Picture of the Month—Diagnosis

The radiograph of the lower extremity lesion (Figure 2) showed microcalcifications limited to the subcutaneous region. The biopsy specimen (Figure 3) revealed mature lamellar bone limited to the epidermis and dermis, diagnosed as osteoma cutis. In light of these findings, as well as physical features of round facies and poor growth, a diagnosis of pseudohypoparathyroidism type 1a (PHP1a) was considered. Results of laboratory examination to explore potential associated endocrine abnormalities revealed an elevated thyrotropin (TSH) level of 8.82 mIU/L (reference range, 0.27-4.2 mIU/L), a normal free thyroxine level of 1.520 ng/dL (reference range, 1.01-1.79 ng/dL) (to convert to picomoles per liter, multiply by 12.871), and normal calcium, phosphorous, and parathyroid hormone levels. The child started thyroid hormone therapy.

Osteoma cutis, or ectopic extraskeletal ossification, is a rare disorder that typically presents in childhood with erythematous, hard subcutaneous nodules. Unlike many of the benign, nonspecific exanthems of childhood, osteoma cutis is a finding that heralds disorders with significant morbidity. These disorders can be divided into PHP1a or progressive osseous heteroplasia (POH), both associated with mutations of the alpha subunit of the adenylate cyclase stimulatory G protein (GNAS1)or fibrodysplasia ossificans progressiva, the latter associated with malformation of the great toes and mutations in the ACVR1gene.^1-5In our patient, the absence of ectopic calcification of deep tissues (muscle and deep connective tissue) and the finding of short stature and elevated TSH level were strongly suggestive of the diagnosis of PHP1a, although recent reports suggest that POH-like ossification (associated with progressive, restricting ossification of deep tissues similar to fibrodysplasia ossificans progressiva) may occur in patients with clinical PHP, making a definitive diagnosis more difficult.^6-11

Pseudohypoparathyroidism was first described by Fuller Albright, MD, in 1942. Classic findings include short stature, round facies, brachydactyly, soft tissue ossifications, and neurobehavioral and developmental problems, a phenotype known as Albright hereditary osteodystrophy. The disorder is inherited in an autosomal dominant manner with variable penetrance and tissue-specific resistance secondary to paternally determined imprinting of the GNASgene. Classically, maternal inheritance/imprinting results in PHP and paternal inheritance/imprinting results in pseudopseudohypoparathyroidism (clinical features without endocrine abnormalities) or pure POH. The mechanism of how GNASmutations lead to altered mesenchymal differentiation and resultant ectopic ossification is not understood.

With this in mind, the parents consented to have GNAS1mutation analysis performed on their son, with results revealing a Tyr37X alteration in exon 1, a termination mutation resulting in truncation of the GNAS protein. This result, with the physical examination findings and laboratory findings consistent with thyroid hormone resistance (elevated TSH level with normal free thyroxine level), confirmed the suspected diagnosis of PHP1a. Parents were provided genetic counseling for a 50% risk of future offspring carrying the same disorder and maternal mutation analysis was sent. The patient is being followed up for growth, neurodevelopment, and risk of associated endocrine abnormalities.

Osteoma cutis is a rare disorder that has mainly been reported in the orthopedic and dermatologic literature. However, it is important that pediatricians recognize this condition with the understanding that the initially mild cutaneous manifestations may herald a more progressive ossification disorder and/or be associated with multiple endocrine hormone resistance and neurobehavioral and developmental problems.

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Correspondence:Andrew Bauer, MD, Department of Pediatrics, Walter Reed Army Medical Center, 6900 Georgia Ave, Washington, DC 20307 (abauer@usuhs.mil).

Accepted for Publication:April 30, 2008.

Author Contributions:Study concept and design: Darling and Bauer. Acquisition of data: Darling and Bauer. Analysis and interpretation of data: Darling and Bauer. Drafting of the manuscript: Darling and Bauer. Critical revision of the manuscript for important intellectual content: Darling and Bauer. Administrative, technical, and material support: Darling and Bauer. Study supervision: Bauer.

Financial Disclosure:None reported.

Disclaimer:The opinions or assertions contained in this article are the private views of the authors and are not to be construed as reflecting the views of the US Army, Air Force, or the Department of Defense.