A case report of Septo-Optic Dysplasia (de Morsier's Syndrome): the importance of establishing a precise diagnosis in adults with severe and profound mental retardation. (The American Academy of Developmental Medicine and Denistry).
A significant transfer of services from institutional to community-based settings has occurred during the past 20 years for adults with mental retardation. As a result, primary care physicians in the community are now being asked to provide health services to a population of individuals that had previously received health care out of the mainstream of usual generic practice. In addition, because these patients had received medical services by nontraditional providers, there is relatively little clinical data to guide the practitioner in the community. Many of these previously institutionalized individuals have never been adequately evaluated to determine the etiology of the brain dysfunction that caused the mental retardation in the first place, and if an evaluation had been performed it was not based on modern diagnostic methods and technology. As de-institutionalization continues, there will therefore be a progressive need for community-based primary-care physicians to become aware of the various diagnostic possibilities found in those adults with mental retardation who will be seeking their professional services.
The importance of establishing a precise etiology has been addressed by others, and is not merely an academic exercise. Important genetics counseling and clinically significant treatment information can be derived from determination of the cause of a person's developmental disability, even when that determination is made in adulthood.
The etiologic diagnosis of the case reported here (Septo-Optic Dysplasia) was made post-mortem. Had the diagnosis been made before death, the clinical management might have been different. This report therefore underscores the importance of establishing a diagnosis even in adults with profound mental retardation. Furthermore, it is suggested that neuropathological evaluation post-mortem might play an important role in much-needed expansion of a medical data base pertaining to adults with severe developmental disabilities.
CASE REPORT: P.R. was a 22-year-old man who resided in a 650-bed State institution for the mentally retarded located in Clinton, NJ since the age of 11.
He was an only child, the product of a normal full-term gestation and spontaneous delivery and was felt to be normal at birth. There was no history of maternal substance abuse. The pregnancy was however complicated by the fact that the mother was battered during the first trimester and sustained abdominal trauma on more than one occasion. In addition, even before gestation occurred, the mother developed an anxiety disorder from spousal abuse, which resulted in frequent, premature beats requiring treatment with oral quinidine.
There was no other maternal illness during the pregnancy. Chromosome analysis revealed a 46 XY pattern. It was noted by his parents that at six months of age he appeared to be visually impaired and was not developing normally. Medical evaluation at 12 months of age revealed that he was legally blind. At that time he was not able to sit and subsequently was never able to walk because of severe spasticity. At 24 months of age he developed generalized seizures and was placed on phenytoin and Phenobarbital. He never speech nor attended public school. At 10 years of age he underwent extensive orthopedic surgery in an attempt to correct contractures which resulted from long-standing spastic rigidity. At age 11 he was 47 inches and at age 13 he was 49 inches tall, both well below the third percentile for height. He attained a maximum height of 62 inches at age 22 (even though his mother was 5' 7" and his father was 5' 8" tall). The patient did, however, go through puberty and developed secondary sex characteristics.
NORMAL MRI: Compare with the patient's MRI, which demonstrates agenesis of corpus callosum (CC) and absence of septum pellucidum on coronal view (see on right).
PATIENT'S MRI: Note agenesis of corpus callosum and absence of septum pellucidum (see page 95).
Thyroid function tests, fasting blood sugar and electrolyte determinations were normal. At age 20 he developed a swallowing abnormality secondary to oro-pharyngeal dysfunction and esophageal spasms. Also, at age 20 he developed severe myoclonic-dystonic movements of the upper extremities. EEG was difficult to interpret because of muscle artifact. Brain MRI revealed agenesis of the corpus callosum and absence of the septum pellucidum (see figure). His clinical course for the year prior to death was characterized by "spells" of hyperventilation, tachycardia, hypertension, diaphoresis and hyperthermia associated with dystonic-myoclonic muscle spasms of the upper extremities. He expired suddenly and unexpectedly following one of these spells, most likely secondary to aspiration.
Autopsy Findings: Autopsy was limited to the brain. The meninges and external arteries were unremarkable. The optic chiasm, tracts and nerves were moderately to markedly underdeveloped. The frontal lobes were also underdeveloped but with a normal gyral pattern. The caudal cerebellar vermis was not developed. Sectioning of the brain revealed a markedly underdeveloped thalamus and hypothalamus. The corpus callosum was absent anteriorly and the septum pellucidum was absent in entirety. The basal ganglia (caudate and putamen) and hippocampal areas of the temporal lobes were also underdeveloped. The pituitary gland was not submitted for examination.
