In 1950, Larsen et al. described a condition characterized by multiple large joint dislocations and flat face. The condition occurs in approximately 1 in 100,000 births.
GENETICS/BASIC DEFECTS
1. Subtypes
a. Sporadic form
b. Autosomal dominant form
c. Autosomal recessive form: clinical phenotype more debilitating with higher mortality than the autosomal dominant form
d. Possible lethal form
2. The first known gene mutated in Larsen syndrome, LAR1, for autosomal dominant form: mapped to 3p21.1- 14.1 in the proximity of, but distinct from, the COL7A1 locus
3. Unilateral manifestation of typical skeletal defects in some patients indicates that this condition might represent unilateral somatic cell-line mosaicism
CLINICAL FEATURES
1. Broad inter- and intrafamilial clinical variability 2. Characteristic flat facial appearance (“dish face”)
a. Prominent forehead (frontal bossing) b. Hypertelorism
c. Hypoplastic midface d. Depressed nasal bridge e. Micrognathia
f. Occasional cleft palate, lip or uvula 3. Bilateral multiple joint dislocations
a. Shoulders b. Elbows c. Wrists d. Hips e. Patella
f. Ankles g. Knees
4. Variable handicap due to joint luxations 5. Hand abnormalities
a. Long, cylindrical, and tapering fingers (pseudoclub- bing)
b. Spatulate/bifid thumbs
c. Dislocation of distal radioulnar joint d. Delayed carpal ossification
e. Supernumerary ossification centers f. Brachymetacarpia
g. Brachytelephalangia
h. Hyperextension of distal interphalangeal joints 6. Feet abnormalities
a. Spatulate hallux
b. Equinovarus or valgus deformities of the feet
7. Respiratory distress due to tracheolaryngomalacia a. Stridor
i. Inspiratory reflecting laryngomalacia or extratho- racic cervical tracheomalacia
ii. Expiratory reflecting intrathoracic tracheomalacia b. Cyanosis
c. Obstructive apnea d. Possibly life-threatening 8. Bronchomalacia
a. Lobar atelectasis b. Hyperinflation c. Pneumonias
9. Respiratory embarrassment in infancy due to soft trache- olaryngeal cartilage
10. Soft/collapsing thorax 11. Cardiovascular abnormalities
a. Congenital defects i. Bicuspid aortic valve ii. Subaortic stenosis iii. Atrial septal defect
iv. Ventricular septal defect v. Patent ductus arteriosus vi. Pulmonary stenosis vii. Endocardial fibroelastosis b. Acquired lesions
i. Dilated aortic root ii. Elongated aorta iii. Mitral valve prolapse
iv. Aneurysm of ductus arteriosus v. Arterial tortuosity and dilatation 12. Associated spinal anomalies
a. Cervical spine involvement
i. More often affected than thoracic or lumbar spine ii. Results in:
a) Midcervical kyphosis, usually at the C4–C5 region
b) Cervicothoracic lordosis c) Spinal instability
iii. Flattened, hypoplastic, and often bifid cervical vertebrae
b. Atlantoaxial instability i. A rare finding
ii. May be associated with other abnormalities of the upper cervical spine
a) Occipitalization of the atlas b) Basilar impression
c. Lumbosacral dysraphism: may lead to neurological impairment
d. Thoracic scoliosis
e. Hypoplasia of the vertebral bodies or posterior elements f. Quadriplegia secondary to segmentation abnormali-
ties of the vertebrae
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13. Mixed hearing loss due to ossicular abnormality 14. CNS anomalies
a. Hydrocephalus (rare)
b. Glial proliferation in the brain 15. Short stature
16. Normal intelligence 17. Possible lethal form a. Tracheomalacia b. Pulmonary hypoplasia c. Collagen fiber dysmaturity 18. Prognosis
a. Generally good after aggressive orthopedic manage- ment, except some lethal cases due to tracheolaryngo- malacia and/or lung hypoplasia
b. Compatible with successful pregnancy if the maternal and fetal safety issues are properly considered
DIAGNOSTIC INVESTIGATIONS
1. Radiography
a. Bilateral dislocations of shoulders, elbows, wrists, hips, patella, ankles, and knees (anterior dislocation of the tibia on the femur, most characteristic) b. Genu recurvata
c. Talipes deformities (club feet) d. Spatulate thumbs
e. Shortened metacarpals
f. Multiple supernumerary carpal ossification centers (short, small, and increased in number)
g. Poor ossification of phalanges
h. Delayed coalescence (duplication) of calcaneal ossifi- cation centers
i. Occasional abnormal segmentation of vertebrae (± fusion defects of cervical spine)
