Mucocutaneous Lymph Node in the United States Marian E. Melish, MD;
Raquel
M.
Hicks, MD; Eunice J. Larson,
\s=b\ Sixteen patients with an unusual and distinct symptom complex were encountered during a four-year period. Principal features of this syndrome are (1) fever lasting more than seven days; (2) conjunctival injection; (3) changes in the mouth consisting of erythema of the oropharynx, "strawberry tongue," and erythema of the lips; (4) indurative edema of hands and feet with palm and sole erythema followed by desquamation of the fingertips; and (5) an erythematous rash. Associated features were lymphadenopathy, pyuria, aseptic meningitis, diarrhea, arthritis, and arthralgia. Although usually a self-limited illness, one patient died with massive coronary artery thrombosis on the 19th day of illness. This syndrome appears to be clinically and pathologically similar to mucocutaneous lymph node syndrome, an illness prevalent in Japan but previously unrecognized by American clinicians. Pathologic features suggest a relationship to infantile periarteritis nodosa. (Am J Dis Child 130:599-607, 1976)
Received for publication July 16,1975; accepted Nov 17. From the Department of Pediatrics, Kauikeolani Children's Hospital and the University of Hawaii School of Medicine, Honolulu. Dr Melish is now with the University of California at San Diego, La Jolla, and Dr Larson is now with the Earl and Lorraine Miller Children's Hospital Medical Center of Long Beach (Calif). Reprint requests to Kauikeolani Children's Hospital, 226 N Kuakini St, Honolulu, HI 96817
(Dr Hicks).
Syndrome
MD
have seen 16 patients with an unusual and distinct symptom at Kauikeolani Children's since 1971. Although we were Hospital unable to find descriptions of a similar illness in the English-language litera¬ ture, we had grouped these patients together on the basis of remarkable similarities in their presenting signs, symptoms, and the progression of their clinical course. At the time we saw the ninth patient, we became aware that a similar syndrome, known as mucocutaneous lymph node syn¬ drome (MLNS), had been described in Japan in 1967.' More than 6,000 cases have been reviewed by survey to the present. The Japanese experience with MLNS has recently been sum¬ marized in English."
We complex
Clinical Characteristics
The patients were all inpatients at Kauikeolani Children's Hospital dur¬ ing the period from April 1971 to February 1975; all patients were seen by one of us. All 16 of the children manifested the principal features of MLNS. The fever was characteristically hectic with a high spiking pattern, lasting for at least seven days and for as long as three weeks. The mean duration of fever was ten days. Anti¬ biotics or antipyretics given to most of the patients had no apparent effect in reducing fever. Four patients were
treated
with
adrenocorticosteroids
during the course of the illness. In two of the patients in whom corticoste¬ roids were given on day 8 of fever,
defervescence occurred within two The other two patients re¬ mained febrile for several days while receiving corticosteroid therapy. The children were all irritable, often lethargic, and generally appeared moderately to severely ill. All patients had conjunctival in¬ volvement consisting chiefly of dis¬ crete engorgement of the bulbar conjunctival vessels so that individual vessels were prominent (Fig 1). The palpebrai conjunctivae appeared to be less severely involved with mild gen¬ eralized hyperemia. There was no conjunctival edema or discharge. No patient had purulent drainage or evidence of corneal ulcération. Changes in the mouth consisted of dryness, impressive erythema, and mild Assuring of the lips (Color Fig 1). The oropharyngeal mucosa was dif¬ fusely and deeply erythematous. The appearance of the tongue was strik¬ ingly similar to the "strawberry tongue" of streptococcal scarlet fever with diffuse erythema and prominent
days.
papillae. Changes in the hands and feet were most characteristic and appeared to be a distinct aspect of the syndrome.
Soon after the onset of fever, the hands and feet became diffusely indu-
Downloaded From: http://archpedi.jamanetwork.com/ by a Penn State Milton S Hershey Med Ctr User on 05/25/2015
Fig 1 .—Characteristic conjunctival involve¬ ment consists of discrete engorgement of bulbar blood vessels without exúdate corneal scarring.
or
Fig 2.—Acute induration of hands and feet creates woody firmness of tissues.
Color Fig 1.—Lips are reddened with mild fissuring apparent.
Color Fig 2.—Deep erythematous discolor¬ ation of palms and soles is a striking characteristic in acute phase of illness.
Color Fig 5.—In five patients, the erythe¬ matous rash had a multiform character.
