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 Table of Contents  
Year : 2022  |  Volume : 23  |  Issue : 2  |  Page : 126-128

Infantile systemic hyalinosis – Report of two cases with identification of a novel gene mutation

1 Department of Paediatric Dermatology, Institute of Child Health, Kolkata, West Bengal, India
2 Department of Paediatric Dermatology, Cutis Academy of Cutaneous Sciences, Bengaluru, Karnataka, India
3 Department of Paediatric Dermatology, Indira Gandhi Institute of Child Health, Bengaluru, Karnataka, India
4 Department of Pathology, Wizdermpath Lab, Kolkata, West Bengal, India
5 Department of Paediatric Medicine, Institute of Child Health, Wizdermpath Lab, Kolkata, West Bengal, India

Date of Submission22-Apr-2021
Date of Acceptance14-Sep-2021
Date of Web Publication30-Mar-2022

Correspondence Address:
Dr. Rashmi Agarwal
Cutis Academy of Cutaneous Sciences, Bengaluru, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijpd.ijpd_57_21

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Infantile systemic hyalinosis (ISH; MIM #236490) and juvenile hyaline fibromatosis (MIM #228600) represent two spectrums of the rare autosomal recessive disorder, the hyaline fibromatosis syndrome caused by mutations in ANTXR2/CMG2 encoding capillary morphogenesis protein-2. Herein, we report two cases of ISH with different clinical presentations confirmed by CMG2 gene mutations. Homogenous 79 bp deletion of the entire exon 11 reported in one of the cases has not been reported previously.

Keywords: Child, hyaline fibromatosis syndrome, infantile systemic hyalinosis, juvenile hyaline fibromatosis

How to cite this article:
Dhar S, Agarwal R, Srinivas SM, Dhar S, Ghosh A. Infantile systemic hyalinosis – Report of two cases with identification of a novel gene mutation. Indian J Paediatr Dermatol 2022;23:126-8

How to cite this URL:
Dhar S, Agarwal R, Srinivas SM, Dhar S, Ghosh A. Infantile systemic hyalinosis – Report of two cases with identification of a novel gene mutation. Indian J Paediatr Dermatol [serial online] 2022 [cited 2022 May 21];23:126-8. Available from: https://www.ijpd.in/text.asp?2022/23/2/126/341475

  Introduction Top

Infantile systemic hyalinosis (ISH; MIM #236490) and juvenile hyaline fibromatosis (JHF; MIM #228600) represent two spectrums of the rare autosomal recessive disorder, the hyaline fibromatosis syndrome caused by mutations in ANTXR2/CMG2 on chromosome 4q21 encoding capillary morphogenesis protein-2. ISH is the more severe form than JHS with a very early age of onset, even at birth, presenting with characteristic skin lesions, gingival hyperplasia, joint and bone disease, and systemic involvement. Children usually suffer from severe diarrhea, recurrent infections, and malnutrition that lead to death.[1] Only few cases have been reported from India to date.[2] Herein, we report two cases of ISH with different clinical presentations confirmed by CMG2 gene mutations.

  Case Reports Top

Case 1

A 1.5-year-old boy, born of consanguineous marriage, presented with multiple skin swellings and frequent episodes of loose stools for the past 1 year. At 4 months of age, the parents started noticing progressive thickening and darkening of the skin of the extremities along with decreased limb movement and discomfort while handling the child. Antenatal, perinatal, and family history were noncontributory. The child was malnourished, and gross motor activities were delayed. On examination, multiple fleshe colored, crusted, and ulcerated nodules and plaques were present on the scalp, bilateral ear lobes, tip of the nose, chin, and back with features of secondary eczematization and atrophic scarring [Figure 1]a. Multiple tiny skin colored to pinkish papules were present on the perioral, perinasal, periocular area, and forehead [Figure 1]b. Gingival hypertrophy, cervical lymphadenopathy, and joint contractures were also seen. Investigations showed anemia, hypocalcemia, and generalized osteopenia with periosteal reaction of the long bones. Abdominal ultrasound, echocardiography, and MRI brain revealed no major abnormality. Biopsy from the scalp lesion showed edematous papillary dermis and pink homogeneous acellular hyaline deposition throughout the dermis. Genetic analysis revealed mutation in ANTXR2 gene (homogenous 79 bp deletion of entire exon 11) confirming the diagnosis of ISH.
Figure 1: A 1½-year-old boy with multiple nodular swellings on the scalp and ear with ulceration and crusting (a) along with bulbous swelling on the nose and chin with pin-point grouped skin colored fleshy papules on the face (b)

