Klippel Feil Syndrome: Clinical Phenotypes Associated With Surgical Treatment

Laureen D. Hachem, MD; Francois Mathieu, MD; Maria Lamberti-Pasculli, RN; Brian W. Hanak, MD; Reinhard Zeller, MD; Abhaya V. Kulkarni, MD, PhD; James Drake, MD, MS; George M. Ibrahim, MD, PhD

Disclosures

Spine. 2020;45(11):718-726.

Abstract and Introduction

Abstract

Study Design: Retrospective study.

Objective: To define distinct Klippel-Feil syndrome (KFS) patient phenotypes that are associated with the need for surgical intervention.

Summary of Background Data: KFS is characterized by the congenital fusion of cervical vertebrae; however, patients often present with a variety of other spinal and extraspinal anomalies suggesting this syndrome encompasses a heterogeneous patient population. Moreover, it remains unclear how the abnormalities seen in KFS correlate to neurological outcomes and the need for surgical intervention.

Methods: Principal component (PC) analysis was performed on 132 KFS patients treated at a large pediatric hospital between 1981 and 2018. Thirty-five variables pertaining to patient/disease-related factors were examined. Significant PCs were included as independent variables in multivariable logistic regression models designed to test associations with three primary outcomes: cervical spine surgery, thoracolumbar/sacral spine surgery, and cranial surgery.

Results: Fourteen significant PCs accounting for 70% of the variance were identified. Five components, representing four distinct phenotypes, were significantly associated with surgical intervention. The first group consisted of predominantly subaxial cervical spine fusions, thoracic spine abnormalities and was associated with thoracolumbar/sacral spine surgery. The second group was largely represented by axial cervical spine anomalies and had high association with cervical subluxation and cervical spine surgery. A third group, heavily represented by Chiari malformation, was associated with cranial surgery. Lastly, a fourth group was defined by thoracic vertebral anomalies and associations with sacral agenesis and scoliosis. This phenotype was associated with thoracolumbar/sacral spine surgery.

Conclusion: This is the first data-driven analysis designed to relate KFS patient phenotypes to surgical intervention and provides important insight that may inform targeted follow-up regimens and surgical decision-making.

Level of Evidence: 3

Introduction

Klippel-Feil syndrome (KFS) is a rare condition characterized by the congenital fusion of 2 or more cervical vertebrae. The incidence of KFS is estimated to be one in 40,000 with a prevalence close to 0.7%.^[1,2] The clinical triad of a short neck, low posterior hairline, and limited neck range of motion first described by Klippel and Feil in 1912^[3] was originally thought to be the hallmark presentation of this condition. However, this triad is present in <50% of KFS patients. Moreover, numerous other spinal and extraspinal anomalies have been reported in patients with KFS suggesting that this syndrome likely encompasses a heterogeneous patient population.^[4,5]

Various classification systems have been proposed for KFS, many of which are based on patterns of fusion anomalies within the cervical spine.^[3,6,7] However, these classifications have failed to incorporate the range of other abnormalities present in patients with KFS and have yet to show strong associations with clinical outcomes. Vertebral segmentation anomalies or formation defects, depending on location, may predispose to hypermobility and eventual instability. Moreover, specific patterns of anomalies may precipitate aberrant alignment and deformities necessitating surgery. To date, it remains unclear how the abnormalities seen in KFS correlate to neurological outcomes and the need for surgical intervention. It is likely that the natural history of KFS is dictated not only by the nature of vertebral fusions, but also the many other spinal and extra-spinal abnormalities. Determining specific patient phenotypes that may be associated with a higher risk of requiring a surgical intervention is essential in better understanding the natural history of KFS and guiding treatment paradigms.

To better characterize the heterogeneity across KFS patients, we studied patients treated over nearly four decades at our institution. We hypothesized that patients could be subdivided into distinct phenotypes based on patient and disease-related variables and that these phenotypes may have unique associations with the need for surgical intervention. Using principal component analysis (PCA), we identified four distinct phenotypes which were significantly associated with spinal or cranial surgery. This is the first data-driven algorithm designed to relate patient phenotypes to surgery intervention in KFS patients.