Color Fig 4.—In three patients, the rash consisted of diffuse scarlatiniform erythroderma.
Fig 3.—Desquamation occurring convalescent phase begins just under nail and involves tips of digits.
Color
during
Color Fig 6.—Longitudinal section of thrombosed coronary artery aneurysm on left with necrosis of arterial wall. Intact portion of vessel on right has spongiosis of media and inflammation of adventitia and surrounding connective tissue (hematoxy¬
lin-eosin, original magnification
Downloaded From: http://archpedi.jamanetwork.com/ by a Penn State Milton S Hershey Med Ctr User on 05/25/2015
45).
rated and swollen (Fig 2). The skin and underlying tissues often devel¬ oped a woody firmness suggestive of acute scleroderma. Children were un¬ willing to stand and had limited use of their hands during the period of indu¬ rative edema. At the same time, the palms and soles became erythematous and deep-purple-red or magenta (Col¬ or Fig 2). These changes in the hands were prominent for 5 to 15 days. Two to three weeks after the onset, at a time when erythema and induration had disappeared, a characteristic des¬ quamation took place; peeling devel¬ oped at the junction of the tip of the nail and tip of the digit (Color Fig 3). In many cases, there was also flaky desquamation all around the nail bed. Peeling of the skin was absent or minimal in other areas. In two cases a deep transverse groove across the nail bed appeared late in the convalescent phase of the illness. An erythematous rash was seen in all but one patient. The rash typically appeared within one to five days of onset of fever. The rash was erythe¬ matous, widespread, and could be grouped in one of three patterns. In three cases, the rash consisted of diffuse scarlatiniform erythroderma (Color Fig 4). In two of these patients, the rash was diffuse centrally, but had sharply demarcated borders on the extremities. Seven of the children had a
deeply erythematous maculopapular
rash that was pronounced, coalescent in areas, and is best described as morbilliform. The face and trunk were more severely involved than the prox¬ imal part of the extremities. This rash was pruritic in one child. In the remaining five patients, the erythe¬ matous rash had a multiform char¬ acter with areas of small erythema¬ tous macules and larger erythematous with central clearing (iris areas lesions) scattered over the entire body
(Color Fig 5).
Other important associated find¬ ings of this illness were lymphadenop¬ athy, urethritis or urinary sediment abnormalities, aseptic meningitis, ar¬ thritis, and diarrhea. Lymphadenopathy was a prominent associated finding occurring in 11 of the 16 children. Characteristically, a single enlarged node was found in the
cervical region measuring more than 1.5 cm in diameter. The enlarged node
minimally tender, firm, nonerythematous, and nonsuppurative. The finding of a large cervical mass was unilateral in eight cases and bilat¬ eral in one. The mass appeared within the first three days of fever and subsided very rapidly at the time of defervescence. Aspiration of the mass was attempted in three patients. Scant amounts of bloody fluid were was
obtained and
were
sterile
on
culture.
Pyuria was seen in ten of the 16 patients. Clean-voided urine sediment
showed between 10 and 100 white blood cells (WBCs) per high-power field for two to five consecutive days. Trace amounts of protein were de¬ tected in the urine samples of two patients, and one had 25 red blood cells per high-power field in addition to pyuria. In all cases, the urine was sterile and the abnormal urine find¬ ings disappeared spontaneously. In four of the patients with pyuria, bladder taps were performed; bladder urine was free of WBCs, while voided urine continued to show pyuria, sug¬ gesting that urethral inflammation was the source of the WBCs. Small meatal ulcers were seen in four male
patients.
