Challenges and solutions in the treatment of spinal disorders in patients with skeletal dysplasia: A comprehensive review

Abstract

Skeletal dysplasia includes numerous genetic disorders marked by abnormal bone and cartilage growth, causing various spinal issues. The 2023 nosology identifies 771 distinct dysplasias involving 552 genes, with achondroplasia being the most common and significantly affecting the spine. Other disorders include type II collagenopathies, sulphation defects, Filamin B disorders, and osteogenesis imperfecta, presenting with short stature, limb deformities, joint contractures, and spinal abnormalities. Spinal pathology often impacts physeal growth areas, leading to conditions like foramen magnum stenosis, atlantoaxial instability, spinal stenosis, kyphosis, and scoliosis. Non-orthopaedic symptoms can include hearing and vision loss, neurological issues like hydrocephalus, and cardiac abnormalities. The incidence is around 1 in 4000 to 5000 births, with achondroplasia at about 1 in 30000 live births. Advances in genetics and imaging enable prenatal diagnosis, though milder cases may go undetected. Effective management requires a multidisciplinary approach involving various specialists. This review emphasises early diagnosis, continuous monitoring, and comprehensive management of spinal pathology in skeletal dysplasia. In the current article, the authors present a thorough review on spinal conditions associated with skeletal dysplasia, their pathophysiology and management options.

Key Words: Skeletal dysplasia; Spinal disorders; Achondroplasia; Spondyloepiphyseal dysplasia; Mucopolysccharidosis; Osteogenesis imperfecta

Core Tip: Spinal disorders are commonly encountered in patients with skeletal dysplasia. Skeletal dysplasias often impacts physeal growth areas, leading to conditions like foramen magnum stenosis, atlantoaxial instability, spinal stenosis, kyphosis, and scoliosis. The current article provides a detailed review of the various types of skeletal dysplasia and its associated spectrum of spinal disorders, along with common clinical presentation and management options and outcomes as described in literature.

INTRODUCTION

Skeletal dysplasia encompasses a diverse group of genetic disorders defined by atypical bone or cartilage growth and development, resulting in various spinal manifestations[1]. The 2023 nosology of skeletal disorders comprises 771 diseases with 552 genes classified into 41 groups based on their clinical, radiographic, and/or molecular phenotypes[2].

Among these, the most prevalent is achondroplasia, which belongs to the fibroblast growth factor receptor 3 (FGFR3) chondrodysplasia group and is well-known for its spinal involvement[3]. Other disorders with significant spinal manifestations include type II collagen disorders, sulphation disorders, Filamin B disorders, the transient receptor potential vanilloid type 4 (TRPV4) group, pseudoachondroplasia, the bent bone dysplasia group, the chondrodysplasia punctata group, osteogenesis imperfecta (OI), and lysosomal storage diseases. These disorders result in a wide array of phenotypic manifestations, including disproportionate short stature, limb deformities, joint contractures, and significant spinal abnormalities. Spinal pathology often occurs where there is physeal growth, such as the skull base (foramen magnum), odontoid process, neuro-central synchondrosis, and vertebral endplates[2]. Disturbances in these growth areas can lead to conditions like foramen magnum stenosis (FMS), atlantoaxial instability, spinal stenosis, kyphosis, and scoliosis. Additionally, non-orthopaedic features such as hearing and vision loss, characteristic facial appearances, neurological issues like hydrocephalus, and cardiac and pulmonary abnormalities may also be present. The overall incidence of skeletal dysplasia is relatively uncommon, estimated at one in every 4000 to 5000 births, though this may be an underestimation as some disorders are not apparent at birth[4,5].

Traditionally, the diagnosis of skeletal dysplasia was based on family history, clinical observations, and radiographic findings. The key radiographs to aid diagnosis are an anteroposterior view of both lower extremities from hip to ankle and a lateral view of the spine. However, advances in molecular genetics and imaging techniques have made genetic testing routine, enabling prenatal diagnosis through molecular screening panels when ultrasonography raises concerns for skeletal dysplasia[4]. Despite these advancements, milder cases, late-onset phenotypes, or those without prenatal screening might go undetected at birth. Spinal disorders are a major cause of morbidity and mortality in skeletal dysplasia, often presenting early and progressively worsening. Spinal cord (SAC) compression, which can result in paralysis or death, is particularly concerning. Prevention of these severe outcomes requires early detection, close monitoring, and sometimes immediate surgical intervention. Unfortunately, spinal manifestations are frequently missed due to misdiagnosis or insufficient understanding of the disorders' natural progression.

Effective management requires a collaborative approach involving orthopaedic surgeons, neurologists, geneticists, and rehabilitation specialists to address the diverse and evolving spinal issues associated with skeletal dysplasia. By comprehending the specific spinal complications linked to various types of skeletal dysplasia, healthcare providers can devise more effective treatment strategies and improve long-term outcomes for affected individuals.

This review aims to provide a general overview of spinal manifestations in various skeletal dysplasias (Table 1) with an emphasis on early diagnosis, continuous monitoring, and management of spinal pathology.

Table 1 Spinal disorders associated with skeletal dysplasia.

Group/name of disorder	Inheritance	Gene	Case-control studies	Cohort studies	Hydroxy	Choline kinase	Atlantoaxial instability	Basilar invagination	Chronic viral B-hepatitis	Thoracolumbar kyphosis	Scoliosis	Lumbar canal stenosis
Achondroplasia	AD	Fibroblast growth factor receptor 3	+++			+				+++		+++
Hypochondroplasia											++	+++
Thanatophoric dysplasia			+++	+++						+++
Diastrophic dysplasia	AR	Solute carrier 26A		++	+++	+++			+++	++	++
Spondyloepiphyseal dysplasia congenita	AD/AR	Collagen type alpha 1 chain			+++		+++	+++
Kneist syndrome	AD			+		+	++	+		++	++
Pseudoachondroplasia	AD	Cartilage oligomeric matrix protein			+++		+++				++	+
Metatrophic dysplasia	AD	Transient receptor potential vanilloid type 4		+	+
Campomelic dysplasia	AD	Sex determining region Y (SRY)-box 9		++	++					++	++
MPS I	AR	Iduronidase	++	++	++		++			+++		+
MPS IV		Galactosamine-6-sulfate	+++	+	+++		+++			++	++
MPS VI		Arysulfatase B	++	+	++		++			++

AD: Autosomal dominant; AR: Autosomal recessive; MPS: Mucopolysaccharidoses; +: Case report; ++: Common; +++: Ubiquitous.

