CASE STUDIES
FIGURE 2. Histologic appearance of the resected antrum. Hyperplastic foveolar epithelium, a dilated and thrombosed mucosal vessel (arrow), and smooth muscle bands extending into the lamina propria from the muscularis mucosa are seen. (Hematoxylin-eosln stain; magnification ~66.)
LARSEN’S
SYNDROME
WITH
NOVEL
CONGENITAL
ANOMALIES
1.x~11’s syndrome is a I-arc inherited disot-der of cottnective tissue and collagen formation. resulting in numerous congenital anomalies.‘.’ Its most prominent features include multiplejoint dislocations and a flattened facies. In 1950, Larsen et al” reported their sidered bilateral anterior
evaluation dislocation
of six patients; they cottof the tibia on the femut
To he the most frequent deformity and noted1 other skeletal and nonskeletal deformities. These’included wide-spaced eyes, depressed nasal bridge, cleft palate, club feet, and cylindricall) shaped fmgers.” Since then. various deformities have been associated with this syndrome, which now include a constellation of anotttalies st1c.h as hydrocephalus. cardiac zanomalies, and tracheal defects.’ We report the case of a full-term female infant born with Larsen’s syndrottte who died after 2 days of life. Detailed postmortetn analysis revealed multiple congenital anomalies characteristically associated with Larsen’s syndrome. In addition. we identified two novel congenital anomalies: anal agenesis, with thy terminal colon ending in a ctd-tlr-sac . and the presence of a hifid uterus. The appearance of the abnormalities presented here mav be associated with a lethal variant of Larsen’s s\~IlrlImm~.’
1055
‘I
HUMAN PATHOLOGY
CASE
Volume 22, No. 10 (October
was unremarkable, but sectioning revealed that the uterine cavity was divided by a septum into two smaller spaces, resuIting in a bifid uterus (not shown).
REPORT
The patient was a newborn white female of 39 weeks gestational age who was delivered by cesarean section. The infant had been diagnosed in utero with hydrocephalus, oligohydramnios, decreased fetal movement, and an atria1 septal defect. Prenatal cytogenetics indicated a normal 46,xX katyotvpe. The mother was a 27-year-old with one previous normal c’hild. The family history was negative for any congenital anomalies. On delivery, the infant exhibited no sp(~tltalleous respiratory efti,rts and was intubated. The infant weighed 2.3 kg at birth. The head circumference was 42.5 cm (normal, 34.1 cm).” She had a flat nasal bridge, low-set ears, and cleft palate. Cardiac examination revealed the presence of loud systolic and diastolic tnurmurs with a “machinery” quality. There was an i~np~rfo~dte anus externally. The extremities had multiple ma~fot~~~~ati~~~~s. The infant had bilateral clubbed feet. The left hand had only four digits. and all fingers were noted to be stubby and short. The infant had a hypoplastic fourth digit on the right hand and there were hypoplastic hind feet bilaterally. Difficulty in fully advancing the endotracheal tube on intllbatior~ resulted in a brorlcllosc(~py. This procedure showed tracheomalacia. The patient died after 2 days of progressiveiy deteriorating cardiopulmonary function. Autopsy Findings A radiograph of the lower extremities is presented in Fig 1. In this figure, anterior dislocations of the tibias on the femurs are apparent. especially on the right. In the lateral orientation of the right lower extremity in the radiograph, the tibia and fib& are superimposed. Other anomalies discovered radiographically included bilateral dislocations of the radial heads. Examination of the brain revealed biventricular hydrocephalus. The heart contained an ostium priIil~lII~-type atrial septal defect, with right atriai dilatation. The trachea was probe-patent, but was markedly stenotic in the distal third portion. Several segments of tracheal cartilage were malfortned and constricting. Examination of the abdominal cavity revealed anal agenesis, and the descending colon ended in a cul-de-sac that was dilated and filled with rlleconiut~l (Fig 2). The external genitalia were that of a normal female infant. Externally, the uterus
FIGURE 1. Radiograph of lower extremities, showing the anterior dislocation of the right tibia on the femur (the right tibia and fibula are superimposed).
