- Email: [email protected]
Familial nemaline myopathy: Case reports
Familial nemaline myopathy: Case reports Kostas Antoniades, DDS, MD,a Nikos Taskos, MD,b John Mavromatis, MD,b Leon Sakkas, MD,b and Dimitris Karakasis, DDS, iUD,a Thessaloniki, Greece UNIVERSITY OF THESSALONIKI Two siblings of two generations in the same family with nemaline myopathy are described. The disease affects all skeletal muscles, especially the facial muscles, producing a typical facial appearance. The diagnosis was made by light microscopy of histologically stained sections of muscle biopsy. The disease in our patients seems to be transmitted in an autosomal dominant manner. The purpose of this article is to emphasize the importance of recognition of the facial appearance by maxillofacial surgeons and the appropriate referral of patients for further neurologic examination. (ORAL SURC ORAL MED ORAL PATHOL 1991;72:51-4)
N
emaline myopathy is a rare syndrome with distinctive clinical and pathologic features and is characterized by abundant rod bodies within the muscle fibers. It presents as hypotonia, generalized symmetric muscle wasting and weakness,typical facial “fish mouth” appearance, frequent skeletal deformities, reduced or absent tendon reflexes, and a myopathic electromyogram (EMG).’ Nemaline myopathy was originally identified and described in 1963 by Shy et a1.2The name “nemaline” or “rod” myopathy was given because of the presence of threadlike or rodshaped structures in muscle fibers. There is another name for the abnormal aggregates in this disease, “myogranules,” which was suggestedby Conen el al.,3 also in a 1963 report. The course of diseaseis usually either slow or nonprogressive when it occurs in older children and adults, although numerous severe and fatal casesin infants and neonates have been reported in the literature.4‘10 Although many cases are sporadic, a genetic baseis generally admitted; however, it has not been possible to determine a uniform mode of inheritance.4 We report four cases,in two siblings in two generations, of a familial nemaline myopathy. The purpose of the present article is to report four casesof this rare syndrome and to present the typical facial characteristics of persons with this syndrome, that should be recognized by maxillofacial surgeons.
aDepartment of Oral and Maxillofacial Surgery. bDepartment of Neurology. T/13/23266
CASEREPORTS Case 1
A 12-year-old boy with dentofacial deformities was referred to our department for evaluation and consultation. He was the older of two children and was born at term after an uncomplicated pregnancy and delivery. Clinical examination of the patient showeda long, narrow face, facial weakness,tented upper lip and shortened philtrum, absenceof nasolabial folds, and a fish-mouth appearancewith drooping corners. The nosewas short with a broad base, and the ears were larger than average and drooping. A bilateral mild ptosis of the upper eyelids and a mild antimongoloid slant of the palpebral fissureswere also present. In addition, there was a high-angle skeletal deformity of the mandible with anterior open bite. The height of the lower lip was relatively short in relation to the anterior lower facial height (Fig. 1). The lateral cephalometric evaluation revealed a long face deformity with high gonial angle (137 degrees)and anterior open bite. The basal plane angle (M x P - MP) was 44 degrees,and the inclination of the mandibular plane to the anterior cranial base(SN - MP angle) was 47 degrees.The anterior facial height from nasion to menton was 138mm and was divided into anterior upper (52 mm) and anterior lower (86 mm) facial heights (Fig. 2). The body appearance showed a slender build, lumbar lordosis, and thoracic kyphosis. Becausethesefindingssuggested a diagnosis of a generalized myopathy, the patient was referred to the neurology department for additional evaluation. For similar reasons we asked to see the other members of his family. Neurologic evaluation demonstrated that besidesthe facial weaknessthere was a long-standing moderate proximal weaknessof the arms and legs but no obvious atrophy; the patient was able to stand on one leg but was not able to hop. In addition, he was mentally retarded (intelligence quotient [IQ] 55 to 60). Blood laboratory workup included normal creatine kinase (CK) level. EMG showed normal nerve 51
52
Antoniades et al.
