ESPE Abstracts (2019) 92 P1-100

RNPC3 Mutations Associate Prolactin Deficiency and Ovarian Insufficiency, Expanding the Phenotype Beyond Isolated Growth Hormone Deficiency Type V (MIM#618860)

Gabriel Á. Martos-Moreno1,2,3,4, Lourdes Travieso-Suárez1,2, Jesús Pozo1,2,3,4, Julie Chowen1,2,3,5, Luis A. Pérez-Jurado6,7,8,9, Jesús Argente1,2,3,4,5


1Departments of Pediatrics & Pediatric Endocrinology. Hospital Infantil Universitario Niño Jesús, Madrid, Spain. 2La Princesa Research Institute, Madrid, Spain. 3Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain. 4Department of Pediatrics, Universidad Autónoma de Madrid, Madrid, Spain. 5IMDEA Food Institute, Madrid, Spain. 6Genetics Unit, Universitat Pompeu Fabra, Barcelona, Spain. 7Hospital del Mar Research Institute (IMIM), Barcelona, Spain. 8Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain. 9South Australian Health and Medical Research Institute (SAHMRI), Adelaide, Australia


Background: The first three children reported to have biallelic mutations in RNPC3 presented with growth hormone (GH) deficiency and pituitary hypoplasia (MIM#618860). RNPC3 codes for a minor spliceosome protein required for U11/U12 small nuclear ribonucleoprotein formation and splicing of U12-type introns. The underlying mechanism causing GH deficiency in these patients is not fully understood. Moreover, whether the association of further hormonal deficiencies occurs throughout lifespan is unknown.

Objective: To analyze the evolving hormonal phenotype throughout childhood and adolescence in the first three patients identified with RNPC3 mutations.

Results: Clinical follow-up and rhGH replacement of the three sisters started at age 15.5 (patient-1), 8.1 (patient-2) and 6.0 (patient-3) years (y), respectively. Patient-1 showed slightly decreased serum prolactin levels at diagnosis (0.78 ng/ml [NV: 1.6-25]), with normal levels in patient-2 (2.12 ng/ml) and 3 (1.83 ng/ml). In contrast, when these patients reached ages of 23, 15.7 and 13.7 y, respectively, in all three serum prolactin was undetectable in three separate baseline determinations and after TRH stimulation. Patient-1 was Tanner stage I at diagnosis, with baseline FSH: 30.3 (NV:2-22) and LH: 6.7 mU/ml (NV: 0.6-56) peaking after LHRH stimulation at 40.1 and 35.5 mU/ml, respectively, and concomitant low serum estradiol levels [7.4 pg/ml (10-400)]. Three months after rhGH treatment was started, Tanner stage II spontaneously developed, progressing to Tanner stage IV after 12 months and presenting a spontaneous 4-day menarche after 16 months on therapy. No further menstrual cycles occurred, with low serum estradiol levels persisting and normal to high FSH and LH levels both at baseline and after LHRH stimulation, thus requiring hormone replacement. Patient-2 spontaneously started puberty (Tanner stage II) at 11.6 y, progressing to Tanner stage IV at age 13 y, but remaining without menarche up to her last evaluation (age 15.7 y), with baseline estradiol 9.8 pg/ml, FSH 44.2 and LH 12 mU/ml, peaking after LHRH stimulation to 63.1 and 49.5 mU/ml, respectively. Patient-3 started spontaneous pubertal development at age 13.0 y, progressing to Tanner stage II in the following 6 months (last visit). Normal size ovaries but with sparse or absent follicles were found in patients 1 and 2 by ultrasonography.

The tyrotrophic and corticotrophic axes have shown no impairment during the follow-up to date.

Conclusion: Patients with RNPC3 mutations, initially presenting as isolated GH deficiency, can develop additional pituitary (prolactin) or peripheral (estradiol) hormone deficiencies throughout lifespan.

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