退行性颈椎不稳的手术治疗

目的 应用手术治疗退行性颈椎不稳．观察其疗效，并探讨手术适应证。方法 自1998年4月～2001年4月，对15例影像学上有颈椎不稳、伴体位性症状、经1年以上严格保守治疗无效的非脊髓型颈椎病患者施行手术治疗，男6例，女9例；年龄44～65岁．平均55．2岁。病程1．5～4年．平均28个月，体位性症状主要包括：随颈椎屈伸或旋转出现的神经根型、交感型以及椎动脉型颈椎病样症状，所有病例均采取前路颈椎不稳节段融合加铁板内固定术。自体髂骨植骨7例,其中单节段3例；双节段4例,双节段者行开槽植骨。应用椎间融合器(钛网)8例．其中单节段2例，植骨取自异体骨；双节段6例，行开槽植骨．植骨取自椎体切除部分，结果 随访时间8个月～4年，平均25个月。15例患者症状均获明显改善．12例症状完全消失，3例偶有颈背部酸胀感。融合节段均获得骨性愈合。结论 影像学上出现退行性颈椎不稳同时伴有颈椎体位性症状，且两者可相互解释者．通过行不稳节段的融合术可获得良好的治疗效果，退行性颈椎不稳有良性转归的可能，因此应严格掌握手术适应证。     

Total stabilization of the cervical spine in patients with cervical spondylotic myelopathy

Certain patients with cervical spondylotic myelopathy demonstrate instability in the upper cervical vertebral column associated with marked narrowing of the vertebral canal in the neighboring lower cervical segments. This combination of causative mechanisms creates difficulty in using routine surgical procedures, especially in elderly and severely debilitated patients. We present three cases that typify this situation and illustrate marked resolution of debilitating myelopathy through total posterior fusion of the cervical spine usually incorporating the occiput.     

Pathophysiology and treatment for cervical flexion myelopathy

Previous studies have suggested that spinal cord compression by the vertebral bodies and intervertebral discs during neck flexion cause cervical flexion myelopathy (CFM). However, the exact pathophysiology of CFM is still unknown, and surgical treatment for CFM remains controversial. We examined retrospectively patients with CFM based on studies of the clinical features, neuroradiological findings, and neurophysiological assessments. The objectives of this paper are to investigate the pathophysiology of CFM, and to examine an optimal surgical treatment. Twenty-three patients (20 male, three female) with age of onset ranging from 11 to 23 years (mean 15.7 years) were examined for the study. All patients were inspected by magnetic resonance imaging (MRI), myelogram, or computed tomographic myelogram (CTM) of the cervical spine. In eight patients, dynamic motor evoked potentials (MEP) studies were performed. Five patients underwent surgical treatment; two patients had cervical duraplasty with laminoplasty, two patients had musculotendinous transfer, one patient had both of these procedures, and the remaining 18 patients were treated conservatively. Amyotrophy of the hand intrinsic and flexor muscle group of the forearm except the brachioradial muscle was observed hemilaterally in 20 patients and bilaterally in three patients. In three patients, T1-weighted MRI with neck flexion showed linear high intensity regions in the epidural space. In all patients, axial MRI/CTM demonstrated flattening of the spinal cord with the posterior surface of the dura mater shifting anteriorly. The amplitude of MEPs decreased after cervical flexion in two patients with progressive muscular atrophy. In three patients, dysesthesia of the upper extremities disappeared following cervical duraplasty. Musculotendinous transfer for three patients significantly improved the performance of their upper extremity. The findings of this study suggest that degenerative changes of the dura mater may be a characteristic pathology of CFM. Cervical duraplasty with laminoplasty is effective for cases at an early stage, and musculotendinous transfer should be selected in patients at a late stage.     

