Freeman-Sheldon syndrome

Infobox_Disease
Name = Freeman-Sheldon syndrome


Caption =
DiseasesDB = 31817
ICD10 =
ICD9 = ICD9|759.89
ICDO =
OMIM = 193700
MedlinePlus =
eMedicineSubj =
eMedicineTopic =
MeshID =

Freeman-Sheldon syndrome (FSS), also termed distal arthrogryposis type 2A (DA2A), craniocarpotarsal dysplasia (or dystrophy), or whistling-face syndrome, was originally described by Freeman and Sheldon in 1938.cite journal | last = Freeman | first = EA | authorlink = | coauthors = Sheldon JH | title = Cranio-carpo-tarsal dystrophy: undescribed congenital malformation | journal = Arch Dis Child | volume = 13 | issue = | pages = 277–83 | publisher = | year = 1938 | url= | doi = | id = | accessdate = ] Freeman-Sheldon syndrome is a rare form of multiple congenital contracture (MCC) syndromes (arthrogryposes) and is the most severe form of distal arthrogryposis (DA).OMIM|193700] cite journal | last = Stevenson | first = DA | authorlink = | coauthors = Carey JC, Palumbos J, Rutherford A, Dolcourt J, Bamshad MJ | title = Clinical characteristics and natural history of Freeman-Sheldon syndrome | journal = Pediatrics | volume = 117 | issue = 3 | pages = 754–62 | publisher = | month = March | year = 2006 | url=http://pediatrics.aappublications.org/cgi/content/full/117/3/754 | doi = | id = | accessdate = | pmid = 16510655 ] cite journal |author=Bamshad M, Jorde LB, Carey JC |title=A revised and extended classification of the distal arthrogryposes |journal=Am. J. Med. Genet. |volume=65 |issue=4 |pages=277–81 |year=1996 |month=Nov |pmid=8923935 |doi=10.1002/(SICI)1096-8628(19961111)65:4<277::AID-AJMG6>3.0.CO;2-M |url=]

Signs and symptoms

Features include: talipes equinovarus, camptodactyly, scoliosis, abnormalities of the muscles of the eye, microstomia, high-arched palate, attenuated movement of the muscles of facial expression, and various other primary anomalies involving the musculoskeletal system.cite journal |author=Savini R, Gualdrini G |title=Report on two cases of Freeman-Sheldon syndrome ("whistling face) |journal=Ital J Orthop Traumatol |volume=6 |issue=1 |pages=105–15 |year=1980 |month=Apr |pmid=7203992 |doi= |url=]

Diagnosis

Freeman-Sheldon syndrome is a type of distal arthrogryposis, related to distal arthrogryposis type 1 (DA1).cite journal |author=Hall JG, Reed SD, Greene G |title=The distal arthrogryposes: delineation of new entities—review and nosologic discussion |journal=Am. J. Med. Genet. |volume=11 |issue=2 |pages=185–239 |year=1982 |month=Feb |pmid=7039311 |doi=10.1002/ajmg.1320110208 |url=] In 1996, more strict criteria for the diagnosis of Freeman-Sheldon syndrome were drawn up, assigning Freeman-Sheldon syndrome as distal arthrogryposis type 2A (DA2A).

On the whole, DA1 is the least severe; DA2B is more severe with additional features that respond less favourably to therapy. DA2A (Freeman-Sheldon syndrome) is the most severe of the three, with more abnormalities and greater resistance to therapy.

Freeman-Sheldon syndrome has been described as a type of congenital myopathy.cite journal |author=Vanĕk J, Janda J, Amblerová V, Losan F |title=Freeman-Sheldon syndrome: a disorder of congenital myopathic origin? |journal=J. Med. Genet. |volume=23 |issue=3 |pages=231–6 |year=1986 |month=Jun |pmid=3723551 |pmc=1049633 |doi= |url=]

In March 2006, Stevenson et al. published strict diagnostic criteria for distal arthrogryposis type 2A (DA2A) or Freeman-Sheldon syndrome. These included two or more features of distal arthrogryposis: microstomia, whistling-face, nasolabial creases, and 'H-shaped' chin dimple.

