Disorders we test for

This information is designed for clinicians and GPs.

This information outlines the clinical features, laboratory tests, screening considerations and treatment options for a range of conditions.

Looking for information for parents? Have a look at our information sheets.

Congenital Adrenal Hyperplasia

Clinical features: CAH is an inherited condition affecting about 1 in 15,000 babies. The adrenal gland is a walnut sized gland which sits on top of the kidneys and produces 3 main hormones which are necessary for healthy body function

  • Cortisol which is essential for energy, blood pressure, blood glucose levels and helping the body to fight infection, illness and injury
  • Aldosterone which regulates salt and water balance
  • Androgens which are hormones involved in the development of genitalia and reproductive system.

The effects of CAH can vary significantly from person to person depending on how much the levels of each hormone are affected. The severe form or “classic” CAH has symptoms of salt wasting and virilising. A lack of cortisol and aldosterone can lead to a life threatening adrenal crisis with the baby vomiting, getting very lethargic and dehydrated. Also as a result of the enzyme block, the adrenal glands get bigger to try and compensate and end up making more androgens which may affect the appearance of the genitalia which is more evident in girls than in boys.

Laboratory test: The initial screening test measures the level of a steroid in the blood, 17-hydroxy progesterone, which is increased in babies with classic CAH but also in sick or premature babies. On the same blood spot, a second tier test measures the levels of several steroids in the blood and by determining the balance between these steroids assesses the likelihood of the baby having CAH. Babies with an imbalance of the steroid profile are referred for diagnostic testing.

Treatment: Correct and electrolyte imbalance. Replace the cortisol and aldosterone with oral medication and restore the balance of the adrenal gland hormones. This involves lifelong treatment.

Screening considerations: An affected infant must be detected early if major problems and intensive care admission are to be prevented.

Congenital Hypothyroidism (CH)

Congenital hypothyroidism occurs in babies who are born without the ability to produce adequate amounts of thyroid hormone. Thyroid hormone is important for normal function of all of the body's organs and is essential for normal brain development. If detected early a child will develop normally. Treatment is thyroid medication daily. Congenital Hypothyroidism affects about one in every 3,500 babies.

Clinical features: Deficiency of thyroid hormone may result in mental and growth retardation. If congenital hypothyroidism is not diagnosed and treated early in life, most infants will still appear clinically normal before 3 months of age, by which time some brain damage has usually occurred. Symptoms or signs, when present, may include prolonged neonatal jaundice, constipation, lethargy and poor muscle tone, poor feeding, a large tongue, coarse facies, wide fontanelle, distended abdomen and umbilical hernia.

Causes of congenital hypothyroidism: The most common cause of primary congenital hypothyroidism is dysgenesis (various abnormalities in the formation of the thyroid gland). There may be either athyrosis (no gland), ectopic thyroid (small displaced gland) or rarely a hemithyroid (only one half present). Less commonly, hypothyroidism is due to dyshormonogenesis, a hereditary inability to manufacture thyroid hormones due to various rare enzyme defects.

Laboratory tests: The initial screening test is the TSH (Thyroid Stimulating Hormone) assay. When TSH is slightly increased an urgent repeat sample is requested by letter. When screening results are significantly abnormal the infant's physician is notified by telephone. A blood sample should be collected to perform thyroid function tests (T3, T4, TSH). As well, further diagnostic studies, a thyroid scan, possibly by ultrasound, and bone age x-ray (knee), are used to determine the type, age of onset and severity of hypothyroidism.

Treatment: Treatment of congenital hypothyroidism with thyroxine is simple and effective. If treatment is started early, the development remains normal. Infants should be seen approximately every 3 months for an examination and blood test to check blood thyroid hormone levels to ensure that the dose of medication is adequate. As infants increase in size, the dose of thyroid hormones is increased.

Screening considerations: There is a TSH surge in the first 24 to 36 hours of life. Screening before 48 hours produces a high rate of false positive results due to this surge. The results can also be affected by maternal thyroid antibodies, medication for maternal thyroid disease, maternal iodine deficiency, excessive dietary iodine and external application of iodine to mother or baby.

