Hypermobility and Ehlers-Danlos Syndromes in Children Under Five Years of Age

Abstract

Generalised Joint Hypermobility (GJH) is common in early childhood and reflects the physiological laxity of developing connective tissues. Distinguishing benign hypermobility from Hypermobility Spectrum Disorders (HSD) and Ehlers-Danlos Syndromes (EDS) in children under five is challenging due to developmental variability, limited cooperation with examination and the age‑dependence of diagnostic criteria. Early recognition of EDS is essential to prevent secondary musculoskeletal complications, optimise motor development and identify children with syndromic or high‑risk features. This review synthesises current evidence on epidemiology, pathophysiology, clinical manifestations, diagnostic challenges, assessment tools, management strategies and research gaps relating to hypermobility and EDS in young children under 5 years of age. A clearer paediatric‑specific diagnostic framework is urgently needed to improve early recognition and long‑term outcomes.

Keywords: Joint hypermobility, Early childhood, Paediatric connective tissue disorders, Beighton score, Developmental delay, Hypotonia, Differential diagnosis, Homocysteinaemia, Homocystinuria

Abbreviations: GJH: Generalised Joint Hypermobility; HSD: Hypermobility Spectrum Disorders; EDS: Ehlers-Danlos Syndromes; JIA: Juvenile Idiopathic Arthritis; ECM: Extracellular Matrix

1. Introduction

Hypermobility in early childhood is common and, in many children, represents physiological laxity rather than disease. Immature connective tissues, reduced muscle tone and ongoing neuromuscular maturation produce a wide range of normal flexibility in children under five and this range varies by age, sex and ethnicity¹. For clinicians, the central challenge is deciding when joint laxity is an isolated, self‑limiting trait and when it is a marker of symptomatic Hypermobility Spectrum Disorder (HSD) or a heritable connective‑tissue disorder, most notably an Ehlers-Danlos Syndrome (EDS).

Distinguishing physiological hypermobility from pathological forms is particularly difficult in this age group. Standardised assessment can be limited by cooperation and many features used in current diagnostic frameworks for hypermobile EDS (hEDS)-including chronic widespread pain, recurrent dislocations and some characteristic skin and systemic findings-are age‑dependent and may not be evident until later childhood or adolescence². As a result, early childhood assessment often relies on careful clinical pattern recognition, identification of red‑flag features that warrant specialist evaluation and longitudinal follow‑up to clarify trajectory. Early recognition nonetheless matters: timely advice and physiotherapy‑led interventions can support motor development, reduce injury risk and provide families with appropriate anticipatory guidance, while enabling surveillance and genetic evaluation in children suspected of rarer, higher‑risk EDS subtypes. This narrative review synthesises current evidence on epidemiology, mechanisms, clinical manifestations, diagnostic challenges, assessment tools, management strategies and research gaps relating to hypermobility and EDS in children under five, highlighting priorities for developing paediatric‑specific diagnostic frameworks.

1.1. Epidemiology of Hypermobility in Early Childhood

Joint laxity is highly prevalent in early childhood and declines with age as connective tissues mature³. In a large UK cohort of adolescents, generalised joint hypermobility was present in 27% of girls and 11% of boys, with even higher prevalence expected in younger children⁴. Ethnicity influences baseline flexibility: children of African, Middle Eastern and Asian descent often demonstrate greater physiological laxity, complicating the interpretation of Beighton scores⁵.

Before age five, hypermobility is frequently asymptomatic. When symptoms occur, they often include delayed motor milestones, clumsiness or fatigue-features that overlap with normal developmental variation⁶. This overlap contributes to diagnostic uncertainty and delays in recognising children with underlying connective‑tissue disorders.

2. Pathophysiology of Hypermobility and EDS

Hypermobility arises from increased elasticity or reduced stiffness of connective tissues, particularly collagen and from the balance between passive ligamentous restraint and active neuromuscular control. In the Ehlers-Danlos Syndromes (EDS), pathogenic variants disrupt collagen synthesis, structure, post‑translational modification or Extracellular Matrix (ECM) assembly, producing multisystem manifestations involving skin, joints, vasculature and internal organs². In addition to primary collagen gene disorders, several metabolic pathways can secondarily influence ECM integrity by altering collagen cross‑linking, redox state and methylation capacity-mechanisms that may be relevant in a small subset of children presenting with marked laxity or marfanoid features.

In early childhood, the relative contribution of ligamentous laxity, hypotonia and neuromuscular immaturity complicates the interpretation of hypermobility. The pathophysiology of hypermobile EDS (hEDS) remains incompletely understood, with no confirmed monogenic cause, although familial clustering suggests autosomal dominant inheritance with variable penetrance⁵. Beyond structural gene disorders, one‑carbon (folate–methionine) metabolism intersects with connective‑tissue biology through regulation of homocysteine and methyl‑donor availability. Dietary folate (including folic acid) is reduced within the folate cycle and ultimately converted to 5‑methyltetrahydrofolate (5‑MTHF), the key methyl donor used (with vitamin B₁₂) for remethylation of homocysteine to methionine. Methionine is then converted to S‑adenosylmethionine (SAM), the principal cellular methyl donor for DNA, RNA, proteins and lipids; impaired flux through this pathway can increase homocysteine and alter methylation‑dependent regulation of ECM gene expression.

