Several syndromes associated with skeletal dysplasias may manifest with abnormalities of the feet. Often these are hereditary, and identification of a proband patient may have significant implications for the whole family. A careful clinical inspection and examination as well as evaluation of radiographic abnormalities may lead to the identification of a broader syndrome that may require a multidisciplinary management approach.

Genetic disorders of the skeleton are a clinically and genetically heterogeneous group of disorders of bone and/or cartilage characterized by abnormalities in growth, development, and/or homeostasis of the human skeleton.¹ They include the osteochondrodysplasias (primarily affecting bone and/or cartilage), the dysostoses (affecting a single bone or group of bones), the brachydactylies (primarily involving the hands and feet), and the lysosomal storage diseases. Although relatively rare individually, the skeletal dysplasias have an estimated birth prevalence of nearly 1/5,000.² It is now apparent that there are over 450 distinct genetic disorders of the skeleton that must be distinguished for specific genetic counseling, prognosis, and treatment. Of these conditions, 316 are associated with one or more of 226 different genes.

Fibrous dysplasia of bone (FD) (OMIM #174800) is an uncommon skeletal disorder with a broad spectrum of clinical presentation. On one end of the spectrum, patients may present in later life with an incidentally discovered, asymptomatic radiographic finding that is of no clinical consequence. On the other end of the spectrum, patients may present early in life with a disabling disease. The disease may involve one bone (monostotic FD), multiple bones (polyostotic FD), or the entire skeleton (panostotic FD).¹⁵,¹⁶,¹⁷ FD may be associated with extraskeletal manifestations, the most common of which is areas of cutaneous hyperpigmentation commonly referred to as café au lait macules. These lesions vary widely in size but have characteristic features that include jagged, “coast of Maine” borders, some relationship with the midline, and sometimes follow the developmental lines of Blaschko. FD can also be associated with hyperfunctioning endocrinopathies, including precocious puberty, hyperthyroidism, growth hormone (GH) excess, and Cushing syndrome. FD in combination with one or more of the extraskeletal manifestations is known as McCune-Albright syndrome (MAS).¹⁸,¹⁹,²⁰,²¹ A renal tubulopathy, which includes renal phosphate wasting, is one of the most common extraskeletal dysfunctions associated with polyostotic disease.²² More rarely, FD may be associated with myxomas of skeletal muscle (Mazabraud syndrome)²³ or dysfunction of the heart, liver, pancreas, or other organs within the context of the MAS.²⁴

FD is caused by missense mutations of the GNAS complex locus on chromosome 20q13.3.²⁵,²⁶,²⁷ GNAS encodes the alpha subunit of the stimulatory G protein (G_sα) involved in the cyclic adenosine monophosphate (cAMP)-dependent signaling pathway. The mutation impairs the intrinsic GTPase activity of G_sα, leading to persistent stimulation of adenylyl cyclase and aberrant production of cAMP (gain-of-function mutations).²⁸ Mutations of GNAS associated with FD and related disorders are never inherited and could theoretically occur at any time during postzygotic development. However, there is involvement of a pluripotent cell as the initial target of the disease, thus explaining how the mutation can be transmitted to derivatives of all three germ layers and be broadly distributed in patients with severe forms of the disease. At the same time, differences in the size and viability of the clone arising from the original mutated pluripotent cell could account for the variability of the clinical phenotype observed in the majority of FD patients.²⁹

The pathology of FD is characterized by the development of fibro-osseous lesions that replace normal skeletal structures and impair normal skeletal functions.

The sites of skeletal involvement (the “map” of affected tissues) are established early in patients with FD. Ninety percent of the craniofacial lesions are established before the age of 5, and 75% of all sites of FD are evident by the age of 15; the implication is that essentially all clinically significant disease is present very early in life, probably by the age of 5.17 Pathologic effects of G_sα mutations in osteogenic cells are most pronounced and evident during the phase of rapid bone growth, and account for the fact that childhood and adolescence are the periods during which the disease most commonly presents, is the most symptomatic, and is the period of peak rate of fractures.³⁰,³¹ The most common presenting features are a limp, pain, or a fracture. Any bone can be affected including the feet, although most commonly the ribs, long bones, and craniofacial bones are affected, whereas lesions in the spine and pelvis are typically less painful.³² Pathologic fractures of weight-bearing limb bones are a major cause of morbidity. Deformity of limb bones, which is a common finding, is caused by expansion and abnormal compliance of lesional FD, fracture treatment failure, and occasionally local complications such as cyst formation.²⁹ Malignancy in FD is rare (less than 1%).³³ Rapid lesion expansion and disruption of the cortex on radiographs should alert the clinician to the possibility of sarcomatous change. Osteogenic sarcoma is the most common, but is not the only type of bone tumor that may complicate FD.

Diagnosis of FD must be established based on expert assessment of clinical, radiographic, and histopathologic features. Markers of bone turnover are usually elevated.²² The extent of the skeletal disease is best determined with total body bone scintigraphy, which can be used to assess the skeletal disease burden and predict functional outcome.³⁴ Patients should be referred to an endocrinologist for screening and treatment of the metabolic derangements associated with FD, especially hypophosphatemia and GH excess.

Mutation analysis may be helpful in distinguishing FD from unrelated fibro-osseous lesions of the skeleton, which may mimic FD both clinically and radiographically (osteofibrous dysplasia, ossifying fibromas).²⁹ Multiple nonossifying fibromas, skeletal angiomatosis, and Ollier disease may sometimes enter the differential diagnosis. Distinction from these entities relies on histology and mutation analysis.

The hypoparathyroidism-retardation-dysmorphism syndrome (HRD, MIM #241410), also known as the Sanjad-Sakati syndrome, is a rare form of autosomal recessive hypoparathyroidism due to mutations in the TBCE gene encoding a protein required for the folding of tubulin. In addition to parathyroid dysgenesis, affected patients have severe growth and mental retardation, microcephaly, microphthalmia, small hands and feet, and abnormal teeth. This disorder is found almost exclusively in individuals of Arab descent.

PHP or PPHP may be suspected in patients who present with somatic features of AHO. However, several aspects of AHO, such as obesity, round face, brachydactyly, and mental retardation, also occur in other congenital disorders (e.g., Prader-Willi syndrome, acrodysostosis, Ullrich-Turner syndrome).