity; type II tyrosinemia shows elevation of INFORMATION tyrosine only in blood and urine. The following disorders are not currently part of state newborn screening programs. Several commer- Accuracy of ScreeningTest cial newborn screening programs test for a battery of False-Negative Rate. Undetermined. other metabolic disorders using dried blood filter False-Positive Rate. CORN data from 1991 showed paper blots. Some university-based laboratories and an initial positive screening test in 288 of 94 000 commercial laboratories are able to test blood and newborns tested (1 in 330) with 2 positive confirmed urine specimens for specific metabolic disorders as cases. The true-positive to false-positive ratio is well. Consideration for newborn screening for met- 1:144. Available data on second screens performed abolic disorders may include a previously affected between 1 and 4 weeks of age showed 85 positive child, a positive family history, the history of a pre- tests in 155 365 infants (1 in 1828); no cases of ty- vious infant who died in early infancy with a sus- rosinemia were confirmed among this group. pected metabolic disorder, or parental consanguinity Ongoing Studies. The incidence and pathogenetic (ie, first-cousin marriages), particularly in at-risk eth- mechanisms of specific disorders associated with el- nic populations. evated levels of tyrosine require clarification. The Newborn screening for adenosine deaminase consequences of early diagnosis and treatment for (ADA) deficiency, arginase deficiency (AD), urea cy- type I tyrosinemia (the most formidable disorder in cle defects, Duchenne muscular dystrophy (DMD),

Downloaded from www.aappublications.org/news by guest on September 29, 2021 AMERICAN ACADEMY OF PEDIATRICS 497 glucosed-phosphate dehydrogenase (G-6-I’D) defi- incidence of ASD of 1 in 73 000; ALD, 1 in 250 000; ciency, pyroglutamic aciduria, medium-chain acyl- and AD, 1 in 225 000. In contrast to ASD and ALD, CoA dehydrogenase deficiency (MCAD), and other AD is not usually associated with symptomatic neo- organic acidemias are available through a few com- natal hyperammonemia but results in progressive mercial laboratories. Neuroblastoma has also been spastic tetraplegia (with the lower limbs more se- suggested as a target for universal screening on verely affected than the upper limbs), seizures, psy- young infants 3 to 6 months of age. chomotor retardation, hyperactivity, and growth failure. Patients with AD would more likely benefit ADA Deficiency; Autosomal Recessive Severe from early detection and treatment with restriction of Combined Immunodeficiency Disease dietary protein intake; the true incidence of this rare Autosomal recessive deficiency of ADA causes ab- disease is unknown. Two other disorders of the urea normalities in purine nucleoside metabolism that are cycle, carbamylphosphate synthetase deficiency and selectively toxic to lymphocytes. Most patients with ornithine transcarbamylase deficiency, result in mas- ADA deficiency are severely lymphopenic and lack sive neonatal hyperammonemia in most affected pa- both cell-mediated (T-cell) and humoral (B-cell) im- tients. Mild and later-onset forms of these disorders munity, resulting in severe combined immunodefi- are also known. Patients with these deficiencies have ciency disease. Untreated children with ADA usually reduced plasma levels of citrulline. A newborn filter die before 2 years of age of overwhelming and op- paper spot test that measures arginase activity by a portunistic infections. Accumulation of toxic metab- fluorescent assay and citrulline by tandem mass olites can disturb neurologic function. The actual spectrometry is being piloted commercially. Confir- prevalence of this condition has not been deter- mation is by quantitative measurement of arginase mined, but estimates of frequency are about 1 in activity and plasma amino acid profiles. The useful- 225 000. Enzymatic activity of ADA can be measured ness of neonatal screening testing for these disorders from dried blood filter paper blots. Bone marrow seems promising for AD and the mild and later-onset transplantation, erythrocyte replacement therapy, forms of the other disorders, but detection of the enzyme replacement with polyethylene glycol-ADA, severe forms remains difficult. and, more recently, recombinant gene transfer have been effective