Long-Term Follow-Up of Three Family Members with a Novel NNT Pathogenic Variant Causing Primary Adrenal Insufficiency

Abstract

Nicotinamide nucleotide transhydrogenase (NNT) deficiency causes primary adrenal insufficiency (PAI) and possibly some extra-adrenal manifestations. A limited number of these patients were previously described. We present the clinical and genetic characteristics of three family members with a biallelic novel pathogenic variant in the NNT gene. The patients were followed until the ages of 21.6, 20.2, and 4.2 years. PAI was diagnosed in the eldest two brothers after an Addisonian crisis and the third was diagnosed at the age of 4.5 months in the asymptomatic stage due to the genetic screening of family members. Whole exome sequencing with a targeted interpretation of variants in genes related to PAI was performed in all the patients. The urinary steroid metabolome was determined by gas chromatography-mass spectrometry in the asymptomatic patient. The three patients, who were homozygous for c.1575dup in the NNT gene, developed isolated glucocorticoid deficiency. The urinary steroid metabolome showed normal excretion of cortisol metabolites. The adolescent patients had slow pubertal progression with low-normal testicular volume, while testicular endocrine function was normal. Bone mineral density was in the range for osteopenia in both grown-up siblings. Echocardiography revealed no structural or functional heart abnormalities. This article is among the first with a comprehensive and chronologically-detailed description of patients with NNT deficiency.

Keywords: NNT deficiency; bone density; hearth sonography; nicotinamide nucleotide transhydrogenase; nucleotide duplication; primary adrenal insufficiency; pubertal development; testicular volume.

Figure 1

General characteristics of family members. Full symbols indicate patients with confirmed PAI, half-filled symbols confirmed carriers of pathogenic NNT variant, and “?” family members without PAI, but no information on carrier status. Family member indexes, age at last follow-up, relevant comorbidities, genetic status, the age at diagnosis of PAI, and laboratory results indicative of PAI are written. Patients 1 and 2 presented with an acute adrenal crisis and as probands drove the early identification of PAI in patient 3. Children of members III–VI and IX–XIII were not affected and are therefore excluded from the genogram. Member XVI died at the age of 1 year from an unidentified cause. Abbreviations: ACTH—corticotropin; He/HoNNT—heterozygous/homozygous for NM_182977:c.1575dupA in NNT; NG—genetic testing for NNT variant not performed; NNT—gene for nicotinamide nucleotide transhydrogenase; P—plasma; PAI—primary adrenal insufficiency; S—serum.

Figure 2

Skin coloration at last visit in patient 1 (A) and patient 2 (B). Patient 2 was significantly more hyperpigmented—particularly around elbows—than patient 1 who had the same skin tone as their parents and patient 3.

Figure 3

Body height and body mass index (BMI). Pubertal growth spurt was earlier in patient 1, and also growth stopped earlier in this patient, resulting in a lower final height. Black lines represent the 5th, 10th, 25th, 50th, 75th, 90th, and 95th percentiles. Dots represent individual measurements: red for patient 1, green for patient 2, and blue for patient 3. Dashed lines represent final heights of the father (♂) and mother (♀). In the corner, there is a magnified part of the graph up to age 4.

Figure 4

Hydrocortisone dosing and ACTH monitoring. ACTH (orange) was measured from morning plasma sample and hydrocortisone dose (blue) was adjusted to BSA in patient 1 (A), 2 (B), and 3 (C). Abbreviations: ACTH—corticotropin; BSA—body surface area; P—plasma.