Full Penetrance of Morgagni-Stewart-MorelSyndrome in a 75-Year-Old Woman: Case Report andReview 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 frontalisinterna, variably associated with metabolic, endocrine, and neuropsychiatric disorders. The pos-sible cause-effect relationship of these associations remains uncertain.

Case Presentation:A 75-year-old woman presented with severe frontal headache and a history ofpsychotic disorders. On instrumental examination she was found to have extensive frontal hyper-ostosis and cortical atrophy. These findings, associated to the metabolic and neuropsychiatricpattern of the patient, are consistent with a high penetrance of Morgagni-Stewart-Morelsyndrome.

Evidence Acquisition and Synthesis: In this clinical case seminar, we summarize the current un-derstanding of the association between hyperostosis frontalis interna and Morgagni-Stewart-Morel, based on aMEDLINE search (case reports, original articles, and reviews published between1928 and 2011) on this topic. Possible pathophysiological mechanisms underlying both the head-ache and the hyperostosis frontalis interna are discussed.

Conclusion: A case of full penetrance of Morgagni-Stewart-Morel syndrome is reported, present-ingmany of the clinical features described in the literature.Metabolic and endocrine dysfunctionsshould be interpreted not only as isolated components of the syndrome, but also as the reasonbehind its pathogenesis. Endocrine or nutritional disorders may have led to an altered bone me-tabolism with frontal bone apposition. On the other hand, the severity of our patients neuro-logical and psychiatric symptoms correlates well with the severity of her hyperostosis frontalisinterna and the cortical atrophy. (J Clin Endocrinol Metab 98: 453457, 2013)

Hyperostosis frontalis interna (HFI) is amorphologicalpattern of the frontal bone that usually presents assingle or multiple bilateral nodules on the inner lamina,characteristically sparing the diploe and the calvarial mid-line (1, 2). The postmortem prevalence is reportedlyaround 11.9% (3), and recent studies suggest that the in-cidence of this condition has increased over the centuries(4). HFI mostly affects women, and the severity of thephenomenon increases with age (5).

HFI can occur in isolation or accompany many differ-ent syndromeswith various etiologies,makinganaccuratedifferential diagnosis necessary. It is usually an incidental

finding in x-ray, cranial computed tomography (CCT), ormagnetic resonance imaging (MRI) studies. According toHershkovitzs morphological and histopathological clas-sification, HFI is divided into 4 grades of severity (Table1). It is usually asymptomatic but, if the bony nodulesprotrude extensively (bullet-like) or they become toolarge, the underlying soft tissues, eg, the dura mater andbrain, may be compressed (6, 7). Some studies underlinethe presence of brain atrophy in relation with HFI (7, 8).It is not clear yet whether HFI causes brain atrophythrough chronic cerebral compressionorwhether thenod-ules grow to occupy the space created by brain degener-

ISSN Print 0021-972X ISSN Online 1945-7197Printed in U.S.A.Copyright 2013 by The Endocrine Societydoi: 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.

S P E C I A L F E A T U R E

C l i n i c a l C a s e S e m i n a r

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ation (9). Frontal dysfunctions, epilepsy, cognitive impair-ments, andmigraine are someneurological symptoms thatin literature were correlated with compression of the cor-tical area in patients affected by HFI (8, 10, 11). Thephenomenon seems to be common because behavioraldisturbances and the need for psychiatric care were theprominent features in all medical histories accessed on 13cases of HFI on an autopsy study (9). Nevertheless, a sig-nificative correlation between neurological disorders andHFI is yet to be proven (12).

Morgagni-Stewart-Morel (MSM) syndrome is definedas thepresenceofHFI, variably associatedwithmetabolic,endocrine, and neuropsychiatric disorders. The conditionwas first described in 1719 by Giovanni Battista Mor-gagni, who noted an association between a thickening ofthe frontal bone and both obesity and hirsutism (13).Three centuries later, despite extensive research, still verylittle is known about this condition. In the early 1930s,Stewart and Morel documented neuropsychiatric symp-toms and persistent headache (14, 15). Nowadays, MSMsyndrome is associated with metabolic and hormonal dis-orders (mainly obesity, diabetes mellitus, hirsutism), andneuropsychiatric disorders. The reported clinical patternremains variable as a consequence of the diversity of theassociated symptoms and the variable penetrance of thecondition. The very existence of the syndrome is evenquestionedby someexperts,whoclaim that the conditionsinvolved may occur independently in elderly women (2,16). The exact etiology of HFI and MSM syndrome re-mains unclear; the most interesting theories relate to es-trogen dysfunction, obesity and leptin dysfunction, andgenetics (1719).

