Fragile but flexible: A rare case report of COL1-related overlap disorder

INTRODUCTION

Osteogenesis imperfecta (OI) is an inherited connective tissue disorder with a broad clinical spectrum that can overlap with Ehlers–Danlos syndrome (EDS).^[1] We report a 3.5 years old who came to our attention due to short stature.

CASE REPORT

A 3.5-year-old boy, second-born of a non-consanguineous parentage with no significant antenatal and neonatal complaints presented with delay in attaining age-appropriate milestones. Head control was attained at 6 months of age; he sat without support by 11 months and walked by 18 months of age. There was a history of recurrent fractures following trivial injuries. The first fracture occurred at the age of 1 year, affecting the first metacarpal bone of the right hand. The second fracture took place at 1½ years, involving the proximal region of the radius in the right arm. The third fracture was located at the proximal phalanx of the left toe. The mother reported easy bruising too. Failure to thrive was noted during follow-up visits. His weight was 10 kg (−3.52 standard deviation [SD]) and height at 3.5 years was 85 cm (−3.75 SD). His upper-segment to lower-segment ratio was 1.2. Mid-parental height was 160 cm (−1.5 SD). He had a large head, frontal bossing, blue sclera, generalized joint laxity, hypotonia, contractures in the fingers of the left hand, and loose skin folds. There were no dental or visual abnormalities. The Beighton score was 7/9 [Figures 1 and 2]. Serum calcium was 10.3 mg/dL (normal 8.8 mg/dL), serum phosphorus 5 mg/dL (normal 4–7 mg/dL), vitamin D 59 ng/mL (normal >20 ng/mL), alkaline phosphatase 233 U/L (normal 140– 330 U/L), and parathyroid hormone 17 pg/mL (normal 10–65 pg/mL). The radiographs indicated the presence of osteopenia. The dual-energy X-ray absorptiometry (DXA) scan confirmed the presence of osteoporosis (lumbar spine; Z-score −3.8 SD). Echocardiography was normal.

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Figure 1:

Passive apposition of thumb to forearm.

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Figure 2:

Hypermobility – he can place the entire palm flat on the floor while keeping the knees straight.

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History of similar complaints was noted in the father; he had a history of delayed walking and fractures following trivial trauma, with a large head and hypermobile joints. Father’s Beighton score was 7/9. Consequently, a suspicion of collagenopathy, specifically EDS-OI spectrum, was raised. Whole-exome sequencing showed a pathogenic heterozygous mutation of COL1A2 gene at intron 9 (c.432+1G>A), suggestive of combined OI and EDS–2. Genetic testing on the father could not be done due to financial constraints. The child was started on regular calcium and vitamin D supplementation. He was also started on zoledronic acid twice a year to help prevent further fractures. He has been on follow-up for the past 1 year with no further fractures.

DISCUSSION

Mutations in the collagen gene are linked to a variety of diseases with a broad spectrum of clinical and radiological characteristics. The two genes COL1A1 and COL1A2 have been shown to contain over 1,600 different pathogenic variations. Both OI and EDS have the characteristics of diversity in clinical expression. Although the two conditions are collagenopathies and the affected patients may exhibit many similarities, they often have different features.^[2]

OI is a heritable skeletal condition brought on by abnormal bone formation. Dominant or recessive mutations resulting in bone fragility and other skeletal symptoms, including short stature, osteoarticular abnormalities, and chronic pain, are characteristic features of OI. In addition to bone fragility, the OI phenotype is classically described by anomalies in the tooth structure known as dentinogenesis imperfecta and blue or gray discoloration of the sclera.^[3] The incidence of OI varies from approximately 1 in 15,000 to 20,000 and the presentation ranges from the fatal types of intrauterine fractures to late cases where fractures manifest in adolescence or adulthood.^[4]

EDS, on the other hand, is a diverse collection of hereditary connective tissue diseases sharing a triad of joint hypermobility, skin fragility, and skin hyperextensibility. According to Callewaert, over 80% of patients with EDS have EDS hypermobility (type 4) and 1 in 5,000 have EDS classical (types 1 and 2).^[5] The connective tissue disorder known as OI/EDS overlap syndrome is caused by mutations in the COL1A1 (17q21.33) or COL1A2 (7q21.3) genes. The clinical symptoms of this new clinical entity are diverse with a mixed phenotype that includes aspects of OI and EDS. According to Orphanet, the combination of OI and EDS is extremely rare (>1 in 10,00,000). Recently, several authors coined the term “COL1-related overlap disorder” (C1ROD) to characterize cases where people first suspected as having EDS turned out to be carriers of pathogenic variations of genes known to largely cause OI.^[6] In our index case, the child had an unusually early age of presentation (3.5 years), a similar phenotype in the father, and a confirmed COL1A2 gene mutation.

