Congenital hypothyroidism (CH) occurs when infants are unable to produce sufficient amounts of thyroid hormone (thyroxine, or T4),

which is necessary for normal metabolism, growth and brain development.

Clinical Symptoms
Although the clinical signs of hypothyroidism may be subtle, infants with CH may exhibit some of the following symptoms: feeding problems, lethargy, prolonged postnatal jaundice, delayed stooling and constipation, enlarged protruding tongue, hoarse cry, protruding abdomen with an umbilical hernia, cold mottled skin, sluggish reflexes, patent posterior fontanelle with widely spread cranial sutures or delayed skeletal maturation for gestational age.

Newborn Screening and Definitive Diagnosis

In Illinois, primary newborn screening for CH utilizes fluorometric assay to determine the thyroid stimulating hormome (TSH) level. If the TSH is elevated, the T4 level also is tested. False positive and false negative results are possible with this screening. Specimen collection prior to 24 hours of age, prematurity and illness can affect this screening. Infants with a presumptive positive screening test (seriously elevated TSH and/or low T4) require prompt follow-up and, when notified of these results, the clinician should immediately check on the clinical status of the baby and refer the infant to a pediatric endocrinologist. Collection of serum TSH and T4 level also is recommended. Suspect abnormal results (moderately elevated TSH) indicate the need for repeat filter paper screening. Nearly 90 percent of CH cases are detected by newborn screening; however, the remaining 10 percent must be detected clinically. A small number of children may test normal on the newborn screen but later develop hypothyroidism. Clinicians must remain alert to signs indicative of possible hypothyroidism and clinical symptoms and/or family history of thyroid disorders indicate the need for thyroid testing, regardless of newborn screening results. Same birth siblings (twins, triplets) of infants diagnosed with CH should be re-screened; additional testing of these siblings also may be indicated.

Treatment
Immediate diagnosis and treatment of congenital hypothyroidism in the neonatal period is critical to normal brain development and physical growth. Treatment is usually effective if started within the first few weeks of life. Delayed treatment may result in decreased intellectual capacity. Recommended treatment is lifetime daily administration of levo-thyroxine. Only the tablet form of levo-thyroxine should be prescribed. The U.S. Food and Drug Administration has not approved liquid suspensions. Suspensions prepared by pharmacists may lead to unreliable dosage. The tablets should be crushed daily, mixed with a few milliliters of water, formula or breast milk and fed to the infant. Levo-thyroxine should not be mixed with soy formula or with formula containing iron, as these products interfere with absorption of the medication. Dosage will need to be gradually increased as the infant grows.

Incidence
Congenital hypothyroidism occurs in one of every 3,500 to 5,000 births; it is twice as common in females as in males. CH also is more common in Caucasians than African Americans by 5:1. The incidence of CH may be 40 percent higher among Hispanic populations than among Caucasians. Incidence is believed to be still greater among Native American and Asian populations. Illinois began screening for congenital hypothyroidism in 1979 and has since identified more than 1,500 cases. On average, the Newborn Screening Program identifies 60-70 new cases of CH each year.

Inheritance Pattern
Congenital hypothyroidism occurs sporadically and is not usually an inherited disorder. The disorder is not associated with any prenatal lifestyle or risk factors. A more rare form of CH (about 15 percent of the cases) does involve an inborn (autosomal recessive) error in thyroid hormone synthesis.

Congenital adrenal hyperplasia (CAH) is an inborn error of steroid biosynthesis. Individuals with CAH due to 21 hydroxylase enzyme deficiency cannot produce adequate amounts of cortisol and, in some cases, also are aldosterone deficient. These hormones are essential to glucose metabolism and salt reabsorption; untreated CAH can very suddenly lead to adrenal insufficiency with dehydration, shock and even death.

Clinical Symptoms
Female infants with 21 hydroxylase deficient CAH usually have some degree of virilization (ambiguous genitalia) due to their exposure to excessive androgen levels in utero. Although male infants usually appear normal at birth, they may have an enlarged penis and scrotum with increased pigmentation. Symptoms of salt wasting CAH include frequent urination and, in some cases, poor feeding, which can rapidly progress to vomiting, dehydration, electrolyte changes and cardiac arrhythmia. Infants with CAH who are not diagnosed and treated early are particularly susceptible to sudden death in the first few weeks of life. In older children, CAH may result in rapid growth and precocious puberty with premature skeletal maturation.

Newborn Screening and Definitive Diagnosis

In Illinois, newborn screening for CAH due to 21hydroxylase deficiency is by fluorometric assay to measure the 17 hydroxy (OH) progesterone level. False positive and false negative results are possible with this screening. Specimen collection prior to 24 hours of age, prematurity and illness can affect this screening, as physiological stress can cause a normal elevation of the 17-OH progesterone level. Treatment with

hydrocortisone or dexamethasone may result in false negative screening results. Infants with a presumptive positive screening test (seriously elevated 17-OH progesterone level) require prompt follow-up and, when notified of these results, the clinician should immediatelycheck on the clinical status of the baby and refer the infant to a pediatric endocrinologist. Measurement of serum 17-OH progesterone level and serum electrolytes is also recommended. Suspect abnormal (moderately elevated 17-OH progesterone) results require repeat filter paper screening as soon as possible. The seriousness of CAH requires additional testing for all abnormal test results, although monitoring of pre-term or sick neonates in a neonatal intensive care setting may be at the discretion of the neonatologist.