Long-term results of tension-band laminoplasty for cervical stenotic myelopathy: a ten-year follow-up

We reviewed 75 patients (57 men and 18 women), who had undergone tension-band laminoplasty for cervical spondylotic myelopathy (42 patients) or compression myelopathy due to ossification of the posterior longitudinal ligament (33 patients) and had been followed for more than ten years. Clinical and functional results were estimated using the Japanese Orthopaedic Association score. The rate of recovery and the level of postoperative axial neck pain were also recorded. The pre- and post-operative alignment of the cervical spine (Ishihara curve index indicating lordosis of the cervical spine) and the range of movement (ROM) of the cervical spine were also measured. The mean rate of recovery of the Japanese Orthopaedic Association score at final follow-up was 52.1% (SD 24.6) and significant axial pain was reported by 19 patients (25.3%). Axial pain was reported more frequently in patients with ossification of the posterior longitudinal ligament than in those with cervical spondylotic myelopathy (p = 0.027). A kyphotic deformity was not seen post-operatively in any patient. The mean ROM decreased post-operatively from 32.8° (SD 12.3) to 16.2° (SD 12.3) (p < 0.001). The mean ROM ratio was 46.9% (SD 28.1) for all the patients. The mean ROM ratio was lower in patients with ossification of the posterior longitudinal ligament than in those with cervical spondylotic myelopathy (p < 0.001). Compared to those with cervical spondylotic myelopathy, patients with ossification of the posterior longitudinal ligament had less ROM and more post-operative axial neck pain.     

Surgical treatment of subaxial cervical myelopathy in rheumatoid arthritis.

Between 1978 and 1988 a total of 27 operations were performed on 26 patients for cervical myelopathy due to rheumatoid disease in the subaxial spine. Three different causes were recognised: the first group had cord compression due to subluxation of the cervical spine itself (6 patients); the second had cord compression occurring from in front, with rheumatoid lesions of vertebral bodies or discs (6); the third had compression from behind the cord due to granulation tissue within the epidural space (14). Group I was treated by closed reduction of the subluxation followed by surgical fusion either from in front or behind. Group II was decompressed by subtotal resection of the involved vertebral bodies and discs, followed by interbody fusion. The patients in group III were decompressed by laminectomy and excision of fibrous granulation tissue from the epidural space. Good recovery of neurological function was observed after 18 of the operations, fair recovery after five, poor recovery followed three, and one was worse. Myelopathy recurred in four patients, all of whom had had anterior interbody fusion.     

颈椎手术中并发椎动脉损伤的诊断与治疗

 目的 探讨颈椎手术中并发椎动脉损伤的发生原因、治疗及预防。方法 回顾性分析2002年10月至2012年4月颈椎手术中并发椎动脉损伤的7例患者资料,男6例,女1例;年龄23～65岁,平均48.9岁;脊髓型颈椎病5例,颈椎外伤合并C^4,5半脱位1例,氟骨症致颈椎管狭窄1例。椎动脉损伤均为单侧,左侧4例,右侧3例。分析颈椎手术中并发椎动脉损伤的原因、处理过程及预后。结果颈椎前路手术4例,其中2例用环钻减压时偏离中线损伤椎动脉,1例切除椎间盘时刮匙过于偏外损伤椎动脉,1例颈椎外伤患者由于Ｃ^4,5半脱位造成椎动脉迂曲,减压时冲击式咬骨钳损伤椎动脉。颈椎后路手术3例,其中2例为行C4侧块螺钉固定时钻头偏外损伤椎动脉;1例氟骨症致颈椎管狭窄者在切除寰椎后弓时咬骨钳损伤椎动脉,术中出现椎动脉损伤后,迅速填塞压迫止血并关闭伤口,但术后4周发生迟发性出血,采用椎动脉栓塞止血及颈后路血肿清除术治疗。7例患者均未发生脑梗塞,其中2例患者术后出现一过性头晕。结论 椎动脉损伤是颈椎手术的严重并发症,其损伤原因与手术失误、解剖变异等有关;采用直接压迫及椎动脉栓塞治疗效果确切。     

