Research Proposal
Principle Investigator: Patrick Knott, PhD, PA-C
Professor and Associate Vice President
Rosalind Franklin University of Medicine and Science
Senior Investigator:
Steven Mardjetko, MD
Clinical Assistant Professor
Department of Orthopaedic Surgery
Rush University
Co-Investigators:
Michelle Cameron, MD, PGY3, University of Illinois at Chicago
Michal Szczodry MD, PGY 2, University of Illinois at Chicago
Emily Mayeker MD, PGY 1, University of Illinois at Chicago
Eden Pappo (MS3) University of Illinois at Chicago
Title: The Natural History of Spinal Deformity in Patients with Coffin Lowry Syndrome
Research Question:
In patients with Coffin Lowry Syndrome (CLS), what are the initial spinal deformities that are
seen, and how do these deformities change over time?
Formal Hypothesis:
Up to 80 percent of male patients with CLS will have spinal deformities. These can
exacerbate already existing cardiopulmonary compromise as well as cause paralysis, yet the
treatment to fix these deformities is not benign. There is a significantly higher rate of morbidity
and mortality associated with the treatment of spinal deformities in CLS. Thus our goal is to
elucidate the natural history of this disorder as it relates to the spine, so as to better identify an
appropriate timeline for intervention.
Significance of Information Gained:
If the natural history of the spinal and orthopaedic manifestations of CLS can be better
understood, then a more comprehensive plan and treatment timeline to minimize the
cardiopulmonary and psychosocial complications can be developed.
Literature Review:
Coffin Lowry Syndrome (CLS) is a rare x-linked disorder that affects between 1/ 50,000
and 100,000 people, with males being severely affected and carrier females often being mildly
affected due to x inactivation1. It is associated with severe developmental disability,
characteristic facies, hypotonia, premature dental eruption, short stature, delayed bone age,
hyperextensile doughy tapered fingers, pectus carinatum, pes planus and multiple spinal
abnormalities23. It is caused by a mutation in the RSK2 gene4, 70-80 percent of the time this is
a new mutation.
There are many variations in the RSK2 mutation and currently there is no known
correlation between the degree of the protein truncation and the severity of the phenotypic
outcomes. Furthermore, the exact etiology by which RSK2 affects the musculoskeletal system is
still unknown; though it is likely to be a multifactorial problem. The hypotonia may be due to
lack of differentiation of neural precursors, as RSK2 knockout mice have been found to have
abnormal gliogenesis and neurogenesis56. The osseous and collagenous abnormalities likely
stem at least in part from RSK2's lack of phosphorylation and activation of ATF4 and CREB,
CREB which ultimately causes the transcription of c-Fos7. ATF4 is a transcription factor which
is an important component of osteoblast differentiation and gene expression as well as regulation
of type 1 collagen synthesis7 and mutations are associated with delayed bone age. C-Fos
contributes to the differentiation of osteoclasts and c-Fos deficient mice closely resemble those
with CLS8.
The RSK2 mutations have a significant effect on the spine and approximately 80 percent
of male patients will have a spinal abnormality including but not limited to scoliosis, kyphosis,
degenerative disc disease, and kyphosis; 47 percent of patient’s will develop some degree of
kyphoscoliosis9. In his review article on CLS, Hanauer proposed that the osseous changes in
association with ligamentous laxity may contribute to the progression of the kyphosis and
kyphoscoliosis10. In 1990 Padly et al described the radiographic findings associated with CLS.
These included coarctation of the foramen magnum, narrowing of the intervertebral spaces,
irregular endplates, and anterior wedging11. These spinal abnormalities fall along a broad
spectrum, but can be very severe and there are several case reports of rapidly progressive
kyphosis and acute paralysis both of which can exacerbate preexisting or cause cardiopulmonary
disorders. This is a significant problem as patients with CLS have a significantly shorter life
span with a mean of 20.5 years, several of the reported deaths were due to cardiopulmonary
compromise which may have been contributed to by their progressive kyphosis21213.
Unfortunately little is known about the natural history or frequency of some of these
spinal manifestations. Herrera Soto’s article in 2002 discussed their experience with 10 CLS
patients with spinal abnormalities, 7 of which had kyphosis or kyphoscoliosis. Of these 7patients
4 required surgical intervention14. Both Hunter and Miyazaki had patients that developed
significant calcifications of ligamentum flavum. Hunter’s patient developed acute onset
quadriplegia that had a waxing and waning course. The patient was 20 at the time of
presentation and was found to have multilevel compression secondary to calcifications and
hypertrophy of his ligamentum flavum as well as kyphoscoliosis and four years later underwent
cervical decompression and fusion. Unfortunately the patient remained confined to a wheelchair
for the remainder of his life1. Mizayaki’s patient was 22 when he developed increasing difficulty
ambulating as well as evidence of cord compression. He was found to have calcifications of the
ligamentum flavum of his cervical and lumbar spine, though on review of his prior imaging
studies showed these were present when he was 14 years old. He subsequently underwent
decompression and fusion. His ligamentum flavum was compared to a patient with AIS and a
CLS patient whose ligamentum flavum were not calcified. They found that a 5-fold increase in
the hexuronate content compared with the AIS patient. The predominate glycosaminoglycan
was chondroitin sulfate15. While it is not uncommon to develop calcifications in the ligamentum
flavum, this is primarily seen in the elderly16. In reviewing the records of these patients we hope
to identify any additional individuals with previously undiagnosed calcification of their
ligamentum flavum, dystrophic changes that may contribute to the progression of their disease,
the age of onset of the degenerative changes to the spine and to further clarify the course of their
spinal disease.
