Response to growth hormone in patients with RNPC3 mutations

EMBO Mol Med (2018) e9143The etiology of GHD remains unknown in most cases (Alatzoglou et al , 2009). RNPC3 mutations emerged as a novel cause of familial isolated GHD and pituitary hypoplasia (Argente et al , 2014). RNPC3 encodes a 65‐kDa protein that is a structural component of the U11/U12 small nuclear ribonucleoprotein of the minor spliceosome (Verma et al , 2018). Mutations in RNPC3 lead to structural destabilization of the 65‐kDa protein, impaired binding of U12 snRNA, and global defects in splicing of U12‐type introns (Argente et al , 2014; Norppa et al , 2018).We describe the effects of rhGH therapy on growth, body composition, bone mineral density (BMD), and bone microarchitecture in the first three patients identified with this condition.Written informed consent was obtained from all subjects and their parents for all studies and their publication. Studies conformed to the principles set out in the WMA Declaration of Helsinki and the Department of Health and Human Services Belmont Report.Three sisters were born to non‐consanguineous average‐height [target: 155.6 (−0.99 SDS)] Romanian parents. The father is a heterozygous carrier of a nonsense mutation (c.1504Cu003eT, p.R502X), and the mother and only unaffected daughter are heterozygous for a missense mutation in RNPC3 (c.1320Cu003eA, p.P474T). The three affected girls, compound heterozygous for both mutations, were born at term with normal length and weight, developing severe postnatal growth failure, typical phenotypic features of GHD, and delayed bone age (BA; Table 1 and Fig 1). They were referred to our clinic at 15.5, 8.1, and 6.0 years of age with extremely short stature (Table 1), undetectable serum IGF‐1, IGFBP‐3 and GH after stimuli (insulin and clonidine), and no clinical or hormonal signs of associated pituitary hormone deficiencies. Anterior pituitary hypoplasia was found in MRI.View this table:Table 1. Anthropometric data at baseline and after rhGH therapy onsetFigure 1. Growth charts of the three sisters after GH therapyFacial appearance at baseline and growth charts of patients 1 (A), …