February, 1971 T h e Journal of P E D I A T R I C S 2 9 2

Larsen's syndrome: A skeletal dysplasia with multiple joint dislocations and unusual facies

An infant is described who has multiple joint dislocations, unusual facies, and

boney abnormalities, which constitute a syndrome first reported by Larsen. This report

expands Larsen's syndrome with the following additional findings: apparent

diminished rigidity of cartilage in early infancy, extra finger creases, short fingernails,

and an unusual juxtacalcaneal "'accessory" bone. Both infant and mother have a

flattened nasal bridge. Recognition of this syndrome is important because of the

implications /or counseling. Affected individuals can be expected to have normal

central nervous system development, but the joint abnormalities require prolonged

orthopedic treatment; achievement of completely normal function is unlikely.

Rober t J. La t t a , M.D. , C. Benjamin Graham, M.D. , Jon Aase, M.D.,

S tewar t M. Seham, M.D. , and Dav id W. Smith, M.D. '~

S E A T T L E ~ W A S H .

L A R S E N AND co-workers, 1 in 1950, de- scribed 6 sporadic cases of a disorder charac- terized by mul t ip le jo int dislocations and unusual facies wi th a low nasal bridge. The jo int deformities typically included anter ior dislocations of the knee, hip and elbow dis- locations, and an equinovarus or valgus de- formity of the foot. This repor t of an infant wi th this apparen t ly rare and distinctive jo int and skeletal dysplasia describes ad- di t ional clinical findings and discusses the possible mode of inheri tance.

From the Dysmorphology Unit, Departments of Pediatrics, Radiology, and Orthopedics, University of Washington School of Medicine.

Supported by a grant from the Children's Bureau. -"~Reprtnt address: Department or Pediatrics, RR234, University of Washington Medical School, Seattle, Wash. 98105.

CASE R E P O R T

At the time of our patient's birth, the unre- lated Caucasian parents were 31 years of age. Previous pregnancies resulted in 2 normal chil- dren with a fuIl-term stillborn baby with no evident malformation. Neither parent had a his- tory of joint problems; radiographs of the moth- er's hands, wrists, and elbows were normal. However, she had a flattened nasal bridge, a "saddle nose," which apparently was not an ob- vious feature until she was about 20 years of age (Fig. 1). An unresolved question was whether this nasal deformity was developmental, degen- erative as a result of a tennis ball blow to the nose at 18 years of age, or both. There is no history in the mother's family of any type of inherited defect including nasal deformity.

The patient was born via an uncomplicated vertex delivery following a 42 week gestation during which the mother had recurrent urinary tract infections treated with sulfisoxazole. Mul-

Vol. 78, No. 2, pp. 291-298

2 9 2 Latta et al. The Journal o/ Pediatrics February 1971

Fig. 1. Mother of patient at age 31 showing flat- tened nasal bridge or "saddle nose."

tiple joint dislocations were readily apparent at birth and were initiaIty diagnosed as "arthro- gryposis." At 10 days of age he was 47 cm. long and weighed 3.8 Kg. He had an unusually low and broad nasal bridge, contributing to a relatively flat facial contour (Fig. 2). At 6 months of age the inner canthal distance was 3.0 cm. He had severe bilateral knee disloca- tions with anterior and lateral displacement of the tibia on the femur. In addition, both hips were dislocated and there was bilateral adduction of the forefoot and a valgus deformity of the hindfoot. Both elbows were dislocated. The fingers (Fig. 3) appeared relatively long in rela- tion to short palms and had one or more extra creases; the thumbs were relatively broad, the fingernails were short~ and the fifth fingers curved inward. There were marked respiratory sternal retractions which increased with crying; the rib cage was unusually hypermobile at the costochondral areas. Direct laryngoscopy showed a flabby epiglottis which partialIy cdlapsed on inspiration and mobile, infolding arytenoid cartilage. Developmental assessments during hos- pitalization suggested normal progre~ during the first 3 months of life; re-evaluation at 8 months of age again showed normaI developmentaI progress Mth the exception of limb function.