LITERATURE REVIEWS

This review was conducted following established guidelines for systematic literature reviews. A comprehensive search was performed in PubMed, Scopus, and Web of Science databases using the following keywords: (1) Skeletal dysplasia; (2) Spinal disorders; (3) Achondroplasia; (4) Spondyloepiphyseal dysplasia; and (5) Mucopolysaccharidosis. Articles published between 2000 and 2024 were included, with a preference for high-quality studies, clinical trials, and systematic reviews. The inclusion criteria were studies reporting spinal manifestations, treatment outcomes, and management strategies in skeletal dysplasia. Exclusion criteria included non-English articles, and studies without spinal focus. Data extraction was performed independently by two authors, with disagreements resolved through discussion.

DISCUSSION

FGFR3 related disorders

FGFR3 disorders comprise a spectrum of disorders that include achondroplasia, thanatophoric dysplasia, and hypochondroplasia. They are all inherited as autosomal dominant disorders due to heterozygosity for mutations in FGFR3 (4p16.3)[5]. All three disorders are osteochondrodysplasias characterized by varying degrees of skeletal abnormalities. Achondroplasia is nonlethal with some rare exceptions. Hypochondroplasia can phenotypically mimic achondroplasia but is usually milder. Thanatophoric dysplasia is lethal without very aggressive interventions[6].

Achondroplasia

Achondroplasia is the most common hereditary skeletal dysplasia requiring treatment of the spinal disorder. It follows either an autosomal dominant pattern of inheritance with 100% penetrance or a sporadic mutation. Achondroplasia occurs in approximately 1:20000 to 1:30000 live births per year[7,8]. The homozygous form is lethal resulting in stillbirth, while advanced paternal age has been related to sporadic cases[9].

Pathophysiology: Achondroplasia is typically characterized by rhizomelic (proximal) limb shortening, protuberant abdomen, macrocephaly, hypotonia, frontal bossing, and midface hypoplasia[9]. There is a decrease in endochondral ossification caused by activating mutation of FGFR3 in its transmembrane domain. Bones formed due to membranous ossification (skull vault, clavicle, and pelvis) are unaffected.

Spinal manifestations of achondroplasia include the following: (1) Foramen magnum stenosis and short clivus; (2) Craniocervical spinal canal stenosis resulting in cervicomedullary compression; (3) Posterior vertebral scalloping; (4) Thoracic spine stenosis; (5) Thoracolumbar kyphosis and lumbar hyperlordosis; and (6) Reduced pedicle length and interpedicular distance particularly in the lumbar spine causing spinal stenosis[9-12].

At birth, an infant with achondroplasia has hypotonia in the trunk and the extremities. The cause of hypotonia remains unclear regarding whether it is the result of partial neurological deficit secondary to FMS[12]. There is an increased frequency of sleep apnea in these infants, sometimes leading to sudden death. Sleep apnea monitors are often used for the first several months in many of these infants, and if sleep apnea is found clinically significant, evaluation for FMS is needed as there may be underlying cord compression[13]. Although atlantoaxial instability is commonly seen in other skeletal dysplasias, it is rarely seen in achondroplasia[14,15].

Management: FMS is a serious and potentially life-threatening complication in achondroplasia patients. Almost all infants with achondroplasia have a foramen magnum size less than 3 SD below the mean[15]. Infants and younger children are at greater risk of developing FMS. FMS can lead to cervicomedullary compression, resulting in sleep apnea and sudden death in infants. Mortality rate as high as 7.5% has been reported in the literature[16]. As per the European Achondroplasia Forum, all infants should be monitored clinically for FMS every 3-4 months from birth to the age of 1 year, thereafter every 3-6 months until the age of 3 years. After the age of 3 years, monitoring for FMS should be based on individual needs and local protocols. Magnetic resonance imaging (MRI) should be undertaken as routine monitoring for FMS at 3-6 months of age and repeated according to findings in other routine assessments[17].

The best approach to treatment and who should receive it remains unclear. One study of 32 children with achondroplasia found that 28% had sleep apnea, and 22% had abnormal sleep study results. Both conditions improved in the 6 children who underwent foramen magnum decompression[18]. It has been noted that combining foramen magnum decompression with external ventricular drainage can enhance safety and effectiveness by addressing abnormal cerebrospinal fluid (CSF) flow[19-21]. Symptoms like ataxia, incontinence, and breathing difficulties have been successfully treated with foramen magnum decompression and atlas laminectomy in patients ranging from 7 months to 30 years old. Some experts suggest performing cervicomedullary decompression in asymptomatic children if SAC changes appear on T2-weighted MRI[22,23]. However, it is rarely necessary to perform foramen magnum decompression in older children or adults[24].

In the cervical spine below the foramen magnum in achondroplasia, the principal disorder is diffuse spinal stenosis. Although a small spinal canal is present at birth, signs and symptoms of neural compression in the subaxial cervical spine are commonly not seen until middle age or later. The reason behind this may be the presence of degenerative changes in an already compromised spinal canal[25]. The clinical features could range from mild pain and sensory changes in the upper extremities to cervical myelopathy. If the motor deficit in the upper or lower extremities is present, laminectomy at multiple levels may be needed. MRI defines the level of compression, which is usually multiple. Laminectomy is the mainstay of treatment but this leads to instability and progressive deformity requiring complex fixation. To mitigate this risk, Afshari et al[26] developed a novel modified augmented laminoplasty that increases spinal canal diameter while preserving the posterior column stability. The study showed promising outcomes in terms of improvement of symptoms and prevention of deformity, suggesting augmented laminoplasty as a viable alternative to fixation.