ORAL SURC ORAL
Fig.
Fig.
1.
Facial appearance of patient with nemaline my-
opathy.
MED ORAL. PATHOL July 1991
2. Lateral cephalograph of patient.
mild variation in fiber size, and with trichrome stain revealed red-staining nemaline bodies (rods) in isolated fibers. Case 3
conduction velocities and low-amplitude short-duration potentials, suggestive of a myopathy. A biopsy specimen from the left deltoid muscle, showed variation in fiber size on routine hematoxylin-eosin staining. The diameters of the fibers ranged from 10 to 40 pm (normal 21 to 30 Km). Nemaline bodies stained bright red on trichrome staining. These structures were scattered mostly throughout the smaller fibers (Fig. 3). The diagnosis of nemaline myopathy was made in accordance with these findings. Case 2
The secondsibling was a 9-year-old girl born after a normal pregnancy and delivery. Her facial appearance was characterized by an open mouth with drooping corners and drooling. There was facial weakness,bilateral ptosis of upper eyelids, and antimongoloid slant of the palpebral fissures.The soft and hard tissue abnormalities were milder than her brother’s features (Fig. 4). Neurologic evaluation revealed facial weaknessand mild proximal weakness of the legs without reduction of the muscle bulk. Her IQ was 75 to 80. The CK level was normal, and the EMG mildly myopathic. Muscle biopsy of the right bicepswith routine hematoxylin-eosin staining showed
The 36-year-old mother of the two siblings was in good genera1condition and mentally normal. She had a long, narrow face with mild weaknessof facial muscles. Symptoms and signs of generalized weaknesswere not present. Blood laboratory workup, EMG, and biopsy from the deltoid muscle were normal. The possible diagnosis of nonprogressive nemaline myopathy, localized to the face, was made in accordance with these findings (Fig. 5). Case 4
The brother of the mother of the previously mentioned siblings also had a narrow and long face, with weaknessof facial muscles. He had no other sign of generalized disease. CK level, EMG, and biopsy from the deltoid muscle were normal. The possible diagnosis of nemaline myopathy with facial localization was made. DISCUSSION
These four casesappear to be congenital nemaline myopathy in siblings in two generations of the same family. The facial appearance of congenital nemaline myopathy is typical. The face is usually narrow and long
Familial nemaline myopathy
Volume 72 Number I
Fig. 3. Biopsy specimen of deltoid muscle demonstrating nemaline bodies. (Trichrome stain; original magnification, x1250.)
with a fish-mouth appearance. Other common soft tissue features of this condition are ptosis of the upper eyelids, absenceof the nasolabial folds, short nose, tented upper lip, drooping corners of the mouth, drooling, and open mouth. 6-‘o Although all our cases had the typical facial characteristics of this syndrome, the myopathic face was more prominent in cases1 and 2. In addition, these characteristics were associated with skeletal deformities similar to long face highangle skeletal deformity with anterior open bite and lip incompetence. The disease affects all skeletal muscles, including the diaphragm, sparing the cardiac and other muscles. In a clinical follow-up study of 12 patients, WallgrenPetterson found that the weakest muscles are the facial muscles, the flexors of the neck and trunk, the dorsiflexors of the feet, and the extensors of the toes. The distal limb muscles and the limb-girdle muscles are clearly weaker than the proximal limb muscles. The two children fit the typical clinical picture of the disease that has been found in all reported cases,4% 6-8 whereas the other two cases (3 and 4) should be considered as a mild nemaline nonprogressive myopathy with facial weaknessonly. Recent studies have shown that the main component of the nemaline myopathy is a-actinin.” The nemaline bodies tend to be located beneath the sarcolemma in the younger patients and inside the muscle fibers in the older patients. The quantity of bodies seemsto increase with age. The clinical deterioration and the defective myofiber maturation in the patient, together with an increase in internal nuclei and endomysial fat or fibrosis, indicate an active disease process.9 Arts et al.’ reported two types of nemaline myopathy with different modesof transmission, an autosoma1dominant trait and an autosomal recessivetrait. They were unable to distinguish these two diseaseson
Fig.
