Alternative titles; symbols
SNOMEDCT: 124287008, 4887000; ORPHA: 28378; DO: 0050725;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 16q22.2 | Tyrosinemia, type II | 276600 | Autosomal recessive | 3 | TAT | 613018 |
A number sign (#) is used with this entry because tyrosinemia type II (TYRSN2) is caused by homozygous or compound heterozygous mutation in the tyrosine aminotransferase gene (TAT; 613018) on chromosome 16q22.
Tyrosinemia type II (TYRSN2) is an autosomal recessive disorder characterized by keratitis, painful palmoplantar hyperkeratosis, mental retardation, and elevated serum tyrosine levels. The disorder is caused by deficiency of hepatic tyrosine aminotransferase (Natt et al., 1992).
Richner (1938) and Hanhart (1947) described an oculocutaneous syndrome characterized by herpetiform corneal ulcers and painful punctate keratoses of digits, palms, and soles. Richner (1938) described skin lesions in brother and sister. Only the brother had corneal lesions. Hanhart (1947) reported that the parents of this patient were second cousins. Hanhart (1947) also described associated severe mental and somatic retardation. The pedigree he reported was reproduced by Waardenburg et al. (1961). Waardenburg et al. (1961) described children of a first-cousin marriage, one with the full syndrome and one with only corneal changes. Ventura et al. (1965) described the syndrome in 2 sons of first-cousin parents.
Buist (1967) referred to studies of a child with tyrosinemia and tyrosine transaminase deficiency, but normal p-hydroxyphenylpyruvic acid oxidase. Phenylalanine level was normal. Hydroxyphenylpyruvic acid was elevated in the urine. Fellman et al. (1969) reported chemical studies on the same patient. Only the mitochondrial form of tyrosine aminotransferase was present in the liver. The soluble form of tyrosine aminotransferase was lacking. The patient had markedly elevated tyrosine blood levels and an increase in urinary p-hydroxyphenylpyruvate and p-hydroxyphenyllactate.
Goldsmith et al. (1973) demonstrated tyrosinemia and phenylacetic acidemia in this disorder. Their patient was the 14-year-old son of consanguineous Italian parents. The urine contained excessive P-hydroxyphenylactic acid. Urinary P-hydroxyphenylpyruvic acid was normal. Clinical and biochemical improvement accompanied low phenylalanine-low tyrosine diet. They suggested that soluble TAT may be deficient. Mitochondrial tyrosine transaminase was normal. Bienfang et al. (1976) described the ophthalmologic findings in the patient reported by Goldsmith et al. (1973). This condition is also known as tyrosinemia with palmar and plantar keratosis and keratitis.
Garibaldi et al. (1977) observed this disorder, which they called oculocutaneous tyrosinosis, in a 42-month-old girl and her maternal aunt. The parents of the maternal aunt were first cousins. They emphasized the importance of early diagnosis in order to prevent mental retardation by means of a diet restricted in phenylalanine and tyrosine.
Hunziker (1980) reported brother and sister with unusually late onset (about age 15). Their patients' skin lesions were improved with a diet restricted in phenylalanine and tyrosine.
In a consanguineous sibship, Rehak et al. (1981) reported 4 cases of Richner-Hanhart syndrome. Cutaneous manifestations were typical but the eyes were not involved, suggesting heterogeneity in this disorder.
Bohnert and Anton-Lamprecht (1982) reported unique ultrastructural changes: thickening of the granular layer and increased synthesis of tonofibrils and keratohyalin; in the ridged palmar or plantar skin, large numbers of microtubules and unusually tight packing of tonofibrillar masses, which contained tubular channels or inclusions of microtubules. The authors assumed that increased cohesion and tight packing of tonofilaments prevent normal spreading of keratohyalin and result in its globular appearance. Further, they suggested that excessive amounts of intracellular tyrosine enhance crosslinks between aggregated tonofilaments.
In an Ashkenazi Jewish family, Chitayat et al. (1992) observed 2 adult sibs, offspring of a first-cousin marriage, with persistent hypertyrosinemia. A curious feature was that the affected female sib, aged 41 years, had hypertyrosinemia and characteristic oculocutaneous signs; the brother, aged 39 years, had hypertyrosinemia but no oculocutaneous disease. Both sibs had 2 children; none had signs of metabolic fetopathy.
