Red flags for genetic disorders

Contemporary PEDS JournalVol 35 No 10
Volume 35
Issue 10

At a minimum, the pediatrician should be familiar with genetic disease on the newborn screen and other genetic diseases they may see in their office. It’s also important to recognize the child with multiple medical issues who also may need referral to a genetic or metabolic specialist.

Genetic and metabolic disorders are relatively uncommon in the day-to-day practice of a pediatrician. However, there are a number of disorders every pediatrician should be able to recognize and for which he or she may need to make appropriate referral and provide care.

Consider the following 4 cases and think about what is the most likely diagnosis and what a pediatrician would do in the office. A brief discussion of each of the cases follows.

Case 1

You receive a note from your nurse that the newborn screen for a 5-day-old neonate that you recently discharged from the hospital was positive for phenylketonuria (PKU). What are your essential next steps?

Diagnosis: PKU

Phenylketonuria is asymptomatic in the newborn period, and nearly 100% of cases are diagnosed in the newborn period by screening. Without identification and treatment, irreversible mental retardation, hyperactivity, autistic-like features, and seizures will occur.1 Phenylketonuria can result in severe hyperphenylalaninemia.


Phenylalanine levels are elevated in PKU as a result of deficient liver phenylalanine hydroxylase (PAH) preventing ingested phenylalanine from being metabolized to tyrosine. Any infant with elevated phenylalanine should also have levels of tetrahydrobiopterin (BH4), itself an essential cofactor for PAH. Defects in BH4 metabolism may have progressive neurologic deterioration in infancy.1


Treatment of PKU is best done through an interdisciplinary team consisting of nutritionists, psychologists, social workers, metabolic specialists, and pediatricians. Lifelong restriction of phenylalanine is the mainstay of treatment and requires medical foods with phenylalanine-free protein substitutes.2,3

The goal of treatment is normalization of phenylalanine levels as this prevents the neurological defects associated with PKU.

Sapropterin (Kuvan) is a pharmacologic treatment that can decrease phenylalanine levels in patients who are sensitive to BH4.1


Cognitive outcomes correlate with control of phenylalanine concentration in the blood, especially in early childhood. Even with strict adherence, some suboptimal cognitive outcomes may still occur.1

Attention deficit and information processing are noticed in adults with current elevated levels of phenylalanine as well as in those with elevated phenylalanine in the past. There is also a higher incidence of mental health issues such as anxiety, depression, phobias, and panic attacks among patients who discontinue therapy in the second decade of life.1

Next steps

The pediatrician who receives a positive screening result for a patient should:1

·      Contact the family and inform them of the positive result.

·      Contact a metabolic specialist to discuss confirmatory diagnostic testing, evaluation, and treatment.

·      See the patient in clinic for an evaluation and initiate confirmatory/diagnostic tests in consultation with the metabolic specialist.

·      Report results to the newborn screening program.

·      The National Institutes of Health (NIH) Consensus Development Conference Statement on PKU recommends phenylalanine testing weekly in the first year and then bimonthly until age 12 years.3

Case 2

 A 2-year-old toddler presents with progressive joint stiffness, progressive short stature, coarse facies, and macrocephaly. The family history is significant for the mother’s brother who died at age 12 years from complications of heart failure and loss of cognition (neuroregression). What is your diagnosis?

Diagnosis: Hunter syndrome/Mucopolysaccharidosis type II

Mucopolysaccharidosis type II (MPS II), also known as Hunter syndrome, is an X-linked disorder with an early progressive component and a slowly progressive form of disease.4

Suggestive findings

The initial case in a family is a male aged between 18 months and 4 years with the following features predominating: short stature, hepatosplenomegaly, joint contractures, and coarse facies.4 Although nonspecific, frequent ear and sinus infections as well as an umbilical hernia are noted. Skeletal survey may show dysostosis multiplex.4

Pathophysiology and diagnosis

Mucopolysaccharidosis type II is an X-linked recessive disorder resulting from a deficiency of the lysosomal enzyme iduronate 2-sulphatase (I2S). This leads to a pathologic, progressive increase in lysosomal storage of glycosaminoglycans (GAGs) in nearly all cell types, tissues, and organs. There is significant variability in age of onset and rate of progression.4

Definitive diagnosis cannot be made on clinical findings alone and requires either absent or reduced I2S enzyme activity or the Identification of a hemizygous IDS pathogenic variant via molecular genetic testing.4


Age-appropriate testing to establish the extent of disease may include:4

·      Echocardiogram.