53
4. Photograph of second sibling.
Fig. 5. Family photograph showslong, narrow face characterizing all members.
a clinical and histopathologic basis. However, Arts and de Groot12observedfurther that the frequency of consanguinous marriages in parents of children with nemaline myopathy is increased. This is a further argument in favor of an autosomal recessivetype of the diseasein addition to the autosomal dominant variety. Kondo and Yuasar3 in their review note that autosoma1 recessive and X-linked recessive or dominant modesof inheritance are not compatible with the observed patterns, which could be explained by an autosomal dominant mode with a reduced penetrance. According to the same authors, normal relatives who carry rods are presumably unaffected heterozygotes of the same gene. Bender and Willnerr4 also report only his&chemical changes without rod bodies in the muscle of an asymptomatic mother of a patient with nemaline myopathy. In our familial casesthe disease was present in two generations, and we believe it was transmitted by the autosomal dominant mode. The differential diagnosis should include the other
54 Antoniades et al. congenital myopathies, myopathies with early onset, eyelid ptosis syndromes, and masklike face syndromes. The myopathic face and the “swan neck” are someof the main features of the nemaline myopathy,9 although these signs may be present in many myopathies with early onset. The facial features are useful diagnostic aids in the initial stages,but the histologic examination of affected muscles is the only way in which the diagnosis can be clearly established. We emphasize the importance of recognition by maxillofacial surgeons of the typical facial appearance of patients with nemaline myopathy and appropriate referral for further neurologic examination. REFERENCES 1. Hopkins IJ, Lindsay JR, Ford FR. Nemaline myopathy: a long-term clinicopathologic study of an affected mother and daughter. Brain 1966;89:299-3 10. 2. Shy GM, Engel WK, Somers JE, Wanko T. Nemaline myopathy: a new congenital myopathy. Brain 1963;86:793-8 10. 3. Conen RE, Murphy GE, Donohue WL. Light and electron microscopic study of “myogranules” in a child with hypotonia and muscle weakness. Can Med Assoc J 1963;89:983-6. 4. Scarlato G, Pellegrini G, Moggio M, et al. Familial nemaline myopathy. Neuropediatrics 1982; 13:2 I I-5. 5. McMenamin JB, Curry B, Taylor GP, Becker LE, Murphy EG. Fatal nemaline myopathy in infancy. Can J Neural Sci 1984;11:305-9.
ORAL SURG ORAL MED ORAL PATHOS July 1991 6. Kuitunen P, Rapola J, Nopenen AL, Donner M. Nemaline myopathy: report of four cases and review of the literature. Acta Paediatr Stand 1972;61:353-61. 7. Acts WF, Bethlem J, Dingemans KP, Eriksson AW. Investigations on the inheritance of nemaline myopathy. Arch Neurol 1978;35:72-7. 8. Taskos N, Bostantzopoulou S, Logothetis J. Nemaline (rod) myopathy occurring in a male boy as a sporadic case with review of the literature. Neural Psychiatr 1986;1:37-40. 9. Wallgren-Petterson C. Congenital nemaiine myopathy, a clinical follow-up study of twelve patients. J Neural Sci 1989;89: l-4. 10. Martinez BA, Lake BD. Childhood nemaline myopathy: a review of clinical presentation in relation to prognosis. Dev Med Child Neurol 1987;29:8 15-20. 11. Jennekens FGI, Roord JI, Veldman H, Willense J, Jockush BM. Congenital nemaline myopathy: defectiveorganization of cu-actinin is restricted to muscle. Muscle Nerve I983;6:61-8. 12. Arts WF, De Groot CJ. Congenital nemaline myopathy: two patients with consanguineous parents, one with a progressive course. J Neurol 1983;230:123-30. 13. Kondo K, Yuasa T. Genetics of congenital nemaline myopathy. Muscle Nerve 1980;3:308- 15. 14. Bender AN, Willner JP. Nemaline (rod) myopathy: the need for histochemical evaluation of affected families. Ann Neurol 1978;4:37-42. Reprint requests. K. Antoniades, DDS, MD Department of Oral and Maxillofacial School of Dentistry University of Thessaloniki 54006 Thessaloniki, Greece
