American Journal of Medical Genetics 37:578-582 (1990)
The Syndrome of Mobius Sequence, Peripheral Neuropathy, and Hypogonadotropic Hypogonadism Masahiko Kawai, Toru Momoi, Tatsuya Fujii, Shozo Nakano, Yasuko Itagaki, and Haruki Mikawa Department of Pediatrics, Kyoto Un,iversityFaculty of Medicine (M.K.,T.M.,T.F.,S.N.Jf.M.), and Department of Pediatrics, Utano National Hospital (Y.I.),Japan
We report on a 17-year-oldJapanese boy with Mobius sequence, peripheral neuropathy, and hypogonadotropic hypogonadism, the fourth such case known to us. The association of peripheral neuropathy and hypogonadotropic hypogonadism in Mobius sequence seems to be more than coincidence. Pulsatile gonadotropin-releasing hormone administrationfor 3 months showed the effectiveness of this treatment for this patient.
sion, strabismus, and ophthalmoplegia were noted. Early psychomotor development was delayed; head control occurred a t 6 months, talking at 18, and walking at 19 months. The boy’s school performance was normal. Operation for strabismus was performed a t 1 and 5 years. Orchidopexy was performed a t 3 years. There was no family history of neurological or endocrinological disorders. The patient’s younger 12-year-old brother showed normal secondary sexual development for his age. At age 15% years, he was admitted for a thorough evaluation. On physical examination, his face was KEY WORDS: Mobius sequence, hypomask-like and his constitution eunuchoidal with a gonadotropic hypogonadheight of 151.1 cm ( - 2.7 SD) and a weight of 41.1 kg. ism, peripheral neuropathy His growth rate had been about 5 cm every year for the previous 10 years, so that the adolescent growth spurt had failed to occur (Fig. 1).The testes were about 1ml in INTRODUCTION volume. The penis was infantile, pubic and axillary hair Mobius described a “syndrome” of congenital facial was absent. Ocular movements were impaired except for diplegia and ophthalmoplegia in 1988. Autosomal domi- abduction of the right eye and adduction of the left eye. nant inheritance has been suggested LMcKusick, 19881, Binocular vision was impossible due to right external although most cases are sporadic. This condition, known strabismus. The optic fundi were normal, but pupillary as Mobius “syndrome” [McKusick 15790, McKusick, light reactions were sluggish in both eyes. Facial mus19881, is sometimes associated with other cranial nerve cles were totally paretic and bilateral ptosis was noted. involvement including the third, fourth, fifth, ninth, Other cranial nerves, including the olfactory nerve, tenth, and twelfth nerves. About 15% of the patients were normal. Muscle tone and deep tendon reflexes were reportedly have mental deficiency. There have been 3 normal. Peripheral sensation to temperature, pain, reported cases of Mobius sequence, peripheral neuropa- light touch, and vibration was intact. Intelligence was thy, and hypogonadotropic hypogonadism (HH) [Olson normal: I& score of 111 a t age lO9/12. The patient was et al., 1970; Rubinstein et al., 1975; Abid et al., 19781. very sensitive about his appearance, and was emoHere we report another case of Mobius sequence with tionally labile. peripheral neuropathy and HH. Taking into account the phenotypic variabilities in the reported cases of Mobius Laboratory Tests sequence, the association of Mobius sequence, periphChromosomes were normal (46,XY).The aerobic exereral neuropathy, and HH seems more than coincidence. cise test (15 watt x 15 minutes) showed a normal increment of plasma lactate and pyruvate levels. Results of CLINICAL REPORT the oral glucose tolerance test were normal; neither Our patient, a Japanese boy (K.O.),was born a t term. nor electroretinography The pregnancy was uneventful and the parents were not electroencephalography showed any abnormalities. The auditory brainstem reconsanguineous. Soon after birth, a lack of facial expressponse was also normal, but the visually evoked potentials showed slightly decreased pl00 on the right side (89.4 versus 104). The computer-assisted tomography Received for publication J a n u a r y 22, 1990; revision received and magnetic resonance imaging of the brain showed no April 25, 1990. abnormal findings. The patient’s bone age was moderAddress reprint requests to Masahiko Kawai, M.D., Department of Pediatrics, Sumitomo Hospital, 5-2-2 Nakanoshima, Kita-ku, ately delayed: 14 years a t a chronological age of 15% years. Osaka 530, Japan.
