ESPE Abstracts

P1 was referred with short stature aged 2.4 yrs (HtSDS -2.1). Mother’s height 165 cm (+0.5 SD), father’s 185 cm (+1.55 SD). Growth hormone (GH) deficiency was diagnosed following two GH stimulation tests (Peak GH 6.8 ng/ml at 3.2 yrs, 5.17 ng/ml at 3.7 yrs) IGF1 4.6 nmol/l (1.7-27.6) at 2.5 yrs. Pituitary MRI was normal. GH treatment was started at 5 years at HtSD –2.2. Once P1 demonstrated catchup growth (up one centile in 7 months), P1’s older sister P2 was referred for investigation of short stature (HtSDS –1.5). She was not dysmorphic but her mother noted antenatal scans had short foetal femur lengths on the 5th centile. Birth weight was on the 10th centile at 2.65 kg at 38 weeks gestation. Short stature was present from age 3 with height tracking along the 2nd centile. Her GH was 7.17 ng/ml at time 0 on a growth hormone stimulation test, IGF1 25.9 nmol/l (3.1 - 51.9). This was performed during the COVID pandemic and could not be repeated. It was felt that GH deficiency was unlikely so a skeletal survey was requested. This showed mild Madelung deformity and short 4th/5th metacarpals. Subsequent SHOX analysis revealed that she was heterozygous for 2 SHOX dosage abnormalities in cis. The first was a deletion located between 133 kb and 163 kb downstream of the SHOX gene. The second was a duplication that included the final exons of the SHOX gene (exons4-6a). Family testing revealed the same SHOX variants in P1’s father, who was the smallest in class in early childhood and had grown late into adulthood, reaching a tall final height at aged 21. Mother and P1 did not have these SHOX variants. P1 has demonstrated excellent catch-up growth on GH treatment, HtSDS +0.4. IGF1 36.5 nmol/l (2.7-45.5) at 7.3 years. P2 has been on GH treatment for over a year, latest HtSDS - 1.

Conclusion: Both siblings were short for the family target. Following a diagnosis of GH deficiency in one sibling, the investigative pathway for the other was assumed. Routine karyotype was performed after GH stimulation test with SHOX analysis requested after the skeletal survey report. The siblings' father has the same SHOX variants as P2 and is tall. Biological effects of SHOX deletion appears to be variable in this family and is present in P2 radiologically. The duplication is of uncertain significance.