Are You Confident of the Diagnosis?
What you should be alert for in the history
Usually a triad of photophobia (with excessive lacrimation and conjunctival suffusion), painful keratoderma associated with hyperhidrosis, and abnormal behavioral patterns in a neonate or infant. Not all patients present the classic features of the triad.
Characteristic findings on physical examination
Ophthalmological features: The ocular manifestations are often the earliest and may occur within 2 weeks of birth. Features include superficial or deep dendritic ulcerations, corneal scarring, central and paracentral opacities, neovascularization and opacities leading to blindness (Figure 1).
Cutaneous manifestations typically develop during the first 2 years of life and include painful, erythematous hyperkeratotic acral plaques. The keratoderma is usually symmetric and can be striate or circumscript. Lamellar patches and xerosis may be present with associated hyperhidrosis. In some, vesicular hyperkeratosis on the tips of the fingers and toes may be seen.
On the soles, these plaques are localized to the weight-bearing areas, and on the palms, involve the thenar and hypothenar eminences. The keratoderma is painful in nature. Nail dystrophy has been reported in some cases. Hair and teeth are unaffected.
There is often a delay of acquisition of motor skills in early life and varying severities of learning disabilities.
Expected results of diagnostic studies
High plasma (normal 26–110mmol/L) and urinary tyrosine and normal plasma phenylalanine levels on high pressure chromatography or tandem mass spectrometric assay.
Elevated tyrosine levels in newborn screening can be a pointer to the diagnosis.
Histology is not diagnostic. Common features include orthokeratosis, acanthosis, and parakeratosis. Other features reported include thickening of the granular layer, increased synthesis of tonofibrils and keratohyalin. Ultrastructurally, multinucleated keratinocytes may be visualized with aggregation of keratin-intermediate filaments and intracytoplasmic tyrosine crystals.
Palmoplantar keratoderma associated with learning difficulties can be seen in Buschke–Fischer–Brauer (autosomal dominant, punctate palmoplantar keratoderma, hyperhydrosis) and Lelis syndromes (ectodermal dysplasia, acanthosis nigricans, nail abnormalities and pigmentary abnormalities) but other findings of Richner-Hanhart syndrome are absent and plasma tyrosine levels are normal.
Who is at Risk for Developing this Disease?
This rare autosomal recessive disorder occurs in less than 1 in 250,000 individuals. Children of consanguineous marriages are at risk of developing Richner-Hanhart syndrome.
What is the Cause of the Disease?
The genetic abnormality in tyrosinaemia type II has been mapped to chromosome 16q21.1-q22.3. Tyrosine, a non-essential amino acid, is metabolized to p-hydroxyphenylpyruvic acid (p-HPPA) by the enzyme tyrosine aminotransferase (TAT) and subsequently to homogentisic acid by p-HPPA oxidase. This is further metabolized to fumarate and acetoacetate.
Tyrosinaemia type 1 or hepato-renal tyrosinosis is due to a deficiency of p-HPPA oxidase.
Richner-Hanhart syndrome is due to a deficiency of TAT and resultant very high levels of tyrosine in serum and urine.
The pathophysiology of Richner-Hanhart syndrome is unclear but excessive intracellular tyrosine concentration has been shown to affect microfibril number and stability.
Noncovalent cross-linking of tonofilaments through increased intracellular levels of L-tyrosine has been implicated in abnormal keratinization.
Systemic Implications and Complications
Complications include corneal ulcers, scarring and blindness, cognitive impairment manifested by low intelligence and behavioral problems.
Treatment options are summarized in the Table I.
|Medical Approach||MulMultidisciplinary Approach||Surgical Considerations|
|Low-phenylalanine, low-tyrosine diet or a low-protein dietOral retinoids||Physiotherapy, psychiatric and ophthalmologic assessments||Skin autografts|
Optimal Therapeutic Approach for this Disease
Early diagnosis is key as scarring of ophthalmic features and cognitive complications are irreversible if the diagnosis and treatment are delayed. Early ophthalmic, physiotherapy and psychiatric assessments are required.
