In 1938, Freeman and Sheldon described a syndrome char- acterized by a whistling face with a long philtrum, a puckered mouth, microstomia, H-shaped cutaneous dimpling on the chin, multiple joint contractures with camptodactyly, ulnar deviation of the fingers, bilateral talipes equinovarus, and kyphoscoliosis.
The syndrome is also known as craniocarpotarsal dysplasia or
“whistling face” syndrome.
GENETICS/BASIC DEFECTS
1. Genetic heterogeneity
a. Autosomal dominant inheritance:
i. Usually with normal psychomotor development, although mild motor delay attributable to joint anomalies might be present
ii. A variant of autosomal dominant inheritance, mapped to chromosome 11p15.5-pter
b. Autosomal recessive inheritance: severe developmental retardation reported in a few patients
2. Pathogenesis
a. Considered a form of distal arthrogryposis i. Closely related to distal arthrogryposis type 1
a) Similar limb phenotypes but distinguished only by differences in facial morphology b) Reports of families in which different indi-
viduals were diagnosed with distal arthrogry- posis type 1 or Freeman-Sheldon syndrome ii. Proposed to classify Freeman-Sheldon syn-
drome as distal arthrogryposis type 2 (a distinct disorder from distal arthrogryposis type 1 with overlapping phenotypes) in a revised classifica- tion of distal arthrogryposis
b. Primary brain anomalies suggested to explain many manifestations of the syndrome
c. Also considered possibly a nonprogressive or slowly progressive myopathy
CLINICAL FEATURES
1. Variable clinical severity and phenotypic abnormalities 2. Normal intelligence
3. “Whistling face” appearance a. Long philtrum
b. Microstomia c. Puckered mouth d. Pursed lips
e. H-shaped cutaneous dimpling on the chin 4. Musculoskeletal anomalies
a. Multiple joint contractures b. Camptodactyly
c. Ulnar deviation of fingers
d. Windmill vane hand (bilateral ulnar deviation and contracture of fingers 2–5 at the metacarpophalangeal joints with adduction of thumbs)
e. Normal hands in a few reports f. Bilateral talipes equinovarus g. Kyphoscoliosis
5. Growth retardation 6. Other craniofacial features
a. Masklike rigid face b. Flat midface
c. Deep-sunken eyes with hypertelorism d. Antimongoloid slant of the palpebral fissures e. Blepharophimosis
f. Convergent strabismus g. Full cheeks
h. Small nose
i. Coloboma alae of the nose j. Micrognathia
k. Cleft palate or high-arched palate l. Choanal atresia
m. Low-set and malformed ears n. Hearing loss
7. Other features a. Nasal speech b. Short neck c. Inguinal hernia d. Cryptorchidism e. Spina bifida occulta 8. Complications
a. Difficulty in swallowing attributed to the mouth deformity
b. Pulmonary problems due to decreased thoracic expansion
DIAGNOSTIC INVESTIGATIONS
1. Radiography a. Skull
i. Shallow anterior cranial fossa ii. Hypoplastic mandible iii. Small malar bones
b. Ulnar deviation and flexion contractures of the fingers c. Talipes equinovarus
d. Kyphoscoliosis
2. Polysomnography for sleep-disordered breathing 3. Muscle biopsy findings: structural changes predominantly
involving type I fibers suggesting that the muscle lesion is a form of congenital fiber type disproportion
GENETIC COUNSELING
1. Recurrence risk a. Patient’s sib
i. Autosomal dominant inheritance: low unless a parent is affected
ii. Autosomal recessive inheritance: 25%
iii. Empirical risks for sibs of sporadic cases: 7%
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428 FREEMAN-SHELDON SYNDROME
b. Patient’s offspring
i. Autosomal dominant inheritance: 50%
ii. Autosomal recessive inheritance: low unless the spouse is affected
iii. Empirical risk for children of sporadic case: 37%
2. Prenatal diagnosis made by ultrasonography at 20 week of gestation in a fetus with a positive family history
i. Bilateral equinovarus and abnormally positioned toes
ii. Clenched hands with overlapping thumbs iii. An abnormally appearing mouth with pursing of
the lips 3. Management
a. Tracheostomy required for severe upper airway narrowing
b. Management of anesthetic risks
i. Risks primarily related to severe microstomia ii. Combinations of myopathic and skeletal abnor-
malities predisposing affected patients to signif- icant postoperative respiratory difficulty iii. Awake endotracheal intubation or fiberoptic
nasotracheal intubation in infants before induc- tion of general anesthesia
c. Functional hand reconstruction for hand deformities d. Orthopedic correction of clubfeet and scoliosis
REFERENCES
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‘whistling face’. J Med Genet 14:139–141, 1977.
Burzynski NJ, Podruch PE, Howell J, et al.: Craniocarpotarsal dysplasia syn- drome (whistling face syndrome). Case reports and survey of clinical findings. Oral Surg Oral Med Oral Pathol 39:893–900, 1975.
Dallapiccola B, Giannotti A, Lembo A, et al.: Autosomal recessive form of whistling face syndrome in sibs. Am J Med Genet 33:542–544, 1989.
Duggar RG Jr, DeMars PD, Bolton VE: Whistling face syndrome: general anesthesia and early postoperative caudal analgesia. Anesthesiology 70:545–547, 1989.
Fitzsimmons JS, Zaldua V, Chrispin AR: Genetic heterogeneity in the Freeman- Sheldon syndrome: two adults with probable autosomal recessive inheri- tance. J Med Genet 21:364–368, 1984.
Freeman E, Sheldon J: Cranio-carpotarsal dystrophy: Undescribed congenital malformation. Arch Dis Child 13:277–283, 1938.
Gross-Kieselstein E, Abrahamov A, Ben-Hur N: Familial occurrence of the Freeman-Sheldon syndrome: cranio-carpotarsal dysplasia. Pediatrics 47:1064–1067, 1971.
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Fig. 1. Freeman-Sheldon syndrome in a father and son showing whistling face appearance of the face and ulnar deviation and fixed position of the thumbs.
Fig. 2. Freeman-Sheldon syndrome in a neonate showing characteris- tic “whistling face”, ulnar deviation of the fingers with contractures, and talipes equinovarus.
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Fig. 3. Another neonate showing characteristic “whistling face” with H-shaped cutaneous dimpling on the chin and ulnar deviation and con- tractures of the fingers
Fig. 4. A newborn with Freeman-Sheldon syndrome showing whistling appearance of the face, tight mouth opening, hypoplastic alae nose, arthrogryposis of the hands and fingers with contractures and ulnar deviation of the wrists, and metatarsus adductus. Intrauterine growth retardation and Dandy-Walker malformation were detected prenatally by ultrasound.
