Polyostotic Fibrous Dysplasia in a Child with Bone Fractures and Neuropsychiatric Symptoms, Case Report

Introduction

Fibrous dysplasia of the bone in children is a rare sporadic, genetic disorder. It can be monostotic or polyostotic and may be associated with extra-skeletal manifestations in the Mc Cune Albright Syndrome. It results from a post-zygotic activating mutation in the (GNAS) gene coding for the stimulatory (Gs alfa) protein, resulting in increased intracellular levels of cAMP, leading to replacement of the lamellar bone with under- mineralized fibrous tissue and is associated clinically with pain, bone deformities and pathological fractures. Extra skeletal manifestations associated with fibrous dysplasia in the McCune Albright Syndrome include: café au lait spots, precocious puberty, autonomous hyper functioning of the endocrine system, phosphaturia, hepatic involvement, cardiac involvement and neuropsychiatric symptoms.

Discussion

Fibrous dysplasia (FD) of the bone in children is a rare non-inheritable genetic disorder with an incidence rate of 1 in 15,000 – 30,000 per year. It can be monostotic (MFD) in 70% of the cases, or polyostotic (PFD), 30% of the cases [1]. It may be associated with extra-skeletal manifestations in the McCune Albright Syndrome which is classically defined by the triad of PFD, café au lait skin hyperpigmentation and hyper functioning endocrinopathies: hyperthyroidism, precocious puberty, Cushing Syndrome, and phosphaturia [2]. Other less common associations include: gastrointestinal, hepatic or cardiac involvement and neuropsychiatric manifestations [3]. FD may also be associated with myxomas of the skeletal muscle in the Mazabraud Syndrome [4]. Our patient had one café au lait spot on the trunk below the umbilicus, which was first noticed at around 3 years of age but disappeared 2 and a half years later and was not detected even with wood light examination. This could have been on skin that was pulled in as the naval got deeper. He also had neuropsychiatric symptoms in the form of stuttering of speech and myoclonic jerks while sleeping. The stuttering improved with speech therapy and the myoclonic jerks became much less with no medication. Neuropsychiatric symptoms have been described in the McCune Albright Syndrome in the form of mental sub normality, speech apraxia, learning disorders, and global developmental delays, [3]. In a cohort of 140 patients (1-24 years of age) with the McCune Albright Syndrome, 9% had neuropsychiatric manifestations, out of which 44% of the subjects had Cushing Syndrome, [5]. This could indicate that high levels of cortisol negatively affect brain development. In our patient, there was no Cushing Syndrome; the etiology of the symptoms could have been psychological or as a result of affection of the nervous system, or both. In addition, there was a family history of Addison’s disease, which could indicate a familial tendency to neuropsychiatric manifestations [6]. McCune Albright Syndrome results from a post-zygotic activating mutation in the gene (GNAS) on chromosome 20, coding for stimulatory G-protein (Gs alfa); decreasing the GTPase activity and resulting in increased intracellular levels of cAMP (6). In our patient, genetic analysis of the GNAS gene in the blood came as negative. However, mutation analysis on the tissue surrounding the affected bone tissue is considered, as GNAS mutations represent different patterns of somatic mosaicism [7, 8, 9].

The proximal femur is the most commonly reported site of pathological fractures in individuals with PFD in association with the ‘shepherd crook deformity’, as a result of the weight bearing forces acting on the lower extremity. The majority of fractures occur in the first decade of life [10]. Surgical approaches to treatment of fibrous dysplasia of the femur should include treatment and prevention of pathological fracture as well as correction of deformities [11]. Our subject had 2 pathological fractures in the proximal end of the right femur in less than a year; a hair line fracture at 3 years and 8 months of age and a 45 degrees fracture at 4 years and 5 months. This is considered a relatively young age for fracture development in FD [12]. The first fracture was treated with a slab for 6 weeks and the second was treated with an intramedullary nail and rod. One year later, he was re-operated in the USA by angled plate insertion and prophylactic pinning. For the femoral head mal-rotation, bone grafting of the fibro dysplastic part of the femoral head and wedge resection was done. He is now freely mobile and pain free. Either angled plate or intramedullary rod with nail can be used to treat fibrous dysplasia of the proximal femur. Both modalities give good results in regards to function, pain, and fracture prevention. However, in the Majoor and Leithner cohort, 2 out of 27 patients treated with angled plate had fracture distal to the plate and 7 experienced pain due to traction of the iliotibial tract, necessitating removal of the plate. Allogeneic grafting has a place, in selected cases, in the management of impending fractures and pain due to FD of the proximal femur [13]. The risk of failure or recurrence of deformity or fracture is high in young and growing patients and the need for revision surgery in such cases with a customized device providing stability and preventing further deformation of the femur should be considered.

Our patient received 3 six-monthly injections of Zoledronate for the known advantage of Biphosphanates in the management of fibrous dysplasia in terms of functional improvement, increased bone mineral density and reduced bone pain and bone turnover markers [14, 15]. However, no refilling of the osteolytic lesions on radiography was observed [16, 17]. Vigilant follow up and treatment focused on maintaining hip strength and range of motion and correcting leg length discrepancies and hip deformities at a young age is mandatory to preserve ambulatory function [18].

Our patient did well at school and was quite happy and emotionally stable during his clinic visits, however, no formal Quality of Life assessment was performed. Bas et al in their study on determinants of impaired quality of life in patients with fibrous dysplasia found that there was impairment in all the quality of life parameters except ‘Mental health’ and ‘Role emotional’ [19].

Conclusion

Polyostotic fibrous dysplasia is a rare cause of limping and recurrent pathological fractures in children. Medical treatment with Biphosphanate injections can positively affect the clinical course of the disease. A negative blood genetic analysis of the GNAS gene does not exclude the McCune Albright Syndrome, indicating analysis from the affected tissue. Neuropsychiatric symptoms may manifest with fibrous dysplasia with or without any endocrine involvement.