Metabolic disorders are due to a deficiency of enzymes, which can severely impact health or cause serious complications without treatment. This study aimed to identify the molecular causes of an infant death who had been hospitalized with complicated health problems and metabolism syndrome. Whole-exome sequencing (WES) was used to screen pathogenic variants in the patient’s genome, followed by examination of variants segregation in her parents. The WES analysis identified two homozygous variants, c.[614C>G; 649A>G] in the HMGCL gene of the patient. These two variants co-locate within the exon 7 of the HMGCL gene, resulting in 2 amino acid substitutions, p.[T205S; M217V], in the conservative region of enzyme protein. Sanger sequencing showed that the patient’s unaffected mother and father carried one mutant allele of the HMGCL gene containing two c.[614C>G; 649A>G] variants. The HMGCL gene encodes the 3-hydroxy-3-methylglutaryl-CoA lyase enzyme, which is critical in the ketogenic pathway. The deficiency of this enzyme was reported to be a life-threatening illness in the neonatal period, and two variants detected in this study were also found in a Japanese patient with sudden, unexpected death in infancy. The frequency of these two variants in the Vietnamese in-hour database and their further functional analysis were also reported in this study. The results of this study have explored the molecular etiology that causes the severe, deadly condition of the patient and provide an understanding of the risk of disease in her family.

Type 2 diabetes mellitus (DM) and hypertension (HT) are common major cardiovascular disease (CVD) risk factors. They share common pathophysiological mechanisms and are commonly co-existent. Prevalence of HT is increased among diabetic patients but also DM is more common in hypertensive patients. CVD risk increases multiplicatively in coexistence of HT and DM. Lowering blood pressure (BP) has been shown to be associated with improved morbidity related to both macro- and micro-vascular complications. Although there is debate about target BP levels, in many randomized controlled trials and guidelines a goal of < 130/80 mmHg is advocated in patients with DM, if well tolerated. However, an individualized approach should be cared for depending on risk factors, co-morbidities, and frailty of patients. Lifestyle modifications including weight loss, regular exercise, avoiding smoking and excessive alcohol consumption, and a healthy diet including limitation of salt and fat and total energy intake, are important both as a part of preventive therapy and treatment modality for both DM and HT. Among antihypertensive drugs angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) are warranted due to their potential advantages for slowing albuminuria and progression to kidney failure which is more common in DM. Usually, their combination with calcium-channel blockers (CCBs) or thiazide/thiazide-like diuretics, in a step-wise manner, is recommended. Resistant HT is more common in DM and requires the addition of mineralocorticoid receptor antagonists (MRAs). New antidiabetic drugs like glucagon-like peptide 1 (GLP-1) agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors have been found to lower BP. Apart from their antihypertensive effects they also improve CVD and renal outcomes. There’re ongoing new trials for new agents. Development of more potent and longer-term effective BP lowering drugs, single pill multiple drug combinations of antiHT agents and combination of antiHT agents with glucose-lowering and antilipidemic agents will probably improve compliance to treatment and achievement of goals in diabetic patients.

The clinical case presented describes a 44-year-old woman with a history of mucinous carcinoma in the right breast, who is diagnosed with a pituitary adenoma. Physical examination revealed signs of acromegaly, such as macroglossia and palmar hyperhidrosis. Hormonal tests were performed and showed elevated levels of insulin-like growth factor type 1 (IGF-1). The patient received GnRH analogues for breast cancer; and started medical treatment with somatostatin analogues for acromegaly, which provided improvement in symptoms. Pituitary bleeding was detected during hormone treatment, which caused the growth of the adenoma, causing it to contact the optic chiasm, although no symptoms of pituitary apoplexy were present. Transsphenoidal endoscopic surgery was performed to remove the adenoma, and the diagnosis of pituitary adenoma was confirmed by pathology. The importance of the evaluation of comorbidities in patients with acromegaly is discussed. Pituitary apoplexy as an uncommon complication of pituitary adenomas, which may be associated with the use of GnRH analogues, is addressed. Pre-surgical medical treatment in acromegaly is also discussed, highlighting the importance of a comprehensive assessment of prognostic factors and appropriate treatment selection to improve clinical outcomes. In conclusion, the importance of a multidisciplinary and personalized approach in the management of patients with GH-producing pituitary adenomas to improve quality of life and clinical outcomes is highlighted.

Pheochromocytomas (PCCs) and paragangliomas (PGLs; together PPGLs) are uncommon neuroendocrine tumors arising from adrenal medullary chromaffin cells and sympathetic/parasympathetic paraganglia. Though PPGLs predominate in adult populations, pediatric cases of PPGLs represent more aggressive disease outcomes with 12% being diagnosed as metastatic. Metastatic disease (spread to bone, lung, lymph nodes, or liver) occurs in a subset of PPGLs, ranging from 15% to 17% depending on the underlying pathogenic variants. Historically, pulmonary metastases present clinically as multiple small lesions; however, cases of PPGLs with innumerable small metastases (a miliary pattern) overwhelming lung parenchyma define a novel yet exceptionally challenging disease presentation. This pattern of pulmonary lesions upon treatment and/or cellular lysis may lead to both respiratory decompensation as well as prolific catecholamine release, incurring significant morbidity and mortality if not appropriately managed. Of the 2,649 PPGL patients enrolled in our protocol from January 1, 2000, to April 30, 2023, 500 had metastatic disease, 122 were children/adolescents, and 3 of the 122 children/adolescents had extensive pulmonary metastatic disease. All three adolescent patients with extensive pulmonary metastases had cluster 1 PPGLs and suffered hypoxemia (due to pulmonary metastases) leading to overactive hypoxia signaling and catecholamine-induced signs and symptoms [among them hypertension and/or tachyarrhythmia(s)]. Interventions including surgery, chemotherapy, and radiotherapy were pursued. Two patients achieved disease stability, while one patient succumbed to disease. Ultimately these divergent outcomes emphasize the importance of recognizing poor prognostic factors and aggressive disease early, to select appropriate treatments. Optimal management of these patients must consider complications of catecholamine excess and the profound influence of hypoxia. Herein, we describe three adolescent cases of extensive pulmonary metastatic PPGL and the unique clinical challenges faced in treating these tumors alongside relevant literature to provide guidance on appropriate interventions (ClinicalTrials.gov identifier: NCT00004847).