Surgery
N
emaline myopathy is a rare syndrome with distinctive clinical and pathologic features and is characterized by abundant rod bodies within the muscle fibers. It presents as hypotonia, generalized symmetric muscle wasting and weakness,typical facial “fish mouth” appearance, frequent skeletal deformities, reduced or absent tendon reflexes, and a myopathic electromyogram (EMG).’ Nemaline myopathy was originally identified and described in 1963 by Shy et a1.2The name “nemaline” or “rod” myopathy was given because of the presence of threadlike or rodshaped structures in muscle fibers. There is another name for the abnormal aggregates in this disease, “myogranules,” which was suggestedby Conen el al.,3 also in a 1963 report. The course of diseaseis usually either slow or nonprogressive when it occurs in older children and adults, although numerous severe and fatal casesin infants and neonates have been reported in the literature.4‘10 Although many cases are sporadic, a genetic baseis generally admitted; however, it has not been possible to determine a uniform mode of inheritance.4 We report four cases,in two siblings in two generations, of a familial nemaline myopathy. The purpose of the present article is to report four casesof this rare syndrome and to present the typical facial characteristics of persons with this syndrome, that should be recognized by maxillofacial surgeons.
aDepartment of Oral and Maxillofacial Surgery. bDepartment of Neurology. T/13/23266
CASEREPORTS Case 1
A 12-year-old boy with dentofacial deformities was referred to our department for evaluation and consultation. He was the older of two children and was born at term after an uncomplicated pregnancy and delivery. Clinical examination of the patient showeda long, narrow face, facial weakness,tented upper lip and shortened philtrum, absenceof nasolabial folds, and a fish-mouth appearancewith drooping corners. The nosewas short with a broad base, and the ears were larger than average and drooping. A bilateral mild ptosis of the upper eyelids and a mild antimongoloid slant of the palpebral fissureswere also present. In addition, there was a high-angle skeletal deformity of the mandible with anterior open bite. The height of the lower lip was relatively short in relation to the anterior lower facial height (Fig. 1). The lateral cephalometric evaluation revealed a long face deformity with high gonial angle (137 degrees)and anterior open bite. The basal plane angle (M x P - MP) was 44 degrees,and the inclination of the mandibular plane to the anterior cranial base(SN - MP angle) was 47 degrees.The anterior facial height from nasion to menton was 138mm and was divided into anterior upper (52 mm) and anterior lower (86 mm) facial heights (Fig. 2). The body appearance showed a slender build, lumbar lordosis, and thoracic kyphosis. Becausethesefindingssuggested a diagnosis of a generalized myopathy, the patient was referred to the neurology department for additional evaluation. For similar reasons we asked to see the other members of his family. Neurologic evaluation demonstrated that besidesthe facial weaknessthere was a long-standing moderate proximal weaknessof the arms and legs but no obvious atrophy; the patient was able to stand on one leg but was not able to hop. In addition, he was mentally retarded (intelligence quotient [IQ] 55 to 60). Blood laboratory workup included normal creatine kinase (CK) level. EMG showed normal nerve 51
52
Antoniades et al.
ORAL SURC ORAL
Fig.
Fig.
1.
Facial appearance of patient with nemaline my-
opathy.