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Table 1. Patient Variables
Variables	Total
Demographics
Age, median (IQR)	4.8 (6)
Sex, male (%)	58 (44)
Initial symptoms, n (%)
Asymptomatic	48 (36)
Neck pain	7 (5)
Neurological deficits	8 (6)
Torticollis	30 (23)
Syndromic/Deformity	52 (39)
Defects of vertebral segmentation, n (%)
No. Fused Cervical Vertebrae, mean (SD)	2.7 (2)
O-C1	25 (19)
C1-C2	21 (16)
C2-C3	87 (66)
C3-C4	52 (39)
C4-C5	52 (39)
C5-C6	63 (48)
C6-C7	41 (31)
C7-T1	19 (14)
Contiguous cervical fusions	79 (60)
Defects of vertebral formation, n (%)
Axial cervical spine	45 (34)
Subaxial cervical spine	28 (21)
Defects of Thoracic Vertebrae*, n (%)	46 (35)
Alignment abnormalities, n (%)
Subluxation (CCJ and axial cervical spine)	33 (25)
Subluxation (subaxial cervical spine)	20 (15)
Scoliosis	77 (58)
Other neurological abnormalities, n (%)
Sacral agenesis	7 (5)
Syrinx	18 (14)
Chiari malformation	11 (8)
Encephalocele	4 (3)
Hydrocephalus	7 (5)
Other^†	14 (11)
Non-neurological abnormalities, n (%)
Cardiopulmonary	32 (24)
ENT	29 (22)
GI/GU	27 (20)
Musculoskeletal (extremity)	14 (11)
Ribs	46 (35)
Sprengel deformity	31 (23)

CCJ indicates craniocervical junction; ENT, ear nose throat; GI, gastrointestinal; GU, genitourinary; IQR, interquartile range; PC, principal component; SD, standard deviation.
*Includes segmentation and formation abnormalities.
^†Includes epilepsy, developmental delay, cerebral palsy, arachnoid cyst, cortical dysplasia.

Table 2. Summary of Spinal/Cranial Surgeries
Surgical Procedure	Frequency
Cervical spine*
Decompression/fusion	13
Insertion syringopleural shunt	1
Repair cervical meningocele	1
Thoracic, lumbar, sacral spine
Decompression/fusion	11
Cord de-tethering	5
Cranial
Posterior fossa decompression	5
CSF diversion	8
Encephalocele repair	3
Cranial vault repair	1

*Includes surgery at the cervicothoracic junction. CSF indicates cerebrospinal fluid.

Table 3. Variable Contributions to PCs Associated With Outcomes
Variables*	PC1 (11.5)	PC2 (6.5)	PC3 (6.1)	PC4 (6.0)	PC9 (4.1)
Demographics
Age	3.03	3.87	4.8	1.01	0.03
Sex	0.37	2.59	0.07	0.55	3.38
Initial symptoms
Asymptomatic	2.18	2.23	12.35	2.06	0.06
Neck pain	0	0.09	0.15	0.08	0.05
Neurological deficits	0.4	0	3.07	2.11	5.01
Torticollis	0.22	0.42	6.67	0.04	4.18
Syndromic/Deformity	3.2	3.38	2.22	1.51	0.61
Defects of vertebral segmentation
No. fused cervical vertebrae	20.02	0.26	0.06	0.27	0.31
O-C1	0.49	5.84	4.83	0.42	1.48
C1-C2	0.3	9.62	2.53	1.63	1.59
C2-C3	0.52	0	14.69	0	1.14
C3-C4	5.89	0.02	3.29	1.56	0.1
C4-C5	6.54	0.05	5.06	1.08	4.43
C5-C6	9.26	0.77	4.42	1.37	3.14
C6-C7	8.42	1.71	0.27	0.72	0.75
C7-T1	2.22	1.79	0.94	0.4	0.83
Contiguous cervical fusions	13.76	0.71	0.18	0.88	3.44
Defects of vertebral formation
Axial cervical spine	1.2	0.32	5.42	0.28	5.69
Subaxial cervical spine	2.85	0.75	0.94	0.56	1.6
Defects of thoracic vertebrae^†	5.09	0.06	0.32	0.05	13.14
Alignment abnormalities
Subluxation (CCJ and axial cervical spine)	0.04	0.68	1.99	0	0.99
Subluxation (subaxial cervical spine)	1.32	0.17	10.66	0.58	0.27
Scoliosis	2.71	0.61	1.57	0.1	28.11
Other neurological abnormalities
Sacral agenesis	0.38	0	0.1	0.44	9.11
Syrinx	0.01	12.25	0.17	13.21	0.15
Chiari malformation	0.3	12.09	0.04	12.58	3.08
Encephalocele	0.07	2.83	0.43	1.29	3.86
Hydrocephalus	0.27	7.68	0.33	15.25	0.54
Other^‡	0.54	8.47	0.96	0.42	0.81
Non-neurological abnormalities
Cardiopulmonary	0.38	5	0.05	13.41	1.18
ENT	0.19	5	0.54	9.09	0.86
GI/GU	0.08	3.56	9.06	8.35	0.03
Musculoskeletal (extremity)	0.42	2.85	1.81	2.98	0.01
Ribs	6.31	4.32	0.02	2.89	0
Sprengel deformity	1.05	0.02	0	2.86	0.02

