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Oral clinicopathologic manifestations in maple syrup urine disease
Oral clinicopathologic manifestations in maple syrup urine disease D. Gazit,” R. Zeltser,b 0. Galili,’ and E. Kaufman,
Jerusalem, Israel
HEBREW UNIVERSITY HADASSAH SCHOOL OF DENTAL MEDICINE Maple syrup urine disease is a rare inborn error of metabolism that manifests mainly by neurologic deterioration, coma, and death in early childhood. Oral manifestations described in this article were gingival enlargement and rampant caries, while histopathologic findings revealed a picture compatible osteomyelitis. (ORAL SURC ORAL MED ORAL PATHOL 1989;67:694-7)
mostly with
A
ccording to current literature more than 50 cases of maple syrup urine disease (MSUD) have been reported since its initial description in 1954 by Menkes.’ None of the described cases presented oral manifestations. MSUD is also known as branched-chain ketoaciduria. This inborn error of metabolism results from a primary defect in oxidative decarboxylation of the ketoacid derivates from the branched-chain amino acids leucine, isoleucine, and valine.2 This autosomal recessive disease is characterized by lethargy, poor appetite, vomiting, alternating periods of hypertonicity and flaccidity, progressive neurologic deterioration, seizures, and coma.3 MSUD has been classified into the following grades: grade 1, classic; grade 2, intermediate; grade 3, intermittent; and grade 4, thiamine-responsive. The degrees are distinguished according to time of onset, severity of symptoms, tolerance for dietary protein, and levels of residual branched chain-alfa ketoacid-dehydrogenase activity.4 Diagnosis and proper treatment are of paramount importance in improving the otherwise grim prognosis of this rare disease. CASEREPORT A 14%-year-old white, mentally retarded male patient was referred to the Hospital Oral Medicine Service of Hadassah Hospital for dental treatment under general anesthesia. The diagnosis of MSUD had been made when the patient was 8 days old. Family history revealed that the boy was the fifth of nine children. Two of his brothers died
“Division of Oral Pathology. bDepartment of Oral and Maxillofacial ‘Hospital Oral Medicine Service. 694
Surgery
Fig.
1. Pale, elongated,
retrognathic
facial appearance.
shortly after birth of an undiagnosed disorder. The parents were first cousins. The patient’s medical history indicated mental psychomotor retardation, bilateral mastoidectomy due to recur-
Oral manifestations
Volume67 Number 6
Fig.
in maple syrup urine disease
695
2. Massive gingival enlargement with wide areas of oozing, clotting, and necrosis.
Fig.
3. Healing, 2 weeks after procedure.
rent middle ear infections, and burns of the right knee treated by plastic surgery for contracture revision. On admission the patient was receiving no medication except for a MSUD diet. Physical examination revealed a somewhat pale, undernourished, incoherent, and uncooperative patient. Vital signs and other values were as follows: pulse, 90/min; blood pressure, lOO/SO mm Hg; respirations, 16/min; weight, 24.5 kg (low for his age); hemoglobin percentile values, 10.8 gm/lOO ml. Other complete blood count parameters were within normal limits. Leucine serum levels were elevated to 1.2 pmol/ml (normal, 0.2 pmol/ ml). Isoleucine and valine levels were also somewhat elevated-O.55 and 0.15 rmol/ml, respectively (normal, 0.25 and 0.15 pmol/ml). Other biochemical values were within normal limits.
Physical examination revealed a slim, underdeveloped male patient with postural problems and uncoordinated movements. His head was normal in size and was elongated. The hair was fair and thick. The bridge of the nosewas narrow, and the ears were low and abnormally shaped. The neck was long, and the chest was also unnaturally long. Extraoral examination showed (Fig. 1) a pale, elongated, symmetric face with a retrognathic mandible. Mouth breathing was a result of incompetent lips and bulging upper front teeth and gingiva. Intraoral examination showed an Angle class 11 intermaxillary relationship accompanied by crowding of the upper and lower teeth. Multiple rampant carious lesions were recorded. The most impressive intraoral finding was massivegingival enlargement with wide areas of oozing, clotting, and necrosis(Fig. 2) that resulted from constant impingement and trauma by
696
Gazit et al.
