ESPE2022 Poster Category 1 Adrenals and HPA Axis (52 abstracts)
Long-term follow-up of three male siblings with a novel NNT pathogenic variant causing primary adrenal insufficiency
Primoz Kotnik 1,2 , Tjasa Krasovec 2 , Jaka Sikonja 2 , Mojca Zerjav Tansek 1,2 , Marusa Debeljak 3 , Sasa Ilovar 4 , Katarina Trebusak Podkrajsek 3,2 , Sara Bertok 1 , Tine Tesovnik 3 , Jernej Kovac 3,2 , Jasna Suput Omladic 1,2 , Michaela F Hartmann 5 , Stefan A Wudy 5 , Magdalena Avbelj Stefanija 1,2 , Tadej Battelino 1,2 & Urh Groselj 1,2
1Department of Endocrinology, Diabetes, and Metabolic Diseases, University Children's Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia; 2Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia; 3Clinical Institute of Special Laboratory Diagnostics, University Children’s Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia; 4Department of Pediatric Cardiology, University Children's Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia; 5Steroid Research and Mass Spectrometry Unit, Laboratory for Translational Hormone Analytics, Division of Pediatric Endocrinology and Diabetology, Center of Child and Adolescent Medicine, Justus Liebig University, Giessen, Germany
Nicotinamide nucleotide transhydrogenase (NNT) is expressed in the heart, thyroid, and testicles, where it maintains the balance of reactive oxygen species in the mitochondria. It is linked, by an insufficiently described mechanism, to primary adrenal insufficiency (PAI) with or without mineralocorticoid insufficiency and several extra-adrenal manifestations (i.e. gonadal adrenal rest tumors, cardiomyopathy, hypothyroidism, and precocious puberty). A comprehensive and chronologically detailed clinical long-term follow-up of three siblings with a novel pathogenic variant in the NNT gene is presented. A novel homozygous frameshift pathogenic variant c.1575dup in the NNT gene was identified in 3 males (age 21.6, 20.2, and 4.2 years at final clinical evaluation) by whole-exome and confirmatory Sanger sequencing. Both parents were heterozygous for the variant and in good general health at the age of 45 and 43 years. PAI was diagnosed in the two eldest brothers after an Addisonian crisis at the age of 1.4 and 1.1 years, respectively. Cascade sibling screening led to the identification of PAI by an ACTH stimulation test in the third sibling at the age of 4.5 months in the asymptomatic stage. A normal urinary steroid profile, performed by gas chromatography-mass spectrometry, was determined in this patient. Following the PAI diagnosis, no further adrenal crises were determined. The average hydrocortisone dose for the whole follow-up in the two eldest patients was 16.6 mg/m2 body surface and 13.0 mg/m2 in the youngest. None had impaired mineralocorticoid secretion. Thyroid function and morphology were normal. Echocardiography revealed no structural or functional heart abnormalities. Adolescent patients had a normal start of puberty (aged 11–12), while pubertal progression to Tanner 5 stage was prolonged to 19–20 years. The final testicular volume was 15 mL and testicular endocrine function (testosterone, inhibin B, basal and GnRH-stimulated LH and FSH) was normal in both. No adrenal rest tumors were identified by ultrasound. In the eldest two patients, bone mineral density in the range of osteopenia was identified. Presented data suggest that adrenal impairment in NNT deficiency is progressive, thus early hormonal testing might not rule out this condition. NNT gene is a good candidate gene for neonatal screening panels and could prevent life-threatening Addisonian crises in these patients. Early genetic testing is required in siblings of patients with the determined mutation. Presented results identify pubertal progression dysregulation and decreased bone mineral density as additional extra-adrenal manifestations in NNT disfunction.
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