Genetic Insights Into Hyaline Fibromatosis Syndrome: A Case Report of an ANTXR2 Mutation Featuring a Rare Variant c.697+1G>A

ABSTRACT

Hyaline fibromatosis syndrome (HFS) is a rare genetic disorder encompassing juvenile hyaline fibromatosis (JHF) and infantile systemic hyalinosis (ISH), caused by mutations in the anthrax toxin receptor 2 gene (ANTXR2). This condition leads to the accumulation of hyaline plaques in the skin and organs, resulting in symptoms such as skin lesions, joint contractures, and digestive issues, often culminating in early mortality due to infections or diarrhea. By 2005, 20 mutations in ANTXR2 linked to ISH and JHF had been documented, impairing cellular adhesion to the laminin matrix. In this study, we present a case of a 6‐month‐old Iranian female of western Asian ethnicity, born to consanguineous parents. She exhibited hyperpigmentation of the proximal interphalangeal (PIP) joints, knee flexion contractures, persistent diarrhea, and failure to thrive. Initial assessments suggested arthrogryposis; however, the presence of hyperpigmented nodules and perianal plaques prompted further investigation. Genetic analysis confirmed a homozygous mutation in ANTXR2 and incidental heterozygous mutations in the HEXA and PAH genes. The patient will undergo regular monitoring and may require immunosuppressive therapy and orthopedic interventions. Hyaline fibromatosis syndrome presents unique diagnostic challenges due to its overlap with other conditions like arthrogryposis. While arthrogryposis typically lacks systemic symptoms, HFS is marked by significant pain and systemic manifestations due to hyaline deposits in tissues. The case presented aligns with existing literature regarding HFS characteristics, including joint contractures and skin lesions. The identification of the c.697+1G>A mutation at a splice site within the ANTXR2 gene highlights potential mechanisms contributing to HFS pathology. This finding emphasizes the necessity for comprehensive genetic profiling when diagnosing rare syndromes. Furthermore, low allele frequencies of this variant across population databases underscore its rarity and potential significance in disease manifestation. Hyaline fibromatosis syndrome (HFS) is an uncommon autosomal recessive disorder that is marked by notable clinical features, such as the deposition of hyaline material in various tissues, joint contractures, and systemic complications. The case discussed illustrates the diagnostic challenges associated with HFS, particularly in a young patient who presented with atypical symptoms that initially indicated arthrogryposis. Genetic analysis revealed a homozygous mutation in the ANTXR2 gene, specifically the c.697+1G>A variant, which interferes with normal splicing and results in the absence of functional protein. This observation emphasizes the critical role of genetic testing in the precise diagnosis of rare syndromes and in differentiating them from other hereditary disorders.

Summary.

• Hyaline fibromatosis syndrome (HFS) is an exceedingly rare genetic disorder that presents considerable diagnostic difficulties, particularly in pediatric populations.

• This case underscores the importance of early and thorough genetic testing to accurately distinguish HFS from other conditions, such as arthrogryposis, which may exhibit similar clinical manifestations.

• The detection of a homozygous mutation in the ANTXR2 gene (c.697+1G>A) not only substantiates the diagnosis but also highlights the essential role of genetic analysis in informing treatment decisions and management approaches.

• Clinicians should maintain a heightened awareness of HFS in young patients displaying atypical symptoms, as prompt diagnosis and intervention can enhance patient outcomes and overall quality of life.

• This case serves as a pertinent reminder of the necessity of incorporating genetic knowledge into clinical practice for rare syndromes, thereby reinforcing the demand for specialized expertise in pediatric rheumatology and genetics.

1. Introduction

Hyaline fibromatosis syndrome (HFS), initially described by Nofal et al. (2009), encompasses two distinct manifestations of a degenerative disorder characterized by both disfigurement and disability. These manifestations are referred to as juvenile hyaline fibromatosis (JHF) and infantile systemic hyalinosis (ISH). HFS is an exceptionally rare autosomal recessive condition that does not demonstrate any ethnic predisposition. It is attributed to loss‐of‐function mutations in the anthrax toxin receptor 2 gene (ANTXR2) which is situated on chromosome 4q21 [1].

