Last Modified: 31 May 2011
The following interview took place via telephone in spring 2009. Responses are modified periodically, to ensure the information remains current. The FSRG Secretary is MI Poling, who is also the site administrator.
What exactly is Freeman-Sheldon syndrome (FSS)?
Freeman-Sheldon syndrome (FSS), which is also known by several other designations, namely distal arthrogryposis type 2A (DA2A), craniocarpotarsal dysplasia (or dystrophy), and ‘whistling face-windmill vane hand syndrome', was originally described by Freeman and Sheldon (1938). FSS is considered a rare form of multiple congenital contracture (MCC) syndrome (arthrogryposis) and is the most severe form of distal arthrogryposis (DA). Notably, some classify it as a skeletal dysplasia; others call it a myopathy; still, others call it a craniofacial syndrome. Unfortunately, none of the above nosological classifications consider the global multi-systemic impact FSS has on patients. The best way I can think to explain it is to say that FSS is a non-progressive congenital human neuromusculoskeletal syndrome.
Are there specific characteristics of this syndrome?
Yes, features abound, trying to contain them is another matter. I’ll give you a list, if that would be helpful?
Major features include: talipes equinovarus, camptodactyly with ulnar deviation and overlapping of digits, scoliosis, ocular abnormalities, microstomia, high arched palate, attenuated movement of facial musculature, and various other primary myopathic anomalies.
Are there different forms or stages of FSS?
FSS is a non-progressive congenital human neuromusculoskeletal syndrome, and as such, there are not stages, per se. One caveat is that infants have a particularly difficult time with respiratory, alimentary, and metabolic complications that seem to stabilise later. We don’t yet understand this phenomenon. There are different forms of FSS. Classic FSS is the most severe. Sheldon-Hall is less severe. Distal arthrogryposis type 1 (DA1) may have similar problems with hands, feet, arms, and legs, but there are no facial deformities. DA1 is much less severe than SHS.
Is it genetic?
Yes, it is heritable, though most probands represent de novo allelic variations (mutations). It has at least three modes of inheritance: autosomal dominant, autosomal recessive, and x-linked recessive. Stevenson et al. (2006) accepted only autosomal dominant inheritance and argued the other purposed modes were either that a parent had a nonpenetrant somatic mosaicism or there was germ-line mosaicism. They cite evidence of this in their experience with two patients with Sheldon-Hall syndrome. The gene identified as harbouring the missense mutations being responsible for FSS is the gene encoding embryonic myosin heavy chain (MYH3) on the short arm of chromosome 17. The mutations are located at the myosin heads and may interfere with ATP-binding sites. But, these explanations do not consider the nature of FSS, so we suspect it is actually polygenic.
Is it more common in males or females?
Though no good data exist, we believe the demographics are equal in all races and both sexes. There are papers published throughout Asia, Europe, Australia, India, Africa, North, and South America.
What is the most common form of FSS?
The more common form is probably Sheldon-Hall syndrome, which is a less severe phenotype. The genotype is quite different, however.
Does FSS require any form of therapy?
FSS requires vigilant medical monitoring and prudent surgical intervention to minimise negative life impacts.
Does it take someone with FSS longer to heal from something like an operation as opposed to someone without FSS?
We are not aware this is the case.
If you have FSS, are you more prone to getting sick?
We are not aware of any immunological problem, but respiratory illnesses are a common complication.
Do the individuals with FSS have to take precautions during cold and flu season?
They should get a flu shot and pneumovax. They should be especially vigilant.
If you have FSS, do you have to eat a special diet?
Well, that is a loaded question. You must first understand we don’t yet understand much of the underlying biology of FSS, so all of the following must be interpreted in that context. Yes, FSS patients do require a special diet, but that varies. FSS is characterised by dysphagia, microstomia, micrognathia, high palate, microglossia, and malocclusion; these anatomical and physiological aberrations create a substantial problem.
Usually, a diet of purée food is required. I know of at least two cases of patients that have a definite metabolic component, as well. They develop a hypoglycaemic syndrome, just as a diabetic, if they don’t have adequate intake, but their labs have excluded diabetes mellitus. This means that their eating schedules must mirror that of a diabetic: frequent feeds. The difference is that FSS patients, especially in infancy and early childhood, have failure-to-thrive, and throughout life, are small stature, with thin habitus. So, this observation supports advice for high caloric diet, which obviously differs considerably from a diabetic’s diet.
Do you enjoy doing research on FSS?
Yes, I think we could agree that we both enjoy our work with FSRG and find it very rewarding and fulfilling.
Do you like to teach people about FSS?
I think it is very important to educate the medical and lay communities about FSS, especially diagnosis, and I’ve been brought up in medicine to strongly value patient education. But, one reason there us such minimal and poor quality research is everyone seems to have their own personal definition of what constitutes FSS. So, that means no one has come to a broad and generally accepted diagnostic criteria. As I’ve mentioned, Stevenson et al. (2006) went a long way in this direction, but further studies with larger sample sizes are required to validate their criteria. There are some major flaws in their study design, statistical analyses, and presuppositions.
But, I won’t go intro that, now. If one cannot diagnose and do high-quality research, then, please tell me how we are supposed to understand FSS, a frightfully heterogeneous group of pathological entities, and if we don’t understand it, for Pete’s sake tell me, how we are to know the best ways to treat it? It just won’t hold water. You can’t do things that way, and teaching is an essential tool—element—of the whole enterprise. It is the essence of scholarly communication. And well, I come from three generations of educators, so I guess teaching is a heritable trait, and I know that Dr. McCormick had a great aunt who taught second grade for forty-nine years, so it must be for him, as well.
What is your favourite or least favourite part of researching FSS?
My favourite part, well, I’ve been raised in an education family, who stressed an intellectual, methodical approach to problems, scientific inquiry, if you will. I abhor what I see to be unscientific medicine, especially in the grossly exaggerated state I find it in relation to FSS. I guess that is my least favourite part—dealing with a system that is, at times, a farce of what it should epitomise and set up to fail patients. It is simply the scientific pursuit of knowledge that absolutely thrills me, but it is the clinical application of that knowledge to help individual patients, who are suffering and desperate, that sustains me.
How long have you been researching FSS?
I began to think about doing some work on FSS in 2001, but I really began doing clinical work on it in earnest in 2003, which is when the research team was initially created.
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