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Case report: infantile systemic hyalinosis: a dental perspective.


Infantile systemic hyalinosis (ISH) is a rare genetic (CMG2) disorder caused by a mutation in the gene coding the protein responsible for the morphogenesis of capillary blood vessels (capillary morphogenetic protein 2) [Raham et al., 2002; Shin et al., 2004; Aghighi et al., 2007]. The gene locus is on chromosome 4q21. The disease is inherited in an autosomal recessive manner (OMIM 236490). It is an allelic variant of a similar, less severe condition, i.e. juvenile systemic hyalinosis (OMIM 228600) [Hahn et al., 2004; Lindvall et al., 2008].

The disease becomes overt within the first months of life, and is manifested by painful articular contractures and oedema, hyperpigmentation in the skin areas exposed to even minor trauma, e.g. when lying on a firm surface, and cutaneous nodules. However, the most characteristic feature in patients with ISH is gingival hypertrophy, which, at a later stage, is followed by labial and buccal hypertrophy. In the course of the disease, the patient develops persistent diarrhoeas due to protein-losing enteropathy. The latter is caused by intestinal lymphangiectases. Progressive emaciation associated with recurrent infections may lead to death at that stage. However, if the patient survives until early childhood, the articular pain decreases in severity. It is worth noting that in patients with ISH the central nervous system is not involved; misdiagnosis of muscle hypertonia at the initial stage of the disease usually leads to stubborn rehabilitation which increases the pain [Chaudhary and Dayal 1995; Aghighi et al., 2007; Borge et al., 2007].

Tissue biopsy specimens obtained from ISH patients reveal an accumulation of hyaline deposits. They are usually found in the skin, skeletal and cardiac muscles, lymph nodes, suprarenal glands, gastrointestinal tract, thyroid gland and spleen (without resultant splenomegaly) [Shin et al., 2004; Editor Desk 2007].

The differential diagnosis should also include other congenital diseases of the connective tissue, i.e. Winchester syndrome (OMIM 277950), systemic fibromatosis (OMIM 228550), stiff skin syndrome (OMIM 184900), lipoid proteinosis (OMIM 247100), and storage diseases including mucopolysacharoses, sphingolipidoses and mucilipidoses [Osterby et al., 2002; Zolkpi et al., 2003; Lim et al., 2005; Yayli et al., 2006; Al-Mayouf 2007; ,Al-Malik et al., 2007; Shieh et al., 2008; Al-Mubarak et al., 2009].

The authors' objective was to present the phenotype characteristics of infantile systemic hyalinosis with a particular focus on oral lesions, and obstacles in the therapeutic management in the case reported.

Case presentation

A two year old boy with infantile systemic hyalinosis was referred to the Department of Oral Pathology, The Children's Memorial Health Institute, Warsaw, Poland because of gingival hypertrophy that was impairing normal nutrition.

The boy was the first child of his parents and the pregnancy was complicated by oligohydroamnion. He was delivered by caesarean section due to a threatened asphyxia, with a body weight of 2,800 grams at birth and an Apgar score of 9 points. During the neonatal period patient assessment showed tactile hypersensitivity and contractures of the major joints.

At the age of six months, the patient was found to have a flattened occiput and an enforced body position caused by a limited range of movement of the upper and lower limb joints and the vertebral column without signs of inflammation or oedema. Articular abnormalities of the elbows and knees were present. Attempts to extend the joints were accompanied by severe pain. The patient's emotional and mental development was normal.

The diagnosis of infantile systemic hyalinosis was confirmed at the age of 12 months was based on the presence of mutation 1601PinsC on both alleles. At the age of thirteen months the boy had an abnormal body proportion (the trunk was unproportionately long in relation to the limbs), facial dysmorphism, disproportion between the cranial and facial bones (a large head with a prominent forehead) (Fig. 1). There were also cutaneous lesions, i.e. nodules and hyperpigmentation, mainly in the areas exposed to pressure, gingival hypertrophy and osseoarticular contractures progressing despite physical therapy. At this time the patient was scheduled for consultation in the Department of Oral Pathology.

Extra-oral examination showed a mild eminence of the subnasal area and excessive, elastic and firm, non-tender lips. Intra-oral assessment showed massive gingival hypertrophy completely covering the maxillary and mandibular teeth. The gingival and oral mucosa was firm, smooth and glistening (Fig. 2).



A skin biopsy specimen was obtained from the inner area of the forearm for histopathology. A decision was made to perform both maxillary and mandibular gingivectomy, although the procedure was postponed because the patient's general condition had deteriorated as the boy had signs of neurological impairment and malnutrition associated with intestinal protein depletion syndrome, and a presumed angiomatosis. In order to reduce the severity of his diarrhoea and to improve the patient's nutritional status the treatment regimen included non-steroidal anti-inflammatory drugs (NSAIDs) and medium chain triglyceride (MCT) oil. Gingivectomy and dental extraction of 61, 71, and 81 due to caries was performed when a normal general condition had been achieved (April 2009). The procedure was accomplished under general anaesthesia. The patient was discharged from hospital in a good general condition on the sixth post-operative day. The intraoperative material obtained from the hypertrophied gingiva revealed a polypoid hypertrophy of the abundant connective stroma with multiple partially dilated lymphatic vessels, nonspecific inflammatory infiltrates and focal mucosal ulceration.

