ARTICLE
Auteur(s) : Felicidade Santiago,
Ricardo Vieira, Margarida Cordeiro, Óscar Tellechea, Américo
Figueiredo
Dermatology Department, Hospitais da Universidade de Coimbra,
Praceta Mota Pinto, 3000-075 Coimbra, Portugal
accepté le 15 Decembre 2008
Progressive osseous heteroplasia (POH) is a distinct disorder of
mesenchymal differentiation, described by Kaplan in 1994 in
children initially thought to have atypical progressive
fibrodysplasia ossificans [1]. It may either be sporadic or
inherited as an autosomal dominant trait [1]. POH is characterized
by dermal ossification during childhood with progressive
heterotopic ossification of cutaneous, subcutaneous and deep
connective tissues [1, 2]. Fewer than 60 cases have been identified
worldwide [3].
Recently, Shore et al. reported that paternally inherited,
inactivating mutations in the GNAS gene are implicated in the
pathogenesis of POH [4]. GNAS encodes for the alpha subunit of the
stimulatory G protein of adenylyl cyclase and is thought to be a
critical negative regulator of osteogenesis in non-osseous
connective tissues, especially in skin, fat, and skeletal muscle
[4, 5].
Case report
A 50-year-old male patient was observed with subcutaneous nodules
and plaques which had been noticed since infancy, below the age of
1. These lesions had progressively expanded in number and size. On
examination they were firm, relatively well-demarcated,
skin-coloured or slightly blue, with a gritty texture. Only the
left side of the body was affected, predominantly the scapular
region, arm, forearm, digits I-III, thigh, leg, dorsal aspect of
the foot and heel (figure 1). The patient
complained of functional impairment in the tibio-tarsic joint. No
acute flares of the disease were reported, nor exacerbation with
trauma or intramuscular injections.
He was otherwise healthy, mentally normal and attended normal
school. There was no family history of skeletal disorders, nor were
the parents consanguineous. He had no facial dysmorphism, nor
musculoskeletal deformities. The patient was of normal weight and
height. Serum and urine levels of calcium and phosphate were
normal, as were those of parathyroid and thyroid hormones and
vitamin D metabolites. Lactate dehydrogenase and alkaline
phosphatase levels were also within the normal ranges.
A skin biopsy revealed islands of well-differentiated bone in
the reticular dermis, typical of osteoma cutis (figure 2). Skeletal
radiological imaging of the affected areas showed extensive
ossification involving the subcutaneous and deep tissues and
pronounced at the ankle with continuity within the muscular plane
(figure 3).
Genomic DNA was extracted from peripheral blood samples and
subsequent analysis showed no mutations in the gene encoding for
the alpha subunit of the stimulatory G protein of adenylyl cyclase
(GNAS).
The final diagnosis was unilateral POH, based on clinical
features, clinical evolution, normal phospho-calcium metabolism,
skin biopsy findings and radiological imaging.
Discussion
This case report corresponds to a rare ossifying disorder with few
other cases previously reported, particularly if we take into
account that it exists in a sporadic and unilateral form in a male
patient [6-10]. Furthermore, the absence of mutation in the protein
coding region of the GNAS gene is a relevant event. However, this
mutation seems to be present in only 64% of POH patients, as found
in a recent study [5]. It is interesting to note that individuals
without detectable mutations were clinically indistinguishable from
those with mutations. The occurrence of mutations in a regulatory
region of the GNAS gene, or in another gene, is probable in those
cases but has never been reported until now.
Not only most cases of POH, but also plate-like osteoma cutis
and Albright’s hereditary osteodystrophy (AHO), can result from
heterozygous inactivating germ-line mutations of GNAS localized to
20q13, causing abnormal expression or function of the alpha subunit
of the stimulatory G protein of adenylyl cyclase [4]. GNAS-alpha is
imprinted in a tissue-specific manner: maternal inheritance of a
mutation in GNAS leads to an AHO phenotype with hormonal
resistance, whereas paternal inheritance leads to AHO phenotype
without hormonal resistance or POH [4, 11, 12]. However, the
mechanism by which a mutation in the paternally derived GNAS gene
results in heterotopic ossification originating in the fat cells,
which would seem to require the conversion of fat cells to
osteoblasts, remains unknown [12]. GNAS somatic (postzygotic)
activating mutations play a role in another skeletal disease: the
McCune-Albright syndrome [12].
The asymmetric mosaic distribution of lesions is an important
feature of POH and some unilateral cases have already been reported
[1, 7, 8]. The anatomical distribution of lesions suggests that the
pathogenesis may involve a variable expression of the mutant gene
in mesenchymal stem cells destined for widespread mosaic
distribution [1, 2]. In addition to the highly variable phenotypic
expression present in POH, non-penetrance cases have also been
observed in some families. These could be due to epigenetic
modifications, complex regulatory mechanisms, influences from other
genetic loci, or environmental factors [4]. Many questions about
the genotypic complexity and phenotypic variability in POH are
waiting for answers, however studies are being conducted to
complete the puzzle.
Finally, to our knowledge, this is the first case of unilateral
POH reported in Portugal, even though a case of heterotopic
cutaneous ossification in a 12-month-old child was described in
2006 [13].
Acknowledgments
We thank E.M. Shore, Ph.D. and Frederick S. Kaplan, M.D. from the
University of Pennsylvania for performing the mutational analysis
of GNAS. Financial support: none. Conflict of interest: none.
References
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