Gigantism in a McCune-Albright’s syndrome with calcified GH-releasing pituitary adenoma: Case report and literature review

Highlights • There have been very few cases of pituitary calcified associated with McCune Albright syndrome.• Pituitary calcification is quite rare by itself.• Unlike this is a benign disease, its behavior is very aggressive and this highlights the need of a multidisciplinary team.• It is mandatory to rule out a whole work up when McCune Albright syndrome is suspected to stratify risks and survival.


Introduction
McCune-Albright's Syndrome (MAS) is a rare disorder characterized by café au lait macules, fibrous dysplasia of the skull and pituitary endocrinopathies like hyperfunctional pituitary adenomas with high plasma levels of Growth Hormone (GH) [1,2]. The hypersecretion of GH due to a pituitary hyperplasia or Pituitary Adenoma (PA) is a rare condition that only can be proven in 20-30% of patients with MAS [3][4][5]. On the other hand, the presence of a calcification in a PA is an uncommon feature that appears radiologically in 0.2-14% of the cases [6,7], and it has been slightly more common in the microscopic analysis, ranging from 5.4 to 25% [8,9]. Nevertheless, the presence of dystrophic calcification associated to PA is a very rare condition that has been described in 6.75% of the series [10], but never in the context of a MAS.
Identifying dystrophic calcifications in a PA in the preoperative imaging studies may represent a key role on the surgical decisión, since the scope in achieving a gross total resection can be more difficult to accomplish in the occurrence of extensive calcification [6,11]. Medical treatment has been the only option in MAS patients with GH excess mainly because the transsphenoidal surgery is quite and hardly restricted due to the massive thickening of the skull base [12].
We reported a rare case of a 43 year old male with gigantism due to an invasive PA in association of MAS that showed extensive dystrophic calcifications that calcified the pituitary tumor. The present case has been reported in accordance with the SCARE guidelines for case reports [13].

History and examination
A 43-year-old man with pituitary gigantism from the age of 16 secondary to a GH-functional PA. He underwent microsurgical trans sphenoidal surgery for resection of a PA in 1990 and adjuvant radiotherapy given in 2011 (radiotherapy scheme, original radiology and  pathology unavailable). In 2016, almost 27 years after the initial surgery, he presented progressive decrease in vision on the left eye for six months. He also complained of excessive perspiration and sweating and had a past history of carpal tunnel syndrome. He was found to have gigantism features as extreme physical size (2.07 mts height) and pigmentation around eyes, neck and flexures.
In ophtalmologic examination, a left ptosis with both exophthalmos and upward/inward limitation on left eye movements was achieved, and in the Goldmann's test perimeter an ipsilateral amaurosis and right hemianopia (Octopus 900 Haag Streit Inc., Bern, Switzerland) (Fig. 1).
Random serum GH level was 0.071 ng/ml (0.003-0.97 ng/mL) with a normal GH concentration during the Oral Glucose Tolerance Test (OGTT) with a GH-nadir of 0.13 ng/ml (the gold standard for diagnosis is that GH excess fails to suppress serum GH level to less than 1 ng/ml after OGTT). The Insulin-like Growth Factor-1 (IGF-1) 84.3 ng/ml (64-210 ng/mL); the rest of hormones are listed and shown in Table 1.

Hormone
Result a large policystic selar lesion with extensive osteophytic reaction and invasion of the ipsilateral orbital apex associated with fibrous dysplasia (see Fig. 2A and B) with a T2-weighted hypointense and enhancing selar mass lesion with Calcium intensity on the Gradient echo sequences (GRE) (Fig. 2C). Also the skull CT-scan (Siemens SOMATOM Sensation 64-slices) revealed an osteolytic lesion on the right orbital apex with thickness of the diploe (Fig. 2E) and pituitary gland with a calcified rim around the tumor (Fig. 2D, F and G). There was no personal or family history of prior endocrine disease.

Treatment course
A second surgical resection was performed in 2016 by a left orbitozygomatic approach for tumor removal with no acute complications ( Fig. 3A-C). Three days after the resection, the patient presented sudden unresponsiveness with an asymmetrically larger left pupil and rostrocaudal deterioration due to an ischemic stroke on left Anterior Cerebral Artery (ACA) and Middle Cerebral Artery (MCA), performing an urgent ipsilateral decompressive craniectomy. Unfortunately after surgery the patient continued unresponsive, leading to his death.

