Clinical insights of the TBX19 C.856 C>T variant: a case report and literature review on neonatal isolated ACTH deficiency

Introduction

TBX19, also known as T-pit, is a critical transcription factor in the T-box family, predominantly expressed in the pituitary gland. It plays an essential role in the development of corticotrope cells, which produce adrenocorticotropic hormone (ACTH) from proopiomelanocortin (POMC) [1], [2], [3]. Studies indicate that the ablation of TBX19 in experimental models leads to the dysfunction of pituitary corticotrophs [4].

Variants in TBX19 result in congenital isolated adrenocorticotropic hormone deficiency (IAD), a condition marked by diminished ACTH and cortisol levels, resulting in adrenal insufficiency [2]. Homozygous or compound heterozygous variants of TBX19 are implicated in IAD, with affected individuals exhibiting significant metabolic disturbances during the neonatal period, such as hypoglycemic seizures and cholestasis [5]. These patients frequently display decreased maternal estriol plasma levels during gestation, a critical diagnostic indicator. Conditions such as placental sulfatase deficiency and Smith–Lemli–Opitz syndrome must be ruled out [6]. IAD can exhibit a mortality rate of up to 25 % during infancy, making early diagnosis essential. Neonatal-onset IAD is associated with TBX19 variants, while juvenile forms of IAD are generally not linked to these variants. Consequently, TBX19 analysis is highly advised for neonates or young children exhibiting IAD [7], 8].

TBX19 variants have been identified in approximately 100 cases in the literature, with more than 45 distinct variants documented. The majority of these cases were diagnosed during the neonatal and infancy periods [5], [9], [10], [11]. These findings underscore the importance of early recognition and genetic analysis, particularly in infants presenting with adrenal insufficiency and its associated symptoms. Due to the rarity of cases, a clear genotype–phenotype correlation has not been established for congenital IAD. The reporting of cases harboring such rare variants is valuable. In this study, we present a case with the c.856 C>T (p.Arg286Ter) (p.R286*) variant in the TBX19, contributing to the literature on this rare genetic variant.

Case presentation

A male infant, born at 41 weeks’ gestation weighing 3,600 g, to a 30-year-old mother, G2P1Y1, experienced hypoglycemic convulsions within 10 h postnatally, prompting initiation of neonatal sepsis treatment. Despite interventions, severe hypoglycemia persisted, accompanied by mild hyponatremia and hyperkalemia during subsequent monitoring. The neonatal intensive care unit was consulted on the 8th postnatal day. His body weight was 4,300 g, height: 49 cm, head circumference: 38 cm, anterior fontanel: 3 × 3 cm, and the posterior fontanel was closed. Physical examination revealed notable facial features, including mild hypertelorism, epicanthus, prominent low ears, depressed nasal root, and a long philtrum (Figure 1). Other systemic examinations revealed normal findings, with the testes located in the scrotum and a penis size of 3.5 cm. In addition, it was noted in the family history that the patient’s parents were cousins. Laboratory investigations at the time revealed abnormal metabolic parameters consistent with hypoglycemia and hormonal assays indicative of isolated ACTH deficiency. Blood glucose: 22 mg/dL, BUN: 18 mg/dL, creatine: 0.3 mg/dL, Na: 135 mmol/L, K: 5.6 mmol/L, Ca: 9 mg/dL, P: 5.5 mg/dL, ALT: 37 U/L (0–50), AST: 25 U/L (0–50), total bilirubin: 0.22 mg/dL, direct bilirubin: 0.05 mg/dL, GGT: 171 U/L. In the tests performed during hypoglycemia, blood ketones were positive, growth hormone was 5.9 ng/mL, ACTH was <0.1 pg/mL (5–50), and cortisol was 0.4 μg/dL [2], [3], [4], [5], [6], [7], [8], [9], [10]. The peak cortisol response in the low-dose ACTH stimulation test was 0.57 μg/dL. Other anterior pituitary hormones were normal (Table 1). Hydrocortisone treatment at a dose of 20 mg/m2/day was started. Genetic analysis revealed a homozygous stop-gain variant (NM 005149.3 c.856 C>T (p.Arg286Ter) (p.R286*)) in TBX19. Imaging studies revealed a small pituitary gland (2.2 mm, n: 3.54 ± 0.5) with subtle abnormalities in pituitary morphology and the white matter regions of the brain. At the latest follow-up at 3.2 years of age, the patient demonstrated normal growth (18.2 kg, height: 96.5 cm (0.546 SDS), BMI%: 123) and neurodevelopment, with stable clinical and laboratory parameters on 9 mg/m2/day hydrocortisone treatment. Neuromotor development was age-appropriate, and no recurrent seizure or hypoglycemia was observed during follow-up. No recurrent seizures or hypoglycemic episodes were observed during the follow-up period.