0 1990 Wiley-Liss, Inc.
Mobius Syndrome With Neuropathy and Hypogonadism
170 160 -
150
-
100 B.Wt.
140
-
(kd 90
130
-
no 70 60
50 40
30 20
Fig. 1. Growth chart of the patient.
579
Nerve Conduction Velocity and Electromyography Motor nerve conduction velocity (MCV) in the lower limbs was subnormal compared to the mean values: median nerve, 44.8 misec (normal, 47-68 misec), and posterior tibia1 nerve, 34.8 misec (normal, 40-61 misec). Electromyography (EMG) of the anterior tibialis and orbicularis oris muscles showed mildly to moderately myopathic units, although the EMG of the abductor pollicis brevis muscle was normal. Manual muscle testing of the limbs showed no abnormalities. Muscle Biopsy A portion of the right quadriceps femoris muscle was obtained and processed for light and electron microscopic studies. In light microscopic examination, hematoxylin and eosin (HE) staining showed a few angular fibers (Fig. 2). Staining for succinate dehydrogenase, cytochrome c oxydase, and NADH-reductase showed mild subsarcolemmal aggregation of mitochondria (Fig. 3); the modified Gomori-trichrome stain did not show ragged-red fibers. No significant changes were noted in electron microscopic studies. Enzyme activities of the mitochondria1 electron transport system (NADHcytochrome c reductase, succinate-cytochrome c reductase, and cytochrome c oxidase) were normal. These findings, together with the subnormal MCV, indicated the presence of a lower motor neuron lesion in this patient. Endocrine Examinations The basal level of serum testosterone was
The Syndrome of Mobius Sequence, Peripheral Neuropathy, and Hypogonadotropic Hypogonadism Masahiko Kawai, Toru Momoi, Tatsuya Fujii, Shozo Nakano, Yasuko Itagaki, and Haruki Mikawa Department of Pediatrics, Kyoto Un,iversityFaculty of Medicine (M.K.,T.M.,T.F.,S.N.Jf.M.), and Department of Pediatrics, Utano National Hospital (Y.I.),Japan
We report on a 17-year-oldJapanese boy with Mobius sequence, peripheral neuropathy, and hypogonadotropic hypogonadism, the fourth such case known to us. The association of peripheral neuropathy and hypogonadotropic hypogonadism in Mobius sequence seems to be more than coincidence. Pulsatile gonadotropin-releasing hormone administrationfor 3 months showed the effectiveness of this treatment for this patient.
