ESPE Abstracts (2018) 89 P-P2-268

aDepartment of Woman, Child And of General and Specialist Surgery Università Degli Studi Della Campania ‘Luigi Vanvitelli’, Naples, Italy; bDepartment of Biochemistry, Biophysics and General Pathology Università Degli Studi Della Campania ‘Luigi Vanvitelli’, Naples, Italy; cTelethon Institute of Genetics and Medicine (TIGEM), Pozzuoli(NA), Italy

Introduction: Heterozygous mutations in IHH are known to cause Brachydactyly type A1 (BDA1), in which the typical clinical features are bilaterally short-ening or absence of the middle phalanges of most digits of hands and feet, shortness of 1st proximal bone and short stature; althougt short stature is considered part of BDA1, in most reported cases is not always present or unrelevant compared to the stature of unaffected relatives. Recently heterozygous mutations in IHH were found in children and adults with short stature without specific skeletal signs of BDA1, adding IHH defects among genetic causes of short stature. Our case is in line with this findings but with several phenotypic differences.

Case description: A girl of 11 years and 7 months was referred to our clinic for short stature. She was born from unrelated parents at 40 weeks, birth parameters were weight 2.7 kg (−1.85DS), length 48 cm (−1.32DS), head circumference 35 cm (0.53DS). The mother’s height was 150.2 cm (−2.1 DS), the father’s height was 166.1 cm (−1.6 DS) with target height 151.6 cm (−1.8 DS). After one year of life she had poor growth, psycomothor development was normal, menarche occurred at 11 years. At our visit she showed height 129.1 cm (−2.9 SDS), sitting height 65.6 cm, sitting height/ height ratio 0.51 (−0.65 DS), armspan 127.5 cm, armspan/height ratio 0.98, head circumference 49 cm (−2.7 SDS), weight 30.8 kg (−1.64DS), BMI 18.5 (−0.34DS), pubertal stage PH4 B3, cubitus valgus and scoliosis. The karyotype, thyroid function and IGF1 were normal, SHOX gene defects were excluded, hand radiograph showed adult bone age without classical features of BDA1, but with overtubulation of distal phalanges. Considering the poor height prognosis given the very advanced bone age, we performed a next generation sequencing (NGS) analysis by a panel including 254 genes causing short stature. The NGS analysis revealed a new mutation in IHH gene, exon3:c.G1045A:p.A349T, that was confirmed by Sanger sequencing and found also in the mother. The prediction software SIFT, Polyphen and Mutation Tester confirmed the pathogenicity of the identified variant, located in the C-terminal domain of IHH protein.

Conclusions: Our case confirms the role of IHH gene in short stature and adds new phenotypic features: very severe short stature, SGA, very mild radiographic features and great phenotypic variability in the same family.

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