Thoracolumbar kyphosis: When an infant begins to sit upright, features such as a large head, flat chest, protuberant abdomen, and trunk hypotonia can highlight thoracolumbar kyphosis (TLK), which is a condition that is frequently observed in newborns. When the child lies prone, the apparent deformity might get better. On X-rays, T12 and L1 apical wedging is commonly observed, usually affecting vertebrae from T10 to L4. TLK frequency peaks at 87% in the first two years of life and falls to 11% in the fifth and tenth years. Apical vertebral translation (5% of cases) and apical vertebral wedging (6%) are radiographic indicators of persistent TLK. Unresolved TLK is also linked to developmental motor delay.

Patients with kyphotic curves between 20 degrees and 40 degrees should be monitored for progressive deformity and symptoms of SAC compression. As the child begins to stand and walk, lumbosacral hyperlordosis may become apparent, likely due to excessive anterior pelvic tilt while standing. Management of TLK in achondroplasia involves a combination of monitoring, physical therapy, and, in severe cases, surgical intervention. Early detection is crucial, especially since TLK can be resolved as children grow. Regular radiographic assessments help track progression. Physical therapy aims to strengthen trunk muscles, improving posture and stability. Surgical management of TLK in achondroplasia is considered when conservative measures fail or if there is significant progression of the deformity, neurological compromise, or severe pain. The primary goals of surgery are to stabilize the spine, correct the deformity, and prevent further neurological deterioration. Surgical techniques include spinal arthrodesis and instrumentation[27]. The authors have summarized the studies describing surgical management in achondroplasia in Table 2[28-32].

Table 2 List of studies on surgical management of spinal disorders in achondroplasia.

Ref.	Spinal disorder	Type of study	Sample size (male/female)	Mean age (years) (SD)	Total surgeries	Surgical levels decompressed	Median follow-up	Indications of primary surgery	Revision surgery indications (early)	Revision surgery indications (late)	Late revision surgery types	Complications	Outcomes
Urbanschitz et al[30], 2024	Thoracolumbar spinal stenosis	Retrospective	15 (8/7)	52 (10.4)	31 (primary: 12/revision: 19)	79	24 months (interquartile range: 34 months; range: 4-85 months)	Myelopathy: 5; spinal claudication: 4; paraparesis: 2; acute foot drop: 1	3/19 (complication within 30 days: Dural tear, wound healing disorder, adjacent segment collapse)	16/19 (spinal stenosis: 7; hyperkyphosis: 4; adjacent segment disease: 2; pseudoarthrosis: 2; posttraumatic deformity: 1)	Decompression: 5; decompression + fusion: 8; alignment correction with osteotomy: 3)	Dural tear: 11; implant failure: 2; wound disorder: 2; urosepsis: 1	Full recovery: 5; partial recovery: 11; no improvement: 2
Hariharan et al[31], 2024	Spinal stenosis	Retrospective	33	18.7 (10.1)	33 (24 selected for analysis)		-	-	-			Caudal pseudarthrosis: 8; proximal junctional kyphosis: 7; new neurological symptoms: 7
Tanaka et al[28], 2022	TLK	Retrospective case series	3 (2/1)	22.3	3	Posterior vertebral column resection	9.3 years	Severe TLK with neurological deficits and urinary disturbance	Surgery: Posterior vertebral column resection with cage and segmental instrumentation			Rod breakage, surgical site infection	Average Japanese Orthopedic Association score improved from 8.3/11 to 10.7/11 (mean recovery rate: 83%); 67% kyphotic angle correction
Sciubba et al[29], 2007	Spinal stenosis. Surgery: Decompression +/- fusion	Retrospective	44 (25/19)	12.7	60 decompressive surgeries	Thoracolumbar (65.3%), lumbar (20.4%), cervical (8%), cervicothoracic (4%), thoracic (2%)	34 months	Neurogenic claudication (91%), pain (95.4%), cauda equina syndrome (25%), myelopathy (4.5%)	Disc herniation at L2-3 within a previous laminectomy	Progressive deformity, junctional stenosis, and recurrence of symptoms		Dural tear: 4, wound breakdown: 2, radicular pain: 3	32 patients showed improvement in symptoms
Matsumoto et al[32], 2006	TLK, surgery: Posterior osteotomy with segmental instrumentation	Case report	4 (3/1)	32.5	4	Thoracolumbar	35 months	Severe TLK with neurologic deficit				Dural tear and partial nerve root laceration: 2	Mean recovery rate: 75%

TLK: Thoracolumbar kyphosis.

During in utero spine development, impaired longitudinal growth of the posterior arches occurs, resulting in premature fusion of pedicles with vertebral bodies leading to shortened pedicles, and reduced cross sectional area of spinal canal leaving less space available for neural elements[33]. Neurologic issues from spinal stenosis are the primary concern for adolescents and adults with achondroplasia, often presenting as back pain, claudication, and bladder incontinence[34]. Laminectomy with fusion is a commonly performed surgical intervention. Surgical decompression for spinal stenosis in achondroplasia patients typically results in good symptom relief and functional improvement, particularly if done within six months of symptom onset. However, significant risks, including complications, recurrence of stenosis, and spinal destabilisation, must be managed. Thinning of the dura after extensive laminectomy can cause pseudomeningoceles, leading to neurological problems or pain. In skeletally immature patients, instrumented stabilization may be more effective than decompression alone to prevent spinal deformity[35].

In cases of lumbar stenosis with TLK, both contribute to neurological symptoms, requiring MRI to assess all compression levels[36,37]. For lumbar stenosis with anterior SAC compression at the kyphosis apex, anterior decompression and fusion, along with posterior multilevel laminectomy and instrumented fusion, is recommended. Anterior decompression may be done via vertebrectomy and bone graft fusion or through the pedicles using cages and bone grafts. Pedicle screws and rods are placed during posterior decompression, followed by bone graft fusion[28,29,35].