Complications of transpedicular screw fixation in the cervical spine

Today, posterior stabilization of the cervical spine is most frequently performed by lateral mass screws or spinous process wiring. These techniques do not always provide sufficient stability, and anterior fusion procedures are added secondarily. Recently, transpedicular screw fixation of the cervical spine has been introduced to provide a one-stage stable posterior fixation. The aim of the present prospective study is to examine if cervical pedicle screw fixation can be done by low risk and to identify potential risk factors associated with this technique. All patients stabilized by cervical transpedicular screw fixation between 1999 and 2002 were included. Cervical disorders included multisegmental degenerative instability with cervical myelopathy in 16 patients, segmental instability caused by rheumatoid arthritis in three, trauma in five and instability caused by infection in two patients. In most cases additional decompression of the spinal cord and bone graft placement were performed. Pre-operative and post-operative CT-scans (2-mm cuts) and plain X-rays served to determine changes in alignment and the position of the screws. Clinical outcome was assessed in all cases. Ninety-four cervical pedicle screws were implanted in 26 patients, most frequently at the C3 (26 screws) and C4 levels (19 screws). Radiologically 66 screws (70%) were placed correctly (maximal breach 1 mm) whereas 20 screws (21%) were misplaced with reduction of mechanical strength, slight narrowing of the vertebral artery canal (<25%) or the lateral recess without compression of neural structures. However, these misplacements were asymptomatic in all cases. Another eight screws (9%) had a critical breach. Four of them showed a narrowing of the vertebral artery canal of more then 25%, in all cases without vascular problems. Three screws passed through the intervertebral foramen, causing temporary paresis in one case and a new sensory loss in another. In the latter patient revision surgery was performed. The screw was loosened and had to be corrected. The only statistically significant risk factor was the level of surgery: all critical breaches were seen from C3 to C5. Percutaneous application of the screws reduced the risk for misplacement, although this finding was not statistically significant. There was also a remarkable learning curve. Instrumentation with cervical transpedicular screws results in very stable fixation. However, with the use of new techniques like percutaneous screw application or computerized image guidance there remains a risk for damaging nerve roots or the vertebral artery. This technique should be reserved for highly selected patients with clear indications and to highly experienced spine surgeons.     

DISCOVER人工颈椎间盘置换在颈椎病治疗中的初期疗效观察

目的 探讨应用DISCOVER人工颈椎间盘置换治疗颈椎病的短期临床疗效.方法 采用DISCOVER人工颈椎间盘置换术治疗颈椎病患者12例,其中脊髓型8例,神经根型4例.统计并分析患者术前和术后1、6个月及末次随访时颈椎运动范围、置换节段活动度、相邻节段活动度进行影像学评估,术前及末次随访时NDI脊髓功能评分及颈部疼痛及...     

Anthropometrical analysis of cervical spine injuries

To date the principal focus of the mechanism of cervical spine fracture has been directed towards head/neck circumference and vertebral geometric dimensions. However the role of other measurements, including chest circumference and neck length, in a standard cervical fracture population has not yet been studied in detail. Cervical fractures often involve flexion/extension type mechanisms of injury, with the head and cervical spine flexing/extending, using the thorax as an end point of contact. Thus, the thorax may play an important role in neck injuries. STUDY DESIGN: We prospectively studied all patients with cervical spine fractures who were admitted to the National Spinal Injuries Unit from 1 July 2000 to 1 March 2001. Anthropometrical measurement of head circumference, neck circumference, chest circumference, and neck length were analysed. Ages ranged from 18 to 55 years, and all patients with concomitant cervical pathology were excluded from the study. Mechanism of injury involved flexion/extension type injuries in all cases; those with direct axial loading were excluded. A control group of 40 patients (age 18-50 years) involved in high velocity trauma with associated long bone fractures, in whom cervical injury was suspected, but who were without any cervical fracture, or associated pathology, were similarly measured. RESULTS: Our analysis revealed a statistically significant increase in chest size in the male control group versus the male fracture group (97.89 cm versus 94.19 cm, P < 0.05, Student's t-test). There was a correspondingly significant increase in chest circumference between the female controls versus the female fracture group (92.33 cm versus 88.88 cm, P < 0.05, Student's t-test). Our results revealed no statistical difference in head circumference, neck circumference, or neck length between each of the groupings. These results indicate a proportionately larger chest may be a protective factor in cervical spine fractures.     

Radiologic diagnosis of cervical spine injuries]

This investigation was designed to evaluate the radiological methods used for diagnosis of cervical spine injuries. In the time from 1977 to 1990, a total of 102 patients with 113 fractures or fracture-dislocations of several segments of the cervical spine were diagnosed and treated in the University Surgical Clinic in Graz; 36 of these patients had lesions of the upper cervical spine and 66, lesions of the lower cervical spine. All trauma patients with disturbances of consciousness or neck discomfort reported on questioning or elicited by palpation underwent three-view radiographic screening for cervical spine injuries (lateral, AP and open-mouth views). This led us to suspect cervical spine injuries in all 102 patients. Computerized tomography was performed in 76 cases, which yielded additional information in 55 cases about the middle and posterior column and the adjacent vertebral bodies. In 13 cases conventional tomograms were important to confirm the diagnosis of dens fracture. Except for the diagnosis of hanged-man and dens fractures, computerized tomography is accepted as the second step for the evaluation of cervical spine injuries. We performed 8 investigations with magnetic resonance imaging in 7 patients, and noted spinal cord lesions of low signal intensity in 3 of these cases.     

