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C A S E R E P O R T

Neurofibromatosis and fibrous dysplasia manifesting in the same patient: a rare case report

Sampangi Sujatha & Deepa Jatti

Department of Oral Medicine, Diagnosis and Radiology, M.S. Ramaiah Dental College and Hospital, Bangalore, India

Keywords

fibrous dysplasia, hyperparathyroidism, neurofibromatosis, osteomalacia, osteoporosis.

Correspondence

Professor S. Sujatha, Department of Oral Medicine, Diagnosis and Radiology, M. S.

Ramaiah Dental College & Hospital, Msrit Post, New Bel Road, Bangalore, Karnataka 560054, India.

Tel: +9109448974887 Fax: +91-080-360-1825

Email: s_sujathajanardhan@yahoo.com Received 26 September 2012; accepted 1 October 2012.

doi: 10.1111/jicd.12059

Abstract

Neurofibromatosis and fibrous dysplasia show the presence of cafe-au-lait spots, bone lesions, and endocrinopathies. There has been speculation whether neurofibromatosis and fibrous dysplasia are different manifestations of the same disease or if these conditions are in some way related. We provide a case of whether neurofibromatosis and fibrous dysplasia complicated by hyperpara- thyroidism and osteoporosis.

Case report

A 45-year-old female patient reported to the department of Oral Medicine and Radiology at our institution with a complaint of swelling on the right body of the mandible that had persisted for 6 months. The swelling was initially small, and gradually increased to the present size of 39 4 cm. On inspection, the swelling was oval in shape.

It extended superiorly from the line joining the angle of the mouth to the pinna of the ear, inferiorly, approxi- mately 1.5 cm below the lower border of the mandible, and anteroposteriorly extended from the corner of the mouth to approximately 1 cm from the angle of the man- dible (Figure 1). On palpation, the swelling was of nor- mal temperature on touch, tender and firm in consistency, and the skin over the swelling was pinchable.

Past dental history revealed surgery for a similar swelling at the same site, and extractions of the lower right first and second molars during her second decade of life.

Intraoral examination revealed no obliteration of the ves- tibule in relation to the extraoral swelling. Previous histo- pathological reports of the swelling were suggestive of fibrous dysplasia (FD).

The patient’s medical history revealed the presence of neurofibromatosis (NF)1 for 20 years, with neurofibromas all over the body and cafe au lait spots present on the thigh and back with regular borders (resembling the

“coast of California” in contrast to McCune–Albright syn- drome where the cafe-au-lait spots have irregular borders resembling the “Coast of Maine”). The patient reported that a history of NF1 ran in the family, and complained of generalized weakness, headache, fatigue, and pain in the lower limbs, joints, and back, which caused difficulty in walking. The patient was also a known hypertensive since 5 years of age, and was on medication. She had attained menarche at the age of 15 years. Based on her medical history and the clinical examination, a provi- sional diagnosis of (recurrent) FD was given. Central ossi- fying fibroma, McCune–Albright syndrome (MAS), and intraosseous lesions of NF-1 were considered under the differential diagnosis.

Panoramic radiograph demonstrated a well-defined mixed radio-opaque and radiolucent lesion on the right body of the mandible, with ballooning of the inferior bor- der. A computed tomography scan of the right body of the mandible showed an expansile mixed lesion (hypodense

ª 2013 Wiley Publishing Asia Pty Ltd 77

Journal of Investigative and Clinical Dentistry (2015), 6, 77–80

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and hyperdense), with thinning of cortices and areas of hard and soft tissue attenuation, with densities ranging from 60 to 150 HU, suggestive of FD (Figure 2). The ante- roposterior (AP) and lateral view of the spine showed the presence of scoliosis (Figure 2), and the lateral view showed thinning of the ribs. The AP and lateral view of the lower limbs showed an ill-defined mixed lytic-sclerotic lesion in the lower end of the right fibula with cortical thickening, suggestive of FD.

