Hyaline fibromatosis syndrome (HFS) is an extremely rare autosomal recessive disorder which appear in infancy or childhood. It is characterized by excessive deposition of amorphous hyaline substance in numerous tissues and organs, with the exception of brain tissue. HFS is caused by a mutation of the ANTXR2 gene (Anthrax Toxin Receptor - 2) located on chromosome 4q21, which encodes a transmembrane cell receptor that participates in strengthening and supporting connective tissue by reacting with the extracellular matrix (1). This transmembrane protein is called CMG2 (Capillary Morphogenesis Protein Gene - 2) and has four components. The extracellular component of the receptor consists of the von Willebrand type A domain (vWA), which continues to the immunoglobulin-like domain, followed by the transmembrane domain and finally the intracellular cytoplasmic tail (2). ANTXR2 was named after primarily being discovered as a receptor for the anthrax toxin of Bacillus anthracis. The pathogenesis of HFS has not been fully explained, but it seems that the mutation of the ANTXR2 causes the synthesis of a receptor that has impaired ability to interact with extracellular matrix components, leading to the accumulation of hyaline deposits in tissues (3). The first clinical signs may be present at birth or appear during infancy. Given the time of the disease onset, the severity of the clinical picture and survival, two syndromes with similar clinical presentation and pathological findings were described in the literature: Infantile Hyaline Fibromatosis (IHF) and Juvenile Hyaline Fibromatosis (JHF). IHF occurs earlier with more pronounced clinical picture and shorter survival, whereas JHF develops later, with milder clinical picture and longer survival. Today, after the discovery of a common genetic cause, it is clear these are stages of the same disease. In 2012, HFS was classified into 4 stages, according to severity, incidence, and survival (1, 4). Multiple nodular subcutaneous lesions, painful progressive joint contractures, hyperpigmentation of the skin, enteropathy with extensive protein loss and chronic diarrhea, frequent infections, bone lesions, gingival hypertrophy and thickening of the lip and cheek tissue belong to the characteristic manifestations of HFS (4). In this report we present a five-year-old girl with HFS who, to the best of our knowledge, is the first patient in Croatia with a confirmed ANTXR2 gene mutation described in the literature.
A 5-year-old girl was referred to the Department of Maxillofacial and Oral Surgery from the pediatric clinic having the chief complaint of difficulty feeding and speaking due to extensive generalized gingival hypertrophy. She was previously diagnosed with HFS, during early infancy. Although she was born in the third trimester of pregnancy, there was an increased risk for preterm delivery managed by medications. The baby was born after full term pregnancy, without complications during delivery. The family history revealed no similar illnesses. The non-consanguineous parents already had one healthy female child. The first symptoms appeared at the age of two months, in the form of upper extremities joint stiffness. This progressed to joint contractures (Figure 1. A). At the age of two years, the patient presented hyperpigmented macules over bony prominences and stunted growth, hypotonia with normal cognitive development (Figure 1.B). As the disease progressed further, pink pearly skin papules appeared on the skin of the neck, condyloma-like growths in the perianal region, and subcutaneous nodules on the trunk and lower extremities (Figure 1.C). A biopsy of the skin and subcutaneous nodules revealed a normal structure of the epidermis and dermis with hyaline deposits in the subcutaneous tissue along with multiplied fibroblasts and blood vessels. A molecular analysis confirmed the mutation of the ANTXR2 gene. The patient underwent orthopedic correction of knee contractures at the age of three.
During a clinical examination of the head and neck, skeletal deformities of viscerocranium and neurocranium (broad forehead, depressed nasal bridge, low set ears) were recorded (Figure 1.D). An intraoral clinical examination showed a limited mouth opening due to diffusely thickened skin of the oral commissures and extensive gingival hypertrophy that completely covered the crowns of the teeth (Figure 1.E).
Due to the functional impairments, a gingivectomy with electrocautery was performed, in general endotracheal anesthesia, resulting in satisfactory postoperative appearance, with healthy deciduous teeth (Figure 1.F and 1.G). During the same anesthesia, subcutaneous nodules from the lower extremities were removed by a plastic surgeon.
