Optic Neuropathy in McCune-Albright Syndrome: Effects of Early Diagnosis and Treatment of Growth Hormone Excess

Department of Radiology (M.G.), Massachusetts General Hospital, Boston, Massachusetts 02114
The Journal of Clinical Endocrinology and Metabolism (Impact Factor: 6.31). 10/2012; 98(1). DOI: 10.1210/jc.2012-2111
Source: PubMed

ABSTRACT Context:GH excess is a serious complication of McCune-Albright syndrome (MAS) and has been associated with craniofacial morbidity.Objective:The aim of the study was to determine whether early diagnosis and treatment of MAS-associated GH excess prevents optic neuropathy and hearing impairment, the major morbidities associated with GH excess.Design and Setting:A retrospective cross-sectional analysis was conducted at a clinical research center.Patients:Twenty-two subjects with MAS-associated GH excess and 21 control MAS subjects without GH excess were included in the study.Intervention:Biochemical testing included random GH, nadir GH after glucose load, nadir GH on frequent sampling, and IGF-I Z-score. Subjects underwent imaging, ophthalmological, audiological, and otolaryngological assessment. Treatment included octreotide, pegvisomant, transphenoidal surgery, and/or radiotherapy as indicated.Main Outcome Measure:Association of optic neuropathy and hearing impairment to age at GH excess diagnosis/treatment was measured.Results:Of 129 MAS subjects, 26 (20%) were diagnosed with GH excess based on elevation of two measures of GH function. Of these, 22 subjects were candidates for pharmacological intervention. Optic neuropathy was significantly correlated with intervention status, with no cases in the early intervention group (diagnosed/treated before age 18) or the control group, and four of seven (57%) in the late intervention group (diagnosed/treated after age 18) (Fisher's exact test; odds ratio, 0.027; P = 0.0058). Early diagnosis/intervention was not associated with reduction in hearing deficits (odds ratio, 1.25; P = 1.00). Mean head circumference sd score was significantly higher in the late (6.08; range, 2.70 to 22.56) than the early intervention (2.67; range, -0.65 to 6.72) or control groups (2.13; range, -2.06 to 7.79) (P = 0.003).Conclusions:Early diagnosis/treatment of GH excess in MAS is important to prevent optic neuropathy and craniofacial expansion. The relationship between hearing deficits and GH excess remains less clear and requires further study.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Context: McCune Albright syndrome (MAS) is a clinical association of endocrine and non-endocrine anomalies caused by post-zygotic mutation of the GNAS1 gene, leading to somatic activation of the stimulatory α subunit of G protein (Gsα). Important advances have been made recently in describing pathological characteristics of many MAS-affected tissues, particularly pituitary, testicular and adrenal disease. Other rarer disease related features are emerging. Objective: To study pathological and genetic findings of MAS on a tissue-by-tissue basis in classically and non classically affected tissues. Design: A comprehensive autopsy and genetic analysis Setting: Tertiary referral University Hospital Patients: Adult male patient with MAS and severe disease burden including gigantism Intervention(s): Clinical, hormonal and radiographic studies; gross and microscopic pathology analyses, conventional PCR and droplet digital PCR analyses of affected and non affected tissues Main Outcome Measure: Pathological findings, presence of GNAS1 mutations Results: The patient was diagnosed with MAS syndrome at six years of age based on the association of café-au-lait spots and radiological signs of polyostotic fibrous dysplasia. Gigantism developed and hyperprolactinemia, hypogonadotropic hypogonadism and hyperparathyroidism were diagnosed throughout adult period. The patient died at the age of 39 from pulmonary embolism. A detailed study revealed mosaiscism for the p.R201C GNAS mutation distributed across many endocrine and non-endocrine tissues. These genetically implicated tissues included rare or previously undescribed disease associations including primary hyperparathyroidism, and hyperplasia of the thymus and endocrine pancreas. Conclusions: This comprehensive pathological study of a single patient highlights the complex clinical profile of MAS and illustrates important advances in understanding the characteristics of somatic GNAS1 related pathology across a wide range of affected organs.
    Journal of Clinical Endocrinology &amp Metabolism 07/2014; 99(10):jc20141291. DOI:10.1210/jc.2014-1291 · 6.31 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Fibrous dysplasia (FD) is a rare disease caused by a sporadic postzygotic missense mutation that leads to abnormal fibroblast proliferation, defective osteoblast differentiation, and increased bone resorption. It may affect one or several bones. Both the mono-ostotic and polyostotic types may be associated with hyperfunctional endocrinopathies and hyperpigmentation of the skin (café-au-lait spots) in the so-called McCune-Albright syndrome (MAS). Due to its rarity, only a few case series are available, making it difficult for most clinicians to judge the severity of the disease. To improve our knowledge of FD, we reviewed all cases of FD treated at our department of endocrinology. Among 26 patients, 17 (65 %) had polyostotic FD, with four being diagnosed with MAS. Patients with polyostotic FD were diagnosed at an earlier age (median 13, range 0.5-64 years) than patients with the mono-ostotic form (median 21, 1-70 years). Craniofacial bones were affected in 80 % of cases, and 66 % complained of bone pain at the affected site, with no difference between patients with mono- and polyostotic FD. Two patients with mono-ostotic and three with polyostotic FD had cranial nerve impairments. Fourteen underwent, at least, one surgery, six (67 %) with mono-ostotic and eight (47 %) with polyostotic FD. Most received treatment with bisphosphonates, but therapy did not result in any clear relief of symptoms or radiological improvements. In conclusion, bone pain is common in patients with FD. The severity of the disease depends on affected bones as mono-ostotic may be as debilitating as polyostotic FD. In our case series, bisphosphonate treatment did not show clear beneficial effects.
    Calcified Tissue International 01/2014; 94(4). DOI:10.1007/s00223-013-9829-0 · 2.75 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: McCune-Albright syndrome (MAS) includes the triad of poly/monostotic fibrous dysplasia, café-au-lait spots and hyperfunctioning endocrinopathies. Acromegaly affects around 20% of MAS patients. Aims: The objective was to review all reported cases of acromegaly associated with MAS. Methods: All studies and case reports of acromegaly in patients with MAS were systematically sought in the world literature up to January 2013. We also included new data (from three unreported cases) and updated data on 23 previously reported patients from our two centers. Results: We reviewed the cases of 112 patients (65M). Mean age at diagnosis of acromegaly was 24.4 y (range, 3-64). Among the 40 pediatric patients, 23 (57%) had precocious puberty. GH/IGF-I excess was suggested by accelerated growth in 85% of pediatric cases. Acromegaly was almost always associated with skull-base fibrous dysplasia. Modern imaging techniques (CT or MRI) revealed an adenoma in 54% of the patients (macroadenoma in more than two-thirds). Median GH levels and mean IGF-I standard deviation score (SDS) at diagnosis were 57 μg/l (2.8 to 291 μg/l) and 8 (2.3 to 24), respectively. Hyperprolactinemia was present in 81% (mean, 149 μg/l; range, 21-600). Pituitary surgery, performed in 25 cases, very rarely cured the GH/IGF-I excess. Somatostatin analogs improved GH/IGF-I levels in most patients but achieved control of acromegaly in only 17 (30%) of 56 patients. Pegvisomant achieved normal IGF-I levels in 10 of 13 cases. Conclusion: Acromegaly which is present in 20-30% of patients with MAS raises particular diagnostic and therapeutic issues.
    The Journal of Clinical Endocrinology and Metabolism 02/2014; 99(6):jc20133826. DOI:10.1210/jc.2013-3826 · 6.31 Impact Factor


Available from
Nov 10, 2014