Spontaneous kyphotic collapse followed by autostabilisation secondary to cervical osteomyelitis in an intravenous drug abuser

There is a high risk of cervical osteomyelitis in intravenous drug abusers due to the use of jugular veins for administration of drugs. Here described is a case of rapid vertebral body destruction at two levels leading to a progressive kyphotic deformity followed by autofusion, secondary to cervical osteomyelitis. The case report goes on to hypothesise about the unique manner of progression of untreated cervical osteomyelitis with a rapid onset of kyphotic deformity and associated severe bone destruction in an intravenous drug abuser. Due to the high incidence of osteomyelitis in intravenous drug abusers, there should be a low threshold to investigate for this condition and early magnetic resonance imaging is vital. It alerts the treating spine surgeon to the fact that early immobilisation is crucial in these cases to prevent a severe impending deformity that can be surgically challenging.     

Clinical long-term results of anterior discectomy without interbody fusion for cervical disc disease

There were 55 patients (soft disc, 21 and spondylosis, 34) who underwent anterior cervical discectomy without fusion (ACD) using an operating microscope. Discectomy of a single level was performed on 48 cases and two levels on 7. There were 37 patients with radiculopathy, and 18 patients with myelopathy or myeloradiculopathy who were followed clinically for 2-13 years postoperatively. Overall 81% of patients were improved in soft disc herniation, and no significant differences were noted between the group of radiculopathy and myelopathy. In spondylosis all but one patient reported initial relief of their preoperative symptoms; however, overall improvement was noted in only 16 patients (47%). The causes of symptomatic deterioration after ACD for spondylosis were later symptomatic recurrence in 5 patients, severe neck pain in 4, and development of new symptoms due to adjacent spur formation in 2. The authors eventually added interbody fusion in 4 cases. Cervical spine roentgenograms almost always showed a loss of height of the interspace and an anterior angulation immediately after ACD, but the alignment of the spine tended to improve with time, so that, at last follow-up, 82% had a good alignment. A spontaneous osseous fusion occurred in 74% of cases. An adjacent spur formation was observed in 3 patients with spondylosis. The most troublesome complication was neck and/or scapular pain. This pain usually subsided spontaneously, but this continued for more than 4 years postoperatively in 4 patients with spondylosis. Using an operating microscope ACD is a safe and effective procedure for patients with soft disc herniation, but the authors still prefer anterior cervical discectomy with interbody fusion for the patients with advanced spondylosis.     

颈椎病发病机制的研究

目的 研究颈椎病的发病机制。方法 通过比较脊髓型颈椎病患者的临床表现、影像学资料和颈前路手术切除的颈椎减压标本的组织学表现,分析与颈椎病相关的因素和机制。结果 48例脊髓型颈椎病患者前路减压术后优良率占83％（40例）;18个患者的20例减压完整标本中,以颈椎盘突出为颈椎病主要发病原因者14个占70％,以椎体后缘骨赘压迫为颈椎病主要发病原因的5个占25％。颈椎间盘后缘有炎细胞浸润的占55％,1例退变的非突出的的颈椎间盘也有明显的炎细胞浸润。有炎细胞浸润的患者,其脊髓神经功能损害程度比无炎细胞浸润者重（神经功能评分,P＜0．01）。结论 除了突出的颈椎间盘和椎体后缘形成的骨赘压迫,退变突出的颈椎间盘产生的炎症反应在颈椎病的发病中同样起重要作用。     

Subtotal vertebrectomy and spinal fusion for cervical spondylotic myelopathy

To perform decompression of the spinal cord and stabilization of the cervical spine in the patients with cervical spondylotic myelopathy, subtotal vertebrectomy and spinal fusion of the cervical spine were carried out in 30 patients. In 18 patients, three vertebrectomies and a spinal fusion were carried out, and in 12 patients, four vertebrectomies and a spinal fusion were carried out. Neurologic symptoms that were present before the operations ranged from transverse lesion type myelopathy to motor system syndrome. The patients' symptoms improved significantly after the operations. By the final consultation, the cervical spine motion reduced by about half in the four level vertebrectomy patients and about one third in the three level vertebrectomy patients. No patients reported cervical pain or pain in the arms.     

