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PEDIATRICS Vol. 118 No. 3 September 2006, pp. e934-e963 (doi:10.1542/peds.2006-1783)
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TECHNICAL REPORT |
ABSTRACT
Newborn screening fact sheets were last revised in 1996 by the American Academy of Pediatrics Committee on Genetics. This revision was prompted by advances in the field since 1996, including technologic innovations, as well as greater appreciation of ethical issues such as those surrounding informed consent. The following disorders are discussed in this revision of the newborn screening fact sheets: biotinidase deficiency, congenital adrenal hyperplasia, congenital hearing loss, congenital hypothyroidism, cystic fibrosis, galactosemia, homocystinuria, maple syrup urine disease, medium-chain acyl-coenzyme A dehydrogenase deficiency, phenylketonuria, sickle cell disease and other hemoglobinopathies, and tyrosinemia. A series of topics related to newborn screening is discussed in a companion publication to this electronic publication of the fact sheets (available at: www.pediatrics.org/cgi/content/full/118/3/1304). These topics are newborn screening as a public health system; factors contributing to the need for review of the newborn screening system; informed consent; tandem mass spectrometry; DNA analysis in newborn screening; status of newborn screening in the United States; and the effect of sample timing, preterm birth, diet, transfusion, and total parenteral nutrition on newborn screening results.
Key Words: newborn screening • screening • genetic disorder • biotinidase deficiency • congenital adrenal hyperplasia • congenital hearing loss • congenital hypothyroidism • cystic fibrosis • galactosemia • hemoglobinopathies • homocystinuria • maple syrup urine disease • medium-chain acyl-CoA dehydrogenase deficiency • phenylketonuria • sickle cell disease • tyrosinemia • tandem mass spectrometry
Abbreviations: OMIM, Online Mendelian Inheritance in Man • MS/MS, tandem mass spectrometry • CoA, coenzyme A • BTD, biotinidase gene • CAH, congenital adrenal hyperplasia • 21-OH, 21-hydroxylase • SW, salt wasting • SV, simple virilizing • AG, ambiguous genitalia • ACTH, adrenocorticotropic hormone • 17-OHP, 17-OH-progesterone • AABR, automated auditory brainstem response • OAE, otoacoustic emission • CH, congenital hypothyroidism • T4, thyroxine • HPT, hypothalamic-pituitary-thyroid • CF, cystic fibrosis • CFTR, cystic fibrosis transmembrane conductance regulator • IRT, immunoreactive trypsinogen • GALT, galactose 1-phosphate uridyltransferase • GALK, galactokinase • GALE, galactose-4'-epimerase • CBS, cystathionine ß-synthase • BIA, bacterial inhibition assay • MSUD, maple syrup urine disease • BCKD, branched-chain 
-keto acid dehydrogenase • BCAA, branched-chain amino acid • BCKA, branched-chain -keto acid • E3, dihydrolipoyl dehydrogenase • E1, thiamine pyrophosphate–dependent decarboxylase • E2, transacylase • MCAD, medium-chain acyl-coenzyme A dehydrogenase • FAO, fatty acid oxidation • SIDS, sudden infant death syndrome • ADHD, attention-deficit/hyperactivity disorder • PKU, phenylketonuria • PAH, phenylalanine hydroxylase • BH4, tetrahydrobiopterin • SCD, sickle cell disease • HPLC, high-performance liquid chromatography • Hb, hemoglobin • HbF, fetal hemoglobin • HbA, normal adult hemoglobin • FA, fetal and adult hemoglobin • MCV, mean corpuscular volume • FAH, fumarylacetoacetate hydrolase • TAT, tyrosine aminotransferase • NTBC, 2-(2-nitro-4-trifluoromethylbenzyl)-1,3-cyclohexanedione
Newborn screening fact sheets were last revised in 1996 by the American Academy of Pediatrics Committee on Genetics. This revision was prompted by advances in the field since 1996, including technologic innovations, as well as greater appreciation of ethical issues such as those surrounding informed consent. The following disorders are discussed in this revision of the newborn screening fact sheets: biotinidase deficiency, congenital adrenal hyperplasia (CAH), congenital hearing loss, congenital hypothyroidism (CH), cystic fibrosis (CF), galactosemia, homocystinuria, maple syrup urine disease (MSUD), medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency, phenylketonuria (PKU), sickle cell disease (SCD) and other hemoglobinopathies, and tyrosinemia. A series of topics related to newborn screening is discussed in a companion publication to this electronic publication of the fact sheets (available at: www.pediatrics.org/cgi/content/full/118/3/1304). These topics are newborn screening as a public health system; factors contributing to the need for review of the newborn screening system; informed consent; tandem mass spectrometry (MS/MS); DNA analysis in newborn screening; status of newborn screening in the United States; effect of sample timing, preterm birth, diet, transfusion, and total parenteral nutrition on newborn screening results.
BIOTINIDASE DEFICIENCY
Biotinidase deficiency (Online Mendelian Inheritance in Man [OMIM] database No. 253260)1 is a disorder of biotin recycling. Biotin is a water-soluble vitamin of the B complex that acts as a coenzyme in each of 4 carboxylases in humans (pyruvate carboxylase, propionyl-coenzyme A [CoA] carboxylase, ß-methylcrotonyl CoA carboxylase, and acetyl-CoA carboxylase).2 Missing a diagnosis of biotinidase deficiency, a condition that is easily treated with vitamin supplementation, can have severe consequences, including seizures, developmental delay, and sensorineural deafness.