Neuropathology
After the informant consent was obtained, brain autopsy was performed. Neuropathologic examination of the pituitary lesion removed in 2016 (first neuropathology report was unavailable) was characterized macroscopically by a 40 × 40 mm mass with grayish outer surface and inner yellowish-irregular zones thickened by "sand-like" calcifications ( Fig. 4A and B). Histologically micro-hemorrhage with ossification areas within a thick pseudocapsule and multiple calcifications with a diffuse desmoplastic stromal component even within blood vessels were observed ( Fig. 4C and D). Immunohistochemistry stains were positive for Growth Hormone and osteoconine (Fig. 4F-G). Brain autopsy showed perivascular granular-dystrophic calcifications in thalamus, hypothalamus and basal ganglia (Fig. 4D, H-J).

Discussion
The MAS has been thought as a consequence of postzygotic mutations in GNAS1, located on 20q13.3, a complex gene that uses several promoters to produce gene products like the ubiquitously expressed ␣-subunit of the Gs stimulatory protein (Gs␣) [2,14]. This involving a couple hormones and seven-transmembrane receptors to adenylyl cyclase that facilitate the production of intracellular cyclic AMP leading to the receptor activation results in overproduction of hormones, manifested clinically as hyperfunctioning endocrinopathies and increased skin pigmentation [1,15,16]. MAS arise sporadically and there are no confirmed cases of vertical transmission.
Recently, some molecular and genetic etiologies of pituitary gigantism have been revealed to produce several genetic diseases like Multiple Endocrine Neoplasia (MEN) type 1 and 4, MAS, Carney complex, familial isolated PA or in association to defects in the familial succinate dehydrogenase-genes and the recently identified X-linked acrogigantism (X-LAG) syndrome [2,17].
The biological activities of Bone Morphogenetic Proteins (BMPs) in the endocrine system have been revealed. For example, the BMP-4 plays a key role in the initial development of the adenohypophysis and is also active and functionally involved in the differentiation of pituitary tumors, including prolactinomas and Cushing's disease but not in GH-releasing hormone PA [18]. Specifically in the primary pituitary tumors, one of the main neurosurgical cases that represents 10% of intracranial tumors and 10% in autopsy series as well [19,20]. The presence of proven calcifications in a PA has been scarcely reported with a prevalence rate of 0.2% to 14% in radiologic series [6,7] and ranges from 5.4 to 25% in histopathological cases [8,9]. Also some specific clinical features in PA, as hormonal markers and genetic variations, may predict the treatment course [9].
It is known that the presence of calcification in a PA is more frequent with prolactinomas, because the ossification derived from the osteo-metaplasia from the mesenchymal fibroblasts due to the effects from secondary ischemia by the tumoral outgrowth and the autocrine effects of prolactin hormone (Prl) [8,18].
Only eleven cases of a calcified PA have been described, comprising 5 reports with prolactinomas, 3 patients with a GH-secreting adenomas, 2 patients due to a so-called "TSHomas" and one patient with a gonadotrophin-secreting tumor [8]; but there are not previous reports associated to a MAS.
Additionally, matrix proteins are considered to be essential for biomineralization and to be important factors in cranioharyngioma calcification, like the Osteopontin (OPN) as a noncollagenous, acidic bone-matrix glycoprotein, which binds tightly to hydroxyapatite and appears to form an integral part of the mineralized matrix, probably important to the integrity of cell-matrix interactions [21].
Since the surgical management in craniofacial deformities is complicated in particular by the frequent post-operative FD regrowth, the treatment should be focused on the correction of functional deformities and notably in the optic nerve decompression in patients with objective vision loss [22]. Conversely, the decompression increases the risk of vision loss when is preserved, this last has been considered as contraindicated [1,23].

Conclusion
This is a rare case of gigantism with micro-calcifications in a GH-releasing PA associated to MAS. There has been a recognized association between Gigantism and MAS, however the presence of dystrophic calcifications in PA is rare and has to be recognized in the preoperative imaging as an important finding to consider on the surgical decision-making, since it may determine the com-plexity of its resection caused by struggling technical issues in the trans sphenoidal surgery due to thickening of the skull base [6,12]. Further investigations have to be done to clarify this rare disease.

Conflicts of interest
All authors report no conflict of interest.

Funding
None funding.

Ethical approval
The internal review board of the National Institute of Neurology and Neurosurgery does not require ethical approval for case reports when informed consent was taken, if required by the journal it could be granted.

Consent
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

Author contribution
Miguel Vega Arroyo: Writing the paper, analysis, design and reviewing literature.
Martha Lilia Tena-Suck: Data collection and data analysis. Celia Teresa de Jesús Álvarez Gamiño: Translating, design and reviewing literature.
Salinas-Lara Citlaltepetl: Data collection and data analysis. Gómez-Amador Juan Luís: Concept of paper, getting approval and interpretation.

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Not commissioned, externally peer reviewed.

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Data availability
All relevant data are within the paper.