Congenital isolated ACTH deficiency (СIAD) is an orphan autosomal recessive disease caused by ТВХ19 (1q24.2) gene pathogenic variants. The article presents two cases with a classic manifestation of the СIAD in neonatal period which were confirmed genetically, one of cases revealed the first described TBX19 gene variant. Despite the appearance of significant symptoms in the newborn period in both patients diagnoses were established at the 8th and 22nd months of life. Clinical manifestations of hypoglycemia were present in both patients: from the 1st day of life (episode of apnoea) in patient № 2 and from 7 months (seizures) in patient № 1. Cholestatic jaundice, hepatomegaly, signs of hepatocyte cytolysis, impaired protein-synthetic liver function were the main manifestations of the disease in 1st patient. This may indicate non-infectious cholestatic hepatitis. Improvement and gradual normalization of clinical and laboratory symptoms during hydrocortisone therapy confirmed the association of liver damage with hypocortisolemia. 2nd patient had no signs of cholestasis. Low cortisol levels were observed with reduced or low-normal ACTH, which confirmed central hypocorticism. Genetic study in both patients revealed TBX19 gene pathogenic variants in a homozygous state: c.82C>T(p.Q28X) in patient №1, not previously described variant c.469-1G>A in patient №2. Врожденный изолированный дефицит адренокортикотропного гормона (ВИДА) — орфанное аутосомно-рецессивное заболевание, обусловленное патогенными вариантами в гене ТВХ19 (1q24.2). В статье представлено описание двух клинических случаев с классической манифестацией ВИДА в неонатальном периоде, подтвержденного генетически, причем в одном из них выявлен впервые описанный вариант в гене TBX19. Диагноз установлен на 8-м и 22-м месяцах жизни, несмотря на появление клинически значимых симптомов в периоде новорожденности у обеих пациенток. Клинические проявления гипогликемии присутствовали у обеих пациенток: у пациентки №2 — с первых суток жизни (эпизод апноэ), у пациентки №1 — с 7 месяцев (судороги). У пациентки №1 основными проявлениями заболевания были холестатическая желтуха, гепатомегалия, признаки цитолиза гепатоцитов, нарушение белковосинтетической функции печени, что может свидетельствовать о развитии неинфекционного холестатического гепатита. Связь поражения печени с гипокортизолемией подтверждают улучшение и постепенная нормализация клинико-лабораторных изменений на фоне терапии гидрокортизоном. У пациентки №2 признаки холестаза отсутствовали. Лабораторно отмечались низкие уровни кортизола при сниженном или низконормальном — адренокортикотропного гормона (АКТГ), что подтверждает центральный гипокортицизм. При молекулярно-генетическом исследовании у обеих пациенток обнаружены патогенные варианты в гене ТВХ19 в гомозиготном состоянии: у пациентки №1 c.82C>T(p.Q28X), у пациентки №2 — c.469-1G>A, ранее не описанный.

We report on a male patient who was investigated for frequent apneic episodes, feeding problems, hypotonia, and left-sided middle cerebral artery infarction in the magnetic resonance imaging at 2 weeks of age. Primary diagnosis of dihydropyrimidinase (DPYS) deficiency was suspected following the analysis of urine for organic acid; DPYS deficiency was strongly suggested by the presence of dihydrouracil, thymine, and uracil. Subsequent genetic evaluation by whole exome sequencing revealed 2 separate mutations, homozygous pathogenic variant c.1010T>C p.Leu337Pro of the DPYS gene, resulting in DPYS deficiency, and homozygous pathogenic variant c.535C>T p.Arg179* of TBX19 gene, which is associated with autosomal recessive congenital isolated adrenocorticotrophic hormone deficiency. Currently, the patient is 2 years old, and he has gross motor retardation and seizure disorder. We suggest that the clinical phenotype of the proband can be a result of mixed expression of both mutations.