Cystic Fibrosis (CF)

Cystic fibrosis is a recessively inherited disease involving the chloride channels in the apical membrane of epithelial cells. It is characterised principally by pancreatic and respiratory dysfunction. One in every 2,500 babies has CF. One in every 25 people in the NSW population is a carrier of CF. CF is commonest in persons of a Northern European background, but it is also relatively common in Mediterranean and Middle Eastern populations and possibly in parts of India. Early diagnosis and treatment are important, as recent medical and scientific advances have greatly improved the outlook for babies with CF.

The most common mutation in the CF gene, CFTR, which causes the disorder of cystic fibrosis is a three-base-pair deletion resulting in the loss of a phenylalanine residue at position 508. This mutation is called F508.

Clinical features: Cystic fibrosis is classically characterised by the triad of pancreatic insufficiency, recurrent and eventually chronic lung disease, and increased sweat electrolytes. The pancreatic disease causes meconium ileus (a bowel blockage) in about 20% of CF babies. It is also responsible for fatty motions, failure to thrive, and various specific nutritional deficiencies. Approximately 10% of CF patients show only partial pancreatic insufficiency, and retain enough function to prevent the syndrome of malabsorption. The respiratory disease is associated with thick and sticky mucus, causing a suppurative lung disease. The disease is almost invariably associated with elevated levels of electrolytes in the sweat, and this has been used as a definitive test.

Laboratory tests: The initial screening test measures immunoreactive trypsin (IRT) in the blood sample. The 1% of samples with the highest IRT are further investigated by a mutational analysis for F508 deletion. Babies who are homozygous for F508 are referred to a CF clinic. Babies who are heterozygous for F508 are referred for sweat testing to an experienced sweat testing laboratory.

Treatment: Treatment of CF is complex, and needs to be assessed for each individual. There are two main areas of treatment strategy: those dealing with pancreatic insufficiency and poor nutrition, and those concerned with improvement of lung function.

Screening considerations: Detection of CF in the neonate depends on the presence of an elevated IRT concentration in the blood sample, followed by a DNA analysis of samples with high IRT values. In babies with meconium ileus the IRT levels may not be very elevated. Therefore, information about meconium ileus should be indicated on the sample card to ensure that mutation analysis is carried out, even if the IRT falls into the normal range.

Fatty acid oxidation defects

Medium-chain acylCoA dehydrogenase (MCAD) deficiency

Clinical features: Well babies or children who present with vomiting, lethargy proceeding to coma and liver disease in the course of an intercurrent illness such as gastroenteritis or with prolonged fasting. Some patients never have symptoms.

Laboratory tests: Elevation of octanoyl carnitine is determined using tandem mass spectrometry. Follow-up tests include a DNA test, urine organic acids, and plasma acyl carnitines.

Treatment: Avoidance of fasting, especially during intercurrent illness, when intravenous glucose may be needed.

Screening considerations: Can be reliably detected unless the baby is already ill and carnitine-depleted at the time of the test.

Other fatty acid oxidation disorders

Screening by tandem mass spectrometry can detect many of the fatty acid oxidation disorders including disorders of the carnitine cycle, and short chain and long chain disorders.

Clinical features: The clinical features in untreated patients vary, and may involve liver disease, skeletal muscle and cardiac muscle disease.

Laboratory tests: Measurement of several acyl carnitines are performed using tandem mass spectrometry. Follow-up tests may include a DNA test, urine organic acids, plasma acyl carnitines and a skin biopsy for analysis of relevant enzymes and/or metabolites.

Treatment: Most of the disorders are treatable by dietary means and in one, carnitine medication is clearly indicated.

Screening considerations: Reliability of detection for most disorders is not yet certain.


Galactosaemia caused by galactose-1-phosphate uridyl transferase deficiency has a birth incidence of 1:40,000. The disorder is caused by the accumulation in the blood of one of the sugars (galactose) in milk. Prompt treatment with a special formula that does not contain galactose will completely prevent serious illness. Untreated babies with galactosaemia may become very sick and die.

Clinical features: The severe form of this disease is due to almost total deficiency of galactose-1-phosphate uridyl transferase (Gal-1-PUT) enzyme activity in all cells of the body. The early clinical features include neonatal hypoglycaemia, vomiting, jaundice, and liver failure. Death may result from liver failure or gram-negative sepsis within one to two weeks of birth. If the infant survives the neonatal period, failure to thrive, cirrhosis, kidney disease (proximal renal tubular acidosis), cataracts and mental retardation may develop.

