From the University of Crete, School of Health Sciences (GDK, VPK, GAK) and the 1st Department of Ophthalmology (NGZ), Aristotle University of Thessaloniki, Thessaloniki, Greece.
The authors have no financial or proprietary interest in the materials presented herein.
Address correspondence to George D. Kymionis, MD, PhD, Vardinoyiannion Eye Institute of Crete, University of Crete, School of Health Sciences, GR 71 003 Voutes, Heraklion, Crete, Greece. E-mail: firstname.lastname@example.org
Tyrosinemia type II is an inherited autosomal recessive disorder, characterized by photophobia, bilateral pseudodendrites, palmo-plantar keratosis, and elevated plasma tyrosine concentrations. It may also be associated with mental retardation and variable central nervous system involvement. Importantly, patients may present with only ocular symptoms. Therefore, ophthalmologists should be able to make an early diagnosis. Ocular symptoms include epiphora, photophobia, and blepharospasm, whereas signs consist of corneal clouding, pseudodendritic corneal lesions, and, rarely, corneal or conjunctival plaques.1 Pseudodendrites are often misdiagnosed as herpetic keratitis and treated with antiviral agents for a long duration of time. This may result in ocular surface toxicity due to antiviral medications and delay in appropriate diagnosis, thus leading to progression of the disease. We report isolated corneal pseudodendrites as the initial manifestation of tyrosinemia type II in monozygotic twins.
Fifteen-month-old male twins were referred to cornea services for the management of nonresponding bilateral herpes simplex virus (HSV) keratitis. They presented with repeated eye rubbing, photophobia, and tearing for the previous 6 months. A local ophthalmologist made the diagnosis of bilateral HSV keratitis and both patients were treated with topical trifluridine 1% drops five times per day for 2 months prior to presentation. There was no sign of improvement despite prolonged treatment. Their developmental history was age appropriate. Both patients were fixating and following light. Slit-lamp biomicroscopy revealed the presence of filamentous superficial haze with dendritiform pattern, which was composed of multiple raised clear intraepithelial lesions (Fig. 1). There was no staining of the lesion with fluorescein. Biomicroscopic examination of the anterior chamber, lens, and fundus was within normal limits. There were no coexistent dermatological or neurological abnormalities as evaluated by the pediatrician.
Figure 1. Slit-lamp photograph of the (A) right and (B) left eye of the first patient and the (C) right and (D) left eye of the second patient, respectively, demonstrating presence of filamentous superficial haze with dendritiform pattern, which was composed of multiple raised clear intraepithelial lesions.
Bilateral corneal pseudodendrites, nonresponse to antiherpetic treatment, and simultaneous presentation in twin patients made us consider the possibility of tyrosinemia type II. On investigation, plasma tyrosine levels were 1,369 and 1,523 umol/L (normal range: 24 to 105 umol/L), respectively, whereas urine tyrosine levels were 346 and 402 umol/L, respectively (normal range: 13 to 48 umol/L). On further investigation, hepatic and renal function test results were within normal limits. Diagnosis of tyrosinemia type II was confirmed on the basis of raised tyrosine levels in the blood and urine with normal hepatic and renal function tests. A tyrosine- and phenylalanine-restricted diet was initiated with the help of a nutritionist and pediatrician. Both patients were symptomatically better after 2 weeks of treatment; at the 2-month follow up examination, both were asymptomatic and corneal lesions had completely resolved. Blood tyrosine levels at 2 months were reduced to 476 and 593 umol/L, respectively. Parents were counseled about the importance of adhering to the prescribed diet to prevent recurrence of the corneal lesions and avoid development of cutaneous and neurological manifestations.
Tyrosinemias are a group of heritable inborn errors of metabolism, caused by defective enzymes that break down the amino acid tyrosine into its byproducts, thus resulting in elevated tyrosine levels in serum and urine. There are three types of tyrosinemia, each with distinctive symptoms and caused by the deficiency of a different enzyme. They are classified into type I (deficiency of fumarylacetoacetate hydrolase enzyme) with hepatorenal disease, type II (deficiency of hepatic tyrosine aminotransferase enzyme) with oculocutaneous manifestations, and the rare type III (deficiency of 4-hydroxyphenyl-pyruvate enzyme) with intermittent neurological anomalies.1 Hepatorenal involvement occurs only in type I and corneal involvement is known to occur only in type II.2
Tyrosinemia type II (Richner–Hanhart syndrome, oculocutaneous tyrosinemia) is an autosomal recessive disease caused by mutations of the gene ‘TAT’ (chromosome 16 q 22), resulting in reduced activity of hepatic tyrosine amino transferase enzyme. This leads to increased levels of tyrosine in blood and urine.3 Deposition of tyrosine crystals in the eye and skin produces an inflammatory response in the form of pseudodendritic keratitis and painful palmo-plantar keratosis.4 It may also be associated with mental retardation and variable central nervous system abnormalities.5 Skin lesions occur in 80%, eye lesions in 75%, and mental retardation in 60% of reported cases.6 Elevated plasma tyrosine levels (typically 2.5 to 25 times greater than normal) combined with classic clinical presentation is usually sufficient for diagnosis of tyrosinemia type II. Presentation with isolated ocular manifestations in the absence of cutaneous involvement is not uncommon.5
Most of the ocular manifestations develop before the age of 1 year. Ocular symptoms include photophobia, eye rubbing, tearing, and blepharospasm. The most typical ocular finding is bilateral dendritiform keratitis, which is commonly misdiagnosed as herpetic keratitis, especially in the absence of cutaneous manifestations.5 In addition, corneal lesions in tyrosinemia type II can undergo spontaneous remission and recurrence, giving the illusion of response to antiherpetic therapy. These patients are treated with antiherpetic medications for a variable time.