·      Pulmonary function testing.

·      Sleep study.

·      Hearing test.

·      Eye examination.

·      Developmental assessment.

·      Magnetic resonance imaging (MRI) of the brain.

·      Nerve conduction study.

When specific organ systems are involved, the patient requires specific treatments such as cardiac valve replacement or repair; mechanical ventilation or tracheostomy; tonsillectomy; or shunting for hydrocephalus.


Central nervous system (CNS) involvement is the most significant feature of early progressive disease and progressive cognitive deterioration is the norm. Combined with airway and cardiac problems, death usually occurs before age 20 years.4

In the slowly progressive form of the disease, CNS is less affected, but GAG accumulation is similar to the early progressive. Survival into early adulthood with normal intelligence is common.4

Presence of the following symptoms is associated with poor cognitive outcome:4

·      Sleep disturbance.

·      Increased activity.

·      Behavior difficulties.

·      Seizure-like behavior.

·      Perseverative chewing behavior.

·      Inability to achieve bowel and bladder training.

Idursulfase (Elaprase) is a recombinant form of human I2S. Enzyme replacement therapy with recombinant forms of human I2S have been shown to improve functional outcomes. However, it does not alter CNS disease as it does not cross the blood-brain barrier.4

Case 3

A 4-month-old girl presents for evaluation for hypotonia, generalized muscle weakness, feeding difficulties, failure to thrive, and respiratory distress. Family history is negative, and physical exam of parents is normal. What is your diagnosis?

Diagnosis: Pompe disease/Glycogen storage disease II

Pompe disease, also known as glycogen storage disease type II (GSD II) is an autosomal recessive disorder with a variable presentation depending on age of presentation.5

Suggestive findings

Both infantile-onset and late-onset Pompe disease should be suspected with a combination of clinical findings and test abnormalities.5

Infantile-onset Pompe disease (IOPD) is suggested with a combination of:5

·      Poor feeding and failure to thrive.

·      Motor delay and muscle weakness.

·      Respiratory infections.

·      Cardiomyopathy or other cardiac problems.

Additional symptoms may include hepatomegaly, enlarged tongue, absent deep tendon reflexes, enlarged tonsils, and normal cognition. Glycogen deposition may lead to conduction defects manifesting as a shortened PR interval on electrocardiogram (ECG).5

Late-onset Pompe (LOPD) is characterized by proximal muscle weakness and respiratory problems without cardiac involvement. Lower limb weakness often requires use of a wheelchair. Adults often describe difficulty in participating in sports as a child and seek medical attention later in life with fatigue, difficulty going from sitting to standing, or walking up stairs.5

Newborn screening may be abnormal but is not diagnostic of Pompe disease. Creatinine kinase is elevated but is nonspecific.5

Pathophysiology and diagnosis

Acid alpha-glucosidase (GAA) deficiency leads to accumulation of glycogen in lysosomes and cytoplasm and results in tissue destruction.

Diagnosis is established via 1 of the following:5

·      Decreased GAA enzyme activity.

·      Single- or multigene testing.

·      Targeted analysis for pathogenic variant (requires certain ancestry, (eg, African American or Chinese).


Enzyme replacement therapy is initiated as soon as possible with an IOPD diagnosis or as soon as a symptomatic Pompe disease is diagnosed.5

Testing examines the extent of disease progression and includes:5

·      Chest radiography.

·      Electrocardiography.

·      Echocardiography.

·      Age-appropriate pulmonary function.

·      Nutritional assessments.

·      Hearing screening.

·      Motor functioning.


If IOPD is not treated, cardiomegaly and hypertrophic cardiomyopathy may occur in the first 2 weeks of life. This will progress to left ventricular outflow obstruction, and death occurs in the first 2 years of life because of cardiopulmonary insufficiency.5 Early IOPD treatment with enzyme replacement therapy is associated with both improved cardiac and respiratory outcomes as well as improved motor skills.5

In LOPD, enzyme replacement therapy improves motor functions, respiratory function, and quality of life.5

Case 4

 A 4-month-old infant presents with a hypoglycemic seizure noted by the parents in the morning when they go to wake him. He is noted to have hepatomegaly and splenomegaly. The mother reports his pediatrician has been worried about the baby’s height being short, and she has been worried about her child’s protuberant abdomen. What is your diagnosis?