Cause

FSS is caused by genetic changes. Krakowiak et al (1998) mapped the distal arthrogryposis multiplex congenita (DA2B; MIM #601680) gene, a syndrome very similar in phenotypic expression to classic FSS, to 11p15.5-pter.cite journal |author=Krakowiak PA, O'Quinn JR, Bohnsack JF, "et al" |title=A variant of Freeman-Sheldon syndrome maps to 11p15.5-pter |journal=Am. J. Hum. Genet. |volume=60 |issue=2 |pages=426–32 |year=1997 |pmid=9012416 |doi=] cite journal |author=Krakowiak PA, Bohnsack JF, Carey JC, Bamshad M |title=Clinical analysis of a variant of Freeman-Sheldon syndrome (DA2B) |journal=Am. J. Med. Genet. |volume=76 |issue=1 |pages=93–8 |year=1998 |pmid=9508073|doi=10.1002/(SICI)1096-8628(19980226)76:1<93::AID-AJMG17>3.0.CO;2-K] Other mutations have been found as well.cite journal |author=Sung SS, Brassington AM, Krakowiak PA, Carey JC, Jorde LB, Bamshad M |title=Mutations in TNNT3 cause multiple congenital contractures: a second locus for distal arthrogryposis type 2B |journal=Am. J. Hum. Genet. |volume=73 |issue=1 |pages=212–4 |year=2003 |pmid=12865991 |doi=10.1086/376418 |url=http://linkinghub.elsevier.com/retrieve/pii/AJHG035048] cite journal |author=Sung SS, Brassington AM, Grannatt K, "et al" |title=Mutations in genes encoding fast-twitch contractile proteins cause distal arthrogryposis syndromes |journal=Am. J. Hum. Genet. |volume=72 |issue=3 |pages=681–90 |year=2003 |pmid=12592607 |doi=10.1086/368294 |url=http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)60583-7] In FSS, inheritance may be either autosomal dominant, most often demonstrated.cite journal |author=Aalam M, Kühhirt M |title= [Windmill vane-like finger deformities] |language=German |journal=Z Orthop Ihre Grenzgeb |volume=110 |issue=3 |pages=395–8 |year=1972 |pmid=4263226 |doi=] cite journal |author=Jorgenson RJ |title=M--craniocarpotarsal dystrophy (whistling face syndrome) in two families |journal=Birth Defects Orig. Artic. Ser. |volume=10 |issue=5 |pages=237–42 |year=1974 |pmid=4220006 |doi=] cite journal |author=Wettstein A, Buchinger G, Braun A, von Bazan UB |title=A family with whistling-face-syndrome |journal=Hum. Genet. |volume=55 |issue=2 |pages=177–89 |year=1980 |pmid=7450762 |doi=] or autosomal recessive (MIM 277720).cite journal |author=Kousseff BG, McConnachie P, Hadro TA |title=Autosomal recessive type of whistling face syndrome in twins |journal=Pediatrics |volume=69 |issue=3 |pages=328–31 |year=1982 |pmid=7199706 |doi=] cite journal |author=Kaul KK |title=Whistling face syndrome (craniocarpotarsal dysplasia) |journal=Indian Pediatr |volume=18 |issue=1 |pages=72–3 |year=1981 |pmid=7262998 |doi=] cite journal |author=Guzzanti V, Toniolo RM, Lembo A |title= [The Freeman-Sheldon syndrome] |language=Italian |journal=Arch Putti Chir Organi Mov |volume=38 |issue=1 |pages=215–22 |year=1990 |pmid=2136374 |doi=] cite journal |author=Sánchez JM, Kaminker CP |title=New evidence for genetic heterogeneity of the Freeman-Sheldon syndrome |journal=Am. J. Med. Genet. |volume=25 |issue=3 |pages=507–11 |year=1986 |pmid=3789012 |doi=10.1002/ajmg.1320250312] Alves and Azevedo (1977) note most reported cases of DA2A have been identified as new allelic variation.cite journal |author=Alves AF, Azevedo ES |title=Recessive form of Freeman-Sheldon's syndrome or 'whistling face', |journal=J. Med. Genet. |volume=14 |issue=2 |pages=139–41 |year=1977 |pmid=856233 |doi=] Toydemir et al (2006) showed that mutations in embryonic myosin heavy chain 3 (MYH3; MIM *160270), at 17p-13.1-pter, caused classic FSS phenotype, in their screening of 28 (21 sporadic and 7 familial) probands with distal arthrogryposis type 2A.cite journal |author=Toydemir RM, Rutherford A, Whitby FG, Jorde LB, Carey JC, Bamshad MJ |title=Mutations in embryonic myosin heavy chain (MYH3) cause Freeman-Sheldon syndrome and Sheldon-Hall syndrome |journal=Nat. Genet. |volume=38 |issue=5 |pages=561–5 |year=2006 |pmid=16642020 |doi=10.1038/ng1775] OMIM|160720|MYOSIN, HEAVY CHAIN 3, SKELETAL MUSCLE, EMBRYONIC; MYH3
b .0001 c .0002 d .0004 e .0006, .0003] In 20 patients (12 and 8 probands, respectively), missense mutations (R672H; MIM *160270.0001 and R672C; MIM *160270.0002) caused substitution of arg672, an embryonic myosin residue retained post-embryonically. Of the remaining 6 patients in whom they found mutations, 3 had missense private de novo (E498G; MIM *160270.0006 and Y583S) or familial mutations (V825D; MIM *160270.0004); 3 other patients with sporadic expression had de novo mutations (T178I; MIM *160270.0003), which was also found in DA2B; 2 patients had no recognized mutations.