Incidence
Neonatal screening for biotinidase deficiency has been instituted in many states (25 at the time of this publication) as well as many countries (approximately 25) since the biochemical basis was elucidated by Wolf et al3 in 1983. Of slightly more than 8.5 million newborn infants screened worldwide up to 1990, 142 affected infants have been identified, with 76 having profound (<10% activity) deficiency (approximate incidence 1 in 112000) and 66 having partial (10%–30% activity) deficiency (approximate incidence 1 in 129000).4 Most affected individuals who have been identified are of European descent; however, individuals of Turkish, Saudi Arabian, and Japanese descent have been described.5
Clinical Manifestations
Biotinidase deficiency can present with clinical symptoms as early as the first week of life up to 10 years of age. Most infants first exhibit clinical symptoms between 3 and 6 months of age.2 The most commonly affected systems are the central nervous system and skin. Affected children usually have myoclonic seizures, hypotonia, seborrheic or atopic dermatitis, partial or complete alopecia, and conjunctivitis.2 Other features may include developmental delay, sensorineural hearing loss, lethargy, ataxia, breathing problems, hepatosplenomegaly, and coma.6,7 Laboratory findings vary and can include ketolactic acidosis, organic aciduria, and mild hyperammonemia.2
Individuals with partial biotinidase deficiency can present with skin manifestations and no neurologic symptoms.8 Several children with profound deficiency have presented later in childhood or during adolescence with hemiparesis and eye findings (scotoma).9,10 With therapy, the eye problems resolved quickly, but the neurologic findings remained for a longer period of time.11 There are even reports of adults with profound biotinidase deficiency who have never had symptoms but were diagnosed because their children had positive results of newborn screening.2
Pathophysiology
Each of the 4 carboxylases in humans requires biotin as a cofactor. The carboxylases are first synthesized as inactive apoenzymes. After synthesis, biotin is added to the inactive proteins through 2 partial reactions, each of which is catalyzed by the enzyme holocarboxylase synthetase. Ultimately, each of these active, biotin-containing enzymes is degraded. The biotin-containing products of degradation are acted on by biotinidase to liberate biotin, which is recycled and enters the free-biotin pool. Biotinidase deficiency results in inability to recycle endogenous biotin and to release dietary protein-bound biotin. Thus, the brain may be unable to recycle biotin adequately. This may lead to dependence on the biotin that crosses the blood-brain barrier, resulting in decreased pyruvate carboxylase activity in the brain and accumulation of lactate. The neurologic symptoms may be secondary to accumulation of lactic acid in the brain.2
Inheritance
Biotinidase deficiency is inherited as an autosomal recessive trait. The biotinidase (BTD) gene has been mapped (chromosome 3p25), cloned, and characterized.12–14 Sixty-two mutations of the BTD gene have been described to date.14 Interestingly, when testing a US population, mutations occur at different frequencies in children with symptoms than in children who were only identified through newborn screening. Two mutations accounted for 52% of the mutations found in symptomatic patients, and 3 other mutations accounted for 52% of mutations in children identified through newborn screening. Partial BTD deficiency is predominantly caused by the 1330G
C mutation on one allele in combination with one of the mutations causing profound deficiency on the other allele.14
Benefits of Newborn Screening
Biotinidase deficiency has been identified as an appropriate disorder for newborn screening by numerous countries and states because of its prevalence, the potentially tragic outcome if not diagnosed, and availability of effective, low-cost treatment. Unfortunately, once symptoms have occurred, some of the findings are not reversible with therapy. This is particularly true in the case of the neurologic findings. For example, sensorineural hearing loss is common (detected in approximately 75% of symptomatic children with profound deficiency) and is usually irreversible.6
Screening
The best method of screening is a semiquantitative colorimetric assessment of biotinidase activity that can be performed on whole blood spotted on filter paper.2,15,16 Although the majority (>80%) of patients with biotinidase deficiency demonstrate organic aciduria when symptomatic, a significant percentage (20% in one study) may not; therefore, tandem mass spectrometry (MS/MS) testing should not be used for newborn screening of biotinidase deficiency.2
Follow-up and Diagnostic Testing
A positive screening result for biotinidase deficiency should be followed up with definitive testing for diagnosis. Quantitative measurement of enzyme activity should be performed on a fresh serum sample. Residual enzyme activity determines whether the patient has profound (<10% activity) or partial (10%–30% activity) biotinidase deficiency. Most patients with profound deficiency present early in life, whereas those with partial deficiency can present later or with a cutaneous phenotype and no neurologic findings.
Brief Overview of Disease Management
Children with profound biotinidase deficiency have been treated successfully with biotin. Pharmacologic doses of biotin (5–20 mg/day) were determined empirically.8,17 One patient required a dose of 30 mg/day to resolve dermatitis.18 For most patients, the currently prescribed dose is probably much more than is needed to overcome the deficiency. It should be stressed that the biotin must be in the free, not bound, form to be effective. There are no known adverse effects of the currently recommended dosage of 5 to 20 mg/day.19
Once therapy is instituted, cutaneous symptoms resolve quickly, as do seizures and ataxia. Some of the symptoms (as mentioned previously) are less reversible, including hearing loss and optic atrophy. Children who have developmental delay have been noted in some cases to achieve new milestones and regain lost milestones after beginning therapy.19 There are individuals reported who have profound biotinidase deficiency, have never been treated, and have never had any associated symptoms.11
Partial biotinidase deficiency can probably be treated with lower doses of biotin (1–5 mg/day) and/or only during times of metabolic stress.19 There are children with partial deficiency who have never had any related illness. In others with partial deficiency, it has been noted that mild intercurrent illnesses such as gastroenteritis can lead to development of typical clinical symptoms that resolve with biotin therapy.19
Current Controversies
As noted above, it is difficult to determine if individuals with partial biotinidase deficiency need daily therapy. When such individuals are identified in newborn screening programs, follow-up happens routinely and care is instituted. The negative psychological aspects of learning through newborn screening that an infant potentially has a genetic disorder and the parental anxiety generated should be weighed against the positive aspects, including that the treatment is simple and inexpensive and some individuals with partial deficiency would (at some point) have symptoms. Although this is mildly controversial, it is truly not of enough significance to negate the value of newborn screening for the disorder.
