1.0 INTRODUCTION:

Freeman-Sheldon syndrome (FSS) is a rare autosomal dominant genetic disorder characterized by multiple congenital contractures and abnormalities. Usually the movements around two or more areas become restricted due to contractures at the joints of limbs. It is also associated with abnormalities of head and face area, defects of hands and feet and also skeletal malformations ¹.

Freeman and Sheldon were the first to discover this disorder during year 1938. They first described this syndrome as craniocarpotarsal dystrophy². Not long after that, FSS was rediscovered the entity and known as “Whistling Face Syndrome” by Burian et al³. Although the cases occur sporadically, it is suggested that it is an autosomal recessive inheritance since affected siblings are from unaffected parents. This support a study by Toydemir et al in which showed mutations in embryonic myosin heavy chain (MYH3) gene at 17p13.1-pter to cause FSS ⁴.

Affected infants may have a triangular face, prominent nasolabial folds, small mouth, high arced palate, attached earlobes, down slanting palpebral fissures, short statue, severe camptodactyly, mild cervical webbing, ulnar deviation and vertical talipes equinovarus ⁵. In addition, children with FSS may have distinctive facial appearance with a small mouth likely as a ‘whistling face’, given as its name ⁶.

Based on one article ⁶, there are other names for FSS, which are as below:

1. Cranialcarpotarsal dysplasia / dystrophy

2. Distal arthrogryposis, type 2A

3. DA2A

4. Whistling face syndrome / face-windmill vane hand syndrome

2.0 CLINICAL DESCRIPTION:

Most of affected individuals exhibit as in summarization of Table 1. It is very highly between families and both within but limited to hands and feet ⁵.

2.1 Facial Manifestations

Commonly facial characteristics would be a triangular face in such a narrow face is pointed at the chin. Other common things are high arched palate and micrognatia and some individuals may have show appearance of down slanting palpebral fissures. Besides that also include bulbous nose, high nasal bridge, small mouth, hypertolerism, facial asymmetry and posteriorly angulated ears ⁷.

2.2 Limbs

Congenital contractures at the distal joints of hands, wrists, feet and ankles are most common findings for diagnosis of FSS. It is usually severe only during birth and non-progressive. Proximal joints at the elbow, shoulder, knee and hip can also be seen. As for lower limbs, common findings are valgus abnormalities, talipes equinovarus, overlapping toes, tarsal fusion and vertical talus. In the upper limbs, it manifest as overlapping fingers, ulnar deviation and camptodactyly. An individual may posses equinovarus and calcaneovalgus abnormalities in feet ⁵.

2.3 Growth And Development

Prenatal and perinatal periods of affected infants are often within a normal range. Speech and language are rarely delayed but still a few may exhibit speech impairment. The cognitive abilities and life expectancy are not affected and absolutely normal ⁵.

3.0 ETIOPATHOGENESIS:

FSS is an inherited disorder, an autosomal dominant trait. It is caused by mutations in genes that encode fast twitch skeletal muscle isoforms of troponin I (TNNI2) and troponin T (TNNT3) and embryonic myosin (MYH3) ^8,9,10. There are also other causes such as genes deleted or any mutations in other as of yet unidentified genes. TNNI2 gene is located in the short arm of chromosome 17 (17P13.1), it encodes fast twitch skeletal muscle isoforms of troponin I. The troponins are muscle proteins of contractile apparatus. The fast twitch skeletal muscle isoform of troponin T encoded by TNNT3. The location is on chromosome 11p15.5. Same as troponin I, troponin T is also part of contractile apparatus of fast twitch myofibres ⁵. A case was reported that a mother with two affected children had missense mutation. The mutation caused a substitution of an arginine with histidine (p.R63H) ¹⁰. Two causes of PSS were from defects of contractile apparatus of fast twitch myofibres. Affected patients were screened with genes encoding myosin heavy chains, the major component of contractile apparatus and positive result were found in patients whom had no mutation of either TNNI2 or TNNT3. Instead, it led to screening of gene that encodes embryonic myosin heavy chain (MYH3). This mutation had been found in 5 out of 12 families and 27% of sporadic cases ⁸. Region of MYH3 that encodes for head domain of myosin showed seven missense mutation (p.S261F, p.S292C, p.E375K, p.D517Y, p.G769V, and p.T178I ) and two (p.D1622A, p.A1637V) were located in the region that encodes the tail domain.

4.0 DIAGNOSIS:

FSS can be diagnosis based on the their clinical characteristics^7,11. The major criteria are triangular face with pointed chin, high arched palate, short neck, small mouth, overriding fingers, hypoplastic flexion creases, talipes equinovarus, ulnar deviation and calcaneovalgus abnormalities¹¹. Meanwhile, minor criteria are short stature, down slanting palpebral fissure, attached ear lobes, a small mandible and cervical webbing ⁵.

4.1 Antenatal Diagnosis

Diagnosis of FSS can be done at prenatal stage through ultrasonography in which some pregnant women can feel less fetal movement and they might also be normal. The detection by ultrasonography can only be done after 24 weeks of gestation. Positive findings usually be seen in family with case history and mutation ¹².

4.2 Differential Diagnosis

FSS shows same clinical characteristics with distal arthrogryposis 1 (DA1). Affected individuals do not have major contractures of facial muscles or facial abnormalities and their findings are limited to contractures at the distal joints of hands and feet ¹³.

