Endocrine Abstracts

JOINT1004

Introduction: Growth disorders are one of the main challenges in pediatric endocrinology, significantly affecting the quality of life of children and adolescents. The use of next-generation sequencing technologies, such as whole-exome, has revolutionized the investigation of genetic disorders.

Objective: This study aimed to identify new genetic-molecular alterations in patients with growth disorders and characterize the phenotype of rare genetic causes of monogenic growth disorders in the Amazon region.

Methods: Twenty-two patients (15 males; 7 females) clinically diagnosed with idiopathic short stature with or without syndromic features, treated in Santarem, Brazil were selected for exome sequencing.

Results: The average age of the participants at their first presentation to the clinic was 6.7 ±3.7 years. Bone age minus chronological age showed a mean delay of -1.0 ±1.7 years in relation to chronological age. The participants Z-score for height was -3.0 ±1.0. Three patients were born small for gestational age. Of the seven syndromic children, one was found with heterozygous deletion of Xp22.33 confirmed by MLPA and another child had homozygous deletion involving the CLCNKB gene which confirmed Bartter syndrome type 3. Two other children harbored heterozygous likely pathogenic and VUS variants in LZTR. LZTR germline mutations have been known to cause dominant and recessive forms of Noonan syndrome. Another child harbored heterozygous pathogenic variant in CDK13, and this is clinically associated with congenital heart defects, dysmorphic facial features, and intellectual developmental disorder. One syndromic child had a negative result in exome sequencing. There were fifteen non-syndromic cases. Ten of the non-syndromic children had negative results in exome sequencing however two of these children had secondary findings: Lynch syndrome and malignant hyperthermia. One child harbored heterozygous deletion of Xp22.33 which confirmed SHOX deficiency disorder. The other four children harbored candidate genes including IBR4, IHH, RARA and MAU genes.

Conclusions: This research enabled patients from the Brazilian Amazon to benefit from the use of exome sequencing in the investigation of idiopathic short stature, allowing the identification of new genes that may be involved in growth disorders and the detection of monogenetic diseases, such as SHOX deficiency disorder, Bartter syndrome type 3 and secondary findings having significant implications in the clinical segment, therapeutic decision and genetic counseling. This made it possible to rationally and viable apply genomic medicine in clinical and research practice.