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Case 2

A 1-year old child, born of consanguineous marriage presented with multiple reddish lesions on the body for the past 3 months along with painless swelling on the wrist for the past 1 month. Antenatal, perinatal, and family history were noncontributory. The child had recurrent episodes of fever, cough, and diarrhea. On examination, there were multiple skin-colored to pinkish 1–5 mm papules on the forehead, scalp, and perianal area. One firm erythematous scaly plaque was present in the right retroauricular area. Two pink, fleshy, linear plaques were seen in the anal cleft [Figure 2]a. Soft, nontender subcutaneous swellings were present on both wrists [Figure 2]b along with hyperpigmentation of the dorsum of the hands, wrists, elbows, and knees. The child had joint contractures, gingival hyperplasia, depressed nasal bridge, bulbous nasal tip, and excessive facial hair. Complete blood count and biochemical investigations were within the normal range for age. X-rays of the long bones of the limbs showed osteopenia and osteolytic lesions. Abdominal ultrasound, echocardiography, and MRI brain were normal. Histopathological examination of papular lesion from the perianal region showed hyperkeratosis and edematous dermis with abundant eosinophilic homogeneous acellular material throughout the papillary dermis with periodic acid–Schiff stain [Figure 3]. Genetic testing showed mutation in ANTXR2 gene (homogenous for insertion mutation c.277_278ins ATTATTT in exon 3) confirming the diagnosis of ISH.
Figure 2: A 1-year-old girl with subcutaneous swelling and hyperpigmentation of the overlying skin on both wrist joint (a) and skin colored to pinkish small papules on the buttocks with pink, fleshy, and linear plaques on the anal cleft (b)

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Figure 3: Hematoxylin and eosin stain lesion from a papule on the perianal region shows hyperkeratosis and edematous dermis with abundant eosinophilic homogeneous acellular material throughout the papillary dermis (periodic acid–Schiff stain)

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  Discussion Top

Murray et al., in 1873, were the first to describe a condition termed molluscum fibrosum,[3] which was later renamed by Kitano et al., in 1972 as JHF.[4] Patients with HFS are usually normal at birth with abnormalities beginning in the first few months of life. Noncancerous tissue proliferations of the skin, gingiva, joints, bone, and internal organs are the hallmarks of HFS.[2] The characteristic skin lesions include pink pearly papules and plaques located on the chin, nasolabial folds, forehead, ears, back of the neck, and perianal region along with large subcutaneous tumors over the scalp and less frequently on the trunk, extremities, and eyelids. Thickened hyperpigmented plaques may occur over bony prominences of the joints. Gingival hyperplasia may interfere with feeding and result in poor oral hygiene, infection, and dental caries. Painful flexion contractures of the large joints are the most debilitating problem, resulting in severe limitation of mobility. Osteoporosis, fractures, and osteolytic lesions of the long bones may occur. ISH can be distinguished from JHF by the presence of thickened skin, erythema, or hyperpigmentation over bony prominences, visceral involvement, persistent diarrhea, frequent severe infections, failure to thrive, and death usually by 2 years of age. Though with better pediatric care in severely affected infants, the chances of survival beyond infancy have increased.[5] In a recent study, males were found to be more frequently diagnosed with ISH rather than with JFH.[6] The exact pathogenesis is still elusive. CMG2, an integrin-like cell surface receptor plays a role in basement membrane matrix assembly and endothelial cell morphogenesis. A defect in ANTXR2 can lead to the extravasation of hyaline material (plasma components) through the basement membrane into the perivascular space.[7] The loss of ANTRX2 function has been shown to cause accumulation of collagen VI in the extracellular matrix, which with time may lead to tissue disruption and disease.[8] Around 50 mutations have been reported with ANTXR2 gene.[9],[10] The majority of mutations are homozygous with frameshift and splice site leading to premature stop codon followed by missense mutations in the vWA domain.[11] Exon 13 is the mutational hotspot with the most common mutations being c.1073dup and c.1074del. 10 In the present two cases described there was deletion in exon 11 and insertion in exon 3, respectively, and phenotypically, they presented with the severe phenotype. The mutation found in case 1, homogenous 79 bp deletion of the entire exon 11 is a novel mutation and has not been reported previously. However, we were not able to confirm this mutation in the parents due to logistic reasons. According to the modified grading system of HFS proposed by Denedai et al.,[12] both our cases belong to grade 3 severity. HFS shows some clinical overlap with Farber disease, a recessive lysosomal storage disorder. Cozma et al. in a recent study, examined untargeted blood-based metabolomics and found the metabolomics profiles of HFS patients to highly overlap with Farber disease.[6] Management of HFS requires multidisciplinary approach. Treatment is only symptomatic. Early surgical excision of skin lesions is recommended as they may enlarge and ulcerate causing immense discomfort. However, local recurrence is common. Intralesional steroids for subcutaneous nodules have also been suggested. In case of joint involvement, physiotherapy, cortisone or D-penicillamine, and capsulotomy may provide temporary relief. Adequate analgesia with nonsteroidal anti-inflammatory drugs, gabapentin, and opiates is important. Partial or radical gingivectomy along with the maintenance of good oral hygiene is important factor in decreasing the growth rate of the gingivae.[8] Genetic counseling is the mainstay of management in HFS. These two cases are being reported because ISH is a rare entity and early diagnosis is essential to minimize the morbidity caused by the cutaneous lesions and joint contractures.

