Ocular Manifestations of Freeman-Sheldon (Whistling Face) Syndrome
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Freeman-Sheldon/Freeman-Burian Syndrome (FBS) is a rare syndrome of multiple congenital contractures and has been described previously under various names: Whistling Face Syndrome, Whistling Face-Windmill Vane Hand Syndrome, Distal Arthrogryposis Type 2A, Craniocarpotarsal dysplasia, and Craniocarpotarsal dystrophy.[1][2][3] The disease is named for Ernest Arthur Freeman and Joseph Harold Sheldon, who first described it in 1938.[1] It was confirmed as an independent disease entity by Fredrick Burian in 1963.[1] Although FBS is rare, it is important for ophthalmologists to be able to recognize the diagnosis, manage its ocular manifestations, and participate in multidisciplinary coordination aimed at functional rehabilitation.
Disease Entity
Genetics
The disease is thought to be caused by variants in the MYH3 gene.[2][3] MYH3 encodes for myosin heavy chain 3 and is located on chromosome 17p13.1.[2] Most variants occur sporadically, but the disease is also inherited in an autosomal recessive or autosomal dominant pattern.[2]
Epidemiology
FBS is exceptionally rare with an estimated prevalence of 0.9 per 1 million worldwide.[1] It occurs in all ethnicities, biologic genders, and geographic regions evenly.[1]
Diagnosis
Clinical Features
FBS is the most severe of the distal arthrogryposis and is well-known due to its severe orofacial contractures resulting in a “whistling” facial appearance.[2][4] Symptoms of FBS typically are recognized in the newborn period.[4] The disease is most frequently characterized by microstomia, a “whistling” facial appearance, an ‘H-shaped’ or ‘V-shaped’ chin dimple, and prominent nasolabial folds.[4] Patients may also have limb malformations, such as talipes equinovarus and joint contractures.[1] Orofacial abnormalities may include long philtrum, high-arched palate, small nose, short neck, and mask-like facies.[1][5]
Due to the involvement of orofacial muscles, periocular manifestations are common in FBS and include:[1][4][5][6][7][8][9]
- Blepharoptosis
- Blepharophimosis
- Blepharospasm
- Strabismus
- Hypertelorism
- Prominent supraorbital ridge
- Deep-set eyes
- Down-slanting palpebral fissures
- Enophthalmos
- Epicanthal folds
Periocular features are thought to arise secondary to fibrosis of the involved muscles.[5] Histopathologically, white fibrous and adipose tissue are observed to replace normal muscle fibers.[1] Blepharophimosis may be precipitated by blepharospasm early in development when muscle in the eyelid is still present.[1]
Clinical Diagnosis
Prenatal diagnosis of FBS can be accomplished via ultrasound examination, but contractures are frequently not evident until 18 to 24 weeks of gestation and distinguishing the disease features from other distal arthrogryposis is challenging.[4] More often, diagnosis of FBS is made at birth and is based on symptoms and clinical exam.[1][4] Genetic testing confirmation is used to identify MYH3 allelic variations, although at least 7% of clinical FBS cases are not explained by known pathological allelic variations.[1]
The diagnostic criteria for FBS are the inclusion of two or more of the following features:[4]
- Microstomia
- Whistling-face (pursed lips)
- Prominent nasolabial creases
- ‘H-shaped or “V-shaped’ chin dimple
Neonates suspected of having FBS should be evaluated by their primary care provider and several specialists including a clinical geneticist, orthopedic surgeon, craniofacial surgeon, speech/occupational therapist, and physical therapist.[4]
Differential Diagnosis
There are multiple disorders that present similarly and may overlap with FBS. These disorders include other distal arthrogryposes, Sheldon-Hall Syndrome, CLIFAHD, Schwartz-Jampel Syndrome, and non-syndromic distal contractures.[1]
Management
Possible Therapy
Multidisciplinary care is important to address the wide range of clinical manifestations and improve functional outcomes in patients with FBS. While there is no specific treatment for FBS, optimal treatment is best achieved through a combination of early craniofacial reconstructive surgery and intensive physiotherapy.[1] Therapeutic intervention is targeted towards fibrous tissue replacement, which involves either operative release of fibrous bands or stretching with physiotherapy to reduce contractures.[1]
Treatment for periocular complications of FBS is focused on vision preservation.[1] Surgical correction of blepharoptosis, blepharophimosis, and other eyelid abnormalities is often needed to prevent deprivational or strabismic amblyopia.[9] For the greatest physiologic benefit and least psychosocial consequences, craniofacial reconstruction for FBS is recommended before early school years.[10] However, craniofacial surgeries often require revision after reformation of fibrous tissue-contracting bands within normal muscle.[10]
Previously reported approaches to blepharophimosis and blepharoptosis correction include modified bilateral therapeutic blepharoplasty with a static sling to the epicranius frontalis,[11] complete forehead reshaping with use of static sling to epicranius frontalis,[12] and correction of blepharophimosis with canthotomy and canthoplasty.[13]
Operative intervention can be complicated by patients’ abnormal musculature.[4][9] Strabismus correction can pose challenges due to patients’ stiff extraocular muscles.[5] In addition, patients with FBS have an increased susceptibility to anesthetic complications such as malignant hyperthermia, and tracheal intubation is challenging in patients due to their small mouth.[4][9] Thus, presurgical evaluation should include an assessment of potential anesthetic risks.[4]
Prognosis
If untreated, patients with FBS may have poor mobility secondary to limb and skeletal abnormalities and experience diminished occupational and quality of life outcomes.[1] Psychosocial problems such as depression, anxiety, low self-esteem, poor social relationships, and changes in body image have been reported in association with craniofacial abnormalities.[1] These psychosocial consequences are underrecognized and are associated with functional limitations and substance abuse.[1] However, with early and appropriate treatment, most persons with FBS have good prognosis and can lead normal, healthy, independent lives.[1]
References
- ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18 1.19 Poling MI, Dufresne CR, Chamberlain RL. Freeman-Burian syndrome. Orphanet J Rare Dis. 2019 Jan 10;14(1):14. doi: 10.1186/s13023-018-0984-2. PMID: 30630514; PMCID: PMC6327538.
