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,iversity Faculty 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-old Japanese boy with Mobius sequence, peripheral neuropathy, and hypogonadotropic hypogonadism, the fourth such case known to us. The association of peripheral neuropathy and hypo- gonadotropic hypogonadism in Mobius se- quence seems to be more than coincidence. Pulsatile gonadotropin-releasing hormone administration for 3 months showed the effec- tiveness of this treatment for this patient.

KEY WORDS: Mobius sequence, hypo- gonadotropic hypogonad- ism, peripheral neuropathy

INTRODUCTION Mobius described a “syndrome” of congenital facial

diplegia and ophthalmoplegia in 1988. Autosomal domi- nant inheritance has been suggested LMcKusick, 19881, although most cases are sporadic. This condition, known as Mobius “syndrome” [McKusick 15790, McKusick, 19881, is sometimes associated with other cranial nerve involvement including the third, fourth, fifth, ninth, tenth, and twelfth nerves. About 15% of the patients reportedly have mental deficiency. There have been 3 reported cases of Mobius sequence, peripheral neuropa- thy, and hypogonadotropic hypogonadism (HH) [Olson et al., 1970; Rubinstein et al., 1975; Abid et al., 19781.

Here we report another case of Mobius sequence with peripheral neuropathy and HH. Taking into account the phenotypic variabilities in the reported cases of Mobius sequence, the association of Mobius sequence, periph- eral neuropathy, and HH seems more than coincidence.

CLINICAL REPORT Our patient, a Japanese boy (K.O.), was born at term.

The pregnancy was uneventful and the parents were not consanguineous. Soon after birth, a lack of facial expres-

Received for publication January 22, 1990; revision received April 25, 1990.

Address reprint requests to Masahiko Kawai, M.D., Department of Pediatrics, Sumitomo Hospital, 5-2-2 Nakanoshima, Kita-ku, Osaka 530, Japan.

0 1990 Wiley-Liss, Inc.

sion, strabismus, and ophthalmoplegia were noted. Early psychomotor development was delayed; head con- trol 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 mask-like and his constitution eunuchoidal with a height of 151.1 cm ( - 2.7 SD) and a weight of 41.1 kg. 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 1 ml in volume. The penis was infantile, pubic and axillary hair was absent. Ocular movements were impaired except for abduction of the right eye and adduction of the left eye. Binocular vision was impossible due to right external strabismus. The optic fundi were normal, but pupillary light reactions were sluggish in both eyes. Facial mus- cles were totally paretic and bilateral ptosis was noted. Other cranial nerves, including the olfactory nerve, were normal. Muscle tone and deep tendon reflexes were normal. Peripheral sensation to temperature, pain, light touch, and vibration was intact. Intelligence was normal: I& score of 111 a t age lO9/12. The patient was very sensitive about his appearance, and was emo- tionally labile.

Laboratory Tests Chromosomes were normal (46,XY). The aerobic exer-

cise test (15 watt x 15 minutes) showed a normal incre- ment of plasma lactate and pyruvate levels. Results of the oral glucose tolerance test were normal; neither electroencephalography nor electroretinography showed any abnormalities. The auditory brainstem re- sponse was also normal, but the visually evoked poten- tials showed slightly decreased pl00 on the right side (89.4 versus 104). The computer-assisted tomography and magnetic resonance imaging of the brain showed no abnormal findings. The patient’s bone age was moder- ately delayed: 14 years a t a chronological age of 15% years.

Mobius Syndrome With Neuropathy and Hypogonadism 579

170 -

160 -

150 -

140 -

130 -

Fig. 1. Growth chart of the patient.

100 B.Wt. ( k d 90

no

70

60

50

40

30

20

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 moder- ately myopathic units, although the EMG of the abduc- tor 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 micro- scopic studies. In light microscopic examination, hema- toxylin 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 (NADH- cytochrome c reductase, succinate-cytochrome c reduc- tase, and cytochrome c oxidase) were normal. These findings, together with the subnormal MCV, indicated the presence of a lower motor neuron lesion in this pa- tient.

