Acromegaly with Fibrous Dysplasia: McCune-Albright Syndrome

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1 Endocrine Journal 2003, 50 (6), NOTE with Fibrous Dysplasia: McCune-Albright Syndrome Clinical Studies in 3 Cases and Brief Review of Literature ANIL BHANSALI, BHAWANI S SHARMA*, POLUPOINA SREENIVASULU, PARAMJIT SINGH**, RAKESH K. VASHISTH*** AND RADHARAMAN J DASH Department of Endocrinology, Postgraduate Institute of Medical Education and Research, Chandigarh, , India *Department of Neurosurgery, Postgraduate Institute of Medical Education and Research, Chandigarh, , India **Department of Radio-Diagnosis, Postgraduate Institute of Medical Education and Research, Chandigarh, , India ***Department of Pathology, Postgraduate Institute of Medical Education and Research, Chandigarh, , India Abstract. The McCune-Albright syndrome (MAS) is characterized by a triad of poly/monostotic fibrous dysplasia, caféau-lait macules and hyperfunctioning endocrinopathies including growth hormone (GH) excess. bone lesions and café-au-lait macules are common while monostotic bone lesions are rare. Similarly, acromegaly as a manifestation of endocrine hyperfunction with MAS is uncommon and in most of the instances somatotropinoma has not been documented. We report 3 patients, two of them had monostotic lesion, none had café-au-lait macules and all had GH secreting pituitary macro. All of them underwent transfrontal pituitary adenomectomy and had histopathological confirmation of GH secreting pituitary. A brief review of literature is also presented. Key words:, Fibrous dysplasia, Somatotropinoma (Endocrine Journal 50: , 2003) Received: February 28, 2003 Accepted: July 7, 2003 Correspondence to: Dr. Radharaman J. DASH, Department of Endocrinology, PGIMER, Chandigarh , India THE original description of McCune-Albright syndrome (MAS) included osteitis fibrosa dissemina, café-au-lait macules and precocious puberty [1, 2]. fibrous dysplasia and café-au-lait macules are invariably present while monostotic lesions are less common [3]. Endocrine hyperfunction other than precocious puberty in association with MAS include hyperthyroidism, hypercortisolism, hypersomatotropism and hypophosphatemic rickets [13]. Association of MAS with hypersomatotropism is rare, and pituitary is demonstrable in only 4050% of these patients [3, 4]. Till 2002, only 51 cases of MAS with acromegaly have been reported in English literature [332, 34]. However, pathological examination of the pituitary either at surgery or necropsy has been reported in only 8 of them [3, 6, 7, 10, 14, 24, 28, 30]. We report 3 patients, in the existing repertoire of this rare entity, who had fibrous dysplasia and acromegaly due to growth hormone (GH) secreting pituitary. Case 1 Case Studies A 28-year-old man presented with progressive increase in height, acral enlargement and coarse and asymmetrical facial features from the age of 10 years. He gave no history of headache, visual field loss, symptoms of raised intracranial tension or features of any endocrine deficiencies or hyperfunctions other than GH excess. Initiation and development of his secondary sex features were normal. On examination, his height was 212 cm, weight 120 kg, body mass index (BMI) 27.2 Kg/m 2 and BP 150/90 mmhg. He had

2 794 BHANSALI et al. facial asymmetry with coarse features and acral enlargement with excessive sweating but no café-au-lait macules, bony swelling or goitre. Systemic examination and pubertal maturation indices (A 3, P 6, testicular volume 25 ml bilateral) were normal. On investigation, basal GH was 86 ng/ml that paradoxically rose to 130 ng/ml (N<2 ng/ml) following 75 gm oral glucose load. In response to 100 g IV bolus thyrotropin releasing hormone (TRH), GH increased from 84 ng/ml to 218 ng/ml. Serum PRL was 500 miu/l (N, miu/l), T ng/ml (N, ), T 4 70 ng/ml (N, 60150), cortisol at 8 am 400 nmol/l (N, ) and at 4 pm 270 nmol/l (N, ), LH 2.6 IU/L (N, 515), FSH 3.2 IU/L (N, 515) and testosterone 