The typical pseudodendrites in tyrosinemia type II are bilateral, stain poorly with fluorescein, lack terminal bulbs, respond poorly to antiviral drugs, and demonstrate exacerbation with increased dietary proteins, thus differentiating them from dendrites of HSV keratitis.5 In our study, monozygotic twin boys presented simultaneously with photophobia and blepharospasm. They were misdiagnosed as having HSV keratitis elsewhere and were taking antiherpetic medications for 3 months without response. Typical bilateral pseudodendrites that demonstrated clear vacuoles in dendritiform configuration on high magnification were initial clues for diagnosis. Furthermore, simultaneous presentations in our twin patients led us to investigate for tyrosinemia type II even in the absence of skin or neurological findings. Elevated levels of tyrosine in blood and urine samples confirmed the diagnosis in our patients. To our knowledge, this is the first report of simultaneous occurrence of tyrosinemia type II in twins.
A tyrosine- and phenylalanine-restricted diet is currently the most effective treatment for tyrosinemia type II. Dietary control appears to be more important to the outcome than the genetic mutation responsible for the disease. Studies have shown that if diet control is achieved in infancy, it is associated with normal psychomotor development.7,8 Furthermore, a tyrosine-restricted diet started as early as 40 months may be inadequate to prevent some language disorders.9 These studies stress the importance of early diagnosis and dietary intervention. Early intervention is rewarding because it may reverse ocular and skin manifestations and also prevent neurological involvement. Importantly, early accurate diagnosis will prevent untoward effects of long-term antiviral drugs (trifluridine = partial nasolacrimal duct obstruction, acyclovir = ocular surface damage) in patients who are misdiagnosed as having HSV keratitis. On the contrary, delay in intervention may result in permanent visual deficit due to chronic keratitis and corneal opacity. This will subject patients to the morbidities related to keratoplasty; moreover, the lesions can recur in the graft.10
Bilateral pseudodendritic keratitis may be the initial or the only manifestation of tyrosinemia type II. Bilateral corneal pseudodendrites, lack of response to antiherpetic treatment, and simultaneous presentation in twins as in our patients should alert ophthalmologists to screen for tyrosinemia type II. This will help in early diagnosis and avoid long-term untoward effects of antiviral medications. Most importantly, prompt dietary intervention will stop progression of disease, reverse oculocutaneous manifestations, and prevent neurological complications.
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- Burns RP. Tyrosinemia. In: Gold DH, Weingeist TA, eds. The Eye in Systemic Disease. Philadelphia: J. B. Lippincott; 1990:327–329.
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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 Dermatol. 1982;79:68–74. doi:10.1111/1523-1747.ep12500027 [CrossRef]
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- Paige DG, Clayton P, Bowron A, Harper JI. Richner-Hanhart syndrome (oculocutaneous tyrosinemia, tyrosinemia type II). J R Soc Med. 1992;85:759–760.
- Rabinowitz L, Williams L, Anderson C, Mazur A, Kaplan P. Painful keratoderma and photophobia: hallmarks of tyrosinemia type II. J Pediatr. 1995;126:266–269. doi:10.1016/S0022-3476(95)70558-9 [CrossRef]
- Bardelli AM, Borgogni P, Farnetani MA, et al. Familial tyrosinaemia with eye and skin lesions: presentation of two cases. Ophthalmologica. 1977;175:5. doi:10.1159/000308631 [CrossRef]
- Sayar RB, Von Domarus D, Schafer HJ, Beckenkamp G. Clinical picture and problems of keratoplasty in Richner-Hanhart syndrome (tyrosinemia type II). Ophthalmologica. 1988;197:1–6. doi:10.1159/000309909 [CrossRef]