CCJ indicates craniocervical junction; ENT, ear nose throat; PC, principal component; GI, gastrointestinal; GU, genitourinary.
*The top six variables contributing to each principal component are bolded.
^†Includes segmentation and formation abnormalities.
^‡Includes epilepsy, developmental delay, cerebral palsy, arachnoid cyst, cortical dysplasia.

Table 4. Patient Phenotypes Associated With Surgery
PC	Phenotype	Associated Outcome	OR (95% CI, P)
PC1	Number of cervical fused vertebrae Contiguous cervical fused vertebrae Subaxial fusions (C3, C4, C5, C6, C7)	Thoracolumbar/sacral spine surgery	1.6 (1.1–2.5; 0.04)
PC2	Chiari, hydrocephalus, syrinx Neurological abnormalities O-C1, C1/C2 fusions	Cranial surgery	3.5 (1.3–9.1; 0.01)
PC3	Cervical subluxation C2/3 fusion Initial symptoms torticollis or asymptomatic Axial cervical spine formation abnormalities	Cervical spine surgery	1.8 (1.2–2.8; 0.01)
PC4	Chiari, hydrocephalus, syrinx Non-neurological abnormalities (cardiopulm., ENT, GI/GU, musculoskeletal)	Cranial surgery	4.7 (1.7–12.8; 0.003)
PC9	Scoliosis Defects in thoracic vertebrae and axial cervical spine Sacral agenesis Initial neurological symptoms	Thoracolumbar/sacral spine surgery	4.2 (2.0–11.7; 0.001)

CI indicates confidence interval; ENT, ear nose throat; GI, gastrointestinal; GU, genitourinary; OR, odds ratio; PC, principal component.

Table 5. Proposed Classification of KFS Patient Phenotypes
Type	Description	Clinical Implications
Type I Cervical–subaxial	Multiple segmentation anomalies within the subaxial cervical spine. May have vertebral anomalies in the thoracic spine.	Pattern of cervical fusions less likely to predispose to instability or subluxation at the level of fusion
Type II Cervical–axial	Axial cervical spine anomalies (commonly C2/3 fusion, axial cervical spine formation defects)	Pattern of anomalies may predispose to cervical spine subluxation
Type III Chiari	Chiari malformation ± hydrocephalus/syrinx Axial cervical spine fusions more common than subaxial fusions	May be associated with non-neurological anomalies (cardiopulmonary, GI/GU, ENT)
Type IV Thoracolumbar/sacral	Vertebral anomalies within the thoracic spine. May have axial cervical spine formation abnormalities. May be associated with sacral agenesis	Pattern of anomalies may predispose to scoliosis

ENT indicates ear nose throat; GI, gastrointestinal; GU, genitourinary.

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Klippel Feil Syndrome: Clinical Phenotypes Associated With Surgical Treatment

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