in improving immune function and Duchenne Muscular Dystrophy correcting the biochemical abnormalities. This disor- DMD is the most common childhood form of mus- der also has been the first condition successfully cular dystrophy resulting in a progressive deteriora- treated with recombinant gene therapy. Incorpora- tion of muscles beginning in infancy and leading to tion of screening for this disorder in a pilot program death in the second or third decade of life. It is may help provide data concerning prevalence and inherited as an X-linked trait, and with few excep- the cost-benefit ratio of screening for rare but poten- tions only boys are affected. The Duchenne-Becker tially treatable disorders. gene is now known to be one of the largest human genes characterized thus far and has been mapped to AD and Other Urea Cycle Defects the short arm of the X chromosome (Xp21). This gene As a group, the disorders of the urea cycle are encodes a protein, dystrophin, the properties and estimated to have an incidence of at least 1 in 60 000. distribution of which suggest a key role in maintain- Most affected patients with urea cycle disorders be- ing the integrity of myofibrillar structure and func- come severely ill with neonatal hyperammonemic tion. A wide variety of mutational defects with par- coma, which usually occurs before the results of tial or complete gene deletions has been noted in the neonatal screening are available. However, milder majority of patients. Distribution is worldwide, with forms of the disorders exist that have less severe and an incidence of 1 in 3000 to 1 in 5000 male live births later onset of symptoms and may benefit from early for DMD and 1 in 18 500 male live births for Becker detection and treatment through newborn screening. muscular dystrophy (BMD). There is no medical The Guthrie blood test using appropriate Bacillus treatment for DMD, which has a progression rate subtilis auxotrophs has been proposed for neonatal that is variable, although early death in the second or screening for argininosuccinic acid synthetase defi- third decade of life is the rule. An allelic form of ciency (ASD), argininosuccinic acid lyase deficiency BMD is a similar but more slowly progressive disor- (ALD), and AD. These disorders are associated with der with longer survival. Patients with DMD and marked accumulation of citrulline, argininosuccinic BMD may be at risk for malignant hyperthermia. acid, and arginine, respectively. Moderate increases Newborn screening using dried blood filter paper in citrulline levels are also noted in ALD and AD. blots is available through a voluntary commercial Because many patients with ASD and ALD have laboratory (Supplemental Newborn Screening Pro- severe forms of the disorder, and neonatal hyperam- gram in Pennsylvania) that also includes a Muscular monemic coma will develop, screening may not be of Dystrophy Association pilot screening program in benefit for therapeutic purposes in these cases. How- Puerto Rico and hospitals in New York and Texas. ever, patients with milder and later-onset disease The voluntary program in Germany tests infants be- may benefit from early detection and treatment with tween 4 weeks and 1 year of age. Pilot programs in restricted protein intake, supplemental arginine, and, France (Lyon), Belgium (Antwerp), Canada (Mani- in cases of ASD, drugs that use alternative means for toba), and the United Kingdom (Wales) also test excess nitrogen excretion. Previous urine screening newborns. Testing involves the determination of cre- programs in Massachusetts and Quebec found an atine kinase (CK) by fluorescent spot assays. Normal

Downloaded from www.aappublications.org/news by guest on September 29, 2021 498 NEWBORN SCREENING FACT SHEETS specimens exhibit no fluorescence, whereas speci- erythrocytes in high concentrations. GSH plays an mens with CK levels greater than 500 U/L exhibit important role in erythrocyte metabolism and in the fluorescence. Confirmation requires CK activity in transport of amino acids across membranes. It also serum with an isoenzyme pattern. The dystrophin serves as a reductant of toxic peroxidases protecting status of muscle biopsy specimens by immunoblot hemoglobin and other protein sulfhydryl groups and immunofluorescent assays helps confirm disease against the destructive effect of oxidation. Deficient