Management

Surgical and anaesthetic considerations

Patients must have early consultation with craniofacial and orthopaedic surgeons, when craniofacial,cite journal |author=Vaitiekaitis AS, Hornstein L, Neale HW |title=A new surgical procedure for correction of lip deformity in cranio-carpo-tarsal dysplasia (whistling face syndrome) |journal=J Oral Surg |volume=37 |issue=9 |pages=669–72 |year=1979 |month=Sep |pmid=288890 |doi= |url=] cite journal |author=Nara T |title=Reconstruction of an upper lip and the coloboma in the nasal ala accompanying with Freeman-Sheldon syndrome |journal=Nippon Geka Hokan |volume=50 |issue=4 |pages=626–32 |year=1981 |month=Jul |pmid=7316645 |doi= |url=] cite journal |author=Ferreira LM, Minami E, Andrews Jde M |title=Freeman-Sheldon syndrome: surgical correction of microstomia |journal=Br J Plast Surg |volume=47 |issue=3 |pages=201–2 |year=1994 |month=Apr |pmid=8193861 |doi= |url=] clubfoot,cite journal |author=Malkawi H, Tarawneh M |title=The whistling face syndrome, or craniocarpotarsal dysplasia. Report of two cases in a father and son and review of the literature |journal=J Pediatr Orthop |volume=3 |issue=3 |pages=364–9 |year=1983 |month=Jul |pmid=6874936 |doi= |url=] or hand correctioncite journal |author=Call WH, Strickland JW |title=Functional hand reconstruction in the whistling-face syndrome |journal=J Hand Surg [Am] |volume=6 |issue=2 |pages=148–51 |year=1981 |month=Mar |pmid=7229290 |doi= |url=] cite journal |author=Martini AK, Banniza von Bazan U |title= [Hand deformities in Freeman-Sheldon syndrome and their surgical treatment] |language=German |journal=Z Orthop Ihre Grenzgeb |volume=121 |issue=5 |pages=623–9 |year=1983 |pmid=6649810 |doi= |url=] cite journal |author=Martini AK, Banniza von Bazan U |title= [Surgical treatment of the hand deformity in Freeman-Sheldon syndrome] |language=German |journal=Handchir Mikrochir Plast Chir |volume=14 |issue=4 |pages=210–2 |year=1982 |month=Dec |pmid=6763591 |doi= |url=] cite journal |author=Wenner SM, Shalvoy RM |title=Two-stage correction of thumb adduction contracture in Freeman-Sheldon syndrome (craniocarpotarsal dysplasia) |journal=J Hand Surg [Am] |volume=14 |issue=6 |pages=937–40 |year=1989 |month=Nov |pmid=2584652 |doi= |url=] is indicated to improve function or aesthetics. Operative measures should be pursued cautiously, with avoidance of radical measures and careful consideration of the abnormal muscle physiology in Freeman-Sheldon syndrome. Unfortunately, many surgical procedures have suboptimal outcomes, secondary to the myopathy of the syndrome.

