Infantile systemic Hyalinosis in a 6-month-old male: identification of homozygous ANTXR2 gene mutation

Abstract

This case report presents a 6-month-old male infant with a diagnosis of infantile systemic hyalinosis (ISH) and describes the diagnostic difficulties and findings of clinical examinations, laboratory analyses, and imaging studies. A 6-month-old male infant was admitted with abdominal distension, persistent diarrhea, and joint tenderness. His history included profuse watery diarrhea and a hospitalization for hypoalbuminemia. Upon arrival, he presented with multiple episodes of non-bloody diarrhea, oxygen desaturation, and signs of failure to thrive. Physical examination revealed joint swelling, spasticity, failure to thrive, short stature and developmental delays. Imaging studies including abdominal and pelvic ultrasound showed free fluid, intestinal distension, and renal microlithiasis. Imaging results included a chest X-ray showing mild interstitial markings and a brain MRI showing dilatation of subarachnoid space. Laboratory studies demonstrated an elevated white blood cell count (13 300 cells/mm³), high levels of ammonia, and relatively low hemoglobin. Ultimately, the diagnosis of ISH was confirmed by a homozygous ANTXR2 gene mutation. This case accentuates the need for an integrated approach to the diagnosis of nonspecific infant symptoms. Diagnosis should be made early and accurately with a high index of suspicion; it forms the cornerstone for any treatment or prevention of complications. Furthermore, the early recognition of ISH is important in effective management and family counseling with the aid of genetic analysis. The findings add to the knowledge about ISH and its clinical implications, pointing to the need for continued research into rare genetic disorders.

Introduction

Infantile systemic hyalinosis (ISH) is a rare, progressive autosomal recessive disorder typically presenting at birth or within the first few months of life [1]. It is linked to mutations in the anthrax toxin receptor 2 gene (ANTXR2) gene, which encodes a protein (capillary morphogenesis protein 2) involved in the degradation of hyaline material [2]. ISH is a disease characterized by infantile skin lesions and other various manifestations depending on the accumulation of amorphous hyaline in many organs [3, 4]. Skin thickening, short stature, non-malignant papulonodular lesions, gingival hypertrophy, hyperpigmentation over bony prominences and joints, perianal nodules, joint contractures, osteoporosis, bone fractures, growth retardation, and failure to thrive are the clinical features observed since birth or early infancy [3–6]. Other common symptoms may include gastrointestinal issues (persistent diarrhea), respiratory difficulties, and neurological abnormalities [4, 5].

Diagnosis often arises from diminished spontaneous movements due to joint contractures [3]. However, due to ISH’s rarity and phenotypic variability, diagnosis is complicated, and genetic testing is necessary for mutation detection in the ANTXR2 gene. Prognosis is poor for patients as survival beyond three years is exceedingly rare [4, 7, 8]. There is no established cure for SIH; management is mainly supportive to alleviate symptoms and improve the quality of life, including physical therapy, pain management, and nutritional interventions [5]. Because of its rarity, much of what is known about ISH’s clinical spectrum, the difficulties in diagnosis, and possible treatments come from case reports and small series. The management and improving the quality of life of such patients depend directly on early diagnosis. We are representing a case of atypical ISH in a six-month-old male patient.

Case presentation

A 6-month-old male infant was admitted to the hospital presenting with complaints of abdominal distension, persistent diarrhea, neurodevelopmental delay, failure to thrive and joint dryness with tenderness. The patient had a history of profuse watery diarrhea starting 14 days before admission, which led to a 12-day hospitalization at a hospital, where he received antibiotic treatment and albumin for hypoalbuminemia. Though improved partially, persisting dryness, joint pains, and restlessness called for his shifting to other Hospital, Tehran. At admission, the patient had about seven episodes of non-bloody and non-severe diarrhea per day, with no fever, restlessness, vomiting, or decreased appetite. He developed hypoxemia, and his oxygen saturation decreased to about 84% without evident respiratory distress, improving above 94% on supplemental oxygen. He was born at 32 weeks of gestation with a birth weight of 1780 grams to consanguineous parents (cousins) and had spent a month in the NICU for prematurity. Moreover, at 45 days, he underwent bilateral inguinal hernia surgery. Notably, around two months of age, he demonstrated generalized spasms, swelling, and joint stiffness for which physical therapy was administered. No relevant family history was mentioned. He did not any other sibling or any other such sibling and there were not any fetal losses too.