REFERENCES
Congenital adrenal hyperplasia (CAH) is a family of inherited disorders of the adrenal cortex that impair steroidogenic enzyme activity essential for cortisol biosynthesis.20,21 Newborn screening focuses exclusively on the most common 21-hydroxylase (21-OH) deficiency CAH (>90% of all CAH cases [OMIM database No. 201910]),22 which impairs production of cortisol and often aldosterone.20,21 Prompt diagnosis and treatment of CAH is essential to prevent potential mortality as well as physical and emotional morbidity.20–23
Incidence
Health organizations in 13 countries (including 36 US states) screen or will screen for CAH in their newborn screening programs. On the basis of newborn screening data, the incidence of CAH ranges from a low of 1 in 21270 (New Zealand) to a high of 1 in 5000 (Saudi Arabia) live births.24 The incidence is 1 in 15981 live births (Hispanic > American Indian > white > black > Asian) in North America, 1 in 14970 live births in Europe, and 1 in 19111 live births in Japan.25 An exceedingly high CAH incidence (1 in 282 live births) exists among Yupik Eskimos in western Alaska.26
Clinical Manifestation and Variability
The spectrum of disease in CAH ranges from the "classic, severe" salt-wasting (SW) form, to "classic, less severe" simple-virilizing (SV), to "mild, nonclassic" forms.20,21
Symptomatic Presentation and Morbidity
Neonates with the SW form exhibit adrenal crisis during the first through fourth weeks of life, peaking at approximately 3 weeks of age. This manifests as poor feeding, vomiting, loose stools or diarrhea, weak cry, failure to thrive, dehydration, and lethargy. These symptoms may not be evident until serum sodium concentrations are below 125 mEq/L. If untreated, circulatory collapse, shock, and death are inevitable. Permanent brain injury attributable to shock, lower cognitive scores, and learning disabilities are observed in some with the SW form.20 Affected females have ambiguous genitalia (AG) (but normal internal reproductive anatomy), prompting a clinical diagnosis in many. Affected males have no obvious physical signs of CAH. Therefore, without newborn screening and in the absence of a positive family history, all male and a minority of female neonates are undiagnosed until adrenal crisis. The SW form affects approximately 70% of patients with CAH that is diagnosed through newborn screening programs.25,26 If inadequately treated, postnatal virilization (girls), pseudo- or true-precocious puberty (boys), and premature growth acceleration (boys and girls) occur, leading to early growth cessation.20–23 Patients with the SV form do not manifest adrenal-insufficiency symptoms unless subjected to severe stress but exhibit virilization as in patients with SW.20,21 Males and some females with the SV form are not diagnosed until much later when symptoms of virilization, precocious pseudopuberty, or growth acceleration occur.20–23 The markedly advanced skeletal age of patients with the SV form diagnosed late contributes to their short adult stature. Late discovery of incorrect male sex assignment in females with the SW and SV forms causes extreme distress to the family and matured patients. Mild 21-OH deficiency produces no symptoms at birth and manifests as premature sexual hair, acne, and mild growth acceleration in childhood and hirsutism, excessive acne, menstrual disorder, and infertility later in life.20,21 This milder disorder may be missed by newborn screening programs.
Mortality
The mortality rate for infants with the SW form not detected through newborn screening was 11.9%, which was fivefold higher than that of the general population (2.29%).23
Pathophysiology
21-OH deficiency results in cortisol deficiency with or without aldosterone deficiency. Cortisol deficiency from early fetal life leads to increased adrenocorticotropic hormone (ACTH) secretion,20,21 which then stimulates excess secretion of the precursor steroids including 17-OH-progesterone (17-OHP) and causes hyperplastic changes of the adrenal cortex.20,21 The precursor steroids can only be metabolized by way of the androgen biosynthetic pathway, resulting in excess androgen production that virilizes the genitalia.20,21 Aldosterone deficiency contributes to SW. The increased circulating 17-OHP concentration is diagnostic for 21-OH deficiency.
Inheritance and Genotype
21-OH deficiency is an autosomal recessive disorder caused by a mutation of the CYP21 gene.20,21 There is an active CYP21 gene and an inactive pseudo-CYP21P gene in normal individuals. Both genes are in the HLA complex on chromosome 6p21.3.20,21 Most mutations in the CYP21 gene are the pseudogene sequences, suggesting that the mutations in CYP21 were caused by a gene conversion or recombination between CYP21 and CYP21P. The genotypes from 5 different populations of individuals with CAH correlated well with the phenotype in approximately 90% of affected subjects but did not correlate well in the remaining patients.21
Rationale for and Benefits of Newborn Screening
The goals of newborn screening are to (1) prevent life-threatening adrenal crisis, thereby averting shock, brain damage, and death, (2) prevent male sex assignment for life in virilized female newborns, and (3) prevent progressive effects of excess adrenal androgens, which cause short stature and psychosexual disturbances in boys and girls. Kovacs et al23 found the average serum sodium concentration at diagnosis of the SW form of CAH to be 135 mEq/L in individuals detected through newborn screening programs and 125 mEq/L in those detected after development of clinical symptoms. Thus, prevention of severe SW CAH by newborn screening was demonstrated. Worldwide newborn screening data showed that screening prompted early diagnosis of CAH before clinical suspicion in 67% of newborn infants with CAH, including many females with AG.26 The mortality rate of individuals with CAH identified through newborn screening has not been established yet. Other newborn screening benefits include (1) improved case detection evidenced by twofold higher incidence versus that of case-survey reports (North America and Japan), (2) improved detection of patients with SW CAH (70% with newborn screening vs 43%–60% in patients with clinical symptoms), and (3) improved detection of males, as evidenced by a 1:1 sex ratio in subjects identified through newborn screening versus a male/female ratio of 0.6:1 in patients with clinical symptoms leading to diagnosis.
Screening
Screening for 21-OH deficiency is accomplished by measurement of 17-OHP concentration in the dried blood spot. Newborn screening for CAH requires a rapid process to prompt the diagnosis before the onset of SW symptoms. Sampling at less than 1 day is associated with a high rate of false-positive results, and sampling beyond 5 to 7 days of age reduces the benefit of screening. Normal preterm infants have higher concentrations of 17-OHP than do term infants; therefore, it is important to have 17-OHP reference concentrations in blood spots of preterm and term unaffected infants according to birth weight or gestational age.27,28 17-OHP is not influenced if drawn several hours after transfusion.
Dissociation-enhanced lanthanide fluorescence immunoassay, radioimmunoassay, and enzyme-linked immunosorbent assay with a commercial kit are used to measure 17-OHP concentrations in blood spots.25,26 The screening 17-OHP assays are nonspecific, and the result on a screening study is not equivalent to the diagnostic serum concentrations.21,26,29 Affected neonates had screening 17-OHP concentrations of 35 to 900 ng/mL of blood, with preterm infants having higher concentrations.27,29
MS/MS may have the advantage of rapid 17-OHP detection and may eliminate the variable 17-OHP cutoff concentrations influenced by different reagents/assays. However, comparative studies of immunoassays versus MS/MS are necessary, and because of the complexity of the MS/MS assay for 17-OHP detection, MS/MS may be used as a complementary test. CYP21 genotyping is not currently used in newborn screening, but it may be helpful in uncertain cases and for genetic counseling.
