Tyrosinemia is a clinical entity describing abnormally high circulating concentrations of the amino acid tyrosine and may be seen due to various genetic mutations. Three distinct types of tyrosinemia are recognized [1] [2] [3] [4] [5] [6] [7]:

• Tyrosinemia type 1 - Develops on the grounds of fumarylacetoacetase (FAH) deficiency, the enzyme involved in the final steps of converting tyrosine to fumarate [1] [5]. The pathogenesis stems from the generation of toxic metabolites that accumulate in various tissues, most notably in the liver and kidneys [1] [2]. The clinical presentation of tyrosinemia type 1 starts in early infancy and childhood, with principal features being growth failure, coagulation deficits, and neurological crises consisting of neuropathy, abdominal pain, mental state changes and life-threatening respiratory insufficiency [1]. Mortality rates are very high in the absence of an early diagnosis, usually from hepatic/respiratory failure or hepatocellular carcinoma, a well-known complication of tyrosinemia type 1 [1] [2] [5]. The incidence rate of this autosomal recessive disorder is around 1 in 125,000 individuals, with more frequent cases observed in Turkey, India, and the Canadian province of Quebec [5].
• Tyrosinemia type 2 - Also known as Richner-Hanhart syndrome, tyrosinemia type 2 is a rare disorder of tyrosine metabolism, arising from tyrosine aminotransferase enzyme deficiency [3] [4]. Very few reports of this disease exist, that mainly describe cutaneous (palmoplantar keratosis) and ocular symptoms (corneal lesions that are not responsive to commonly prescribed antiviral therapy), in addition to intellectual disability and other neurological signs [3] [4].
• Tyrosinemia type 3 - With only a few cases described in the literature and a poorly understood clinical presentation, tyrosinemia type 3 stems from 4-hydroxyphenylpyruvate dioxygenase (4-HPPD) deficiency [6] [7].

• Fatigue

  Tyrosinemia Type 1 Symptoms Bloody stools Cabbage like odor Diarrhea Fatigue Poor weight gain Failure to thrive Vomiting Tyrosinemia Type 2 Symptoms Painful lesions on the skin Red eyes and light sensitivity Corneal clouding Intellectual disability Behavioral [stlouischildrens.org]

• Hunting

  Mamunes, P, Prince, PE, Thornton, NH, Hunt, PA, Hitchcock, ES, Laupus, WE. Intellectual deficits after transient tyrosinemia in the term neonate. Pediatr Res. 1976 ;8(4): 344. doi:10.1203/00006450-197404000-00026. Google Scholar Crossref 16. [doi.org]

• Multiple Congenital Anomalies

  We have restudied a patient with typical symptoms of tyrosinemia II who in addition suffers from multiple congenital anomalies including severe mental retardation. [ncbi.nlm.nih.gov]

• Aspiration

  Of the remaining nine who survived the operation, one died at six months as a result of bronchial aspiration and aspiration pneumonia, and a second transplanted for hepatoma died five months later with metastases. [ncbi.nlm.nih.gov]

• Failure to Thrive

  Similarities include failure to thrive with hypoproteinemia, micronodular cirrhosis, alpha-fetoprotein positive hepatocellular carcinoma, renal Fanconi syndrome with renal tubular ectasia, hypermethioninemia, and hypoglycemia associated with islet cell [ncbi.nlm.nih.gov]

  At a Glance Approximate Incidence in Ontario 1 in 100, 000 Marker Measured Tyrosine and succinylacetone Screening can Prevent Liver and kidney damage and sequelae, failure to thrive, coagulopathy Treatment Special diet, medication Screening is Important [newbornscreening.on.ca]

  Affected individuals present with gastrointestinal problems leading to a failure to thrive, jaundice, and a cabbage-like odor to the body or urine. Kidney failure may lead to bleeding, ascites, and sepsis. Liver disease may occur. [sema4genomics.com]

  Tyrosinemia Type 1 Symptoms Bloody stools Cabbage like odor Diarrhea Fatigue Poor weight gain Failure to thrive Vomiting Tyrosinemia Type 2 Symptoms Painful lesions on the skin Red eyes and light sensitivity Corneal clouding Intellectual disability Behavioral [stlouischildrens.org]