MED ORAL. PATHOL July 1991
2. Lateral cephalograph of patient.
mild variation in fiber size, and with trichrome stain revealed red-staining nemaline bodies (rods) in isolated fibers. Case 3
conduction velocities and low-amplitude short-duration potentials, suggestive of a myopathy. A biopsy specimen from the left deltoid muscle, showed variation in fiber size on routine hematoxylin-eosin staining. The diameters of the fibers ranged from 10 to 40 pm (normal 21 to 30 Km). Nemaline bodies stained bright red on trichrome staining. These structures were scattered mostly throughout the smaller fibers (Fig. 3). The diagnosis of nemaline myopathy was made in accordance with these findings. Case 2
The secondsibling was a 9-year-old girl born after a normal pregnancy and delivery. Her facial appearance was characterized by an open mouth with drooping corners and drooling. There was facial weakness,bilateral ptosis of upper eyelids, and antimongoloid slant of the palpebral fissures.The soft and hard tissue abnormalities were milder than her brother’s features (Fig. 4). Neurologic evaluation revealed facial weaknessand mild proximal weakness of the legs without reduction of the muscle bulk. Her IQ was 75 to 80. The CK level was normal, and the EMG mildly myopathic. Muscle biopsy of the right bicepswith routine hematoxylin-eosin staining showed
The 36-year-old mother of the two siblings was in good genera1condition and mentally normal. She had a long, narrow face with mild weaknessof facial muscles. Symptoms and signs of generalized weaknesswere not present. Blood laboratory workup, EMG, and biopsy from the deltoid muscle were normal. The possible diagnosis of nonprogressive nemaline myopathy, localized to the face, was made in accordance with these findings (Fig. 5). Case 4
The brother of the mother of the previously mentioned siblings also had a narrow and long face, with weaknessof facial muscles. He had no other sign of generalized disease. CK level, EMG, and biopsy from the deltoid muscle were normal. The possible diagnosis of nemaline myopathy with facial localization was made. DISCUSSION
These four casesappear to be congenital nemaline myopathy in siblings in two generations of the same family. The facial appearance of congenital nemaline myopathy is typical. The face is usually narrow and long
Familial nemaline myopathy
Volume 72 Number I
Fig. 3. Biopsy specimen of deltoid muscle demonstrating nemaline bodies. (Trichrome stain; original magnification, x1250.)
with a fish-mouth appearance. Other common soft tissue features of this condition are ptosis of the upper eyelids, absenceof the nasolabial folds, short nose, tented upper lip, drooping corners of the mouth, drooling, and open mouth. 6-‘o Although all our cases had the typical facial characteristics of this syndrome, the myopathic face was more prominent in cases1 and 2. In addition, these characteristics were associated with skeletal deformities similar to long face highangle skeletal deformity with anterior open bite and lip incompetence. The disease affects all skeletal muscles, including the diaphragm, sparing the cardiac and other muscles. In a clinical follow-up study of 12 patients, WallgrenPetterson found that the weakest muscles are the facial muscles, the flexors of the neck and trunk, the dorsiflexors of the feet, and the extensors of the toes. The distal limb muscles and the limb-girdle muscles are clearly weaker than the proximal limb muscles. The two children fit the typical clinical picture of the disease that has been found in all reported cases,4% 6-8 whereas the other two cases (3 and 4) should be considered as a mild nemaline nonprogressive myopathy with facial weaknessonly. Recent studies have shown that the main component of the nemaline myopathy is a-actinin.” The nemaline bodies tend to be located beneath the sarcolemma in the younger patients and inside the muscle fibers in the older patients. The quantity of bodies seemsto increase with age. The clinical deterioration and the defective myofiber maturation in the patient, together with an increase in internal nuclei and endomysial fat or fibrosis, indicate an active disease process.9 Arts et al.’ reported two types of nemaline myopathy with different modesof transmission, an autosoma1dominant trait and an autosomal recessivetrait. They were unable to distinguish these two diseaseson
Fig.