Almost all neonates with SW CAH have been identified with the first sample test.26 Newborn screening for CAH is not intended to detect mild cases, although some are detected. In a study performed in Texas, testing again at 1 to 2 weeks increased detection of SV CAH and the mild form.29 Despite the birth weight- or age-adjusted 17-OHP cutoff concentrations, preterm birth or low birth weight and samples taken at less than 1 day of age are major factors for false-positive results.24–30 In an international study, 7% of neonates later determined to have CAH (mostly the SV form) were not detected in newborn screening for a variety of reasons (human error, prenatal dexamethasone therapy, or high 17-OHP cutoff concentrations).25
Follow-up and Diagnostic Testing
In most newborn screening programs, 2-tiered 17-OHP cutoff concentrations are established to guide evaluation in term and preterm newborn infants. Exceptionally high (urgent) and moderately high (suspected) 17-OHP concentrations are reported. Pediatricians need to be familiar with these concentrations as reported by their local newborn screening program. Most newborn screening programs that screen for CAH report the presumed positive results with instructions. Immediate evaluation (serum electrolytes, 17-OHP) is necessary in newborn infants with AG, in sick or asymptomatic male newborn infants with urgent or suspected 17-OHP concentrations, and in sick female infants with urgent 17-OHP concentrations. The evaluation is necessary in asymptomatic normal female infants with urgent 17-OHP concentrations and in sick female infants with normal genitalia and suspected 17-OHP concentrations, but these newborns are at low risk of having SW CAH. Normal females with suspected 17-OHP concentrations are not at risk of SW CAH but need at least a second screening to be sure that a mild deficiency is not missed.
Diagnosis
Quantitative serum 17-OHP concentration is used for the diagnosis of CAH. Concentrations are generally higher in individuals with the SW form.29 Care must be taken to use the appropriate term or preterm normal values for comparison.26 With age, serum 17-OHP concentrations decrease in unaffected neonates but increase in those with CAH.30 Concentrations in neonates with SW and SV CAH are higher than the concentrations in infants with the mild form.21,29 In neonates with mildly elevated 17-OHP concentrations (4–10 ng/mL), the ACTH-stimulation test helps to rule out nonclassic CAH.20,21 In asymptomatic infants, serial evaluation of electrolytes throughout the neonatal period is necessary if serum electrolyte concentrations remain normal.
Brief Overview of Disease Management
Treatment for CAH involves replacement of cortisol, which suppresses increased ACTH, 17-OHP, and androgen secretion. Replacement of aldosterone with an analog of mineralocorticoid (Florinef) is required for patients with SW CAH. Adequate medical therapy restores normal energy, glucose and electrolyte concentrations, and fluid balance and prevents excess adrenal androgen effects. Special medical care is needed in case of stress. The rate of mortality is 4.3% for treated patients.23 In virilized female infants, surgical correction is generally performed before 1 year of age and, if necessary, again before menarche. With standard glucocorticoid therapy, adults with classic CAH do not always reach their genetic potential for height, and obesity is common. Inadequate medical therapy causes infertility. Experimental antiandrogenic/antiestrogenic drug therapy to improve height outcome is ongoing in children with CAH. Adrenalectomy is recommended when medical therapy is ineffective.
Carrier testing for CAH is performed most accurately using CYP21 genotyping.
Pregnant women known to be at risk of having a fetus with CAH can receive prenatal dexamethasone therapy. First-trimester prenatal diagnosis is indicated for these women. An elevated 17-OHP concentration in amniotic fluid by a specific assay (>6–18 ng/mL) is also diagnostic, but normal concentrations do not exclude SV or nonclassic forms of CAH, and concentrations may be normal in mothers who are on dexamethasone therapy. Prenatal treatment is only indicated for female fetuses with classic virilizing CAH. Maternal dexamethasone therapy at 20 µg/kg per day beginning at 5 to 8 weeks' fetal age prevents or reduces AG in most affected females.31 Controversy regarding prenatal therapy is related to the fact that (1) this treatment must begin before fetal sex can be determined or CAH diagnosis can be made, and 7 of 8 fetuses are thus unnecessarily subjected to this therapy, and (2) long-term safety of early exposure to dexamethasone in utero is unproven to date.31 Maternal adverse effects include cushingoid features of excessive weight gain, intense striae, edema, discomfort, and emotional instability. In a consensus meeting concerning prenatal CAH therapy, representatives from the US Lawson Wilkins Pediatric Endocrine Society and European Pediatric Endocrine Society recommended that designated teams undertake this specialized therapy using a national protocol approved by institutional review boards. Treatment is preceded by informed consent about the risks and benefits of the therapy, and prospective follow-up and evaluation are needed.31
Current Controversy
The major controversy regarding newborn screening for CAH is the cost and impact of evaluating those whose test results are false-positive.32 A second issue is the use of prenatal dexamethasone therapy for CAH. A large national multicenter study on long-term cognitive and psychological development and other health-related outcomes is required to resolve this issue.
REFERENCES
Congenital hearing loss, for the purposes of this fact sheet, is defined as permanent and is bilateral or unilateral, is sensory or conductive, and averages 30 dB or more in the frequency region important for speech recognition. Congenital hearing loss has many etiologies, with at least half associated with genetic risk factors. Congenital nonsyndromic hearing loss is usually categorized by mode of inheritance—autosomal recessive, autosomal dominant, X-linked, or mitochondrial.33–35
Newborn hearing screening programs became possible after the development of hearing screening technologies. Although most states have begun screening for congenital hearing loss, the integration of these programs with ongoing screening and early intervention programs remains a challenge.36
Prevalence
Estimates of the prevalence of moderate-to-profound bilateral hearing loss vary, depending on the criteria used to define the different degrees of hearing loss and the characteristics of the studied population.37 The prevalence of congenital hearing loss also depends on race, birth weight, and other risk factors.38 Profound and permanent congenital hearing loss is estimated to occur in approximately 1 in 1000 births.39,40
Clinical Manifestations
The spectrum of congenital hearing loss ranges from mild to profound hearing loss. In syndromic hearing loss, the auditory pathology may be conductive and/or sensorineural, unilateral or bilateral, symmetrical or asymmetrical, and progressive or stable. The auditory pathology of nonsyndromic hearing impairment is usually sensorineural.41,42
Pathophysiology
Approximately half of the cases of congenital hearing loss are thought to be attributable to environmental factors (acoustic trauma, ototoxic drug exposure [aminoglycosides], bacterial or viral infections such as rubella or cytomegalovirus).39,41,42 The remaining cases are attributable to genetic mutations. Although these cases may seem to be part of a recognizable syndrome, approximately 70% are nonsyndromic (the deafness is not associated with other clinical findings that define a recognized syndrome) and, therefore, clinically undetectable at birth. In the remaining 30%, 1 of more than 400 forms of syndromic deafness can be diagnosed because of associated clinical findings.39,42
Inheritance
Approximately 77% of congenital nonsyndromic hearing impairment is autosomal recessive, 22% is autosomal dominant, and 1% is X-linked. As a general rule, individuals with autosomal recessive congenital nonsyndromic hearing impairment have profound prelingual deafness, and dominant mutations lead to a more variable phenotype. More than 90% of children with congenital profound autosomal recessive congenital nonsyndromic hearing impairment are born to parents with normal hearing, and the remaining 10% or less are born to deaf parents.41
There has been significant progress in identifying and sequencing autosomal dominant, autosomal recessive, and sex-linked genes for deafness.41,43 However, it is clear that more genes and mutations await discovery. This knowledge may lead to mutation-specific therapies that can delay or prevent certain forms of genetic deafness, such as the avoidance of aminoglycoside therapy in those with specific mitochondrial mutations.