Case Report

A 75-year-old woman, married without children, was re-ferred as an inpatient to ourGeriatric Unit complaining ofsevere frontal headache of which she had suffered for sev-eral years, but which had gradually worsened in the pre-vious month, failing to respond to nonsteroidal antiin-flammatory drugs. She had already been seen formigraineand she was being followed up by a psychiatrist for ahistory of psychotic symptoms and several suicide at-tempts since 2002. She had a medical history of diabetesmellitus (under treatmentwithoral antidiabetics), obesity,osteoporosis, a thyroid disorder for which she had under-gone hemithyroidectomy, osteoarthritis, diverticulitis,and arterial hypertension (grade I retinopathy). On initialassessment, she was cooperative and oriented, with nor-mal findings on neurological examination. She com-plained of upper lip dyskinesia, but the results of cranialnerve examination were negative. Findings on examina-tion of her cardiovascular, respiratory, and gastrointesti-nal systemwereunremarkable.Herpersonalhygienic con-ditions were poor at the time of hospitalization and atsubsequent outpatient consultations. She had never pre-viously undergone any instrumental brain tests. Cranialx-ray revealed extensive frontal hyperostosis. CCT (Fig-ure 1) and MRI (Figure 2) confirmed type D HFI, withmultiple bullet-like nodules.

Both CCT and MRI revealed cortical atrophy, espe-cially in the frontal but also in the dorsolateral areas. Abattery of neuropsychological tests was administered toassessher cognitive status: theoutcomeof theMiniMental

Table 1. HFIs Classificationa

Grade ofSeverity Morphological DescriptionType A Single or multiple isolated bony elevations

less than 10 mm in diameter located onthe endocranial surface of the frontalbone.

Type B Nodular bony formations occupying less than25% of the frontal bone.

Type C Nodular bony formations occupying up to50% of the frontal bone.

Type D Continuous nodular bony overgrowthinvolving over 50% of the frontalendocranium.

Type Eb Severe hyperostosis frontalis interna with softtissue expansion.

a HFIs classification by Hershkovitz et al (16).b Modified by Raikos et al (3).

Figure 1. Axial cranial CT scan evidences the bilateral thickening ofthe inner table of the frontal bone (circle) and the atrophy in thefrontoinsular regions bilaterally (white arrows).

454 Attanasio et al HFI and Morgagni-Stewart-Morel Syndrome J Clin Endocrinol Metab, February 2013, 98(2):453457

Status Examination (MMSE)was normal (30/30); and theClockDrawingTest resultwas very slightly altered (9/10).

As for her endocrine system, the patient had type 2diabetes poorly controlled with metformin 500 mg, withhigh glycated hemoglobin levels (Table 2). She was over-weight (body mass index 28.7 kg/m2), and her waist cir-cumference was 105 cm. She also revealed hypercholes-terolemia and high uric acid levels (Table 2). Triglycerideswere normal. These data, combined with arterial hyper-tension, prompted us to diagnose metabolic syndrome(20). The patient showed signs of mild hirsutism and hada history of severe acne, but her progesterone, testoster-one, and 17--estradiol levels were normal. She reportedhaving experienced two spontaneous miscarriages. Herhistory of thyroid disease was not documented. She had ascar due to hemithyroidectomy; her TSH, free T3 and freeT4 levels were within normal range without any specifictherapy; tests for thyroid peroxidase antibodies, thyro-globulin antibodies, and TSH receptor antibodies werenegative; we found hyperparathyroidism secondary to vi-tamin D deficiency (Table 2). A diagnosis of osteoporosiswas established on bone densitometry (femoral T score

4.0, spinal L1-L4 T score 3.5) and treatment wasstarted. To further investigate the patients endocrinemal-function, we measured her serum cortisol, antidiuretichormone, and human GH levels, which were all normal,whereas her ACTH level was slightly elevated (Table 2).Lastly, we investigated the patients rheumatological se-rumpattern; rheumatoid factor, anti-DNAantibodies, an-tineutrophil cytoplasmic antibodies, and extractable nu-clear antigen antibodies were all normal, whereas apositive reaction to antinuclear antibodies emerged at adilution of 1:320.