Tallab (1996) described 2 brothers with Richner-Hanhart syndrome from Saudi Arabia. They were sons of consanguineous parents. They showed typical symptoms and signs of the disease. Physical examination revealed patchy hyperkeratotic yellow-white papules and plaques on palms and soles and linear and star-like corneal opacities. Their IQs were 61 and 75. Serum tyrosine levels were markedly elevated with excessive excretion of tyrosine and its metabolites in the urine. A low tyrosine and low phenylalanine diet was given.
Cerone et al. (2002) reported a female patient with tyrosinemia type II who underwent 2 untreated pregnancies. The patient presented at 28 years of age for reevaluation. She was 34 weeks pregnant with a plasma tyrosine of 1302 micro mol/L and phenylalanine of 37 micro mol/L; all other amino acids were within the normal range. Her protein intake ranged from 60 to 90 grams per day. Her first child was evaluated at age 1 year and 4 months. The boy was born at term after an uneventful labor and delivery with a birth weight of 1.9 kg. At 26 months of age he was 66 cm (-3.5 SD), weight was 6.5 kg (-4.3 SD), and head circumference was 43 cm (-2.4 SD). Physical examination showed unremarkable results except for microcephaly and maxillary hypoplasia. Developmental testing indicated a DQ of 72. The second child was evaluated at the age of 12 months with a length of 74 cm (25th percentile), weight of 8.3 kg (3rd percentile), and head circumference of 45 cm (3rd percentile). He also had microcephaly and was not able to walk. Speech delay was also noted. Both children had plasma tyrosine levels in the normal range. The experience from these 2 pregnancies suggested that maternal tyrosinemia has an adverse effect on the developing fetus.
Pena-Quintana et al. (2017) reported 15 patients and reviewed 128 previously reported patients with tyrosinemia type II. For those with age of diagnosis available, 20 were diagnosed in the first year of life, 27 between ages 1 and 5 years, 13 between ages 5 and 13 years, and 26 over the age of 13 years. The most common diagnostic signs in the youngest age group were ocular alterations (70%), including bilateral pseudodendritic keratitis, redness, pain, tearing, and photophobia. Skin lesions (typically painful palmoplantar hyperkeratosis) were seen in 35% of those with onset in the first year of life. Only one of the younger patients had neurologic symptoms, which were mild. Skin lesions and neurologic symptoms were more often seen in patients diagnosed between ages 1 and 5 years, with higher penetrance later in life. Skin lesions typically presented on both the palms and soles, although 2 patients had only affected soles and 1 patient had vesicular lesions in the fingertips. Only 2 patients presented with severe cognitive impairment. Among patients diagnosed between ages 5 and 13 years, 75% had neurologic symptoms. Pena-Quintana et al. (2017) noted that early bilateral pseudodendritic keratitis should lead to a suspicion of the disorder, especially in patients with a family history or from areas of high prevalence, since bilateral involvement occurs in only about 5% of patients with herpesvirus infections. The skin lesions sometimes begin as bullae and erosions that progress to hyperkeratotic papules and plaques. These lesions suggest epidermolysis bullosa, dyskeratosis congenita, or other palmoplantar keratodermas. Intellectual impairment usually became more apparent as the age of diagnosis increased, suggesting that early intervention might prevent the occurrence of these symptoms. Oculocutaneous lesions improved after dietary treatment, but neurologic symptoms did not. Compliance with a strict dietary regimen is needed to avoid symptom recurrence.
In an addendum in proof, Natt et al. (1986) reported that a patient with multiple congenital anomalies, including tyrosinemia II, showed a small interstitial deletion with breakpoints at 16q22.1 and 16q22.3. Natt et al. (1987) presented the full report of this patient, who had multiple congenital anomalies and severe mental retardation in addition to typical symptoms of tyrosinemia II. Southern blot analysis using a human TAT cDNA probe showed complete deletion of both TAT alleles in the patient. Molecular and cytogenetic analysis of the patient and his family showed one deletion to have been inherited from the mother, extending over at least 27 kb and including the complete TAT structural gene, whereas loss of the second TAT allele resulted from a small de novo interstitial deletion, del 16(pter-q22::q22.3-qter), in the chromosome 16 inherited from the father. The haptoglobin locus (140100) was codeleted on the chromosome inherited from the father; no HP allele was inherited by the proband from the father. In situ hybridization likewise was consistent with loss of one haptoglobin gene. On the other hand, 2 metallothionein genes, MT1 (156350) and MT2 (156360), as well as the LCAT gene (606967), were not deleted.