Endocrine Examinations The basal level of serum testosterone was <0.3 ngiml.

After intramuscular injection of 2000 IU of human cho- rionic gonadotropin (hCG) for 3 days, the serum tes-

Fig. 2 . Hematoxylin and eosin staining ofquadriceps fernoris muscle shows a few angular fibers ( x 200).

580 Kawai et al.

Fig. 3. NADH-reductase staining of quadriceps femoris muscle shows mild subsarcolemmal aggregation of mitochondria ( x 200).

tosterone level increased to 1.0 ngiml. Serum luteiniz- ing hormone (LH) and follicle-stimulating hormone (FSH) showed a weak response to gonadotropin-releas- ing hormone (GnRH) loading (100 pg intravenously). The high basal value of serum LH seemed to be due to the presence of hCG in the serum because the test was done 5 days after the final hCG injection (2000 U for 3 days). However, after an intravenous infusion of 400 p.g of GnRH for 6 days, serum LH and FSH showed normal response to GnRH loading (Table I). Growth hormone (GH) showed a delayed and cortisol a normal response to insulin loading (regular insulin, 0.1 U/kg). The thy- rotropin-releasing hormone (TRH) loading test (TRH 5 p.g/kg) showed hyperresponsiveness of prolactin and a weak response of thyroid-stimulating hormone (TSH). However, the thyroid functions were normal. After 12

hours of water deprivation the plasma antidiuretic hor- mone (ADH) level was normal (6.9 pg/ml). Since the patient's secondary sexual development was still in the prepubertal stage at age 17 years, we started pulsatile GnRH administration (5 pg subcutaneously every 90 minutes) with the aid of a portable infusion pump, Nipro SP-31 (Osaka, Japan). After 2 months, his serum tes- tosterone level rose from <0.3 ngiml to 1.0 ngiml.

DISCUSSION Three cases of Mobius sequence associated with pe-

ripheral neuropathy and HH have been reported [Olson et al., 1970; Rubinstein et al., 1975; Abid et al., 19781. The review article by Henderson [19391 cites one patient (a 35-year-old man) with this syndrome associated with "infantilism, vasomotor disturbances in the legs and a

TABLE I. Results of Endocrine Examinations*

Minutes _ _ _ - - -~ - - .~ - -

Loding Hormone measured 0 30 60 90 120 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ - _ _ _ _ GnRH Before" LH (IUiliter) 24.0 25.8 26.8 26.9 20.7

FSH (IUiliter) 3.8 6.6 7.9 8.3 8.3 After" LH (IUiliter) 9.1 61.0 53.9 38.4 22.2

FSH (IUiliter) 3.4 10.8 10.4 9.6 7.5

GH (ngiml) 2.2 7.9 4.3 3.8 16.1 Cortisol (pgidl) 7.4 10.2 19.5 21.3 16.9

Prolactin (ngiml) 4.8 108.9 68.3 50.8 17.4 *Abbreviations: GnRH, gonadotropin releasing hormone; LH, luteinizing hormone; FSH, follicle-stimulating hormone; GH, growth hormone; TRH, thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone. "Before and after GnRH loading (400 pg) for 6 days.

Insulin Glucose (mgidl) 91 51 66 79 86

TRH TSH (pU/ml) 1.3 8.5 7.8 7.1 5.4

Mobius Syndrome With Neuropathy and Hypogonadism 581

TABLE 11. Mobius Sequence With Peripheral Neuropathy and Hypogonadotropic Hypogonadism"