Thanatophoric dysplasia

It is another condition linked to FGFR3 mutations, is usually lethal in the perinatal period. Respiratory insufficiency typically results in early neonatal death and is due to a small chest cavity and/or foramen magnum narrowing with brain stem compression[38,39]. However, long-term survivors have been reported, including rare reports of survival to adulthood with aggressive ventilatory support and surgical management of neurologic complications. Other spinal manifestations include a cloverleaf skull, platyspondyly, and generalized hypotonia[40].

Hypochondroplasia

A milder form of skeletal dysplasia compared to achondroplasia and caused by FGFR3 gene mutations, often results in lumbar spinal stenosis and mild kyphosis[41]. Patients may develop neurogenic claudication and back pain due to stenosis, while mild kyphosis in the thoracolumbar region generally causes less severe issues. Shortened pedicles contribute to the development of lumbar stenosis, often requiring surgical decompression. Compared to achondroplasia, hypochondroplasia presents with less pronounced skeletal abnormalities, but careful monitoring and intervention are still necessary[9,24].

Solute carrier 26A related disorder

Diastrophic dysplasia: Diastrophic dysplasia is a rare genetic disorder characterized by distinctive clinical features that typically allow for diagnosis at birth. The incidence is approximately 1 in 1 million in most countries, but Finland reports a significantly higher number of cases, contributing to much of the current literature on the condition. The disorder is linked to a genetic defect in diastrophic dysplasia sulfate transportase, located on chromosome 5q31-q34[42].

Pathophysiology: The pathophysiology of diastrophic dysplasia is rooted in a genetic defect affecting sulfate transport, leading to abnormal cartilage and bone development. Key diagnostic features include micromelia (markedly short stature), "hitchhiker’s thumb", stiff proximal interphalangeal joints of the fingers, severe equinovarus foot deformity, and the development of external ear cysts within weeks of birth, resulting in the characteristic "cauliflower ear". The spine is notably affected, with all patients exhibiting spina bifida of the cervical spine, though this does not typically cause symptoms. The most significant spinal issue is mid-cervical kyphosis, which, if progressive, can lead to severe deformity and SAC compression[43,44].

Clinical features: Patients with diastrophic dysplasia display a range of clinical features, including short stature, joint stiffness, and various skeletal deformities. Approximately 25% of affected individuals have a cleft palate. Spinal abnormalities are common, with mild cervical kyphosis often resolving by age 7, but in some cases, progressive kyphosis leads to severe spinal deformity. Kyphoscoliosis is the primary spinal disorder in the thoracic region, with varying degrees of severity. Severe thoracic kyphoscoliosis can cause significant physical issues, such as swallowing difficulties, though neurologic symptoms are rare.

Management: Management of diastrophic dysplasia focuses on early detection and treatment of spinal deformities to prevent progression to severe kyphosis or scoliosis. In cases of progressive cervical kyphosis, cervical fusion is recommended to stabilize the spine and prevent SAC compression. For thoracic kyphoscoliosis, treatment may include the use of a brace or, in more severe cases, anterior and posterior spinal fusion with instrumentation. Monitoring and early intervention are crucial to managing these deformities effectively. In patients with marked lumbosacral lordosis, conservative management is usually sufficient, with decompressive laminectomy rarely required.

Collagen type alpha 1 chain related disorder

Spondyloepiphyseal dysplasia: Spondyloepiphyseal dysplasia (SED) is a heritable dysplasia manifested at birth with dysgenesis of vertebral bodies, extremities, and pelvis resulting in short stature. It has two variants, SED congenita (SEDc) and SED tarda (SEDt)[24].

SEDc is a rare autosomal dominant genetic disorder with an incidence of approximately 3/1000000[45]. The collagen type alpha 1 chain (COL2A1) gene, which controls the synthesis of type II collagen, a crucial component of cartilage and other connective tissues, is mutated in SEDc. SEDc is related to other skeletal dysplasias with type II collagen defects, such as Kniest syndrome, Stickler syndrome, and Strudwick spondylometaphyseal dysplasia[46].

Pathophysiology: SEDc is noticeable at birth, often characterized by short-trunk dwarfism and specific imaging findings. The condition leads to delayed ossification in the vertebral bodies and coxa vara, while the hands and feet usually appear normal in size. As the child grows, ossification delays in the femoral heads and irregularities in the long bones epiphyseal and metaphyseal areas continue to manifest[47].

One of the primary concerns in SEDc is atlantoaxial instability, which affects nearly half of affected children[47]. This instability, often due to odontoid hypoplasia, results in abnormal cervical spine motion in flexion or extension. Infants may show hypotonia, which generally resolves with age, but failure to reach motor milestones could indicate cervical spine issues. Atlantoaxial instability is frequently detected early, sometimes as early as one year of age.

Clinical features and management: The presence of atlanto axial subluxation with hypoplasia of the odontoid and/or lax ligaments leads to myelopathy in these cases[48]. Detecting atlantoaxial instability in young children with SEDc can be difficult due to the increased flexibility of the cervical spine and the delayed ossification of posterior elements. Although initial assessments use cervical spine radiographs, MRI in flexion-extension positions provides a more detailed view of anatomical abnormalities, SAC compression, or canal narrowing.

The approach to treating atlantoaxial instability in SEDc depends on the level of instability and the involvement of the SAC. Posterior upper cervical fusion is recommended if radiographs show movement exceeding 8 mm or if MRI reveals SAC compression or signal changes. In more severe cases, where SAC compression is significant, additional procedures like a C1 laminectomy may be required along with an occiput-to-C2 fusion. The typical surgical procedure involves fusing the occiput to C2, usually without additional wiring or instrumentation, to accommodate the developing bones of the child. A corticocancellous bone graft is utilized, followed by immobilization in a halo brace for three months to ensure the fusion is successful[49]. When deciding on the best surgical approach for atlantoaxial subluxation associated with myelopathy in SEDc, it's essential to consider whether the subluxation can be reduced and whether the space available for the SAC is narrow, especially in the presence of os odontoideum. For patients with a narrow SAC, a combination of C1 laminectomy and occipital-cervical fusion is advised[48].

