When flesh becomes bone: A rare case of progressive osseous heteroplasia

Dear Editor,

We report a case of a 3-year-old girl, born to non-consanguineous parents. She presented with a gradually enlarging, painful, firm swelling on the lateral side of her right leg since 1 month of age. Initially, the lesions appeared around the right ankle and gradually progressed over the course of a year to involve the lateral side of the right leg, extending up to mid-thigh. These lesions began as small pea-sized, painful solid, raised skin-coloured nodules that eventually expanded to attain the present size associated with difficulty in walking. There was no significant family history of similar conditions, nor a history of trauma or prior inflammatory episodes. The child was born preterm at 36 weeks’ gestation, weighing 800 g at birth, and suffered from severe intrauterine growth restriction, requiring a 2-week stay in the NICU. The child was immunised as per age and had achieved developmental milestones appropriate for her age.

On physical examination, multiple small, tender, hyperpigmented subcutaneous nodules were present on the lateral aspect of the right thigh and knee, with the smallest measuring about 1 × 1 cm and the largest 3 × 3 cm. These nodules were interspersed with surrounding atrophic areas, and the skin over the lesions was pinchable [Figure 1]. Additionally, a large skin-coloured nodule measuring 5 × 6 cm was noted on the anterior aspect of the ankle with surface atrophy and restricted movement of the right ankle joint. The child had short stature (<3 standard deviation) and showed no signs of cognitive impairment or skeletal deformities. Differentials considered were fibrodysplasia ossificans progressive, morphoea profunda with dystrophic calcification, osteoma cutis, Albright hereditary osteodystrophy, myositis ossificans, and calcinosis universalis in dermatomyositis [Table 1]. Radiographs of the lower limbs in anteroposterior and lateral views revealed calcified regions within the subcutaneous tissue, corresponding to the areas of skin atrophy [Figure 2]. Serum levels of calcium, phosphorus, parathyroid hormone, creatine phosphokinase, alkaline phosphatase, and lactate dehydrogenase were all normal, and the antinuclear antibody profile was negative. Histopathological examination revealed heterotopic ossification of the skin [Figures 3a and b].

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Figure 1:

Multiple well-defined subcutaneous nodules smallest measuring 1×1 cm and the largest measuring 3×3 cm, present over the lateral aspect of the thigh and knee, interspersed with areas of atrophy.

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Figure 2:

X-ray image of the right leg in the AP (left) and lateral (right) position. The circle denotes the predominant calcification in the dermis and subcutaneous tissue.

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Figure 3a:

Scanner view displaying a normal epidermis, orange arrow corresponds to osteoblast cells forming ossification in mid dermis extending into lower dermis impinging on the subcutis layer, blue arrow corresponds to calcification (Haematoxylin & eosin, 40x)

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Figure 3b:

High-power view highlighting osteoblast cells forming intramembranous ossification within the dermis (Haematoxylin & eosin, 100x).

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Genetic testing identified a heterozygous 3’splice-site variant in exon 8 of the GNAS gene, which is associated with progressive osseous heteroplasia (POH). Genetic testing was recommended to the parents; however, due to financial constraints, it could not be pursued. Based on the clinical, radiological, histopathological, and genetic findings, the diagnosis of POH was confirmed. The parents were counselled regarding the prognosis of the condition and were informed that the active interventions would not be effective in managing the disease.

POH is an uncommon inherited disorder marked by the gradual formation of bone tissue in deep connective tissues and skeletal muscles.¹Since its first description in 1994, there have been only a few individual cases and case series published worldwide. This limited number of reports has hindered our understanding of this rare disease¹ [Supplementary Table 1].^8-21

Disorders of extra-skeletal bone formation are categorised into nonhereditary and hereditary types. Non-hereditary types manifest later in life and are associated with trauma, surgical procedure, or joint disease. Hereditary forms include conditions such as fibrodysplasia ossificans progressiva, Albright hereditary osteodystrophy, pseudohypoparathyroidism, plate-like osteoma cutis, and POH. POH typically presents as firm maculopapular lesions that gradually merge into plaques, spreading into deeper connective tissues like fascia, skeletal muscles, tendons, and ligaments. In some cases, small bone spicules may protrude through the epidermis. With disease progression, widespread ossification of deep connective tissues may result in joint ankylosis and impaired growth of the affected limbs. POH is marked by preserved kidney function and normal blood levels of calcium, phosphate, and parathyroid hormone, without any signs of PTH resistance.¹ The criteria used for the diagnosis of POH has been outlined in Supplementary Table 2.

Currently, there are no established therapeutic options available for POH. Surgical excision often leads to recurrence in cases with widespread lesions, and it can yield successful long-term outcomes when the lesions have clear borders. Physiotherapy aids in maintaining movement and preventing skin breakdown.²Targeting the Sonic hedgehog pathway and the yes associated protein (SHH-YAP) signalling pathway, involved in abnormal bone formation, may offer a new treatment option for POH. These inhibitors, under study for other diseases, show promise. Effective management also requires translational research, multidisciplinary care, and personalised treatment strategies for this complex and rare condition.³