Previous reports highlight overlapping symptoms caused by COL1 gene mutations. Literature supports the term COL1-related overlap disorder (CIROD) to describe the spectrum of clinical phenotypes – ranging from OI to EDS and related syndromes – given their shared pathophysiology and molecular basis. Morabito et al. reported a 10-year-old girl with severe short stature, with no family history and clinical features similar to our case. Notably, she was diagnosed with neuroblastoma at 11 months of age with a heterozygous missense mutation in the COL1A1 gene.^[1] Morlino et al. reported five children with heterozygous variants of COL1A1 and COL1A2 genes with blue sclerae, mild long bone bowing, vertebral fractures, skin hyperextensibility and fragility, atrophic scars, neonatal hypotonia.^[6] There are a few reports of children of OI/EDS features.^[7] However, to the best of our knowledge, there are no reported cases of CIROD from India.

Autosomal-dominant mutations in COL1A1 and COL1A2, encoding the α1 and α2 chains of type I collagen, the predominant extracellular matrix protein, account for ~85–90% of OI cases. The majority are missense mutations, particularly glycine substitutions within the triple-helical domain. The remaining ~20% arise from autosomal recessive mutations in genes involved in collagen biosynthesis and modification, such as CRTAP. OI with EDS overlap is typically associated with heterozygous mutations near the N-proteinase cleavage site of the α1(I) or α2(I) chains. Intronic splice-site variants have been implicated in combined OI/EDS phenotypes. These mutations disrupt N-terminal propeptide cleavage and inter-helical cross-linking, resulting in abnormally small and biomechanically weak collagen fibrils.^[8] Clinical assessment is key in identifying suspected OI, with diagnosis often prompted by features such as dentinogenesis imperfecta, conductive hearing loss, blue sclerae, or short stature. While phenotypic overlap is common, definitive diagnosis requires genetic testing, typically next-generation sequencing of COL1A1 and COL1A2.^[9] Mixed OI-EDS phenotypes may present with blue sclerae, joint hypermobility, flat feet, and hyperextensible skin. Minor features include hearing loss, fractures, joint dislocations, and soft tissue ruptures. Exclusion criteria for classic EDS include long bone deformities, congenital fractures, valvular heart disease, and dentinogenesis imperfecta. The prognosis is generally good; bisphosphonates may reduce fracture frequency, though joint hypermobility often persists and requires continued management.^[4]

There is currently very little information available to create a customized management regimen for adults and children with C1ROD. A multidisciplinary approach (including physiotherapy, orthopedic surgery, or bracing) is advised to address both skeletal and extra-skeletal aspects. Bisphosphonates are still the cornerstone of treatment, but novel approaches including transforming growth factor-beta inhibition and sclerostin inhibitory antibodies are being investigated to target both the poor bone mineral density (BMD) and the innate fragility of the bone.^[10,11] The US and EU regulatory bodies have not approved any treatments for OI, yet bisphosphonates are frequently used off-label in children to treat those at risk of fractures. A multidisciplinary team offering a range of services of occupational therapists, physiotherapists, orthoptists, psychologists, dieticians, orthopedic surgeons, and clinical specialists with expertise in providing pharmacological support would be necessary for the best management of OI.^[12] Bisphosphonates can raise BMD, lower the risk of bone fractures, and cause reshaping of the vertebra, but the optimal duration of therapy is not clear.^[13] In children with CIROD, DXA scans are recommended for evaluating BMD. Annual DXA scans and monitoring growth velocity every 6 months would help.

Despite COL1A1 or COL1A2 mutations, long-term outcomes in these patients often resemble EDS more than OI. Soft tissue issues – joint dislocations, chronic pain, and tissue fragility – are more disabling than skeletal or dental findings.^[11] Physical therapy guidelines for hypermobility disorders may be more appropriate than OI protocols. Accurate phenotyping is critical for genetic counseling, especially with parental history of fractures. Although long bone deformities are uncommon, OI-related follow-up is advised if pathogenic variants are present. Annual screening for ocular, dental, and auditory complications is recommended. Limited data from South Asia, particularly India, highlight the importance of reporting cases to improve the recognition and management of C1ROD.^[14,15]

CONCLUSION

Although it is acceptable on a molecular basis, the term OI/EDS overlap may cause confusion for both affected individuals and non-specialist professionals. For these individuals, a more specific term like “COL1-related overlap disorder” may be helpful for genetic counseling and medical management. CIROD is a rare collagenopathy requiring high clinical suspicion for diagnosis. This case underscores the role of genetic testing in confirming the disorder, especially with a positive family history. Early bisphosphonate therapy can reduce fracture risk, thereby enhancing the quality of life for affected individuals.