The association of optic-nerve hypoplasia with absence of the corpus callosum and septum pellucidum combined with pituitary hormone deficiency is known as Septo-Optic Dysplasia (SOD), or the Syndrome of de Morsier. Septo-Optic Dysplasia is an infrequently diagnosed disorder that typically presents in early infancy with blindness and growth retardation. SOD appears to be a disorder of embryological development of brain midline structures. There is evidence for both genetic and environmental etiologic factors, but the majority of evidence favors an environmental etiology.
The cause of the case reported here remains unknown, but one might speculate that abdominal trauma sustained by the mother during the first trimester resulted in disruption of blood flow to critical areas of the developing fetal brain. This is consistent with the hypothesis proposed by others that at least some cases of SOD are caused by vascular disruption. Alternatively, it is possible that quinidine and/or the arrhythmia treated by quinidine might have played a role.
While various pituitary hormone deficiencies have been reported, the case reported here demonstrated clear evidence only for growth hormone deficiency, which, according to others, is the most frequent pituitary hormone deficiency associated with SOD. Growth hormone deficiency appears to be secondary to a lack of Growth Hormone Releasing Hormone, which is normally produced by the hypothalamus. Therefore, a defective hypothalamus encountered in cases of SOD is not able to adequately stimulate production and release of Growth Hormone from an otherwise normal pituitary gland. Since Growth Hormone is important in maintaining glucose homeostasis, it has been previously suggested that the Growth Hormone deficiency associated with SOD is responsible for severe recurrent bouts of hypoglycemia, which are known to occur in newborns with the disorder. It has also been suggested that young children with SOD should be given Growth Hormone injections to prevent growth retardation. As for the case reported here, it is likely that his short stature was related to growth hormone deficiency and one might speculate that the severe seizure-like activity was related to spells of hypoglycemia. Unfortunately, serum glucose was never determined during one of these spells.
It is also possible that these "spells" were secondary to seizures, which are known to occur with SOD or alternatively, Aicardi's Syndrome (infantile spasms, optic nerve atrophy and agenesis of the corpus callosum).
The clinical course for the year prior to death was characterized by "spells" of dysregulation of hypothalamic-autonomic activity. There were frequent transient "fevers" for which no infectious etiology could be determined. Abnormal thermoregulation, having been previously reported to be associated with hypoplasia of the corpus callosum, is known as Shapiro's syndrome if associated with hypothermia and "Reverse" Shapiro's syndrome if associated with paroxysms of fever.
A formal pituitary "workup" was never performed; nonetheless there is evidence that secretion of pituitary hormones other than Growth Hormone was intact in our patient. Since he had secondary sex characteristics, it is likely that gonadotropin and adrenocortictropin production was adequate. In addition, thyroid function tests, which are routinely obtained at the facility where the patient resided, were found to be normal. We cannot say with certainty, however, that pituitary "reserve" was normal. One study reported on a series of five individuals with SOD who experienced sudden death. The author suggested a role for "adrenal crisis" since it appeared that these patients were not able to mount an adequate adrenal response to infection and/or stress, even though baseline studies were normal. Whether "adrenal crisis" played a role in the sudden death of our patient can unfortunately not be determined.
In conclusion, while SOD may be infrequently diagnosed, individuals with mental retardation who are visually impaired and are of short stature are commonly seen. When encountered by primary care physicians who serve these patients, neuroimaging studies should be performed. If midline developmental abnormalities are discovered, such as absence of corpus callosum, septum pellucidum and hypoplasia of the optic system, a complete evaluation to determine adequacy of pituitary function should be determined.
Finally, this case raises another important issue: the value of postmortem evaluation designed to determine the nature of the underlying brain disorder that is responsible for the developmental disability in the first place. This type of study has the potential for providing a wealth of information, which is desperately needed by clinicians so that a higher level of health services can be provided.
The American Academy of Developmental Medicine and Dentistry (AADMD) is established as a 501(c)(3) non-profit organization of physicians, dentists, students and associate members, whose collective mission is to work together, as clinicians, educators and advocates, in our spheres of influence, to improve the overall health of children and adults with developmental disabilities.
Philip B. May Jr., MD, Clinical Associate Professor of Medicine, Director,, mental Medicine Program, Department of Medicine, UMDNJ/Robert Wood Johnson Medical School New Brunswick, NJ and Staff Physician Hunterdon Developmental Center Clinton, NJ.
William G. Johnson MD, Professor of Neurology Chief, Division of Neurogenetics Department of Neurology UMDNJ/ Robert Wood Johnson Medical School New Brunswick, NJ.
Karl O. Schwarz MD, Professor of Clinical Pathology Chief, Neuropathology Section Department of Pathology UMDNJ/Robert Wood Johnson Medical School New Brunswick, NJ.
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|Author:||May, Philip B., Jr.; Johnson, William G.; Schwarz, Karl O.|
|Publication:||The Exceptional Parent|
|Date:||May 1, 2003|
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