5.0 MANAGEMENT:

5.1 Surgical an anaesthetic considerations

Approach of surgical to correct craniofacial^14-16, clubfoot¹⁷ or hand correction^18-21 are believed can enhance aesthetics purpose and their function as well. The patients should meet an appointment with craniofacial and orthopedic surgeons first and have consultation with them. However, safety and operative measure should be taken seriously with consideration of the abnormal muscle physiology in FSS ²².

5.2 Psychiatric Considerations

Early interventions hold the possibility to minimize depression secondary to chronic illness and posttraumatic stress disorder (PTSD). Patients with FSS and their parents must receive psychotherapy that includes marriage counseling. They should also have pre-emptive and ongoing mixed cognitive therapy-psychodynamic psychotherapy and cognitive-behavioral therapy (CBT). Plus, neuropsychiatry, imaging studies and physiological stated that PTSD is only physical syndromes²². Ecsh stated that those psychiatrists are very helpful to address the balance of positivity and negative stressors²³.

6.0 TREATMENTS:

Treatments suggested for patients with FSS are different and apparent to every single individual. Pediatrics, physicians, orthopedic surgeon, dental specialists, speech pathologist are the professional team who specialize in giving appropriate treatment to this syndrome. Patients with small mouth, known as microstomia can be corrected by a surgery or use a special device that can expand the mouth. It is important to treat the mouth since a very small mouth can lead to other problem such as malocclusion. Specific or physical therapy can be done to improve the ability to walk and perform other movements independently. Surgery can be successfully addresses for club feet, abnormalities of hands and contractures of knees and elbows. Difficulty in swallowing (dysphagia) is treated by using a special device to maintain tension on the neck and other further procedures are need to correct the stiffness of the neck muscles, commonly refers to posterior occipital-cervical decompression and fusion ¹.

7.0 CONCLUSION:

FSS or also called as Whistling Face Syndrome is a very rare disease which is inherited from blood ties. Some studies evaluated that mutation on short arm of chromosome caused FSS and yet, the etiology still remains unknowns. This syndrome is commonly associated with joint contractures and abnormalities. For instance, microstomia with pointed toward the chin, talipe equinovarus and camptodactyly with ulnar deviation of the hand. Both sexes can be affected and ultrasonography is very helpful to diagnose at prenatal stage. Some surgical procedures may be required to improve aesthetic and function ²⁴.

8.0 REFERENCES:

1. "Freeman Sheldon Syndrome - NORD (National Organization for Rare Disorders)." NORD National Organization for Rare Disorders Freeman Sheldon Syndrome Comments. Web. 30 April 2016.

2. Freeman E A, Sheldon J H. Cranio-carpotarsal dystrophy: undescribed congenital malformation. Arch Dis Child 1938; 13: 277–283

3. Hall JG, Reed SD, Greene G. The Distal arythrogyposes: delineation of new entities review and nosologic discussion. Am J Med Genet 1982 ; 11: 185-239

4. Bamshad M, Watkins WS, Zenger RK, Bohnsack JF, Carey JC, Otterud B, Krakowiak OA, Robertson M, Jorde LB () A gene for distal arthrogyposis type 1 maps to the pericentromeric region of chromosome 9. Am J Hum Genet 1994; 55 : 1153-8

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8. Toydemir RM, Rutherford A, Whitby FG, Jorde LB, Carey JC, Bamshad MJ: Mutations in embryonic myosin heavy chain (MYH3) cause Freeman-Sheldon syndrome and Sheldon-Hall syndrome. Nature Genetics. 2006, 38: 561-565

9. Sung SS, Brassington AE, Grannatt K, Rutherford A, Whitby FG, Krakowiak PA, Jorde LB, Carey JC, Bamshad M: Mutations in genes encoding fast-twitch contractile proteins cause distal arthrogryposis syndromes. American Journal of Human Genetics. 2003, 72: 681-690

10. Sung SS, Brassington AE, Krakowiak PA, Carey JC, Jorde LB, Bamshad M: Mutations in TNNT3 cause multiple congenital contractures: a second locus for distal arthrogryposis type 2B. American Journal of Human Genetics. 2003, 73: 212-214

11. Krakowiak PA, O'Quinn JR, Bohnsack JF, Watkins WS, Carey JC, Jorde LB, Bamshad M: A variant of Freeman-Sheldon syndrome maps to 11p15.5-pter. American Journal of Human Genetics. 1997, 60: 426-432

12. Jiang M, Bian C, Li X, Man X, Ge W, Han W, Bao H, Li Y, Yi D, Guan Y: Molecular prenatal diagnosis for hereditary distal arthrogryposis type 2B. Prenatal Diagnosis. 2007, 27: 468-470

13. Bamshad M, Jorde LB, Carey JC: A revised and extended classification of the distal arthrogryposes. American Journal of Medical Genetics. 1996, 65: 277-281

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21. Wenner SM, Shalvoy RM (November 1989). "Two-stage correction of thumb adduction contracture in Freeman-Sheldon syndrome (craniocarpotarsal dysplasia)". J Hand Surg [Am] 14 (6):937–40.doi:10.1016/S0363-5023(89)80040-1. PMID 2584652

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Received on 18.05.2016 Modified on 28.05.2016

Research J. Pharm. and Tech 2016; 9(10):1773-1776.

DOI: 10.5958/0974-360X.2016.00358.9