A bone scan revealed an increased uptake of pertechte- nate in the right body of the mandible and the lower end of the right fibula, suggestive of polyostotic FD. Dual- energy X-ray absorptiometry scan showed decreased bone mineral density (BMD), with a T score of 2.7, sugges- tive of osteoporosis.

The patient was subjected to various investigations to assess the cause of generalized body weakness and bone pain (serum calcium, 8.4 mg/dL; serum alkaline phospha- tase, 151 u/L; serum parathormone [PTH], 105 mg/mL;

1,25-dihydroxyvitamin D3, 18 pg/mL).These levels were found to be suggestive of secondary hyperparathyroidism due to vitamin D deficiency. Investigations for hypothy- roidism, gigantism, and Cushing syndrome were per- formed to exclude MAS. Serum and urinary levels of calcium, phosphorous, and creatinine were assessed and were suggestive of hypophosphatemia (Serum phospho- rous, 2 mg/dL). These levels were also used to evaluate the ratio of the renal tubular maximum reabsorption rate

of phosphate to the glomerular filtration rate (TmP/

GFR), and the levels were found to be reduced (TmP/

GFR, 0.08 mmol/L).

Through an intraoral approach, curettage of the lesion was performed, followed by histopathological examina- tion, which revealed trabeculae of woven bone with osteo- blastic and osteoclastic activity without rimming of osteoblasts, suggestive of FD.

A final diagnosis of NF1, polyostotic FD associated with osteoporosis, and secondary hyperparathyroidism

Figure 1. Diffuse swelling on the right lower half of the face with multiple nodules.

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Figure 2. Axial computed tomography scan showing ground glass appearance (a), and anteroposterior view of spine showing scoliosis (b).

78 ª 2013 Wiley Publishing Asia Pty Ltd

Neurofibromatosis and fibrous dysplasia S. Sujatha and D. Jatti

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due to vitamin D deficiency was established. The patient was prescribed vitamin D and calcium supplements. Fol- low up of the patient after 3 and 6 months showed remission in her symptoms.

Discussion

Neurofibromatosis has been linked with FD of bone by various physicians, notably Aegerter, who emphasized the various expressions of NF, such as skin nodules, pigmented spots, and endocrine manifestations, which are often seen in FD.1 Rosenberg et al. indicated that some relationship exists between the two, although it certainly cannot be interpreted to mean that these con- ditions are different manifestations of the same disease.

He also pointed out that only more severe states of FD, such as polyostotic FD, are likely to be associated with evidence of NF, as seen in our case. The onset of FD is most often seen in the first decade of life, and usually ceases its progressive course at skeletal matura- tion, whereas NF does not manifest before the second decade.2 In the present case, both NF1 and polyostotic FD manifested almost at the same time, at approxi- mately the second decade of the patient’s life. Rosen- berg et al. reported a case series in which FD and NF were present in a family of nine, and Schotland reported concurrent occurrence of NF and FD in a family of four; in the father and three children.2,3 It has been speculated that this is more than a chance occurrence. During embryogenesis, a regulator gene mutation with variable penetrance was responsible for both these diseases.

The overlapping clinical signs and symptoms and the similarity in cell morphology and pattern strongly suggest that these conditions are in some way related.3This prop- osition can be substantiated in the present case. Addition- ally, the secondary manifestations of NF and FD, such as osteoporosis, hyperparathyroidism, and osteomalacia, are investigated in the present case, which has not been con- versed in the literature to date. The ongoing discussion will shed light on the implications of NF and FD in causing these secondary manifestations.