Objective: To investigate the clinical and genetic characteristics of congenital isolated adrenocorticotropic hormone (ACTH) deficiency. Methods: The clinical and laboratory characteristics of 5 cases with congenital isolated ACTH deficiency diagnosed in the Department of Endocrinology of the Children's Hospital, Capital Institute of Pediatrics from January 2019 to March 2021 were retrospectively analyzed. The general conditions, clinical manifestations, laboratory examinations, genetic charcteistics, treatment and follow-up (up to October 2021) were analyzed. Results: Of the 5 cases, 1 was female and 4 were males, aged from 13 months to 6 years at the time of consultation. The symptoms of hypoglycemia and convulsion were presented in infancy, and 4 cases had infantile cholestasis. Glucose level of 5 cases ranged from 0.79-2.20 mmol/L, ACTH ranged from <1.00-4.17 ng/L, and cortisol ranged from 0.2-3.8 μg/L. Whole exon sequencing revealed that 3 cases carried homozygous TBX19 variations, and 2 cases had compound heterozygous TBX19 variations, including 3 variants that had been reported before and 3 novel variants were found. After the diagnosis was confirmed, all the cases were treated with hydrocortisone. Hypoglycemia was all corrected during the follow-up, and 4 cases no longer had convulsions. Conclusion: Congenital isolated ACTH deficiency should be considered in neonates and infants with cholestasis and hypoglycemia, and the diagnosis can be confirmed by genetic testing. 目的： 探讨先天性孤立性促肾上腺皮质激素缺乏症的临床和遗传学特征。 方法： 回顾性分析2019年1月至2021年3月首都儿科研究所附属儿童医院内分泌科诊治的5例先天性孤立性促肾上腺皮质激素缺乏症患儿的临床资料，对其一般情况、临床表现、实验室检查、基因检测结果、治疗及随访（截至2021年10月）等进行分析。 结果： 5例患儿中女1例、男4例，就诊时年龄范围13月龄至6岁，均在婴儿期出现低血糖、抽搐，4例婴儿期有胆汁淤积。5例患儿血糖范围在0.79~2.20 mmol/L，促肾上腺皮质激素范围<1.00~4.17 ng/L，皮质醇范围0.2~3.8 μg/L。全外显子测序发现3例患儿携带TBX19纯合变异，2例患儿为复合杂合变异，包含3种已报道变异和3种新变异。明确诊断后予以氢化可的松治疗，随访中患儿低血糖症状全部改善，4例患儿未再出现抽搐发作。 结论： 新生儿期和婴儿期以低血糖、抽搐为表现伴有胆汁淤积的患儿，应注意考虑先天性孤立性促肾上腺皮质激素缺乏症，通过基因检测可明确诊断。.

Congenital isolated adrenocorticotrophic hormone (ACTH) deficiency due to T-box transcription factor-19 (TBX19 mutation) (MIM 201400; ORPHA 199296) usually presents in the neonatal period with severe hypoglycemia, seizures, and sometimes prolonged cholestatic jaundice. We report a case with an unusual presentation that delayed the diagnosis. A 9-month-old female patient with no relevant personal history was admitted to the emergency department due to a hypoglycemic seizure in the context of acute gastroenteritis. There was rapid recovery after glucose administration. At age 4, she presented with tonic-clonic seizures, fever, and gastrointestinal symptoms and came to need support in an intensive care unit. Low serum cortisol was documented and hydrocortisone was initiated. After normalization of inflammatory parameters, the patient was discharged with hydrocortisone. The genetic investigation was requested and compound heterozygous mutations in TBX19 were detected. This is a rare case of presentation of TBX19 mutation outside the neonatal period and in the setting of acute disease, which presented a diagnostic challenge. Congenital isolated adrenocorticotrophic hormone deficiency due to TBX19 mutation usually presents with neonatal hypoglycemia and prolonged cholestatic jaundice. An uneventful neonatal period, however, does not exclude the diagnosis as the disease may be asymptomatic at this stage. In the context of idiopathic hypoglycemia, even in the context of acute disease, hypocortisolism must always be excluded. Genetic evaluation should be performed in cases of congenital central hypocortisolism to allow proper counselling.

Congenital isolated ACTH deficiency (IAD) is a rare condition characterised by low plasma ACTH and serum cortisol with normal production of other pituitary hormones. TBX19 (also known as TPIT) is a T-box pituitary restricted transcription factor important for POMC gene transcription and terminal differentiation of POMC-expressing cells. TBX19 gene mutations have been shown to cause neonatal-onset congenital IAD. We report a neonate of Romanian origin, who presented at 15 h of life with respiratory arrest and hypoglycaemia which recurred over the following 2 weeks. Biochemical investigations revealed IAD, with undetectable serum cortisol (cortisol < 1 μg/dL; normal range (NR): 7.8-26.2) and plasma ACTH levels within the normal range (22.1 pg/mL; NR: 4.7-48.8). He responded to hydrocortisone treatment. Patient DNA was analysed by a HaloPlex next-generation sequencing array targeting genes for adrenal insufficiency. A novel homozygous synonymous mutation p.Thr96= (Chr1:168260482; c.288G>A; rs376493164; allele frequency 1 × 10-5, no homozygous) was found in exon 2 of the TBX19 gene. The effect of this was assessed by an in vitro splicing assay, which revealed aberrant splicing of exon 2 giving rise to a mutant mRNA transcript whereas the WT vector spliced exon 2 normally. This was identified as the likely cause of IAD in the patient. The predicted protein product would be non-functional in keeping with the complete loss of cortisol production and early presentation in the patient. Synonymous variants (a nucleotide change that does not alter protein sequence) usually thought to be benign may still have detrimental effects on RNA and protein function causing disease. Hence, they should not be ignored, especially if very rare in public databases. In vitro splicing assays can be employed to characterise the consequence of intronic and exonic nucleotide gene changes that may alter splicing. Establishing a diagnosis due to a TBX19 mutation is important as it defines a condition of isolated ACTH deficiency not associated with additional pituitary deficiencies.