On examination, the infant was in a conscious state and followed with his eyes but had features of failure to thrive, weighing 4500 grams. Developmentally, he was also delayed, unable to sit with support and unable to hold up his head. Initial vital signs were within normal limits, anterior fontanel 2 × 2 cm with evidence of bilateral periorbital edema. He had perioral stiffness. The cardiac examination was unremarkable, while bilateral generalized crackles were auscultated in the lungs; there were no noted thoracic deformities. Abdominal examination revealed distention and tenderness on palpation, without organomegaly. All joints were spastic, swollen, and tender, and exhibited both active and passive range of motion restrictions. Proximal limbs appeared shortened, and multiple nodules were present on the dorsal surfaces of the joints, with no deep tendon reflexes (DTR) observed. Peripheral pulses were full and symmetric, and capillary refill time (CRT) was normal. (Fig. 1).

Figure 1.

Joint nodularity and spasm.

The X-ray showed only gaseous distension of the loops of the intestine, and the surgical consultation only recommended follow-up of the infant and an abdominal and pelvic ultrasound. The chest X-ray also shows mild increased interstitial marking in the central lungs. On the ultrasound, there were slightly distended, fluid-filled small bowel loops with hyperperistalsis, increased wall thickness, and mild free fluid in the abdomen and pelvis and two regions of increased echogenicity 2 mm in diameter on the middle calyx of both kidneys consistent with microlithiasis.

Furthermore, the infant had gluteal atrophy, and the head circumference was measured at 40.5 cm. The lung CT scan suggests aspiration pneumonia or pulmonary edema due to peribronchial thickening, opacities, and bilateral pleural effusion (Fig. 2A). He was initially given empiric intravenous antibiotics encompassing meropenem, metronidazole, and vancomycin for broad Gram-negative coverage. Considering the abdominal distension of the patient and tenderness during the examination, a thoracoabdominal X-ray and surgical consultation were requested (Fig. 2B).

Figure 2.

(A) Lung CT-scan; peribronchial thickening and opacities in the posterior regions of both lungs, along with bilateral pleural effusion (mild on the right side and minimal on the left), which is highly suggestive of either aspiration pneumonia or pulmonary edema. (B) Thoracoabdominal x-ray; mild pleural effusion of both sides of lungs and normal abdominal x-ray despite abdominal distention and stiffness.

Stool samples were sent for analysis and culture, including Clostridium difficile, which turned out to be negative.

The infant’s formula was then changed to Aptamil Pepti Junior after initial stabilization, with recommendations for high-dose fat-soluble vitamins, testing for celiac disease, and immunoglobulin evaluations. A request for endoscopy was also made following further stabilization of the patient. A neurology consult noted the wide fontanel and developmental delay, recommending a brain MRI to rule out any underlying conditions, such as very-long-chain fatty acid (VLCFA) for ruling out rhizomelic chondrodysplasia, and EMG/NCV tests due to absent deep tendon reflexes (DTRs). At the same time, consultation with a geneticist led to the request for whole exome sequencing (WES) in pursuit of arthrogryposis etiologies. Systemic infantile hyalinosis was one of the differential diagnoses, antxgastroenteritis including zinc, vitamin A, probiotics, and daily albumin for hypoalbuminemia. In the patient’s brain MRI, it was observed that there was a dilatation of the subarachnoid space in the frontal regions and the Sylvian fissure, with mild dilatation of the anterior horn of the lateral ventricles.

An electromyography-nerve conduction velocity (EMG-NCV) test was performed once, but due to the patient’s severe and generalized edema, it could not be evaluated, and it was recommended to repeat the test. A genetic test was conducted, and ultimately, due to the need for the patient to be hospitalized for a long period and the fact that the parents had traveled from another city to Tehran, the patient was transferred back to their home city for supportive treatment with a preliminary diagnosis of ISH. He was admitted there for about 2.5 month. Nutritional support (high calorie, protein-rich diets) was started for him to manage FTT and protein losing enteropathy. Pain management, oxygen therapy, family support, diarrhea management (zinc, fat soluble vitamins, probiotics, and careful fluid/electrolyte balance monitoring and albumin replacement for significant protein loss were done.