Dietary restriction of tyrosine, phenylalanine and methionine by avoiding foods like milk and dairy products, meat, fish chicken, eggs, beans and nuts is recommended.
Keratolytics and emollients can be used for hyperkeratotic skin lesions.
Oral retinoids (acitretin, etretinate) can be used for persistent keratoderma. There is no specific guidance on dosage or duration of treatment with retinoids as treatment has to be tailored for each case.
Regular follow-ups are essential to monitor for recurrence of skin and ophthalmic symptoms. Follow up intervals may vary from a few months to annually.
As there are no specific pharmacological interventions aimed at the pathogenesis of the disease, patients should be maintained on a long-term low tyrosine, phenylalanine and methionine diet.
Unusual Clinical Scenarios to Consider in Patient Management
The challenges are early diagnosis and institution of low tyrosine, low phenylalanine formulas e.g., Tyrex 1® and Tyros 1®. Care has to be taken to meet the nutritional requirements of the growing child and the diet plan has to be individualized, depending upon the patient’s age and weight.
Fortification of foods with minerals are vitamins is necessary to meet the nutrient requirements and to maintain the growth of the child. Careful dietary monitoring is complemented by regular measurements of blood levels of tyrosine and phenylalanine.
What is the Evidence?
Zaleski, WA, Hill, A, Kushniruk, W. “Skin lesions in tyrosinosis: response to dietary treatment”. Br J Dermatol. vol. 88. 1973. pp. 335-40. (One of the early case reports demonstrating reversible skin changes in response to a low protein diet.)
Goldsmith, LA, Thorpe, J, Roe, CR. “Hepatic enzymes of tyrosine metabolism in tyrosinemia II”. J Invest Dermatol. vol. 73. 1979. pp. 530-2. (Low-tyrosine diet results in fall in plasma tyrosine and clearing of the hyperkeratosis of the soles in a patient with tyrosinaemia II. Hepatic enzyme alterations in response to dietary restriction of tyrosine are discussed.)
Natt, E, Westphal, EM, Toth-Fejel, SE, Magenis, RE, Buist, NR, Rettenmeier, R. “Inherited and de novo deletion of the tyrosine aminotransferase gene locus at 16q22.1—-q22.3 in a patient with tyrosinemia type II”. Hum Genet. vol. 77. 1987. pp. 352-8. (Of the loci studied, only haptoglobin was codeleted with TAT on chromosome 16.)
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. vol. 79. 1982. pp. 68-74. (Thickening of the granular layer and increased synthesis of tonofibrils and keratohyalin was seen in skin biopsies of three patients with tyrosinaenia II. The authors suggested that excessive amounts of intracellular tyrosine enhance crosslinks between aggregated tonofilaments and modulate the number and stability of microtubules.)
Crovato, F, Desirello, G, Gatti, R, Babbini, N, Rebora, A. “Richner-Hanhart syndrome spares a plantar autograft”. Arch Dermatol. vol. 121. 1985. pp. 539-40. (Case report showing lack of involvement of hyperkeratosis in plantar skin graft and that hyperkeratosis elsewhere subsided with a low-tyrosine, low-phenylalanine diet.)
Viglizzo, GM, Occella, C, Bleidl, D, Rongioletti, F. “Richner-Hanhart syndrome (tyrosinemia II): early diagnosis of an incomplete presentation with unusual findings”. Pediatr Dermatol. vol. 23. 2006. pp. 259-61. (A low tyrosine and phenylalanine diet resulting in complete resolution of the oculo-cutaneous symptoms in a patient with tyrosinaemia II in a month.)
Tallab, TM. “Richner-Hanhart syndrome: importance of early diagnosis and early intervention”. J Am Acad Dermatol. vol. 35. 1996. pp. 857-9. (Two brothers with Richner-Hanhart are presented; both treated by diet and etretinate.)
Madan, V, Gupta, U. “Tyrosinaemia type II with diffuse plantar keratoderma and self-mutilation”. Clin Exp Dermatol. vol. 31. 2006. pp. 54-6. (Case report of tyrosinaemia type II with additional features of self-harm and diffuse plantar keratoderma.)
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