Mild variants: There are several genetic variants with only partial enzyme deficiency. One very common one is the Duarte variant. Babies with variant galactosaemia are asymptomatic and do not need treatment. They may be detected because of a mild elevation of galactose metabolites due to reduced activity in the Gal-1-PUT enzyme assay in the first three months of life.

Galactokinase deficiency: This rare defect is associated only with the development of cataracts in infancy and possibly with some degree of mental retardation. The life-threatening symptoms of severe galactosaemia do not occur.

Laboratory tests: Elevations of galactose metabolites are detected using a manual fluorometric assay for galactose and/or galactose-1-phosphate. Blood galactose metabolites are quite frequently elevated (1 mmol/L) in normal neonates. They are greatly elevated in infants with galactose-1-phosphate uridyl transferase (Gal-1-PUT) and galactokinase deficiency, but only when they are receiving lactose-containing feeds. When galactose metabolites are elevated, a follow up test is thin layer chromatographic separation of the sugars. This allows the determination of levels of galactose or galactose-1-phosphate. The metabolite increase gives an indication of the enzyme defect leading to galactosaemia. Samples with elevated galactose metabolites are tested urgently for Gal-1-PUT activity.

Treatment: The galactosaemia syndromes are effectively treated by a rigid dietary exclusion of all galactose.

Screening considerations: The Gal-1-PUT assay should be abnormal in all severe (classical) galactosemic infants even if the specimen is obtained before lactose is ingested, unless the infant has had an exchange transfusion. Obtain a specimen before an exchange transfusion. Galactose accumulation depends on lactose ingestion so that blood galactose is normal in infants receiving soy-based formula or other forms of nutrition. Galactosaemia may be rapidly fatal and should be considered in any infant with non-glucose reducing substances in the urine, although this is not a reliable test for galactosaemia.Rare aminoacidopathies (other than PKU)

Homocystinuria (cystathionine synthase deficiency)

Clinical features: Untreated children and adults with homocystinuria may have dislocation of the lenses, generalised osteoporosis, premature clotting in arteries or veins (thromboembolic disease), and intellectual retardation. Affected individuals have a 30% risk of a blood clotting event by the age of 30 years.

Laboratory tests: Elevation of the amino acid, methionine, is determined using tandem mass spectrometry.

Treatment: Treatments that reduce plasma homocysteine levels prevent or delay the onset of symptoms. Approximately half the patients are responsive to medication with vitamin B6 (pyridoxine) and folate. The other patients require the addition of betaine. Babies can be started on a low-methionine diet with methionine-free aminoacid supplement. All patients will need extra vitamin B12 also.

Screening considerations: Detection depends on the amount of protein ingested by the infant. Not all infants may develop methionine levels high enough to be detected in the first days of life. B6-responsive patients are especially likely to be missed. Homocystinuria due to remethylation defects, (cobalamin C,D,E,F, and G defects) may also be missed by screening as methionine is not elevated in these cases. These cases may however have a mild elevation of another analyte, propionyl carnitine, and may therefore be detected.

Maple Syrup Urine Disease (MSUD)

Clinical features: MSUD is a rare disorder associated with progressive neurological damage within a few days of birth. A high pitched cry, irritability, convulsions, spasticity, and central nervous system depression leading to coma are usual. If not treated, the disease leads to death in 2-4 weeks. Biochemically, there is pronounced ketosis, without a metabolic acidosis in the neonate, and hypoglycaemia may occur. Urine has a sweet maple syrup odour which gives the disease its name. As with all hereditary disorders, there are less severe variants, the mildest of which may go undetected for months or years until some intercurrent illness unmasks the biochemical abnormalities.

Laboratory test: Elevation of the amino acids, leucine + isoleucine, are determined using tandem mass spectrometry.

Treatment: Rapid assessment is needed. Detected babies may need intensive care for a few days. A low-protein diet with amino acid formula free of branched chain amino acids is the long-term regimen.

Screening considerations:
Detection depends on protein ingestion. An affected infant must be detected early if major problems are to be prevented. Mild forms of MSUD may be missed as the blood levels may not be elevated in the first few weeks of life.

Organic acidopathies

A range of these disorders may be detected, including those mentioned below.

Clinical features: Methylmalonic aciduria, propionic acidaemia and isovaleric acidaemia may present with severe metabolic acidosis in the newborn period or later. A more insidious presentation is also possible. Several other even rarer disorders can also present in this way. Glutaric aciduria type I can present during an intercurrent illness with severe dystonia (abnormal movements) of sudden onset, or may present insidiously with hypotonia and milder dystonia. There is usually macrocephaly (a large head).