Benefits of Newborn Screening
The goals of newborn screening are to identify those infants with hearing loss early for prompt intervention to diminish the morbidity associated with congenital hearing loss. Left undetected and untreated, hearing impairment can affect speech and many other cognitive abilities. For children without risk factors, hearing loss frequently escapes detection until the age when hearing children normally begin to talk (9 months or older).44–48 Current theory views auditory stimulation during the first 6 months of life as critical to development of speech and language skills. Children who are identified early as having hearing loss and receive intensive early intervention perform better on school-related measures (reading, arithmetic, vocabulary, articulation, percent of the child's communication understood by non–family members, social adjustment, and behavior) than children who do not receive such intervention.49 Early intervention resulted in improvements in receptive language50 and prevented developmental delays.51 However, the efficacy of universal newborn hearing screening to improve long-term language outcomes remains uncertain.52–54
Screening
Newborn hearing screening is accomplished through the use of a variety of computerized equipment that uses automated auditory brainstem response (AABR), distortion product otoacoustic emissions (OAEs), or transient evoked OAEs. Screening is performed before discharge from the nursery.55 Screening for congenital hearing loss is a simple process and in some cases may be performed by specially trained volunteers under the supervision of nurses or audiologists. Screening with AABR is accomplished by placement of soft earphones through which a series of soft clicks are introduced, usually at the 30- to 40-dB level. An auditory brainstem response detected through electrodes attached to the infant's forehead and neck indicates that there is no significant sensorineural hearing loss. If OAE technology is selected as the screening test, a tiny microphone that detects sounds generated by the outer hair cells of the cochlea is introduced into the infant's auditory canal. Presence of those sounds indicates a functioning inner, middle, and outer ear. Each of these tests has advantages and disadvantages that should be considered carefully when selecting equipment. AABR tends to be somewhat more expensive and must be used in a quiet setting. OAE screening may result in higher false-positive rates if the infant's ear canal is blocked by fluid or debris.56,57 Some hospitals use a combination of screening tests or repeat the OAE screening to reduce the false-positive rate and thereby minimize the need for follow-up after hospital discharge, which may reduce costs overall.58
Follow-up and Diagnostic Testing
Infants who do not "pass" the screening are either rescreened before discharge or given an appointment for rescreening as outpatients. Results of the screening are generally transmitted to the primary care physician of record, to the parents, and to the state health department. Failure to pass the screening results in a recommendation for referral to a qualified audiologist for confirmatory testing for congenital hearing loss.
In areas where universal newborn hearing screening is occurring, appropriate and timely diagnosis and intervention continue to be a major challenge. Attrition rates as high as 50% between initial referral and diagnostic confirmation still are not unusual.36 Linkages between hospital-based screening programs and early intervention programs may not be well established, and data management and tracking of infants through the screening and diagnostic process also may be in the developmental stage.49 As state programs assume more responsibility for the tracking and follow-up, these linkages will be more firmly established.36
Brief Overview of Disease Management
Appropriate management of all persons identified with congenital hearing loss requires a comprehensive pediatric and genetic evaluation.33 Core personnel include individuals with expertise in the genetics of hearing loss, dysmorphology, audiology, otolaryngology, and genetic counseling. Qualified interpreting services may be needed when the parents are deaf. On the basis of the outcome of the evaluation, other types of professional expertise also may be needed, including professionals with experience with syndromal hearing loss (eg, ophthalmology, cardiology, nephrology, neurology).
After a family history, patient history, and physical examination, it may be possible to ascribe an etiology to the hearing loss. However, in approximately 30% of patients, there will be no obvious etiology.33 An important goal of the genetic evaluation is to attempt to distinguish isolated or simplex cases, in which the risk of deafness in subsequent offspring may be 25%, from sporadic cases, which have a low risk of recurrence.33
After diagnosis of hearing loss, continuity of care for the affected infant is important to reduce morbidity. The pediatrician should ensure referral to the state early intervention program and/or the state program for children with special health care needs as appropriate. Referral to these programs at hospital discharge helps to minimize loss to follow-up.
Current Controversy
The US Preventive Services Task Force did not find evidence for the benefit of (nor evidence against the benefit of) universal newborn hearing screening.53 They argued that, among low-risk infants, the prevalence of hearing impairment was very low, and substantial numbers of infants would be misclassified. They found that evidence for the efficacy of early intervention for patients diagnosed by screening was incomplete.
Additional controversy centers on the generally inadequate integration of these programs with ongoing newborn screening and early intervention programs.36 The Newborn Screening Task Force suggested that child health–related programs such as newborn genetic and hearing screening programs would avoid unnecessary duplication of effort if they were more closely aligned with each other.59
REFERENCES
Thyroid hormone deficiency at birth is one of the most common treatable causes of mental retardation. There are multiple etiologies of this disorder, both heritable and sporadic, varying in severity. There is an inverse relationship between age at diagnosis and neurodevelopmental outcome; the later treatment is started, the lower the IQ will be. Most infants seem to be protected for the first few weeks of life by the fraction of maternal thyroid hormone that crosses to the fetus. Because of the urgency in detection and initiating treatment to prevent mental retardation, screening newborns for this disorder was added to existing programs in the mid-1970s.
Incidence
Congenital hypothyroidism (CH) occurs in 1 in 4000 to 1 in 3000 newborns. Programs reporting a higher incidence may include some transient cases. CH seems to occur more commonly in Hispanic and American Indian/Alaska Native people (1 in 2000 to 1 in 700 newborns) and less commonly in black people (1 in 3200 to 1 in 17000 newborns). Programs report a consistent 2:1 female/male ratio, which is unexplained but speculated to be related to an autoimmune risk factor. Newborn infants with Down syndrome are at increased risk of having CH (approximately 1 in 140 newborns).