Intermittent cervical traction and thoracic manipulation for management of mild cervical compressive myelopathy attributed to cervical herniated disc: a case series

STUDY DESIGN: Case series. OBJECTIVE: To describe the management of 7 patients with grade 1 cervical compressive myelopathy attributed to herniated disc using intermittent cervical traction and manipulation of the thoracic spine. BACKGROUND: Intermittent cervical traction has been indicated for the treatment of patients with herniated disc and has been suggested to be helpful for patients with cervical compressive myelopathy. Manipulation of the thoracic spine has been utilized to safely improve active range of motion and decrease pain in patients with neck pain. METHODS AND MEASURES: Seven women with neck pain, 35 to 45 years of age, were identified as having signs and symptoms consistent with grade 1 cervical compressive myelopathy. Symptom duration ranged from less than 1 week to 52 weeks. All patients were treated with intermittent cervical traction and thoracic manipulation for a median of 9 sessions (range, 2-12 sessions) over a median of 56 days (range, 14-146 days). Numeric Pain Rating Scale and Functional Rating Index scores served as the primary outcome measures. RESULTS: The median decrease in pain scores was 5 (range, 2-8) from a baseline of 6 (range, 4-8), and median improvement in Functional Rating Index scores was 26% (range, 10%-50%) from a baseline of 44% (range, 35%-71%). Dizziness was eliminated in 3 out of 4 patients and chronic headache symptoms were improved in 3 out of 3 patients. There were no adverse events or outcomes. CONCLUSIONS: Intermittent cervical traction and manipulation of the thoracic spine seem useful for the reduction of pain scores and level of disability in patients with mild cervical compressive myelopathy attributed to herniated disc. A thorough neurological screening exam is recommended prior to mechanical treatment of the cervical spine.     

矩形钛质颈椎椎间融合器在颈椎前路融合术中的应用以及近期效果观察

目的 探讨矩形钛质颈椎椎间融合器(SynCage-C)在颈椎前路椎问盘切除、椎体间植骨融合术中的应用价值。方法应用SynCage-C行颈椎病前路椎间盘切除后椎体间融合19例,平均随访9个月(6～14个月)。结果本组均为颈椎病患者,脊髓型16例、神经根型3例。平均年龄48岁(34～66岁),男性13例,女性6例。单节段融合16例,双节段3例。每节段平均手术时问40min,平均出血60ml。术后平均围领保护8．5周。3个月时颈椎侧位X线片显示融合良好。19例患者中仅有1例因戴围领超过3个月而感颈部僵直,1例有短暂髂骨取骨区疼痛。本组未见融合节段曲度不良、反曲、Cage下沉、融合不良。结论SynCage-C操作简单,可以有效恢复和维持椎间隙高度,植入后即刻稳定,椎间融合良好,取骨区创伤小。     

纳米羟基磷灰石／聚酰胺66椎体支撑体在脊髓型颈椎病前路手术重建中的应用

目的探讨纳米羟基磷灰石／聚酰胺66（nano—hydroxyapatite polyamide66,n—HA／PA66）椎体支撑体在脊髓型颈椎病前路减压,脊柱稳定性重建中的可行性及优点。方法2008年8月至2009年5月,行前路椎间盘切除或椎体次全切除、椎管减压,以n—HA／PA66椎体支撑体支撑植骨、钢板螺钉内固定治疗24例脊髓型颈椎病患者,男18例,女6例;年龄44～72岁,平均58．6岁。随访以日本矫形外科学会（Japan Orthopaedic Assoctiation,JOA）评分改善率评价患者神经功能恢复情况,复查X线片及三维CT评估支撑植骨融合情况,包括椎间高度、生理弧度及支撑体下沉。结果24例患者均成功完成颈椎前路减压手术以及支撑体的安放固定,并获得随访,随访时间3～9个月,平均5．6个月,所有患者的术前症状均得到不同程度的改善,术后3、6、9个月的JOA改善率分别为78．8％、83．4％、83．3％。影像学检查显示所有患者植骨融合,颈椎序列、椎间高度、颈椎稳定性以及支撑体的位置维持良好,人工椎体无下沉、移位。结论n—HA／PA66椎体支撑体具有早期支撑稳定功能,可有效维持颈椎生理序列和椎间高度;术后植骨融合率高且便于X线片观察,是进行颈椎退变前路手术植骨的理想支撑材料,但长期效果需进一步随访观察。     