Patients with NF1 are shorter than expected, and often have low BMD. Our patient was of short stature at 127 cm, with decreased BMD, suggestive of osteoporosis. Various studies have found high serum PTH concentrations and lower serum 1,25-hydroxy vitamin D3 concentrations to be associated with lower BMD among NF1 patients. Individu- als with NF1 have increased osteoclastic activity that leads to increased bone breakdown and increased frequency of fractures, indicating a generalized abnormality of bone metabolism. Further studies are needed to elucidate the precise nature of this abnormality.4

Renal phosphate wasting and hypophosphatemia are also commonly observed among polyostotic FD patients.5 Fibroblastic growth factor-23 (normal levels: 18–108 RU/mL) can be elevated in patients with FD.6 It decreases phosphate tubular reabsorption, thus lowering serum phosphate and 1,25-dihydroxy vitamin D3, which con- tributes to the worsening of lesional osteomalacia that is observed in FD.7 Compared to unaffected bone, lesional FD bone is very sensitive to the effects of PTH and renal phosphate wasting, which bring about hyperparathyroid or osteomalacic changes.8 The TmP/GFR, which is regu- lated by PTH, is an index used to assess the sensitivity of renal threshold for phosphorous, and it can be decreased in many conditions, including secondary hyperparathy- roidism and NF. PTH, which is elevated in secondary hyperparathyroidism due to vitamin D deficiency, decreases the TmP/GFR by reducing renal tubular reabsorption of phosphorous, and increases its excretion, as seen in our patient (Table 1).9 All of the abovementioned mechanisms could lead to the occurrence of secondary hyperparathyroidism, as seen in our case.

McCune–Albright syndrome, central ossifying fibroma, and intraoral lesions of NF were considered under a dif- ferential diagnosis. MAS,10 which is considered the most severe form of FD, was ruled out, as her menstrual his- tory was normal and other endocrine investigations were within normal limits. In NF1, cafe-au-lait macules (CALM) are uniformly hyperpigmented, with smooth borders resembling the “coast of California” in contrast to MAS, in which they tend to be very large and unilat- eral, with irregular and ragged borders resembling the

“coast of Maine”. They have a tendency to follow the developmental lines of Blashko. In our case, more than

Table 1. Biochemical investigations

Laboratory values Normal levels Observed levels Serum calcium (mg/dL) 9.00–10.40 8.40 Serum alkaline phosphatase (u/L) 40.00–136.00 151.00 Serum parathormone (mg/mL) 10.00–60.00 105.00 Serum phosphorous (mg/dL) 3.00–4.50 2.00 Serum creatinine (mg/dL) 0.60–1.20 0.60 Urinary phosphorous (mmol/L) 0.60–1.40 1.48 Urinary creatinine (mmol/L) 0.60–1.20 0.88

TmP/GFR (mmol/L) 0.15–0.24 0.08

1,25-dihydroxyvitamin D3 (pg/mL) 25.00–40.00 18.00 Thyroid stimulating hormone (Mu/L) 0.30–0.40 0.32 Thyroxin, total T4 (lg/dL) 4.50–10.90 8.50 Triiodothyronine, total T3 (ng/dL) 60.00–181.00 102.00

Growth hormone (ng/mL) 0.50–1.70 1.20

Cortisol, free (lg/24 h) 20.00–70.00 34.00 TmP/GFR, ratio of the renal tubular maximum reabsorption rate of phosphate to the glomerular filtration rate.

ª 2013 Wiley Publishing Asia Pty Ltd 79

S. Sujatha and D. Jatti Neurofibromatosis and fibrous dysplasia

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six CALM were present on the thigh and back, with regu- lar borders and of varying size (1.5–2.5 cm), further emphasizing that these are manifestation of NF1.11 The central ossifying fibroma was excluded, as it is radio- graphically well defined with varying degrees of calcifica- tion, but rarely radiopaque. It has a symmetric growth pattern, which is equal in all directions, and occasionally has a soft tissue capsule, unlike FD, which blends with surrounding bone.12 Intraosseous lesions of NF1 were ruled out, as these lesions exhibit either radiopacity due to bone hypertrophy or radiolucency due to pressure from overlying tumors or central bone tumors, unlike the mixed radiolucent–radiopaque appearance of FD.13