Clinical Manifestations
Most affected infants appear normal at birth, without obvious manifestations of CH. This is likely the result of transplacental passage of some maternal thyroid hormone; cord thyroxine (T4) concentrations are approximately one third of maternal concentrations. In addition, many infants have some functioning thyroid tissue. Gestational age is 42 weeks or greater in approximately one third of these infants. Their birth weight and length fall into the normal range, and their head circumference may be at a slightly higher percentile because of brain myxedema. Approximately 5% of these infants, generally those who are more severely affected, have recognizable features at birth, including large fontanels and wide suturae, macroglossia, distended abdomen with umbilical hernia, and skin mottling. As maternal thyroid hormone is excreted and disappears in the first few weeks, clinical features gradually become apparent. These infants are slow to feed, constipated, lethargic, and sleep more ("sleep through the night" early), often needing to be awakened to feed. They may have a hoarse cry, may feel cool to touch, may be hypotonic with slow reflexes, and may have prolonged jaundice because of immaturity of hepatic glucuronyl transferase. A goiter is seen in 5% to 10% of these infants, most commonly in those with an inborn error of T4 synthesis. If hypothyroidism goes undiagnosed beyond 2 to 3 months of age, infants will begin to manifest slow linear growth. If this disorder is untreated, studies show a loss of IQ proportionate to the age at which treatment is started: if treatment is started at 0 to 3 months of age, mean IQ is 89 (range: 64–107); if treatment is started at 3 to 6 months of age, mean IQ is 71 (range: 35–96); if treatment is started at older than 6 months, mean IQ is 54 (range: 25–80). Other long-term neurologic sequelae include ataxia, gross and fine motor incoordination, hypotonia and spasticity, speech disorders, problems with attention span, and strabismus. Approximately 10% of these infants will have an associated sensorineural deafness, and approximately 10% will have other congenital anomalies, most commonly cardiac defects.60 Some newborn screening programs also detect secondary or hypopituitary hypothyroidism in infants. These infants may have associated midline defects, such as the syndrome of septooptic dysplasia or midline cleft lip and palate. Other pituitary hormones, such as growth hormone, may also be missing.
Pathophysiology
The most common cause is some form of thyroid dysgenesis: aplasia, hypoplasia, or an ectopic gland; thyroid ectopy accounts for two thirds of thyroid dysgenesis. The cause of thyroid dysgenesis is unknown; rare cases result from mutations in the genes that control thyroid gland development, including thyroid transcription factor (TTF-2) and paired box-8 protein (PAX-8). Inborn errors of T4 synthesis, secretion, or utilization account for two thirds of heritable cases. Errors in iodide trapping, organification of iodide to iodine by thyroid peroxidase (most common inborn error), coupling of monoiodothyronine and diiodothyronine, deiodinase, and an abnormal thyroglobulin molecule all have been described. In mothers with autoimmune thyroiditis, transplacental passage of a thyrotropin-receptor–blocking antibody is associated with transient hypothyroidism. Infants born to mothers with Graves' disease treated with antithyroid drugs also may have transient hypothyroidism. Worldwide, iodine deficiency resulting in endemic cretinism is the most common cause of hypothyroidism at birth. Exposure of the neonate to excess iodine, as with topical antiseptics, can also cause hypothyroidism.
Inheritance
Approximately 85% of cases are sporadic, and 15% are hereditary. Each of the inborn errors of T4 synthesis is autosomal recessive except thyroid hormone receptor defects, which are autosomal dominant. In the cases associated with transplacental passage of a maternal blocking antibody, future siblings are at risk of having the same problem.
Rationale for and Benefits of Newborn Screening
Most newborn screening programs report no difference in global IQ score compared with sibling or classmate controls, whereas some report a reduction in IQ ranging from 6 to 15 points. Even if there are no differences in global IQ, some show differences in subtest components, such as language or visual-spatial skills. These results are more likely in severely affected infants,61 those started on too low an initial dose of levothyroxine sodium, or those who are not optimally managed or poorly compliant in the first 2 years of life. However, these differences in IQ nearly disappeared if higher starting doses of levothyroxine, averaging 11.6 µg/kg per day, were used.62 Recent data suggest that a starting dose of 10 to 15 µg/kg per day normalized serum thyrotropin by 1 month and resulted in a higher IQ as compared with infants started on a lower treatment dose.63
Screening
Most screening programs in the United States measure T4 initially, with a thyrotropin determination on infants whose T4 level is less than the 10th percentile for that specific assay. Some US newborn screening programs and more in Canada now are screening with an initial thyrotropin measurement. Because there is a thyrotropin surge after birth that decreases over the next 5 days, infants with screening specimens obtained at less than 48 hours of age may have false-positive thyrotropin increases. Each screening program must establish its own T4 and thyrotropin cutoff levels. Primary T4 screening programs may identify infants with delayed thyrotropin increase (usually preterm infants) and secondary hypothyroidism. Primary thyrotropin screening programs identify infants with subclinical hypothyroidism (high thyrotropin, normal T4). The false-positive rate is generally higher for primary T4 programs compared with primary thyrotropin programs (0.30% vs 0.05%, respectively). Preterm infants have reduced T4 concentrations and, thus, make up a disproportionate percentage of infants with false-positive results. Neither screening is affected by diet or transfusion, except total exchange transfusion.
Follow-up and Diagnostic Testing
Infants with abnormal screening results must have confirmatory serum T4 testing and some measure of thyroid-binding proteins (eg, triiodothyronine [T3] resin uptake), or a free T4 level, and thyrotropin determination. Once a diagnosis of hypothyroidism is confirmed, studies may be undertaken to determine the underlying etiology. Most useful are imaging studies, either thyroid ultrasound or thyroid uptake and scan, using either technetium 99m pertechnetate or iodine 123. In general, information gained from these studies does not alter management, so they are considered optional; they should never delay onset of treatment. If there is evidence of maternal autoimmune thyroid disease, measurement of thyrotropin-binding inhibitor immunoglobulin in the mother and infant can identify those with likely transient hypothyroidism. If iodine exposure or deficiency is suspected, measurement of urinary iodine can confirm this etiology.
Brief Overview of Disease Management
Levothyroxine is the treatment of choice; only tablets should be used, because liquid preparations are not stable. The recommended starting dose is 10 to 15 µg/kg per day62,63; it is important that the initial dose correct hypothyroxinemia as rapidly as possible.64–66 Treatment can be started after confirmatory studies are obtained, pending results. Treatment goals are to keep the serum T4 or free T4 in the upper half of the reference range (10–16 µg/dL [130–204 nmol/L] or 1.2–2.3 ng/dL [18–30 pmol/L], respectively) and the thyrotropin in the reference range (<6 mU/L). Laboratory evaluation should be conducted (1) at 2 and 4 weeks after initiation of T4 treatment, (2) every 1 to 2 months during the first year of life, (3) every 3 to 4 months between 1 and 3 years of age, and (4) 2 to 4 weeks after any change in dosage.67 Prolonged overtreatment can lead to disorders of temperament and craniosynostosis and should be avoided. Close monitoring is essential in the first 2 to 3 years of life, a time at which the brain still has a critical dependence on thyroid hormone. If permanent hypothyroidism has not been established by 3 years of age, levothyroxine treatment can be discontinued for 1 month and endogenous thyroid function can be reevaluated.