Common functional variants in MTHFR (e.g. C677T and A1298C) reduce enzyme activity and can predispose to mild hyper-homocysteinaemia, particularly in the context of low folate or riboflavin status. Although these variants are prevalent in the general population and are not, in isolation, diagnostic of a connective‑tissue disorder, raised homocysteine has biologically plausible links to ECM pathology. Experimental work suggests that homocysteine can interfere with collagen maturation by reacting with aldehyde intermediates required for intermolecular cross‑link formation, potentially reducing fibril stability and can promote oxidative stress and inflammatory signalling that may influence matrix remodelling. These mechanisms provide a rationale for considering homocysteine as a modifier of tissue resilience rather than a primary explanation for most cases of childhood hypermobility.

More marked disturbances occur in classical homocystinuria due to biallelic CBS (cystathionine β‑synthase) mutations, in which trans-sulphuration of homocysteine to cystathionine is impaired, leading to accumulation of homocysteine/homocystine and often methionine. Clinically, CBS deficiency can produce a marfanoid habitus, scoliosis, osteoporosis and joint laxity and may therefore mimic heritable connective‑tissue disorders; distinguishing features include ectopia lentis (typically downward), neurodevelopmental involvement and a high risk of thromboembolism. Mechanistically, elevated homocysteine has been associated with reduced collagen cross‑linking and abnormal connective‑tissue architecture, supporting a metabolic contribution to laxity and tissue fragility in severe hyperhomocysteinaemia⁷. In young children presenting with disproportionate tall stature, lens abnormalities, unexplained thrombosis or a compatible family history, plasma total homocysteine and related metabolic testing should be considered as part of the differential diagnosis alongside genetic evaluation for monogenic EDS subtypes.

3. Clinical Features in Children Under Five

3.1. Musculoskeletal Features

Musculoskeletal manifestations are the most common presenting features in young children with hypermobility or EDS. These include:

Delayed gross‑motor milestones

Hypotonia

Clumsiness or frequent falls

Joint instability or recurrent soft‑tissue injuries

Hypotonia is particularly prominent in infants with connective‑tissue disorders and may contribute to delayed sitting, crawling or walking⁸.

3.2. Skin and Soft‑Tissue Features

Skin hyperextensibility, easy bruising and delayed wound healing may be early clues to classical or hypermobile EDS². Atrophic scarring, if present, is highly suggestive of classical EDS. However, many skin features are subtle or absent in early childhood.

3.3. Pain and fatigue

Chronic pain is less common in children under five but may occur in those with significant instability or repeated soft‑tissue trauma⁹. Fatigue may reflect poor proprioception, reduced muscle endurance or compensatory movement strategies.

3.4. Autonomic and Gastrointestinal Features

Some young children exhibit feeding difficulties, reflux, constipation or autonomic dysregulation¹⁰. These symptoms are non‑specific but may support a syndromic diagnosis when combined with musculoskeletal findings.

4. Diagnostic Challenges and Limitations of Current Criteria

The 2017 international classification of EDS provides detailed criteria for hEDS, but these criteria explicitly exclude children because many features-such as chronic pain, recurrent dislocations and characteristic skin findings-are age‑dependent^2,11.

Key diagnostic challenges include:

Developmental variability: flexibility is naturally high in toddlers.

Limited cooperation: some Beighton manoeuvres are difficult to perform.

Age‑dependent features: many diagnostic signs emerge later.

Overlap with normal development: delayed milestones and clumsiness are common in healthy children.

Lack of validated paediatric criteria: no consensus exists for diagnosing hEDS in young children.

Red‑flag features suggesting a monogenic connective‑tissue disorder include marked skin fragility, congenital hip dislocation, severe hypotonia, early progressive scoliosis, vascular events or ocular abnormalities^2,12.

5. Importance of Early Diagnosis

Early recognition of EDS in childhood is essential because timely diagnosis enables targeted intervention that can prevent secondary musculoskeletal complications and optimise developmental outcomes. Children with hypermobility or EDS often present with hypotonia, delayed motor milestones, recurrent soft‑tissue injuries and inefficient movement patterns that, if unaddressed, contribute to chronic pain, fatigue and functional impairment later in life^1-3. Early diagnosis facilitates physiotherapy‑led strengthening, proprioceptive training and activity pacing, which improve stability and reduce injury risk^3,4,6.

Importantly, identifying EDS early reduces unnecessary investigations and prevents misdiagnosis, particularly in children with bruising, joint dislocations or delayed wound healing, where safeguarding concerns may otherwise be raised². Early recognition of rarer EDS subtypes-such as vascular or kyphoscoliotic EDS-allows appropriate cardiovascular, ophthalmic and spinal surveillance, which can be lifesaving². Early consideration of important metabolic differentials such as homocysteinaemia / homocystinuria is also valuable, as timely diagnosis may prompt thrombosis risk assessment, ophthalmic evaluation and targeted metabolic treatment¹³. Family‑level benefits include genetic counselling, anticipatory guidance and assessment of siblings who may also be affected¹¹.