Discussion

HFI is quite a common finding in the clinical setting now-adays (3). The associated signs and symptoms are gener-ally nonspecific and benign, but they may cluster togetherin some cases, giving rise to various syndromes. MSMsyndrome is characterized by HFI, obesity, virilism, andmental disturbances, but these associations are mostlybased on case reports, and no clear consensus exists on thedefinition of the syndrome (2, 16).

Our patient presented with a full expression of MSM,with HFI, cortical atrophy, recurrent depressive disorder,and ahistory of psychotic symptoms, headache,metabolicand endocrine disorders (obesity, diabetes mellitus, thy-roid disease), hirsutism, osteoporosis, and a short stature.She had severe HFI (type D), which is known to be asso-ciated with advanced age (3, 16). We believe that the se-verity of the HFI and the complex picture of neuropsy-chiatric and metabolic symptoms in our 75-year-oldpatient are consistent with a high penetrance of MSMsyndrome. Observing this case prompted us to review theliterature in search of a possible explanation for the etio-pathogenesis of this disorder.

Anthropological/archeological studiesHFI has been identified in archeological digs at various

ancient sites in Europe and Asia, but the phenomenonsprevalence is usually low, with only isolated findings (18,21). Its occurrence seems to be much higher now than inpast ages (4, 16), with some exceptions: in an archeolog-ical excavation study conducted at Pueblo Bonito in NewMexico, a high prevalence of HFI was found among fe-males (22). Although it is not possible to isolate the causeof the high prevalence of HFI in this site, the anthropol-ogist hypothesized that this population had a life cyclesimilar to that ofmodern populations,with a long intervalbetween menarche and menopause and few pregnancies.This might point to a role of endocrine imbalances or aninfluence of dietary phytoestrogens, which were plentiful

Figure 2. Sagittal T1-weighted MRI cranial scan evidences nodularbony overgrowth (circle) involving over 50% of the frontalendocranium (type D HFI) and moderate cortical atrophy (whitearrows).

Table 2. Laboratory Studies

Biohumoral MarkerPatientsValue

NormalValue

Glycated hemoglobin (HbA1c), % 8.4 4.05.6Total cholesterol, mmol/L 6.20 5.18Uric acid, mmol/L 0.50 0.150.35ACTH, ng/L at 0800 h 71 1050PTH, ng/L 73 4.626.825-Hydroxyvitamin D, nmol/L 10 75250

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in the populations local foods. A similar finding emergedin a recent excavation in Qatna Bronze-Age area in Syria.From the observationof the skeletal remains, the research-ers hypothesized favorable living conditions and high ca-loric energy intake. The authors speculated a correlationbetween the populations lifestyle and the high prevalenceof HFI (19).

The period of the Industrial Revolution seems to marka turning point in the prevalence of HFI, when social andsanitary conditions, food availability, and calorie intakedramatically improved for a large portion of the popula-tion. In an extensive study on 1706 early 20th-centuryskulls compared with 2019 pre-19th-century skulls,Hershkovitz et al (16) found that the incidence ofHFIwashigher in the 20th century among females, while remain-ing constant among males.

Sex hormonesThe etiology of MSM syndrome has yet to be thor-

oughly explained, although endocrine imbalances involv-ing sex hormones have been suggested by numerous au-thors as the leadingmechanismbehindHFI.Asmentionedearlier, HFI is less common in males, in which case it oc-curs almost exclusively in patients with gonadal distur-bancesor inadequate testicular response toandrogen stim-ulation (10, 16, 23). Even the famous castrato singerFarinelli, exhumed in 2006 for research purposes, wasfound to have HFI (24). In a study group of 127 patientswith prostate cancer submitted to pharmacological an-drogen blockade, May et al (25) documented a positiverelationship between HFI and androgen suppression. Thesex hormone hypothesis could also explain the rarity ofHFI in preindustrial populations, exposed to estrogens fora shorter part of their lives given themore numerous preg-nancies, later age of menarche, and earlier menopause.