Figure 1:

Fascial appearance of the case.

Discussion

The c.856C>T (p.R286) variant in TBX19 has been recognized as a pathogenic variant linked to congenital IAD. This variant produces a premature stop codon, resulting in the loss of functional TBX19, essential for the expression of POMC, the precursor to ACTH [1], 3]. The p.R286 variant results in diverse clinical manifestations [3], 12]. Recent case reports have demonstrated the phenotypic variability linked to the c.856C>T variant (Table 2). Neonatal patients frequently exhibit severe symptoms such as hypoglycemia, jaundice, and an elevated risk of adrenal crisis [11], 12].

Studies suggest that a delayed diagnosis may arise if clinicians fail to include IAD in differential diagnoses, especially in instances where symptoms coincide with other neonatal conditions, such as infections or metabolic disorders [5], 11]. A cohort study conducted by Charnay et al. [1] identified several instances of early-onset IAD associated with TBX19 variants, underscoring the importance of prompt diagnosis for effective management. Clinical presentations varied, with a few cases exhibiting more complex manifestations that persisted beyond the neonatal period. Vieira et al. [12] documented a case of delayed diagnosis in a 9-month-old patient exhibiting severe hypoglycemia during an acute illness, highlighting the difficulties this mutation presents in clinical practice. In Ünal et al. [13], a case of a 2-month-old patient diagnosed with recurrent hypoglycemic episodes showed developmental delay, whereas her sibling, diagnosed at 7 days and started on treatment, had normal neuromotor development. Similarly, Kardelen et al. [11] reported that a 2-year-old patient, diagnosed early, had normal progression, whereas a patient diagnosed at 4 months had learning difficulties by the age of 14.5 years. CNS-related findings in other cases have included Arnold Chiari type 1 malformation, hypoplastic anterior pituitary, and transient growth hormone deficiency [5], 8]. Delayed diagnosis and inadequate treatment may lead to permanent CNS damage, raising questions about whether MRI findings like epilepsy, arachnoid cysts, and small pituitary are due to TBX19 mutations or the consequences of early hypoglycemia. Despite frequent neonatal symptoms such as hypoglycemia and cholestasis in TBX19 variants, late diagnoses may still occur [12], 14]. The frequency of hypoglycemic episodes and other severe symptoms that necessitate immediate glucocorticoid intervention to prevent adrenal crisis is demonstrated by cases reported by Dang et al. [3]. The age of onset of symptoms in these cases varies, with our case presenting the earliest onset at birth (on the first day of life). Similarly, the cases reported by Ünal et al. [13], Case 2, and Akcan et al. [14] were presented within the first few days or months of life, emphasizing the importance of early recognition of hypoglycemia and related metabolic disturbances in neonates. In contrast, the case by Ünal et al. [13], in Case 1, diagnosed at 2 months, showed a delayed presentation with more prolonged cholestatic jaundice and respiratory distress. This situation highlights the variability in the onset and clinical course of TBX19-related IAD, even within the same genetic variant, c.856C>T (p.R286) (Table 2).

