SUN-286 Growth Hormone Deficiency and Gingival Fibromatosis Due to Missense Mutation of KCNQ1

Abstract

Background: Multiple genes have been implicated in the genetic etiology of growth hormone deficiency (GHD) including genes that contribute to hypothalamus and pituitary development. Mutations of these genes can be associated with additional pituitary hormone deficiencies and developmental abnormalities. KCNQ1 gene encodes the alpha subunit of the voltage-gated ion channel Kv7.1, which has been previously implicated in cardiac arrhythmia syndromes. In 2017, two missense mutations, c.347G>T p.(Arg116Leu) or c.1106C>T p.(Pro369Leu), in KCNQ1 were reported for the first time in three unrelated families causing GHD and maternally inherited gingival fibromatosis (GF) (1). Members of these families displayed variable phenotypes including GHD, multiple pituitary hormone deficiencies, small pituitary on MRI, GF, craniofacial dysmorphic features, and short QT syndrome. Many had hypogonadotropic hypogonadism. Clinical Case: 9 year old male was referred to pediatric endocrinology for short stature and slow growth. He maintained height around 6%ile (Z=-1.55) until the age of 9 years with subsequent slowing to 0.95%ile (Z=-2.34). He had history of significant gingival hyperplasia requiring 5 surgical interventions in the past. He has done well developmentally. No history of cardiac arrhythmia. Physical exam showed coarse facial features and normal pre-pubertal genitalia. Family history was negative for short stature, arrhythmia, gingival hyperplasia, or coarse facial features. Studies showed delayed bone age of 6 years, low IGF-1 of 57 ng/ml, max growth hormone level of only 3 ng/ml on Arginine-Glucagon tolerance test, and normal other pituitary hormones. EKG and MRI of brain and pituitary were normal. Given his coarse facial features and gingival problem, he had a detailed work up for lysosomal storage disorders with negative results. Whole exome sequencing showed a missense variant in the maternal KCNQ1 gene denoted as c.1106C>T p.(Pro369Leu). Neither of his parents were found to have this KCNQ1 variant. He was started on growth hormone therapy with appropriate catchup growth. He was noticed 9 months later to have pubertal changes with testicular volume of 4-5 ml, LH 1.1 mIU/ml, and testosterone level of 98 ng/dl. Conclusion: To our knowledge, this is the first case of GHD and GF due to KCNQ1 mutation to be reported in the United States. Our patient had many unique features in contrast to previous report including lack of identified parental mutation, lack of clinical features in the family and early puberty indicating that there is still more to learn about clinical spectrum of KCNQ1 mutations in children. Reference: (1) Two missense mutations in KCNQ1 cause pituitary hormone deficiency and maternally inherited gingival fibromatosis. J.Tommiska et al, Nat Commun. 2017 Nov 3;8(1):1289.