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A Novel TBX19 Gene Mutation in a Case of Congenital Isolated Adrenocorticotropic Hormone Deficiency Presenting with Recurrent Respiratory Tract Infections

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A Novel TBX19 Gene Mutation in a Case of Congenital Isolated Adrenocorticotropic Hormone Deficiency Presenting with Recurrent Respiratory Tract Infections CASE REPORT published: 18 April 2017 doi: 10.3389/fendo.2017.00064 A Novel TBX19 Gene Mutation in a Case of Congenital Isolated Adrenocorticotropic Hormone Deficiency Presenting with Recurrent Respiratory Tract Infections Nese Akcan1, Nedime Serakıncı2, Burcu Turkgenc3, Ruveyde Bundak4, Nerin Bahceciler5 and Sehime G. Temel6,7* 1 Faculty of Medicine, Department of Pediatric Endocrinology, University of Near East, Nicosia, Cyprus, 2 Faculty of Medicine, Department of Medical Genetics, University of Near East, Nicosia, Cyprus, 3 Genetic Diagnostic Center, University of Acıbadem, Istanbul, Turkey, 4 Faculty of Medicine, Department of Pediatric Endocrinology, University of Kyrenia, Kyrenia, Cyprus, 5 Faculty of Medicine, Department of Pediatric Allergy and Immunology, University of Near East, Nicosia, Cyprus, 6 Faculty of Medicine, Department of Histology and Embryology, University of Near East, Nicosia, Cyprus, 7 Faculty of Medicine, Department of Histology and Embryology, University of Uludag, Bursa, Turkey Introduction: Congenital isolated adrenocorticotropic hormone deficiency (CIAD) is a rare disease characterized by low adrenocorticotropic hormone (ACTH) and cortisol levels. To date, recurrent pulmonary infections in infancy have not been reported as an Edited by: Mohamad Maghnie, accompanying symptom of CIAD. University of Genoa, Italy Case presentation: A 7-year-old boy was hospitalized nine times for recurrent lower Reviewed by: Laurie E. Cohen, respiratory tract infections. The results of all tests for the possible causes of wheezing Boston Children’s Hospital, USA were within the normal limits. His ACTH and cortisol levels were persistently low. All Marco Cappa, Bambino Gesù Ospedale other pituitary hormone levels, and adrenal ultrasound and pituitary magnetic resonance Pediatrico (IRCCS), Italy imaging results, were normal. Molecular analyses confirmed the diagnosis of CIAD by *Correspondence: identifying compound heterozygosity for two mutations in the TBX19 gene. The first was Sehime G. Temel a novel frameshift c.665delG variant in exon 4 of the TBX19 gene, leading to prema- [email protected] ture termination that was predicted to result in a non-functional truncated protein. The Specialty section: second was a nonsense C-to-T transition in exon 6 of the TBX19 gene, resulting in an This article was submitted to arg286-to-ter mutation (dbSNP: rs74315376). Both parents were heterozygous for one Pediatric Endocrinology, a section of the journal of the mutations. Frontiers in Endocrinology Conclusion: Here, we presented a new mutation in the TBX19 gene in a patient with Received: 25 January 2017 Accepted: 23 March 2017 CIAD who presented with recurrent respiratory tract infections. This expands the muta- Published: 18 April 2017 tion spectrum in this disorder. To conclude, adrenal insufficiency should be considered in Citation: patients with unexplained recurrent infections to prevent a delay in diagnosis. Akcan N, Serakıncı N, Turkgenc B, Bundak R, Bahceciler N and Keywords: adrenal insufficiency, adrenocorticotropic hormone, cortisol, respiratory infections, TBX19 gene Temel SG (2017) A Novel TBX19 Gene Mutation in a Case of Congenital Isolated INTRODUCTION Adrenocorticotropic Hormone Deficiency Presenting with Recurrent Congenital isolated adrenocorticotropic hormone deficiency (CIAD) is a rare disease characterized Respiratory Tract Infections. by low plasma adrenocorticotropic hormone (ACTH) and cortisol levels while the other pituitary Front. Endocrinol. 8:64. hormone levels remain normal. CIAD occurs as a result of homozygous or compound heterozygous doi: 10.3389/fendo.2017.00064 mutations in the T-box 19 (TBX19) gene, which is located on chromosome 1q24 (1, 2). Frontiers in Endocrinology | www.frontiersin.org 1 April 2017 | Volume 8 | Article 64 Akcan et al. TBX19 Mutation with Recurrent Infections Twenty-one different mutations were identified in the TBX19 TABLE 1 | Clinical findings and laboratory results. gene in the largest series (n = 91) of CIAD patients. Most CIAD On admission Final cases present with severe hypoglycemia, seizures, or prolonged examination jaundice in the neonatal period (1). TBX19 shares 94% amino Age 34 months 7.2 years acid identity with the mouse Tpit gene (2). Here, we report a Weight (kg)/weight-SDS 17.2/1.3 28.3/1.1 CIAD case with a novel mutation presented with recurrent pul- Height (cm)/height-SDS 97.5/0.5 123.7/0.3 monary infections. To our knowledge, this is the first reported BMI (kg/m2)/BMI-SDS 18/1.30 18.5/1.4 case of CIAD presenting with recurrent pulmonary infection in Tanner stage (pubic hair development) 1 1 infancy. Testes volumes Testes 2/2 mL Testes 2/2 mL Laboratory tests (reference ranges) FBG (60–100 mg/dL) 65 90 CASE PRESENTATION Na (135–145 mmol/L) 142 140 K (3.5–5 mmol/L) 4.6 4.9 A 34-month-old boy was referred to our hospital