Laboratory tests: Detection of a range of acyl carnitines is performed using tandem mass spectrometry. Follow-up tests include urine organic acids and plasma acylcarnitines.

Treatment: Often a low protein diet is needed, plus specific medications in some of the disorders. Carnitine supplementation is helpful in many of the disorders.

Screening considerations: Reliability of detection is not known, but should be high for most organic acidopathies. For glutaric aciduria type I, a proportion of patients are "low excretors" and detection may be difficult or impossible.

Primary immune deficiencies (Pilot study)

Clinical features: Children with PIDs have little or no functioning immune system and are vulnerable to recurrent infections. Babies appear normal at birth but start showing signs of illness in the first 6 months of life.  They develop persistent thrush, chronic diarrhoea, failure to thrive, eczematous rash, and recurrent severe and life-threatening infections.  If undiagnosed they usually die by the age of 2 years.

Laboratory test: Levels of T and B cell numbers are detected using an assay for TREC (T-cell receptor excision circles) and KREC (Kappa recombination excision circles) which are small circles of DNA created during maturation of the cells. The fragments are made in large numbers in healthy newborns but are low in immune deficiencies.

Treatment:  Infections need to be treated and preventative therapies such as antibody replacement and long term antibiotics commenced. For some PIDs, curative therapy is bone marrow transplantation to replace the faulty immune system. For some PIDs, treatment is lifelong replacement with antibodies, derived from donated blood, to prevent infections.

Screening considerations: Newborn screening tests will not detect all immune deficiencies. Premature babies and babies born to mothers on some medications may have falsely low levels of T and/or B cells and require further testing to determine if they have a condition needing on going treatment.

Phenylketonuria (PKU)

This disorder is caused when a baby's body cannot breakdown the amino acid, phenylalanine, which is in protein. PKU is a rare condition due to a recessively inherited deficiency of the enzyme phenylalanine hydroxylase. If the baby is detected by NBS and given a diet low in phenylalanine (very low protein plus a special formula) there will be normal growth and development. Untreated PKU causes severe mental deficiency, which can be avoided if treatment is started in the first weeks of life.

Although severe mental deficiency is usual in untreated cases, occasional asymptomatic adults are found with normal or near normal intelligence. Overall, PKU occurs in about 1 in 10,000 babies born in NSW.

Variant forms of PKU (hyperphenylalaninaemia)

There are several intermediate forms of hyperphenylalaninaemia in which the plasma phenylalanine levels are lower. At present we advocate treatment if phenylalanine levels in the untreated baby are 400 umol/L or more.

In about 1% of cases of high blood phenylalaninaemia, the hyperphenylalaninaemia is caused by enzyme defects of biopterin metabolism. These patients need different treatment. Definitive tests can differentiate these variant forms of PKU. In view of the severity of this group of diseases, all infants with persistently abnormal levels of phenylalanine should be tested by analysis of the Dihydropteridine reductase activity in the blood spot. As well, urine tests for biopterin should be performed at the Biochemistry Department.

Maternal PKU and hyperphenylalaninaemia: Women with phenylketonuria who are not on a low phenylalanine diet have a very high risk of having a baby with the maternal phenylketonuria syndrome - microcephaly, mental retardation, growth retardation, and in some, congenital heart disease. A phenylalanine-restricted diet before conception and during pregnancy can prevent damage to the foetus. Babies of mothers with untreated PKU have a transient elevation of phenylalanine (200-1000 umol/L) which falls to normal within 24 hours. A screening test for the mothers of infants with transient hyperphenylalaninaemia, particularly if the infant's sample was collected in the first 24 hours after birth, is recommended, as is a screening test for mothers of babies with unexplained microcephaly.

Laboratory tests: PKU is screened for using Tandem Mass Spectrometry. The normal phenylalanine level of babies in the first week of life is <200 umol/L. Confirmatory testing of elevated results is performed using capillary electrophoresis. Measurement of not only phenylalanine but also tyrosine quantitation allows differentiation of secondary causes of hyperphenylalaninaemia eg due to TPN.