Current Controversies
Preterm infants with hypothyroidism can have a delayed thyrotropin increase,68 most likely because of immaturity of the hypothalamic-pituitary-thyroid (HPT) axis. Such infants may be missed by either the primary T4 or thyrotropin screening approach. Some programs, therefore, have undertaken or are considering a routine second screening between 2 and 6 weeks of age in preterm infants. Programs that undertake a routine second screening report an additional 10% of cases. In addition, some studies suggest that infants less than 28 weeks' gestational age who lose the maternal contribution of thyroid hormone may benefit from treatment until the HPT axis matures.69 Additional studies are needed before this can be considered standard of care. Last, some infants seem to have altered feedback of the HPT axis, manifested as persistently high serum thyrotropin concentrations despite apparent adequate treatment.
Special Issues/Concerns
Managing CH presents challenges with stakes that are far greater than management of acquired hypothyroidism. Laboratory evaluation occurs much more frequently, and target T4 or free T4 ranges are different for infants. Infants with an altered HPT axis and persistently high thyrotropin concentrations are difficult treatment challenges. With a goal of ensuring optimal treatment and, therefore, optimal neurodevelopmental outcome, these cases should be managed by pediatricians in consultation with pediatric endocrinologists.
REFERENCES
Cystic fibrosis (CF) (OMIM database No. 219700)70 is a hereditary disease that has primary effects on the lungs, pancreas, intestine, liver, sweat glands, and male reproductive tract as well as important secondary effects on growth and nutrition.71 The clinical course is variable, but most patients succumb to lung disease in early adulthood.
Incidence
The incidence of CF is approximately 1 in 3500 in white newborn infants. The incidence in black and Hispanic newborn infants (approximately 1 in 15000 and approximately 1 in 7000, respectively) is higher than previously suspected. There is a low incidence in Asian infants.
Clinical Manifestations
CF usually presents in infancy. Meconium ileus, a neonatal intestinal obstruction, occurs in approximately 17% of infants with CF. Beyond the perinatal period, CF presents as failure to thrive secondary to exocrine pancreatic insufficiency, chronic respiratory symptoms, or both. Nutritional deficits can be severe at presentation and may lead to edema and hypoproteinemia from protein-calorie malnutrition. Infants may present with hypoelectrolytemia from sweat salt loss. The most common chronic respiratory symptoms are cough and wheeze. If infants are not diagnosed in the newborn period, they often undergo months of illness with concomitant stress on the parents. Patients are prone to chronic endobronchial infections with Pseudomonas aeruginosa, Staphylococcus aureus, and other characteristic bacteria throughout childhood. Many of these patients suffer from recurrent intestinal blockages, and a small percentage of patients have severe liver disease. Diabetes is increasingly common during adolescence and young adulthood. Fifteen percent of these patients have mutations that do not lead to exocrine pancreatic insufficiency. They are at risk of recurrent pancreatitis, however. The median predicted age of survival is 33 years.72
Pathophysiology
CF results from abnormalities in the CF transmembrane conductance regulator (CFTR) protein, a membrane glycoprotein that regulates ion flux at epithelial surfaces. Abnormalities in CFTR cause thick secretions that obstruct pancreatic ductules, leading to exocrine pancreatic destruction. In the airway, dehydration of airway surface liquid leads to chronic infection and neutrophil-dominated inflammation. Bronchiectasis and progressive obstructive lung disease then follow.
Inheritance
CF is autosomal recessive. More than 1000 mutations in the CFTR gene have been described, but one mutation, 
F508, accounts for more than 70% of affected chromosomes in individuals of European ancestry. Several-dozen mutations have been characterized as pancreatic sufficient or insufficient on clinical grounds. The American College of Medical Genetics has developed standards and guidelines for population-based CF-carrier screening that include a panel of 25 mutations.73
Rationale for and Benefits of Newborn Screening
The principal benefit of newborn screening and early diagnosis is improved height and weight at least through adolescence, demonstrated in a well-controlled clinical trial.74 Improvement in height and weight likely occurs from early institution of pancreatic enzyme, fat-soluble vitamin and salt supplementation, as well as the general nutritional follow-up that is part of care at a CF center. In addition, it is likely that early diagnosis and attention to nutrition can help patients avoid severe nutritional complications of infancy, although this has not been shown in a controlled trial. Severe nutritional complications of CF in infancy include anemia from vitamin E deficiency, zinc deficiency, linoleic acid deficiency, hypoelectrolytemia, and protein-calorie malnutrition. In addition, vitamin E deficiency at symptomatic diagnosis of CF is associated with cognitive deficits. Thus, early diagnosis through newborn screening is likely to improve developmental outcome. Observational studies support improved pulmonary outcome after newborn screening. In addition, height in CF is correlated with improved pulmonary outcome. Thus, the increase in height in patients identified through screening also may be beneficial. Another benefit of screening is that parents of children identified through screening have been shown to have greater trust in the medical establishment than parents whose children are identified only after symptoms appear.75
Screening
Methodology
Determination of immunoreactive trypsinogen (IRT) concentrations from dried blood spots serves as the basis for the first tier in all newborn-screening programs for CF. IRT concentration is high in the blood of infants with CF, presumably from leakage of the protein into the circulation after exocrine pancreatic injury. Two approaches can be taken if the IRT concentration is high. The more common approach is to perform mutation analysis from the dried blood spot for a set of CF mutations. Another approach is based on persistent elevation of IRT concentration, which requires a second dried blood spot taken 2 to 3 weeks after birth.
The value at which the initial IRT concentration is considered abnormal varies from program to program. If mutation analysis is performed from the first dried blood spot, a second specimen is not required. Thus, the IRT cutoff can be set to include a substantial fraction of the newborn population. In some programs, the top 5% of all IRT concentrations are considered abnormal and mutation analysis is performed. In other programs, the cutoff is set at the top 1%.
Programs that are based on persistent elevation of IRT concentration require a second dried blood spot taken at 2 to 3 weeks of age in infants with a high concentration on the first specimen. These programs set the cutoff value for IRT at a higher concentration (0.5% of newborn infants) than programs that perform mutation analysis. Diagnosis through persistent elevation of IRT concentration can identify infants with CF who do not carry mutations included in most mutation-analysis panels.