Initial partial skeletal roentgen survey demon-

strated complete dislocation of both hips and marked anterior and lateral dislocations of the tibias, with increased anterior bowing (Fig. 4). Fibulas were short, especially proximally; there was bilateral heel valgus with forefoot varus. The metatarsals and phalanges were relatively short. The distal half of each hmnerus was hypoplastic and tapered to the elbow (Fig. 5). All components of the hands and wrists were grossly deformed (Fig. 6); the metacarpals, par- ticularly I I I to V, were short, the phalanges were thickened and unusually "squared" gen- erally, with the exception that the fifth middIe phalanges were small and triangular, and the distal radial epiphyses were large for age.

Subsequent radiographic studies up to age 8 months showed evolution of the previously known abnormatlties and revealed some additional fea- tures. A curious, large, separate, spherical ossicle developed immediately posterior to each cal- caneus (Fig. 7). The middle phalanges of all but the large toes remained poorly ossified. The hand changes were accentuated, with incurring of the fifth fingers. Subluxation of shoulders and elbows could be demonstrated on several exam- inations. Ahhough the appearance sequence of ossification centers was somewhat unusual, over- all skeletal maturation was within normal limits.

Spine films reveaIed multiple anomalies be- tween C-1 and T-8, with a dramatically abnor- mal curvature (Fig. 8). These vertebrae were generally flattened and hypoplastic, more so posteriorly and on the left. In the skull, the facial bones and base were relatively small com- pared to the calvarium, and the orbits were some- what shallow (Fig. 9). The sella turcica ap- peared normal.

During elective knee surgery at 8 months of age, the lateral portion of the vastus lateralis muscle appeared on visual examination to be partially replaced by fibrous tissue. Specimens for microscopic examination were obtained from this muscIe, the left knee capsule, cartilage from the left femoral condyle, and from the skin. Staining with hematoxylin and eosin, Verhoff's- Van Gieson, reticulin, toluidine blue, and Gomaritrichrome revealed no distinctive histo- logic abnormality.

Treatment during the first 8 months was di- rected at the knee dislocations, since these most inhibited normal developmental progress. Im- provement in the posture of the feet was obtained by serial casting incidental to treatment of the knees. Several attempts at manipulation of the knees under sedation failed, as did a trim of

Volume 78 Larsen's syndrome 2 9 3 Number 2

Fig. 2. A, Patient at 10 days of age. B, At 6 months of age with bilateral knee dislocations and relatively flat facial contour.

Fig. 3. A, Patient's hands at 10 days of age. B and C, At 6 months of age. A and B, Showing improvement of altered finger alignment. C, Extra finger creases with a relatively short palm.

skeletal traction via the tibiae with the patient prone in bed. Two attempts at open reduction had to be abandoned due to respiratory compli- cations, one during intubation and one during induction of caudal anesthesia. Open reductions were then done according to the technique of Curtis and Fisher. 2 Postoperative stability was

not satisfactory; improvement was subsequently obtained by the serial use of wedged casts.

D I S C U S S I O N

The features of this syndrome are sum-

marized in Table I. Dislocation of large joints other than the hip is rare; the presence

2 9 4 Lat ta et al. The Journal o/ Pediatrics February 1971

Fig. 4. A, Hips are dislocated bilaterally. B, Knee and lower leg demonstrate anterior and lateral dislocation. The fibula is short and the tibia is bowed to an abnormal degree.

Fig. 5. The upper extremity shows hypoplasia of the distal humerus.

of several such dislocations in combination with the low nasal bridge, abnormalit ies of the fingers, and short metacarpals should allow for easy recognition of this entity. Vertebral anomalies have also been noted as well as occasional palatal defects. The present report documents several additional features, none of which was alluded to in Larsen's report. 1 Diminished rigidity of car- tilage was indirectly evident during early infancy for the costochondral cartilage, epi- glottis, arytenoid, and possibly the tracheal cartilage. This feature, which improved with time, caused early respiratory difficulty and was apparent ly responsible for inability to carry out inhalation anesthesia in early in- fancy. One or more extra creases on the fingers and short fingernails which con- tribute to the appearance of broad thumbs were additional distinctive features.

The roentgenologic abnormalit ies in our patient are virtually identical to those origi- nally described by Larsen. 1 T h e highly un- usual juxtacalcaneal "accessory" bone noted in our pat ient is also clearly identifiable,

Volume 78 Larsen's syndrome 2 9 5 Number 2

Fig. 6. Note the short metatarsals and metacarpals plus unusual phaIangeal deformities.