For scoliosis, initial treatment with a thoracolumbosacral orthosis may be effective, but progressive cases might require posterior spinal instrumentation and fusion. Intraoperative SAC monitoring is essential for ensuring safety during these procedures.

SEDt, primarily affecting males, is caused by mutations in the SEDt gene. Spinal manifestations include platyspondyly, kyphoscoliosis, and early-onset osteoarthritis. Atlantoaxial instability is a significant risk, requiring careful monitoring and potential surgical intervention. Patients often experience short stature and joint pain, necessitating ongoing orthopedic and rehabilitative care.

Kniest syndrome

Kniest syndrome is a rare skeletal dysplasia resulting from mutations in the COL2A1 gene, characterized by short stature, scoliosis, kyphosis, joint contractures, and various skeletal abnormalities[50]. Although individuals with Kniest syndrome generally have a normal life expectancy and cognitive function, they often encounter significant orthopedic challenges, particularly involving the spine and long bones. Early identification and appropriate management of these features are essential to enhance the patient's quality of life and prevent complications.

Clinical features and management: Kniest syndrome shares many clinical features with SEDc. Affected individuals typically display metaphyseal widening of the long bones, coxa vara, delayed epiphyseal ossification, and sometimes angular deformities of the lower limbs[51,52]. Due to femoral external rotation, these children often exhibit a pronounced external foot progression angle when walking. Imaging studies frequently reveal coronal and sagittal vertebral clefts in about 63% of infants with Kniest syndrome, providing a valuable diagnostic clue[51].

Odontoid hypoplasia, which can result in atlantoaxial instability, is the most prevalent spinal issue requiring treatment in Kniest syndrome. It is recommended to monitor this instability with serial flexion-extension lateral cervical spine radiographs or flexion-extension sagittal MRI scans. If surgical intervention is necessary, posterior occipitoaxial fusion may be performed, following similar criteria as those used for SEDc[53].

Scoliosis is also commonly seen in Kniest syndrome, but due to the limited growth of the trunk, it does not always require intervention. Regular thoracolumbar spine radiographs are advised to assess the progression of spinal deformities and to determine if orthotic management or surgery is needed. If surgery becomes necessary, standard spinal instrumentation, though small, is generally adequate[24].

Beyond orthopedic issues, individuals with Kniest syndrome may also experience early-onset osteoarthritis, hearing loss, and visual impairments. These additional conditions necessitate a multidisciplinary approach to care, ensuring that the wide range of health challenges associated with this syndrome are comprehensively managed[54].

TRPV4 related disorder

Metatropic dysplasia: Metatropic dysplasia, caused by TRPV4 gene mutations, is characterized by short-limbed, short-trunk dysplasia with articular abnormalities, kyphoscoliosis, platyspondyly, and progressive spinal stenosis[55]. The pronounced spinal curvature typically presents early and progresses over time, often requiring complex surgical interventions. Progressive kyphoscoliosis leads to a reversal of body proportions during childhood, characterized by trunk shortening and relatively long extremities. Radiographic findings include significant platyspondyly with wafer-thin vertebral bodies, widened metaphyses giving tubular bones a dumbbell-like appearance, small epiphyses, and a distinctive pelvic shape. The severe kyphoscoliosis is relentless and does not respond well to conservative bracing. Surgical treatment remains controversial due to the high risk of deformity recurrence despite aggressive correction[56]. Bauer et al[57] conducted a 12-year retrospective review of 20 metatropic dysplasia patients and examined severe thoracic kyphosis treatments, including observation, bracing, anterior release with growing constructs, and final fusion. Surgical patients, presenting with an average kyphosis of 86.7°, showed significant reduction, particularly with staged thoracoscopic release, halo traction, and growing rods, which achieved an average correction of 71°. Observation showed minimal progression, indicating initial non-surgical management may be viable, with effective surgical options available for progressing cases.

Cartilage oligomeric matrix protein related disorder

Pseudoachondroplasia: Pseudoachondroplasia is a type of short-limbed dwarfism inherited in an autosomal dominant manner, caused by a defect in cartilage oligomeric matrix protein (COMP) located on chromosome 19p13.1[58]. Unlike some skeletal dysplasias, this condition is not usually identified at birth due to its normal facial appearance

Pathophysiology: Pseudoachondroplasia arises from a defect in COMP, which impairs cartilage and bone development. On radiographic imaging, this condition shows characteristic changes in the epiphyses and metaphyses of long bones, and spinal images reveal flattened vertebral bodies with a central, anterior tongue-like projection. Despite these abnormalities, trunk height generally remains within normal limits.

Clinical features and management: Individuals with pseudoachondroplasia have a normal facial appearance but may develop angular deformities in the lower limbs and early-onset hip osteoarthritis.

Spinal features include increased lumbar lordosis, often due to hip flexion contractures. Proximal femoral extension osteotomies can help if the lordosis is flexible, though it tends to become more rigid with age. Thoracic kyphosis may initially be a compensatory response to lumbar lordosis but can progress into a fixed deformity requiring treatment. Initial management may involve orthotic devices, with surgery considered if anterior vertebral body wedging is observed. Unlike achondroplasia, which affects only a few vertebrae, pseudoachondroplasia kyphosis impacts multiple vertebrae with varying degrees of wedging.

Scoliosis may be present but is not distinctive for pseudoachondroplasia. When spinal fusion or instrumentation is necessary, standard-sized equipment can be used, as opposed to achondroplasia where avoiding the spinal canal is crucial.

Atlantoaxial instability, often due to general joint laxity rather than odontoid hypoplasia, is relatively common in pseudoachondroplasia. Up to 60% of patients may experience upper cervical instability, although surgery is rarely needed. Shetty et al[59] studied 15 Korean patients with pseudoachondroplasia for upper cervical spine instability and concluded that, although instability was increased, none of the patients developed cervical myelopathy, suggesting that regular monitoring is crucial while surgery may not be required.

