ESPE Abstracts

SHOX gene haploinsufficiency is a well-documented cause of short stature and skeletal abnormalities; SHOX duplications appear very rare and of uncertain clinical significance. If relatively extended, they can result in SHOX overexpression with normal or tall stature. Partial SHOX duplications seems to have a more deleterious effect on skeletal dysplasia and short stature than complete SHOX duplications. MLPA (Multiplex Ligation-dependent Probe Amplification) analysis of SHOX/PAR1 contributes to the identification of partial and complete SHOX duplications associated with Léri-Weill dyschondrosteosis (LWD) or idiopathic short stature (ISS), suggesting that they may represent a further class of mutations involved in the aetiology of LWD or ISS. We describe the case of a 4-month-old infant with the prenatal diagnosis of mixed gonadal dysgenesis associated with mosaic karyotype 46,X,i(Y)(p10)[94]/45,X[13], confirmed, after birth, in peripheral blood lymphocytes karyotype. FISH showed an isochromosome of the short arm of Y i(Yp) containing SRY gene; MLPA showed 25% duplication extending from the telomere of the short arm to the boundary of the PAR1 region, including SHOX. The probe of VAMP7 gene, in Xq28 (PAR2 region), very close to the q-telomere X and Y, is 50% deleted. He was born at 40.5 weeks, SGA (small for gestational age); weight: 2480g (-2.83DS), length: 47 cm (-2.44DS), head circumference: 33 cm (-1.82DS). At the admission: length 61 cm (-2.22DS), weight: 5.860g (-2.12DS), head circumference: 40.5 cm (-0.66DS); normal male external genitalia, PH1G1, with testicles of 2 ml in situ. Haematological tests, carried out to exclude organic aetiology of short stature, showed normal results; TSH, fT4, ACTH, cortisol, IGF-1were in the normal range. Given the high risk of gonadoblastoma in subjects with chromosomal aberrations involving the Y chromosome, we tested, during the follow-up, alpha-fetoprotein, beta-chorionic gonadotropin checks and testicular ultrasound. Blood chemistry investigations and testicular ultrasound during the follow-up, were normal. Over a four-year follow-up, the growth velocity, initially adequate, showed a slowdown at the last visit (0.31 cm/year: -6.97 SD on the Rikken scale). The coexistence in our patient of haploinsufficiency of SHOX (cell line 45,X) and duplication, raised a therapeutic dilemma, in which clinical data made the difference and guided therapeutic decisions. We adopted a "wait-and-see" attitude since growth was adequate for age; when a deflection of growth occurreded, we started growth hormone (GH) treatment, with satisfactory results. Furthermore, our child was eligible to GH treatment for 2 reasons: he was born SGA and showed SHOX gene involvement.