Follow up

An assessment at three months revealed angular cheilitis, evident thickening of the area including the lower lip and gingiva without hypertrophy (Fig. 3). Other findings included unsatisfactory oral hygiene and dental caries. In view of the patient's non-compliance, essential hygienic and prophylactic procedures were only performed. Additionally, progressive cutaneous lesions (hyperpigmented nipples, perianal nodules), malnutrition and contractures of interphalangeal joints were noted.


On a subsequent hospital admission to the Department of Metabolic Diseases, Endocrinology and Diabetes, The Children's Memorial Health Institute, Warsaw, Poland (November, 2009) anthropometric evaluation was performed. The findings included a mild macrocephaly, progressively restricted range of movement in all joints, lack of body weight gain (approx. 200 grams since the previous measurement) and progressive emaciation caused by chronic diarrhoea. The lack of possible normal oral nutrition, the decision was to provide a partial parenteral nutrition protocol. Oral examination showed enlargement of the subnasal area and the lower lip, reduced nasal openings, angular fissures, and a mild gingival hypertrophy in the anterior portion of the maxilla. The oral hygiene status was again assessed as unsatisfactory.


Infantile systemic hyalinosis is a rare genetic disorder which involves accumulation of hyaline. Paediatric clinical assessment reveals cutaneous nodules, articular contractures, gingival hyperthrophy, recurrent diarrhoea, and frequent infections. The mental development is within the normal range. The majority of children with ISH die before their second birthday [Raham et al., 2002; Shin et al., 2004; Aghighi et al., 2007]. Only one boy, reported by El-Kamah, survived four years [El-Kamah and Mostafa 2009].

Juvenile hyaline fibromatosis (JHF) is a similar disease to ISH and has often been described as a different disease, but there are histological similarities and the hyaline material is the same in both. ISH is a more severe form, has an early onset and short survival, whilst JHF is milder with a later onset of the disease [Buyukgebiz et al., 2003; Al-Najjadah et al., 2003]. Both the reported case and those presented by other authors of children with hyalinosis, show a full constellation of clinical manifestations of the disease [Aghighi et al., 2007; El-Kamah and Mostafa 2009] These include nodular cutaneous lesions, painful contractures, mainly in the shoulder, elbow and knee joints, massive gingival hypertrophy and significant thickening of the subnasal area with hypertrophy of the lower lip [Aghighi et al., 2007; El-Kamah and Mostafa 2009].

In our patient the oral hygiene was unsatisfactory and was due to a combined effect of the gingival hypertrophy (with no improvement post-surgery) but primarily due to the unsatisfactory parental hygiene procedures, the high caloric dietary intake, diarrhoea and malabsorption which are features of this syndrome [Devlin et al., 1991].

All previous patients with ISH also experienced recurrent diarrhoea and frequent infections [Shin et al., 2004; Yayli et al., 2006; Aghighi et al., 2007; Lindvall et al., 2008;, El-Kamah and Mostafa 2009]. Progressive malnutrition, and even emaciation associated with protein-losing enteropathy is a major, frequently fatal complication in children with congenital hyalinosis. Hyaline accumulation in the gingivae, cheeks and lips may render oral nutrition difficult or even impossible. In these patients hyaline accumulation could cause significant narrowing of the pharynx, trachea and airway with bronchoscopic examination becoming much more complicated than in other patients [Norman et al., 1996]. Additionally, neck immobility and temporomandibular joint contracture are also observed which cause further difficulties during intubation procedures [Pollard et al. 2008].


In spite of its limited effectiveness, surgical treatment of the gingival hypertrophy in hyalinosis cases appears to be the treatment of choice and oral hygiene instructions should be rigorously implemented.


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D. Olczak-Kowalczyk *, E. Krasuska-Stawinska **, D. Rokicki ***, M. Pronicki ****

* Pediatric Dentistry Department, Medical University of Warsaw, * Department of Oral Pathology and *** Department of Metabolic Diseases, Endocrinology and Diabetes, **** Department of Pathology, The Children's Memorial Health Institute, Warsaw, Poland

Postal address: Dr D. Olczak-Kowalczyk, Department of Pediatric Dentistry, Medical University of Warsaw, ul. Miodowa 18 Warsaw 00-246, Warsaw, Poland.

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Author:Olczak-Kowalczyk, D.; Krasuska-Stawinska, E.; Rokicki, D.; Pronicki, M.
Publication:European Archives of Paediatric Dentistry
Article Type:Report
Geographic Code:4EXPO
Date:Aug 1, 2011
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