As indicated by its name, the condition is defined by the presence of hyaline amorphous plaques that accumulate in the skin and various organs of affected individuals. These benign tissue proliferations are the most prominent visible signs observed in patients. Typically, the condition manifests during infancy or early childhood, marked by the appearance of papulonodular skin lesions, gingival hypertrophy, joint contractures, osteolytic lesions, and the deposition of amorphous hyaline material within the extracellular matrix of the dermis and soft tissues [2].

Furthermore, other clinical presentations of this condition encompass severe diarrhea, recurrent infections, and insufficient growth. A significant proportion of individuals diagnosed with this disorder do not survive beyond early childhood, with recurrent respiratory infections and severe diarrhea being the primary contributors to mortality [3]. As of 2005, investigations have identified 20 pathogenic mutations in the ANTXR2 gene that are linked to ISH and JHF [4, 5, 6, 7, 8, 9, 10, 11, 12].

These mutations are of particular significance given the involvement of ANTXR2 in capillary morphogenesis, a process linked to elevated levels of laminin and collagen IV. Additionally, ANTXR2 exhibits a high binding affinity for both laminin and collagen IV. Further functional analyses have revealed that fibroblasts obtained from individuals with JHF and ISH demonstrate an impaired ability to adhere to a laminin matrix. However, no notable differences were observed in their capacity to attach to collagen types I and IV [4, 13, 14, 15].

This report presents a case of hyaline fibromatosis syndrome in a 6‐month‐old female infant of Western Asian descent, who was referred to a specialized pediatric rheumatology clinic in southern Iran. The patient exhibited a highly uncommon mutation in the ANTXR2 gene, a finding that has been infrequently reported in the existing literature.

2. Case History and Physical Examination

This case study focuses on a 6‐month‐old female patient of Iranian descent, representing a Western Asian ethnic group, who was born as a result of a consanguineous marriage. At the time of birth, the patient had a weight of 2.5 kg and a height of 43 cm. She was delivered through a breech cesarean section at 32 weeks of gestational age. According to the growth chart, her measurements corresponded to approximately the 50th percentile.

The parents indicated that there is no known family history of comparable clinical symptoms, and this child is their firstborn. The patient presented with ongoing and resistant diarrhea for a duration of 3 months prior to her appointment at our clinic, which led her parents to pursue medical intervention due to concerns about her failure to thrive (FTT). At 6 months of age, the subject's weight had increased to 8.0 kg, indicating a significant gain; however, her height at this stage raised concerns when compared to established growth standards. To accurately assess her growth trajectory, we employed World Health Organization (WHO) growth charts to plot her height and weight, as well as to calculate z‐scores and percentiles (see Chart 1). The data revealed that at birth, the patient's weight was 2.5 kg, corresponding to the 3rd percentile for weight‐for‐age. By 6 months, her weight had risen to 8.0 kg, which is closer to the 50th percentile. In contrast, the patient's height at 6 months was measured at 68 cm, which falls within the expected range of the WHO height‐for‐age percentiles.

CHART 1.

Patient's growth chart analysis according to the WHO metrics.

However, the primary concern expressed by the parents was the congenital flexion of the knees and mild inversion of the feet, which prompted them to seek the expertise of a pediatric orthopedic specialist.

The orthopedic surgeon decided against surgical intervention, citing intrauterine growth retardation and the breech delivery as contributing factors to the observed clinical presentation. Consequently, the parents were referred to our clinic for further assessment. During the initial evaluation, a thorough examination was performed, leading to a preliminary diagnosis of Arthrogryposis. The observation of hyperpigmented diffuse nodules located on the proximal interphalangeal (PIP) joints, accompanied by stiffness, restricted mobility, and pain during movement of the affected joints (refer to Figure 1), alongside the presence of perianal plaque accumulations (refer to Figure 2), constitutes a notable departure from the standard clinical characteristics typically associated with Arthrogryposis.

