Freeman-Sheldon Syndrome
A rare congenital, distal arthogryposis syndrome characterized by microstomia, whistling-face appearance, Chin with V- or H- shaped creased, and prominent nasolabial folds; most patients present club foot and congenital joint contractures of the hands and feet. It is the most severe form of distal arthrogryposis.
Epidemiology
Approximately 100 cases of Freeman-Sheldon syndrome (FSS) have been reported to date; no gender predominance is reported and the distribution is worldwide.
Clinical description
Facial features include prominent forehead and eyebrow ridges, hypertelorism, epicanthus, telecanthus, down-slanting palpebral fissures, deep-set eyes, full cheeks, low-set ears, midface hypoplasia, a short nose and long philtrum, deep nasolabial folds, high-arched palate, and chin with a V- or H-shaped crease. The hallmark feature is small mouth with a whistling appearance. Dental crowding and difficulty in maintaining oral hygiene are reported, as well as hearing loss. Multiple contractures in the hands and feet are found at birth and are non-progressive; they cause camptodactyly, ulnar deviation of wrist and fingers, clubfoot, and overlapping fingers. Kyphoscoliosis is a frequent feature; congenital dislocation of the hip is rare. Ocular features include hypertelorism, strabismus, ptosis and blepharophimosis. Delayed growth is almost universal, but cognitive performances are generally normal. Infancy may be characterized by failure-to-thrive, due to microstomia, micrognathia and high palate. Other problems occurring with higher frequency in FSS are sleep apnea, dysglycemia, hyperhidrosis, diarrhea, constipation and gastro-esophageal reflux disease. An increased risk of adverse event during anesthesia is reported, mainly due to difficult intubation (because of orofacial contractures and structural anomalies, limited neck mobility, spinal deformities), difficult vascular access, and susceptibility to malignant hyperthermia.
Etiology
FSS is caused by homozygous mutations in MYH3, encoding for embryonic myosin heavy chain 3, a primary component of fetal myotubules; this protein has a central role during fetal muscular development, while postnatally it is progressively replaced by other isoforms. The switch in myosin expression pattern could explain why contractures are congenital and non-progressive. Mutations in NALCN have been identified in a few cases.
Diagnostic methods
Diagnosis is based on both physical findings and genetic testing on MYH3. Diagnostic criteria have been proposed and include two or more of the following signs: distal arthrogryposis, microstomia, whistling-face, nasolabial creases, and H-shaped chin dimple. In some cases of clinically diagnosed FSS, mutations in NALCN have been detected. Of note, at least 7% of clinical FSS cases are not explained by known pathological allelic variations.
Differential diagnosis
Differential diagnosis mainly includes other distal arthrogryposis such as digitotalar dymorphism (which lacks craniofacial features), Sheldon-Hall syndrome (clinically less severe), Gordon syndrome, trismus-pseudocamptodactyly syndrome, and autosomal dominant multiple pterygium syndrome. Schwartz-Jampel syndrome and CLIFAHDD (congenital contractures of the limbs and face, hypotonia, and developmental delay) are also to be considered.
Antenatal diagnosis
Pre-conception and pre-natal tests are possible, when a relative carries a known pathogenic variant. Prenatal ultrasound can also be useful.
Genetic counseling
Most cases are sporadic (de novo) autosomal dominant mutations; an autosomal recessive inheritance pattern has also been described and seems to be associated with a more severe clinical presentation. Genetic counselling may be offered for patients who have a child with FSS.
Management and treatment
No specific pharmacological therapy is available. Patients should have craniofacial and orthopedic consultation as early in life as possible, in order to undertake proper operative measures (e.g. oral commissuroplasties, dental treatment, blepharoplasty, myringotomies). Operative correction of lower deformities often results in poor outcome. Bracing and physiotherapy (including the Ponseti method) are the cornerstones of non-operative therapy.
Prognosis
Aspiration and respiratory complications may lead to early mortality. Surviving infants usually have normal life expectancy. Quality of life is generally impaired by the multiple malformations and functional repercussions.