The growth and developmental outcomes demonstrate variability among the cases. At the most recent follow-up, 3.2 years after the initial diagnosis, our case exhibited normal neurodevelopment and growth, with no recurrence of seizures or hypoglycemia, and stable clinical and laboratory parameters while undergoing hydrocortisone treatment. This contrasts with the findings of Kardelen et al. [11] and Ünal et al. [13], which documented cognitive and neurodevelopmental delays in long-term follow-up. Our patient is currently under follow-up, with regular assessments of growth and development. During the most recent follow-up, the patient exhibited normal growth and neurodevelopment, indicating a favorable result from the continued hydrocortisone therapy. Nonetheless, as with all instances of TBX19-related IAD, prospective challenges concerning growth, development, and endocrine function persist as a concern.

The genetic underpinnings of this condition emphasize the importance of family history and genetic counseling, particularly in populations with a higher incidence of consanguinity, where variants like c.856C>T may be more common [11]. The recognition of TBX19-related IAD has substantial implications for clinical practice and genetic screening, underscoring a vital area for further research aimed at advancing early detection methods and improving patient outcomes.

Here, we seek to contribute to the expanding understanding of the genetic and clinical aspects of IAD. Our case additionally showed distinct facial dysmorphisms, including mild hypertelorism, epicanthus, prominent low ears, a depressed nasal root, and a long philtrum. As far as the literature indicates, this is in contrast to the absence of facial dysmorphisms in the other reported cases, where no significant craniofacial abnormalities were noted. The variability in facial features may be an important marker for differential diagnosis, although it is not universally present in all cases with the same variant.

Furthermore, this variant serves as an example of more discussions about genotype–phenotype correlations in IAD caused by TBX19. Numerous variants that cause IAD have been identified, with a focus on each one’s distinct presentation and possible founder effects in certain populations [1], 3]. The variety of variants may lead to differing severities of ACTH deficiency and various clinical manifestations, including recurrent respiratory infections or developmental delays. Therefore, individuals with the c.856C>T mutation require long-term follow-up to monitor growth, development, and overall endocrine function. As case reports and studies continue to explore the molecular mechanisms and genetic variations associated with TBX19, refining management strategies and improving outcomes for affected individuals becomes increasingly critical [3], 12], 14].

The limitations of this case include a relatively short follow-up duration of 3.2 years, which limits the assessment of long-term outcomes, and the lack of comparative imaging data from other reported cases. The variability in clinical presentations and the necessity for additional genetic research, including functional analysis to clarify the genotype–phenotype correlation, highlight the limitations.

In conclusion, the prompt assessment of adrenal function in neonates and infants exhibiting hypoglycemia, especially when accompanied by conditions like cholestasis, is essential for the early diagnosis and treatment of IAD. Variants of TBX19 are the predominant molecular etiology of neonatal-onset IAD, frequently exhibiting severe symptoms, such as hypoglycemic seizures, which may lead to life-threatening consequences if not treated expeditiously. Timely identification and initiation of hydrocortisone replacement therapy are significant for improving survival rates and preventing long-term complications. Moreover, comprehensive documentation of any dysmorphic characteristics may provide important diagnostic insights. Prolonged follow-up is essential for clarifying the genotype–phenotype correlation and enhancing management strategies, thereby fostering a deeper understanding of the condition and its clinical implications.

Learning points

1. Congenital IAD should be considered in neonates presenting with early-onset hypoglycemia, cholestasis, or seizures.

What is new?

1. Our case had mild but distinct craniofacial dysmorphisms associated with this variant, including long philtrum, depressed nasal root, epicanthus, prominent low-set ears, and mild hypertelorism.

2. This case report adds to the limited genotype–phenotype correlation data for the TBX19 c.856C>T variant, suggesting phenotypic variability even among patients with the same mutation.