FIGURE 1.

Hyperpigmented and mobility‐restricted proximal interphalangeal joints.

FIGURE 2.

Hyaline plaques accumulation in the perineal region.

As a result, the patient was advised to participate in further medical evaluations, which included standard radiographic imaging, echocardiographic assessment, abdominal and pelvic ultrasonography, a metabolic panel, biochemical analyses (notably serum cobalamin), an iron profile (including serum ferritin), electromyography, genetic testing, and a bone survey. The findings from these assessments revealed no significant abnormalities.

However, genetic analysis revealed a homozygous mutation in the ANTXR2 gene, specifically the C.697+1G>A variant, which adheres to an autosomal recessive inheritance pattern. Additionally, incidental genetic findings uncovered the presence of heterozygous mutations in several autosomal recessive disorders, including HEXA on chromosome 15 and PAH on chromosome 12, associated with pathogenic variants C.622delG and C.898G>T, respectively, which are linked to Tay‐Sachs disease and phenylketonuria.

The patient was arranged for routine outpatient follow‐up appointments to assess the progression of the disease and to facilitate the possible commencement of immunosuppressive therapy in the future. Furthermore, a referral was issued to an orthopedic surgeon for the administration of intra‐articular injections. Ultimately, the patient was directed to our medical facility due to the presence of symptoms including hyperpigmentation of the proximal interphalangeal (PIP) joints, flexion deformities in both knees, erythematous and hyalinosis plaques in the perianal area, as well as failure to thrive characterized by persistent and uncontrollable diarrhea.

Subsequent medical evaluations were carried out; however, no notable abnormalities were detected, including those related to bony dysplasia, enzyme deficiencies, peripheral neuropathy, cardiac anomalies, respiratory complications, abdominal irregularities, or structural brain abnormalities. In order to differentiate arthrogryposis from other hereditary syndromes, a whole exome sequencing genetic test was requested, which ultimately confirmed a diagnosis of hyaline fibromatosis syndrome. This diagnosis was associated with a rare, albeit not unprecedented, mutation variant in the ANTXR2 gene, specifically characterized by the c.697+1G>A alteration.

3. Methods

3.1. Differential Diagnosis

The differential diagnosis for this patient included conditions such as arthrogryposis, connective tissue disorders, and other genetic syndromes presenting with similar clinical features. A thorough clinical evaluation was conducted to differentiate between these conditions.

3.2. Investigations

Comprehensive investigations included:

• Genetic testing: Whole exome sequencing was performed to identify mutations in the ANTXR2 gene.

• Imaging studies: Standard radiographic imaging, echocardiography, and abdominal/pelvic ultrasonography were conducted to rule out structural anomalies.

• Biochemical analyses: Metabolic panels and specific tests for serum cobalamin and iron profiles were performed.

• Electromyography: This was utilized to assess neuromuscular function.

The reference genome utilized in this study was Human Genome 19 (hg19). Whole exome sequencing was conducted by a private medical laboratory, yielding the following results: Gene: ANTXR2; variant: c.697+1G>A; chromosome position: 4:80957125; zygosity: homozygous; inheritance pattern: autosomal recessive; classification: pathogenic.

The identified variant, c.697+1G>A, is situated at a splice site on chromosome 4 within the ANTXR2 gene. This alteration is anticipated to disrupt normal splicing processes, resulting in the absence of functional protein. The homozygous nature of this mutation indicates that both alleles harbor the pathogenic variant, which aligns with the autosomal recessive inheritance pattern associated with Hyaline Fibromatosis Syndrome.