Ultimately, after two months, the genetic test results revealed a diagnosis of ISH, identified as a homozygous mutation in the ANTXR2 gene, which had not been reported in the ClinVar database. According to the latest ACMG classification, it was categorized as a variant of uncertain significance. The variant coordinates was; chr4 80 977 232 80 977 232 A -: NM_001145794.1(3/15): c.297-65delT, apparently involved in spicing. Given the patient’s genetic testing, a skin biopsy was deemed unnecessary.

Laboratory data show that the condition of the patient significantly improved from admission to discharge, as shown in Table 1. Key findings include a reduction in BUN from 14 to 9 mg/dL, which indicates an improvement in renal function, and a significant reduction in ammonia levels from 280 to 74 μg/dL, indicating improved metabolic function. Hematological parameters similarly improved: WBC count decreased from 13 300 to 4200 cells/mm³, while hemoglobin increased from 10.4 to 14.4 g/dL, thus indicating resolution of infection and increased oxygen-carrying capacity. Whereas the albumin decreased from 3.6 to 3.1 g/dL, the total protein slightly increased, requiring a further evaluation of nutritional status or liver function. Overall, the results reflect a recovery from the acute effects of ISH, supporting the patient’s stable discharge.

Table 1.

The initial laboratory data and discharge laboratory data for the case.

General Laboratory Tests	Initial Lab Data	Discharge Lab Data
BUN (mg/dL)	14	9
Creatinine (mg/dL)	0.4	0.5*
Sodium (mEq/L)	134	132
Potassium (mEq/L)	4	4.4
Calcium (mg/dL)	8.5	8.6
Phosphorus (mg/dL)	3.7	3.9
Magnesium (mg/dL)	1.3	1.8
Chloride (mEq/L)	102	Not recorded
Complete Blood Count
WBC (cells/mm3)	13 300 (36% seg, 4% band, 50% lymph)	4200 (13% seg, 77% lymph)*
Hemoglobin (g/dL)	10.4	14.4
Platelets (cells/mm3)	503 000	201 000
Liver Function Tests
AST (IU/L)	110	73
ALT (IU/L)	130	85
Alkaline Phosphatase (IU/L)	660	690
LDH (IU/L)	270	283
Renal Function Tests
Urine Culture	Negative	Not recorded
Urine Specific Gravity	1.018	Not recorded
Protein in Urine	Positive	Not recorded
WBC in Urine	16–18	Not recorded
Electrolytes and PH
pH	7.34	7.37
pCO2 (mmHg)	40.3	38
HCO3 (mmol/L)	22	23
Critical and Specific Tests
Lactate (mmol/L)	30	7*
Ammonia (μg/dL)	280	74*
Blood Culture	Negative	Not recorded
Nutritional Status
Total Protein (g/dL)	4	4.5
Albumin (g/dL)	3.6	3.1
Vitamin D (ng/mL)	21	Not recorded
Stool Tests
Stool Culture	Negative	Not recorded
Clostridium difficile	Negative	Negative
Stool Exam	WBC: 15–20, RBC: 1–3, pH: 6, Yeast: Moderate, Fat Droplets: 6–8	Not recorded
Thyroid Function Tests	Normal	Not recorded
Immunological Tests
Anti-TTG IgA	Negative	Not recorded
Serum Immunoglobulin	Normal	Not recorded

Discussion

This case involves a 6-month-old male infant presenting with complex clinical manifestations, including abdominal distension, chronic intermittent watery diarrhea, joint and perioral stiffness and tenderness, and failure to thrive, hypotonia, developmental delay, joint contracture with nodular swelling somewhere, ultimately leading to the diagnosis of ISH due to a homozygous mutation in the ANTXR2 gene.

The history and examination findings in this infant underscore several critical aspects of this rare condition. Even though ISH typically presents in early life with symptoms such as growth retardation, painful limb movements, joint contractures, osteoporosis, and hyperplastic thickening of the skin (diffuse and nodular) [3–10], this case has some distinguishing characteristics such as severe perioral stiffness and abdominal distension which are not very highlighted in other case reports.