Goals:
With the goal of this study is to further elucidate the etiology and natural history of the spinal
manifestations of CLS, so as to better identify a treatment timeline that can minimize the
complications of both the progression of the spinal disease as well as the complications
associated with the surgery and to minimize the cardiopulmonary complications that frequently
result in morbidity in these patients
Procedures:
Research Subjects:
This will be a retrospective chart and imaging review of patients with CLS who were seen in the
orthopaedic offices of Illinois Bone and Joint Institute between the years of 1990 and 2012 and
patients will be recruited from across the country through a notice placed on the Coffin Lowry
Syndrome Foundation website. The Coffin Lowry Syndrome Foundation is an on-line website
that provides patients with resources and information about treatment of and studies on CLS.
Those who to participate in the study will be provided with a copy of the research protocol and
will sign the standard Illinois Bone and Joint release of medical records. Patients will be
between the ages of 10 and 40 years old.
Research tools/instruments:
This will be a retrospective study, utilizing chart review from the medical, orthopaedic and
genetic clinics. Review of existing radiographs will also be done.
Risks to human subjects:
This is a retrospective study. Therefore it will pose no risk to patients other than the loss of their
confidential medical information.
Procedures developed to minimize risks:
All electronic information will be stored in a password protected computer and all hard copies of
patient information will be kept in a locked office. Those patients that are recruited from outside
the Illinois Bone and Joint Institute will send their records directly to our Principal Investigators
office at Rosalind Franklin University. All information will be stored in a de-identified fashion
using the patient’s initials only and removing all other identifiers. HIPAA regulations will be
followed at all times.
Budget: This is a retrospective study so there will be no cost.
Timeline for Completion: The project will be completed over the next 6 months.
1
Pereira RM, et al. Coffin–Lowry syndrome. European Journal of Human Genetics (2010) 18,
627–633.
2
Hunter AGW, Partington MW, Evans JA. 1982. The Coffin-Lowry syndrome. Experience from
four centres. Clin Genet 21:321–335.
3
Young ID. The Coffin-Lowry syndrome. J Med Genet 1988; 25:344–348.
4
Trivier E, De Cesare D, Jacquot S, Pannetier S, Zackai E, Young I,Mandel JL, Sassone-Corsi P,
Hanauer A. Mutations in the kinase Rsk-2 associated with Coffin-Lowry syndrome. Nature
1996; 384:567–570.
5
Gauthier, A.S., Furstoss, O., Araki, T., Chan, R., Neel, B.G., Kaplan, D.R., Miller, F.D., 2007.
Control of CNS cell-fate decisions by SHP-2 and its dysregulation in Noonan syndrome. Neuron
54, 245–262.
6
Dugani CB, et al. Coffin–Lowry syndrome: A role for RSK2 in mammalian neurogenesis.
Developmental Biology 2010; 347: 348–359
7
Yang X, Matsuda K, Bialek P et al: ATF4 is a substrate of RSK2 and an essential regulator of
osteoblast biology; implication for Coffin-Lowry syndrome. Cell 2004; 117: 387–398.
8
Grigoriadis, A. E., Wang, Z. Q., Cecchini, M. G., Hofstetter, W., Felix, R., Fleisch, H. A. &
Wagner, E. F.
c-Fos: A Key Regulator of Osteoclast-Macrophage Lineage Determination and Bone
Remodeling . Science 1994; 266: 443–448.
9
Hunter AG. Coffin Lowry syndrome: a 20-year follow-up and review of long-term outcomes.
Am J Med Genet. 2002;111-4:345-355.
10
Hanauer A, Young ID. Coffin-Lowry syndrome: clinical and molecular features. J Med Genet
2002;39:705–713
11
Padley S, Hodgson SV, Sherwood T. The radiology of Coffin-Lowry syndrome. Br J Radiol
1990;63:72-5.
12
Ishida Y, Oki T, Ono Y, Nogami H. Coffin-Lowry syndrome with calcium pyrophosphate
crystal deposition in the ligamenta flava. Clin Ortho Rel Res 1992 ; 275:144–151.
13
Hunter AG: Coffin-Lowry syndrome; in Cassidy S, Allanson J (eds): Management of Genetic
Syndromes, 2nd edn. Hoboken, NJ: Wiley-Liss, 2005; 127–138.
14
Herrera-Soto, JA. et al. The Musculoskeletal Manifestations of the Coffin Lowry Syndrome. J
Pediatr Orthop. 2007; 27- 1: 85-89
15
Miyazaki K.,Yamanaka T, Ishida Y, Oohira A. Calcified Ligamenta Flava in a Patient With
Coffin-Lowry Syndrome: Biochemical Analysis of Glycosaminoglycans. Jpn. J, Human
Genet.1990; 35: 215-221.
16
Nakijima, K et al. Cervical radiculomyelopathy due to calcification of the ligamenta flava.
Surg Neurol 1984;21:479-88