Before any orthopedic procedure requiring anesthesia, it is recommended to perform flexion and extension lateral cervical radiographs to check for instability. If atlantoaxial instability is found, posterior atlantoaxial instrumentation and fusion may be required.

Mucopolysaccharidoses

Mucopolysaccharidoses (MPS), a group of lysosomal storage disorders characterized by the accumulation of glycosaminoglycans (GAGs), significantly affect skeletal development[60-62]. While Sanfilippo syndrome (MPS type III) and Scheie syndrome (MPS type V or I-S) rarely involve spinal complications, Scheie syndrome can lead to dural thickening and subsequent neurological deficits[63]. Diagnosis is usually established by appropriate serum and urine studies and by culture of either fibroblasts or leukocytes to elucidate the specific MPS syndromes. In some MPS syndromes, particularly Hurler syndrome, survival has been significantly enhanced using enzyme replacement therapy and bone marrow transplantation[64]. These modalities have advantages regarding soft tissues; however, these therapeutic modalities are not effective for bone or cartilage and MPS-related bone deformity including the spine. Because spinal disorders show the most serious deterioration among patients with MPS, spinal surgeries are required although they are challenging and associated with high anesthesia-related risks[65,66].

Pathophysiology: All spinal problems in MPS are caused by a combination of factors that include spinal canal stenosis, hypermobility/joint laxity, and skeletal deformity. Skeletal deformity arises from GAG accumulation in the prenatal chondrocytes of primary and secondary ossification centers affecting normal systemic endochondral and membranous bone growth[67,68]. It begins in the prenatal period and lasts until the growth of new bone stops. While GAG accumulation in the connective tissue of the anterior extradural space and ligamentum flavum results in spinal canal stenosis, it can also cause inflammation and degradation of surrounding tissue in the spinal ligament and capsule of facet joints, leading to hypermobility and joint laxity[69,70]. Atlantoaxial instability is frequently observed in MPS IV followed by MPS VI and MPS I. TLK is a well-known hallmark of MPS I but is also common in MPS II, IV, and VI. Cervical stenosis is broadly recognized in all MPS types except for MPS III[69,71,72].

Clinical features and surgical management

Atlantoaxial instability: Atlantoaxial instability is common in MPS IV and VI, associated with dens hypoplasia, ligamentous laxity, and GAG accumulation. This can lead to severe complications like SAC damage, sudden death, or quadriparesis. Neurological symptoms vary and can include numbness, clumsiness, and gait instability, often complicating diagnosis due to communication issues or joint contractures in patients.

Diagnosis typically involves flexion/extension radiographs and MRI, though computed tomography (CT) scans offer a better assessment of odontoid hypoplasia. Surgical intervention, such as fixation/decompression, is crucial before irreversible damage occurs, but the timing remains controversial. It should be reserved for demonstrable cervical instability rather than performed prophylactically. Challenges in surgery include the difficulty of instrument fixation in small vertebrae and the potential need for revision surgery due to adjacent instability[73-75]. In pediatric cervical spine surgery, rigid fixation of the C1-C2 joint promotes higher fusion[76]. Occipital plates, multiaxial lateral mass, intralaminar, trans articular, and pedicle screws allow various construct options. Laminoplasty or laminectomy is recommended depending on the stability and maturity of the cervical vertebrae. Long-term follow-up is necessary due to the risk of stenosis recurrence and complications[69].

Cervical stenosis: Cervical stenosis is widely recognized in MPS I, II, VI, and VII. There are two pathophysiological factors in spinal stenosis in MPS: (1) Developmental factors; and (2) Acquired factors. Developmental spinal canal stenosis is classified into two types: (1) Hereditary-idiopathic stenosis; and (2) Skeletal growth disorder-related stenosis-like MPS[69]. Acquired factors are related to GAG accumulation in the connective tissues surrounding the epidural space, especially in the subligamentous membrane between the dura and the ligamentum flavum, a hypertrophied ligamentum flavum, degenerated facet joints, and intervertebral discs[77]. Therefore, for complete decompression, these deposits must be removed. Symptoms depend upon the level [craniovertebral junction (CVJ) is the most common level] and the severity of stenosis. C1 hypoplasia with atlantoaxial instability is commonly seen in MPS IV and VI. In most cases, the initial symptom of cord compression is numbness in both hands. Neck extension test, Phalen’s test and Tinel’s sign is necessary for diagnosis, as carpal tunnel syndrome is also common in MPS[72]. MRI is required to establish the diagnosis. Hypertrophic changes in circumferential epidural space caused by GAG accumulation and thickened ligamentum flavum compressing on underlying cord (loss of CSF rim) with intramedullary T2 hyperintensity is suggestive of irreversible cord damage[78]. Patients with cervical stenosis should undergo decompressive surgery before irreversible cord damage occurs. Posterior decompression surgery without instrumented fixation is appropriate for patients without obvious cervical instability. Laminoplasty with hydroxyapatite spacers is preferred over total laminectomy to avoid complications, instability, and post-laminectomy fibrosis. C1 laminectomy is often recommended with C2-C7 laminoplasty, and suboccipital decompression should be considered for occipital-cervical stenosis. In young patients with immature cervical laminae, total laminectomy is the only option, requiring long-term monitoring for recurrence due to instability or fibrosis[69,79]. A study by Kawaguchi et al[80] found that 49.2% of patients who underwent laminoplasty more than 20 years ago experienced worsened outcomes, often requiring additional surgeries.