6 nmol/l (N, 927). X-ray skull showed sellar enlargement with destruction of clinoid process and radiodense lesions in left nasal cavity and paranasal sinuses with thickening of base of the skull (Fig. 1a). Long bones and pelvic girdle X-ray did not reveal any abnormalities. Contrast enhanced computerized tomography (CECT) of head revealed lesions with ground glass appearance in paranasal Fig. 1. (a): X-ray skull (lateral view) showing enlarged sella and dense lesions in paranasal sinuses and base of skull. (b): Coronal section of CT head (bone window) shows bone thickening with ground glass appearance involving left maxillary sinus and nasal cavity. (c): CECT head (coronal view) showing hyperdense sellar mass with suprasellar extension. (d): 99m T c MDP bone scan (lateral view) with increased tracer uptake in bony lesions in skull and maxilla. sinuses and hyperdense mass lesion (15 10 mm) in sellar, left parasellar and suprasellar region, extending up to 3rd ventricle (Fig. 1b, c). CECT adrenal was normal. He underwent transfrontal pituitary adenomectomy followed by external beam radiotherapy (45 Gy) over six weeks. Immunostaining for GH on tumour tissue sections was positive and histopathology of bone lesion confirmed fibrous dysplasia. GH dynamics 3 months later showed high basal GH (72 ng/ml) with paradoxical rise (104 ng/ml) after glucose load. He refused to undergo resurgery because he could not afford medical treatment. In May 97, he presented in stuporose state due to bronchopneumonia and septicemia to which he succumbed. Case 2 A 25-year-old man presented with progressively increasing multiple hard swellings over head and right half of the face for 15 years and retro-orbital headache and acral enlargement for last 2 years. He gave no history of visual disturbance, seizures, sexual dysfunction or any neural deficit. Onset and development of his secondary sex features were normal. On examination, his height was 161 cm, weight 71 kg, BMI 29 Kg/m 2, BP 120/70 mmhg and was normally virilized (A3, P6, testicular volume of 20 ml). He had facial asymmetry with coarse features and acral enlargement with excessive sweating. He had no café-au-lait macules and goitre but had multiple, non-tender, bony swellings over right frontal and occipital regions of vault and right maxilla including the alveolar process. Systemic examination was normal. On investigation, basal GH was 92 ng/ml that paradoxically rose to 350 ng/ml following 75 gm oral glucose. In response to 100 g IV bolus TRH, GH increased from 85 ng/ml to 189 ng/ml. Serum PRL was 450 miu/l, T ng/ml, T 4 54 ng/ml and cortisol at 8 am 600 nmol/l and at 4 pm 300 nmol/l, LH 1.56 IU/L, FSH 1.25 IU/L and testosterone 8 nmol/l. X-ray skull showed radiodense lesions in frontoparietal bone and base of skull. CECT head revealed isodense sellar mass (20 10 mm) with suprasellar extension and ground glass lesions in skull bones and in maxilla. Long bones and pelvic skeletal survey did not reveal any other abnormalities. The typical findings of increased tracer uptake in skull bones and in maxilla but nowhere else on 99m T c methelyne diphosphonate (MDP) bone scan is shown in Fig. 1d. Fine

3 ACROMEGALY WITH FIBROUS DYSPLASIA 795 needle aspiration cytology from maxillary lesion confirmed fibrous dysplasia. He underwent transfrontal adenomectomy uneventfully. Immunostaining on tumour tissue sections for GH was positive. GH dynamics 3 months later showed basal GH was 25 ng/ml and suppressed to 10 ng/ml after glucose load. He received prednisolone and testosterone replacement therapy and 45 Gy external beam irradiation over 6 weeks for residual tumour. He is well for the last 4 years with GH levels of 5 ng/ml after glucose load. Case 3 A 19-year-old man presented with erectile dysfunction for last few months. He experienced progressive gain in height, and had headache and acral enlargement for last 45 years. He gave no history of visual symptoms, seizures or neural deficits. On