J. Murray (1873) was the first to mention HFS, under the name of "molluscum fibrosum" as an unusual form of neurofibromatosis (5). B. Puretić et al. (1962) described a patient with similar manifestations and named the disease mesenchymal dysplasia. For the years to come, different names have been used for the same disease, until Y. Kitano (1972) concluded that it was the same syndrome with variable clinical presentation and introduced the term hyaline fibromatosis (3). To date, 84 cases of HFS have been described in the literature. It is equally common in males and females. Forty six ANTXR2 gene mutations have been identified so far, divided into four classes, depending on the receptor domain affected by the mutation. Recent studies showed that mutations affecting the transmembrane, immunoglobulin-like domain and von Willebrand type A domain cause a more severe disease (formerly called IHF), while mutations in the gene responsible for the intracellular part of ANTXR2 receptor cause milder disease (formerly referred to as JHF) with later onset, milder clinical presentation and longer survival (4). In 2012, R. Denadai et al. developed a 4-grade classification system. The first stage is the mildest form of the disease and involves skin changes and gingival hypertrophy. In the second stage, changes in the joints and bones are present, while in the third stage, the internal organs are affected. The fourth stage is the most severe (severely shortened life expectancy). It is, usually, diagnosed earlier than the first three stages, during the first three months of life, the first symptom being joint stiffness. The median survival in stage 4 is 15 months (6). Although our patient was diagnosed very early, at the age of two months, internal organs were not affected which would indicate that her condition is most likely stage two.
Clinically, the two most common manifestations are subcutaneous nodules (85.7%) and gingival hypertrophy (92.9%). Although subcutaneous nodules are most often found on the scalp, they were present only on the hands of our patient, on her feet and behind her ears. In the majority of cases reported in the literature these signs were the ones that led to the diagnosis (4).
Gingival hypertrophy results in impaired oral hygiene that can cause odontogenic infections and difficulties in feeding. Our patient had great difficulties in eating, however, gingival hypertrophy didn’t cause tooth decay. Perhaps, the fact that the gingiva covered the entire crowns of the teeth completely acted as a protective mechanism. Hypertrophic gingiva was enlarged but painless, hard and normal in color. Gingival hypertrophy can cause difficulties in permanent teeth eruption. In older children, it can cover the entire occlusal surfaces of the teeth, causing difficulty in chewing and speaking. As a part of HFS, gingival hypertrophy can be localized or generalized. Hypertrophy is most commonly localized on the palatal side of the tuber of the upper jaw or the lingual side of the lower alveolar ridge (7, 8).
The characteristic pathological features are the accumulation of amorphous, eosinophilic hyaline substance in many tissues and organs as found in the presented case (Figure 1.H) (9). Although the composition and origin of the hyaline substance is not yet fully known, some studies indicate that mutation of the ANTXR2 gene, due to receptor dysfunction, leads to destabilization and dysregulation of extracellular matrix components. Type IV and VI collagen and laminin have been shown to be the major ligands of receptors, and, in case of ANTXR2 dysfunction, they accumulate in the extracellular space. In addition, there is a proliferation of spindle and inflammatory cells (4). Pathological differential diagnosis includes Farber disease, I-cell disease (mucolipidosis II), Pseudo-Hurler polydistrophy (mucolipidosis IIIa) and lipoid proteinosis of Urbach and Wiethe (7). Given that there is no cure for HFS today, treatment is symptomatic and involves surgical removal of the gingiva and subcutaneous nodules. Unfortunately, poor results have been reported in the literature using interferon alfa-2B, corticosteroids, penicillamine and methotrexate (4, 10). Due to the extreme rarity of HFS and the short life span of patients, there is no consensus on treatment modalities to date. The most common cause of death in HFS is persistent diarrhea, frequent infections, and organ failure (6). Due to the recurrence of gingival hypertrophy, additional surgery is needed; however there is no doubt that gingivectomy greatly improves the quality of life in these patients (7, 8). In our case, one year follow up shows satisfactory results without local recurrence. After the procedure, the patient gained weight which is significant considering her stunted growth.
Until the cure for HFS has been found, it is necessary to focus on a multidisciplinary approach in the diagnosis and treatment of these patients and provide psychological support for the family. Although these patients suffer from a range of symptoms, it is necessary to address gingival hypertrophy in the earliest opportunity to allow proper nutrition, which is imperative bearing in mind their slower growth and development.