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"Child`s Health" 4 (64) 2015

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Orphan disease: infantile systemic hyalinosis (case study)

Authors: Ponochevnaya E. V., Okhotnikova E. N. - National medical academy of postgraduate education named after P. L. Shupyk; Zarudnaya O. F. - National children''s specialized hospital "OHMATDYT", Kyiv; Doronina Y. V., Usova E. I. - National medical academy of postgraduate education named after P. L. Shupyk

Categories: Pediatrics/Neonatology

Sections: Specialist manual

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Hyaline fibromatosis syndrome is a rare, progressive, autosomal recessive disease with a fatal outcome, characterized by severe joint contractures, multiple subcutaneous nodules on the skin, gum hypertrophy, osteopenia, delayed psycho-motor and speech development.

There are some types of hyaline fibromatosis syndrome:

- Infantile systemic hyalinosis (ISH) – it has bad prognosis. The most of the children die in the first years of life;

- Juvenile hyaline fibromatosis (JHF) also known as "Fibromatosis hyalinica multiplex juvenilis,"[1] "Murray–Puretic–Drescher syndrome"[1]) - mild forms of the disease, initially described in adolescents.

Infantile systemic hyalinosis (ISH) and juvenile hyaline fibromatosis (JHF) - two types of the same disease, now called hyaline fibromatosis syndrome (HFS). The term was first named by Nofal, etc. [4, 13]. The first medical case of HFS was reported in 1873 in an English family. The disease at first was called "fibrosic clam" [8, 10, 24]. And then, in 1962 Puretici reported about a case called mesenchymal dysplasia. In 1964, Ishikawa and Hori named the term systemic hyaline fibromatosis [16].

Juvenile hyaline fibromatosis (JHF) is a rare autosomal recessive hereditary disease with different clinical and histological features. Review of the literature was revealed 60 cases had been registered worldwide [8]. Manifestation of symptoms begins during the first two years of life, and then progress rapidly. Gingival hypertrophy usually develops during the first year of life. Skin rash (papules and nodules) are located mostly in the ears and nose, genitals and thighs. Usually the skin lesions are exposed to infection.  Contractures are developing. Adolescent patients usually are bedridden due to progressive and painful contractures.

Infantile systemic hyalinosis (ISH, hyaline fibromatosis in children, infantile hyalinosis) is clinically similar to juvenile hyaline fibromatosis, but it has more severe course and poor prognosis. Infants are suffering during the first several weeks or months of life. Already in the first year of life recurrent pyogenic infections, diarrhea and severe osteoporosis develop. Intensive arthralgia, contractures with limitation of motion in the joints,lead to immobility, development congestion in the lungs and respiratory failure. Protein loss enteropathy occurs because of hyaline infiltration of the intestinal wall and, as a results, feeding problems, malnutrition, cachexia [1, 3, 8]. Death occurs due to sepsis with multi-organ failure, usually before the age of two years. The prevalence of this disease is less than 1 case per 1 million in the population. Until 1994, there were registered 11 patients with infantile systemic hyalinosis and all of them died in infancy mainly due to severe diarrhea, lung infections and sepsis. Since, more than 150 cases have been registered. The disease was detected in families of different ethnic groups on several continents. [5; 19; 20; 21].

Infantile systemic hyalinosis is an autosomal recessive disease, which means that both copies of the gene in each cell have mutations, each of. The child's parents carrie one copy of the mutated gene, as a rule, and they do not have any symptoms of the disease. The disease is associated with CMG2 (ANTXR2) genes coding protein 2, located on the long arm of chromosome 4 (4q21) [4; 6; 7; 14]. Now it is known that the gene ANTXR2 is a single gene, mutations in which cause the occurrence of infantile systemic hyalinosis. ANTXR2 gene provides synthesis of protein, makes the formation of small blood vessels (capillaries). It is thought that this protein maintains the normal structure of the basement membranes, which are the structure of the support cells in various tissues. Signs and symptoms of infantile systemic hyalinosis are determined by the accumulation of hyaline in various tissues of the body. The nature of this substance is not definitively established, it is believed that it consists of molecules of protein and glucose.

Diagnosis of ISH is based on the clinical features, results of histological tests of the affected tissues and genetic testing. Clinical features include 11 symptoms presented in the order of their diagnostic specificity:  

1. Painful joint contractures with progressive restriction of moving.  

2. The specific skin lesions and mucous membranes: a manifestation of ISH is a cutaneous syndrome characterized by the appearance of the maculopapulouse rash, white to pink-pearl colors, different sizes and degrees of intensity neck, head , ears, hands are favorite localizations of rash.  

3. Hyperpigmentation of skin with purple spots develope on the medial and lateral sites of ankle, over the metacarpophalangeal and interphalangeal joints of the hands, over the spine. 

4. Gingival hypertrophy. 

5. Development delay: children with systemic hyalinosis have severe physical restrictions.  

6. Features phenotype: coarse facial features, brachycephaly, broad face, flat head, blue sclera, gingival hyperplasia, cartilage on the gums, high palate, short neck, wide and short thorax.