examination, his height was 208 cm, weight 110 kg, BMI 25.4 Kg/m 2 and BP 130/90 mmhg. He had coarse facial features and acral enlargement with excessive sweating but no café-au-lait macules, bony swelling or goitre. Systemic examination was normal. He was poorly virilized (A 2 P 4, testicular volume 12 ml with sparse facial hairs). On investigation, his basal GH was 88 ng/ml and paradoxically rose to 130 ng/ml following 75 gm glucose. In response to 100 g IV bolus TRH, GH increased from 78 ng/ml to 130 ng/ml. Serum PRL was 1150 miu/l, T ng/ml, T 4 40 ng/ml, cortisol at 8 am 330 nmol/l and at 4 pm 280 nmol/l, LH 2.1 IU/ml, FSH 1.25 IU/ml and testosterone 1.6 nmol/l. X-Ray skull showed radiodense lesions in base of skull, ethmoid and sphenoid bone and orbital plate with enlarged sella, while skeletal survey for other areas did not show any abnormalities. CECT head showed pituitary macro (21 30 mm) with suprasellar extension and ground glass appearance in above mentioned areas. He received L-thyroxine and prednisolone replacement therapy and underwent transfrontal pituitary adenomectomy. Immunostaining on tumor tissue sections for GH and PRL was positive. Histopathology of bone lesion confirmed fibrous dysplasia consisting of immature woven bone trabeculae characteristically lacking osteoblastic rim against a background of spindle cell stroma. The periphery of the tumour adjacent to uninvolved bone showed a rim of reactive new bone formation (Fig. 2). GH dynamics 3 months later showed high basal GH (30 ng/ml) that Fig. 2. Microscopic examination of the bone lesion showed spindle cell proliferation with immature woven bone lacking a rim of osteoblasts. Trabeculae were short and variably curved (H & E 250). was suppressed to 15 ng/ml after 75 gm glucose load. Serum PRL became normalized (600 miu/l) and his adrenocortical reserve was normal. He is on L-thyroxine and testosterone replacement therapy and received 45 Gy external beam radiotherapy over 6 weeks for residual tumour. He is well for the last 2 years with GH levels of 10 ng/ml after glucose load. The clinical profile of these 3 patients is summarized in Table 1. Discussion Two of the following lesions, namely poly/monostotic fibrous dysplasia, cutaneous pigmented macules and hypersecretory endocrinopathies are suffice to make the diagnosis of MAS [1, 2]. Two of our patients (case 1 and 3) had monostotic lesions and one (case 2) polyostotic (skull and maxilla) but none had café-au-lait macules. This is in contrast to all (51 patients) but eight of the reported patients who had café-au-lait macules and only four of them had monostotic lesions (Table 2). In almost every case, the base of the skull was involved as seen in all of our patients. However, the course of dysplastic bone disease is independent of the time of onset and degree of disease activity [3]. No endocrine organ other than the pituitary was involved in our patients. This contrasts with the reported prevalence of sexual precocity (34%), thyrotoxicosis (11%) and hypercortisolism (3%) in patients with MAS associated with acromegaly [3]. Only one pa-

4 796 BHANSALI et al. Table 1. Clinical and hormonal characteristics of 3 patients with McCune-Albright syndrome Sr.No. Age/Sex Café-aulait macule Fibrous dysplasia GH response to OGTT (ng/ml) GH response to TRH (ng/ml) PRL (miu/l) Tumor localization Basal Peak Basal Peak 1 28 M Monostotic Sellar mass with suprasellar extension 2 25 M Sellar mass with suprasellar extension 3 19 M Monostotic Sellar mass with suprasellar extension GH growth hormone, PRL Prolactin Immunostaining positivity on tumor tissue GH GH GH and PRL Table 2. Reviews and case reports on McCune-Albright syndrome with acromegaly Sr.No Author Year No. of cases Age (yrs.) Sex Caféau-lait macules Fibrous dysplasia Mono/ polyostotic Endocrine hyperfunction 1 Scurry et al F Precocious puberty 2 Lightner et al M Precocious puberty Tumor Localization Histopathology Confirmation (suprasellar extension) Eosinophilic 