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Endocrine Abstracts (2023) 97 027 | DOI: 10.1530/endoabs.97.027

BES2023 BES 2023 Section (29 abstracts)

Two family members with partial hypopituitarism and gingival fibromatosis caused by a missense mutation in KCNQ1

Sabbe A 1 , De Block C 1,2 , Eyskens F 2,3 , De Rademaecker M 4 & De Herdt C 1

1Department of Endocrinology-Diabetology-Metabolism, Antwerp University Hospital, B-2650 Edegem, Belgium; 2University of Antwerp, Faculty of Medicine and Health Sciences, B-2610 Wilrijk, Belgium; 3Department of pediatrics and metabolic disease, Antwerp University Hospital, B-2650 Edegem, Belgium; 4Department of genetics, Antwerp University Hospital, B-2650 Edegem, Belgium

Background: Childhood growth hormone deficiency (GHD) is a clinically heterogeneous condition and may have a genetic basis. Association with abnormalities of eyes, ears, palate and other parts of the forebrain or familial occurrence of GHD suggest a genetic cause (1). The occurrence of childhood GHD in association with gingival fibromatosis led to the identification of two autosomal dominant KCNQ1 missense variants (Arg116Leu and Pro369Leu). KCNQ1 gene encodes the alpha subunit of the voltage gated-channels, well known in the context of cardiac arrhythmia syndromes (long QT syndrome) (2). We present the case of a Belgian family, of which two family members were diagnosed with a heterozygous Pro369Leu mutation in KCN1Q1.

Case report: We report the clinical picture of a mother (45 years, subject 1) and a son (11 years, subject 2), both affected by the above-mentioned Pro369Leu mutation. The mother had been diagnosed with a GHD since childhood based on growth retardation. Evaluation of the other pituitary axis showed a thyrotrophic and gonadotropic deficiency. Dynamic testing of the HPA axis with revealed no adrenal insufficiency. Prolactin levels were fluctuating mildly elevated. MRI of the pituitary was normal (2021). She is being treated with growth hormone, thyroid hormone and female hormone (estradiol gel and Progebel). Cardiologic evaluation revealed no prolonged QT interval. A dilatation of the ascending aorta up to 40 mm was seen, for which further investigations are planned. She has no intellectual impairment and no obvious gingival hyperplasia. The current clinical picture is dominated by complaints of exercise intolerance and muscle pain, further deteriorated after a complicated covid-19 infection. The patient had two successful, assisted pregnancies through IVF, which resulted in the birth of two sons (°2011 and °2014). The firstborn child presented himself at the age of 7 years at the pediatric department due to short stature. Hormonal examination revealed a deficiency of the somatotropic and thyrotrophic axis for which substitution was started. Since he is in prepuberty, the gonadal axis cannot yet be assessed. He has a history of gingival hyperplasia for which surgical intervention was needed, adenotonsillectomy and a hydrocele. On physical examination facial dimorphism with coarse features and bilateral epicanthus was reported. He is diagnosed with severe learning disabilities (ADD, dyslexia, dyscalculia). Cardiac evaluation is scheduled. The son and his mother were referred to the geneticist. Genetic testing showed a heterozygous missense mutation c.1106C>T p.(Pro369Leu) in the KCNQ1 gene and a heterozygous variant c.1159G>A p.(Ala387Thr), presumably not pathogenic, in the ARID1B gene.

Table 1 Clinical picture in individuals with the pathogenic Pro369Leu KCNQ1 mutation
GROWTH RETARDATION AS CHILDYes, before 2 yoYes, before 2 yoFrom 2 yoNDnoFrom 11-12 yoyesYes; from 9 yo
MRI PITUITARYNormalNDnormalSmall hypophysisNDnormalnormalND
GH DEFICIENCYyesyesyesyesyesNDyesyes
MUTATION INHERITEDNAYes/maternallyNDYes/maternallyYes/maternallynonono
-COARSE FACEyesyesYesyes
-PALPEBRAL FISSURESyesdownwardupward
-BROAD NOSEyesyesyesyesyes
-THICK EARLOBULESyesyesYesyesyes
QT LENGTH (MS)443ND317399358349normal
YO: years old; ND: not defined; MS: milliseconds

Conclusion: KCN1Q variants are well described in the context of cardiac arrhythmias (2). Recently, two autosomal KCNQ1 missense variants (Arg116Leu and Pro369Leu) have been shown to cause childhood GHD and gingival fibromatosis (3-5). To our knowledge, these are the seventh and eighth published case reports with a heterozygous Pro369Leu mutation to date. An overview of the clinical picture in individuals previously published with this pathogenic KCNQ1 variant are shown in Table 1. KCNQ1 are expressed in hypothalamic and pituitary cells and pathogenic variants may lead to reduced pituitary hormone secretion. The endocrine phenotypic spectrum is heterozygous ranging from a mild GHD to multiple pituitary hormone deficiencies. KCNQ1 are also expressed in gingival fibroblasts where it may have a proliferative effect (3). Gingival hypertrophy seems to be maternally inherited. This case report illustrates the diversity within and between affected families. With this abstract we wish to increase the awareness of this rare etiology of childhood GHD to learn more about the clinical spectrum and pathomechanism of KCNQ1 mutations.

References: 1. Gregory L, et al. Identification of genetic variants and phenotypic characterization of a large cohort of patients with congenital hypopituitarism and related disorders. Genet Med. 2023,25: 100881.2. Adler A, et al. An International, Multicentered, Evidence-Based Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome. Circulation. 2020; 141:418-428.3. Tommiska J, Känsäkoski J, Skibsbye L, Vaaralahti K, Liu X, Lodge EJ, et al. Two missense mutations in KCNQ1 cause pituitary hormone deficiency and maternally inherited gingival fibromatosis. Nat Commun. 2017;8:1289.4. Dekelbab B, Chopra K,. SUN-286 Growth Hormone Deficiency and Gingival Fibromatics Due to Missense Mutation of KCNQ1. J Endocr Soc. 2019;3.5. Bauer CK, Holling T, Horn D, Laço MN, Abdalla E, Omar OM, et al. Clinically Relevant KCNQ1 Variants Causing KCNQ1-KCNE2 Gain-of-Function Affect the Ca2+Sensitivity of the Channel. International Journal of Molecular Sciences. 2022;23:9690.

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