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S P E C I A L C l i n i c a l C a s e F E A T U R E S e m i n a r Full Penetrance of Morgagni-Stewart-Morel Syndrome in a 75-Year-Old Woman: Case Report and Review of the Literature Francesca Attanasio,* Serena Granziera,* Valter Giantin, and Enzo Manzato Geriatric Unit, Department of Medicine, Padova University, 35100 Padova, Italy Context: Morgagni-Stewart-Morel syndrome is defined as the presence of hyperostosis frontalis interna, variably associated with metabolic, endocrine, and neuropsychiatric disorders. The possible cause-effect relationship of these associations remains uncertain. Case Presentation: A 75-year-old woman presented with severe frontal headache and a history of psychotic disorders. On instrumental examination she was found to have extensive frontal hyperostosis and cortical atrophy. These findings, associated to the metabolic and neuropsychiatric pattern of the patient, are consistent with a high penetrance of Morgagni-Stewart-Morel syndrome. Evidence Acquisition and Synthesis: In this clinical case seminar, we summarize the current understanding of the association between hyperostosis frontalis interna and Morgagni-StewartMorel, based on a MEDLINE search (case reports, original articles, and reviews published between 1928 and 2011) on this topic. Possible pathophysiological mechanisms underlying both the headache and the hyperostosis frontalis interna are discussed. Conclusion: A case of full penetrance of Morgagni-Stewart-Morel syndrome is reported, presenting many of the clinical features described in the literature. Metabolic and endocrine dysfunctions should be interpreted not only as isolated components of the syndrome, but also as the reason behind its pathogenesis. Endocrine or nutritional disorders may have led to an altered bone metabolism with frontal bone apposition. On the other hand, the severity of our patient’s neurological and psychiatric symptoms correlates well with the severity of her hyperostosis frontalis interna and the cortical atrophy. (J Clin Endocrinol Metab 98: 453– 457, 2013) yperostosis frontalis interna (HFI) is a morphological pattern of the frontal bone that usually presents as single or multiple bilateral nodules on the inner lamina, characteristically sparing the diploë and the calvarial midline (1, 2). The postmortem prevalence is reportedly around 11.9% (3), and recent studies suggest that the incidence of this condition has increased over the centuries (4). HFI mostly affects women, and the severity of the phenomenon increases with age (5). HFI can occur in isolation or accompany many different syndromes with various etiologies, making an accurate differential diagnosis necessary. It is usually an incidental H finding in x-ray, cranial computed tomography (CCT), or magnetic resonance imaging (MRI) studies. According to Hershkovitz’s morphological and histopathological classification, HFI is divided into 4 grades of severity (Table 1). It is usually asymptomatic but, if the bony nodules protrude extensively (bullet-like) or they become too large, the underlying soft tissues, eg, the dura mater and brain, may be compressed (6, 7). Some studies underline the presence of brain atrophy in relation with HFI (7, 8). It is not clear yet whether HFI causes brain atrophy through chronic cerebral compression or whether the nodules grow to occupy the space created by brain degener- ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2013 by The Endocrine Society doi: 10.1210/jc.2012-3242 Received August 31, 2012. Accepted November 8, 2012. First Published Online January 2, 2013 * F.A. and S.G. contributed equally to this work. Abbreviations: CCT, Cranial computed tomography; HFI, hyperostosis frontalis interna; MRI, magnetic resonance imaging; MSM, Morgagni-Stewart-Morel. J Clin Endocrinol Metab, February 2013, 98(2):453– 457 jcem.endojournals.org 453 454 Attanasio et al HFI and Morgagni-Stewart-Morel Syndrome Table 1. HFI’s Classificationa Grade of Severity Type A Type B Type C Type D Type Eb Morphological Description Single or multiple isolated bony elevations less than 10 mm in diameter located on the endocranial surface of the frontal bone. Nodular bony formations occupying less than 25% of the frontal bone. Nodular bony formations occupying up to 50% of the frontal bone. Continuous nodular bony overgrowth involving over 50% of the frontal endocranium. Severe hyperostosis frontalis interna with soft tissue expansion. a HFI’s classification by Hershkovitz et al (16). b Modified by Raikos et al (3). ation (9). Frontal dysfunctions, epilepsy, cognitive impairments, and migraine are some neurological symptoms that in literature were correlated with compression of the cortical area in patients affected by HFI (8, 10, 11). The phenomenon seems to be common because behavioral disturbances and the need for psychiatric care were the prominent features in all medical histories accessed on 13 cases of HFI on an autopsy study (9). Nevertheless, a significative correlation between neurological disorders and HFI is yet to be proven (12). Morgagni-Stewart-Morel (MSM) syndrome is defined as the presence of HFI, variably associated with metabolic, endocrine, and neuropsychiatric disorders. The condition was first described in 1719 by Giovanni Battista Morgagni, who noted an association between a thickening of the frontal bone and both obesity and hirsutism (13). Three centuries later, despite extensive research, still very little is known about this condition. In the early 1930s, Stewart and Morel documented neuropsychiatric symptoms and persistent headache (14, 15). Nowadays, MSM syndrome is associated with metabolic and hormonal disorders (mainly obesity, diabetes mellitus, hirsutism), and neuropsychiatric disorders. The reported clinical pattern remains variable as a consequence of the diversity of the associated symptoms and the variable penetrance of the condition. The very existence of the syndrome is even questioned by some experts, who claim that the conditions involved may occur independently in elderly women (2, 16). The exact etiology of HFI and MSM syndrome remains unclear; the most interesting theories relate to estrogen dysfunction, obesity and leptin dysfunction, and genetics (17–19). J Clin Endocrinol Metab, February 2013, 98(2):453– 457 Case Report A 75-year-old woman, married without children, was referred as an inpatient to our Geriatric Unit complaining of severe frontal headache of which she had suffered for several years, but which had gradually worsened in the previous month, failing to respond to nonsteroidal antiinflammatory drugs. She had already been seen for migraine and she was being followed up by a psychiatrist for a history of psychotic symptoms and several suicide attempts since 2002. She had a medical history of diabetes mellitus (under treatment with oral antidiabetics), obesity, osteoporosis, a thyroid disorder for which she had undergone hemithyroidectomy, osteoarthritis, diverticulitis, and arterial hypertension (grade I retinopathy). On initial assessment, she was cooperative and oriented, with normal findings on neurological examination. She complained of upper lip dyskinesia, but the results of cranial nerve examination were negative. Findings on examination of her cardiovascular, respiratory, and gastrointestinal system were unremarkable. Her personal hygienic conditions were poor at the time of hospitalization and at subsequent outpatient consultations. She had never previously undergone any instrumental brain tests. Cranial x-ray revealed extensive frontal hyperostosis. CCT (Figure 1) and MRI (Figure 2) confirmed type D HFI, with multiple bullet-like nodules. Both CCT and MRI revealed cortical atrophy, especially in the frontal but also in the dorsolateral areas. A battery of neuropsychological tests was administered to assess her cognitive status: the outcome of the Mini Mental Figure 1. Axial cranial CT scan evidences the bilateral thickening of the inner table of the frontal bone (circle) and the atrophy in the frontoinsular regions bilaterally (white arrows). J Clin Endocrinol Metab, February 2013, 98(2):453– 457 jcem.endojournals.org 455 ⫺4.0, spinal L1-L4 T score ⫽ ⫺3.5) and treatment was started. To further investigate the patient’s endocrine malfunction, we measured her serum cortisol, antidiuretic hormone, and human GH levels, which were all normal, whereas her ACTH level was slightly elevated (Table 2). Lastly, we investigated the patient’s rheumatological serum pattern; rheumatoid factor, anti-DNA antibodies, antineutrophil cytoplasmic antibodies, and extractable nuclear antigen antibodies were all normal, whereas a positive reaction to antinuclear antibodies emerged at a dilution of 1:320. Discussion Figure 2. Sagittal T1-weighted MRI cranial scan evidences nodular bony overgrowth (circle) involving over 50% of the frontal endocranium (type D HFI) and moderate cortical atrophy (white arrows). Status Examination (MMSE) was normal (30/30); and the Clock Drawing Test result was very slightly altered (9/10). As for her endocrine system, the patient had type 2 