- ↑ 2.0 2.1 2.2 2.3 2.4 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. Nat Genet. 2006 May;38(5):561-5. doi: 10.1038/ng1775. Epub 2006 Apr 16. PMID: 16642020.
- ↑ 3.0 3.1 “Freeman-Sheldon Syndrome.” https://www.ncbi.nlm.nih.gov/gtr/conditions/C0265224/
- ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 Stevenson DA, Carey JC, Palumbos J, Rutherford A, Dolcourt J, Bamshad MJ. Clinical characteristics and natural history of Freeman-Sheldon syndrome. Pediatrics. 2006 Mar;117(3):754-62. doi: 10.1542/peds.2005-1219. PMID: 16510655.
- ↑ 5.0 5.1 5.2 5.3 O'Keefe M, Crawford JS, Young JD, Macrae WG. Ocular abnormalities in the Freeman-Sheldon syndrome. Am J Ophthalmol. 1986 Sep 15;102(3):346-8. doi: 10.1016/0002-9394(86)90009-7. PMID: 3752200.
- ↑ Kapoor S. A unique and often overlooked cause of Blepharophimosis: "Whistling face syndrome". Orbit. 2016 Dec;35(6):350. doi: 10.1080/01676830.2016.1193540. Epub 2016 Sep 13. PMID: 27625150.
- ↑ Leung KCP, Ko TCS. Novel ophthalmic features of Freeman-Sheldon syndrome. J Fr Ophtalmol. 2021 May;44(5):e315-e316. doi: 10.1016/j.jfo.2020.08.012. Epub 2021 Feb 4. PMID: 33551110.
- ↑ Bowman S, Noble G, Rahmani B, Mets M, Ralay Ranaivo H, Castelluccio V. A case of blepharophimosis: Freeman Sheldon syndrome. Ophthalmic Genet. 2022 Feb;43(1):130-133. doi: 10.1080/13816810.2021.1989603. Epub 2021 Oct 19. PMID: 34664542.
- ↑ 9.0 9.1 9.2 9.3 Heinze K, Akella SS, Setabutr P. Periocular Anomalies in Freeman-Sheldon Syndrome. Ophthalmic Plast Reconstr Surg. 2023 Jan-Feb 01;39(1):e28. doi: 10.1097/IOP.0000000000002207. Epub 2022 Jun 3. PMID: 35657657.
- ↑ 10.0 10.1 Poling MI, Dufresne CR, Portillo AL. Identification and Recent Approaches for Evaluation, Operative Counseling, and Management in Patients With Freeman-Burian Syndrome: Principles for Global Treatment. J Craniofac Surg. 2019 Nov-Dec;30(8):2502-2508. doi: 10.1097/SCS.0000000000005968. PMID: 31567769.
- ↑ Portillo AL, Poling MI, McCormick RJ. Surgical Approach, Findings, and Eight-Year Follow-Up in a Twenty-Nine Year Old Female With Freeman-Sheldon Syndrome Presenting With Blepharophimosis Causing Near-Complete Visual Obstruction. J Craniofac Surg. 2016 Jul;27(5):1273-6. doi: 10.1097/SCS.0000000000002781. PMID: 27380584.
- ↑ Guyuron B, Winkler PA. Craniocarpotarsal dysplasia: the whistling face syndrome. Ann Plast Surg. 1988 Jan;20(1):86-8. PMID: 3341720.
- ↑ Bekir N, Bayraktaroğlu Z, Coşkun Y, Karaaslan C. Whistling face (Freeman-Sheldon) syndrome in two siblings. Turk J Pediatr. 1994 Oct-Dec;36(4):329-32. PMID: 7825240.
