Infantile systemic hyalinosis: Report of a rare inherited disorder from Northern India

No abstract available
Sri Lanka Journal of Child Health, 2023: 52(2): 223-227

On examination, child had involvement of both flexor and extensor groups of muscles at elbow, wrist and knee joints and dorsiflexors, plantar flexors, invertors, and evertors at ankle joints (Figures 1 and 2) and hyperpigmentation of knuckles ( Figure 3). His weight was 4.72kg (<1 st centile), length 55cm (<1 st centile), head circumference 40cm (<3 rd centile), upper segment 34cm, lower segment 21cm (growth centiles according to Indian Academy of Paediatrics growth charts) The couple also had two other children whose details were as follows. The firstborn was a female with uneventful antenatal history, who also developed multiple joint contractures a few months after birth, and died due to respiratory distress when she was one year old. The third child was a female, who also died at 1 year of age due to respiratory failure. with similar complaints of multiple joint contractures soon after birth. Genetic analysis of the above two deceased siblings was not done. The second child of this couple is healthy and alive ( Figure 4) Blood investigations revealed iron deficiency anaemia. Biochemical analysis was normal. X-ray of wrist showed looser zones ( Figure 5).
Ultrasonographic (USG) screening of joints was grossly normal. Magnetic resonance imaging (MRI) of joints showed generalized muscle atrophy with soft tissue thickening at the right shoulder region and contractures of elbow and wrist joints. Nerve conduction study showed decreased amplitude with normal latency and nerve conduction velocity, indicating decreased compound muscle action potential. Sensory conduction was within normal range. Ear nose and throat (ENT) and ophthalmologic evaluation revealed no abnormality and 2D echocardiography screening of the heart was normal. No skin biopsy was done Clinical exome sequencing of the child showed heterozygous single base pair duplication in exon 13 of the ANTXR2 gene (chr4: g.79984832dupG; Depth: 41x) that results in a frameshift and premature truncation of the protein 13 amino acids downstream to codon 359, which was diagnosed as infantile hyaline fibromatosis syndrome. Genetic analysis of parents and live sibling was advised but could not be done due to financial constraints.
Supportive treatment and symptomatic rehabilitation were started with an occupational therapist. Assessment of range of motion in all joints was done passively along with grading of muscle tone. Techniques used to improve mobility of joints were: • Myofascial release and gentle stretching. Parents were trained for these exercises and advised to continue on a daily basis. Bilateral whole length lower limb casting was done ( Figure 4).
The initial degree of flexion of the shoulder joint was 60 0 -70 0 (normal range 170 0 -180 0 ), elbow joint was 80 0 (normal range 135 0 ) and wrist joint was 5 0 -18 0 (normal range 65 0 ). Nutritional supplements in the form of oral iron and multivitamins were also started. This infant was under regular follow-up. At the next visit, when the infant was around 6 months of age, there was a slight improvement in the range of motions (10 0 -20 0 ).

Discussion
HFS is caused by mutations in the gene encoding the ANTXR2/ CMG2 gene on chromosome 4q21 4,5 .
Various studies have shown that ISH and JHF exist within a continuum of disease with varying phenotypic expressions 5 . Table 1 gives the grading system of HFS.  6 . Hyaline deposition in the GI tract causes intestinal lymphangiectasia and thus persistent diarrhoea and protein-losing enteropathy, which may be suspected based on increased stool alpha 1-antitrypsin 7 . The main causes of death in these children are usually intractable diarrhoea, recurrent infections, and organ failure Our case report describes a family in which three out of four offspring were affected with abnormal joint contractures. The first and the third born children, both girls, died. They presented with complaints of severe joint contractures at birth and died within the first year of life. The second child, a girl, is 6 years old and is alive and healthy. The fourth sibling, a male child, presented to us with severe joint contractures. Gene mutation analysis done showed heterozygous single base pair duplication in exon 13 of the ANTXR2, confirming the diagnosis of hyaline fibromatosis syndrome.
ANTXR2 gene encodes type I transmembrane protein which contains a signal peptide, followed by an extracellular von Willebrand type A domain (vWA), an immunoglobulin-like domain, a transmembrane domain, and a cytosolic tail 8 ; vWA domains interact with extracellular matrix proteins with a metal ion-dependent adhesion site (MIDAS) motif. ANTXR2 may be a receptor for type VI collagen and may mediate its transport to lysosomes for degradation, and hence loss of ANTXR2 function leads to accumulation of type VI collagen in the extracellular matrix 9 . The immunoglobulin-like domain helps proper folding for protein with the help of disulfide bonds formed in the endoplasmic reticulum 10 .
ANTXR2 mutations were classified into four major classes: which include: I-missense mutations in the vWA domain which thus impair ligand binding; IIother missense mutations in exons 1-11 usually affect the Ig-like domain and hence affect folding, leading to endoplasmic reticulum retention and degradation; in some cases Class III mutations contain frameshift mutations that lead to a premature stop codon and splicing mutations, and they have been predicted or proven to lead to unstable mRNA that is rapidly degraded 9 . Class IV mutations affect the cytosolic tail 10,11 . ISH is associated with missense, truncating, and frameshift mutations, affecting the extracellular vWA domain, whereas inframe and missense mutations are associated with phenotypically milder JHF 9,10 .
According to genetic exome analysis, our patient had frameshift and premature truncation of protein 13 amino acids downstream to codon 359 which has been predicted or proven to lead to unstable mRNA that is rapidly degraded. Phenotypically the patient presented to us with joint contractures, pigmentation over the joints, and with a history of recurrent episodes of diarrhoea which belongs to grade 3 (severe) according to Denadai R, et al 5 severity classification. There was a history of recurrent episodes of diarrhoea in first and third siblings who died at the age of 10-11 months. The stool examination was normal.
The treatment is mainly palliative and supportive. Pain is managed with nonsteroidal antiinflammatory drugs and opiates. Physiotherapy is done for joint contracture to improve the range of movements and for the management of pain [11][12][13] . In patients with failure to thrive, nasogastric tube or gastrostomy feeding should be considered [14][15][16] . In severe conditions such as in cases of intestinal lymphangiectasia and protein-losing enteropathy, we can consider albumin infusions, hydration and dietary therapies 15,16 .