ORAI-
SURG ORAL
MED
ORAL. PATINN .lunc
4. Low-power micrograph demonstrates inflammatory processin periodontal apparatus (arrow). (Hematoxylin and eosin stain. Original magnification X50.)
1989
Fig.
Fig. 6. Necrotic trabecular bone jarrow]. (Hematoxylin and eosin stain. Original magnification X100.)
tion. A combination of constant gingival oozing and poor oral hygiene resulted in intensive halitosis. The patient was brought to the main operating theater after oral premeditation with 10 mg of diazepam. Anesthesia was achieved by thiopentone (175 mg), succinylcholine (45 mg given intravenously), halothane l%, gallamine (40 mg), and morphine (4 mg administered intramuscularly). After nasotracheal intubation was achieved and an oropharyngeal pack was applied, the patient underwent multiple extractions and gingivoplasty. Gingival tissue and teeth were sent for histological evaluation. The anesthetic course and the dental surgical procedures were uneventful. The patient was sent to the recovery room in a satisfactory condition. Postoperative course was uneventful. Healing was complete within 2 weeks (Fig. 3). Low-power microscopy revealed acute and chronic inflammation in the periodontal apparatus (Fig. 4). Foci of necrotic tissue were found in both the periodontal ligament (Fig. 5) and the trabecular bone (Fig. 6). The findings of necrosis in the trabecular bone and the bone marrow were compatible with osteomyelitis (Fig. 7). The teeth were found to be normal. DISCUSSION
5. Foci of necrotic tissue in periodontal ligament furrow). (Hematoxylin and eosin stain. Original magnification X200.) Fig.
opposing teeth. A remarkable inflammation of the gingivae was noticed. The earlier mentioned mouth breathing was a major factor contributing to tissue fragility and inflamma-
Classic full-blown grade 1 MSUD is usually fatal in early childhood unless it is diagnosed and treatment is administered. The case presented here manifested a severe form of the disease that turned into a
chronic course by dietary treatment. This case gave us a unique opportunity to follow the oral changes that occurred over time in this rare disorder.
Volume 67 Number 6
Oral manifestations
in maple syrup urine disease
697
tissue pathosis has been proven.’ Moreover, in in vitro studies branched-chain amino acids added to isolated rat muscle tended to stimulate protein synthesis and to inhibit protein degradation. A possible mechanism for soft tissue and bone necrosis can be attributed to the chronic gingivally destructive inflammatory process and to the contributing local factors such as bad oral care, heavy calculus, and extremely decayed teeth. The extensive dental caries was attributed mainly to the highcarbohydrate MSUD diet. Malnutrition can obviously be ruled out because of the high-carbohydrate and well-calculated protein-replacement diet. Massive tissue enlargement and central necrosis similar to that occurring in tumors may be advanced as a possible mechanism for the necrosis. In conclusion, our clinical and pathologic experience with this disease has not disclosed any basic biochemical or metabolic explanation for the findings. However, this experience gave us the rare opportunity to describe the disease’s oral clinicopathologic manifestations. REFERENCES
Fig. 7. Low-power micrograph of osteomyelitis. Note necrotic trabecular bone and necrotic bone marrow (double arrow). (Hematoxylin and eosin stain. Original magnification X40.)
