ESPE Abstracts

Background: Isolated Growth Hormone Deficiency (IGHD) is usually associated with a delayed bone age. A genetic cause for IGHD is more frequently found in patients with familial cases and/or consanguineous parents.

Objective and hypotheses: To diagnose the genetic cause of IGHD and clarify the unusual clinical presentation of advanced bone age in one patient born to consanguineous parents.

Method: Sanger sequencing of GH1, GHRH, GHRH receptor and CYP21A2 followed by whole-exome sequencing.

Results: A Caucasian boy presented at 7.5 years with severe short stature (102.5 cm, SD-3.7), high-pitched voice, blue sclera and prominent forehead. Genital examination revealed Tanner stage I, normal penile length (4 cm) and normal topic testis (length 1.5 cm). He was born at term by vaginal delivery with a length of 50 cm and weight of 3.400 g. Parents were second-degree cousins. Bone age was 6 years. Clonidine and combined pituitary stimulation tests, resulted in a peak of GH=0.6 ng/ml indicating GH deficiency and a peak cortisol of 16.1 mcg/dl initially interpreted as partial ACTH deficiency. Pituitary MRI was normal. The patient was successfully treated with rGH (33 mcg/kg/day) with a first year growth velocity of 11.7 cm. Surprisingly at 10.8 years of age he presented with advanced bone age (13 years) without signs of puberty and with prepubertal serum LH and testosterone levels. An ACTH test showed respectively, basal and peak, cortisol 6.1 and 18.8 mcg/dl, 17 hydroxyprogesterone 9.4 and 52.0 ng/ml and androstenedione 1.2 and 2.0 ng/ml indicating nonclassical 21-hydroxylase deficiency. CYP21A2 sequencing revealed homozygous p.Val281Leu mutation and cortisone acetate was added to his treatment. Sanger sequencing of GH1, GHRH and GHRH receptor were performed and no mutations were found. In order to establish the genetic cause of IGHD, whole-exome sequencing was performed revealing a homozygous c.431C>T, p.Leu144His mutation in GHRH receptor. This mutation had been previously described in unrelated Caucasian patients with IGHD from Sergipe/Brazil, Spain and United States.

Conclusion: Whole-exome sequencing was able to establish the genetic cause of IGHD not previously identified by Sanger sequencing. Clinicians should be aware that patients born to consanguineous parents might have more than one genetic disease.

Funding information: This work was supported by the National Council for Scientific and Technological Development (CNPq) (Grants: 305743/2011-2 to B.B.M. and 304678/2012–0 to A.A.L.J.) and the Sao Paulo Research Foundation (FAPESP) (grant 2013/03236–5 to A.A.L.J.).