TUMORAL CALCINOSIS DUE TO GALNT3 C.516-2A > T MUTATION IN A BLACK AFRICAN FAMILY

Summary: Tumoral Calcinosis due to GALNT3 C.516-2A >T mutation in a black African family: Familial Tumoral Calcinosis (FTC) is a rare autosomal recessive disorder of the phosphocalcic metabolism caused by mutations in the FGF23 or GALNT3 genes. We have identified a Beninese family in which two brothers present FTC caused by a homozygous A>T transversion at the acceptor splice site in intron 1 of GALNT3 gene. We report on the clinical, biochemical, histopathological and molecular spectrum of the disorder in this family. The particularly severe phenotype, the amelogenesis imperfecta, and the carbapatite deposit observed in these patients, seem to be characteristic of our observations. Key-words: Familial Tumoral Calcinosis - Phosphocalcic metabolism disorder - GALNT3 mutation INTRODUCTION Familial Tumoral Calcinosis (FTC) [OMIM 2119000] is a rare autosomal recessive disorder of the phosphocalcic metabolism (14). Patients present periarticular calcium deposits in skin and subcutaneous tissues which often result in local tumefactions on the level of the hips, shoulders and knees. Hyperphosphataemia, secondary to increased renal phosphate retention, is the major metabolic abnormality associated with FTC and is accompanied by normal or elevated 1,25 (OH)2 Vit D3, and normal serum levels of calcium and parathyroid hormone (PTH). Mutations in the FGF23 and UDP-N-acetyl-alpha-D-galactosaminyltransferase 3 (GALNT3) genes which code respectively for a Phosphaturie protein and a Golgi's glycosyltransferase responsible for the O-glycosylation of proteins, account for the majority of FTC cases (4, 16, 20). O-glycolylation by normal GALNT3 regulates intact FGF23 secretion which is required in renal clearance of phosphates (7, 8, 1 1). This condition, although well described by most authors in melanoderm people, has rarely been documented in sub-Saharan Africans. Here we report on a documented case of FTC due to a GALNT3 c.5162A >T mutation in a black African family. CASE REPORT Two brothers, 19 and 17 years old respectively, were referred because of swellings around the hip and shoulder joints. The painless masses appeared during the second year of life and progressively caused limitation of movements because of their increasing size. Sometimes, skin ulcerations occurred with drainage of a chalky milk-like fluid. This condition was recurrent after surgical excision. The clinical examination revealed that tumours were renitent, multiple, and localised near articulations. The articulations affected in the older patient were shoulders, hips and the left knee while those affected in his younger brother were the left shoulder, hips and the right elbow. They showed a generalised gingivitis, multiple tooth decay and many tooth hypoplasia. Moreover, a loss of vision and a light divergent strabismus was noted in the older patient. Blood sampling, X-ray examination, biochemical analyses and tumour biopsies were performed on the patients. From these index-cases, other members of the family were found and examined. Patients' photographs and X-rays are shown in figure 1; their biochemical data are summarised in Table I. In the radiological view, the affected joints showed a hypercondensation in soft tissue with no bony structures involvement (Fig. Ic). The matrix of this condensation was made up of small lodges like honeycombs which is traditional in the FTC. Moreover, in addition to the generalized gingivitis and the multiple teeth decay, an attack of enamel on the vestibular face of the occlusal edge of the higher central incisors in one of the patients and the side incisors in the other was noted (Fig. Id). These morphological aspects evoked a punctual amelogenesis imperfecta in a band limited to the vestibular face of the central higher incisors. Some teeth roots appeared short and bulbous with partial obliteration of the pulp. (Fig. Ie). Moreover, tooth resorption was visible, in particular on teeth number 12 and 22, thus giving a "baby teeth" aspect. …