Seven of the ten patients who had lumbar taps had evidence of aseptic meningitis with very mild cerebro¬ spinal fluid (CSF) pleocytosis. Total WBC counts ranged from 28 to 73/cu mm with a lymphocytic predominance in all cases. Glucose and protein concentrations were normal. One child with CSF pleocytosis had evidence of transiently increased intracranial pressure with a bulging fontanel for four days and an opening pressure of 250 mm H,0 during lumbar puncture. Skull roentgenograms confirmed sep¬ aration of coronal and saggital su¬ tures and an electroencephalogram showed focal slowing in the occipitoparietal region. Brain scan was normal. The fontanel became flat in four days and remained normal after defervescence. One month afterward, skull roentgenograms were normal. Three of the seven patients with CSF pleocytosis had altered states of consciousness ranging from profound lethargy to semicoma for five to seven
days during the
first two weeks of illness. Seven patients had periods of diar¬ rhea with 5 to 15 loose stools per day for two to seven days. Two patients had diarrhea during the first week of illness, but with the remaining five patients, the onset occurred after the tenth day of illness. No recognized bacterial pathogens were found in any stools. Microscopic examinations of the stool showed no polymorphonu¬ clear cells (PMNs), and guaiac tests showed no blood in the stools of these
patients. Although
all patients had indura¬ tive edema of the hands and feet similar to the fusiform swelling of the digits often seen in severe acute rheu¬ matoid arthritis, four patients had evidence of arthritis in other joints with warmth, swelling, pain, and decreased range of motion. The elbows, wrists, and knees were in¬ volved in three patients for periods ranging from five days to one week during the acute phase of the illness. These children did not respond to administration of salicylates, and their symptoms persisted until defer¬ vescence. The fourth patient, a 6-yearold girl, had tenderness, pain, swell¬ ing, and limitation of motion in the left hip for four weeks, two weeks after defervescence, despite mainte¬ nance of serum salicylate levels in the therapeutic range. She has been well subsequently with no evidence of recurrent joint disease. Two children, one of whom had no objective evidence of arthritis, com¬ plained of severe arthralgias. One patient, aged 6 years, had persistent arthralgia in both knees from days 3 through 11. The other patient with arthralgia complained of pain exacer¬ bated by passive motion in both knees and ankles, as well as the left wrist. All of these patients had a back¬ ground of good health and good nutri¬ tion. In one patient, the disease appeared to have been recurrent. This child, an 8-year-old boy, had had a very similar illness at age 2 years. The similarities of the two illnesses were confirmed by review of his hospital chart. The ages of the patients varied from 3 months to 8 years, and 12 of the 16 patients were male. The children's
Downloaded From: http://archpedi.jamanetwork.com/ by a Penn State Milton S Hershey Med Ctr User on 05/25/2015
ethnie background generally repre¬ sented the cosmopolitan origin of the patients at Kauikeolani Children's Hospital, as did their socioeconomic background, the majority of them being middle-class. All patients were cared for by private physicians. Patient characteristics are as fol¬ lows:
Age,
No. of Patients 7 3 4 2
yr
2 2-4 4-6 6-8
Raquel
M.
Hicks, MD; Eunice J. Larson,
\s=b\ Sixteen patients with an unusual and distinct symptom complex were encountered during a four-year period. Principal features of this syndrome are (1) fever lasting more than seven days; (2) conjunctival injection; (3) changes in the mouth consisting of erythema of the oropharynx, "strawberry tongue," and erythema of the lips; (4) indurative edema of hands and feet with palm and sole erythema followed by desquamation of the fingertips; and (5) an erythematous rash. Associated features were lymphadenopathy, pyuria, aseptic meningitis, diarrhea, arthritis, and arthralgia. Although usually a self-limited illness, one patient died with massive coronary artery thrombosis on the 19th day of illness. This syndrome appears to be clinically and pathologically similar to mucocutaneous lymph node syndrome, an illness prevalent in Japan but previously unrecognized by American clinicians. Pathologic features suggest a relationship to infantile periarteritis nodosa. (Am J Dis Child 130:599-607, 1976)
Received for publication July 16,1975; accepted Nov 17. From the Department of Pediatrics, Kauikeolani Children's Hospital and the University of Hawaii School of Medicine, Honolulu. Dr Melish is now with the University of California at San Diego, La Jolla, and Dr Larson is now with the Earl and Lorraine Miller Children's Hospital Medical Center of Long Beach (Calif). Reprint requests to Kauikeolani Children's Hospital, 226 N Kuakini St, Honolulu, HI 96817
(Dr Hicks).
Syndrome
MD
have seen 16 patients with an unusual and distinct symptom at Kauikeolani Children's since 1971. Although we were Hospital unable to find descriptions of a similar illness in the English-language litera¬ ture, we had grouped these patients together on the basis of remarkable similarities in their presenting signs, symptoms, and the progression of their clinical course. At the time we saw the ninth patient, we became aware that a similar syndrome, known as mucocutaneous lymph node syn¬ drome (MLNS), had been described in Japan in 1967.' More than 6,000 cases have been reviewed by survey to the present. The Japanese experience with MLNS has recently been sum¬ marized in English."