Case 1. 18 year male - ~ ~

Endocrine examma- Testosterone: tions low basal level, nor-

ma1 response after 4000 U hCG for 4 days

External genitalia Infantile

Motor nerve conduc- Mildly delayed

Muscle biopsy Minimal neurogenic degeneration

Others Double ureter Mild psychomotor

delay Gvnecomastia

tion velocity

Case 2. 23 year female ~~~-

LH: low FSH: normal GnRH test: normal

response

Normal (under- developed breasts) Moderately delayed

Neurogenic degenera- tion

Anosmia

Case 3. 18 year female _ _ _ _ _ _ _ _ _

LH: normal FSH: low GnRH test: normal

response

Normal (under- developed breasts) Mildly delayed

Neurogenic degenera-

Pes c a m s Bronchial asthma

tion

Present case 15 year male

low basal level, nor- mal response after 2000 U hCG for 3 days

no response at first, LH showed response after 400 kg GnRH for 6 days

~~ ~ __ Testosterone:

GnRH test:

Infantile

Mildly delayed

Mild neurogenic de-

Nocturnal enuresis generation

*Case 1: Olson et al. 119701; Case 2: Rubenstein et al. [19751; Case 3: Abid et al. 119781.

high sugar tolerance"; this case was originally reported by Kahlmeter 119161. However, no endocrine data were available on that patient.

Table I1 summarizes those cases on which endocrine studies were undertaken. One of the cases (case 2) was associated with anosmia. The association of Mobius se- quence with peripheral neuropathy and hypothalamic (or pituitary) hormone deficiency in 4 patients strongly supports the assumption that this combination is more than just coincidence. Recently, Koide et al. 119831 re- ported a 24-year-old man with Mobius sequence associ- ated with an isolated adrenocorticotropic hormone (ACTH) deficiency, although the hypothalamic origin of ACTH (corticotropin releasing factor) deficiency was not confirmed. The increased serum testosterone levels in our patient after pulsatile GnRH administration indi- cate that the pituitary-gonadal axis was not affected.

The progressive nature of peripheral neuropathy was stressed in cases reported by Rubenstein et al. [19751 and Abid et al. [19781, but our patient and the patients reported by Olsen et al. [1970] and Koide et al. 119831 showed no progression in their symptoms.

Endocrine disorders such as diabetes mellitus, hypo- parathyroidism, hypothyroidism, and hypogonadism have been reported in some forms of mitochondrial encephalomyopathy [Julien et al., 1973; Toppet et al., 1977; Doriguzzi et al., 19891. Although some of the manifestations, such as ophthalmoplegia, of Mobius sequence appear similar to those of mitochondrial en- cephalomyopathy with chronic progressive external ophthalmoplegia, the findings on clinical, histo- pathological, and biochemical studies (i.e., congenital and nonprogressive ophthalmoplegia, plasma lactate and pyruvate response to aerobic exercise test and oral glucose tolerance test, and electron microscopic studies

and enzyme assays of the muscle) show the distinct features of Mobius sequence.

The association of hypothalamic dysfunction and pe- ripheral neuropathy in Mobius sequence and the reports of other cases associated with mental deficiency andlor malformation of arms and legs [McKusick, 1988; Hen- derson, 19391 indicate that the pathogenesis of this syn- drome is not simply due to a localized defect in a specific tissue or organ, as already discussed by Henderson [1939]. In addition to the 3 pathogenetic theories, i.e, primary brainstem nuclear hypoplasia [Heubner, 19001, secondary brainstem nuclear degeneration [Mobius, 18881, and brainstem atrophy secondary to muscular defect [Pitner et al., 19651, a new hypothesis of prenatal vascular lesion was introduced by Bavinck and Weaver [1986]. The disruption sequence in the vascular terri- tory of the subclavian artery due to prenatal lesion may explain the phenotypic variabilities in this syndrome; however, the histopathological evidence to support this hypothesis is lacking a t present. Although hypo- thalamic dysfunction may be explained by the above theories, peripheral neuropathy cannot be explained. We cannot clarify the pathogenesis but there must be another unknown mechanism which connects Mobius sequence and peripheral neuropathy.

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