Understanding accusations of child abuse in a missed condition of Osteogenesis / Hypermobile EDS overlap

When the Diagnosis Shifts: Understanding the OI/hEDS Overlap

Pradeep Chopra, MD

Some children begin life with a diagnosis of osteogenesis imperfecta (OI) — the "brittle bone" condition — and then, as they grow, start to look less like a child with fragile bones and more like a child with Ehlers–Danlos syndrome (EDS): loose joints, soft and stretchy skin, easy bruising, and pain that moves from one part of the body to another. Families are often told these are two separate conditions, and they leave one clinic for another, collecting labels that do not seem to fit together.

They may not be separate at all. A growing body of research describes a single connective tissue disorder that carries features of both OI and EDS at once. Understanding it can spare families years of confusion, change how a person is monitored, and, in some situations, protect a family from a serious misunderstanding.

One condition wearing two faces

In 2019, a group of researchers led by Silvia Morlino proposed a name for what earlier reports had circled around for years: the COL1-related overlap disorder. Studying twenty-one people from thirteen families, they described individuals who had been referred with a suspicion of EDS but who could not be neatly classified as OI, nor as any of the recognized EDS types associated with type I collagen. In these families, the picture was dominated by EDS-type features — joint hypermobility, skin changes, bruising — while the OI side showed up only quietly, as mildly reduced bone density, the occasional fracture, and shorter-than-expected stature.

This matters because it reframes the question. Rather than asking whether a person "really" has OI or "really" has EDS, the overlap concept says that a single change in one protein can produce a blend of both, in proportions that differ from person to person and can shift across a lifetime.

The protein at the center of it all

Almost everything in this story comes back to one molecule: type I collagen, the main structural protein in bone, skin, tendon, and ligament. It is built from instructions carried by two genes, COL1A1 and COL1A2. When those instructions contain an error, the collagen that results can be too little in quantity, wrong in shape, or poorly assembled — and the body tissues that depend on it behave accordingly.

The way clinicians usually think about it is that problems reducing the amount of otherwise-normal collagen tend to produce milder, classic OI, while problems changing the structure of collagen tend to produce more severe or more unusual disease. The overlap disorder sits in an especially interesting spot. In the foundational biochemical work by Fransiska Malfait and colleagues in 2013, seven patients referred as EDS — with only subtle OI signs — all carried mutations clustered in the most N-terminal part of the collagen helix, the region involved in a processing step called N-propeptide cleavage. In plainer terms, the collagen molecules were not being trimmed and packed correctly, and the resulting fibers were disorganized. The same neighborhood of the gene keeps appearing across later reports, which is part of why researchers now treat this as a recognizable entity rather than a collection of coincidences.

Why the diagnosis can seem to change over time

For a family living through it, the most disorienting feature is the sense that the diagnosis is moving. A baby fractures easily and is diagnosed with OI. Years later the fractures become less prominent, but hypermobile joints, dislocations, stretchy skin, and chronic pain take center stage, and a clinician raises EDS.

Two threads from the research help explain this. First, the overlap phenotype genuinely leans toward the EDS side in many people, with bone fragility present but understated — so as a child grows and the joint and skin features become more obvious, the clinical impression naturally drifts. Second, the underlying biology can be subtler than a single-gene result suggests. Sara Symoens and colleagues reported a patient whose EDS signs and OI-like fractures were caused by a COL1A1 deletion previously seen only in lethal OI; the reason this person was mildly affected was mosaicism — the mutation was present in only about nine percent of skin-cell reads and was absent in blood. Mosaicism can soften a phenotype, blur it, and even hide it from a standard blood test. The lesson is that a shifting or atypical picture is not a sign of a mistaken diagnosis so much as a sign of how variable this biology can be.

Why a family history of "hypermobile EDS" deserves a second look

Hypermobile EDS (hEDS) is common as a clinical label and, at present, has no confirmed gene test — it is diagnosed by criteria, not by DNA. That makes it easy to assume an hEDS label carries no meaningful fracture risk. The overlap literature pushes back on that assumption.

In a 2023 cohort from Emily Venable and colleagues, thirty-four people carried disease-causing COL1A1 or COL1A2variants, and fifteen had a possible OI/EDS overlap. Strikingly, several had initially been diagnosed with hypermobile EDS before genetic testing reclassified them. The authors suggested that COL1A2 in particular may be the genetic explanation for some cases carrying an hEDS label, and proposed clearer criteria for when to test. The practical takeaway for families is direct: when relatives carry an hEDS diagnosis and there is any bone fragility in the family, collagen genetic testing is a reasonable path rather than an overreach — because a hypermobility label does not, by itself, rule out a fracture-prone collagen problem.

There is one more reason this reclassification is not merely academic. Some overlap patients show vascular or arterial fragility — a risk that changes how closely a person should be monitored. Both the Malfait and Venable reports flag it. Identifying the overlap can therefore alter surveillance in ways that a simple hypermobility label would not.