Timing
Because IRT concentration is frequently high immediately after birth, specificity is improved if the test is performed after the first day of life.
Sensitivity and Specificity
The sensitivity of most CF screening programs, whether based on genotyping or persistent elevation of IRT concentration, is approximately 95%. The specificity of programs that rely on persistent elevation of IRT concentration without genotyping is approximately 99.5% after the first measurement of IRT concentration. The specificity of programs that perform genotyping after the initial elevation of IRT may be as high as 99.9%.
Follow-up and Diagnostic Testing (Short-term)
Timeline
For programs that perform mutation analysis, the diagnosis of CF can be made if 2 mutations are identified from the dried blood spot. If only one mutation is identified from the dried blood spot, then sweat testing, the definitive diagnostic test, should be performed as soon as possible. In programs that do not perform mutation analysis, sweat testing should be performed within a few days of the repeat IRT test. There is some urgency to making the diagnosis. Many patients are pancreatic insufficient in the first weeks of life and are at risk of severe nutritional complications. Pancreatic enzyme-replacement therapy, fat-soluble vitamin supplementation, and salt supplementation should be initiated very soon after diagnosis in pancreatic-insufficient infants.
Test and Procedures
Sweat testing should be performed at more than 1 week of age. Almost all term infants will have adequate sweat amounts by that time.76 Sweat collection amounts may be inadequate in preterm infants; in such a case, mutation analysis can be performed.77 Currently, a sweat chloride value of more than 40 mmol/L is required for the diagnosis of CF in the newborn period; infants with values more than 30 mmol/L, however, require follow-up.78 In programs that perform mutation analysis, confirmatory sweat testing should be obtained even in infants who test positive for 2 mutations.
Brief Overview of Disease Management
Nutrition is an important focus of management beginning in infancy. A recently developed test for fecal elastase may allow convenient determination of need for pancreatic enzyme supplementation. Pancreatic enzyme, fat-soluble vitamin, and salt supplementation will be started in most infants at diagnosis. Outpatient regimens become increasingly complex with age and often include several inhaled medications, nutritional supplements, attention to secretion clearance, and a number of ongoing oral medications to be taken daily. Patients with pulmonary exacerbation require hospitalization to receive intravenous antibiotic therapy and intensive secretion clearance. Every effort should be made to have the infant and family cared for at centers accredited by the Cystic Fibrosis Foundation.
Current Controversies
Three controversies have surrounded newborn screening for CF. One issue has been whether the growth and nutritional benefits of early diagnosis are sufficient to justify screening. Very recently, however, the Centers for Disease Control and Prevention has determined that newborn screening for CF is of benefit.79 Follow-up studies of pulmonary and cognitive outcomes may further address this issue. A second issue is carrier detection, which occurs in all programs that use mutation analysis as part of the screening. It is not known for sure whether identification of otherwise well infants as carriers of CF may do harm, but studies suggest that this is not the case. A third issue is that approximately 5% of newborn infants identified will have borderline sweat tests (sweat chloride levels of 30–40 mmol/L) and "mild" mutations. It is not clear yet how many of these infants will have important medical problems. Follow-up studies are underway.
Counseling
Parents will require education on all aspects of CF. The care team consists of the primary pediatrician and the CF center staff. Genetic counseling should be arranged for all families.80
REFERENCES
Lactose, or milk sugar, is broken down into its constituent simple sugars, glucose and galactose, before absorption in the intestine. Galactosemia, which is an increased concentration of galactose in the blood, has many causes. The genetic disorders that cause galactosemia vary in severity from a benign condition to a life-threatening disorder of early infancy. Early diagnosis and treatment of the latter condition can be life saving; hence, newborn screening for this disease has been instituted in many states.
Incidence
Three distinct enzyme deficiencies may lead to galactosemia. The most common of these, galactose 1-phosphate uridyltransferase (GALT) deficiency (OMIM database No. 606999),81 occurs in approximately 1 in 47000 newborn infants.82 This disorder is often referred to as "classic galactosemia." Galactokinase (GALK) deficiency (OMIM database No. 230200)81 seems to be very rare, although there have been no large population studies to assess its incidence. One study found that 1% of North American people were carriers, suggesting a disease frequency of 1 in 40000.83 However, a newborn screening study conducted in Massachusetts detected no cases among 177000 newborn infants.84 The third disorder, galactose-4'-epimerase (GALE) deficiency (OMIM database No. 230350), occurs in 2 forms; one form is confined to red blood cells and has no symptoms, and the second form, which is exceedingly rare, is generalized, with only a few patients reported nationally.85,86
Clinical Manifestations
Infants with classic galactosemia, or GALT deficiency, generally present within the first weeks after birth with a life-threatening illness. Feeding intolerance, vomiting and diarrhea, jaundice, hepatomegaly, lethargy, hypotonia, and excessive bleeding after venipuncture are characteristic findings. Laboratory studies indicate liver and renal tubular disease. Septicemia, particularly with Escherichia coli, is not uncommon. Cataracts are generally seen at presentation, but they may be mild in the first few weeks of life and only detectable with slit-lamp examination. Less frequently, patients with classic galactosemia may have a more chronic presentation, with failure to thrive, poor feeding, and developmental delay. Black individuals with classic galactosemia, in particular, frequently have a mild presentation.
Infants with GALK deficiency generally present with bilateral cataracts, which have been observed as early as 4 weeks of age. The cataracts are identical to those seen in classic galactosemia.87 The great majority of infants with GALE deficiency have an enzyme deficiency that is confined to the red blood cells and causes no symptoms. Five individuals with generalized GALE deficiency had developmental delay, hypotonia, and poor growth; 3 had sensorineural hearing loss.88
Pathophysiology
The main metabolic pathway for the conversion of galactose to glucose uses 3 enzymes: GALK, GALT, and GALE. Individuals who lack GALK cannot convert galactose to galactose 1-phosphate. As a result, galactose is converted to galactitol by an alternative pathway. The accumulation of galactitol in the lens results in the development of cataracts. Individuals with classic galactosemia, or GALT deficiency, cannot convert galactose 1-phosphate to uridine diphosphate galactose. Galactose, galactitol, galactose 1-phosphate, and other metabolites accumulate. Although it seems clear that increased galactitol is responsible for the development of cataracts in all forms of galactosemia, it is not known which metabolites are responsible for the other clinical findings in classic galactosemia.89
Inheritance
All forms of galactosemia are autosomal recessive in inheritance. More than 150 different mutations have been identified in GALT, the enzyme that is deficient in classic galactosemia. The most