3 Joishy et al M Chromophobe 4 Powell et al F 5 Carr et al F Precocious puberty, HPRL 6 Albin et al F M Precocious puberty HPRL (in both cases) Autopsy-normal pituitary 7 Lipson et al F Precocious puberty, DM 8 Polychronakos et al M Precocious puberty, Acrogiant, HPRL (suprasellar extension) 9 Chung et al F, HPRL 10 Kovacs et al F Precocious puberty, HPRL Somatomammotroph hyperplasia 11 Nakagawa et al M 12 Harris et al M, HPRL 13 Mauras et al M Precocious puberty, Acrogiant, Cushing s disease & Hyperthyroidism 14 Present et al M Hyperthyroidism 15 Geffner et al F Precocious puberty,, HPRL, Hyperthyroidism 16 Misaki et al M, Toxic 17 Cuttler et al M M F Precocious puberty,, HPRL, HPRL (suprasellar extension)

5 ACROMEGALY WITH FIBROUS DYSPLASIA 797 Table 2. (continued) Sr.No Author Year No. of cases Age (yrs.) Sex Caféau-lait macules Fibrous dysplasia Mono/ polyostotic Endocrine hyperfunction Tumor Localization Histopathology Confirmation 18 Pun et al F, HPRL 19 Mortensen et al young F Monostotic (2) 20 Huang et al F Hashimoto s Eosinophilic thyroiditis HPRL 21 Abs et al F HPRL, Toxic MNG 22 Kupcha et al NA NA Micro (1) Macro (1) 23 Sherman et al NA M 24 Premwardhan et al F Precocious puberty 25 Cremonini et al F Monostotic HPRL Eosinophilic 26 Chanson et al M (3) F (2) (4) (1) (4) (5) Monostotic (1) HPRL (4) (4) GH secreting (1) 27 Garcia et al M NA HPRL 28 Gessl et al F HPRL Thyrotropinoma GH, PRL and TSH secreting 29 Feuillan et al F Precocious puberty 30 Ihara et al F 31 Akintoye et al M (3) Precocious puberty (8) (4) F (9) (12) HPRL Hyperprolactinemia, NA Not available tient of MAS with acromegaly and hyperthyroidism has been reported due to mixed somato-thyrotropinoma [30]. GH hypersecretion in MAS differs in several aspects from that observed in classical acromegaly. Patients are generally young (<20 years) at the onset and diagnosed on the basis of growth acceleration rather than facial dysmorphism which is usually difficult to assess due to fibrous dysplasia [3, 4]. Our patients had onset of disease around age 10 and two of them were acro-giants. Only half of the patients with MAS and acromegaly exhibit radiological evidence of pituitary compared with 8090% in classical acromegaly [4]. Only 3 (17%) of 17 patients in the Cuttler et al. [21] series and 4 (33%) of 12 in Akintoye et al. [34] report had a pituitary mass with suprasellar extension. All of our patients had sellar mass with suprasellar extension and immunostaining for GH on tumor tissues was positive. Hyperprolactinemia was observed in only one of our patients in contrast to its reported prevalence of 85% in MAS with GH hypersecretion vis-à-vis 2040% in classical acromegaly [3, 4]. Increase in serum GH after TRH is a consistent feature of MAS with acromegaly, while 7080% of classical acromegaly have this response [3, 21]. All of our patients had rise in GH in response to TRH. GH dynamics during pregnancy in a patient with acromegaly with MAS has been reported recently [33]. It differs in its lack of autonomicity as compared to classic acromegaly with pregnancy where tumour behaviour is entirely autonomous [33]. The pathogenesis of hypersecretory endocrinopathies in MAS involves post-zygotic activating mutation of the camp-regulating protein, GNAS 1 gene product Gs, wherein arginine is replaced by other amino acids at position 201 [32, 33, 35]. This results in the constitutive activation of adenylate cyclase and the subsequent camp formation as a second messenger [33, 34]. However, functionally normal Gs protein mutation in acromegaly with MAS has also been reported suggesting a defect beyond Gs receptor [30]. Characteristically, cells that respond through ac-