When operative measures are to be undertaken, they should be planned for as early in life as is feasible, in consideration of the tendency for fragile health. Early interventions hold the possibility to minimise developmental delays and negate the necessity of relearning basic functions.

Due to the abnormal muscle physiology in Freeman-Sheldon syndrome, therapeutic measures may have unfavourable outcomes.cite journal |author=Aldinger G, Eulert J |title= [The Freeman-Sheldon Syndrome] |language=German |journal=Z Orthop Ihre Grenzgeb |volume=121 |issue=5 |pages=630–3 |year=1983 |pmid=6649811 |doi=] Difficult endotracheal intubations and vein access complicate operative decisions in many DA2A patients, and malignant hyperthermia (MH) may affect individuals with FSS, as well.cite journal |author=Laishley RS, Roy WL |title=Freeman-Sheldon syndrome: report of three cases and the anaesthetic implications |journal=Can Anaesth Soc J |volume=33 |issue=3 Pt 1 |pages=388–93 |year=1986 |pmid=3719442 |doi=] cite journal |author=Munro HM, Butler PJ, Washington EJ |title=Freeman-Sheldon (whistling face) syndrome. Anaesthetic and airway management |journal=Paediatr Anaesth |volume=7 |issue=4 |pages=345–8 |year=1997 |pmid=9243695 |doi=] cite journal |author=Yamamoto S, Osuga T, Okada M, "et al" |title= [Anesthetic management of a patient with Freeman-Sheldon syndrome] |language=Japanese |journal=Masui |volume=43 |issue=11 |pages=1748–53 |year=1994 |pmid=7861610 |doi=] cite journal |author=Sobrado CG, Ribera M, Martí M, Erdocia J, Rodríguez R |title= [Freeman-Sheldon syndrome: generalized muscular rigidity after anesthetic induction] |language=Spanish; Castilian |journal=Rev Esp Anestesiol Reanim |volume=41 |issue=3 |pages=182–4 |year=1994 |pmid=8059048 |doi=] Cruickshanks et al. (1999) reports uneventful use of non-MH-triggering agents.cite journal |author=Cruickshanks GF, Brown S, Chitayat D |title=Anesthesia for Freeman-Sheldon syndrome using a laryngeal mask airway |journal=Can J Anaesth |volume=46 |issue=8 |pages=783–7 |year=1999 |pmid=10451140 |doi=] Reports have been published about spina bifida occulta in anaesthesia managementcite journal |author=Namiki M, Kawamata T, Yamakage M, Matsuno A, Namiki A |title= [Anesthetic management of a patient with Freeman-Sheldon syndrome] |language=Japanese |journal=Masui |volume=49 |issue=8 |pages=901–2 |year=2000 |pmid=10998888 |doi=] and cervical kyphoscoliosis in intubations.cite journal |author=Vas L, Naregal P |title=Anaesthetic management of a patient with Freeman Sheldon syndrome |journal=Paediatr Anaesth |volume=8 |issue=2 |pages=175–7 |year=1998 |pmid=9549749 |doi= |url=http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=1155-5645&date=1998&volume=8&issue=2&spage=175]