Treatment: Babies with a blood phenylalanine concentration of 400 umol/L and above are admitted to the Care by Parents ward to determine whether the baby has classical PKU and not a defect of biopterin (BH4) metabolism. This admission opportunity enables the family to meet the PKU team and be taught the dietary requirements for their baby.

With proper treatment, mental retardation is totally preventable. Treatment should be started as soon after birth as possible in any infant with phenylalanine levels over 400 umol/L, and should be continued preferably for life. Frequent monitoring is required, especially in the first weeks. The expert nutritional supervision required is provided through the PKU clinic.

Screening considerations: Plasma phenylalanine is not detectably elevated in cord blood. The screening test is almost uniformly abnormal within 48 hours of birth whether or not the baby is receiving full milk feeds.

We know of no missed case of PKU in NSW in the last 25 or more years. However, the earlier the test, the more likely that the phenylalanine level could be in the normal range. Thus, a test before 48 hours of age is deemed inappropriate. When a previous sibling has PKU, however, a test may be performed early provided that if it is negative, a follow-up test is performed at 3-4 days.

SMA (Pilot study)

Clinical features: SMA is a hereditary neuromuscular disorder causing progressive muscle weakness, and in severe cases leads to paralysis and respiratory insufficiency. The nerve cells in the brain stem and spinal cord become damaged and are unable to control voluntary muscles. SMA is categorised into four types depending on the severity of health problems and when the symptoms start to appear. The severity depends on the number of copies the individual has of 2 different genes. Current newborn screening cannot distinguish between the four types.

In the most severe cases babies will not ever be able to sit, crawl or walk. In the mildest cases there are no symptoms until well into adulthood.

SMA is a lifelong condition and if untreated can cause the following symptoms:

  • Muscle weakness
  • Delayed motor milestones
  • Loss of skills like sitting and walking
  • Swallowing and feeding difficulties
  • Breathing difficulties
  • Shortened lifespan

Laboratory test: The initial screening test measures the number of copies of one of the genes. If gene 1 is totally absent the severity depends on the number of copies of gene 2. Babies who appear to have no copies of gene 1 are referred to a specialist for further testing

Treatment: options for SMA include:

  • Supportive therapies like physiotherapy and respiratory therapy
  • Drug therapy

Children who have drug therapy started before problems are evident live a healthier and longer life. As the drug is only new, long term outcomes are yet to be known.

Screening considerations: Current newborn screening cannot distinguish between childhood onset and adult onset types.

Tyrosinaemia types I and II

Clinical features: Type I
If untreated may include liver disease (acute liver failure or cirrhosis) and renal tubular acidosis and rickets. Later development of liver cancer.

Clinical features: Type II
Photophobia and corneal ulceration, palmar and plantar hyperkeratosis (painful thickened skin).

Laboratory test: Elevation of the amino acid, tyrosine, is determined using tandem mass spectrometry. Confirmation and quantitation are performed using capillary electrophoresis.

Treatment: Low phenylalanine and tyrosine diet for both types. For Type I, specific drug, NTBC. Later liver transplantation.

Screening considerations: Type I tyrosinaemia will not be detected reliably by the current strategy without a very high resample rate, as tyrosine levels may not be very high in the first days. Type II will be reliably detected.

Urea cycle disorders

Three urea cycle disorders may be detected: argininosuccinnate synthase deficiency (citrullinaemia) and argininosuccinnate lyase deficiency (argininosuccinic aciduria) in which blood citrulline levels are high, and some cases of ornithine transcarbamylase (OTC) deficiency, where citrulline levels are very low.

Clinical features: All three disorders can present with severe life-threatening high blood ammonia levels in the first days of life, or with a milder late onset form, symptoms including intellectual impairment.

Laboratory test: Measurement of the amino acid, citrulline, is determined using tandem mass spectrometry.

Treatment: Low protein diet and medications - arginine, and use of specific medications to reduce ammonia levels.

Screening considerations: Necessity for rapid telephone response to both low and very high citrulline levels, but not to modest elevations. Detection of OTC deficiency may not be reliable.

assay should be abnormal in all severe (classical) galactosemic infants even if the specimen is obtained before lactose is ingested, unless the infant has had an exchange transfusion. Obtain a specimen before an exchange transfusion. Galactose accumulation depends on lactose ingestion so that blood galactose is normal in infants receiving soy-based formula or other forms of nutrition. Galactosaemia may be rapidly fatal and should be considered in any infant with non-glucose reducin