Clinical characteristics.

Tyrosinemia type II is characterized by corneal dystrophy, painful palmoplantar hyperkeratosis, and variable intellectual disability. Individuals diagnosed and treated from early infancy may be asymptomatic or have only mild ocular and skin manifestations. Individuals with delayed diagnosis or lack of treatment present with ocular, skin, and variable cognitive manifestations.

Diagnosis/testing.

The diagnosis of tyrosinemia type II is established in a proband by identification of biallelic pathogenic variants in TAT on molecular genetic testing or – in limited instances – significantly reduced activity of the enzyme tyrosine aminotransferase in liver.

Management.

Targeted therapy: Lifelong restriction of dietary tyrosine and phenylalanine with low-protein diet combined with age-appropriate amino acid (phenylalanine-free and tyrosine-free), vitamin, and mineral supplements.

Supportive care: Lubricating eye drops and ointment; ocular surgery as needed to treat bilateral corneal ulcers; pyridoxine phosphate or a systemic retinoid may be beneficial for skin manifestations; developmental and educational support.

Surveillance: Quantitative analysis of plasma tyrosine and phenylalanine concentrations at each visit; ophthalmology evaluation annually or as needed; evaluation by ophthalmic subspecialist annually or as recommended by ophthalmologist; skin assessment for hyperkeratotic plaques as clinically indicated; monitoring of developmental milestones, neuropsychological testing using age-appropriate standardized assessment batteries, and standardized quality-of-life assessment tools for affected individuals, parents, and/or caregivers annually or at each visit; measurement of plasma calcium, phosphorus, and 25-hydroxyvitamin D concentrations annually or as clinically indicated.

Agents/circumstances to avoid: Increased dietary protein.

Evaluation of relatives at risk: Testing of at-risk sibs of any age is warranted to allow for early diagnosis and treatment.

Genetic counseling.

Tyrosinemia type II is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a TAT pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the TAT pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

Suggestive Findings

Tyrosinemia type II is caused by deficiency of the enzyme tyrosine aminotransferase (TAT) (see Figure 1). Tyrosinemia type II should be suspected in individuals with either abnormal newborn screening (NBS) results or clinical and laboratory findings suggestive of tyrosinemia type II. Note: Tyrosinemia type II is not typically included in NBS panels, but may be detected when screening for tyrosinemia type I.

Figure 1.

The tyrosine catabolic pathway FAH = fumarylacetoacetate hydrolase; HGD = homogentisate 1,2-dioxygenase; HPD = 4-hydroxyphenylpyruvic acid dioxygenase; MAI = 4-maleylacetoacetate cis-trans-isomerase; PAH = phenylalanine hydroxylase; TAT = tyrosine aminotransferase (more...)

Establishing the Diagnosis

The diagnosis of tyrosinemia type II is established in a proband by identification of biallelic pathogenic (or likely pathogenic) variants in TAT on molecular genetic testing (see Table 1) or – in limited instances – significantly reduced activity of the enzyme tyrosine aminotransferase in liver. Because of its relatively high sensitivity, TAT molecular genetic testing can obviate the need for enzymatic testing and, thus, is increasingly the preferred confirmatory test for tyrosinemia type II [Beyzaei et al 2022].

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic TAT variants of uncertain significance (or of one known TAT pathogenic variant and one TAT variant of uncertain significance) does not establish or rule out the diagnosis.

Scenario 1: Abnormal newborn screening (NBS) result. When NBS results and other laboratory findings suggest the diagnosis of tyrosinemia type II, molecular genetic testing approaches can include single-gene testing or use of a multigene panel.

• Single-gene testing. Sequence analysis of TAT is performed first to detect missense, nonsense, and splice site variants and small intragenic deletions/insertions. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
• A multigene panel that includes TAT and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Scenario 2: A symptomatic individual. When the diagnosis of tyrosinemia type II has not been considered (because an individual has atypical findings associated with later-onset tyrosinemia type II or untreated infantile-onset tyrosinemia type II resulting from NBS not performed or false negative NBS result), comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is an option. Exome sequencing is most commonly used; genome sequencing is also possible. To date, the majority of TAT pathogenic variants reported (e.g., missense, nonsense) are within the coding region and are likely to be identified on exome sequencing.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

Tyrosinemia type II is characterized by corneal dystrophy, painful palmoplantar hyperkeratosis, and variable intellectual disability. Individuals diagnosed and treated from early infancy may be asymptomatic or have only mild ocular and skin manifestations. Individuals with delayed diagnosis or lack of treatment present with ocular, skin, and variable cognitive manifestations [Gliagias et al 2022]. To date, more than 70 individuals have been identified with tyrosinemia type II [Beyzaei et al 2022]. The following description of the phenotypic features associated with this condition is based on these reports.