Characteristically reported signs in the literature are gingival hyperplasia, chronic diarrhea, septic infections, and papulonodular benign lesions, along with gingival hypertrophy, hyperpigmentation of bony prominences and joints, perianal nodules, contractures of joints, osteoporosis, fractures of bones, growth retardation, and failure to thrive [3–6]. Other common symptoms may include gastrointestinal issues (e.g. persistent diarrhea), respiratory difficulties, and neurological abnormalities [4, 5]. Our case presented atypically for ISH, lacking the characteristic gingival hyperplasia, hyperpigmentation, perianal nodules, bone fracture, and osteoporosis. This highlights the critical need for proactive disease consideration, even in the absence of overt symptoms. The classical signs and symptoms associated with the severe type of ISH include hypotonia, multiple contractures, persistent diarrhea, skin lesions, osteopenia, bone fractures, and growth deficiency. These manifestations are predominantly reported in affected patients [4, 5, 9] and are more or less consistent with our findings. However, the rarity of ISH poses challenges in diagnosis, highlighting the importance of careful differential diagnosis to distinguish it from other conditions associated with chronic pain, subcutaneous nodules, malformations, and joint contractures [10]. In our case, the early symptoms of persistent diarrhea and abdominal distension required the infant’s hospitalization and treatment for hypoalbuminemia, which is indicative of severe nutritional deficiency and fluid imbalance. The persistence of diarrhea despite antibiotic therapy raises concerns about underlying gastrointestinal pathology that may be associated with systemic conditions like ISH. The absence of fever and vomiting and the non-bloody nature of diarrhea suggest a suspected non-infectious etiology, which further supports comprehensive diagnostic evaluation. In our case, the presence of persistent diarrhea is consistent with findings in the literature that patients with ISH develop protein-losing enteropathy due to thickening and hyaline infiltration of the intestinal walls, leading to persistent diarrhea and malabsorption [5, 10].

This case delineates the importance of proper diagnosis of ISH, especially in the context of joint involvement, which is one of its characteristic features and resembles arthrogryposis. The spastic swollen joints with restricted range of motion presented by the infant are what usually mislead to the diagnosis and thereby result in the application of management strategies that are inappropriate, such as manipulations of the joints and invasive surgeries, which are usually recommended for Arthrogryposis Multiplex Congenita [11].

Initially, we considered evaluating serum ammonia levels to rule out a possible underlying metabolic disorder as a cause of the recurrent diarrhea. The first measurement showed an elevated ammonia level; however, upon repeat testing, it was due to technical error. The subsequent measurement, performed using proper technique, showed a normal ammonia level without any specific intervention.

Chronic pain and joint contractures in infancy are a very narrow differential diagnosis. Recognition of the unique clinical manifestations of ISH, including the characteristic joint nodules and absent DTRs, is paramount. This case reminds the clinician to have a high index of suspicion for early diagnosis in infants presenting with arthrogryposis-like symptoms for various genetic disorders such as ISH, thus ensuring timely and appropriate intervention. In a child with features of IHS or JHF, the differential diagnosis usually includes arthrogryposis multiplex congenita, infantile stiff skin syndromes, Torg-Winchester syndrome, Farber’s syndrome, neonatal onset multisystemic inflammatory disease, and amyloidosis [11]. Although ISH shares clinical features with lysosomal storage disorders, such as Farber disease and mucolipidosis including coarse facial features, progressive contractures, and gingival hyperplasia (was not seen in our case), it is distinctively characterized by the preservation of intellectual capacity in ISH patients [12]. The lab findings, combined with the clinical presentation of the patient, such as anemia, liver enzyme elevation, proteinuria, high ammonia, and lung problems, suggest significant systemic involvement. In reviewing literature regarding ISH, case reports and series often highlight variability in laboratory findings among different cases. Some cases may present with significant, easily identifiable laboratory abnormalities indicative of multi-organ dysfunction, while others might display mild symptoms or laboratory findings that fall within normal ranges [10, 13].

