Balkan Journal of Medical Genetics

TWO BROTHERS FROM MACEDONIA WITH GITELMAN SYNDROME
Janchevska A, Tasic V, Jordanova O, Gucev Z, Jenkins L, Jovanovska N, Plaseska – Karanfilska D, Ashton E, Bockenhauer D
*Corresponding Author: Ass. Prof. Dr. Aleksandra Janchevska, University Children’s hospital, Skopje, Rep. of N. Macedonia; Email: dr.sasha1969@yahoo.com
page: 69

CASE REPORT

A 7-year-old boy was admitted with episodes of carpopedal spasms and muscle aches, after vomiting in the preceding months. He was born at term, in the 39th gestation week of a normal pregnancy, with a birth weight (BW) of 3150gr (-0.58 SDS) and length (BL) 50cm (-0.04 SDS). His past medical history and family history were unremarkable. The carpopedal spasms and muscle aches later also manifested in his younger brother at the age of 7.5 years. His birth parameters, BW of 3670gr (0.23 SDS) and BL (0.16 SDS) were also within reference range with an otherwise unremarkable past medical history. The boys’ height (-0.5 SDS in older versus -0.91 SDS in younger brother) and weight (1.24 SDS versus -1.96 SDS) and pubertal stage, A1B1P1, at the onset of symptoms, and during the follow-up period, have been appropriate for their sex and age. Our patients never had clinical signs of dehydration. The initial and follow-up measured biochemical parameters revealed electrolyte imbalances shown in Tables 1a and 1b. The serum parameters of hepatic and renal function were within reference range, as were those for parathyroid and thyroid function. Although hypokalemia and hypomagnesemia may contribute to prolongation of the Q-T interval [8], the performed electrocardiogram and the measured Q-T interval (0.36 sec) were normal, as were kidney ultrasound, audiogram and electroencephalogram. The molecular analysis was performed after written informed consent had been obtained from the parents. A next generation sequencing (NGS) panel, as described previously [12] was used and revealed in the older brother three heterozygous variants in SLC12A3 (NM_000339.3): c.1805_1806del, c.2660+1G>A and c.2944 A>T, all confirmed by Sanger sequence analysis. The same constellation was found in the younger brother. Their mother was found to be heterozygous for the c.2944 A>T; p. (Ile982Phe) pathogenic variant and their asymptomatic father was heterozygous for the other two pathogenic variants SLC12A3 c.1805_1806del; p. (Tyr- 602Cysfs*31) and c.2660+1G>A, thus confirming that these two variants are on the same allele. The paternal variants are considered pathogenic. The c.2660+1G>A variant affects the canonical donor splice site of exon 22 and has been recurrently identified in Gitelman syndrome [12, 13]. The other variant results in a frameshift. Thus, both are null variants (PVS1), that are absent in controls (PM2) and in a gene that is highly specific for the phenotype (PP3) and are thus annotated as pathogenic. The maternal variant c.2944 A>T; p. (Ile982Phe) is absent in controls (PM2) and was found in trans with a pathogenic variant (PM3). In silico tools predict that this variant is likely damaging (PP3) and as the phenotype is highly specific for this gene (PP4), this variant was classified as likely pathogenic. The boys were advised to maintain an increased salt intake and were prescribed oral potassium and magnesium supplements. The follow up period has been uneventful with occasional episodes of paresthesia.

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