Fig. 7. The complicated foot deformity is apparent; the curious anomalous bone is seen im- mediately posterior to the calcaneus (arrow).

though not specifically ment ioned, in an i l lustrat ion included in Larsen 's paper . This fea ture should not be confused with the rare so-called bifid calcaneus, represent ing two separate ossification centers of which the an- ter ior por t ion is usually the smaller. 3

O t h e r repor ted instances of mul t ip le jo in t dislocations 2, 4, 5 may represent fur ther ex-

amples of Larsen 's syndrome, but the case reports often lack informat ion about short metacarpa ls or a l tered facies. Some pat ients described by Laurence 6 and M c F a r l a n e 7 were similar to Larsen 's patients, but there was insufficient informat ion to allow for a secure diagnosis.

All of the abnormal i t ies noted in this syn-

2 9 6 Lat ta et al. The Journal o[ Pediatrics February 1971

Fig. 9. The skull shows relatively small base and facial bones with shallow orbits.

Fig. 8. The eervicothoracic spine shows markedly abnormal curvature and anomalies of multiple vertebrae.

drome appear to involve mesenchymal tis- sues of support. There is skeletal hypoplasia of the metacarpals, the humeri, the fibulae, and the nasal bone, and incomplete union of vertebrae. Early cartilage tends to be lax, at least in our patient. It is tempting to im- ply that there was early laxity of the sup- porting tissues of joints, allowing for the major joint dislocations, and, secondarily, the fibrotic vastus lateralis muscle.

Each of the 6 patients described by Lar- sen 1 was the only known affected member of the family. McKusick 8 has tentatively categorized this syndrome as autosomal re- cessive based on his knowledge of its oc- currence in siblings whose parents were presumably normal. The mother of our pa- tient has a possible expression of the disorder with a nasal bridge anomaly similar to that of her affected son. Her anomaly was not obvious until late teen-age and may have been at least partially related to a blow to the nose at the age of 18 years. The following 3 possibilities deserve mention relative to the mother's nasal anomaly and Larsen's syn- drome: (1) The mother's anomaly is com-

pletely environmental and bears no etiologi- cal relationship to Larsen's syndrome. (2) Larsen's syndrome might be an autosomal recessive disorder; the heterozygous mother then might have only a minor manifestation of the syndrome, with partial deterioration of the nasal cartilage following trauma. (3) Larsen's syndrome could be a dominantly inherited single gene disorder with wide variability in severity, the mother showing only mild expression but her affected son showing severe expression. The possibility of single gene dominant ~nhm~tance is enhanced by the findings of McFarlane, 7 who reported a woman with congenital dislocation of the knees, hyperextension Of the elbows, and a low nasal bridge, who had 3 children with bilateral knee dislocations, each by a differ- ent father. If this woman did have Larsen's syndrome, she is the only severe case known to have reproduced; the occurrence of 3 presumably affected offspring by 3 different fathers indicates a dominant mode of inheri- tance. The single gene dominant hypothesis w-ould imply that each of Larsen's 6 pa- tients, as well as the mother of our patient, represented fresh mutations. The handi- capping nature of the fully expressed syn- drome would limit reproduction; therefore, most cases would represent sporadic fresh mutations. It is also possible that this clinical syndrome has both single gene dominant

Volume 78 Larsen's syndrome 29 7 Number 2

Tab le I. Fea tures of Larsen 's syndrome

Anomalies 1 l

Face Low nasal bridge +

Joints Knee dislocation + Hip dislocation + Elbow dislocation Club foot +

Hand Abnormal fingers + Additional finger creases ? Short fingernails ? Broad thumbs + Short metacarpals ?+

Other Vertebral anomalies ?

Larsen' s patients Present 2 1 3 1 4 1 5 1 6 patient Total

+ + + + + + 7/7

+ + + + + + 7/7 + ?+ ? + + + 6/6 + + + + + + 6/7 + + + + + + 7/7

+ + + + + + 7/7 ? ? ~ ~ ? + 1/1 ? ? ? ? ~ + 1/1 + ? - ? ~ + 3/4

?+ ?+ ?+ ?+ ?+ + 7/7

? ? ~ + + + 3/3

+ Feature present.

?+ Impl ied that feature is present.