7. Excessive sweating.

8. Hepatomegaly (not in all patients).

9. The high rate of fractures.

10. The high susceptibility to infections.

11. The development of severe diarrhea.

Diagnostic methods include: immunohistochemistry of skin biopsy or mucous (accumulation of hyaline in the derma. Hyaline detected as amorphous eosinophilic material containing collagen and glycoproteins; normal ratio of collagen types I and III in hyaline material); electronic microscopic examination of the skin; biopsy of the intestine; X-rays of the affected joint (revealed osteopenia, periostal reaction, osteolytic lesions and fractures); CBC determined in normal or not dramatically elevated erythrocyte sedimentation rate, anemia and / or thrombocytosis; deficiency in humoral and cellular immunity (hypogammaglobulinemia IgG, lymphopenia; IgA may also drop; IgM in the normal range). According to the absence of specific treatment of hereditary systemic hyalinosis, therapy includes improving the quality of life and physical therapy and symptomatic treatment, prevention of secondary complications. It has been shown, despite treatment started in time , this  disease was progressive, no methods of treatment was  effective [1, 2, 8, 10]. 80% of children died within the first two years of life, mainly due to recurrent respiratory tract infections and severe diarrhea. Patients who survive until 16-years old, mobility is severely limited due to contractures.

As an illustration of hereditary systemic hyalinosis in children, we present you medical history of a small child who was hospitalized with case of infantile systemic hyalinosis. 

A boy, 1 year 3 months, was admitted to the hospital because of development of contractures of the elbow, knee, joints of the hands, feet, with sharp pain and limitation of movement in them, dermatitis, delayed psycho-moving  and speech development.

From disease anamnesis that is known that a child from the birth had hypotension in upper limbs and limiting the extension in the knee joints, shortness of breath. He get consultation of orthopedics, neurology, also he had massage courses. By the 8th month of age  was added cutaneous syndrome. The boy had  reddish-bluish thickening of the skin in the neck, back, small papulose rash on the face; mucosal changes - hypertrophy of the gingivas; hip dysplasia. During the treatment (physiotherapy, massage, immobilization splint, electrical stimulation of upper and lower limbs), it was seen positive effect: he started do active movements of the upper and lower extremities, however contractures progressed. Suspected diagnosis: mucopolysaccharidosis? Dysplasia of the hip joint; contractures of the joints of the upper and lower extremities; consolidated fractures of the proximal parts thigh bones, and the bones of the left forearm. Osteoporosis. Arthrogryposis? To verify the diagnosis, the child was admitted to our hospital

At examination - a boy is concious.  In the phenotype: coarse facial features, brachycephaly, broad face, gingival hyperplasia, cartilage on the gums, high palate, short neck, short wide thorax, contracture of the elbow, knee, hand joints, skin pigmentation over joints, hyperpigmentation of scrotum, hygromas of palms, chondromas of the feet, elbows, papilloma of right ear, redness of the skin of the scalp, back, rump, small papular rash on the face. Skin turgor is satisfactory.  In auscultation of the lungs - vesicular breathing. The boundaries of the heart within the age standart. Heart sounds clear. Abdomen is soft, painless . Liver and spleen are not enlarged. Feces are normal. Urination is free. Delay of body and speech developments. Mentality is saved.

According CBC marked anemia, leukocytosis, thrombocytosis. In blood chemistry: decrease of serum iron and elevated levels of C-reactive protein.

On X-ray of the hips, thighs, legs, hands revealed osteoporosis. In the joint is visualized additional soft tissue formation, subperiostal fracture of metaphyses of thighs. Osteogenesis corresponds to the age. X-ray of the spine, skull and chest organs revealed no pathological changes. According to CT-scan the spine, upper and lower extremities marked cleft arc L5, as well as all arcs sacral vertebrae. In the area of ​​large joints there are additional soft tissue formations. There are define proximal fractures of both thighs with signs of periostal and endostal bone formation.

To verify the diagnosis, the biopsy of the affected skin in the back, the lateral malleolus of the left lower limb was taken. Histopathological conclusion: a fragment of skin and soft tissue with collagen fibrosis, focuses of hyalinosis; ulceration with inflammatory reaction in the underlying tissues and the presence of capillary sinusoids. Thus, confirmed the diagnosis: infantile systemic hyalinosis. Genetic risk in this marriage is 25%.

During his stay in hospital the child was heavy on the underlying disease. The child developed intestinal syndrome. Laboratory signs of anemia remained mixed origin, leukocytosis with a low lymph-monocytic prevalence, high levels of CRP. In the absence of specific treatment for this disease, the child received symptomatic, detoxication and hydratation therapy. Described a clinical case ISH is the first in Ukraine. Mostly young child sick and rapidly progressive course of the disease, which leads to severe disability, often fatal infectious complications require pediatrician knowledge syndrome genetic diseases, as well as a multidisciplinary approach to the diagnosis of this disease.


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