Mazabraud syndrome

Mazabraud syndrome is an exceedinglya rare syndrome characterised by:

• skeletal fibrous dysplasia most commonly polyostotic (84%) 
• associated with and intramuscular myxomas^1-3

Epidemiology

In 2019, onlyOnly 106 cases have been reported in the global literature since it was first described by Henschen in 1926 and Mazabraud in 1967 (as of 2019) ^1,3-5.

Prevalence The prevalence is ~ 1 in 1,000,000.³ Among those with fibrous dysplasia < 1 % have Mazabraud syndrome^1,3. There is with a strong female predilection (68-84%) ^1,3. Recently The age at diagnosis ranges from 35-60 years with a mean age of approximately 40 years ^1,3. Childhood-onset has been reported in four cases ³.

Recently, in a cohort of 372 patients with fibrous dysplasia¹² and a multicenter cohort study of 1446 patients with fibrous dysplasia¹, Mazabraud’s syndrome was reported with a prevalence of 2.4 and 2.2% respectively. It is, therefore, likely that the accepted prevalence of Mazabraud

Associations

• McCune-Albright syndrome (< 1 %) is an underestimation of the true prevalence of myxomas in patients with fibrous dysplasia.  This is because the majority of intramuscular myxomas are asymptomatic: cafè-au-lait skin pigmentations and only patients with persistent unexplained symptoms are referred for MRI.

  The age at diagnosis is variable ranging from 35-60 years old with a mean age of approximately 40 years old

  endocrine dysfunction, such as precocious puberty, diabetes mellitus, goiter and breast fibroadenomatosis ^1,37. Childhood-onset has been reported in 4 cases ³.

Clinical presentation

There is wide anda highly variable clinical presentation ranging from. Patients may be asymptomatic and, may describe painless mass to pain,(es), or may describe painful mass/masses(es), deformities, and/or pathological fractures and rarely, malignant transformation of the fibrous dysplasia^1,2. Malignant transformation of fibrous dysplasia to osteosarcoma, fibrosarcoma, chondrosarcoma and malignant fibrohistiocytoma have been reported ². No reported cases of malignant transformation in intramuscular myxomas have been identified.

Intramuscular myxomas are typically located in the vicinity of the bone lesions with both fibrous dysplasia and intramuscular myxomas most commonly affecting the pelvic girdle and lower limbs (75%). The upper limbs are affected in less than a quarter of reported cases. Interestingly, the right side is most commonly affected (60%). The fibrous dysplasia generally occurs between 6.5-10 years prior to the identification of intramuscular myxomas¹.

Complications

Rarely, there may be malignant transformation of the fibrous dysplasia ^1,2. Malignant transformation of fibrous dysplasia may be to osteosarcoma, fibrosarcoma, chondrosarcoma, and malignant fibrohistiocytoma². No reported cases of malignant transformation in intramuscular myxomas have been identified.

Pathology

There is a strong link with post-zygotic mutations of the GNAS1 gene located on chromosome 20q13.2 – q13-q13.3, which encodes the alpha subunit of G-protein (GSa) involved in cell proliferation^1-3.When this occurs bone, bone is replaced and distorted by poorly organizedorganised, structurally unsound, fibrous tissue ².This mutation affects the mesenchymal precursor cells at the early stages of commitment ³.This may account for the wide range of clinical patterns with earlier mutations proving a more complex clinical phenotype and partly explaining why patients clinically vary from asymptomatic to painful forms with fractures and deformities ³.

Histopathology

Fibrous

Microscopic appearance

• fibrous dysplasia:
  • rimming of osteoblasts is not present around the bone spicules although this change may be focally encountered around areas of adjacent fracture. There
  • there is bland fibrous tissue and irregular spicules of woven bone ⁶.

    Intramuscular

• intramuscular myxomas: grossly there is a glistening grey-white appearance depending on the amount of myxoid material ⁶. Lesions
  • lesions are generally hypocellular and hypovascular although areas of increased vascularity and cellularity may be present ⁷. There
  • there is abundant mucoid material and loose reticulin fibres. The
  • the cells have a stellate shape with small hyperchromatic pyknotic nuclei and scanty cytoplasm. There
  • there is the absence of nuclear atypia, mitotic figures or necrosis ⁶.

