J. Endocrinol. Invest. 14: 599-607, 1991
CASE REPORT
Moebius syndrome in association with hypogonadotropic hypogonadism L.E. Brackett*1, L.M. Oemers**, A.C. Mamourian***, C. Ellenberger Jr.****, and R.J . Santen* Departments of * Medicine, ** Pathology and *** Radiology, The Pennsylvania State University College of Medicine, P.O. Box 850, Hershey, PA 17033, and **** Lebanon Neurological Associates, 206 Hathaway Park, Lebanon, PA 17042, USA ABSTRACT . The association between hypogonadotropic hypogonadism and multiple CNS lesions in a variety of disorders suggests a possible causative link between these clinical findings. Neural afferent input into the hypothalamus from higher CNS centers modulates GnRH secretion and derangements of these neural pathways could potentially result in diminished gonadotropin secretion and hypogonadism. This report describes a patient with multiple CNS defects secondary to Moebius syndrome and hypogonadotropic hypogonadism whose clinical features support the hypothesis that his CNS and endocrine defects may be causally associated. Comprehensive clinical evaluation in this patient revealed severe mental retar-
dation; cranial nerve palsies; motor, reflex, and gait disturbances; and sexual infantilism secondary to hypogonadotropic hypogonadism. An MRI of the brain revealed atrophy or hypoplasia of the third cranial nerve and the olfactory gyri. Numerous syndromes including the Moebius syndrome are now described in which hypogonadotropic hypogonadism and CNS defects are associated. Detailed neuroanatomic and embryologic studies have demonstrated the important functional interrelationships between higher central nervous system centers and the hypothalamus. Taken together, these findings provide support for the causative association of multiple CNS defects and hypogonadotropic hypogonadism.
INTRODUCTION
Based upon an animal model, thehypogonadotropism in Kallmann's syndrome was once thought to reflect a deletion of the GnRH gene, a concept now disproved (2, 3). More recently, developmental studies suggest that one type of Kallmann 's syndrome is due to abnormal migration of GnRH-containing neurons into the hypothalamus (4-8). Many patients with Kallmann's syndrome have been found to demonstrate a variety of CNS abnormalities in structures superior to the hypothalamus (9-17). Taken together, these findings suggest that the GnRH deficiency in Kallmann's syndrome represents not a hypothalamic lesion per se but disruption of the afferent neural pathways into the hypothalamus which control pulsatile GnRH release (1). The emerging concepts regarding Kallmann's syndrome focus attention on the possible pathogenesis of hypogonadism in a variety of other disorders with associated CNS dysfunction and hypogonadotropism. For example, the Laurence MoonBiedl, Prader-Labhart-Willi, Multiple Lentigenes,
Hypogonadotropic hypogonadism in men represents a clinical syndrome consisting of isolated gonadotropin deficiency, partial or complete sexual infantilism, and impaired spermatogenesis (1). Acquired forms of this syndrome exist which usually are attributable to hypothalamic or pituitary lesions resulting from tumors, granulomas, vascular or inflammatory processes (1). Genetic forms of hypogonadotropic hypogonadism also occur. The most common type is Kallmann's syndrome, which is defined as the coexistence of hypogonadotropic hypogonadism with anosmia or hyposmia (1).
lPresent address: National Institute of Diabetes, Digestive and Kidney Disorders, National Institutes of Health. Bethesda, MD 20892 USA. Key-words: Moebius syndrome, Kallmann's syndrome , hypogonadotropic hypogonadism , anosmia. Correspondence.' Dr. Richard J. Santen, Department of Medicine, The Penns ylvan ia State University Co llege of Medicine, P.O. Box 850, Hershey, Pennsylvan ia 17033, USA. Received November 15, 1990; accepted Apri l 11, 1991.
599
L.E. Brackett, L.M Demers, A.C Mamourian, et aJ.
and Rud syndromes and hypogonadotropic hypogonadism with cerebellar ataxia and Freidrich's ataxia all are characterized by both eNS dysfunction and hypogonadotropism (18-23). These constellation of findings suggests the possibility that extrahypothalamic lesions, by disrupting hypothalamic neural input, may also be causative of the multiple syndromes of gonadotropin deficiency. The demonstration of CNS defects and hypogonadotropism in other genetic disorders would serve to strengthen this hypothesis. In this communication, the association of hypogonadotropic hypogonadism with the Moebius syndrome is described in order to provide additional support for the concept that disruption of the hypothalamic neural afferent input may result in hypogonadotropism. Moebius Syndrome The Moebius Syndrome was initially described as a condition characterized by bilateral facial paralysis, lateral rectus paralysis, and webbing of two fingers of the right hand (24). This definition has now been extended to include patients with medial, lateral, or vertical eye movement disorders associated with bilateral or unilateral facial paresis or paralysis. Defects reported to occur in association with the Moebius syndrome include multiple cranial nerve defects (25-28), epilepsy (28), mental retardation (29), limb anomalies (30) such as clubbing, hypoplasia, syndactyly, and brachydactyly; absence or hypoplasia of the pectoralis muscles with ipsilateral limb anomaly (Poland syndrome) (31-34) arthrogryposis multiplex congenita (28, 35); and peripheral neuropathies (15, 36-41). In this comminication, we report the fourth case of Moebius syndrome associated with hypogonadotropic hypogonadism. The findings in this and other patients with diffuse CNS lesions support the possibility that extrahypothalamic lesions may be causative of hypogonadotropic hypogonadism.