1991)
DISCUSSION Larsen’s syndrome describes a group of characteristic deformities affecting the skeleton and other organ systems. It is believed to he a generalized nles~nchymat disorder affecting connective tissue and collagen formation.“,7 The exact nature of the defect in collagen formation is unknown. Histochemiral and electron microscopic studies suggest a disorder of connective tissue resulting in a dysmaturity of collagen fibers and a deficiency of dense mature collagen bundles.’ A reduction in the cross-link density of mature collagen has also been proposed. ’ The diagnosis of Larsen’s syndrome in this case was supported by the patient’s flattened nasal bridge, bilateral anterior dislocations of the tibias, bilateral club feet, and cleft palate. Hydrocephalus has been reported in association with Larsen’s syndrome, and was observed in this case.’ Multiple deformities and dislocations involving the extremities are invariably present.” In this instance, the patient had (~ligodactyty of the left hand, a hypoplastic digit on the right hand, bilateral hypoplastic hindfeet, and bilateral dislocations of the radial heads. Two new findings that have not been reported with Larsen’s syndrome were found at autopsy. There was total agenesis of the anus, with a meconium-filled cul-de-sac present at the descending colon (Fig 2). The entire colon appeared discolored and was distended and enlarged due to the accunlulatiotl of meconium. An additional finding not previously associated with Larsen’s syndrome was a bifid uterus. These combined rectouteral defects arose early in etnbryologic development, and originated when the urorectal septum failed to divide the cloaca completely and fuse with the cloaca1 membrane. The urorectal septum is a sheet of mesenchymal tissue that proliferates caudally by the sixth week of devet[~prneIlt to divide the cloaca into an anterior cavity, the urogenital sinus, which is involved in the formation of the vagina and uterus, and a posterior cavity, which develops into the rectum and upper anal canal. Since anal agenesis and the presence of a bifid uterus can be traced tn anomalous development of the cloaca and the urorectal septum, these findings support the etiology of Larsen’s syndrome as a generalized mesenchy~la1 disorder.‘” Cat-diovascuiar anomalies have been identified in this syndrome. Congenital cardiac septal defects, aortic dilatation, and tortuous cranial and abdominal arteries have been described.“.” This infant was found to have an ostium primnm-type atrial septal defect. Airway abnormalities are present in many instances. Larsen’s syndrome, being a disorder of collagen and connective tissue. frequently affects joint capsules and other cartilaginous structures such as the trachea.’ In the present case, there was narrowing of the cartilage rings in the lower third of the trachea, producing stenosis. Tracheal stenosis has been previously reported.“ Tracheotnalacia, with collapse of the trachea on expiration, is occasionally present, as are Ia~ngoIrlalacia and bronchomaIac~d.‘4-“i The mode of inheritance of this disorder remains controversial; both autosomal dominant”,‘* and recessive’ modes of inheritance have been suggested. Severe anomalies and lethal malformations have been associated with the recessive variant.‘.’ This case most likely represents a recessive expression, since there was no family history and the patient died 2 days after delivery. A majority of the reported cases of Larsen’s syndrome involve nonlethal anomalies. It is possible that many cases are unrecognized: consequently, this syndrome must be considered in patients with multiple congenital joint dislocations and flattened facies, particularly when a familial expression of these traits is present.
1056
CASE STUDIES
FIGURE 2. Isolated colon showing the terminal cul-de-sac due to anal agenesis (arrowhead). Also shown is the appendix and a segment of terminal ileum (left). The marked dilatation and discoloration of the terminal colon are due to meconium retention.
FIGURE 2. Histologic appearance of the resected antrum. Hyperplastic foveolar epithelium, a dilated and thrombosed mucosal vessel (arrow), and smooth muscle bands extending into the lamina propria from the muscularis mucosa are seen. (Hematoxylin-eosln stain; magnification ~66.)
LARSEN’S
SYNDROME
WITH
NOVEL
CONGENITAL
ANOMALIES
1.x~11’s syndrome is a I-arc inherited disot-der of cottnective tissue and collagen formation. resulting in numerous congenital anomalies.‘.’ Its most prominent features include multiplejoint dislocations and a flattened facies. In 1950, Larsen et al” reported their sidered bilateral anterior
evaluation dislocation
of six patients; they cottof the tibia on the femut
To he the most frequent deformity and noted1 other skeletal and nonskeletal deformities. These’included wide-spaced eyes, depressed nasal bridge, cleft palate, club feet, and cylindricall) shaped fmgers.” Since then. various deformities have been associated with this syndrome, which now include a constellation of anotttalies st1c.h as hydrocephalus. cardiac zanomalies, and tracheal defects.’ We report the case of a full-term female infant born with Larsen’s syndrottte who died after 2 days of life. Detailed postmortetn analysis revealed multiple congenital anomalies characteristically associated with Larsen’s syndrome. In addition. we identified two novel congenital anomalies: anal agenesis, with thy terminal colon ending in a ctd-tlr-sac . and the presence of a hifid uterus. The appearance of the abnormalities presented here mav be associated with a lethal variant of Larsen’s s\~IlrlImm~.’
1055
‘I
HUMAN PATHOLOGY
CASE
Volume 22, No. 10 (October
was unremarkable, but sectioning revealed that the uterine cavity was divided by a septum into two smaller spaces, resuIting in a bifid uterus (not shown).
