ESPE Abstracts (2018) 89 P-P2-213

Different Genetic Causes of Short Stature in a Family

Alev Tuluna, Roland Pfäffleb, Denise Rockstrohb, Rami Abou Jamrac, Julia Schmidtd, Gabriele Gillessen-Kaesbachd, Julia Hoppmanna & Olaf Hiorta

aDivision of Pediatrics Endocrinology, Department of Pediatrics, University of Lübeck, Lübeck, Germany; bDivision of Pediatrics Endocrinology, Department of Pediatrics, University of Leipzig, Leipzig, Germany; cInstitute of Human Genetics, University of Leipzig, Leipzig, Germany; dInstitute of Human Genetics, University of Lübeck, Lübeck, Germany

Background: The most common endocrine cause of growth disorders in childhood is growth hormone deficiency (GHD). The rare monogenic forms of GHD are inherited as autosomal dominant or recessive traits and manifest as isolated deficiency or in combination with other hormone deficiencies. Here, we report on a three-year-old girl with a severe growth retardation (height 77 cm, – 5.6 S.D.S.). She is the only child of non-consanguineous parents from northern Iraq, who also showed short stature (mother’s height: 126 cm, father’s height: 132 cm).

Objective: We aimed to investigate the etiology of short stature in the family by using laboratory and genetic tests (Sanger and whole-exome sequencing).

Results: X-ray analysis of the left hand showed a retarded bone age (1.6 years). Basal serum Insulin Growth Factor-1 (IGF-1: < 25 μg/L) and IGF Binding Protein-3 (IGFBP-3: < 0.5 μg/L) levels were abnormally low. Thyroid function tests and calcium, phosphate and urine analyses were within the normal range; however, 2-Plane cranial MRI showed an empty Sella. Next, we performed growth hormone (GH) provocation tests with arginine (maximum of GH-peak after 45 min: 1.28 μg/L) and clonidine (maximum of GH-peak after 60 min: 0.77 μg/L). Both stimulation tests revealed a complete GH deficiency in combination with very low GH serum levels (<3 μg/L). Because of the family history we performed genetic investigations. Sanger sequencing of GH1 revealed a heterozygous mutation (c.291+1G>A) leading to aberrant splicing in our patient and her father that has already been described in other patients with autosomal dominant GHD (Ariyasu et al. 2013, Cogan et al. 1995). The mother does not carry this mutation; however, subsequent trio whole-exome sequencing identified a de novo heterozygous mutation in COL1A2 (c.2565+1G>A) in the mother. This mutation is described to cause Osteogenesis imperfecta Type IV. The mutation in GH1 was not detected by exome sequencing due to low coverage.

Conclusion: Our patient and her father have an isolated GHD Type II with a heterozygous mutation in GH1 gene identified by Sanger Sequencing. Surprisingly this mutation could not be found by performing whole-exome sequencing which revealed the cause of short stature of the mother (OI Type IV). This case shows that a combination of a careful medical history, physical examination and new technologies like exome sequencing can help to make the right diagnosis.

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