Psychiatric considerations

Patients and their parents must receive psychotherapy, which should include marriage counselling.cite journal |author=Doherty WJ, McDaniel SH, Hepworth J |title= [Medical family therapy in children with chronic illness] |language=German |journal=Prax Kinderpsychol Kinderpsychiatr |volume=47 |issue=1 |pages=1–18 |year=1998 |pmid=9522592 |doi=] Mitigation of lasting psychological problems, including depression secondary to chronic illness and posttraumatic stress disorder (PTSD), can be very successfully addressed with early interventions.cite journal |author=Benierakis CE |title=The function of the multidisciplinary team in child psychiatry--clinical and educational aspects |journal=Can J Psychiatry |volume=40 |issue=6 |pages=348–53 |year=1995 |pmid=7585406 |doi=] This care may come from the family physician, or other attending physician, whomever is more appropriate; specialist care is generally not required.cite journal |author=Röhrborn H |title= [Psychotherapy in internal medicine? Systematic considerations on the problem] |language=German |journal=Z Gesamte Inn Med |volume=41 |issue=23 |pages=664–6 |year=1986 |month=Dec |pmid=3577259 |doi= |url=] cite journal |author=Martin JR, Wilikofsky AS |title=Integrating genetic counseling into family medicine |journal=Am Fam Physician |volume=72 |issue=12 |pages=2444, 2446 |year=2005 |month=Dec |pmid=16370402 |doi= |url=] cite journal |author=Dowrick C, May C, Richardson M, Bundred P |title=The biopsychosocial model of general practice: rhetoric or reality? |journal=Br J Gen Pract |volume=46 |issue=403 |pages=105–7 |year=1996 |month=Feb |pmid=8855018 |doi= |url=] Lewis and Vitulano (2003) note several studies suggesting predisposal for psychopathology in paediatric patients with chronic illness.cite journal |author=Lewis M, Vitulano LA |title=Biopsychosocial issues and risk factors in the family when the child has a chronic illness |journal=Child Adolesc Psychiatr Clin N Am |volume=12 |issue=3 |pages=389–99, v |year=2003 |pmid=12910814 |doi=] Esch (2002) advocates preventive psychiatry supports to facilitate balance of positive and negative stressors associated with chronic physical pathology.cite journal |author=Esch T |title= [Health in stress: change in the stress concept and its significance for prevention, health and life style] |language=German |journal=Gesundheitswesen |volume=64 |issue=2 |pages=73–81 |year=2002 |pmid=11904846 |doi=10.1055/s-2002&ndash;20275 |url=http://www.thieme-connect.com/DOI/DOI?10.1055/s-2002&ndash;20275 |doi_brokendate=2008-09-01] Patients with FSS should have pre-emptive and ongoing mixed cognitive therapy-psychodynamic psychotherapyFact|date=April 2008 for patients with FSS and cognitive-behavioural therapy (CBT), if begun after onset of obvious pathology.

Adler (1995) cautioned the failure of modern medicine to implement the biopsychosocial model,cite journal |author=Lesinskiene S, Kajokiene A, Pūras D |title= [Complexity of help to children with developmental disabilities in the context of the establishment of Early Rehabilitation Services] |language=Lithuanian |journal=Medicina (Kaunas) |volume=38 |issue=4 |pages=458–65 |year=2002 |pmid=12474797 |doi= |url=http://medicina.kmu.lt/0204/0204-16l.pdf] which incorporates all aspects of a patient’s experience in a scientific approach into the clinical picture,cite journal |author=Engel GL |title=The clinical application of the biopsychosocial model |journal=Am J Psychiatry |volume=137 |issue=5 |pages=535–44 |year=1980 |month=May |pmid=7369396 |doi= |url=http://ajp.psychiatryonline.org/cgi/pmidlookup?view=long&pmid=7369396] cite journal |author=Engel GL |title=From biomedical to biopsychosocial. Being scientific in the human domain |journal=Psychosomatics |volume=38 |issue=6 |pages=521–8 |year=1997 |pmid=9427848 |doi= |url=http://psy.psychiatryonline.org/cgi/pmidlookup?view=long&pmid=9427848] cite journal |author=Adler RH |title= [Steps to integration or the fight with the Hydra "dualism"] |language=German |journal=Schweiz. Rundsch. Med. Prax. |volume=85 |issue=51-52 |pages=1641–6 |year=1996 |month=Dec |pmid=9026876 |doi= |url=] cite journal |author=Adler RH |title= [Are there psychological factors which lead to iatrogenic disorders?] |language=German |journal=Schweiz Med Wochenschr |volume=126 |issue=15 |pages=612–5 |year=1996 |month=Apr |pmid=8668975 |doi= |url=] often results in chronically-ill patients deferring to non-traditional and alternative forms of therapy, seeking to be understood as a whole, not a part,cite journal |author=Adler RH |title= [Is there a scientific alternative to alternative medicine?] |language=German |journal=Schweiz. Rundsch. Med. Prax. |volume=84 |issue=51-52 |pages=1517–21 |year=1995 |pmid=8571011 |doi=] which may be problematic among patients with FSS.