We complex
Clinical Characteristics
The patients were all inpatients at Kauikeolani Children's Hospital dur¬ ing the period from April 1971 to February 1975; all patients were seen by one of us. All 16 of the children manifested the principal features of MLNS. The fever was characteristically hectic with a high spiking pattern, lasting for at least seven days and for as long as three weeks. The mean duration of fever was ten days. Anti¬ biotics or antipyretics given to most of the patients had no apparent effect in reducing fever. Four patients were
treated
with
adrenocorticosteroids
during the course of the illness. In two of the patients in whom corticoste¬ roids were given on day 8 of fever,
defervescence occurred within two The other two patients re¬ mained febrile for several days while receiving corticosteroid therapy. The children were all irritable, often lethargic, and generally appeared moderately to severely ill. All patients had conjunctival in¬ volvement consisting chiefly of dis¬ crete engorgement of the bulbar conjunctival vessels so that individual vessels were prominent (Fig 1). The palpebrai conjunctivae appeared to be less severely involved with mild gen¬ eralized hyperemia. There was no conjunctival edema or discharge. No patient had purulent drainage or evidence of corneal ulcération. Changes in the mouth consisted of dryness, impressive erythema, and mild Assuring of the lips (Color Fig 1). The oropharyngeal mucosa was dif¬ fusely and deeply erythematous. The appearance of the tongue was strik¬ ingly similar to the "strawberry tongue" of streptococcal scarlet fever with diffuse erythema and prominent
days.
papillae. Changes in the hands and feet were most characteristic and appeared to be a distinct aspect of the syndrome.
Soon after the onset of fever, the hands and feet became diffusely indu-
Downloaded From: http://archpedi.jamanetwork.com/ by a Penn State Milton S Hershey Med Ctr User on 05/25/2015
Fig 1 .—Characteristic conjunctival involve¬ ment consists of discrete engorgement of bulbar blood vessels without exúdate corneal scarring.
or
Fig 2.—Acute induration of hands and feet creates woody firmness of tissues.
Color Fig 1.—Lips are reddened with mild fissuring apparent.
Color Fig 2.—Deep erythematous discolor¬ ation of palms and soles is a striking characteristic in acute phase of illness.
Color Fig 5.—In five patients, the erythe¬ matous rash had a multiform character.
Color Fig 4.—In three patients, the rash consisted of diffuse scarlatiniform erythroderma.
Fig 3.—Desquamation occurring convalescent phase begins just under nail and involves tips of digits.
Color
during
Color Fig 6.—Longitudinal section of thrombosed coronary artery aneurysm on left with necrosis of arterial wall. Intact portion of vessel on right has spongiosis of media and inflammation of adventitia and surrounding connective tissue (hematoxy¬
lin-eosin, original magnification
Downloaded From: http://archpedi.jamanetwork.com/ by a Penn State Milton S Hershey Med Ctr User on 05/25/2015
45).
rated and swollen (Fig 2). The skin and underlying tissues often devel¬ oped a woody firmness suggestive of acute scleroderma. Children were un¬ willing to stand and had limited use of their hands during the period of indu¬ rative edema. At the same time, the palms and soles became erythematous and deep-purple-red or magenta (Col¬ or Fig 2). These changes in the hands were prominent for 5 to 15 days. Two to three weeks after the onset, at a time when erythema and induration had disappeared, a characteristic des¬ quamation took place; peeling devel¬ oped at the junction of the tip of the nail and tip of the digit (Color Fig 3). In many cases, there was also flaky desquamation all around the nail bed. Peeling of the skin was absent or minimal in other areas. In two cases a deep transverse groove across the nail bed appeared late in the convalescent phase of the illness. An erythematous rash was seen in all but one patient. The rash typically appeared within one to five days of onset of fever. The rash was erythe¬ matous, widespread, and could be grouped in one of three patterns. In three cases, the rash consisted of diffuse scarlatiniform erythroderma (Color Fig 4). In two of these patients, the rash was diffuse centrally, but had sharply demarcated borders on the extremities. Seven of the children had a
deeply erythematous maculopapular
rash that was pronounced, coalescent in areas, and is best described as morbilliform. The face and trunk were more severely involved than the prox¬ imal part of the extremities. This rash was pruritic in one child. In the remaining five patients, the erythe¬ matous rash had a multiform char¬ acter with areas of small erythema¬ tous macules and larger erythematous with central clearing (iris areas lesions) scattered over the entire body
(Color Fig 5).