j. Cervical kyphosis k. Spina bifida occulta
l. Scoliosis
m. Craniofacial disproportion
2. Polysomnography for assessing the severity of airway obstruction
3. Echocardiography for cardiovascular lesions 4. MRI of the brain for cerebral malformations
GENETIC COUNSELING
1. Recurrence risk a. Patient’s sib
i. Sporadic form (consider germ-line mosaicism when neither parent appears to be affected) ii. Autosomal dominant inheritance: risk not in-
creased unless a parent is affected
iii. Autosomal recessive inheritance: 25% risk of having sibs affected
b. Patient’s offspring
i. Sporadic form: risk not increased unless the patient has germ-line mosaicism
ii. Autosomal dominant inheritance: 50% risk of having offspring affected
iii. Autosomal recessive inheritance: risk not in- creased unless the spouse is also a carrier
2. Prenatal diagnosis accomplished in rare cases by ultra- sonography in pregnancies at risk
a. Multiple joint dislocations i. Elbow
ii. Knees iii. Hips b. Flat facial profile
i. Prominent forehead ii. Hypertelorism
iii. A depressed nasal bridge iv. Micrognathia
v. Cleft palate c. Genu recurvatum d. Club feet 3. Management
a. Supporting therapy for airway difficulty i. Antibiotics as needed
ii. Supplemental oxygen
iii. Chest physiotherapy to augment mucus clearance iv. Require intubation for severe respiratory distress with positive end-expiratory pressure (PEEP) to maintain a patent airway
b. Cleft palate repair
c. Closed or open reduction and stabilization of dislo- cated joints
i. Securing stability of the knee joints for weight- bearing: primary importance
ii. Correction of foot deformities through operative and nonoperative measures
d. Stabilization of the cervical spine i. Early bracing and stabilization
ii. Stabilization of the neck may be required before surgical correction of joint abnormalities to pre- vent possible complications associated with the induction of anesthesia
e. Care for possible poor wound healing
f. Obstetrical care of an affected mother and fetus i. Regional anesthesia for possible difficulty in
intubation and the cervical spine may be sub- luxated during extension of the neck for intu- bation
ii. Cesarean section if the patient is unable to abduct the hips, making vaginal delivery poten- tially traumatic for both mother and infant iii. Risk of fetal injury includes cervical spine
instability
REFERENCES
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Fig. 1. An infant with Larsen syndrome showing characteristic flat facies with hypertelorism, depressed nasal bridge, cleft palate, dislo- cations of hips, knees, and talipes equinovarus, demonstrated by radio- graphs.
Fig. 2. Another infant with Larsen syndrome showing flat facies with prominent forehead, hypertelorism, depressed nasal bridge, and micrognathia, tracheostomy for tracheomalacia, scoliosis, and dislo- cation of knees, and club feet.
Fig. 3. A girl with Larsen syndrome showing characteristic flat facies with prominent forehead, and depressed nasal bridge, bilateral knee dislocations, long, cylindrical fingers with Spatulate thumbs and great toes. Radiograph shows lateral and anterior dislocation of both knees.
Fig. 4. A girl with Larsen syndrome wearing orthosis showing flat facies. Radiographs show increased number of carpal bones, anterior and lateral dislocation of tibiae, hyperextended cervical vertebrae, and coronal clefting of the lumber vertebrae.
Fig. 5. An infant with lethal, Larsen-like syndrome showing charac- teristic flat facies (prominent forehead, hypertelorism, depressed nasal bridge, micrognathia, cleft palate), multiple dislocations involv- ing shoulders, elbows, wrists, knees, ankles, and hips, and talipes equinovarus. The radiographs showed anterior dislocation of the tibia, lateral dislocation of the hips, hypoplasia of fibulae and of distal ends of the fibulae, cervical kyphosis with the apex at C-4, and coronal clefts of the lower lumbar vertebrae. Necropsy showed tracheomala- sia. The dermal histology showed relatively broad and smudgy colla- gen bundles. The electronmicroscopic study showed a relative increase in small short fibers with a reduction of mature collagen fibers in the hyaline cartilage of the trachea.
