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Advances in Anatomic Pathology:
doi: 10.1097/PAP.0b013e31825347bf
Letters to the Editor

Additional Thoughts About Juvenile Hyaline Fibromatosis and Infantile Systemic Hyalinosis

Denadai, Rafael MD*; Bertola, Debora Romeo MD, PhD; Stelini, Rafael Fantelli MD; Raposo-Amaral, Cassio Eduardo MD*

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*Institute of Plastic and Craniofacial Surgery, Hospital de Crânio e Face SOBRAPAR

Department of Anatomic Pathology Universidade Estadual de Campinas Campinas

Genetics Unit, Department of Pediatrics Universidade de São Paulo São Paulo, Brazil

The authors have no funding or conflicts of interest to disclose.

To the Editor:

We read with interest the review article by Thway et al,1 specifically on the topic juvenile hyaline fibromatosis (JHF)/infantile systemic hyalinosis (ISH), and we have the following comments to offer:

As reported by the authors,1 in recent years, JHF and ISH have been described as different degrees of severity of the same disease, and hence some unifying terms have been proposed.2,3 As in the systemic hyalinosis nomenclature,2 the term “systemic” excludes several JHF/ISH patients with localized disease.3,4 We support4 the adoption of another unifying terminology [hyaline fibromatosis syndrome (HFS)] proposed by Nofal et al3 and subsequently adopted by others.5 HFS is a broader term that seems to make the clinicopathologic correlation to properly diagnosing patients in a clearer and simpler way.3,4 Moreover, instead of describing ISH as a more severe spectrum and JFH as the milder spectrum,1 HFS patients can be divided into mild, moderate, severe, and lethal subtypes according to the severity grading system initially proposed by Nofal et al3 and recently modified by our group.4 This grading system seems to show the complexity of this disease more accurately and it also has direct implications on the management of HFS patients.4

According to our study4 those by and others,2,5,6 lesions usually appear earlier (within the first year of life) than the age (2 to 5 y old) described in the review,1 and the domain of this knowledge is important for a correct diagnosis to be made early in the course of the disease.6

After identifying the anthrax toxin receptor-2 (ANTXR2) gene as being responsible for FHJ/ISH as described in the review,1 attempts were made for a genotype-phenotype correlation.7 In our study,4 we evaluated 28 different mutations and the respective patients but found no relationship between genotype and severity of clinical data, suggesting that other modifying genes and/or environmental factors may also play important roles.

Histologically, besides the aspects discussed by the authors,1 in cutaneous and gingival lesions the proliferation of spindle cells without atypia forming strands in the midst of homogenous and hyaline eosinophilic material that is more abundant in areas of less cellularity and denser around certain blood vessels has been described.4,8,9 In certain areas, fusocellular cords can be close to clear slits, simulating vascular spaces, or otherwise can exhibit clear pericellular halos (so called “chondroid appearance”).4,9,10 In addition, electron microscopy evaluation can reveal a banding pattern with expanded Golgi complexes that are filled with a microfibrillar and fine granular layer,8 and the analysis of stratum spinosum can show big spaces between the adjoining cells and significant decrease of the interdigitating processes.11 The presence of calcospherules (calcium-containing lamellar bodies) has also been described,9 suggesting that they may represent calcification of fibrillogranular material within the multivesicular bodies and constituting a helpful diagnostic marker for the disease.9

Currently, there is no satisfactory treatment for this stigmatizing, debilitating, and potentially lethal disease.2–5 With regard to the treatment approach adopted by the authors,1 surgical excisions have been considered the main form for managing both skin and oral lesions,4,11 but not for joint, bone, and visceral involvement. There is disagreement about the time of initiation of the surgical approach; some authors2,10 are in favor of an intervention soon after the onset of lesions, whereas others4,12 are in favor of a later treatment. At present, our group4 is following up 4 of the 5 HFS patients previously reported. Their lesions are resected only when they become ulcerated (risk of infection) or present with some aesthetic and/or functional conditions, because the lesions may recur after excision and multiple attempts at treatment can sometimes be as crippling as the disease itself.

Finally, as some studies5,13 have found potential targets for pharmacological intervention to achieve more radical and effective treatments, future genetic studies should focus their efforts in the development of potential genetic therapies for this devastating disorder.

Rafael Denadai, MD*

Debora Romeo Bertola, MD, PhD†

Rafael Fantelli Stelini, MD‡

Cassio Eduardo Raposo-Amaral, MD*

*Institute of Plastic and Craniofacial Surgery, Hospital de Crânio e Face SOBRAPAR

‡Department of Anatomic Pathology, Universidade Estadual de Campinas, Campinas

†Genetics Unit, Department of Pediatrics, Universidade de São Paulo, São Paulo, Brazil

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1. Thway K, Fisher C, Sebire NJ. Pediatric fibroblastic and myofibroblastic lesions. Adv Anat Pathol. 2012;19:54–65

2. Urbina F, Sazunic I, Murray G. Infantile systemic hyalinosis or juvenile hyaline fibromatosis? Pediatr Dermatol. 2004;21:154–159

3. Nofal A, Sanad M, Assaf M, et al. Juvenile hyaline fibromatosis and infantile systemic hyalinosis: a unifying term and a proposed grading system. J Am Acad Dermatol. 2009;61:695–700

4. Denadai R, Raposo-Amaral CE, Bertola D, et al. Identification of 2 novel ANTXR2 mutations in patients with hyaline fibromatosis syndrome and proposal of a modified grading system. Am J Med Genet Part A. 2012;158A:732–742

5. Deuquet J, Lausch E, Guex N, et al. Hyaline fibromatosis syndrome inducing mutations in the ectodomain of anthrax toxin receptor 2 can be rescued by proteasome inhibitors. EMBO Mol Med. 2011;3:208–221

6. Al-Mayouf SM, AlMehaidib A, Bahabri S, et al. Infantile systemic hyalinosis: a fatal disorder commonly diagnosed among Arabs. Clin Exp Rheumatol. 2005;23:717–720

7. Hanks S, Adams S, Douglas J, et al. Mutations in the gene encoding capillary morphogenesis protein 2 cause juvenile hyaline fibromatosis and infantile systemic hyalinosis. Am J Hum Genet. 2003;73:791–800

8. Stucki U, Spycher MA, Eich G, et al. Infantile systemic hyalinosis in siblings: clinical report, biochemical and ultrastructural findings, and review of the literature. Am J Med Genet. 2001;100:122–129

9. Ko CJ, Barr RJ. Calcospherules associated with juvenile hyaline fibromatosis. Am J Dermatopathol. 2003;25:53–56

10. Antaya RJ, Cajaiba MM, Madri J, et al. Juvenile hyaline fibromatosis and infantile systemic hyalinosis overlap associated with a novel mutation in capillary morphogenesis protein-2 gene. Am J Dermatopathol. 2007;29:99–103

11. Hakki SS, Ataoglu T, Avunduk MC, et al. Periodontal treatment of two siblings with juvenile hyaline fibromatosis. J Clin Periodontol. 2005;32:1016–1021

12. Dhingra M, Amladi S, Savant S, et al. Juvenile hyaline fibromatosis and infantile systemic hyalinosis: divergent expressions of the same genetic defect? Indian J Dermatol Venereol Leprol. 2008;74:371–374

13. Tzellos TG, Batzios SP, Dionyssopoulos A, et al. Differential expression of matrix metalloproteinases and proteoglycans in juvenile hyaline fibromatosis. J Dermatol Sci. 2011;61:94–100

© 2012 Lippincott Williams & Wilkins, Inc.


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