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Maria Soto-Maior Costa1, Rita Carneiro2, Julia Galhardo

1 - Hospital de Dona Estefania - CHULC, Lisbon, Portugal
2 - Hospital da Luz, Lisbon, Portugal

- Reunião internacional: European Society of Paediatric Endocrinology 2022, publicação sob forma de resumo

Background: Cleidocranial dysplasia (CCD) is a very rare dominantly inherited autosomal bone disorder mainly characterized by hypoplasia or aplasia of clavicles, failure of cranial suture closure, dental anomalies, short stature, and other changes in skeletal patterning and growth. Heterozygous loss-of-function mutations cause the majority of the abnormalities in the run-related transcription factor 2 gene (RUNX2). This gene is located on chromosome 6p21 and its function is linked to osteoblast differentiation and chondrocyte maturation. We report a 3 generations family with a novel RUNX2 mutation.
Case Report: A 12-year-old boy, a descendent of a consanguineous indigenous Brazilian family, was sent to our hospital by his dentist, after short stature, high palate, impacted supernumerary teeth, and persistent temporary milk teeth. On examination, his height was 135cm (-2.27 SDS, according to WHO standards), and a sitting height/ height of 0.53. He had facial dysmorphism with parietal bossing. His Tanner staging was prepubertal. A full skeleton X-ray revealed a broadening of the frontal and lambdoid sutures, hypoplastic clavicles, wide pubic symphysis with ossification delay, rhizomelic shortening of upper and lower limbs, and hand bone abnormalities. There were no vertebrae malformations. Bone age and bone mineral density looked normal. Blood laboratory tests showed normal thyroid function, renal function, ionized calcium, phosphate, magnesium, 25-hydroxyvitamin D, parathyroid hormone, and alkaline phosphatase. IGF-1 was 64ng/mL (NR:49-487 ng/mL) and IGF-BP3 was 5.8 μg/mL (NR: 2.7-8.9 μg/mL).The molecular analysis detected a novel heterozygous mutation NM_001024630.3p.T155P (c.477A>C) in the RUNX2 gene. As his father and his paternal grandfather also presented short stature [160cm (-2.27 SDS), and 155cm (-2.95 SDS), respectively] and several skeletal abnormalities, genetic testing was performed, and the same mutation was found. A clonidine stimulation test preceded by testosterone priming was performed on the boy and the peak growth hormone (GH) response was 9.0 μg/L (NR: > 7 μg/L). Because of his short stature, GH therapy was started at 30 μg/Kg/day, with a good response in one-year time [147cm, (- 2.07 SDS)], and no adverse side effects.
Discussion: CCD is diagnosed clinically (short stature with severe dental and clavicles anomalies) and supported by X-ray. Molecular genetic analysis reveals a RUNX2 mutation in about 70% of the cases. Data on GH treatment for CDC are minimal. In our patient, it has been hopeful, but we are aware of the need for randomized controlled trials involving more patients.

Palavras Chave: Cleidocranial dypslasia; Growth hormone