5.1. Assessment Tools and Emerging Approaches

The Beighton score remains the most widely used measure of generalised joint hypermobility, but its application in toddlers is limited⁷. Alternative tools, such as the Hospital del Mar criteria or paediatric‑specific adaptations, have been proposed but lack widespread validation¹⁴.

Functional assessments-including gait analysis, motor‑skill evaluation and proprioceptive testing-often provide more clinically meaningful information in this age group. Systemic evaluation should include skin examination, assessment for hernias, spinal alignment and cardiovascular screening when indicated. Genetic testing is reserved for children with features suggestive of rarer EDS subtypes².

6. Differential Diagnosis

6.1. Important Differentials Include

Juvenile Idiopathic Arthritis (JIA) should be actively excluded in hypermobile children who present with persistent joint pain, limp or functional decline, because inflammatory arthritis can be misattributed to “growing pains” or mechanical symptoms. Features that should prompt urgent consideration of JIA include objective joint swelling, warmth or effusion; morning stiffness or pain that improves with activity; restricted range of motion; nocturnal pain; systemic features (eg, fever, rash); and persistently raised inflammatory markers (ESR/CRP)¹⁵. Early paediatric rheumatology referral is recommended when inflammatory features are present, because timely treatment reduces the risk of joint damage and improves outcomes.

Other genetic and neuromuscular differentials include:

Congenital myopathies

Metabolic bone disease

Hypotonic cerebral palsy

Chromosomal syndromes (e.g., Down syndrome)

Marfan syndrome

Loeys–Dietz syndrome

Homocysteinaemia / homocystinuria¹³

7. Management Strategies

7.1. Physiotherapy and Motor Development

Physiotherapy is the cornerstone of management¹⁶. Key components include:

Strengthening of core and proximal musculature

Balance and proprioceptive training

Motor‑skill acquisition

Activity pacing and fatigue management

Early intervention improves functional outcomes and reduces compensatory movement patterns.

7.1.1. Orthotics and footwear: Supportive footwear and orthotics can improve stability in children with pes planus or ankle instability¹⁷.

7.1.2. Pain management: Pain in this age group is typically managed conservatively with activity modification, physiotherapy and reassurance⁹. Pharmacological interventions are rarely required.

7.1.3. Family education: Parents benefit from guidance on safe play, joint‑protective strategies and realistic expectations. Over‑medicalisation should be avoided, as most hypermobile children remain active and well¹⁸.

8. Prognosis and Long‑Term Outcomes

Most children with benign hypermobility experience improvement as connective tissues mature. However, children with HSD or EDS may develop persistent pain, fatigue, proprioceptive difficulties or functional limitations. Early intervention improves long‑term outcomes by reducing injury risk, supporting motor development and preventing maladaptive movement patterns.

9. Research Gaps and Future Directions

Key research priorities include:

Development of validated paediatric diagnostic criteria

Improved understanding of the natural history of hEDS in early childhood

Biomarkers for early identification of connective‑tissue disorders

Longitudinal studies on motor development and functional outcomes

Evaluation of physiotherapy protocols tailored to young children

A paediatric‑specific diagnostic framework is urgently needed to improve early recognition and guide management.

10. Conclusion

Hypermobility in children under five is common and most often reflects normal developmental laxity; however, a clinically important minority have symptomatic Hypermobility Spectrum Disorder (HSD) or an underlying Ehlers-Danlos Syndrome (EDS). In this age group, interpretation is complicated by wide developmental variability, limited cooperation with formal examination and the age‑dependence of many features used in current diagnostic criteria. Consequently, diagnosis should be framed as a process of longitudinal assessment rather than a single time‑point label.

Clinically, the priority is to identify children who need closer follow‑up or specialist input-particularly those with red‑flag features (eg, marked skin fragility or atrophic scarring, congenital hip dislocation, severe hypotonia, early progressive scoliosis, vascular or ocular features or a strong family history of a defined connective‑tissue disorder). For most symptomatic children, early, developmentally appropriate intervention is beneficial even while diagnostic uncertainty remains. Physiotherapy‑led strengthening, balance and proprioceptive training, motor‑skill support and advice on pacing and joint‑protective play can reduce injury risk, support participation and help prevent maladaptive movement patterns that contribute to later pain and fatigue. Where indicated, supportive footwear and orthoses may improve function and families benefit from clear anticipatory guidance that avoids both dismissal of symptoms and over‑medicalisation. 

Earlier recognition also has health‑system and family‑level benefits, including more efficient referral pathways, avoidance of unnecessary investigations, appropriate safeguarding interpretation when bruising or injury occurs and opportunities for genetic counselling and assessment of relatives when a monogenic subtype is suspected. Looking forward, progress depends on validated paediatric assessment thresholds, prospective studies describing natural history from infancy and trials of early‑childhood physiotherapy and family‑centred interventions. Developing and implementing paediatric‑specific diagnostic frameworks that integrate joint hypermobility with functional impact and multisystem features is essential to improve timely recognition, guide surveillance for higher‑risk phenotypes and optimise long‑term outcomes.

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