Freeman-Sheldon syndrome

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^[1]. Freeman-Sheldon syndrome is a rare form of multiple congenital contracture (MCC) syndromes (arthrogryposes) and is the most severe form of distal arthrogryposis (DA)^[2][3][4].  

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Classification

Freeman-Sheldon syndrome is a type of distal arthrogryposis, related to distal arthrogryposis type 1 (DA1).^[5] 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).^[4]

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.^[4]

Freeman-Sheldon syndrome has been described as a type of congenital myopathy.^[6]

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^[1][2][3], and various other primary anomalies involving the musculoskeletal system^[7].

Background

Incidence, nosology, and inheritance

As of 1990, 65 patients had been reported in the literature, with no sex or ethnic preference notable^[8]. Some individuals present with minimal malformation; rarely patients have died during infancy as a result of severe central nervous system involvement^[9] or respiratory complications^[10]. Several syndromes are related to the Freeman-Sheldon syndrome spectrum, but more information is required before undertaking such nosological delineation^[11][12][13].

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 [15, 16]. Other mutations have been found as well [17, 18]. In FSS, inheritance may be either autosomal dominant, most often demonstrated [19, 20, 21], or autosomal recessive (MIM 277720) [22, 23, 24, 25, 26]. Alves and Azevedo (1977) note most reported cases of DA2A have been identified as new allelic variation [27]. 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 [28, 29]. 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 [28, 30, 31]. 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 [28, 32, 33, 34].

Abnormal muscle physiology and malignant hyperthermia (MH)

In consideration of the abnormal muscle physiology in Freeman-Sheldon syndrome, therapeutic measures may have unfavourable outcomes [35]. Difficult endotrachial intubations and vein access complicate operative decisions in many DA2A patients, and it is suggested there is a possibility of malignant hyperthermia (MH) in FSS, as well. Dolcourt et al. (2001) and Sobrado et al. (1994) report the onset of MH symptoms in DA2A patients [36, 37]. Cruickshanks et al. (1999) reports uneventful use of non-MH-triggering agents [38]. Namiki et al. (2003) reports spina bifida occulta implications in anaesthesia management [39]. Vas and Naregal (1998) report implications of cervical kyphoscoliosis in intubations [40]. Many authors comment on difficult intubations, venous access, and prophylaxis of MH [41, 42, 43].

Diagnosis

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^[3].

Management

Surgical and anaesthetic considerations

Patients must have early consultation with craniofacial and orthopaedic surgeons, when craniofacial [48, 49, 50], clubfoot [51], or hand correction [52, 53, 54, 55] 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 myopathology of the syndrome. Malignant hyperthermia and difficult intubations during surgery also complicate operative decisions in many FSS patients.

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.

Psychiatric considerations

Patients and their parents must receive psychotherapy, which should include marriage counselling [57]. Mitigation of lasting psychological problems, including depression secondary to chronic illness and posttraumatic stress disorder (PTSD), can be very successfully addressed with early interventions [58]. This care may come from the family physician, or other attending physician, whomever is more appropriate; specialist care is generally not required [59, 60, 61]. Lewis and Vitulano (2003) note several studies suggesting predisposal for psychopathology in paediatric patients with chronic illness [62]. Esch (2002) advocates preventive psychiatry supports to facilitate balance of positive and negative stressors associated with chronic physical pathology [63]. Patients with FSS should have pre-emptive and ongoing mixed cognitive therapy-psychodynamic psychotherapy [64] for patients with FSS and cognitive-behavioural therapy (CBT), if begun after onset of obvious pathology.

Adler (1995) cautioned the failure of allopathic medicine to implement the biopsychosocial model [65], which incorporates all aspects of a patient’s experience in a scientific approach into the clinical picture [66, 67, 68, 69], 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 [70], which, we observe, may be problematic among patients with FSS.

Furthermore, neuropsychiatry, physiological, and imaging studies [71, 72, 73, 74, 75] 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 [76].

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.

Research

Further research to determine the role and nature of MH in FSS must be a high priority, as well. Such knowledge would benefit possible surgical candidates and the anaesthesiology and surgical teams who would care for them. It has been suggested malignant hyperthermia can be triggered by stress in patients with muscular dystrophies [56]. Much more research is warranted to evaluate this apparent relationship of idiopathic hyperpyrexia, MH, and stress.

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

References

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2. ^ ^{a b} Online 'Mendelian Inheritance in Man' (OMIM) 193700
3. ^ ^{a b c} Stevenson, DA; Carey JC, Palumbos J, Rutherford A, Dolcourt J, Bamshad MJ (March 2006). "Clinical characteristics and natural history of Freeman-Sheldon syndrome". Pediatrics 117 (3): 754-762.
4. ^ ^{a b c} Bamshad, M; Jorde LB, Carey JC (1996). "A revised and extended classification of the distal arthrogryposes". Am J Med Genet 11 (65(4)): 277-281.
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