The most serious mimic: fractures in infancy

There is a difficult corner of this topic that deserves honest attention. In infants and young children, unexplained fractures raise the question of non-accidental injury, and mild OI can look, at first, like abuse. Mild forms of OI — the milder ends of what are called types I and IV — may lack the classic tells at the age a child is evaluated: the blue sclerae, the abnormal teeth, the telltale skull findings, or a clear family history may simply not be evident yet.

The consequences of getting this wrong run in both directions. A review by Mininder Kocher and colleagues examined thirty-three confirmed OI cases that had initially been misdiagnosed as abuse; children were removed from their families in a majority of cases. A 2015 review by Marianne Pepin and Peter Byers offers the most actionable testing approach: sequence COL1A1, COL1A2, and IFITM5 together, add deletion and duplication testing, and interpret the results carefully — with parental studies when a variant of uncertain significance turns up. More recent syntheses, such as the 2025 review by Vittorio Cianci and colleagues, emphasize combining a careful history with clinical and radiological analysis, since fracture number, location, and recurrence vary by OI genotype and age.

The essential and balanced point, which the reference literature states plainly, is this: a genetic or metabolic finding does not rule out non-accidental injury, and non-accidental injury does not rule out a coexisting bone disorder. When there is real doubt, both evaluations should proceed together rather than one being used to dismiss the other.

Living with the overlap, and where pain fits in

For people who carry this diagnosis into adulthood, the day-to-day reality is often driven less by fractures and more by the EDS-side features: joints that subluxate or dislocate, fatigue, slow or poor wound healing, easy bruising, and chronic, widespread pain. Pain here is not a single problem with a single fix. It arises from unstable joints, from soft tissue that does not hold as it should, and from the cumulative wear of living in a body built from imperfect collagen. Care tends to work best when it is coordinated — pairing protection of fragile bone with careful, graded strengthening to stabilize joints, and treating pain as its own condition worthy of a deliberate plan rather than an afterthought.

An honest word on the evidence

It is worth being clear-eyed about how much is known. The overlap literature is built largely from case reports and small cohorts. Those studies establish convincingly that the entity exists, describe its features, and tell clinicians how to test for it — but they do not tell us how common it is in the general population. If you or a family member fits this picture, that uncertainty is a reason to seek out a clinical advice from physicians familiar with connective tissue disorders, not a reason to accept a single label as final.

The most useful reframe the research offers is simple. When bone fragility and joint hypermobility appear in the same person or the same family, they may not be two coincidental problems. They may be one connective tissue disorder, written in the collagen, wearing two faces at different ages.

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This article is for educational purposes and does not replace individualized medical advice. Anyone with a personal or family history suggesting a connective tissue disorder should consult a clinical geneticist or specialist familiar with OI and EDS.

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References

1. Morlino S, Micale L, Ritelli M, et al. COL1-related overlap disorder: a novel connective tissue disorder incorporating the osteogenesis imperfecta/Ehlers–Danlos syndrome overlap. Clin Genet. 2019;97(3):396–406. https://doi.org/10.1111/cge.13683
2. Malfait F, Symoens S, Goemans N, et al. Helical mutations in type I collagen that affect the processing of the amino-propeptide result in an osteogenesis imperfecta/Ehlers–Danlos syndrome overlap syndrome. Orphanet J Rare Dis. 2013;8:78. https://doi.org/10.1186/1750-1172-8-78
3. Venable E, Knight DRT, Thoreson EK, Baudhuin LM. COL1A1 and COL1A2 variants in Ehlers–Danlos syndrome phenotypes and COL1-related overlap disorder. Am J Med Genet C Semin Med Genet.2023;193(2):147–159. https://doi.org/10.1002/ajmg.c.32038
4. Symoens S, Steyaert W, Demuynck L, et al. Tissue-specific mosaicism for a lethal osteogenesis imperfecta COL1A1 mutation causes mild OI/EDS overlap syndrome. Am J Med Genet A. 2017;173(4):1047–1050. https://doi.org/10.1002/ajmg.a.38135
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6. Morabito LA, Allegri AEM, Capra AP, et al. Osteogenesis imperfecta/Ehlers–Danlos overlap syndrome and neuroblastoma — case report and review of literature. Genes (Basel). 2022;13(4):581. https://doi.org/10.3390/genes13040581
7. Pepin MG, Byers PH. What every clinical geneticist should know about testing for osteogenesis imperfecta in suspected child abuse cases. Am J Med Genet C Semin Med Genet. 2015;169(4):307–313. https://doi.org/10.1002/ajmg.c.31459
8. Cianci V, Luppino G, Mondello C, et al. Pediatric bone fractures: challenges in differential diagnosis between child abuse and osteogenesis imperfecta. Ann Ig. 2025;176(4):478–486. https://doi.org/10.7417/CT.2025.5251
9. Singh Kocher M, Dichtel L. Osteogenesis imperfecta misdiagnosed as child abuse. J Pediatr Orthop B.2011;20(6):440–443. https://doi.org/10.1097/BPB.0b013e328347a2e1

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