with a pre- ACTH (6–48 pg/mL) <5 – diagnosis of acquired ACTH deficiency. The patient was a term Cortisol (3–21 μg/dL) 0.9 – TSH (0.6–5.5 μIU/mL) 1.2 2.6 baby, delivered by cesarean section. He was intubated as a result fT4 (0.85–1.75 ng/dL) 1.2 1 of respiratory distress and supported by mechanical ventila- PRL (3–18 ng/mL) 16.1 16.3 tion for 21 days in the neonatal intensive care unit. He was DHEAS (13–83 μg/dL) 21 hospitalized nine times because of recurrent lower respiratory A4 (10–17 ng/dL) 13 – 17α-OHP (<91 ng/dL) 11 – tract infections until the age of 10 months. In each period of Peak cortisol response to low-dose (1 µg) 0.1 – hospitalization, he needed systemic steroid, and he also had ACTH stimulation test (≥18 μg/dL) continuously inhaled steroid during this period. Acquired Karyotype 46, XY ACTH deficiency secondary to glucocorticoid therapy or his Bone age (years) 2 7 medical conditions was decreed when the cortisol and ACTH Adrenal USG Normal Cranial and pituitary MRI Normal levels were low at the age of 10 months. Hydrocortisone treat- ment (9 mg/m2/day) was started to prevent life-threatening ACTH, adrenocorticotropic hormone; A4, androstenedione; BMI, body mass index; complications. On admission to our hospital at the age of 34 DHEAS, dehydroepiandrosterone sulfate; FBG, fasting blood glucose; fT4, free thyroxine; K, potassium; Na, sodium; MRI, magnetic resonance imaging; PRL, months, he was on maintenance physiologic dose of hydrocor- prolactin; SDS, standard deviation score; TSH, thyroid-stimulating hormone; USG, tisone, his weight was 17.2 kg (+1.3 SDS), and his height was ultrasonography; 17α-OHP, 17α-hydroxyprogesterone (abnormal findings are shown 97.5 cm (+0.5 SDS). He was normotensive and had natural in bold). skin and hair color, with normal male genitalia. Radiographic and biochemical analyses were normal. The cortisol response to a low-dose (1 µg) ACTH test was impaired (Table 1). an easily treatable disease, in this case the family decided to The hydrocortisone treatment was continued with the same terminate the pregnancy. physiological replacement dose. Other causes of recurrent lung infection were ruled out by the Pediatric Allergy and MOLECULAR ANALYSES Immunology Division. During follow-up, ACTH and cortisol levels were persistently low (ACTH < 5 pg/mL, cortisol < 1 ng/ Written informed consent was obtained from the patient’s legal mL), and he had never demonstrated hypoglycemia or elec- guardians. Molecular analysis was performed when he was trolyte imbalance. Growth hormone tests were not performed 6 years old during the mother’s pregnancy with her second baby. because of the normal stature. Levels of the other pituitary Further molecular genetic testing of the parents was performed to hormones (thyroid hormones, prolactin), 17-hydroxyproges- assess whether both variants were on the same (cis) or a different terone, androstenedione, and adrenal ultrasound and pituitary (trans) TBX19 allele and the abortion material was also analyzed magnetic resonance imaging results were all normal (Table 1). molecularly. The pedigree was shown in Figure 1A. Based on the hormonal profile, CIAD was suspected. On final In the molecular analysis of the index case, a novel assessment at 7 years 2 months, the patient weighed 28.3 kg heterozygous c.665delG (p.Arg222Lys*4) variation in exon (+1.1 SDS), and his height was 123.7 cm (+0.3 SDS). He has 4 (Figures 1B,C) and pathologic heterozygous c.856C>T experienced no further lung infections since the hydrocortisone (p.Arg286Ter) variation in exon 6 (Figure 1D) of the TBX19 treatment was started. gene (NM_005149.2, NP_005140.1) were detected in the In addition, the triple screening test of the mother during compound heterozygous state. The initial genetic test suggested her second pregnancy showed low estriol (E3) and human a possible splice site variation (c.665 + 1delG) in intron 4 of chorionic gonadotropin (hCG) levels, which may be related to the TBX19 gene instead of a c.665delG variant, because of the glucocorticoid deficiency. Genetic counseling was given to the consecutive GG repeat at the exon–intron boundary. Therefore, pregnant woman. It was explained that early disease diagnosis further molecular analyses were performed at the mRNA level allows for immediate commencement of glucocorticoid therapy, to gather information about the location of the variation (the last and proper instructions for stress management were provided. nucleotide of exon 4 or the first nucleotide of intron 4) and to Although this can prevent unnecessary neonatal deaths from identify a possible splicing effect. The mRNA analyses revealed Frontiers in Endocrinology | www.frontiersin.org 2 April 2017 | Volume 8 | Article 64 Akcan et al. TBX19 Mutation with Recurrent Infections FIGURE 1 | The pedigree and mutations of “TBX19 gene” detected in family members. (A) The pedigree of family carrying TBX19 mutations. (B) The image of heterozygous c.665delG (p.Arg222Lysfs*4) deletion in exon 4, which was inherited from the mother. The study was performed from the genomic DNA material. (C) The image of the same frameshift p.Arg222Lysfs*4 deletion studied from the RNA material of the index case and his carrier mother.
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