3.1 Demographics

Overall, 116 of 477 (24.3%) patients had some craniocervical junction concerns at some point in their life. Of these 116 individuals, 39 (33.6% of those with concern, 8.2% of total population) were decompressed before 1 year of age and removed from further analysis here. The remaining 77 individuals (66.4% of those with concern, 16.1% of total population) were not decompressed before 1 year of age, yet had abnormal manifestations of the craniocervical junction beyond 1 year of age (Figure 1).

There was no predilection by sex. Of these 77 individuals, 38 (49.4%) were female and 39 (50.7%) male.

Initial presentation was at a median age of 1.3 years (males: 1.2 years, females: 2.0 years), and mean age of was 4.9 years +/− 9.5 years (males only: 2.7 years +/−3.4 years, females only: 7.2 years +/− 12.8 years). There were several adult female outliers, with initial presentation of craniocervical junction concerns at 70, 29, 28, and 18 years of age.

3.2 Classification of groups

Individuals were grouped based on their age of initial presentation and need for decompression (Figure 1). As shown in Figure 1, Group 1 includes seven individuals whose initial concerns arose prior to 1 year of age but in whom decompressive surgery did not occur until after 1 year of age. A total of 16 individuals are included in Group 2, where concern initially arose prior to 1 year of age, but which concerns became more serious after 1 year of age. Within Group 2, nine patients were decompressed. Group 3 is composed of 36 individuals in whom the initial concerns related to the craniocervical junction arose between one and 5 years of age. Of those in Group 3, 19 were decompressed. Lastly, 18 individuals were placed in Group 4—their initial concerns did not arise until after 5 years of age. Of the 18 individuals in Group 4, eight were decompressed.

3.3 Suboccipital decompression

Within our entire cohort of 477 individuals, our analysis includes 82 individuals (17.1%) who required suboccipital decompression surgery.¹ More than half of all such surgeries were completed after age 1 year (n = 43; 9.0% of entire population, 52.4% of subpopulation) (Figure 1). The most common listed indications for suboccipital decompression after 1 year of age were neuroimaging findings (demonstrated in 41/43, 95.3%) (e.g., foramen magnum stenosis, n = 24; presence of T2 signal abnormality, n = 14; cord indentation, n = 12; obliteration of subarachnoid fluid layer, n = 10; and syrinx, n = 6). Subjects may have presented with multiple types of MRI findings and therefore the number of events exceeds the number of subjects. Other common listed indications for suboccipital decompression included failure of progress in gross motor development (n = 20, 46.6%), and persistent and severe hypotonia (n = 18, 41.9%) (Table 1). Note that of the 43 individuals who had late decompression, 35 had both clinical and imaging indications listed, while in only seven was decompression apparently carried out solely on the basis of imaging features (syrinx development, new T2 signal abnormality). Of the 43 individuals who were decompressed after 1 year of age, four (9.3%) had additional or recurrent symptoms requiring a second decompression surgery.

Of the patients decompressed after 1 year of age, the average duration of time between initial recognition of concern and completion of decompression surgery was 0.65 years ± 0.87 years (median = 0.53 years). Thirty-five of 43 (81.4%) were completed within 1 year of initial identification of craniocervical junction concerns. Group 1 included seven individuals whose initial concerns arose prior to 1 year of age, but who were not decompressed until after 1 year of age. Of these seven individuals, four (57%) had undergone decompression surgery by 13 months, and six (86%) were decompressed by 18 months of age. The average duration between age of initial recognition and completion of decompression surgery within Group 1 was 0.80 years ± 0.42 years.

The distribution of ages at which decompressive surgery occurred is shown in Figure 2.

3.4 Outcomes

The outcomes of all subjects with craniocervical junction concerns after infancy are summarized in Table 2. Overall, 57/77 (74.0%) had an apparently normal outcome, without evidence for any neurological sequelae. Of the 20 patients (26.0%) with an abnormal outcome, the most common abnormalities included persisting hypotonia (n = 11, 14%), persisting motor delays (n = 11, 14%), asymmetric strength (n = 7, 9%), and limited walking (n = 6, 8%). (See also Supporting Information, Tables 1 and 2).

Group 2 included 16 individuals whose initial concern arose prior to 1 year of age, but more serious concerns arose at a later time. Of these 16, only nine (56%) were subsequently neurologically normal. Persisting problems were evident both in those decompressed (4/9, 44%) and in those judged not to require decompression (3/7, 43%).

Individuals within Groups 1 and 2 were the least likely to have a completely normal outcome (71 and 56%, respectively). That is, those with earlier onset of concerns were more likely to have persisting sequelae despite intervention.

