Syndromes With Neonatal Salt Loss: Not Only Congenital Adrenal Hyperplasia Due to 21-hydroxylase Deficiency (21OH-ISC)

Salt loss (SL) is a major cause of neonatal hospitalization and can be life-threatening if not promptly treated. It typically presents with hyponatremia (<130 mEq/L), often accompanied by hyperkalemia, hypochloremia, and metabolic acidosis. Clinical signs are nonspecific-including vomiting, irritability, hypotonia, and, in severe cases, seizures. Newborns are particularly vulnerable to electrolyte disturbances due to reduced glomerular filtration rate, immature distal nephrons, and transient aldosterone resistance.

While infectious gastroenteritis is the most common cause of neonatal SL, several endocrine disorders may present with the same clinical picture. The leading endocrine cause is primary adrenal insufficiency due to 21-hydroxylase deficiency, but other rare genetic conditions must be considered. These include aldosterone synthase deficiency, X-linked adrenal hypoplasia congenita (DAX-1/NR0B1 mutations), and types of pseudohypoaldosteronism, each characterized by impaired aldosterone production or action and early-life salt wasting.

Despite their heterogeneity, treatment generally relies on salt replacement, with mineralocorticoid and/or glucocorticoid therapy required in selected conditions. Only limited epidemiologic data exist; an Italian study (2006-2015) showed that 21-hydroxylase deficiency accounted for 37% of endocrine SL cases, while other congenital adrenal disorders contributed to 25%.

Neonatal screening programs detect 21-hydroxylase deficiency early, but other endocrine causes of SL remain unscreened and must be considered in differential diagnosis. This study aims to quantify the frequency of non-21-hydroxylase endocrine causes of neonatal SL in patients diagnosed at our center, describe their clinical, genetic, and laboratory features, review treatment strategies and outcomes, and characterize each disorder individually.

Inclusion criteria

• Patients with a diagnosis of endocrine-related salt loss, defined by laboratory findings of hyponatremia (serum sodium <130 mEq/L)
• Age at onset of salt loss between 0 and 60 days of life
• Patients born between January 1, 1989 and December 31, 2023 and managed at the Experimental Center
• Obtained Informed consent

Exclusion criteria

• Diagnosis of 21OH ISC