• Proximal Muscle Weakness

  We report a 27-month-old infant who presented with a sudden change in gait owing to proximal muscle weakness. The laboratory evaluation showed carnitine deficiency associated with Fanconi's tubulopathy. Eventually, tyrosinemia type I was diagnosed. [ncbi.nlm.nih.gov]

• Corneal Deposit

  Corneal deposits can be one of the parameters in monitoring the efficacy of diet control. [ncbi.nlm.nih.gov]

• Formication

  The solvent was acetonitrile-water (80:20 by volume) containing formic acid, hydrazine hydrate, and 100 nmol/L 5,7-dioxooctanoic acid as internal standard. Analysis was performed by tandem mass spectrometry in a separate run. [ncbi.nlm.nih.gov]

• Petechiae

  On physical examination he presented petechiae and haematomas, and a slightly enlarged liver. [ncbi.nlm.nih.gov]

Because of the rare occurrence of tyrosinemia in clinical practice, the diagnosis might be difficult to attain. For this reason, the role of a detailed patient history and a proper physical examination are crucial in order to raise suspicion. The physician should obtain all information regarding the onset of symptoms, their progression, as well as severity and duration, either from the patient or from the parents (given the early onset of tyrosinemia type 1). The fact that autosomal recessive patterns of inheritance are confirmed for all tyrosinemias [1] [3] [6], a family history (although not always informative) can provide vital clues into the etiology. The cornerstone of diagnosis, however, rests on the assessment of tyrosine and its metabolites (mainly succinylacetone) in blood and urine, which should be ordered as soon as sufficient evidence is gathered [1] [5]. As a definitive diagnostic method, genetic studies, such as mutational analysis, can be used both prenatally and postnatally [1] [5].

• Tyrosine Increased

  Serum tyrosine increases due to tyrosine aminotransferase deficiency resulting in the deposition of tyrosine crystals in the cornea and in corneal inflammation. Patients are often misdiagnosed as having herpes simplex keratitis. [ncbi.nlm.nih.gov]

• Hepatocellular Carcinoma

  Hepatocellular carcinoma (HCC) was found either preoperatively or incidentally in five patients, all older than 2 years at the time of their transplant. [ncbi.nlm.nih.gov]

1. Sniderman King L, Trahms C, Scott CR. Tyrosinemia Type I. 2006 Jul 24 [Updated 2017 May 25]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.
2. Fernández-Lainez C, Ibarra-González I, Belmont-Martínez L, Monroy-Santoyo S, Guillén-López S, Vela-Amieva M. Tyrosinemia type I: clinical and biochemical analysis of patients in Mexico. Ann Hepatol. 2014;13(2):265-272.
3. Peña-Quintana L, Scherer G, Curbelo-Estévez ML, et al. Tyrosinemia type II: Mutation update, 11 novel mutations and description of 5 independent subjects with a novel founder mutation. Clin Genet. Mar 3, 2017.
4. Iskeleli G, Bilgeç MD, Arici C, Atalay E, Oğreden T, Aydin A. Richner-Hanhart syndrome (tyrosinemia type II): a case report of delayed diagnosis with pseudodendritic corneal lesion. Turk J Pediatr. 2011;53(6):692-694.
5. Mayorandan S, Meyer U, Gokcay G, et al. Cross-sectional study of 168 patients with hepatorenal tyrosinaemia and implications for clinical practice. Orphanet J Rare Dis. 2014;9:107.
6. Heylen E1, Scherer G, Vincent MF, Marie S, Fischer J, Nassogne MC. Tyrosinemia Type III detected via neonatal screening: management and outcome. Mol Genet Metab. 2012;107(3):605-607.
7. Rüetschi U, Cerone R, Pérez-Cerda C, et al. Mutations in the 4-hydroxyphenylpyruvate dioxygenase gene (HPD) in patients with tyrosinemia type III. Hum Genet. 2000;106(6):654-662.