The genetic tyrosinemias are characterized by the accumulation of tyrosine in body fluids and tissue.5,6 Tyrosine is a semiessential amino acid, derived from the liberation of tyrosine from hydrolysis of dietary or tissue protein, or from the hydroxylation of the essential amino acid phenylalanine, and is the starting point for the synthesis of catecholamines, thyroid hormones, and melanogenesis. There are three types of tyrosinemia. The skin is not involved in tyrosinemia types I and III, but it is involved in tyrosinemia II, which is also called the oculocutaneous tyrosinemia and Richner–Hanhart syndrome [Online Mendelian Inheritance in Man (OMIM) #276600]. Tyrosinemia II is a rare distinctive clinical symptom complex involving the eyes, skin, and central nervous system and is potentially treatable. Tyrosine levels are elevated because of a deficiency of hepatic tyrosine aminotransferase (TAT).
Approximately 100 patients with this clinical syndrome have been reported. Goldsmith and Reed were the first to correlate the oculocutaneous syndrome with an underlying tyrosinemia.7 All patients had tyrosinemia, phenolic aciduria, and inflammatory skin and eye lesions. The sexes are affected equally, and the disease is worldwide in distribution. Transmission of tyrosinemia II is autosomal recessive. Consanguinity has been documented, and occurrence in several siblings within a family is well known (pseudodominant pattern). Heterozygotes are unaffected clinically and demonstrate no biochemical alterations of tyrosine or its metabolites in blood or urine.
Patients have hyperkeratotic yellowish skin lesions limited to the palms and soles, which in 80% of cases occur on the peripheral pressure-bearing areas.5,7 Lesions usually begin during the first year of life. The skin lesions are painful, nonpruritic, and frequently associated with hyperhidrosis (Fig. 131-1). Diffuse plantar keratoderma and self-mutilation have been observed in individuals with tyrosinemia II.8 Leukokeratosis of the tongue has been reported. Bullous lesions may occur and progress rapidly to erosions; these then become crusted and hyperkeratotic.9 The fingertips and hypothenar eminences are commonly involved. Rare patients have hyperpigmentation and/or hyperkeratotic subungual lesions, and in older persons hyperkeratosis in the elbows, knees, and ankles may appear.2
Hyperkeratotic (A) and erosive (B) lesions in a patient with tyrosinemia II.
The most important manifestations of oculocutaneous tyrosinemia are those involving the eye, because they can lead to permanent visual impairment.10 Eye lesions occur weeks to months before the skin lesions. Ophthalmologic symptoms start as early as the first day of life and as late as 38 years of age. Tearing, redness, pain, and photophobia are early signs and symptoms; late findings include corneal clouding and central or paracentral opacities, which are initially intraepithelial and can progress to superficial or deep pseudodendritic keratitis (Fig. 131-2). Slit-lamp examination may reveal some degree of corneal ulceration, and occasionally birefringent crystals of tyrosine may be observed. Neovascularization is prominent. The eye disease occurs in 75% of affected patients and may lead to scarring, nystagmus, and exodeviation. Ocular symptoms may show spontaneous remission and recurrences and may occur independently of other manifestations. Topical therapy is ineffective, and herpes simplex virus and bacterial cultures consistently yield negative results.
Corneal changes in tyrosinemia II. A. Cornea before treatment (left eye); corneal opacity and neovascularization are prominent. B. The right eye has even more extensive involvement. C. After 6 weeks of therapy, there is marked clearing of the lesions.
Mental retardation of varying degrees is reported in half the cases, as is normal mental development. Hyperactivity has been observed in several affected children, as has abnormal language development. Untreated tyrosinemia II during pregnancy may be associated with mental retardation or seizures in the children resulting from that pregnancy.11
In establishing the diagnosis in a child with tyrosinemia II, laboratory verification of plasma amino acid and urine organic acid levels is mandatory. The blood and urine tyrosine levels of affected patients are markedly elevated. Levels of other amino acids are not increased. Urinary tyrosine metabolite levels are elevated; these include p-hydroxyphenylpyruvic acid, p-hydroxyphenyllactic acid, p-hydroxyphenylacetic acid, and N-acetyltyrosine (Fig. 131-3). All these metabolic effects are consequences of the deficiency of hepatic TAT. A fluorometric procedure exists as well as a tandem mass spectrometry, which is used for neonatal screening. Recently, an asymptomatic newborn was detected to have Richner–Hanhart syndrome on the third day of life as a result of the newborn screening. Interestingly the 8-year-old brother with persistent plantar hyperkeratotic plaques of the soles of yet unknown origin was subsequently identified to be also affected tyrosinemia type II.12
Metabolic pathway of phenylalanine, tyrosine, and their derivatives.
