KEYWORDS
Freeman-Burian syndrome; Freeman-Sheldon syndrome; malignant
hyperthermia; craniocarpotarsal dystrophy; whistling face syndrome;
distal arthrogryposis type 2A; case reports; rare diseases; craniofacial
abnormalities
We read with interest the article, “Freeman-Sheldon Syndrome with Stiff
Knee Gait – A Case Report,” by Drs Sehrawat, Sural, Sugumar, Khan,
Kar, and Jeyaraman.[1] It is wonderful to see this rare syndrome
discussed. Unfortunately, there were several unclear or inaccurate
points, and recent publications were omitted, suggesting an incomplete
literature search. As Freeman-Sheldon syndrome, now Freeman-Burian
syndrome (FBS),[2] is exquisitely rare, many who believe they have
encountered it in clinical practice are eager to publish their
experience, despite the perils.
The authors present FBS as a variant of distal arthrogryposis,[1]
but FBS is a unique condition.[3] Though similar in physical
appearance, FBS is genetically unique and has a unique clinical
course.[3] Two studies have provided evidence that certain
craniofacial findings are pathognomonic for FBS,[4-5] and a
meta-analysis found distal arthrogryposes are not required for
diagnosis.[4] Though many continue to do so, FBS can no longer be
cogently classed as a distal arthrogryposis syndrome in the face of such
evidence, and the most reasonable classification seems to be as a
complex congenital myopathic craniofacial syndrome.[3]
The authors next discuss the patient’s copper beaten skull
appearance.[1] They do not detail any workup or treatment.[1]
The authors postulate it is related to craniosynostosis but quickly
dismiss it. It is concerning that they seemed to have focused on a
suspected diagnosis of a well-known rare syndrome and ignored a
concerning neurologic finding.
The authors describe FBS as an, “autosomal dominant trait and in rare
cases as autosomal recessive and x-linked recessive”.[1] It is
believed that inherited cases either have a parent with clinical
evidence of FBS or rarely are germline mosaicisms.[4-6]
The authors next speak of, “skeletal abnormalities” and “skeletal
malformations”.[1] In the syndrome, problems involving the skeletal
system are secondary effects of the primary myopathic process of fibrose
tissue replacement of normal muscle fibers.[7] This fibrose tissue
acts as constricting bands, the way collagen behaves in severe
burns.[7] This is correlated with in vitro molecular
myophysiology observations showing problems with the metabolic process
for contraction and extreme muscle stiffness that reduces muscular work
and power.[7] Misunderstanding of etiology in FBS has led to
inappropriate treatment plans, especially surgeries, and has resulted in
tragic, lifelong impairments.[4,7-8] We applaud the authors for
their caution toward surgery and explanation of its potential for
unfavorable outcomes.[1]
Unlike many similar case reports to which we have responded over the
past 2-years, the authors clearly state the standard clinical diagnostic
criteria (microstomia, pursed lips, deep nasolabial folds, and H or
V-shaped chin defect and two major arthrogryposes—typically,
camptodactyly with ulnar deviation and equinovarus).[1,4-5] They
also provide a somewhat fair description of FBS, except as noted.[1]
A major failing of their description of FBS is their summary of findings
suggestive of FBS, Sheldon-Hall syndrome (SHS), and Schwartz Jampel
syndrome.[1] The table lists some required findings as, “Features
not favoring FSS”.[1,4-5] Generally, the construction of the table
is misleading, as structured diagnostic criteria exist for FBS and
SHS.[4-5]
The authors also present a very clear description of their patient, with
acceptable figures.[1] It is mystifying that—despite correctly
stating the FBS diagnostic criteria twice—they diagnosed their patient
with FBS, though she clearly did not meet the diagnostic
criteria.[1,4-5] The patient lacked the V or H-shaped chin defect
and had a small mouth but not microstomia, as judged from included
photographs.[1] The patient’s appearance seems consistent with SHS,
exhibiting a small mouth, short neck, small chin, obvious nasolabial
folds, and triangular face.[1] Such an error is not uncommon; FBS
has an estimated false-positive rate of 30-60%.[4-5]
The authors state there is an association of malignant hyperthermia (MH)
with FBS and urge caution.[1] Some patients with FBS do, indeed,
develop hyperpyrexia during general anesthesia, but these hyperpyrexia
events, which may include tachycardia and increased muscle rigidity,
respond to ibuprofen and also occur where a malignant hyperthermia
protocol was followed and in stressful, non-operative stress
situations.[9] There is no evidence that MH is associated with FBS,
though FBS anesthesia practice guidelines still suggest following an MH
protocol.[9]
Prenatal ultrasound is not considered diagnostic, and prenatal diagnosis
is not considered generally feasible.[6] As suggested by the
authors, molecular diagnosis is very expensive and is not clinically
helpful or needed, given the strong correlation of the clinical
diagnostic criteria with the presence of MYH3 mutations.[1,6]
For women with clinically diagnosed FBS undergoing in vitro fertilization and wishing to avoid use of an FBS-affected egg, polar
bodies testing has been used successfully, as the authors correctly
state.[1,6]
Ten English-language case reports have been published between 2020-2022
purportedly describing FBS that contained similar, preventable
errors.[1,10-18] Not conducting a thorough literature search and
omitting recent articles was the common denominator among the
articles.[19] In trying to address the shortcomings of each, we have
responded to all ten, with four letters already published.[19-22]
This article illustrates the potential perils of describing a rare
condition despite the best intentions.