Prenatal Diagnosis
Westphal et al. (1988) described MspI and HaeIII RFLPs associated with the TAT locus. The authors used the 2 polymorphisms, which have a combined polymorphism information content (PIC) of 0.44, to perform haplotype analysis of the TAT locus in a French family with tyrosinemia type II. The polymorphisms gave a clear delineation of the mutant alleles in each parent and thus provided the opportunity for prenatal diagnosis of this condition in this family.
The transmission pattern of TYRSN2 in the patients reported by Natt et al. (1992) was consistent with autosomal recessive inheritance.
In patients with tyrosinemia type II, Natt et al. (1992) identified homozygous and compound heterozygous mutations in the TAT gene (613018.0001-613018.0005).
In a review of 143 patients in 106 families with tyrosinemia type II, Pena-Quintana et al. (2017) reported 36 mutations in the TAT gene, including 11 novel variants. The mutations included 3 large deletions, 21 missense and 5 nonsense amino acid substitutions, 5 frameshifts, and 2 splice variants. The most common mutation (P406L; 613018.0006) was reported in 5 patients from apparently unrelated families from the island of Gran Canaria, Spain (a population of Mediterranean ancestry). Asymptomatic parents in these families were heterozygous for the mutations, and no genotype-phenotype correlation was apparent. In addition to Gran Canaria, other areas with evidence of founder effects included northern Italy, Tunisia, Palestine, and Lebanon.
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Bohnert, A., Anton-Lamprecht, I. Richner-Hanhart's syndrome: ultrastructural abnormalities of epidermal keratinization indicating a causal relationship to high intracellular tyrosine levels. J. Invest. Derm. 79: 68-74, 1982. [PubMed: 6124575] [Full Text: https://doi.org/10.1111/1523-1747.ep12500027]
Buist, N. Phenylketonuria and related problems.In: Nyhan, W. L. : Amino Acid Metabolism and Genetic Variation. New York: McGraw-Hill (pub.) 1967. P. 117.
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Chitayat, D., Balbul, A., Hani, V., Mamer, O. A., Clow, C., Scriver, C. R. Hereditary tyrosinaemia type II in a consanguineous Ashkenazi Jewish family: intrafamilial variation in phenotype; absence of parental phenotype effects on the fetus. J. Inherit. Metab. Dis. 15: 198-203, 1992. [PubMed: 1356171] [Full Text: https://doi.org/10.1007/BF01799631]
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Fellman, J. H., Vanbellinghen, P. J., Jones, R. T., Koler, R. D. Soluble and mitochondrial forms of tyrosine aminotransferase: relationship to human tyrosinemia. Biochemistry 8: 615-622, 1969. [PubMed: 4389443] [Full Text: https://doi.org/10.1021/bi00830a023]
Garibaldi, L. R., Siliato, F., De Martini, I., Scarsi, M. R., Romano, C. Oculocutaneous tyrosinosis: report of two cases in the same family. Helv. Paediat. Acta 32: 173-180, 1977. [PubMed: 33934]
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Pena-Quintana, L., Scherer, G., Curbelo-Estevez, M. L., Jimenez-Acosta, F., Hartmann, B., La Roche, F., Meavilla-Olivas, S., Perez-Cerda, C., Garcia-Segarra, N., Giguere, Y., Huppke, P., Mitchell, G. A., Monch, E., Trump, D., Vianey-Saban, C., Trimble, E. R., Vitoria-Minana, I., Reyes-Suarez, D., Ramirez-Lorenzo, T., Tugores, A. Tyrosinemia type II: mutation update, 11 novel mutations and description of 5 independent subjects with a novel founder mutation. Clin. Genet. 92: 306-317, 2017. [PubMed: 28255985] [Full Text: https://doi.org/10.1111/cge.13003]
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Westphal, E.-M., Natt, E., Grimm, T., Odievre, M., Scherer, G. The human tyrosine aminotransferase gene: characterization of restriction fragment length polymorphisms and haplotype analysis in a family with tyrosinemia type II. Hum. Genet. 79: 260-264, 1988. [PubMed: 2456982] [Full Text: https://doi.org/10.1007/BF00366248]