To provide further detail regarding the methodology, the authors note that exome sequencing was performed using extracted DNA that underwent fragmentation, adapter ligation, barcoding, and hybridization in a solution phase utilizing the Agilent SureSelect Human All Exon v7. Next‐generation sequencing was subsequently executed on the Illumina NovaSeq 6000 platform. The exomes were sequenced to an average coverage of 100×, with 90%–95% of bases achieving a minimum of 20× coverage. The final target coverage for this sample was established at 60×. Paired‐end reads were aligned to the NCBI reference sequence (GRCh37) employing the Burrows‐Wheeler Aligner (BWA), and variant calls were generated and classified using the GenAP pipeline.

Variants were filtered to identify: (1) variants with a minor allele frequency of less than or equal to 5% in the Exome Aggregation Consortium (ExAC) within the patient‐specific phenotype‐driven gene list; (2) variants classified as disease‐causing mutations in public databases; and (3) predicted loss‐of‐function variants with a minor allele frequency of less than or equal to 1%.

In order to prove the parents' status regarding this mutation, the segregation test was conducted and it was revealed that both parents were carriers for the recessive alleles.

The evidence supporting phenotype causality was subsequently assessed for each variant identified through the aforementioned filtering strategy, and variants were classified in accordance with ACGME guidelines. It is noteworthy that the potential causative effect of this mutation was attributed to the intron retention mechanism.

3.3. Treatment

The patient was monitored regularly and may require immunosuppressive therapy and orthopedic interventions as part of her ongoing care plan. Intra‐articular injections were also considered for managing joint symptoms.

4. Results

4.1. Outcome

The genetic analysis confirmed a homozygous mutation in the ANTXR2 gene (c.697+1G>A), consistent with an autosomal recessive inheritance pattern. The patient's clinical manifestations included hyperpigmentation of the proximal interphalangeal joints, knee flexion contractures, persistent diarrhea, and failure to thrive.

4.2. Follow‐Up

The patient will continue to undergo regular outpatient follow‐ups to monitor disease progression and assess the need for additional therapies. No significant abnormalities were detected in other evaluations that might suggest alternative diagnoses.

5. Discussion

Arthrogryposis frequently occurs in conjunction with other anomalies, including scoliosis and clubfoot; however, it generally does not exhibit systemic symptoms. Also, Individuals with arthrogryposis may experience discomfort resulting from muscle imbalances or pressure sores associated with immobility; however, severe pain is generally not a characteristic symptom unless complications arise. Conversely, pain is a prominent issue for those with HFS, attributable to structural alterations in the joints and adjacent tissues due to the accumulation of hyaline deposits. This pain can significantly hinder participation in physical activities. In contrast, HFS is characterized by systemic manifestations too, which may include gingival hypertrophy, skin lesions, and possible gastrointestinal complications resulting from protein‐losing enteropathy [16, 17].

Hyaline fibromatosis syndrome is a rare genetic condition that displays a variable degree of severity and is frequently linked to elevated mortality rates. The syndrome is characterized by the development of thickened skin, which presents as nodules, papules, and plaques, predominantly located in the periorificial and perianal areas. Additional clinical features may include gingival hypertrophy and joint contractures. Patients frequently present with osteopenia, an increased susceptibility to respiratory infections, and episodes of diarrhea. Our clinical case phenotype and physical examination presentations align with the existing literature on this condition.

A comprehensive analysis of 150 cases of pediatric HFS has identified 34 unique genetic alterations occurring across exons 1 to 15. Exon 13, in particular, exhibits a heightened susceptibility to frameshift mutations, which are characterized by the insertion of one or two nucleotides (c.1073‐1074insC and c.1073‐1074insCC) as well as the deletion of a single nucleotide (c.1074delT). The exome sequencing analysis performed on our patient revealed a mutation at a splicing site, indicating an alternative mutation mechanism. This finding suggests that the ANTXR2 gene may be influenced by multiple mechanisms of mutation, thereby necessitating a precise diagnostic strategy. This observation aligns with the definitive mutation mechanism described by Denadai et al. in relation to the “c.697+1G>A” variant [12].