Other important associated find¬ ings of this illness were lymphadenop¬ athy, urethritis or urinary sediment abnormalities, aseptic meningitis, ar¬ thritis, and diarrhea. Lymphadenopathy was a prominent associated finding occurring in 11 of the 16 children. Characteristically, a single enlarged node was found in the
cervical region measuring more than 1.5 cm in diameter. The enlarged node
minimally tender, firm, nonerythematous, and nonsuppurative. The finding of a large cervical mass was unilateral in eight cases and bilat¬ eral in one. The mass appeared within the first three days of fever and subsided very rapidly at the time of defervescence. Aspiration of the mass was attempted in three patients. Scant amounts of bloody fluid were was
obtained and
were
sterile
on
culture.
Pyuria was seen in ten of the 16 patients. Clean-voided urine sediment
showed between 10 and 100 white blood cells (WBCs) per high-power field for two to five consecutive days. Trace amounts of protein were de¬ tected in the urine samples of two patients, and one had 25 red blood cells per high-power field in addition to pyuria. In all cases, the urine was sterile and the abnormal urine find¬ ings disappeared spontaneously. In four of the patients with pyuria, bladder taps were performed; bladder urine was free of WBCs, while voided urine continued to show pyuria, sug¬ gesting that urethral inflammation was the source of the WBCs. Small meatal ulcers were seen in four male
patients.
Seven of the ten patients who had lumbar taps had evidence of aseptic meningitis with very mild cerebro¬ spinal fluid (CSF) pleocytosis. Total WBC counts ranged from 28 to 73/cu mm with a lymphocytic predominance in all cases. Glucose and protein concentrations were normal. One child with CSF pleocytosis had evidence of transiently increased intracranial pressure with a bulging fontanel for four days and an opening pressure of 250 mm H,0 during lumbar puncture. Skull roentgenograms confirmed sep¬ aration of coronal and saggital su¬ tures and an electroencephalogram showed focal slowing in the occipitoparietal region. Brain scan was normal. The fontanel became flat in four days and remained normal after defervescence. One month afterward, skull roentgenograms were normal. Three of the seven patients with CSF pleocytosis had altered states of consciousness ranging from profound lethargy to semicoma for five to seven
days during the
first two weeks of illness. Seven patients had periods of diar¬ rhea with 5 to 15 loose stools per day for two to seven days. Two patients had diarrhea during the first week of illness, but with the remaining five patients, the onset occurred after the tenth day of illness. No recognized bacterial pathogens were found in any stools. Microscopic examinations of the stool showed no polymorphonu¬ clear cells (PMNs), and guaiac tests showed no blood in the stools of these
patients. Although
all patients had indura¬ tive edema of the hands and feet similar to the fusiform swelling of the digits often seen in severe acute rheu¬ matoid arthritis, four patients had evidence of arthritis in other joints with warmth, swelling, pain, and decreased range of motion. The elbows, wrists, and knees were in¬ volved in three patients for periods ranging from five days to one week during the acute phase of the illness. These children did not respond to administration of salicylates, and their symptoms persisted until defer¬ vescence. The fourth patient, a 6-yearold girl, had tenderness, pain, swell¬ ing, and limitation of motion in the left hip for four weeks, two weeks after defervescence, despite mainte¬ nance of serum salicylate levels in the therapeutic range. She has been well subsequently with no evidence of recurrent joint disease. Two children, one of whom had no objective evidence of arthritis, com¬ plained of severe arthralgias. One patient, aged 6 years, had persistent arthralgia in both knees from days 3 through 11. The other patient with arthralgia complained of pain exacer¬ bated by passive motion in both knees and ankles, as well as the left wrist. All of these patients had a back¬ ground of good health and good nutri¬ tion. In one patient, the disease appeared to have been recurrent. This child, an 8-year-old boy, had had a very similar illness at age 2 years. The similarities of the two illnesses were confirmed by review of his hospital chart. The ages of the patients varied from 3 months to 8 years, and 12 of the 16 patients were male. The children's
Downloaded From: http://archpedi.jamanetwork.com/ by a Penn State Milton S Hershey Med Ctr User on 05/25/2015
ethnie background generally repre¬ sented the cosmopolitan origin of the patients at Kauikeolani Children's Hospital, as did their socioeconomic background, the majority of them being middle-class. All patients were cared for by private physicians. Patient characteristics are as fol¬ lows:
Age,
No. of Patients 7 3 4 2
yr
2 2-4 4-6 6-8