? Unknown.

- Feature absent.

and autosomal recessive modes of inheri- tance.

Al though the small number of repor ted cases implies tha t this syndrome is quite rare, the fact tha t Larsen and associates 1 accumu- la ted 6 pat ients within a per iod of 5 years suggests tha t most cases are going unrec- ognized unde r such categorical designations as "ar throchalas is" or "ar throgryposis ." Ano the r possible explanat ion for l imited recognit ion may be an early lethal effect of the disorder. Fo r example , the present pa- t ient had serious respira tory problems ap- paren t ly re la ted to laxity of the t rachea and rib cage in early infancy. Recogni t ion is ex- t remely impor t an t for prognost ic counseling; all of the affected individuals have had ap- paren t ly normal central nervous system func- t ion and have adap ted surprisingly well to their handicaps.

T o date, the results of a t tempts to correct the jo in t abnormali t ies , whether by man ip - ulat ion, casting, or surgery, have been dis- appoin t ing ; older chi ldren have usually re- qui red braces or o ther mechanica l aids to achieve a reasonable degree of jo int func-

t ion for ambula t ion . Reduc t ion by closed means is usually successful in pat ients having only congenital anter ior knee dislocation (genu r ecu rva tum) . However , this form of t r ea tment has fai led in 13 of the 14 dis- located knees of the 7 chi ldren with Lar - sen's syndrome.

T h o u g h the basic pathophysiology of this condi t ion remains unknown, the na ture of the various defects suggests the presence of a general ized mesenchymal disorder, clinically manifes ted in per ia r t icu la r connective tissue, midfac ia l structures, the bony archi tecture of metacarpa ls and phalanges, and addi t ional ly in this pa t ien t by la ryngomalac ia wi th marked hyperflexibil i ty of the rib cage.

A D D E N D U M

One of the authors (C. B. G.) has recently acquired, through the kind courtesy of Drs. John L. Gwinn and George R. Barnes, radiographs of a previously undiagnosed case of Larsen's syn- drome. The child has bilateral knee, hip, and elbow dislocations, as well as other typical mani- festations. The 6 year follow-up (to 1970) of this patient presents an unusual opportunity to examine the evolution of the curious, possibly

2 98 Latta et aI. The fournal of Pediatrics February 197I

A

C

syndrome-specific, calcaneal ossicle. Lateral views of the right heel at ages 8 months (A), 3 years (B), and 6 years (C) are reproduced below. Note the progressive fusion and eventual appear- ance of an apparently normal calcaneal apoph- ysis. Other intrinsic and surgical deformities are incidentally also seen.

We wish to acknowledge the help of Dr. E. Stanley Ray of Juneau, Alaska, the referring physician, Dr. Waldemar Wenner, who conducted developmental evaluations, Dr. Paul Kotmen, pathologist, and Mrs. Lyle Harrah, research librarian.

R E F E R E N C E S

1. Larsen, L. J., Schottstaedt, E. R., and Bost, F. C.: Multiple congenital dislocations asso- ciated with characteristic facial abnormality, J. PEDIAT. 37: 574, 1950.

2. Curtis, B. H., and Fisher, R. L.: Congenital hyperextension with anterior subluxation of the knee, J. Bone Joint Surg. 51: 255, 1969.

3. KohIer, A., and Zimmer, E. A.: Borderlands of the normal and early pathologic in skeletal roentgenology (3rd American edition, trans- lated and edited by S. P. Wilk): New York, 1968, Grune & Stratton, Inc.

4. Hass, J., and Hass, R.: ArthrochaIasis multiplex congenita. Congenital flaccidity of the joints, J. Bone Joint Surg. 40: 663, 1958.

5. Katz, M. P., Grogono, B. J. S., and Soper, K. C.: The etiology and treatment of congeni- tal dislocation of the knee, J. Bone Joint Surg. 49: 112, 1967.

6. Laurence, M.: Genu recurvatum congenitum, J. Bone Joint Surg. 49: 121, 1967.

7. McFarlane, A. L.: A report on four cases of congenital genu recurvatum occurring in one family, Brit. J. Surg. 34: 388, 1947.

8. McKusick, V. A.: Mendelian inheritance in man, ed. 2, Baltimore, 1968, Johns Hopkins Press.

Figs. A, B, and C.