Ocular manifestations can appear in the first months or first year of life or as late as the fourth decade [Viglizzo et al 2006]. Ocular symptoms include epiphora (increased tearing), photophobia, pain, and blepharospasm. Ocular signs include corneal clouding, pseudodendritic corneal lesions (usually bilateral), dendritic ulcers, and, rarely, corneal or conjunctival plaques. The dendritic lesions on the cornea stain poorly with fluorescein.

• Bacterial, viral, and fungal cultures are typically negative.
• Ocular manifestations may undergo spontaneous remission and/or recurrence and may occur independently of other clinical manifestations.
• Individuals are often misdiagnosed with herpes simplex keratitis [Soares et al 2017].
• Bilateral corneal lesions unresponsive to antiviral therapies should alert the clinician to the possible diagnosis of tyrosinemia type II, even in the absence of skin lesions [Macsai et al 2001].
• Some individuals with tyrosinemia type II report isolated burning and redness of the eyes since childhood [Ghalamkarpour et al 2020].
• Asynchronous bilateral eye disease was the sole clinical feature reported in one child age 15 months with negative NBS for tyrosinemia type II [Gliagias et al 2022]. Following diet modification, tyrosine levels decreased, resulting in significant resolution of ocular symptoms [Gliagias et al 2022].
• Dietary treatment (see Management, Targeted Therapy) has resulted in significant improvement of ocular manifestations in most affected individuals within the first week of treatment [El-Shabrawi & Kamal 2013, Tekin et al 2015].
• Corneal lesions recurred in one individual after discontinuation of dietary restrictions [Macsai et al 2001].

Skin manifestations can appear in the first months of life or be delayed until the second decade [Rabinowitz et al 1995]. They typically present as progressive painful hyperkeratotic plaques on the soles and palms, often associated with hyperhidrosis [da Silva et al 2024]. The fingertips and weightbearing areas of the soles are commonly affected by keratoderma.

• One individual had vesicular lesions on the fingertips [Peña-Quintana et al 2017].
• Skin manifestations rarely resolve spontaneously and often recur.
• The pain experienced with palmoplantar keratoderma is a key diagnostic feature, and it can be severe enough to hinder walking [Viglizzo et al 2006].
• A skin biopsy from a plantar callus showed hyperkeratosis, hypergranulosis, and acanthosis [Al-Ratrout et al 2005].
• Dietary restriction of tyrosine and phenylalanine is a highly effective treatment; significant improvement of skin manifestations in most individuals occurs within the first week of treatment [Tekin et al 2015].
• In one individual, the toenails showed subungual hyperkeratosis and secondary nail dystrophy [Madan & Gupta 2006].

Developmental delay. Infants diagnosed and treated in early infancy typically have normal development. Untreated individuals can have global developmental delay including poor feeding with poor appetite and reduced oral intake [Gliagias et al 2022].

Mild developmental delay with hemiparesis and seizures has been reported in one individual [Charfeddine et al 2006].

Intellectual disability. About half of individuals with tyrosinemia type II have mild intellectual disability, but early dietary treatment may reduce this risk [Legarda et al 2011, Nakamura et al 2015, da Silva et al 2024]. Mild language disorder has been reported in three individuals [Charfeddine et al 2006]. Intellectual disability may be prevented by early dietary restriction of tyrosine and phenylalanine. Language development was reported to improve with dietary treatment [Tsai et al 2006].

Nutritional deficiencies can appear in individuals due to limitations of certain amino acids (phenylalanine, tyrosine, and methionine) in the diet. Deficiency of calcium, phosphorus, and 25-hydroxyvitamin D have been observed.

Other

• Isolated geographic tongue with otherwise normal clinical findings (1 individual) [Bouyacoub et al 2013]
• Self-harm (agitation with paroxysms of head banging and hand and tongue biting) and diffuse plantar keratoderma (1 individual) [Madan & Gupta 2006]

Genotype-Phenotype Correlations

Precise genotype-phenotype correlations are difficult to determine, as most TAT pathogenic variants reported to date are not recurrent [Beyzaei et al 2022].

The most common variant reported to date, p.Arg57Ter, has been reported in ten affected individuals from three families [Peña-Quintana et al 2017, Beyzaei et al 2022]. Individuals homozygous for this pathogenic variant typically present in the neonatal period and have eye and skin manifestations.

Nomenclature

Tyrosinemia type II was previously referred to as keratosis palmoplantaris with corneal dystrophy.