Diagnosis: Glycogen storage disorder type I

Glycogen storage disease type I (GSDI), also known as von Gierke disease, is an autosomal recessive disorder characterized by accumulation of glycogen and fat in the liver and kidney. Although there are 2 subtypes, they are clinically indistinguishable.6

Suggestive findings

Glycogen storage disease type I should be suspected with a combination of clinical, test, and histopathologic abnormalities. These include:6

·      Hypoglycemia.

·      Seizures attributed to hypoglycemia.

·      Hepatomegaly.

·      Growth failure.

·      Elevated blood lactate.

·      Hyperuricemia.

·      Elevated cholesterol and triglycerides.

·      Distention of the liver cells by glycogen and fat.

·      Periodic acid-Schiff (PAS) stain positive.

·      Absence of fibrosis and cirrhosis.

Untreated infants usually present with the symptoms listed above by ages 3 to 4 months. They are often noted to have doll-like faces with fat cheeks, thin extremities, and a protuberant abdomen. Epistaxis may occur because of impaired platelet function.6

Pathophysiology and diagnosis

Most cases of GSDI result from a deficiency in the glucose 6-phosphate hydrolase activity. Because this enzyme is primarily expressed in the liver and kidney, most problems relate to these organ systems.6

Diagnosis is established via either:6

·      Decreased hepatic enzyme activity.

·      Single- or multigene testing.

·      Targeted analysis for pathogenic variant in those of Ashkenazi Jewish or Old Order Amish ancestry.


Management targets medical nutritional therapy with a goal of maintenance of normal blood glucose levels and prevention of hypoglycemia. Allopurinol is often needed to prevent gout if diet does not normalize uric acid level. Lipid-lowering medication is often needed for the management of hyperlipidemia and citrate therapy is needed to prevent renal calculi. Angiotensin-converting enzyme inhibitors are indicated for microalbuminuria and kidney transplant is indicated for end-stage renal disease.6

Testing examines the extent of disease progression and includes:6

·      Measurement of glucose, lactic acid, uric acid, 25-hydroxyvitamin D, liver function tests, and lipids.

·      Nutritional assessment.

·      Liver and kidney imaging.

·      Platelet function tests.

·      Bone density.

·      Screening for pulmonary hypertension.


Most patients with GSDI will live into adulthood. Long-term complications of untreated GSDI include:6

·      Short stature.

·      Osteoporosis.

·      Delayed puberty.

·      Gout.

·      Renal disease.

·      Pulmonary hypertension.

·      Hepatic adenomas with potential for malignant transformation.

·      Polycystic ovaries.

·      Pancreatitis.

·      Changes in brain function.

·      Irregular sense in women.



At a minimum, it is important for the pediatrician to be familiar with the disease on their state newborn screen as well other genetic diseases they may see in their office. Additionally, it is important to recognize that the child with multiple medical issues may have a syndromic condition and need referral to a genetic or metabolic specialist.


1. Regier DS, Greene CL. Phenylalanine hydroxylase deficiency. In: Adam MP, Ardinger HH, Pagon RA, et al. GeneReviews (Internet). Seattle, WA: University of Washington;1993-2018. Available at: Revised January 5, 2017. Accessed September 5, 2018.

2. Feillet F, van Spronsen FJ, MacDonald A, et al. Challenges and pitfalls in the management of phenylketonuria. Pediatrics. 2010;126(2):333-341.

3. National Institutes of Health Consensus Development Panel. National Institutes of Health Consensus Development Conference Statement: phenylketonuria: screening and management, October 16-18, 2000. Pediatrics. 2001;108(4):972-982. Available at: Accessed September 5, 2016.

4. Scarpe M. Mucopolysaccharidosis type II. In: Adam MP, Ardinger HH, Pagon RA, et al. GeneReviews (Internet). Seattle, WA: University of Washington;1993-2018. Available at: Accessed September 5, 2018.

5. Leslie N, Bailey L. Pompe disease. In: Adam MP, Ardinger HH, Pagon RA, et al. GeneReviews (Internet). Seattle, WA: University of Washington;1993-2018. Available at: Accessed September 5, 2016.


6. Dagli A, Sentner CP, Weinstein DA. Glycogen storage disease type I. In: Adam MP, Ardinger HH, Pagon RA, et al. GeneReviews (Internet). Seattle, WA: University of Washington;1993-2018. Available at: Accessed September 5, 2018.

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