Groups 3 and 4 represent 54 individuals who had no evidence for craniocervical junction concerns during infancy but who developed such concerns for the first time later in life. Subjects in Groups 3 and 4 appear to be more likely to be neurologically intact in the long term.

Of 43 individuals who underwent “late” decompression, 30 (69.8%) had a completely normal neurologic outcome. The most common residual abnormalities within the 13 decompressed individuals without a normal outcome included persistent hypotonia (n = 9), persistent motor delays (n = 9), asymmetric strength (n = 6), and limited walking (n = 4).

What follows are two examples of late presentations of craniocervical junction concerns in achondroplasia.

3.5 Case studies

4.1 Craniocervical junction issues in achondroplasia

The most worrisome issue related to the craniocervical junction is the risk for sudden unexpected death early in life (Pauli et al., 1984; Pauli et al., 1995; Reid et al., 1987). However, in addition, individuals with achondroplasia have risk to develop high cervical myelopathy (Yang et al., 1979), which can develop at any age (Mukherjee, Pressman, Krakow, Rimoin, & Danielpour, 2014). Both arise because of compression of the upper cervical spine, adjacent vasculature, and/or brainstem secondary to anatomic differences of the foramen magnum and suboccipital region in achondroplasia (Hecht et al., 1987; Yang et al., 1979). Clinical signs of high cervical myelopathy in children may include persisting hypotonia, asymmetric strength, or reflexes in the arms or legs, ankle clonus, and up going response to Babinski stimulation. Evidence for myelopathy after infancy may include features such as decreased endurance, sudden or transient pain in the arms or legs, decreased fine motor function, or changes in bowel or bladder continence. Additionally, individuals may present with acute myelopathy due to trauma (Pauli, 2019). Individuals presenting with unequivocal chronic or acute evidence for high cervical myelopathy need to undergo cervicomedullary decompression surgery.

4.2 Outcomes of individuals with craniocervical junction concerns after 1 year of age

The majority of individuals (55/77, 71.4%) with craniocervical junction concerns after infancy will have a normal outcome. In fact, of the 54 individuals whose initial concerns did not arise until after 1 year of age (Groups 3 and 4), 43 (79.6%) had what was judged to be a completely normal neurologic outcome, whether decompression surgery was necessary or not. Therefore, while craniocervical issues frequently arise after 1 year of age, with appropriate intervention, a good outcome should be anticipated. These findings are similar to those of Bagley et al., (2006), who described no future recurrent signs/symptoms of cervical myelopathy in 38 of 43 (88.4%) individuals with achondroplasia who underwent decompression surgery.

There were 16 individuals in whom early but worsening symptoms suggest that decompression earlier in life was warranted but was delayed (Group 2). Only nine (56%) of these individuals were subsequently neurologically normal. Such delays are associated with a negative outcome and are particularly concerning.

4.3 Etiologies of craniocervical junction concerns after infancy

Craniocervical junction issues after infancy may arise acutely or chronically. As noted, some may be attributed to delayed management (e.g., Case 1). Others are caused by acute trauma, as described in Case 2. Others may, perhaps, arise from unrecognized, recurrent minor injury at the craniocervical junction. Slower growth of the foramen magnum may also be relevant (Matsushita et al., 2009).

4.4 Limitations

The data described here were retrospective and were all derived from chart review and entry into a REDCap database. No additional clinical evaluations specific to this study were carried out. While there is complete ascertainment of the clinic population, of course biases may be present based on individuals having been assessed through a specialty clinic such as the Midwest Regional Bone Dysplasia Clinic.

Certain of our exclusion criteria may have eliminated a few individuals inappropriately. As noted, patients whose only concern was an isolated abnormal neurologic sign were excluded because such “neurologic leftovers” appear to be common and usually benign findings in achondroplasia (Smid et al., 2020). Polysomnographic results were not considered at all, because our experience suggests that abnormalities of central respiratory control secondary to craniocervical compression probably are confined to the first year of life.

4.5 Recommendations

All individuals with achondroplasia should undergo a neurologic assessment including: neurologic history and neurologic examination, imaging of the craniocervical junction (by computerized tomography or MRI), and polysomnography in early infancy (Mukherjee et al., 2014; Pauli, 2019; Pauli & Legare, 1998; Sanders et al., 2019). After infancy, individuals should be routinely monitored to ensure that no new craniocervical junction concerns arise. If an individual develops new clinical signs and symptoms suggestive of high cervical myelopathy, magnetic resonance imaging should be pursued. Additionally, if an individual experiences trauma to the head or neck, emergent assessment to ensure no acute damage at the craniocervical junction has occurred is essential.