Osteomyelitis of the cervical spine: a potentially dramatic disease

Osteomyelitis of the cervical spine is a rare disease, representing only 3% to 6% of all cases of vertebral osteomyelitis. In contrast with other locations of spinal infections, osteomyelitis of the cervical spine can be a much more dramatic and rapidly deteriorating process, leading to early neurologic deficit. Thus, the disease must be diagnosed quickly and appropriate therapy initiated as soon as possible. The clinical course, therapy, and outcome of 15 patients treated for osteomyelitis of the cervical spine are presented. Nine of 15 patients presented with a neurologic deficit at the time of diagnosis. Surgical treatment consisted of radical debridement of the infected bone and either immediate bone grafting and stabilization as a one-step procedure or interval antibiotic treatment before bone grafting and surgical stabilization as a second procedure. A favorable outcome was achieved by early and aggressive surgical intervention, including complete resolution of neurologic deficits in more than 50% of the patients and complete bony fusion in all but one patient. The authors prefer additional posterior rather than anterior stabilization alone to perform fusion over a shorter distance involving only the infected segments.     

Osteomyelitis of the cervical spine: a potentially dramatic disease

Osteomyelitis of the cervical spine is a rare disease, representing only 3% to 6% of all cases of vertebral osteomyelitis. In contrast with other locations of spinal infections, osteomyelitis of the cervical spine can be a much more dramatic and rapidly deteriorating process, leading to early neurologic deficit. Thus, the disease must be diagnosed quickly and appropriate therapy initiated as soon as possible. The clinical course, therapy, and outcome of 15 patients treated for osteomyelitis of the cervical spine are presented. Nine of 15 patients presented with a neurologic deficit at the time of diagnosis. Surgical treatment consisted of radical debridement of the infected bone and either immediate bone grafting and stabilization as a one-step procedure or interval antibiotic treatment before bone grafting and surgical stabilization as a second procedure. A favorable outcome was achieved by early and aggressive surgical intervention, including complete resolution of neurologic deficits in more than 50% of the patients and complete bony fusion in all but one patient. The authors prefer additional posterior rather than anterior stabilization alone to perform fusion over a shorter distance involving only the infected segments.     

The cervical spine in juvenile chronic arthritis.

BACKGROUND CONTEXT: In patients with juvenile chronic arthritis (JCA) the cervical spine is often affected, leading to pain and functional limitations. PURPOSE: To describe the frequency of the radiographic abnormalities in the cervical spine of a large series of patients with JCA, examined after skeletal maturity. STUDY DESIGN: Consecutive patients with JCA, who had cervical spine radiographs available taken at adult age (>18 years) were included in the study from one outpatient clinic and one rheumatology ward in the Rheumatism Foundation Hospital, Heinola, Finland. PATIENT SAMPLE: The series consisted of 159 patients fulfilling the diagnostic criteria of the European League Against Rheumatism for JCA. OUTCOME MEASURES: Evaluation of cervical spine radiographs for inflammatory changes. METHODS: Inflammatory changes in the cervical spine radiographs were measured as well as the size of the fourth cervical vertebra. Patient records were studied. The statistical analysis was calculated by Student's t-test or Mann-Whitney U test. RESULTS: In 98 cases (62%) some inflammatory changes were detected in the cervical spine. Apophyseal joint ankylosis was noted in 65 patients (41%), anterior atlantoaxial subluxation in 27 (17 %) and atlantoaxial impaction in 39 (25 %). The fourth cervical vertebra was abnormally small in 41 patients (26%). CONCLUSIONS: Radiographically, the most frequent inflammatory change in the cervical spine of patients with JCA was apophyseal joint ankylosis at multiple levels. Atlantoaxial impaction and anterior atlantoaxial subluxation were typical of the upper cervical spine. Clinically, these changes tend to limit neck movements. A small C4 vertebral body was seen in patients with early disease onset and short body stature.