LeptinAn original theory advanced by Ruhli and Henneberg

(17) hypothesizes a role for themost important adipocyte-derived hormone, leptin, in the pathogenesis of HFI. Theysuggest that the decreasing pressure of selection in humansand consequent increase in their life span, with a greateravailability of food and higher metabolic rates, has pro-duced modulations in leptin metabolism responsible foran increase in the prevalence of bony overgrowth in mod-ern populations.

GeneticsGenetic basis was hypothesized in a case report of mo-

nozygotic twins both suffering fromMSMsyndrome (19).However, the symptomswere nonuniform between them,

suggesting phenotypic variability probably due to differ-ent environmental factors.

All these etiopathological hypotheses forHFI could jus-tify the common association between HFI and endocrineand metabolic symptoms described in MSM syndrome.We actually found no specific hormone dysfunctions inour patient, but she had mild hirsutism, diabetes mellitus,osteoporosis, and obesity. In her personal history she re-ported having undergone hemithyroidectomy and, al-though shehadanormal thyroid functionat the timeofherhospitalization, lacking any other documentation we canassume that an autoimmune disorder was behind her thy-roid condition. It isworthnoting thatwe foundourpatientantinuclear antibody-positive, something that has neverhitherto been reported in association with MSM syn-dromeand that could be further investigated in other stud-ies. Finally, we would like to mention the patients ownthoughts about the etiology of her disease: when she wasinformed about her HFI, she claimed that it was probablydue to the forceps being used at the time of her birth.

Neuropsychiatric symptomsThe most invalidating disorders that our patient suf-

fered were of neuropsychiatric origin, ie, persistent inval-idating headache and recurrent major depressive episodeswith a history of psychotic symptoms and several suicideattempts. Devriendt et al (9) showed a clear epidemiolog-ical 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 lit-erature of a selective mental deficit secondary to HFI cor-tical compression (8, 11). We surmise that the severity ofour patients psychiatric disorders correlated with the ex-tension of the frontal nodular bony formations and thecortical atrophy, which was clearly documented on CTand MRI studies.

Conclusion

In conclusion, we describe a case of full penetrance ofMSM syndrome, presenting many of the clinical featuresdescribed in the literature. We believe that the severity ofour patients HFI correlates strongly with her metabolicand endocrine dysfunctions, which should be interpretednot only as comorbidities of the syndrome, but also as thereasonbehind its pathogenesis.Obesity andmetabolic dis-orders may be linked with adipocyte-derived hormonedysfunction, whereas the patients history of severe acneand hirsutism can be seen as indicators of juvenile sexhormone dysfunctions, and thyroid disorders, osteoporo-

456 Attanasio et al HFI and Morgagni-Stewart-Morel Syndrome J Clin Endocrinol Metab, February 2013, 98(2):453457

sis, and diabetes mellitus are evidence of endocrine dys-functions. All these factors may have led to a bone me-tabolism disorder with frontal bone apposition. On theother hand, we believe that the severity of our patientscognitive, neurological, and psychiatric symptoms corre-late well with the severity of her HFI and the corticalatrophy.

Acknowledgments

Address all correspondence and requests for reprints to: FrancescaAt-tanasio, Clinica Geriatrica, Ospedale Giustinianeo, via Giustiniani 2,35100 Padova, Italy. E-mail: attanasio.doc@libero.it.

Disclosure Summary: The authors have nothing to disclose.

References

1. Moore S.Calvarial hyperostosis and accompanying symptom-com-plex. Arch Neurol Psychiat. 1936;35:975981.

2. She R, Szakacs J. Hyperostosis frontalis interna: case report andreview of literature. Ann Clin Lab Sci. 2004;34:206208.

3. Raikos A, Paraskevas GK, Yusuf F, et al. Etiopathogenesis of hy-perostosis frontalis interna: a mystery still. Ann Anat. 2011;193:453458.

4. MayH, Peled N, Dar G, Abbas J, Hershkovitz I.Hyperostosis fron-talis interna: what does it tell us about our health? Am J Hum Biol.2011;23:392397.