53
4. Photograph of second sibling.
Fig. 5. Family photograph showslong, narrow face characterizing all members.
a clinical and histopathologic basis. However, Arts and de Groot12observedfurther that the frequency of consanguinous marriages in parents of children with nemaline myopathy is increased. This is a further argument in favor of an autosomal recessivetype of the diseasein addition to the autosomal dominant variety. Kondo and Yuasar3 in their review note that autosoma1 recessive and X-linked recessive or dominant modesof inheritance are not compatible with the observed patterns, which could be explained by an autosomal dominant mode with a reduced penetrance. According to the same authors, normal relatives who carry rods are presumably unaffected heterozygotes of the same gene. Bender and Willnerr4 also report only his&chemical changes without rod bodies in the muscle of an asymptomatic mother of a patient with nemaline myopathy. In our familial casesthe disease was present in two generations, and we believe it was transmitted by the autosomal dominant mode. The differential diagnosis should include the other
54 Antoniades et al. congenital myopathies, myopathies with early onset, eyelid ptosis syndromes, and masklike face syndromes. The myopathic face and the “swan neck” are someof the main features of the nemaline myopathy,9 although these signs may be present in many myopathies with early onset. The facial features are useful diagnostic aids in the initial stages,but the histologic examination of affected muscles is the only way in which the diagnosis can be clearly established. We emphasize the importance of recognition by maxillofacial surgeons of the typical facial appearance of patients with nemaline myopathy and appropriate referral for further neurologic examination. REFERENCES 1. Hopkins IJ, Lindsay JR, Ford FR. Nemaline myopathy: a long-term clinicopathologic study of an affected mother and daughter. Brain 1966;89:299-3 10. 2. Shy GM, Engel WK, Somers JE, Wanko T. Nemaline myopathy: a new congenital myopathy. Brain 1963;86:793-8 10. 3. Conen RE, Murphy GE, Donohue WL. Light and electron microscopic study of “myogranules” in a child with hypotonia and muscle weakness. Can Med Assoc J 1963;89:983-6. 4. Scarlato G, Pellegrini G, Moggio M, et al. Familial nemaline myopathy. Neuropediatrics 1982; 13:2 I I-5. 5. McMenamin JB, Curry B, Taylor GP, Becker LE, Murphy EG. Fatal nemaline myopathy in infancy. Can J Neural Sci 1984;11:305-9.
ORAL SURG ORAL MED ORAL PATHOS July 1991 6. Kuitunen P, Rapola J, Nopenen AL, Donner M. Nemaline myopathy: report of four cases and review of the literature. Acta Paediatr Stand 1972;61:353-61. 7. Acts WF, Bethlem J, Dingemans KP, Eriksson AW. Investigations on the inheritance of nemaline myopathy. Arch Neurol 1978;35:72-7. 8. Taskos N, Bostantzopoulou S, Logothetis J. Nemaline (rod) myopathy occurring in a male boy as a sporadic case with review of the literature. Neural Psychiatr 1986;1:37-40. 9. Wallgren-Petterson C. Congenital nemaiine myopathy, a clinical follow-up study of twelve patients. J Neural Sci 1989;89: l-4. 10. Martinez BA, Lake BD. Childhood nemaline myopathy: a review of clinical presentation in relation to prognosis. Dev Med Child Neurol 1987;29:8 15-20. 11. Jennekens FGI, Roord JI, Veldman H, Willense J, Jockush BM. Congenital nemaline myopathy: defectiveorganization of cu-actinin is restricted to muscle. Muscle Nerve I983;6:61-8. 12. Arts WF, De Groot CJ. Congenital nemaline myopathy: two patients with consanguineous parents, one with a progressive course. J Neurol 1983;230:123-30. 13. Kondo K, Yuasa T. Genetics of congenital nemaline myopathy. Muscle Nerve 1980;3:308- 15. 14. Bender AN, Willner JP. Nemaline (rod) myopathy: the need for histochemical evaluation of affected families. Ann Neurol 1978;4:37-42. Reprint requests. K. Antoniades, DDS, MD Department of Oral and Maxillofacial School of Dentistry University of Thessaloniki 54006 Thessaloniki, Greece
Surgery