Furthermore, neuropsychiatry, physiological, and imaging studiescite journal |author=Fu CH, McGuire PK |title=Functional neuroimaging in psychiatry |journal=Philos. Trans. R. Soc. Lond., B, Biol. Sci. |volume=354 |issue=1387 |pages=1359–70 |year=1999 |month=Jul |pmid=10466156 |doi=10.1098/rstb.1999.0484 |url=http://journals.royalsociety.org/openurl.asp?genre=article&issn=0962-8436&volume=354&issue=1387&spage=1359] cite journal |author=Sheline YI, Wang PW, Gado MH, Csernansky JG, Vannier MW |title=Hippocampal atrophy in recurrent major depression |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=93 |issue=9 |pages=3908–13 |year=1996 |month=Apr |pmid=8632988 |doi= |url=http://www.pnas.org/cgi/pmidlookup?view=long&pmid=8632988] cite journal |author=Liberzon I, Zubieta JK, Fig LM, Phan KL, Koeppe RA, Taylor SF |title=mu-Opioid receptors and limbic responses to aversive emotional stimuli |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue=10 |pages=7084–9 |year=2002 |month=May |pmid=12011464 |doi=10.1073/pnas.102174799 |url=http://www.pnas.org/cgi/pmidlookup?view=long&pmid=12011464] cite journal |author=Kim JJ, Foy MR, Thompson RF |title=Behavioral stress modifies hippocampal plasticity through N-methyl-D-aspartate receptor activation |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=93 |issue=10 |pages=4750–3 |year=1996 |month=May |pmid=8643474 |doi= |url=http://www.pnas.org/cgi/pmidlookup?view=long&pmid=8643474] cite journal |author=Coplan JD, Andrews MW, Rosenblum LA, "et al" |title=Persistent elevations of cerebrospinal fluid concentrations of corticotropin-releasing factor in adult nonhuman primates exposed to early-life stressors: implications for the pathophysiology of mood and anxiety disorders |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=93 |issue=4 |pages=1619–23 |year=1996 |month=Feb |pmid=8643680 |doi= |url=http://www.pnas.org/cgi/pmidlookup?view=long&pmid=8643680] have shown PTSD and depression to be physical syndromes, in many respects, as they are psychiatric ones in demonstrating limbic system physiological and anatomy disturbances. Attendant PTSD hyperarousal symptoms, which additionally increase physiological stress, may play a part in leading to frequent MH-like hyperpyrexia and speculate on its influence on underlying myopathology of FSS in other ways. PTSD may also bring about developmental delays or developmental stagnation, especially in paediatric patients.cite journal |author=States JH, St Dennis CD |title=Chronic Sleep Disruption and the Reexperiencing Cluster of Posttraumatic Stress Disorder Symptoms Are Improved by Olanzapine: Brief Review of the Literature and a Case-Based Series |journal=Prim Care Companion J Clin Psychiatry |volume=5 |issue=2 |pages=74–9 |year=2003 |pmid=15156234 |doi= |url=http://www.psychiatrist.com/pcc/redirect/v05n02p074.htm |format=subscription required]

With psychodynamic psychotherapy, psychopharmacotherapy may need to be considered. Electroconvulsive therapy (ECT) is advised against, in light of abnormal myophysiology, with predisposal to MH.