MSUD is considered to be a systemic disease. Pathologic changes in the brain, liver, kidney, and lungs have been described.’ Morphologic alterations have also been reported in the muscle.6 In the case reported in this article the most significant findings in the histopathologic examination were wide areas of inflammation and necrosis in the periodontal attachment apparatus. Alveolar bone osteomyelitis was another major observation. Our findings, in particular the foci of necrosis, are in agreement with those of Ferriere and associates,6 who described vacuolated and ghost fibers in muscle. The presence of bone disease and the connective tissue lesions in the oral cavity in this case are perplexing, since no direct relation between accumulation of branchedchain amino acids and muscle, bone, and connective
1. Menkes JH, Hurst PL, Craig JM. New syndrome: progressive familial infantile cerebral dysfunction associated with an unusual urinary substance. Pediatrics 1954;14:462-7. 2. Lippman SM, Arnett FC, Conley CL, Ness PM, Mayers DA, Bias WB. Genetic factor predisposing to autoimmune hemolytic anemia, chronic thrombocytopenic purpura and systemic lupus erythematosus. Am J Med 1982;73:827-30. 3. Digorge AM, Rezvani I, Garibaldi LR, Schwartz BS. Prospective study of maple syrup urine disease for the first four days of life. N Engl J Med 1983;308:1100-1. 4. Verdu J, Lopez Herce I, Pascual Castroviejo A, Artinez Bermejo MU, Garcia MJ. Maple syrup urine disease variant form: presentation with psycho motor retardation and CT scan abnormalities. Acta Paediatr Stand 1985;74:815-8. 5. Schartz JF, Kolendrianos ET. Maple syrup urine disease: a review with a report of an additional case. Dev Med Child Neurol 1969;11:460-2. 6. Ferriere G, Castro M, Rodriguez J. Abnormalities of muscle fibers in maple syrup urine disease. Acta Neuropathol (Berl) 1984;63:249-51. 7. Fulks RM, Li JB, Goldberg AL. Effect of insulin, glucose, and amino acid on protein turnover in rat diaphragm. J Biol Chem 1975;250:290-5. 8. Adibi AS. Roles of branched chain amino acids in metabolic regulation. J Lab Clin Med 1980;95:475-80. Reprint
requests
to:
Dr. Eliezer Kaufman Hospital Oral Medicine Service Hebrew University Hadassah School of Dental Medicine P.O. Box 1172 Jerusalem 91010, Israel
Jerusalem, Israel
HEBREW UNIVERSITY HADASSAH SCHOOL OF DENTAL MEDICINE Maple syrup urine disease is a rare inborn error of metabolism that manifests mainly by neurologic deterioration, coma, and death in early childhood. Oral manifestations described in this article were gingival enlargement and rampant caries, while histopathologic findings revealed a picture compatible osteomyelitis. (ORAL SURC ORAL MED ORAL PATHOL 1989;67:694-7)
mostly with
A
ccording to current literature more than 50 cases of maple syrup urine disease (MSUD) have been reported since its initial description in 1954 by Menkes.’ None of the described cases presented oral manifestations. MSUD is also known as branched-chain ketoaciduria. This inborn error of metabolism results from a primary defect in oxidative decarboxylation of the ketoacid derivates from the branched-chain amino acids leucine, isoleucine, and valine.2 This autosomal recessive disease is characterized by lethargy, poor appetite, vomiting, alternating periods of hypertonicity and flaccidity, progressive neurologic deterioration, seizures, and coma.3 MSUD has been classified into the following grades: grade 1, classic; grade 2, intermediate; grade 3, intermittent; and grade 4, thiamine-responsive. The degrees are distinguished according to time of onset, severity of symptoms, tolerance for dietary protein, and levels of residual branched chain-alfa ketoacid-dehydrogenase activity.4 Diagnosis and proper treatment are of paramount importance in improving the otherwise grim prognosis of this rare disease. CASEREPORT A 14%-year-old white, mentally retarded male patient was referred to the Hospital Oral Medicine Service of Hadassah Hospital for dental treatment under general anesthesia. The diagnosis of MSUD had been made when the patient was 8 days old. Family history revealed that the boy was the fifth of nine children. Two of his brothers died
“Division of Oral Pathology. bDepartment of Oral and Maxillofacial ‘Hospital Oral Medicine Service. 694
Surgery
Fig.