Treatment with bisphosphonates is found to be benefi- cial in FD, resulting in rapid pain relief and normaliza- tion of bone turnover.14 Calcium and vitamin D

supplements in patients with vitamin D deficiency are necessary to limit osteomalacia and hyperparathyroidism.7 The management of NF1 is currently focused on genetic counseling and esthetic treatment of specific lesions, usu- ally through surgery.15

A possible relationship between NF, FD, hyperparathy- roidism, and osteoporosis was found through a literature search, and has been substantiated in our case. An under- standing of this relationship would be more than just academic importance, and might be of therapeutic value.

If this is so, all NF patients should be routinely reviewed for the above associated diseases, which could be rewarded with an early diagnosis and better prognosis, thus preventing the risk of fractures in these individuals.

The benefit of exercise might be especially important in improving BMD in NF1 patients.

References

1 Aegerter EE. The possible relationship of neurofibromatosis, congenital pseudoarthrosis and fibrous dysplasia.

J Bone Joint Surg Am 1950;32: 618–26.

2 Rosenberg RN, Jon S, Zimmerman A, Carter S. The inter-relationship of neurofibromatosis and fibrous dyspla- sia. Arch Neurol 1967;17: 174–9.

3 Schotland HM. Neurofibromatosis 1 and osseous fibrous dysplasia in a fam- ily. Am J Med Genet 1992;43: 815–22.

4 Tucker T, Schnabel C, Hartmann M.

Bone health and fracture rate in indi- viduals with neurofibromatosis1.

J Med Genet 2009;46: 259–65.

5 Collins MT, Chebli C, Jones J, Kush- ner H, Consugar M, Rinaldo P, Wien- troub S, Bianco P, Robey PG. Renal phosphate wasting in fibrous dysplasia of bone is part of a generalized renal tubular dysfunction similar to that seen in tumor- induced osteomalacia.

J Bone Miner Res 2001;16: 806–13.

6 Riminucci M, Collins MT, Fedarko NS. FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting. J Clin Invest 2003;

112: 683–92.

7 Yamamoto T, Imanishi Y, Kinoshita E. The role of FGF-23 for hypo- phosphataemia and abnormal regula- tion of vitamin D metabolism in patients with McCune–Albright syn- drome. J Bone Miner Metab 2005;23:

231–7.

8 Corsi A, Collins MT, Riminucci M et al. Osteomalacia and hyper para- thyroid changes in fibrous dysplasia of bone: core biopsy studies and clini- cal correlations. J Bone Miner Res 2003;18: 1235–46.

9 Marshall WJ, Bangert SK. Calcium, phosphate and magnesium. Clinical biochemistry: metabolic and clinical aspects, 2nd edn. London: Elseveir Publishing, 2008: 125–7.

10 Chapurlat RD, Orcel P. Fibrous dys- plasia of bone and McCune–Albright

syndrome. Best Prac Res Clin Rheu- matol 2008;22: 55–69.

11 Khandpur S, Malhotra AK, Deepak KK, Verma KK. Neurofibromatosis 1 with unusual hypopigmentation

masquerading as Leprosy. J

Assoc Physicians India 2004;52: 1001–3.

12 Speight PM, Carlos R. Maxillofacial fibro-osseous lesions. Curr Diag Pathol 2006;12: 1–10.

13 Lee L, Yan YH, Pharoah MJ.

Radiographic features of the mandible in neurofibromatosis. A report of 10 cases and review of literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996;81:

361–7.

14 Makitie AA, T€ornwall J, M€akitie O.

Bisphosphonate treatment in cranio- facial fibrous dysplasia—a case report and review of the literature. Clin Rheumatol 2008;27: 809–12.

15 Korf BR. Determination of end points for treatment of neurofibromatosis 1.

J Child Neurol 2002;8: 642–5.

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Neurofibromatosis and fibrous dysplasia S. Sujatha and D. Jatti

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