REPORT
The patient was a newborn white female of 39 weeks gestational age who was delivered by cesarean section. The infant had been diagnosed in utero with hydrocephalus, oligohydramnios, decreased fetal movement, and an atria1 septal defect. Prenatal cytogenetics indicated a normal 46,xX katyotvpe. The mother was a 27-year-old with one previous normal c’hild. The family history was negative for any congenital anomalies. On delivery, the infant exhibited no sp(~tltalleous respiratory efti,rts and was intubated. The infant weighed 2.3 kg at birth. The head circumference was 42.5 cm (normal, 34.1 cm).” She had a flat nasal bridge, low-set ears, and cleft palate. Cardiac examination revealed the presence of loud systolic and diastolic tnurmurs with a “machinery” quality. There was an i~np~rfo~dte anus externally. The extremities had multiple ma~fot~~~~ati~~~~s. The infant had bilateral clubbed feet. The left hand had only four digits. and all fingers were noted to be stubby and short. The infant had a hypoplastic fourth digit on the right hand and there were hypoplastic hind feet bilaterally. Difficulty in fully advancing the endotracheal tube on intllbatior~ resulted in a brorlcllosc(~py. This procedure showed tracheomalacia. The patient died after 2 days of progressiveiy deteriorating cardiopulmonary function. Autopsy Findings A radiograph of the lower extremities is presented in Fig 1. In this figure, anterior dislocations of the tibias on the femurs are apparent. especially on the right. In the lateral orientation of the right lower extremity in the radiograph, the tibia and fib& are superimposed. Other anomalies discovered radiographically included bilateral dislocations of the radial heads. Examination of the brain revealed biventricular hydrocephalus. The heart contained an ostium priIil~lII~-type atrial septal defect, with right atriai dilatation. The trachea was probe-patent, but was markedly stenotic in the distal third portion. Several segments of tracheal cartilage were malfortned and constricting. Examination of the abdominal cavity revealed anal agenesis, and the descending colon ended in a cul-de-sac that was dilated and filled with rlleconiut~l (Fig 2). The external genitalia were that of a normal female infant. Externally, the uterus
FIGURE 1. Radiograph of lower extremities, showing the anterior dislocation of the right tibia on the femur (the right tibia and fibula are superimposed).
1991)
DISCUSSION Larsen’s syndrome describes a group of characteristic deformities affecting the skeleton and other organ systems. It is believed to he a generalized nles~nchymat disorder affecting connective tissue and collagen formation.“,7 The exact nature of the defect in collagen formation is unknown. Histochemiral and electron microscopic studies suggest a disorder of connective tissue resulting in a dysmaturity of collagen fibers and a deficiency of dense mature collagen bundles.’ A reduction in the cross-link density of mature collagen has also been proposed. ’ The diagnosis of Larsen’s syndrome in this case was supported by the patient’s flattened nasal bridge, bilateral anterior dislocations of the tibias, bilateral club feet, and cleft palate. Hydrocephalus has been reported in association with Larsen’s syndrome, and was observed in this case.’ Multiple deformities and dislocations involving the extremities are invariably present.” In this instance, the patient had (~ligodactyty of the left hand, a hypoplastic digit on the right hand, bilateral hypoplastic hindfeet, and bilateral dislocations of the radial heads. Two new findings that have not been reported with Larsen’s syndrome were found at autopsy. There was total agenesis of the anus, with a meconium-filled cul-de-sac present at the descending colon (Fig 2). The entire colon appeared discolored and was distended and enlarged due to the accunlulatiotl of meconium. An additional finding not previously associated with Larsen’s syndrome was a bifid uterus. These combined rectouteral defects arose early in etnbryologic development, and originated when the urorectal septum failed to divide the cloaca completely and fuse with the cloaca1 membrane. The urorectal septum is a sheet of mesenchymal tissue that proliferates caudally by the sixth week of devet[~prneIlt to divide the cloaca into an anterior cavity, the urogenital sinus, which is involved in the formation of the vagina and uterus, and a posterior cavity, which develops into the rectum and upper anal canal. Since anal agenesis and the presence of a bifid uterus can be traced tn anomalous development of the cloaca and the urorectal septum, these findings support the etiology of Larsen’s syndrome as a generalized mesenchy~la1 disorder.‘” Cat-diovascuiar anomalies have been identified in this syndrome. Congenital cardiac septal defects, aortic dilatation, and tortuous cranial and abdominal arteries have been described.“.” This infant was found to have an ostium primnm-type atrial septal defect. Airway abnormalities are present in many instances. Larsen’s syndrome, being a disorder of collagen and connective tissue. frequently affects joint capsules and other cartilaginous structures such as the trachea.’ In the present case, there was narrowing of the cartilage rings in the lower third of the trachea, producing stenosis. Tracheal stenosis has been previously reported.“ Tracheotnalacia, with collapse of the trachea on expiration, is occasionally present, as are Ia~ngoIrlalacia and bronchomaIac~d.‘4-“i The mode of inheritance of this disorder remains controversial; both autosomal dominant”,‘* and recessive’ modes of inheritance have been suggested. Severe anomalies and lethal malformations have been associated with the recessive variant.‘.’ This case most likely represents a recessive expression, since there was no family history and the patient died 2 days after delivery. A majority of the reported cases of Larsen’s syndrome involve nonlethal anomalies. It is possible that many cases are unrecognized: consequently, this syndrome must be considered in patients with multiple congenital joint dislocations and flattened facies, particularly when a familial expression of these traits is present.
1056
CASE STUDIES
FIGURE 2. Isolated colon showing the terminal cul-de-sac due to anal agenesis (arrowhead). Also shown is the appendix and a segment of terminal ileum (left). The marked dilatation and discoloration of the terminal colon are due to meconium retention.