1. Pale, elongated,
retrognathic
facial appearance.
shortly after birth of an undiagnosed disorder. The parents were first cousins. The patient’s medical history indicated mental psychomotor retardation, bilateral mastoidectomy due to recur-
Oral manifestations
Volume67 Number 6
Fig.
in maple syrup urine disease
695
2. Massive gingival enlargement with wide areas of oozing, clotting, and necrosis.
Fig.
3. Healing, 2 weeks after procedure.
rent middle ear infections, and burns of the right knee treated by plastic surgery for contracture revision. On admission the patient was receiving no medication except for a MSUD diet. Physical examination revealed a somewhat pale, undernourished, incoherent, and uncooperative patient. Vital signs and other values were as follows: pulse, 90/min; blood pressure, lOO/SO mm Hg; respirations, 16/min; weight, 24.5 kg (low for his age); hemoglobin percentile values, 10.8 gm/lOO ml. Other complete blood count parameters were within normal limits. Leucine serum levels were elevated to 1.2 pmol/ml (normal, 0.2 pmol/ ml). Isoleucine and valine levels were also somewhat elevated-O.55 and 0.15 rmol/ml, respectively (normal, 0.25 and 0.15 pmol/ml). Other biochemical values were within normal limits.
Physical examination revealed a slim, underdeveloped male patient with postural problems and uncoordinated movements. His head was normal in size and was elongated. The hair was fair and thick. The bridge of the nosewas narrow, and the ears were low and abnormally shaped. The neck was long, and the chest was also unnaturally long. Extraoral examination showed (Fig. 1) a pale, elongated, symmetric face with a retrognathic mandible. Mouth breathing was a result of incompetent lips and bulging upper front teeth and gingiva. Intraoral examination showed an Angle class 11 intermaxillary relationship accompanied by crowding of the upper and lower teeth. Multiple rampant carious lesions were recorded. The most impressive intraoral finding was massivegingival enlargement with wide areas of oozing, clotting, and necrosis(Fig. 2) that resulted from constant impingement and trauma by
696
Gazit et al.
ORAI-
SURG ORAL
MED
ORAL. PATINN .lunc
4. Low-power micrograph demonstrates inflammatory processin periodontal apparatus (arrow). (Hematoxylin and eosin stain. Original magnification X50.)
1989
Fig.
Fig. 6. Necrotic trabecular bone jarrow]. (Hematoxylin and eosin stain. Original magnification X100.)
tion. A combination of constant gingival oozing and poor oral hygiene resulted in intensive halitosis. The patient was brought to the main operating theater after oral premeditation with 10 mg of diazepam. Anesthesia was achieved by thiopentone (175 mg), succinylcholine (45 mg given intravenously), halothane l%, gallamine (40 mg), and morphine (4 mg administered intramuscularly). After nasotracheal intubation was achieved and an oropharyngeal pack was applied, the patient underwent multiple extractions and gingivoplasty. Gingival tissue and teeth were sent for histological evaluation. The anesthetic course and the dental surgical procedures were uneventful. The patient was sent to the recovery room in a satisfactory condition. Postoperative course was uneventful. Healing was complete within 2 weeks (Fig. 3). Low-power microscopy revealed acute and chronic inflammation in the periodontal apparatus (Fig. 4). Foci of necrotic tissue were found in both the periodontal ligament (Fig. 5) and the trabecular bone (Fig. 6). The findings of necrosis in the trabecular bone and the bone marrow were compatible with osteomyelitis (Fig. 7). The teeth were found to be normal. DISCUSSION
5. Foci of necrotic tissue in periodontal ligament furrow). (Hematoxylin and eosin stain. Original magnification X200.) Fig.
opposing teeth. A remarkable inflammation of the gingivae was noticed. The earlier mentioned mouth breathing was a major factor contributing to tissue fragility and inflamma-
Classic full-blown grade 1 MSUD is usually fatal in early childhood unless it is diagnosed and treatment is administered. The case presented here manifested a severe form of the disease that turned into a
chronic course by dietary treatment. This case gave us a unique opportunity to follow the oral changes that occurred over time in this rare disorder.