    Associations

  • McCune-Albright syndrome: cafè-au-lait skin pigmentations and endocrine dysfunction, such as precocious puberty, diabetes mellitus, goiter and breast fibroadenomatosis ⁷.
  • Malignant transformation of fibrous dysplasia to osteosarcoma, fibrosarcoma, chondrosarcoma and malignant fibrohistocytoma have been reported ².
    • Myxoid liposarcoma, myxoid malignant fibrous histiocytoma, low-grade fibromyxoid sarcoma, extraskeletal myxoid chondrosarcoma and botryoid type rhabdomyosarcoma are some of the malignant lesions to consider in the differential diagnosis of myxoma ⁸.

  Radiographic features

  Plain radiograph

  Polyostotic (or monostotic) fibrous dysplasia display radiolucency with ground glass matrix appearance surrounded by condensed bone. This is usually smooth and homogenous with endosteal scalloping and cortical thinning usually present. Borders are well defined and the cortex is usually intact but thinned due to the expansive nature of the lesion.

  CT

  SuperiorCT is a superior modality to plain radiographs. Osseous expansion with ground glass appearance usually attenuates at from 60-140 HU. Intramuscular myxomas appear as well demarcated hypodense ovoid lesions close to areas of fibrous dysplasia and usually show mild diffuse enhancement or peripheral and septal enhancement seen in approximately 50% of cases ⁹.

  MRI

  Fibrous dysplasia shows sharply demarcated borders of intermediate to low T1 signal intensity on T1-W1 and intermediate to high T2 signal intensity on T2-WI. The higher the number of bony trabeculae, the lower the T2 signal and vice versa – the- the fewer bony trabeculae, the higher the T2 signal ².

  Active lesions show post contrast-contrast enhancement which may be patchy central, rim, homogenous or a combination.². Diffusion-weighted imageimaging may help in differentiating benign from malignant lesions and ADC values particularly in the skull lesions correlate with cell density and may narrow differential diagnosis ².

  Intramuscular myxomas demonstrate hypointense T1 and hyperintense T2 signal. Four different contrast patterns have been described ⁹:

  • peripheral enhancement
  • peripheral and patchy internal enhancement
  • peripheral and linear internal enhancement
  • heterogeneous internal enhancement

Nuclear Medicinemedicine

Technetium 99m-methyldiphosphonate can be used to detect disease extent in the young ².Rapid increase in 18-FDG uptake may suggest the possibility of sarcomatous change ².Fibrous dysplasia lesions are found positive on In-111 pentriotide (octreoscan), Ga-67 citrate and Tc-99m MIBI scintigraphy as well as 68-Ga-DOTATATE and 11-c choline PET/CT.

Intramuscular myxomas may show 18-FDG avidity on PET/CT however nuclear medicine plays no role in the identification of intramuscular myxomas in Mazabraud syndrome ^2,11.

Treatment and prognosis

Treatment is variable and dependent on the extent of the disease. Fibrous dysplasia causing persistent pain, skeletal deformities, and danger of fracture or pathological fracture require surgical intervention. Medical therapy with anti-resorptive medication may be helpful in relieving pain and possibly reconstituting lesions with normal bone ^3,8,11.   A A recent case study described the use of bisphosphonate therapy providing a clear reduction in the diameter of intramuscular myxoma after the use of zolendronic acid for 4 years ³.

As the myxomas are benign, conservative treatment is recommended ⁸.Myxomas should be excised if they cause pain, pressure symptoms, and neurological symptoms or interfere with functionality.

The most common complication of myxomatous surgical excision is recurrence which occurs in ~ 30% of cases at a median of 8.5 years (range: 1.9 – 16-16 years) ¹.Highly cellular lesions have higher recurrence rates however size, increased number and younger age at diagnosis are not significantly associated with recurrence ¹.

Postoperative follow up-up should be undertaken to detect local recurrences of myxomas not clinically detectable in addition to the potential malignant transformation of fibrous dysplasia. Six reported cases of malignant transformation of fibrous dysplasia into osteogenic sarcoma have been reported in patients with Mazabraud’s syndrome justifying clinical and radiological follow-up ².​

An awareness of Mazabraud’s syndrome as an association with fibrous dysplasia and intramuscular myxomas is important radiologically to help secure appropriate management of the patient.

History and etymology

The first case was described in the literature in 1926 ⁴ but it was Mazabraud in 1967 who first recognised the association between the intramuscular myxomas and fibrous dysplasia ⁵.​