Fig. 1 - Photographs of frontal (left) and side views (ngh!) of patient illustrating bilateral gynecomastia, hypogonadal fat distribution and hypogonadism.
Physical examination revealed a patient with a pale complexion and lack of facial, axillary, and peripheral extremity hair, and the presence of bilateral gynecomastia and hypogonadal fat distribution (Fig. 1). Genital tissue revealed Tanner Stage" pubic hair, microphallus with hypospadias, and an undeveloped, nonrugated scrotum. The right testis was undescended and the left was retractile, < 2 ml in volume, and palpable only with squatting. Rectal examination revealed a non palpable prostate and good sphincter tone. The lower extremities revealed hammer toe deformities. There was no clinical evidence of hypothyroidism or adrenal insufficiency. The arm span was not 2 cm greater than height, thus indicating lack of eunuchoidal proportions. Neurologic examination revealed an alert and oriented, but shy young man who rarely spoke and answered questions only with single words. He could not identify soap, tobacco, or perfume by smell. Vision with correction was 20/50 and 20/40, the reduction probably caused by bilateral exposure keratopathy involving inferior halves of both corneas. Visual fields were full to confrontation. Pupils were 1-2 mm, the left slightly larger; both reacted minimally to light and dilated poorly to mydriatics. The ocular fundi were normal except for myelination of parapapillary nerve fibers bilaterally. There was bilateral ptosis and impaired function of both levator
CASE REPORT A 31-year old white male was brought into our clinic by his relatives for initial evaluation of sexual infantilism. A lifelong history of a seizure disorder, extraocular muscle abnormalities, mental retardation, encopresis, and failure of sexual maturation was reported. The patient had achieved a normal adult stature of 180 cm and had no symptoms suggestive of diabetes insipidus, adrenal insufficiency, or thyroid dysfunction. The family history was negative for anosmia, mental retardation, facial abnormalities, sexual infantilism, delayed puberty, hypogonadism, and limb anomalies.
600
Moebius syndrome and hypogonadotropic hypogonadism
flexes that could be obtained were at the knees where the left was more active. Sensory and cerebellar function were normal. There were no specific abnormalities of gait, however his walk was mildly unsteady and he could not walk in tandem.
palpebrae muscles; he was able to close the left upper lid almost completely but not the right. There was a large exotropia and he preferred to fix with the right eye. He could move either eye left and right from about 15 to about 50 degrees temporal to the primary position, but saccadic velocities were slow in both directions. No vertical movements of either eye were possible. Corneal sensation was reduced bilaterally but facial sensation was normal. Jaw opening and closing was normal, but the only evidence of function of facial muscles was a slight ability to extend the corners of his mouth. Lack of tone in the facial muscles gave his face a smooth, masklike appearance (Fig. 2). The nose was unusually small . Hearing was grossly normal, the palate elevated normally and a gag reflex was present. Muscles innervated by the 11 th and 12th cranial nerves functioned normally. Muscle bulk, tone, and strength were normal, but the only deep-tendon re-
MATERIALS AND METHODS Radioimmunoassay Thyroid hormones (TSH, T4 , T3, T3 resin uptake), growth hormone, somatomedin C, DHEA-sulfate, A4 -androstenedione, testosterone, dihydrotestosterone, prolactin, plasma LH and FSH, and urine LH and FSH were determined by previously described radioimmunoassays (42-47). Psychological evaluation Formal testing included the use of the following standard tests: the Wechsler Adult Intelligence Scale-
Table 1 - Evaluation of pituitary function. Patient
Normal range
TSH (I!u/ml) Thyroxine (I!g/dl) Triiodothyronine (ng/dl) T3 -resin uptake (%) Free Thyroxine Index Growth Hormone (ng/ml) Somatomedin C (I!U/ml) Urine Osmolality (mOSM/kg)
2.6 5.7 133 31.3 178 1.5 0.64 760
0.4-4.0 4.0-13.0 90-240 25-35 120-340
CASE REPORT
Moebius syndrome in association with hypogonadotropic hypogonadism L.E. Brackett*1, L.M. Oemers**, A.C. Mamourian***, C. Ellenberger Jr.****, and R.J . Santen* Departments of * Medicine, ** Pathology and *** Radiology, The Pennsylvania State University College of Medicine, P.O. Box 850, Hershey, PA 17033, and **** Lebanon Neurological Associates, 206 Hathaway Park, Lebanon, PA 17042, USA ABSTRACT . The association between hypogonadotropic hypogonadism and multiple CNS lesions in a variety of disorders suggests a possible causative link between these clinical findings. Neural afferent input into the hypothalamus from higher CNS centers modulates GnRH secretion and derangements of these neural pathways could potentially result in diminished gonadotropin secretion and hypogonadism. This report describes a patient with multiple CNS defects secondary to Moebius syndrome and hypogonadotropic hypogonadism whose clinical features support the hypothesis that his CNS and endocrine defects may be causally associated. Comprehensive clinical evaluation in this patient revealed severe mental retar-