diabetes poorly controlled with metformin 500 mg, with high glycated hemoglobin levels (Table 2). She was overweight (body mass index 28.7 kg/m2), and her waist circumference was 105 cm. She also revealed hypercholesterolemia and high uric acid levels (Table 2). Triglycerides were normal. These data, combined with arterial hypertension, prompted us to diagnose metabolic syndrome (20). The patient showed signs of mild hirsutism and had a history of severe acne, but her progesterone, testosterone, and 17--estradiol levels were normal. She reported having experienced two spontaneous miscarriages. Her history of thyroid disease was not documented. She had a scar due to hemithyroidectomy; her TSH, free T3 and free T4 levels were within normal range without any specific therapy; tests for thyroid peroxidase antibodies, thyroglobulin antibodies, and TSH receptor antibodies were negative; we found hyperparathyroidism secondary to vitamin D deficiency (Table 2). A diagnosis of osteoporosis was established on bone densitometry (femoral T score ⫽ Table 2. Laboratory Studies Biohumoral Marker Glycated hemoglobin (HbA1c), % Total cholesterol, mmol/L Uric acid, mmol/L ACTH, ng/L at 0800 h PTH, ng/L 25-Hydroxyvitamin D, nmol/L Patient’s Value 8.4 6.20 0.50 71 73 ⬍10 Normal Value 4.0 –5.6 ⬍5.18 0.15– 0.35 10 –50 4.6 –26.8 75–250 HFI is quite a common finding in the clinical setting nowadays (3). The associated signs and symptoms are generally nonspecific and benign, but they may cluster together in some cases, giving rise to various syndromes. MSM syndrome is characterized by HFI, obesity, virilism, and mental disturbances, but these associations are mostly based on case reports, and no clear consensus exists on the definition of the syndrome (2, 16). Our patient presented with a full expression of MSM, with HFI, cortical atrophy, recurrent depressive disorder, and a history of psychotic symptoms, headache, metabolic and endocrine disorders (obesity, diabetes mellitus, thyroid disease), hirsutism, osteoporosis, and a short stature. She had severe HFI (type D), which is known to be associated with advanced age (3, 16). We believe that the severity of the HFI and the complex picture of neuropsychiatric and metabolic symptoms in our 75-year-old patient are consistent with a high penetrance of MSM syndrome. Observing this case prompted us to review the literature in search of a possible explanation for the etiopathogenesis of this disorder. Anthropological/archeological studies HFI has been identified in archeological digs at various ancient sites in Europe and Asia, but the phenomenon’s prevalence is usually low, with only isolated findings (18, 21). Its occurrence seems to be much higher now than in past ages (4, 16), with some exceptions: in an archeological excavation study conducted at Pueblo Bonito in New Mexico, a high prevalence of HFI was found among females (22). Although it is not possible to isolate the cause of the high prevalence of HFI in this site, the anthropologist hypothesized that this population had a life cycle similar to that of modern populations, with a long interval between menarche and menopause and few pregnancies. This might point to a role of endocrine imbalances or an influence of dietary phytoestrogens, which were plentiful 456 Attanasio et al HFI and Morgagni-Stewart-Morel Syndrome J Clin Endocrinol Metab, February 2013, 98(2):453– 457 in the population’s local foods. A similar finding emerged in a recent excavation in Qatna Bronze-Age area in Syria. From the observation of the skeletal remains, the researchers hypothesized favorable living conditions and high caloric energy intake. The authors speculated a correlation between the population’s lifestyle and the high prevalence of HFI (19). The period of the Industrial Revolution seems to mark a turning point in the prevalence of HFI, when social and sanitary conditions, food availability, and calorie intake dramatically improved for a large portion of the population. In an extensive study on 1706 early 20th-century skulls compared with 2019 pre-19th-century skulls, Hershkovitz et al (16) found that the incidence of HFI was higher in the 20th century among females, while remaining constant among males. suggesting phenotypic variability probably due to different environmental factors. All these etiopathological hypotheses for HFI could justify the common association between HFI and endocrine and metabolic symptoms described in MSM syndrome. We actually found no specific hormone dysfunctions in our patient, but she had mild hirsutism, diabetes