While previous case reports documented normal abdominal ultrasound in ISH patients [4, 10, 14], our abdominal and pelvic ultrasound revealed free fluid in the abdominal cavity, mild distension of intestinal loops, and right renal microlithiasis. In addition, fluid-filled, hyperperistaltic small bowel loops suggest a functional gastrointestinal derangement, most likely exacerbated by the concomitant systemic illness.

There was no evidence of active infection with negative urine, stool, and blood cultures. Stool cultures were negative to rule out infective causes of diarrhea. Given infantile developmental delays with neurological concerns, brain MRI along with genetic testing is also a prudent decision. An MRI was conducted to exclude any underlying conditions, such as VLCFA to eliminate the possibility of rhizomelic chondrodysplasia, along with an EMG-NCV since the DTRs were not elicited. The MRI finding in the form of dilatation of subarachnoid space and ventricles indicates there may be an underlying neurologic compromise that can result from systemic disease processes. Whereas some brain MRI case reports were normal [15], other imaging has revealed bilateral frontal and anterior interhemispheric extra-axial cerebrospinal fluid spaces, cortical veins traversing dilated subarachnoid spaces, and mild cortical atrophy. These findings are significant in elucidating the neurological manifestations of ISH [16].

This report identifies the critical need for consideration of ISH in infants with joint contractures, subcutaneous nodules and neurological symptoms. In cases where the clinical features are highly suggestive of the disorder, molecular testing can be a definitive diagnostic tool that may even preclude invasive procedures such as skin biopsies [7, 8, 17]. WES was very necessary in determining whether any genetic mutation explained the clinical presentation of the infant. The identification of the novel homozygous mutation in the ANTXR2 gene confirmed ISH, a condition with remarkable morbidity and a grave prognosis. Since the mutation in this gene occurs within an intron and our current knowledge about intron locations is limited, this finding is hard to interpret. There is a possibility that the gene may not be identified, highlighting the need for further studies in this area. However, based on the correlation with the patient’s clinical findings, the above diagnosis remains applicable for this individual. Genetic counseling is crucial for families affected by genetic conditions, as it offers vital information regarding recurrence risks and the availability of prenatal diagnostic options [11].

The management of this infant consisted of supportive care for gastroenteritis, nutritional supplementation, and physical therapy (physiotherapy and occupational therapy), which are all important in the multi-dimensional approach to ISH. There is no cure for ISH at present, but early recognition and supportive interventions can enhance the quality of life for affected individuals [5]. The case illustrates the multidisciplinary approach involving genetics, neurology, and gastroenterology in managing pediatric cases. Overall, the patient’s condition seems improved at the time of discharge. The major improvements were in renal function parameters, lactate, and ammonia, along with normalization of the white blood cell count. However, the liver enzymes are still high, indicating persisting liver stress. In addition to noted improvements in status at discharge, continued attention regarding liver function, nutritional issues, and any possible metabolic background should be pursued.

Conclusion

The described case underlines the difficulties in diagnosis and clinical complicities of ISH, with a need for increased awareness regarding genetic disorders in infants with inexplicable gastrointestinal, musculoskeletal, and developmental issues. It critically underlines including ISH in the differential diagnosis for infants presenting with joint contractures, subcutaneous nodules, and neurological symptoms. Accurate timely diagnosis, necessary for the effective treatment and prevention of complications, depends on a high index of suspicion. It was a comprehensive approach, involving thorough clinical examination, imaging studies, dermatological assessment, and genetic testing that provided the clue to an accurate diagnosis. Further research on genetic mutations, especially CMG2/ANTXR2, is required to elucidate disease mechanisms and improve management strategies. The establishment of a clear diagnosis based on diagnostic guidelines and the inclusion of genetic counseling will help in reducing morbidity-mortality associated with this rare syndrome.

Author contributions

FM, ZH, MJ, AJ and MM provided clinical support and wrote the original draft, reviewed and edited the manuscript. All authors read and approved the final manuscript.

Conflict of interest

No conflicts of interest.

Funding

This work was not supported by any funding sources.

Ethical approval

Not required.

Consent

Written informed consent was obtained from the patient for the publication of the present case report and any accompanying images.