Medical emphasis

General health maintenance should be the therapeutic emphasis in Freeman-Sheldon syndrome. The focus is on limiting exposure to infectious diseases because the musculoskeletal abnormalities make recovery from routine infections much more difficult in FSS. Pneumonitis and bronchitis often follow seemingly mild upper respiratory tract infections. Though respiratory challenges and complications faced by a patient with FSS can be numerous, the syndrome’s primary involvement is limited to the musculoskeletal systems, and satisfactory quality and length of life can be expected with proper care.

Prognosis

Life expectancy is normal.

Epidemiology

As of 1990, 65 patients had been reported in the literature, with no sex or ethnic preference notable.cite encyclopedia | title = Freeman-Sheldon syndrome | encyclopedia = Orphanet Encyclopedia | volume = | pages = | publisher = Comier-Daire | date = | id = | accessdate = ] Some individuals present with minimal malformation; rarely patients have died during infancy as a result of severe central nervous system involvementcite journal |author=Zampino G, Conti G, Balducci F, Moschini M, Macchiaiolo M, Mastroiacovo P |title=Severe form of Freeman-Sheldon syndrome associated with brain anomalies and hearing loss |journal=Am. J. Med. Genet. |volume=62 |issue=3 |pages=293–6 |year=1996 |month=Mar |pmid=8882790 |doi=10.1002/(SICI)1096-8628(19960329)62:3<293::AID-AJMG17>3.0.CO;2-F |url=] or respiratory complications.cite journal |author=Rao SS, Chary R, Karan S |title=Freeman Sheldon syndrome in a newborn (whistling face)--a case report |journal=Indian Pediatr |volume=16 |issue=3 |pages=291–2 |year=1979 |month=Mar |pmid=110675 |doi= |url=] Several syndromes are related to the Freeman-Sheldon syndrome spectrum, but more information is required before undertaking such nosological delineation.cite journal |author=Fitzsimmons JS, Zaldua V, Chrispin AR |title=Genetic heterogeneity in the Freeman-Sheldon syndrome: two adults with probable autosomal recessive inheritance |journal=J. Med. Genet. |volume=21 |issue=5 |pages=364–8 |year=1984 |month=Oct |pmid=6502650 |pmc=1049318 |doi= |url=] cite journal |author=Träger D |title= [Cranio-carpo-tarsal dysplasia syndrome (Freeman-Sheldon syndrome, whistling face syndrome)] |language=German |journal=Z Orthop Ihre Grenzgeb |volume=125 |issue=1 |pages=106–7 |year=1987 |pmid=3577337 |doi= |url=] cite journal |author=Simosa V, Penchaszadeh VB, Bustos T |title=A new syndrome with distinct facial and auricular malformations and dominant inheritance |journal=Am. J. Med. Genet. |volume=32 |issue=2 |pages=184–6 |year=1989 |month=Feb |pmid=2929657 |doi=10.1002/ajmg.1320320209 |url=]

Research directions

Because FSS is an extremely rare condition, systematic research is considered a low priority by major funders, such as governments, large charitable organizations, and businesses. The priority for limited research funds is to determine the role and nature of malignant hyperthermia in FSS. Such knowledge would benefit possible surgical candidates and the anaesthesiology and surgical teams who would care for them. MH may also be triggered by stress in patients with muscular dystrophies.cite journal |author=Litman RS, Rosenberg H |title=Malignant hyperthermia: update on susceptibility testing |journal=JAMA |volume=293 |issue=23 |pages=2918–24 |year=2005 |pmid=15956637 |doi=10.1001/jama.293.23.2918 |url=http://jama.ama-assn.org/cgi/pmidlookup?view=long&pmid=15956637] Much more research is warranted to evaluate this apparent relationship of idiopathic hyperpyrexia, MH, and stress.

Further research is wanted to determine epidemiology of psychopathology in FSS and refine therapy protocols.

References

External links

* [http://www.fspsg.org/Characteristics.htm Information] from the Freeman-Sheldon Parent Support Group