Declaration of consent

The authors certify that they have obtained all appropriate consent forms, duly signed by the parent(s) of the patient. In the form the parent(s) has/have given his/her/their consent for the images and other clinical information of their child to be reported in the journal. The parents understand that the names and initials of their child will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Shah I. Dermal swellings, joint contractures but no gingival hypertrophy. Pediatr Oncall 2017;14:100.  Back to cited text no. 1
Deuquet J, Lausch E, Guex N, Abrami L, Salvi S, Lakkaraju A, 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;3:208-21.  Back to cited text no. 2
Murray J. On three peculiar cases of molluscum fibrosum in children in which one or more of the following conditions were observed: Hypertrophy of the gums; enlargement of the ends of the fingers and toes; numerous connective-tissue tumours on the scalp and other parts of the surface of the body, with various superficial affections of the skin. J R Soc Med 1873;56:235-53.  Back to cited text no. 3
Kitano Y, Horiki M, Aoki T, Sagami S. Two cases of juvenile hyalin fibromatosis. Some histological, electron microscopic, and tissue culture observations. Arch Dermatol 1972;106:877-83.  Back to cited text no. 4
Nofal A, Sanad M, Assaf M, Nofal E, Nassar A, Almokadem S, 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.  Back to cited text no. 5
Cozma C, Hovakimyan M, Iuraşcu MI, Makhseed N, Selim LA, Alhashem AM, et al. Genetic, clinical and biochemical characterization of a large cohort of patients with hyaline fibromatosis syndrome. Orphanet J Rare Dis 2019;14:209.  Back to cited text no. 6
Hanks S, Adams S, Douglas J, Arbour L, Atherton DJ, Balci S, 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.  Back to cited text no. 7
Bürgi J, Kunz B, Abrami L, Deuquet J, Piersigilli A, Scholl-Bürgi S, et al. CMG2/ANTXR2 regulates extracellular collagen VI which accumulates in hyaline fibromatosis syndrome. Nat Commun 2017;8:15861.  Back to cited text no. 8
El-Maaytah M, Jerjes W, Shah P, Upile T, Murphy C, Ayliffe P. Gingival hyperplasia associated with juvenile hyaline fibromatosis: A case report and review of the literature. J Oral Maxillofac Surg 2010;68:2604-8.  Back to cited text no. 9
Härter B, Benedicenti F, Karall D, Lausch E, Schweigmann G, Stanzial F, et al. Clinical aspects of hyaline fibromatosis syndrome and identification of a novel mutation. Mol Genet Genomic Med 2020;8:e1203.  Back to cited text no. 10
Deuquet J, Lausch E, Superti-Furga A, van der Goot FG. The dark sides of capillary morphogenesis gene 2. EMBO J 2011;31:3-13.  Back to cited text no. 11
Denadai R, Raposo-Amaral CE, Bertola D, Kim C, Alonso N, Hart T, 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 A 2012;158A: 732-42.  Back to cited text no. 12


  [Figure 1], [Figure 2], [Figure 3]


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