**3. Description of a New Case of Liddle Syndrome**

The index case is a 13-year-old Caucasian boy referred to our Hypertension Unit by the Pediatric Endocrinology Department for arterial hypertension that had been diagnosed six months before. His mother was normotensive and in general good health. His father, affected by arterial hypertension and hypokalemia, died at the age of 38 of sudden cardiac death. The patient was born at term from an uneventful pregnancy to non-consanguineous parents and his past medical history was unremarkable, with no clinical signs of abnormal sexual development. On physical examination, his height and weight were 165 cm (86th percentile for age and sex) and 55 kg (80th percentile for age and sex), respectively. At diagnosis, blood pressure was 184/109 mmHg (>99th percentile for age, gender and height (SBP, 90th percentile: 125 mmHg; 95th percentile: 129 mmHg; 99th percentile: 136 mmHg. DBP, 90th percentile: 79 mmHG; 95th percentile: 83 mmHg; 99th percentile: 91 mmHg) [92] and serum potassium was 3.2 mmol/L (normal range 3.5–5.0 mmol/L). Assessment of target organ damage revealed neither left ventricular hypertrophy nor microalbuminuria.

The patient was investigated to exclude secondary forms of hypertension. Low PRA (<0.1 ng/mL/h) and low serum aldosterone were detected on different occasions (1.0–5.9 ng/dL). 17-OH-progesterone, dehydroepiandrosterone, 4-δ-androstenedione, urinary cortisol and urinary androgen catabolites resulted in normal range for sex and age. The urinary steroid profile for apparent mineralocorticoid excess syndrome resulted negative (tetra-hydrocortisol + allo-tetra-hydrocortisol/tetra-hydrocortisone = 1.45). After three months of therapy with spironolactone (50 mg daily) without clinical and biochemical response, Liddle syndrome was hypothesized. The patient was treated with amiloride (5 mg daily) that successfully controlled blood pressure (120/65 mmHg) and normalized plasma K+ (4.8 mmol/L). The diagnosis of Liddle syndrome was confirmed by genetic analysis that identified the β ENaC germline mutation p.Pro618Leu. Considering the clinical presentation of the index case's father, the inheritance of the mutation by paternal lineage is highly probable. However, a DNA sample from his father was not available.

## **4. Conclusions**

Liddle syndrome is genetic autosomal dominant form of low renin arterial hypertension caused by germline mutations in the *SCNN1A*, *SCNN1B* and *SCNN1G* genes, encoding, respectively, the α, β and γ subunits of the epithelial sodium channel ENaC. Despite the typical phenotype presenting with severe hypertension and hypokalemia, the disease can be clinically heterogeneous, even with mild phenotypes. Herein, we report a new case caused by the germline p.Pro618Leu mutation of the gene *SCNN1B*. The index case presented with high blood pressure and hypokalemia at the age of 13 and a family history of sudden death. Hypertension and hypokalemia were well controlled by amiloride.

Considering the frequency of early-onset hypertension and severity of correlated complications, a well-timed diagnosis of LS is very important in order to administer the proper therapy.

In conclusion, further studies are needed to better define the clinical manifestations and the real prevalence of LS, an example of actionable genetic disease that warrant a proper therapy in order to prevent target organ damage and associated cardiovascular complications.

**Acknowledgments:** Paolo Mulatero and Barbara Pasini are in receipt of a grant from MIUR (ex-60% 2017).

**Author Contributions:** All the authors contributed extensively to the work presented in this manuscript. Martina Tetti, Jacopo Burrello and Silvia Monticone performed the literature search and wrote the manuscript. Jacopo Burrello and Martina Tetti prepared the art work. Xavier Jeunemaitre performed the genetic analysis. Franco Veglio and Paolo Mulatero conceived the work and critically revised it. Barbara Pasini revised the genetic aspects of the manuscript and the literature review.

**Conflicts of Interest:** The authors declare no conflict of interest.