TLK: TLK is a common feature in MPS I, affecting up to 90% of patients despite hematopoietic stem cell transplantation. It also occurs in MPS II, IV, and VI. Scoliosis may coexist with kyphosis or appear alone in MPS I, II, and III, but surgical intervention for scoliosis is rare unless significant kyphosis is present[60]. The characteristic vertebral shape in MPS, called platyspondyly, results from incomplete endochondral ossification, with terms like coined or beaked vertebrae describing the deformity[81]. TLK leads to sagittal imbalance, requiring compensatory postures to maintain standing balance. There is no consensus on the ideal timing or method of surgery or the effectiveness of bracing for TLK in MPS. Kyphosis exceeding a 40-degree Cobb angle tends to progress, particularly in MPS I, and the impact of enzyme replacement therapy or bone marrow transplantation on spinal deformity remains unclear[82]. Bracing has shown some success in preventing kyphosis progression in MPS I, but further research is needed. Progressive kyphosis with neurological deficits is a clear indication for surgery. Postoperative complications can include death, neurological deficits, pseudarthrosis, infection, junctional deformity, and anesthesia-related issues, with thoracic SAC ischemia possibly leading to paraplegia[60,83].

Lumbar canal stenosis: The incidence of lumbar canal stenosis (LCS) is increasing in MPS cases due to increased life expectancy. Hypertrophy of the ligamentum flavum, degenerative changes in facet joints, and bulging intervertebral discs are key factors in degenerative LCS, with bone deformities contributing to LCS in MPS patients. Symptoms of LCS include intermittent claudication, low-back pain, and bowel/bladder dysfunction. Surgical indications for LCS in MPS patients are similar to those in non-MPS patients, with posterior decompression sufficient if there is no significant spinal instability. Instrumented fusion is indicated only if instability affects symptoms. There are no long-term follow-up data on LCS surgery in MPS patients[69].

Hurler Syndrome (MPS type I)

Infants with Hurler syndrome appear normal at birth. However, short stature and delayed developmental milestones become apparent early. TLK and atlantoaxial instability with thickening of alar ligaments are common. Kyphosis becomes apparent clinically only after the child starts sitting. In the past, surgical management was not indicated as life expectancy was not beyond early childhood. In the present, however, there has been significant improvement in quality of life and survival due to the utilization of enzyme replacement therapy and bone marrow transplantation. In one group of 10 patients followed for a mean of 8.7 years after bone marrow transplantation, all showed a decrease, however, in the amount of odontoid dysplasia[84]. Laboratory studies show excessive dermatan sulfate and heparin sulfate secretion. Yasin et al[85] treated five MPS-I patients with progressive TLK using anterior vascularized rib grafts, correcting the kyphosis angle from 53° to 44°. However, this method has drawbacks such as graft dislodgement and hyperlordosis. Dalvie et al[86] reported on anterior instrumented fusion in seven MPS patients, noting technical challenges and neurological risks. For kyphosis over 60°-70°, combined anterior and posterior fusion is recommended[86].

Hunter syndrome (MPS type II)

Hunter syndrome, an X-linked recessive lysosomal storage disease affecting males, is caused by a defect in iduronate-2-sulfatase, leading to the buildup of GAGs and resulting in neurological issues. Although children with Hunter syndrome appear normal at birth and grow typically for the first two years, abnormalities usually become apparent afterward. While life expectancy can extend into adulthood, cardiopulmonary complications may lead to death in the second decade of life. The syndrome is characterized by non-specific vertebral changes, with some cases of marked lumbar kyphosis requiring surgery. MRI evaluation of the upper cervical spine is crucial due to potential SAC compression from mucopolysaccharide deposition behind the odontoid.

Morquio syndrome (MPS type IV)

Morquio syndrome, a type of MPS, typically presents normal at birth, but by the first year, developmental delays and physical changes like TLK, short stature, genu valgum, pectus carinatum, and corneal clouding become noticeable. The syndrome is marked by anteroinferior vertebral beaking, hip subluxation, and decreased exercise tolerance due to hip instability, knee valgus, or potential SAC compression. Odontoid hypoplasia often leads to atlantoaxial instability, requiring cervical spine evaluation before orthopedic surgery. If instability is detected, posterior cervical fusion is recommended. TLK, present at birth, usually remains stable, with surgery considered if progression occurs, often combining pedicle screw instrumentation with laminectomy or anterior spinal instrumentation for safety.

Maroteaux-lamy syndrome (MPS type VI)

MPS Type VI is a rare autosomal recessive lysosomal storage disease caused by impaired catabolism of dermatan sulfate. Deficiency of the enzyme arylsulfatase B leads to progressive accumulation of partially degraded dermatan sulfate within a variety of tissues with consequent clinical manifestations such as hearing impairment, organomegaly, bone dysplasia, cardiorespiratory and neurological problems. Many of the physical features resemble Hurler syndrome, but intelligence is normal. Neurologic manifestations are often due to bone abnormalities resulting in SAC or nerve root compression, carpal tunnel syndrome, optic nerve compression, jugular foramen stenosis, and communicating hydrocephalus Bulut et al[87] retrospectively evaluated spinal MRI scans and clinical findings in 14 patients of MPS VI. CVJ anomalies (low clivus-canal angle; odontoid dysplasia, FMS, and thickened retrodental tissues ), TLK, platyspondyly and anteroinferior beaking of cervical vertebrae, posterior focal end plate depression in thoracic vertebrae, posterior scalloping and anterior beaking of lumbar vertebrae were the most predominant findings in their study. SAC compression is more commonly found in MPS VI and IV compared to MPS I. CVJ is the most common site of SCC, but can occur at any level. Bony stenosis due to small and thickened posterior elements, thickened retrodental tissue, and odontoid dysplasia are commonly recognized causes of cervical cord compression in MPS VI. Thickening of the retrodental tissue is secondary to hypertrophy of the cruciate and posterior longitudinal ligaments as well as dural accumulation of GAGs, similar to that seen in more common type MPS 1.

Osteogenesis Imperfecta (OI)

OI, known as brittle bone disease, results from mutations in collagen genes (COL1A1 or COL1A2), leading to fragile bones and multiple fractures. Progressive scoliosis is common in severe forms of OI, significantly impacting pulmonary function and quality of life. Recurrent vertebral compression fractures lead to kyphosis and chronic pain. Basilar invagination, the upward displacement of the upper cervical spine into the skull, causes neurological deficits and requires surgical intervention. Management of OI also includes addressing frequent long bone fractures, dentinogenesis imperfecta, and hearing loss, necessitating a comprehensive and multidisciplinary approach.