in patients without identifiable DNA mutations and levels of GSH have been reported in patients with distinguishes the more severe DMD from the milder pyroglutamic aciduria due to glutathione synthetase BMD when DNA mutation analysis is not informa- deficiency. Symptoms characteristic of these disor- tive. An initial CK elevation was noted in 3 of 1000 ders include recurrent episodes of vomiting, diar- screened newborns, with 4.5% having a persistent rhea, and abdominal pain and, if untreated, may elevation on another specimen with a CK-MM or result in congenital nonspherocytic hemolytic ane- CK-MB isoenzyme pattern giving a true-positive- mia, metabolic acidosis, progressive decline in psy- false-positive ratio of 1:17. The worldwide experi- chomotor skills with mild mental retardation, and ence with DMD and BMD based on 935 000 screened pyroglutamic aciduria. Prevalence is estimated at l male infants was summarized in the 1993 report of in 100 000. Inheritance is autosomal recessive. the European Neuromuscular Center Workshop. The Screening is based on a calorimetric assay of a blood recognizable benefit to patients, their families, and spot that measures the presence of GSH. Confirma- society in the absence of any currently available tion requires urine organic acid analysis by gas chro- treatment remains a hotly debated and controversial matography and mass spectrometry. Vitamin E ther- matter. Concerns regarding psychologic and intrafa- apy may be beneficial. The exact prevalence, milial distress with presymptomatic diagnosis (some therapeutic modalities, and long-term outcomes re- 40% of cases occur in families with no previously main uncertain. affected individuals) have been raised. Conversely, the availability of early diagnosis may enable fami- Medium-Chain Acyl-CoA Dehydrogenase Deficiency lies to make practical decisions about the life of a MCAD is an autosomal recessive condition result- child with special needs and to avoid prolonged ing in a defect of fatty acid p oxidation usually “diagnostic odysseys.” Genetic counseling and test- triggered by fasting or infection. The clinical presen- ing of identified families and at-risk family members tation is subtle and variable and can present simi- may be of benefit for some families. larly to other defects of fatty acid oxidation with symptoms of acute encephalopathy and hepatomeg- Glucosed-Phosphate Dehydrogenase (GGPD) aly that mimic Reye’s syndrome. Episodes character- Deficiency ized by nonketotic hypoglycemia can be so rapid and GGPD deficiency results in a defect in the pentose fulminant that the infant seems to have an apparent phosphate pathway that normally helps protect he- life-threatening event or sudden infant death syn- moglobin from oxidant hemolysis. The prevalence drome. Approximately 30% of patients with MCAD and gene frequency is 1 in 10 African-Americans, 1 in die during the first clinical episode; it has been re- 10 Mediterranean families (Italian, Greek, and Mid- ported to account for 2% to 3% of all deaths attrib- dle Eastern), and 1 in 50 southeast Asians. Clinical uted to sudden infant death syndrome. Prevalence disorders associated with the more severe Mediter- has been reported as between 1 in 10 000 and 1 in ranean and Asian forms of the deficiency include 25 000 in the United Kingdom. The common mis- neonatal hyperbilirubinemia, chronic congenital sense mutation A985G accounts for more than 85% of nonspherocytic hemolytic anemia, and drug- or vi- the mutations and can be detected in the newborn by ral-induced hemolytic anemia. In the African-Amer- DNA analysis on Guthrie cards. The overall homozy- ican form, acute hemolytic anemia may occur with gous prevalence of the common mutation was noted infection and certain oxidant drugs; the clinical pic- to be 1 in 6400 in white populations. Heterozygote ture is less severe, because there is some activity of frequencies were noted to be 1 in 40 in Birmingham, the GGPD enzyme. It is inherited as an X-linked United Kingdom, 1 in 71 in Melbourne, Australia, recessive trait. Treatment requires avoidance of oxi- and 1 in 107 in Houston, TX. MCAD has not been dant drugs such as antimalarials, sulfonamides, ni- detected in Japanese families. The prevalence in trofurans, and naphthalene. Fava beans provoke he- more heterogenous populations in the United States molysis