dation; cranial nerve palsies; motor, reflex, and gait disturbances; and sexual infantilism secondary to hypogonadotropic hypogonadism. An MRI of the brain revealed atrophy or hypoplasia of the third cranial nerve and the olfactory gyri. Numerous syndromes including the Moebius syndrome are now described in which hypogonadotropic hypogonadism and CNS defects are associated. Detailed neuroanatomic and embryologic studies have demonstrated the important functional interrelationships between higher central nervous system centers and the hypothalamus. Taken together, these findings provide support for the causative association of multiple CNS defects and hypogonadotropic hypogonadism.
INTRODUCTION
Based upon an animal model, thehypogonadotropism in Kallmann's syndrome was once thought to reflect a deletion of the GnRH gene, a concept now disproved (2, 3). More recently, developmental studies suggest that one type of Kallmann 's syndrome is due to abnormal migration of GnRH-containing neurons into the hypothalamus (4-8). Many patients with Kallmann's syndrome have been found to demonstrate a variety of CNS abnormalities in structures superior to the hypothalamus (9-17). Taken together, these findings suggest that the GnRH deficiency in Kallmann's syndrome represents not a hypothalamic lesion per se but disruption of the afferent neural pathways into the hypothalamus which control pulsatile GnRH release (1). The emerging concepts regarding Kallmann's syndrome focus attention on the possible pathogenesis of hypogonadism in a variety of other disorders with associated CNS dysfunction and hypogonadotropism. For example, the Laurence MoonBiedl, Prader-Labhart-Willi, Multiple Lentigenes,
Hypogonadotropic hypogonadism in men represents a clinical syndrome consisting of isolated gonadotropin deficiency, partial or complete sexual infantilism, and impaired spermatogenesis (1). Acquired forms of this syndrome exist which usually are attributable to hypothalamic or pituitary lesions resulting from tumors, granulomas, vascular or inflammatory processes (1). Genetic forms of hypogonadotropic hypogonadism also occur. The most common type is Kallmann's syndrome, which is defined as the coexistence of hypogonadotropic hypogonadism with anosmia or hyposmia (1).
lPresent address: National Institute of Diabetes, Digestive and Kidney Disorders, National Institutes of Health. Bethesda, MD 20892 USA. Key-words: Moebius syndrome, Kallmann's syndrome , hypogonadotropic hypogonadism , anosmia. Correspondence.' Dr. Richard J. Santen, Department of Medicine, The Penns ylvan ia State University Co llege of Medicine, P.O. Box 850, Hershey, Pennsylvan ia 17033, USA. Received November 15, 1990; accepted Apri l 11, 1991.
599
L.E. Brackett, L.M Demers, A.C Mamourian, et aJ.
and Rud syndromes and hypogonadotropic hypogonadism with cerebellar ataxia and Freidrich's ataxia all are characterized by both eNS dysfunction and hypogonadotropism (18-23). These constellation of findings suggests the possibility that extrahypothalamic lesions, by disrupting hypothalamic neural input, may also be causative of the multiple syndromes of gonadotropin deficiency. The demonstration of CNS defects and hypogonadotropism in other genetic disorders would serve to strengthen this hypothesis. In this communication, the association of hypogonadotropic hypogonadism with the Moebius syndrome is described in order to provide additional support for the concept that disruption of the hypothalamic neural afferent input may result in hypogonadotropism. Moebius Syndrome The Moebius Syndrome was initially described as a condition characterized by bilateral facial paralysis, lateral rectus paralysis, and webbing of two fingers of the right hand (24). This definition has now been extended to include patients with medial, lateral, or vertical eye movement disorders associated with bilateral or unilateral facial paresis or paralysis. Defects reported to occur in association with the Moebius syndrome include multiple cranial nerve defects (25-28), epilepsy (28), mental retardation (29), limb anomalies (30) such as clubbing, hypoplasia, syndactyly, and brachydactyly; absence or hypoplasia of the pectoralis muscles with ipsilateral limb anomaly (Poland syndrome) (31-34) arthrogryposis multiplex congenita (28, 35); and peripheral neuropathies (15, 36-41). In this comminication, we report the fourth case of Moebius syndrome associated with hypogonadotropic hypogonadism. The findings in this and other patients with diffuse CNS lesions support the possibility that extrahypothalamic lesions may be causative of hypogonadotropic hypogonadism.