Cervical myelopathy due to stenosis at the foramen magnum and upper cervical spine can be treated by laminectomy. Early detection and treatment of cord compression are crucial to preclude irreversible neurologic impairment. Lampe et al[74] developed a scoring system using findings of neurological examination, somatosensory-evoked potentials of median nerve and MRI of craniocervical junction to establish objective criteria for decision of cervical decompression surgery in MPS VI. The sum of the scores of each procedure, so-called craniocervical cord compression score, was revealed to be a reliable tool for determining need and correct timing of surgery. Progressive TLK can be treated by posterior instrumentation and fusion. Intraoperative neurophysiological monitoring during posterior instrumentation is recommended to avoid iatrogenic neurological injury as there is a narrow spinal canal.

Multiple epiphyseal dysplasia (MED), caused by mutations in genes such as COMP, COL9A1, and matrilin, especially matrilin-3, affects epiphyseal development, leading to joint and spinal abnormalities[88]. Mild scoliosis and TLK are common, causing discomfort and potential respiratory issues. Early-onset osteoarthritis due to abnormal epiphyseal growth further complicates the clinical picture. Patients with MED may also have short stature, joint pain, and early degenerative changes, necessitating a multidisciplinary approach for optimal management.

Chondroectodermal dysplasia [Ellis-van Creveld (EVC) syndrome] involves skeletal abnormalities, short stature, and polydactyly, caused by mutations in the EVC or EVC2 genes[89]. Spinal manifestations include lumbar lordosis and mild scoliosis, which can lead to mobility issues and discomfort. Additionally, patients often present with congenital heart defects, dental anomalies, and nail dysplasia, requiring comprehensive care from multiple specialties[90].

Spondyloepimetaphyseal dysplasia, Strudwick type encompasses a group of disorders affecting the spine and metaphyses of long bones. Spinal manifestations include kyphoscoliosis, platyspondyly, and spinal stenosis. These conditions lead to significant morbidity due to progressive spinal deformities and neurological impairments. Joint abnormalities and early-onset osteoarthritis further complicate the clinical picture, requiring a comprehensive and multidisciplinary management approach[91-93].

Effective management of spinal manifestations in skeletal dysplasia involves a multidisciplinary approach, including orthopaedic surgeons, neurologists, geneticists, and rehabilitation specialists. Early diagnosis and monitoring through regular imaging (X-rays, MRI, CT scans) and clinical evaluations are crucial to track the progression of spinal deformities and detect complications early. Surgical interventions, such as decompression, spinal fusion, and corrective osteotomies, are indicated for severe deformities or neurological deficits. Non-surgical management, including bracing and physical therapy, helps control the progression of deformities and improve functional outcomes. Genetic counseling is essential for affected families to understand the hereditary nature of these conditions and the risk of recurrence in future pregnancies. Comprehensive care involves coordination among various specialties to address the complex needs of patients, including respiratory care, pain management, and rehabilitation (Table 3).

Table 3 Summary of surgical management of spinal disorders in various skeletal dysplasias.

Skeletal dysplasia (incidence)	Common spinal disorders	Nonsurgical management	Surgical management
Achondroplasia (1:20000-1:30000)	Foramen magnum stenosis neurological complications	Regular monitoring with magnetic resonance imaging and X-rays. Physical therapy for posture and strength. Pain management. Ergonomic modifications	Decompression surgery if severe compression or neurological symptoms occur
Hypochondroplasia (1:15000-1:40000)	Spinal stenosis: Degenerative disc disease	Physical therapy. Pain management. Ergonomic modifications. Regular spinal assessments	Surgical intervention for severe stenosis or radiculopathy. Decompression surgery
Spondyloepiphyseal dysplasia congenita (1:100000)	AAI, OH, scoliosis	Physical therapy. Bracing for scoliosis. Regular monitoring. Pain management. Adaptive mobility devices	Decompression (C1 laminectomy) and OC fusion. Deformity correction
Kniest dysplasia (1:1000000)	AAI, OH, scoliosis	Physical therapy. Bracing for scoliosis. Regular monitoring. Pain management. Adaptive mobility devices	Decompression (C1 laminectomy) and OC fusion. Deformity correction
Diastrophic dysplasia (1:500000)	Cervical kyphosis, kyphoscoliosis	Early orthotic management. Regular monitoring for curve progression. Physical therapy. Pain management	Anterior/posterior correction for severe curves or progressive deformities. Spinal fusion if necessary
Mucopolysaccharidoses (all forms: 1:25000, I: 1:100000, IV: 1:200000-1:300000)	Craniovertebral junction stenosis, Thoracolumbar kyphosis, scoliosis	Regular monitoring and physical therapy. Management of symptoms and pain. Occupational therapy. Supportive care	Deformity correction. Decompression if necessary
Osteogenesis imperfecta (all forms: 1:10000-1:20000)	Spinal deformities (kyphosis, scoliosis)	Regular spinal evaluations. Bracing and physical therapy. Bisphosphonates for bone strength. Pain management	Surgery for severe curves or spinal instability. Spinal fusion in progressive cases

AAI: Atlantoaxial instability; OC: Occipitocervical; OH: Odontoid hypoplasia.

CONCLUSION

Spinal manifestations in skeletal dysplasia demand a multidisciplinary approach encompassing early diagnosis, close monitoring, and individualized treatment strategies. While conservative measures provide symptom relief in some cases, surgical intervention is often warranted for progressive deformities and neurological compromise. Future research should focus on refining surgical techniques, improving long-term outcomes, and exploring novel therapeutic approaches, including gene therapy and targeted molecular treatments. By addressing these challenges, clinicians can enhance the quality of life and functional outcomes for patients with skeletal dysplasia.