5. Nikolic S, DjonicD, Zivkovic V, BabicD, Jukovic F, DjuricM.Rateof occurrence, gross appearance, and age relation of hyperostosisfrontalis interna in females: a prospective autopsy study. Am J Fo-rensic Med Pathol. 2010;31:205207.

6. Chaljub G, Johnson RF III, Johnson RF Jr, Sitton CW. Unusuallyexuberant hyperostosis frontalis interna: MRI. Neuroradiology.1999;41:4445.

7. Talarico EF Jr, Prather AD, Hardt KD. A case of extensive hyper-ostosis frontalis interna in an 87-year-old female human cadaver.Clin Anat. 2008;21:259268.

8. De Zubicaray GI, Chalk JB, Rose SE, Semple J, Smith GA. Deficitson self ordered tasks associated with hyperostosis frontalis interna.J Neurol Neurosurg Psychiatry. 1997;63:309314.

9. DevriendtW, Piercecchi-MartiMD,Adalian P, SanvoisinA,Dutour

O, Leonetti G. Hyperostosis frontalis interna: forensic issues. J Fo-rensic Sci. 2005;50:143146.

10. Ramchandren S, Liebeskind DS. Headache in a patient withKlinefelters syndrome and hyperostosis frontalis interna. J Head-ache Pain. 2007;8:342344.

11. Paulus KS, Magnano I, Aiello I, et al. P300 and executive functionalterations: possible links in a case ofMorgagni-Stewart-Morel syn-drome. Neurol Sci. 2002;22:459462.

12. Smith S,HemphillRE.Hyperostosis frontalis interna. JNeurolNeu-rosurg Psychiatry. 1956;19:4245.

13. Morgagni GB. Adversaria anatomica VI. Animadversio LXXIV.Vulporius, Padua; 1719.

14. Morel F. Lhyperostose frontale interne. Geneva: Chapalay andMottier; 1929.

15. Stewart RM. Localized cranial hyperostosis in the insane. J NeurolPsychopathol. 1928;8:321.

16. Hershkovitz I, Greenwald C, Rothschild BM, et al. Hyperostosisfrontalis interna: an anthropological perspective. Am J Phys An-thropol. 1999;109:303325.

17. Ruhli FJ,HennebergM.Arehyperostosis frontalis internaand leptinlinked? A hypothetical approach about hormonal influence on hu-man microevolution. Med Hypotheses. 2002;58:378381.

18. HajduT, Fothi E, Bernert Z, et al.Appearance of hyperostosis fron-talis interna in some osteoarcheological series from Hungary.Homo. 2009;60:185205.

19. Koller MF, Papassotiropoulos A, Henke K, et al. Evidence of a ge-netic basis of Morgagni-Stewart-Morel syndrome. A case report ofidentical twins. Neurodegener Dis. 2005;2:5660.

20. Grundy SM, Brewer HB Jr, Cleeman JI, Smith SC Jr, Lenfant C.Definition of metabolic syndrome: report of the National Heart,Lung, and Blood Institute/American Heart Association conferenceon scientific issues related to definition. Arterioscler Thromb VascBiol. 2004;24:e13e18.

21. Lazer E. Revealing secrets of a lost city. An archaeologist examinesskeletal remains from the ruins of Pompeii.Med J Aust. 1996;165:620623.

22. Mulhern DM, Wilczak CA, Dudar JC. Brief communication: un-usual finding at Pueblo Bonito: multiple cases of hyperostosis fron-talis interna. Am J Phys Anthropol. 2006;130:480484.

23. Yamakawa K, Mizutani K, Takahashi M, Matsui M, Mezaki T.Hyperostosis frontalis interna associated with hypogonadism in anelderly man. Age Ageing. 2006;35:202203.

24. Belcastro MG, Todero A, Fornaciari G, Mariotti V. Hyperostosisfrontalis interna (HFI) and castration: the case of the famous singerFarinelli (17051782). J Anat. 2011;219:632637.

25. MayH, Peled N, Dar G, Abbas J, Hershkovitz I.Hyperostosis fron-talis interna and androgen suppression.Anat Rec (Hoboken). 2010;293:13331336.

J Clin Endocrinol Metab, February 2013, 98(2):453457 jcem.endojournals.org 457