Volume 67 Number 6
Oral manifestations
in maple syrup urine disease
697
tissue pathosis has been proven.’ Moreover, in in vitro studies branched-chain amino acids added to isolated rat muscle tended to stimulate protein synthesis and to inhibit protein degradation. A possible mechanism for soft tissue and bone necrosis can be attributed to the chronic gingivally destructive inflammatory process and to the contributing local factors such as bad oral care, heavy calculus, and extremely decayed teeth. The extensive dental caries was attributed mainly to the highcarbohydrate MSUD diet. Malnutrition can obviously be ruled out because of the high-carbohydrate and well-calculated protein-replacement diet. Massive tissue enlargement and central necrosis similar to that occurring in tumors may be advanced as a possible mechanism for the necrosis. In conclusion, our clinical and pathologic experience with this disease has not disclosed any basic biochemical or metabolic explanation for the findings. However, this experience gave us the rare opportunity to describe the disease’s oral clinicopathologic manifestations. REFERENCES
Fig. 7. Low-power micrograph of osteomyelitis. Note necrotic trabecular bone and necrotic bone marrow (double arrow). (Hematoxylin and eosin stain. Original magnification X40.)
MSUD is considered to be a systemic disease. Pathologic changes in the brain, liver, kidney, and lungs have been described.’ Morphologic alterations have also been reported in the muscle.6 In the case reported in this article the most significant findings in the histopathologic examination were wide areas of inflammation and necrosis in the periodontal attachment apparatus. Alveolar bone osteomyelitis was another major observation. Our findings, in particular the foci of necrosis, are in agreement with those of Ferriere and associates,6 who described vacuolated and ghost fibers in muscle. The presence of bone disease and the connective tissue lesions in the oral cavity in this case are perplexing, since no direct relation between accumulation of branchedchain amino acids and muscle, bone, and connective
1. Menkes JH, Hurst PL, Craig JM. New syndrome: progressive familial infantile cerebral dysfunction associated with an unusual urinary substance. Pediatrics 1954;14:462-7. 2. Lippman SM, Arnett FC, Conley CL, Ness PM, Mayers DA, Bias WB. Genetic factor predisposing to autoimmune hemolytic anemia, chronic thrombocytopenic purpura and systemic lupus erythematosus. Am J Med 1982;73:827-30. 3. Digorge AM, Rezvani I, Garibaldi LR, Schwartz BS. Prospective study of maple syrup urine disease for the first four days of life. N Engl J Med 1983;308:1100-1. 4. Verdu J, Lopez Herce I, Pascual Castroviejo A, Artinez Bermejo MU, Garcia MJ. Maple syrup urine disease variant form: presentation with psycho motor retardation and CT scan abnormalities. Acta Paediatr Stand 1985;74:815-8. 5. Schartz JF, Kolendrianos ET. Maple syrup urine disease: a review with a report of an additional case. Dev Med Child Neurol 1969;11:460-2. 6. Ferriere G, Castro M, Rodriguez J. Abnormalities of muscle fibers in maple syrup urine disease. Acta Neuropathol (Berl) 1984;63:249-51. 7. Fulks RM, Li JB, Goldberg AL. Effect of insulin, glucose, and amino acid on protein turnover in rat diaphragm. J Biol Chem 1975;250:290-5. 8. Adibi AS. Roles of branched chain amino acids in metabolic regulation. J Lab Clin Med 1980;95:475-80. Reprint
requests
to:
Dr. Eliezer Kaufman Hospital Oral Medicine Service Hebrew University Hadassah School of Dental Medicine P.O. Box 1172 Jerusalem 91010, Israel