Prevalence

Tyrosinemia type II is rare, with an incidence of less than one in 250,000 [Bouyacoub et al 2013]. Fewer than 100 affected individuals from various ethnic backgrounds have been reported to date [Janakiraman et al 2006, El-Shabrawi & Kamal 2013].

Founder pathogenic variants have been reported in populations from northern Italy (Lombardy and Tuscany; p.Arg57Ter), Tunisia (p.Cys151Tyr), Lebanon (p.Arg297Ter), Palestine (p.Arg417Ter), and Gran Canaria (p.Pro406Leu), which has a population of Mediterranean ancestry primarily from continental Spain and northern Africa [Peña-Quintana et al 2017, Beyzaei et al 2022]. Consanguinity is frequently reported in parents of affected individuals, which may contribute to the higher prevalence of this disorder among Arab populations [Charfeddine et al 2006].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with tyrosinemia type II, the evaluations summarized Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

In addition to regular evaluations by a metabolic specialist and metabolic dietician, the evaluations summarized in Table 6 are recommended to monitor existing manifestations, the individual's response to targeted therapy and supportive care, and the emergence of new manifestations.

Agents/Circumstances to Avoid

Avoid increased dietary protein.

Evaluation of Relatives at Risk

Testing of at-risk sibs of any age is warranted to allow for early diagnosis and treatment of tyrosinemia type II.

Prenatal testing of a fetus at risk. When the pathogenic variants causing tyrosinemia type II in the family are known, prenatal testing of fetuses at risk may be performed via amniocentesis or chorionic villus sampling to facilitate institution of treatment at birth.

Newborn sib. If prenatal testing was not performed – in parallel with newborn screening – testing for the familial TAT pathogenic variants or measurement of plasma tyrosine concentration and excretion of 4-hydroxyphenylpyruvate, 4-hydroxyphenyllactate, and 4-hydroxyphenylacetate on urine organic acid analysis can be performed.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Infants born to women with untreated tyrosinemia type II may have an increased risk of intrauterine growth deficiency and developmental delay [Cerone et al 2002]. Careful dietary control of plasma tyrosine concentration during pregnancy is recommended.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Tyrosinemia type II is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are presumed to be heterozygous for a TAT pathogenic variant.
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a TAT pathogenic variant and allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for a TAT pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. Unless an affected individual's reproductive partner also has tyrosinemia type II or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in TAT.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a TAT pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the TAT pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk sibs for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of individuals affected with tyrosinemia type II and individuals known to be carriers of a TAT pathogenic variant, particularly if consanguinity is likely and/or both partners are of the same ancestry (see Prevalence). TAT founder variants have been identified in several populations (see Table 7).

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the TAT pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

TAT encodes the enzyme tyrosine aminotransferase (TAT), the first in a series of five enzymes that catalyze reversible transamination of tyrosine to 4-hydroxyphenylpyruvate. Reduced TAT function results in the accumulation of upstream byproducts of tyrosine and phenylalanine.

TAT is a homodimer and is composed of two identical polypeptide chains. It is expressed in the liver, kidneys, and brain. The enzyme has the highest activity in the liver. In TAT, the first 38 amino acids may not be involved in enzyme dimerization and are not required in the active site stability and enzyme-substrate interactions. This N-terminal fragment, however, is required for targeting by the ubiquitin-proteasome pathway, which degrades proteins to small peptides.

Mechanism of disease causation. Loss of function

Author Notes

Dr Bita Geramizadeh is a molecular pathologist. Her clinical and research interests include transplant hepatology, acute liver failure, and inherited metabolic disorders of the liver. She is the author of numerous (more than 450) original manuscripts and reviews on the subject. Her research has been in both the clinical and basic science spheres. Dr Geramizadeh has launched and established a transplant research center and national registry trial for inherited metabolic disorders with a data coordinating center at the Shiraz University of Medical Sciences. She is the vice president of the Association for Inherited Metabolic Disorders (Ibn Sina).

Dr Seyed Mohsen Dehghani is a professor of pediatric gastroenterology and hepatology with experience in inherited disorders and more than 200 highly cited published papers.

Dr Zahra Beyzaei is a molecular and biochemical geneticist. She is a staff scientist in the transplant research center at the Shiraz University of Medical Sciences. She would be happy to communicate with persons who have any questions regarding tyrosinemia type II disease. Contact Dr Beyzaei to inquire about review of TAT variants of uncertain significance.

Acknowledgments

We extend our gratitude to the individuals with tyrosinemia type II and their families, our institutions, laboratory personnel, and researchers, as well as the Association for Inherited Metabolic Disorders (Ibn Sina), for their dedicated efforts and collaborative work.

Revision History

• 24 October 2024 (sw) Review posted live
• 17 June 2024 (bg) Original submission

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