Moreover, the most prevalent genetic variations identified are c.1073delT and c.1074delT, underscoring the relevance of exon‐specific mutational hotspots in the etiology of HFS. The lack of significant findings from further medical evaluations, apart from the exclusion of other hereditary syndromes such as arthrogryposis, emphasizes the necessity for a thorough diagnostic strategy that integrates genetic profiling.

The allele frequency of the c.697+1G>A variant is significantly low across multiple genomic databases. For example, data from the Genome Aggregation Database (gnomAD) and other population databases indicate that this variant is infrequently observed in diverse populations, suggesting its classification as a rare mutation. Such low frequencies are typical of variants associated with specific genetic disorders, such as hyaline fibromatosis syndrome, which is itself a rare condition. The infrequency of this variant is consistent with clinical observations, as affected individuals are seldom documented in the literature, highlighting its potential relevance in disease manifestation.

Genetic predictive tools, including MutationTaster and PolyPhen‐2, classify the c.697+1G>A variant as likely pathogenic. These tools evaluate various factors, such as evolutionary conservation, biochemical properties, and established disease associations, to determine the potential impact of mutations. The “likely pathogenic” designation implies that this variant is anticipated to significantly disrupt normal gene function, aligning with its association with hyaline fibromatosis syndrome. The predictive models take into account not only the mutation's location but also its effects on splicing and protein function, thereby reinforcing its significance in clinical genetics.

The “c.697+1G>A” variant is identified as a splicing site mutation located on chromosome 4, specifically at the first position of the intron following exon 8, which affects the splice donor site. Splice donor sites are essential for the accurate removal of introns during mRNA processing. A mutation at this site can interfere with normal splicing patterns, resulting in aberrant mRNA transcripts.

In essence, this particular mutation occurs at a critical juncture within the intron‐exon boundary, potentially leading to abnormal splicing of the ANTXR2 mRNA transcript. Consequently, this may result in the production of dysfunctional or truncated proteins, thereby disrupting normal cellular functions related to extracellular matrix regulation and collagen homeostasis—key elements implicated in hyaline fibromatosis syndrome. Such splicing mutations are frequently associated with severe phenotypic outcomes due to their significant effects on gene expression and protein synthesis.

The conservation of the ANTXR2 gene across species highlights its evolutionary significance and functional stability. Comparative genomic analyses reveal that regions surrounding the “c.697+1G>A” variant are highly conserved among vertebrates, suggesting that alterations in this region could have detrimental effects on protein function. This conservation implies that mutations affecting this gene may lead to substantial biological consequences, further substantiating the likely pathogenic classification of this variant [2, 12, 16].

6. Conclusion

This case report highlights a rare instance of hyaline fibromatosis syndrome (HFS) in a 6‐month‐old female patient of Western Asian descent, characterized by a novel homozygous mutation (c.697+1G>A) in the ANTXR2 gene. The clinical presentation, including hyperpigmented nodules, joint contractures, and failure to thrive, underscores the complexity and variability of HFS.

Despite the patient's atypical features initially suggesting arthrogryposis, the genetic analysis ultimately confirmed HFS, illustrating the necessity for differential diagnosis in similar cases. This report contributes to the growing body of literature on HFS, enhancing understanding of its genetic underpinnings and clinical manifestations. Given the rarity of the condition and the associated high morbidity and mortality rates, further research is warranted to explore the full spectrum of clinical features, potential therapeutic approaches, and the implications of genetic variations in the ANTXR2 gene.

Author Contributions

Shabnam Hajiani Ghotbabadi: conceptualization, resources, supervision. Reza Shiari: conceptualization, investigation, validation. Shayan Yousufzai: investigation, project administration, writing – original draft, writing – review and editing. Simin Sharifi: data curation.

Ethics Statement

This research received approval from the Ethics Committee of Shiraz University of Medical Sciences under reference number IR.SUMS.MED.REC.1403.096.

Consent

Informed consent, both written and verbal, was acquired from the patient's legal guardians for the publication of clinical data and images. The written consent document can be made available upon reasonable request to the corresponding author.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

Data is available upon reasonable request by corresponding author.