mellitus, osteoporosis, and obesity. In her personal history she reported having undergone hemithyroidectomy and, although she had a normal thyroid function at the time of her hospitalization, lacking any other documentation we can assume that an autoimmune disorder was behind her thyroid condition. It is worth noting that we found our patient antinuclear antibody-positive, something that has never hitherto been reported in association with MSM syndrome and that could be further investigated in other studies. Finally, we would like to mention the patient’s own thoughts about the etiology of her disease: when she was informed about her HFI, she claimed that it was probably due to the forceps being used at the time of her birth. Sex hormones The etiology of MSM syndrome has yet to be thoroughly explained, although endocrine imbalances involving sex hormones have been suggested by numerous authors as the leading mechanism behind HFI. As mentioned earlier, HFI is less common in males, in which case it occurs almost exclusively in patients with gonadal disturbances or inadequate testicular response to androgen stimulation (10, 16, 23). Even the famous castrato singer Farinelli, exhumed in 2006 for research purposes, was found to have HFI (24). In a study group of 127 patients with prostate cancer submitted to pharmacological androgen blockade, May et al (25) documented a positive relationship between HFI and androgen suppression. The sex hormone hypothesis could also explain the rarity of HFI in preindustrial populations, exposed to estrogens for a shorter part of their lives given the more numerous pregnancies, later age of menarche, and earlier menopause. Leptin An original theory advanced by Ruhli and Henneberg (17) hypothesizes a role for the most important adipocytederived hormone, leptin, in the pathogenesis of HFI. They suggest that the decreasing pressure of selection in humans and consequent increase in their life span, with a greater availability of food and higher metabolic rates, has produced modulations in leptin metabolism responsible for an increase in the prevalence of bony overgrowth in modern populations. Genetics Genetic basis was hypothesized in a case report of monozygotic twins both suffering from MSM syndrome (19). However, the symptoms were nonuniform between them, Neuropsychiatric symptoms The most invalidating disorders that our patient suffered were of neuropsychiatric origin, ie, persistent invalidating headache and recurrent major depressive episodes with a history of psychotic symptoms and several suicide attempts. Devriendt et al (9) showed a clear epidemiological association between HFI and psychiatric disorders, but the mechanisms behind it have yet to be explained. Our patient had cortical atrophy extending to the frontal, temporal, and parietal lobes. There are reports in the literature of a selective mental deficit secondary to HFI cortical compression (8, 11). We surmise that the severity of our patient’s psychiatric disorders correlated with the extension of the frontal nodular bony formations and the cortical atrophy, which was clearly documented on CT and MRI studies. Conclusion In conclusion, we describe a case of full penetrance of MSM syndrome, presenting many of the clinical features described in the literature. We believe that the severity of our patient’s HFI correlates strongly with her metabolic and endocrine dysfunctions, which should be interpreted not only as comorbidities of the syndrome, but also as the reason behind its pathogenesis. Obesity and metabolic disorders may be linked with adipocyte-derived hormone dysfunction, whereas the patient’s history of severe acne and hirsutism can be seen as indicators of juvenile sex hormone dysfunctions, and thyroid disorders, osteoporo- J Clin Endocrinol Metab, February 2013, 98(2):453– 457 sis, and diabetes mellitus are evidence of endocrine dysfunctions. All these factors may have led to a bone metabolism disorder with frontal bone apposition. On the other hand, we believe that the severity of our patient’s cognitive, neurological, and psychiatric symptoms correlate well with the severity of her HFI and the cortical atrophy. jcem.endojournals.org 10. 11. 12. 13. Acknowledgments 14. Address all correspondence and requests for reprints to: Francesca Attanasio, Clinica Geriatrica, Ospedale Giustinianeo, via Giustiniani 2, 35100 Padova, Italy. E-mail: [email protected]. Disclosure Summary: The authors have nothing to disclose. 15. 16. 17. References 1. Moore S. 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