TAT is a pyridoxal phosphate-dependent cytoplasmic enzyme that transaminates tyrosine, forming p-hydroxyphenylpyruvate (PHPPA). The human TAT gene contains 12 exons and transcribes a 2.75-kb messenger RNA (mRNA) that codes for a 454-amino acid protein.5 The liver is the richest source of TAT; this specific TAT is not present in skin. In tyrosinemia II, the liver biopsy specimen shows little or no soluble TAT, although there is normal or slightly increased mitochondrial tyrosine (aspartate) transaminase activity.12,13 Mitochondrial aspartate aminotransferase using tyrosine as a substrate produces increased amounts of PHPPA from the increased amounts of tyrosine available in tyrosinemia II. Because mitochondria do not have PHPPA oxidase activity, PHPPA and its metabolic products increase and appear in the urine, which creates the unusual situation in which metabolites are increased both proximally and distally to the defective enzyme.
Routine histopathologic analysis of the skin is not diagnostic; it shows hyperkeratosis, parakeratosis, and acanthosis.9 In some cases, electron microscopy studies have shown lipid droplets in the cornified layer, increases in tonofibrils and keratohyalin, very tightly packed microtubular and microfibrillar masses, and minute tyrosine crystals in keratinocytes and Merkel cells.14
Mutations occur in the human TAT gene, which results in high levels of tyrosine. TAT maps to the q22-q24 region of chromosome 16 and has been sequenced.5 Multiple point mutations scattered throughout the TAT gene have been associated with tyrosinemia II.15
Interestingly, in mink with the disease TAT unlinked gene regulatory mutation rather than TAT deficiency was thought to be the cause of tyrosinemia.16
PATHOPHYSIOLOGY OF THE SKIN AND EYE LESIONS IN TYROSINEMIA II
Rats fed a 12 percent protein diet with 0.5 percent to 2.0 percent tyrosine developed a syndrome resembling tyrosinemia II, with weight loss, a shortened life span, keratitis, conjunctivitis, alopecia, cheilitis, and inflammatory toe changes.17
The high-tyrosine syndrome in rats was ameliorated by increasing the protein content of the diet or by adding threonine or thiouracil or TAT
In vitro studies showed that tyrosine crystals can cause release of lysosomal enzymes and as yet uncharacterized heat-labile chemotactic factors.18,19 Crystal-induced inflammation has been studied in model systems using calcium pyrophosphate dihydrate and monosodium urate monohydrate.
(See Box 131-1). Corneodermatoosseous syndrome (OMIM #122440), an autosomal dominant symptom complex of volar keratosis and keratitis that is clinically similar to tyrosinemia II, has been described in one family.20 The lesions were more extensive than those in the classic Richner–Hanhart syndrome. In addition, brachydactyly with short distal phalanges, short stature, and soft teeth may occur.
Box 131-1 Differential Diagnosis of Tyrosinemia ||Download (.pdf)
Box 131-1 Differential Diagnosis of Tyrosinemia
- Herpetiform corneal ulcers
- Punctate, painful palmoplantar keratoderma on weight-bearing areas
- Neurologic features
- Mental retardation
- Palmoplantar keratoderma with associated features
- Corneodermatoosseous syndrome
|Always Rule Out|
- Viral and bacterial infection
- Other forms of keratodermas, acquired or genetic
With consumption of a low-tyrosine, low-phenylalanine diet (Mead Johnson, Tyromex-Ross), there is a rapid decrease in tyrosine to normal levels (30–90 μM). Skin and eye lesions cleared within days and weeks in all individuals treated with the diet7,12 (see Fig. 131-2C; Fig. 131-4; Box 131-2).
A. Diffuse plantar hyperkeratosis in an adult with tyrosinemia. B. The hyperkeratosis cleared on a low-tyrosine, low-phenylalanine diet without topical treatment.
Box 131-2 Treatment of Tyrosinemia ||Download (.pdf)
Box 131-2 Treatment of Tyrosinemia
- Low-tyrosine, low-phenylalanine diet
- Etretinate systemically
Some patients have responded objectively to etretinate, although plasma tyrosine levels remained unchanged.21 In none of the patients studied has there been a response to cortisone acetate, ascorbic acid, pyridoxine, or folic acid, which are cofactors or known inducers of TAT and PHPPA oxidase. Surgical treatment is recommended for palmar lesions but not for the plantar form.
Because the consequences of tyrosinemia II are serious and a safe treatment is available, a patient presenting with any atypical bullous or hyperkeratotic disease on the palms and soles in the first months of life should be screened for tyrosine and its metabolites; screening tests are available in most hospital laboratories.22 Amino acid analysis is necessary to confirm the diagnosis and follow the response to diet therapy. Dietary control in pregnancy should be recommended. A patient with tyrosinemia II was reported who had undergone two untreated pregnancies. During the pregnancies, plasma tyrosine level was raised, and the infants were retarded. On the other hand, several normal children of mothers with the disease have been observed.23