Fig. 1 - Photographs of frontal (left) and side views (ngh!) of patient illustrating bilateral gynecomastia, hypogonadal fat distribution and hypogonadism.
Physical examination revealed a patient with a pale complexion and lack of facial, axillary, and peripheral extremity hair, and the presence of bilateral gynecomastia and hypogonadal fat distribution (Fig. 1). Genital tissue revealed Tanner Stage" pubic hair, microphallus with hypospadias, and an undeveloped, nonrugated scrotum. The right testis was undescended and the left was retractile, < 2 ml in volume, and palpable only with squatting. Rectal examination revealed a non palpable prostate and good sphincter tone. The lower extremities revealed hammer toe deformities. There was no clinical evidence of hypothyroidism or adrenal insufficiency. The arm span was not 2 cm greater than height, thus indicating lack of eunuchoidal proportions. Neurologic examination revealed an alert and oriented, but shy young man who rarely spoke and answered questions only with single words. He could not identify soap, tobacco, or perfume by smell. Vision with correction was 20/50 and 20/40, the reduction probably caused by bilateral exposure keratopathy involving inferior halves of both corneas. Visual fields were full to confrontation. Pupils were 1-2 mm, the left slightly larger; both reacted minimally to light and dilated poorly to mydriatics. The ocular fundi were normal except for myelination of parapapillary nerve fibers bilaterally. There was bilateral ptosis and impaired function of both levator
CASE REPORT A 31-year old white male was brought into our clinic by his relatives for initial evaluation of sexual infantilism. A lifelong history of a seizure disorder, extraocular muscle abnormalities, mental retardation, encopresis, and failure of sexual maturation was reported. The patient had achieved a normal adult stature of 180 cm and had no symptoms suggestive of diabetes insipidus, adrenal insufficiency, or thyroid dysfunction. The family history was negative for anosmia, mental retardation, facial abnormalities, sexual infantilism, delayed puberty, hypogonadism, and limb anomalies.
600
Moebius syndrome and hypogonadotropic hypogonadism
flexes that could be obtained were at the knees where the left was more active. Sensory and cerebellar function were normal. There were no specific abnormalities of gait, however his walk was mildly unsteady and he could not walk in tandem.
palpebrae muscles; he was able to close the left upper lid almost completely but not the right. There was a large exotropia and he preferred to fix with the right eye. He could move either eye left and right from about 15 to about 50 degrees temporal to the primary position, but saccadic velocities were slow in both directions. No vertical movements of either eye were possible. Corneal sensation was reduced bilaterally but facial sensation was normal. Jaw opening and closing was normal, but the only evidence of function of facial muscles was a slight ability to extend the corners of his mouth. Lack of tone in the facial muscles gave his face a smooth, masklike appearance (Fig. 2). The nose was unusually small . Hearing was grossly normal, the palate elevated normally and a gag reflex was present. Muscles innervated by the 11 th and 12th cranial nerves functioned normally. Muscle bulk, tone, and strength were normal, but the only deep-tendon re-
MATERIALS AND METHODS Radioimmunoassay Thyroid hormones (TSH, T4 , T3, T3 resin uptake), growth hormone, somatomedin C, DHEA-sulfate, A4 -androstenedione, testosterone, dihydrotestosterone, prolactin, plasma LH and FSH, and urine LH and FSH were determined by previously described radioimmunoassays (42-47). Psychological evaluation Formal testing included the use of the following standard tests: the Wechsler Adult Intelligence Scale-
Table 1 - Evaluation of pituitary function. Patient
Normal range
TSH (I!u/ml) Thyroxine (I!g/dl) Triiodothyronine (ng/dl) T3 -resin uptake (%) Free Thyroxine Index Growth Hormone (ng/ml) Somatomedin C (I!U/ml) Urine Osmolality (mOSM/kg)
2.6 5.7 133 31.3 178 1.5 0.64 760
0.4-4.0 4.0-13.0 90-240 25-35 120-340