6 798 BHANSALI et al. tivation of adenyl cyclase (camp system) are involved in hypersecretory endocrinopathies of MAS [33, 35]. Pituitary surgery in this syndrome is beset with problems mainly related to fibrous dysplasia and the resultant thickening of bones [3, 4, 19, 28]. Occasional instances of sarcomatous transformation of fibrous dysplastic bones have been reported with radiation therapy [18, 23]. Bromocryptine, cabergoline and long acting somatostatin analogue have been used with some success in acromegaly with MAS [3, 4, 28, 31, 33]. Our patients underwent transfrontal adenomectomy with partial removal of tumour. Two of them received megavoltage irradiation for residual tumours because of non-affordability for medical treatment and both are doing well. References 1. McCune DJ (1936) Osteitis fibrosa cystica : the case of nine year old girl who also exhibits precocious puberty, multiple pigmentation of the skin and hyperthyroidism. Am J Dis Child 52: Albright F, Butler AM, Hampton AO, Smith P (1937) Syndrome characterized by osteitis fibrosa disseminata, areas of pigmentation and endocrine dysfunction, with precocious puberty in females: reports of five cases. N Engl J Med 216: Chanson P, Dib A, Visot A, Derome PJ (1994) McCune-Albright syndrome and acromegaly: clinical studies and response to treatment in five cases. Eur J Endocrinol 131: Premawardhana LDKE, Vora JP, Mills R, Scanlon MF (1992) and its treatment in the McCune- Albright syndrome. Clin Endocrinol 36: Scurry MT, Bicknell JM, Fajans SS (1964) fibrous dysplasia and acromegaly. Arch Intern Med 114: Lightner ES, Penny R, Frasier SD (1975) Growth hormone excess and sexual precocity in polyostotic fibrous dysplasia (McCune-Albright syndrome): evidence for abnormal hypothalamic function. J Pediatr 87: Joishy SK, Morrow LB (1976) McCune-Albright syndrome associated with a functioning chromophobe. J Pediatr 89: Powell DGB (1976) fibrous dysplasia with acromegaly (Albright s syndrome). S Afr Med J 50: Carr D, Matthie IK, Manners AR, Colman C (1979) Hyperprolactinaemia in a patient with the McCune- Albright syndrome. Br J Obstet Gynaecol 86: Albin J, Wu R (1981) Abnormal hypothalamicpituitary function in polyostotic fibrous dysplasia. Clin Endocrinol (Oxf) 14: Lipson A, Hsu TH (1981) The Albright syndrome associated with acromegaly : report of a case and review of the literature. Johns Hopkins Med J 149: Polychronakos C, Tsoukas G, Ducharme JR, Letarte J, Collu R (1982) Gigantism and hyperprolactinemia in polyostotic fibrous dysplasia (McCune-Albright syndrome). J Endocrinol Invest 5: Chung KF, Alaghband Zadeh J, Guz A (1983) and hyperprolactinemia in McCune-Albright syndrome. Am J Dis Child 137: Kovacs K, Horvath E, Thorner M, Rogol AD (1984) Mammosomatotroph hyperplasia associated with acromegaly and hyperprolactinemia in a patient with the McCune-Albright syndrome. Virchows Arch (Pathol Anat) 403: Nakagawa J, Nagasaka A, Sugiura T, Nakagawa K, Yabe Y, Nihei N, et al. (1985) Gigantism associated with McCune-Albright s syndrome. Horm Metab Res 17: Harris RI (1985) fibrous dysplasia with acromegaly. Am J Med 78: Mauras N, Blizzard RM (1986) The McCune-Albright syndrome. Acta Endocrinol (Copenh) Suppl 113: Present D, Bertoni F, Enneking WF (1986) Osteosarcoma of the mandible arising in fibrous dysplasia. Clin Orthop Relat Res 204: Geffner ME, Nagel RA, Dietrich RB, Kaplan SA (1987) Treatment of acromegaly with a somatostatin analog in a patient with McCune- Albright syndrome. J Pediatr 111: Misaki M, Shima T, Ikoma J, Morioka K, Suzuki S (1988) and hyperthyroidism associated with McCune-Albright syndrome. Horm Res 30: Cuttler L, Jackson JK, Uz-Zafar MS, Levitski LL, Mellinger RC, Frohman LA (1989) Hypersecretion of growth hormone and prolactin in McCune-Albright syndrome. J Clin Endocrinol Metab 68: Pun KK, Chan G, Kung A, Lam K, Chan FL, Wang C (1989) McCune-Albright syndrome with acromegaly. Horm Metab Res 21: Mortensen A, Bojsen-Moller M, Rasmussen P (1989) Fibrous dysplasia of the skull with acromegaly and sarcomatous transformation. J Neuro-oncol 7: Huang TS, Chang CC, Huang JS, Hsieh HC, Chen FW (1990) Albright s syndrome with acromegaly and Hashimoto s thyroiditis: report of a case. J Formos

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