What are the clinical manifestations of tyrosinemia types I, II, and III in pediatric patients?

Clinical Presentation of Tyrosinemia in Children

Tyrosinemia Type I (Hereditary Tyrosinemia Type 1)

Tyrosinemia Type I is a multisystem disorder that most commonly presents in infancy with profound coagulopathy despite minimally elevated or normal serum aminotransferase levels, accompanied by systemic illness and liver dysfunction. 1

Acute Infantile Form (Most Common)

• Hepatic manifestations: Systemic illness with liver dysfunction typically appearing in infants a few months old, with cirrhosis and hepatocellular carcinoma (HCC) commonly present at diagnosis 1
• Coagulopathy: Profound coagulopathy is often the earliest and most striking feature, occurring even before other signs of hepatic dysfunction become apparent 1, 2
• Laboratory findings: Minimally elevated or normal serum aminotransferases despite severe disease, elevated alpha-fetoprotein (AFP) at presentation (often 10-fold higher than age-appropriate neonatal values), and elevated methionine reflecting impaired hepatocellular function 1, 2, 3
• Diagnostic marker: Elevated blood or urine succinylacetone is pathognomonic and provides definitive diagnosis 1, 4, 3
• Hepatomegaly and ascites: Multiple intrahepatic mass lesions may mimic hepatoma on imaging, with markedly elevated AFP (>97 μg/mL reported) 5
• Renal involvement: Hepatorenal failure can occur in severe cases 6

Chronic Form (Older Children and Adults)

• Presentation: Features of chronic liver disease, including cirrhosis, portal hypertension, and progressive liver failure 1
• Hepatic nodules: Development of hepatic adenomas and HCC risk persists even with NTBC therapy, requiring regular surveillance with AFP and liver imaging 1
• Neurologic crises: Painful neurologic crises can occur, characterized by severe pain episodes 3
• Rickets: Bone manifestations including rickets may develop 3

Critical Diagnostic Pitfalls

• Normal tyrosine levels: Approximately 28% of HT-1 patients may have normal tyrosine levels at the time of newborn screening blood collection, making tyrosine alone an unreliable screening marker 4
• Volatile succinylacetone: In severe acute presentations, succinylacetone may be almost undetectable due to its volatile nature, potentially delaying diagnosis 6
• Masked biochemical abnormalities: Secondary changes from liver failure can mask specific metabolic abnormalities 6

Tyrosinemia Type II (Oculocutaneous Tyrosinemia)

Tyrosinemia Type II presents with dermatologic and ophthalmologic manifestations caused by tyrosine aminotransferase (TAT) deficiency, without the severe hepatic involvement seen in Type I. 3

Clinical Features

• Dermatologic: Hyperkeratotic plaques on the palms of hands and soles of feet due to tyrosine crystal deposition 3
• Ophthalmologic: Photophobia and corneal lesions caused by deposition of tyrosine crystals within the cornea 3
• Absence of hepatic failure: Unlike Type I, severe liver dysfunction is not a characteristic feature 3

Laboratory Findings

• Elevated tyrosine: Plasma amino acid chromatography shows elevated tyrosine 3
• Urine organic acids: Elevated p-hydroxyphenyl organic acids (p-hydroxyphenylacetate, p-hydroxyphenylpyruvate, and p-hydroxyphenyllactate) without succinylacetone 3

Tyrosinemia Type III

Tyrosinemia Type III is an extremely rare disorder caused by 4-hydroxyphenylpyruvic dioxygenase (4-HPPD) deficiency, with variable neurological manifestations and an unclear clinical phenotype. 3, 7

Clinical Spectrum

• Neurological involvement: Ataxia, mild mental retardation, intellectual impairment, and attention deficit hyperactivity disorder (ADHD) have been reported 3, 8
• Behavioral manifestations: Hyperactive behavior and attention span difficulties may develop, with earlier dietary intervention potentially improving outcomes 8
• Variable presentation: The full clinical spectrum remains unknown, with some patients detected via newborn screening remaining asymptomatic with dietary management 7, 8

Prognostic Factors

• Timing of treatment: Earlier initiation of low-protein dietary restriction appears to result in better neurological and behavioral outcomes compared to delayed treatment 8
• Growth and development: Normal growth and psychomotor development can be achieved with mild protein restriction when treatment begins early 7

Laboratory Findings

• Elevated tyrosine: Plasma amino acid analysis shows elevated tyrosine 3, 7
• Urine organic acids: Elevated p-hydroxyphenyl organic acids without succinylacetone 3
• Genetic confirmation: Molecular analysis of the HPD gene confirms diagnosis 7, 8

Key Distinguishing Features

The presence or absence of succinylacetone definitively distinguishes Type I from Types II and III, with succinylacetone being pathognomonic for Type I only. 4, 2, 3

• Type I: Life-threatening hepatic failure, coagulopathy, HCC risk, elevated succinylacetone 1, 4, 3
• Type II: Dermatologic and ophthalmologic manifestations without severe hepatic disease, no succinylacetone 3
• Type III: Primarily neurological/behavioral manifestations with variable severity, no succinylacetone 3, 7, 8