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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 patients 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 diploe 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

finding in x-ray, cranial computed tomography (CCT), or


magnetic resonance imaging (MRI) studies. According to
Hershkovitzs 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

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HFI and Morgagni-Stewart-Morel Syndrome

Table 1. HFIs 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.

HFIs classification by Hershkovitz et al (16).

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 (1719).

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

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455

4.0, spinal L1-L4 T score 3.5) and treatment was


started. To further investigate the patients 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 patients 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

Patients
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
75250

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 phenomenons
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

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Attanasio et al

HFI and Morgagni-Stewart-Morel Syndrome

J Clin Endocrinol Metab, February 2013, 98(2):453 457

in the populations 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 populations 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 patients 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 patients 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 patients 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 patients 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 patients
cognitive, neurological, and psychiatric symptoms correlate well with the severity of her HFI and the cortical
atrophy.

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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: attanasio.doc@libero.it.
Disclosure Summary: The authors have nothing to disclose.

15.
16.

17.

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