Newborn Screening Disorders: Congenital Hypothyroidism, Phenylketonuria, and Galactosemia

All infants must be screened before discharge for phenylketonuria, congenital adrenal hyperplasia, galactosemia, and congenital hypothyroidism. This timing matters because PKU screening can establish the diagnosis before most symptoms, while congenital hypothyroidism can lead to cretinism and galactosemia can produce feeding problems, failure to thrive, cataracts, and sepsis.

Physiologic jaundice is not present on day 1, usually appears on day 3, and disappears by day 7. It should not last longer than one week in term infants or two weeks in preterm infants. Hypothyroidism is listed among causes of unconjugated hyperbilirubinemia and causes prolonged physiologic jaundice; galactosemia, alpha-1 antitrypsin deficiency, tyrosinemia, and growth hormone deficiency are other causes of prolonged neonatal jaundice.

Phenylketonuria is caused by phenylalanine hydroxylase deficiency, impairing hydroxylation of phenylalanine to tyrosine. It is an autosomal recessive trait with a stated frequency of 1 in 10,000. The resulting toxic-metabolite accumulation explains why affected infants can appear normal at birth before the phenotype emerges.

Routine newborn screening establishes PKU before most symptoms and is best performed after 48–72 hours of life. A positive screen should be followed by blood testing: phenylalanine is high, while tyrosine is low to normal. Guthrie’s test and the ferric chloride test are also listed as positive.

Galactosemia is described as involving three enzyme deficiencies, with GPUT deficiency—Galactose 1 Po4 uridyl transferase—identified as most common. It is also described as deficiency of galactose-1-phosphate uridyl transferase, abbreviated GALT. The condition is autosomal recessive, with a stated frequency of 1 in 60,000.

Newborn blood screening and positive reducing substances for galactosemia in the urine support the initial diagnosis; reducing sugar is also described in urine. Confirm with specific red-blood-cell GALT activity. Prenatal testing and carrier testing can also help with diagnosis.

Congenital adrenal hyperplasia may cause errors in steroidogenesis and sexual development; treatment includes mineralocorticoid and glucocorticoid replacement and possible genital reconstruction. Other recommended newborn screens include homocystinuria, which mainly causes thromboembolic complications; biotinidase deficiencies, which cause developmental delays; and beta thalassemia, a serious form of anemia.

In physiologic jaundice, total bilirubin rises less than 5 mg/dL per day and does not exceed 13 mg/dL in term infants or 15 mg/dL in preterm infants. Separately, jaundice on the first day, more than 10 mg/dL in premature infants, or more than 15 mg/dL in full-term infants warrants investigation.

After sufficient toxic metabolites accumulate, PKU can produce fair hair and skin, blue eyes, hypopigmentation, and a musty odor or musty urine. Vomiting may be projectile, resembling pyloric stenosis. Failure to grow is another feature, so the phenotype extends beyond neurologic findings.

Early dietary phenylalanine restriction is the treatment, but its duration has two conflicting formulations. One calls for a special low-phenylalanine diet for at least the first 16 years of life; the other calls for early phenylalanine restriction for a lifetime. The recommendations therefore differ between a minimum 16-year period and lifelong restriction.

GALT deficiency causes galactose-1-phosphate accumulation and brain, liver, and kidney damage. Cataracts are attributed specifically to galactitol accumulation. Galactose-1-phosphate is therefore linked with the named multiorgan damage, whereas galactitol is the stated basis of the cataract.

Rapid diagnosis and rapid removal of galactose from the diet are essential. Treatment is stated as eliminating galactose from the diet or cutting out all galactose-containing products. Even with early diagnosis and treatment, developmental delay and speech or learning disabilities may still occur.

A newborn hypothyroid pattern includes an open or large posterior fontanelle, sluggishness, hypotonia, hypothermia, pallor, constipation, a large tongue, an umbilical hernia, and rough, dry skin. Absent eyebrows and an absent social smile are also described. In children, cold extremities are a common feature.

PKU findings include severe intellectual disability, microcephaly, seizures or convulsions, hyperactivity, and tremor. Unless PKU is diagnosed and treated in time, infants can easily develop intellectual disability, microcephaly, heart disease, and spontaneous abortions.

A newborn with galactosemia may present with feeding problems, failure to thrive or lower body weight with growth delay, vomiting, diarrhea, and jaundice. Hepatomegaly or hepatosplenomegaly may accompany this pattern. In the case description, these findings begin within the first few weeks after an apparently normal birth.

The case course starts with a newborn who appears normal, then develops mild vomiting and diarrhea with jaundice and hepatomegaly within the first few weeks. Visual difficulty is diagnosed as cataracts by five months, and intellectual disability is evident by one year. This sequence is a galactosemia presentation.

Congenital hypothyroidism is associated with growth retardation, delayed puberty, delayed skeletal maturity, epiphyseal dysgenesis, and seminiferous tubule dysgenesis. A childhood case pattern combines lethargy, multiple epiphyseal breaks, Wormian bones, growth retardation, and intellectual disability. This later skeletal-developmental cluster points to hypothyroidism.

Additional galactosemia findings include seizures, hypoglycemia, cataracts—including the oil-drop cataract—and intellectual disability. The infant also has a higher risk of E. coli sepsis. The clinical features are described as a multi-organ presentation that includes neurologic, ocular, metabolic, and infectious findings.

For case recognition, prolonged physiologic jaundice with a large posterior fontanelle, sluggishness, or a large tongue supports congenital hypothyroidism. A normal newborn who later develops hypopigmentation, musty odor, and neurologic findings supports PKU. Early vomiting, diarrhea, jaundice, hepatomegaly, cataracts, or E. coli sepsis supports galactosemia.

Pendred syndrome has two linked formulations: hypothyroidism plus deafness, and goiter plus sensorineural deafness. The second formulation specifically names the deafness as sensorineural. Together, the formulations associate the same named syndrome with thyroid disease and deafness while preserving the more specific hearing-loss label.