in Mediterranean families. Patients should is not known, but in Pennsylvania the incidence from avoid the use of aspirin. The screening method is newborn screening was 1 in 6900. The cost and fea- based on a fluorescent spot test that measures the sibility for the use of newborn blood spots for DNA activity of the GGPD enzyme. Extensive screening is analysis (for this and other genetic disorders) in a being performed in Greece and southeast Asia. Con- universal newborn screening program remain un- firmation requires quantitative measurement of se- clear. Tandem mass spectrometry to measure oc- rum G6PD activity and GGPD electrophoresis for tanoylcarnitine on the filter paper blood spot (nor- specific isoenzyme typing. mally not present) is the initial screening modality, with a urine organic acid profile and DNA mutation Pyroglutamic Aciduria (Oxoprolinuria or Glutathione analysis available for confirmation. Treatment in- Synthetase Deficiency) cludes avoidance of fasting, reduction of dietary fat, The reduced form of glutathione (GSH), an inter- and carnitine supplementation. Because this disorder mediary in the y-glutamyl cycle, is normally found in is relatively common and represents a potentially

Downloaded from www.aappublications.org/news by guest on September 29, 2021 AMERICAN ACADEMY OF PEDIATRICS 499 recognizable cause for acute life-threatening events Neuroblastoma. Pilot projects for screening for neu- in infants, pilot programs will be helpful in provid- roblastoma are currently underway in Quebec, Japan ing important information about the natural history (Sapporo, Kyoto, and currently as a nationwide pro- of this disorder and the feasibility of incorporation in gram) and the northern region of England (New- a newborn screening program. castle-on-Tyne, United Kingdom). Some sporadic screening programs are being carried out in the Organic Acidemias United States (Baltimore, MD, Houston, TX, and Minnesota). Screening has been performed using Methylmalonic Acidemias. A group of defects asso- urine-saturated filter paper at 3 weeks and 6 months ciated with a primary enzyme deficiency in the breakdown of organic acids or a number of defects in of age (Quebec) and 6 months of age (Japan and vitamin B,, transport or activation of organic acids. United Kingdom) for the quantitative analysis of the catecholamine metabolites vanillylmandelic acid and Neonatal presentation occurs with early onset dis- homovanillic acid using a urine organic acid profile ease of metabolic acidosis; milder forms with onset or HPLC. The prevalence rates of neuroblastoma in infancy are associated with mild to severe acido- were approximately 1 in 17 500 (Quebec), 1 in 10 800 sis, neurologic symptoms, and failure to thrive. Com- (Tapan), and 1 in 10 400 (United Kingdom). The sur- bined frequency: 1 in 50 000. Treatment involves di- etary protein restriction, special dietary formulas, vival rate of the large Japanese cohort detected at 6 and/or hydroxycobalamin supplementation. months of age was 97% (348 of 357 cases). Feasibility, cost effectiveness, technical problems in the labora- Pvopionic Acidemia. Deficiency of the enzyme pro- tory screening procedure, natural biological proper- pionyl-CoA carboxylase that leads to a defect in the ties of the tumor itself, and acceptability and out- breakdown of organic acids. Presentation occurs come of screening programs remain to be resolved. within the first days of life, with poor feeding, vom- iting, seizures, metabolic acidosis, and coma. Occa- GENERAL REFERENCES sionally, later onset occurs with ketoacidosis and Dellamonica C, Collombel C, Cotte J, Addis P. Screening for neonatal developmental retardation, Autosomal recessive. Duchenne muscular dystrophy by bioluminescence measurement of cre- Frequency: 1 in 50 000. Treatment involves dialysis, atine kinase in a blood sample spotted on paper. Clin Chem. 1983;29: protein restriction, special dietary formulas, and car- 161-163 nitine and biotin supplementation. Greenberg CR, Jacobs HK, Halliday W, Wrogemann K. Three years’ expe- Isovaleric Acidemia. Autosomal recessive defect in rience with neonatal screening for Duchenne/Becker muscular the breakdown of organic acids caused by a defi- dystrophy: gene analysis, gene expression and phenotype production. Am 1 Med Genet. 