sion, strabismus, and ophthalmoplegia were noted. Early psychomotor development was delayed; head control occurred a t 6 months, talking at 18, and walking at 19 months. The boy’s school performance was normal. Operation for strabismus was performed a t 1 and 5 years. Orchidopexy was performed a t 3 years. There was no family history of neurological or endocrinological disorders. The patient’s younger 12-year-old brother showed normal secondary sexual development for his age. At age 15% years, he was admitted for a thorough evaluation. On physical examination, his face was KEY WORDS: Mobius sequence, hypomask-like and his constitution eunuchoidal with a gonadotropic hypogonadheight of 151.1 cm ( - 2.7 SD) and a weight of 41.1 kg. ism, peripheral neuropathy His growth rate had been about 5 cm every year for the previous 10 years, so that the adolescent growth spurt had failed to occur (Fig. 1).The testes were about 1ml in INTRODUCTION volume. The penis was infantile, pubic and axillary hair Mobius described a “syndrome” of congenital facial was absent. Ocular movements were impaired except for diplegia and ophthalmoplegia in 1988. Autosomal domi- abduction of the right eye and adduction of the left eye. nant inheritance has been suggested LMcKusick, 19881, Binocular vision was impossible due to right external although most cases are sporadic. This condition, known strabismus. The optic fundi were normal, but pupillary as Mobius “syndrome” [McKusick 15790, McKusick, light reactions were sluggish in both eyes. Facial mus19881, is sometimes associated with other cranial nerve cles were totally paretic and bilateral ptosis was noted. involvement including the third, fourth, fifth, ninth, Other cranial nerves, including the olfactory nerve, tenth, and twelfth nerves. About 15% of the patients were normal. Muscle tone and deep tendon reflexes were reportedly have mental deficiency. There have been 3 normal. Peripheral sensation to temperature, pain, reported cases of Mobius sequence, peripheral neuropa- light touch, and vibration was intact. Intelligence was thy, and hypogonadotropic hypogonadism (HH) [Olson normal: I& score of 111 a t age lO9/12. The patient was et al., 1970; Rubinstein et al., 1975; Abid et al., 19781. very sensitive about his appearance, and was emoHere we report another case of Mobius sequence with tionally labile. peripheral neuropathy and HH. Taking into account the phenotypic variabilities in the reported cases of Mobius Laboratory Tests sequence, the association of Mobius sequence, periphChromosomes were normal (46,XY).The aerobic exereral neuropathy, and HH seems more than coincidence. cise test (15 watt x 15 minutes) showed a normal increment of plasma lactate and pyruvate levels. Results of CLINICAL REPORT the oral glucose tolerance test were normal; neither Our patient, a Japanese boy (K.O.),was born a t term. nor electroretinography The pregnancy was uneventful and the parents were not electroencephalography showed any abnormalities. The auditory brainstem reconsanguineous. Soon after birth, a lack of facial expressponse was also normal, but the visually evoked potentials showed slightly decreased pl00 on the right side (89.4 versus 104). The computer-assisted tomography Received for publication J a n u a r y 22, 1990; revision received and magnetic resonance imaging of the brain showed no April 25, 1990. abnormal findings. The patient’s bone age was moderAddress reprint requests to Masahiko Kawai, M.D., Department of Pediatrics, Sumitomo Hospital, 5-2-2 Nakanoshima, Kita-ku, ately delayed: 14 years a t a chronological age of 15% years. Osaka 530, Japan.
0 1990 Wiley-Liss, Inc.
Mobius Syndrome With Neuropathy and Hypogonadism
170 160 -
150
-
100 B.Wt.
140
-
(kd 90
130
-
no 70 60
50 40
30 20
Fig. 1. Growth chart of the patient.
579
Nerve Conduction Velocity and Electromyography Motor nerve conduction velocity (MCV) in the lower limbs was subnormal compared to the mean values: median nerve, 44.8 misec (normal, 47-68 misec), and posterior tibia1 nerve, 34.8 misec (normal, 40-61 misec). Electromyography (EMG) of the anterior tibialis and orbicularis oris muscles showed mildly to moderately myopathic units, although the EMG of the abductor pollicis brevis muscle was normal. Manual muscle testing of the limbs showed no abnormalities. Muscle Biopsy A portion of the right quadriceps femoris muscle was obtained and processed for light and electron microscopic studies. In light microscopic examination, hematoxylin and eosin (HE) staining showed a few angular fibers (Fig. 2). Staining for succinate dehydrogenase, cytochrome c oxydase, and NADH-reductase showed mild subsarcolemmal aggregation of mitochondria (Fig. 3); the modified Gomori-trichrome stain did not show ragged-red fibers. No significant changes were noted in electron microscopic studies. Enzyme activities of the mitochondria1 electron transport system (NADHcytochrome c reductase, succinate-cytochrome c reductase, and cytochrome c oxidase) were normal. These findings, together with the subnormal MCV, indicated the presence of a lower motor neuron lesion in this patient. Endocrine Examinations The basal level of serum testosterone was