Treatment
Treatment for CAH includes lifetime daily medication. Oral hydrocortisone in children, and prednisone or dexamethasone for older individuals, replaces missing cortisol. Hydrocortisone is usually given at regular intervals three times a day. In cases of salt wasting CAH, in addition to hydrocortisone, fludrocortisone is prescribed to correct aldosterone deficiency. Infants and small children with salt wasting CAH also may require salt tablets as a dietary supplement. Regulation of medication dosage is vital, as improper dosage can result in either growth delay or premature bone epiphyseal closure. Female infants with ambiguous genitalia may require re-constructive surgery.

Incidence
Congenital adrenal hyperplasia occurs in one of every 15,000 births. Illinois began screening for CAH in 1987 and has since identified more than 190 cases. On average, 10-15 new CAH cases are identified each year.

Inheritance Pattern
The vast majority (90 percent) of CAH cases result from 21-hydroxylase deficiency. The only form of CAH detected by newborn screening, 21-hydroxylase deficiency is inherited in an autosomal recessive pattern. As with other autosomal recessive disorders, the parents of a child with CAH are unaffected, healthy carriers of the condition and have one normal gene and one abnormal gene. With each pregnancy, carrier parents have a 25 percent chance of having a child with two copies of the abnormal gene, resulting in CAH. Carrier parents have a 50 percent chance of having a child who is an unaffected carrier and a 25 percent chance of having an unaffected, non-carrier child. These risks hold true for each pregnancy. All siblings of infants diagnosed with congenital adrenal hyperplasia should be tested; genetic counseling services should be offered to the family.

Galactosemia is an inherited defect of galactose metabolism caused by an enzyme deficiency that prevents proper metabolism and utilization of galactose, or milk sugar. The main dietary source of galactose is lactose, the principle carbohydrate found in all forms of milk.

Clinical Symptoms
Although infants with galactosemia may appear normal at birth, within a few days to two weeks after initiating milk feedings, the symptoms of untreated galactosemia can become very severe. Early signs of the disease include feeding problems, poor sucking reflex, jaundice and hepatomegaly. Other symptoms may include failure to thrive, lethargy, cataracts, hypoglycemia, coagulation problems and decreased immunity.

Newborn Screening and Definitive Diagnosis

In Illinois, newborn screening for galactosemia is designed to detect classical galactosemia due to a deficiency of the galactose-1-phosphate uridyltransferase (GALT) enzyme; primary screening is performed by fluorometric assay. This test determines the level of galactose in the blood specimen and, when an elevated level is detected, Beutler assay of the specimen is performed to measure GALT enzyme activity. False negative and false positive results are possible with these tests. Infants who have not yet received a lactose (milk) feeding or those who are on soy formula may not have elevated galactose levels and should receive Beutler assay regardless of the galactose level. Infants who have received transfusions prior to specimen collection may have false negative Beutler enzyme results due to the GALT activity of transfused red blood cells. The type of infant feeding and transfusion status should always be indicated on the filter paper specimen. Infants with a presumptive positive screening test (no GALT activity detected or a seriously elevated galactose level) require prompt follow-up. When receiving a presumptive positive result, the clinician should immediately check on the clinical status of the baby and refer the infant to a metabolic disease specialist. The infants feeding should be changed to soy formula. If screening results indicate a mildly elevated galactose level with GALT activity present, filter paper screening should be promptly repeated and, if the second screening is abnormal, the infant should be referred to a metabolic disease specialist. The GALT enzyme is susceptible to damage from heat and filter paper specimens require prompt testing.

Treatment
Early diagnosis and treatment of classical galactosemia is imperative to prevent life threatening complications of sepsis and liver failure and to prevent additional developmental delays. Without early treatment, sepsis due to Escherichia coli may prove fatal in the neonatal period. When a lactose-restricted diet is provided within the first 10 days of life, presenting symptoms may be reversed. Infants with galactosemia are started on milk substitute formula, most likely a lactose-free soybean protein formula. Galactose is a non-essential nutrient, and individuals diagnosed with classical

galactosemia require lactose restricted diets for life. Endogenous production of galactose can complicate dietary treatment of galactosemia and may result in some developmental delays. Close dietary supervision, monitoring and the assistance of a trained dietician are required for infants and children diagnosed with classical galactosemia. Caution concerning administration of certain drugs that may contain lactose is also necessary.

Incidence
The incidence of classical galactosemia is one in 60,000 births. Illinois began testing for galactosemia in 1984 and more than 70 cases of classical galactosemia, 170 carriers and 80 cases with a variant form of the disorder have been identified.

Inheritance Pattern
Galactosemia is inherited in an autosomal recessive pattern. As an autosomal recessive disorder, the parents of a child with galactosemia are unaffected, healthy carriers of the condition and have one normal gene and one abnormal gene. With each pregnancy, carrier parents have a 25 percent chance of having a child with two copies of the abnormal gene, resulting in classical galactosemia. Carrier parents have a 50 percent chance of having a child who is an unaffected carrier and a 25 percent chance of having an unaffected, non-carrier child. These risks would hold true for each pregnancy. All siblings of infants confirmed to have galactosemia also should be tested; genetic counseling services should be offered to the family.

Physiology
Galactose is present in all milk sources and must be metabolized to glucose for absorption from the intestine. Individuals with classical galactosemia have a severe inherited deficiency of galactose-1-phosphate uridyltransferase (GALT). The GALT enzyme is one of three enzymes necessary for galactose metabolism. The biochemical consequence of GALT deficiency is abnormally high concentrations of galactose and its metabolites in body tissues and fluids. Classical galactosemia may result in life threatening crisis in the early neonatal period due to liver dysfunction, bleeding tendencies and septicemia.