1991;39:68 ciency of isovaleryl-CoA dehydrogenase. This disor- der may present in the newborn period as an acute Hildes E, Jacobs HK, Cameron A, et al. Impact of genetic counselling after neonatal screening for Duchenne muscular dystrophy. 1 Med Genet. 1993; episode of metabolic acidosis with vomiting and 30:670-674 coma (characteristic urine odor of sweaty socks) or as Koenig M, Beggs AH, Moyer M, et al. The molecular basis for Duchenne a chronic intermittent form with recurrent episodes versus Becker muscular dystrophy: correlation of severity with type of of acidosis. Infants who survive the acute newborn deletion. Am J Hum Genet. 1989;45:498-506 form later exhibit the chronic form. Frequency 1 in Matsubara Y, Narisawa T, Tada K, et al. Prevalence of K329E mutation in 50 000. Treatment with moderate protein restriction, medium-chain acyl-CoA dehydrogenase gene determined from Guthrie special dietary formulas, and carnitine and/or gly- cards. Lancet. 1991238552-553 tine supplementation generally results in normal de- Naylor EW, Hoffman El’, l’aulus-Thomas J, et al. Neonatal screening for velopment. Duchenne/Becker muscular dystrophy: reconsiderations based on mo- Glutaric Acidemia Type 1. Another autosomal reces- lecular diagnosis and potential therapy. Screening. 1992;1:99-113 sive defect in the breakdown of organic acids pre- Seminar on screening for neuroblastoma. Am J Pediatr Hematol Oncol. 1992; senting within the first years of life with impaired 14312-341 movement and muscle tone dystonia and macro- Striver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular cephaly. After the initial onset, the neurologic course Bases of Inherited Disease. 7th ed. New York, NY: McGraw-Hill; 1995 is gradually progressive, with periodic episodes of Van Ommen GJ, Scheuerbrandt G. Neonatal screening for muscular acidosis, vomiting, seizures, and coma. The highest dystrophy: consensus recommendation of the 14th Workshop sponsored by the European Neuromuscular Center. Neuromusc Disord. 1993;3: frequency is noted among the Amish population in 231-239 Lancaster County, PA; the general frequency is esti- mated at 1 in 30 000. Protein restriction, special di- COMMITTEE ON GENETICS, 1995 TO 1996 etary formulas, and riboflavin and carnitine supple- Franklin Desposito,MD, Chairperson mentation may be beneficial. Sechin Cho, MD The above organic acidemias can be screened on Jaime L. Frias, MD Jack Sherman, MD filter paper blood spots for various carnitine esters RebeccaS. Wappner, MD (eg, propionyl carnitine and isovaleryl carnitine) us- Miriam G. Wilson, MD ing tandem mass spectrometry. These compounds LIAISON REPRESENTATIVES would normally not be present. Confirmation re- Felix de la Cruz, MD quires urine organic acid profiles and specific quan- National Institutes of Health titative enzyme assays. The value of screening for JamesW. Hanson, MD rare metabolic disorders remains unclear, particu- American College of Medical Genetics larly when many forms of these disorders present Jane Lin-Fu, MD clinically in the first few days of life. Health Resourcesand ServicesAdministration

Downloaded from www.aappublications.org/news by guest on September 29, 2021 500 NEWBORN SCREENING FACT SHEETS Paul G. McDonough, MD ACKNOWLEDGMENTS American College of Obstetricians and The committee would like to express deep appreciation to the Gynecologists following consultants for their detailed review, critique, and valuable Godfrey Oakley, MD input in the development of the newborn screening fact sheets: F. Centers for Disease Control and Prevention John Meaney, PhD, Arizona Department of Health Services, Phoenix, AZ; Edwin W. Naylor, PhD, Magee Women’sHospital, Pittsburgh, AAP SECTION LIAISON PA; Kenneth Pass, PhD, State of New York, Department of Health, Beth A. Pletcher, MD Albany, NY; Brad L. Therrell, PhD, President, International Society Section on Genetics and Birth Defects for Neonatal Screening, Texas State Department of Health, Austin, TX; and Barry Wolf, MD, PhD, Department of Human Genetics, CONSULTANT Medical College of Virginia, Richmond, VA. Special thanks are given Margretta R. Seashore,MD to Starlene Femandez, Department of Pediatrics, University of Med- Immediate Past Chairperson, Committee on icine and Dentistry of New Jersey-New Jersey Medical School, for Genetics her expert secretarial assistance.

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