Concomitance of Gitelman Syndrome and Familial Mediterranean Fever: A Rare Case Presentation

Abstract

We report a case that has Gitelman syndrome (GS) and familial Mediterranean fever (FMF) presenting with recurrent arthritis of right knee and heel pain. Investigations showed hypokalemia and hypomagnesemia with urinary magnesium wasting. Genetic analysis revealed the presence of heterozygous E148Q mutation in the MEFV gene. Management with potassium, magnesium supplements, spironolactone for GS, and colchicine for FMF resulted in a significant improvement in symptoms. To the best of our knowledge, this is the first report of association between GS and FMF. Further studies are needed to identify if there is an association between these two diseases and the genes responsible for these diseases.

• Gitelman syndrome
• familial Mediterranean fever
• hypokalemia
• genetics
• hypomagnesemia

INTRODUCTION

Gitelman syndrome (GS) or familial hypokalemia–hypomagnesemia, OMIM 263800, is an autosomal recessive renal tubular disorder characterized by hypokalemic metabolic alkalosis, hypomagnesemia, low urinary calcium excretion, and normal to low blood pressure (BP). The syndrome is associated with increased blood levels of renin and aldosterone. Mutation of the SLC12A3 gene on chromosome 16q13 which encodes the thiazide-sensitive sodium chloride cotransporter in the distal convoluted tubule is the common cause of the syndrome.¹ The prevalence of GS has been estimated to be 1:40,000, so it is one of the most common inherited renal tubular disorders. Patients are mostly diagnosed during adolescence or adulthood. The occurrence of symptoms is rare in early childhood and information on the long-term outcome of GS is quite limited.^2,3 Although the syndrome is often mild, the severity of symptoms may be dramatic. The most frequent symptoms are cramps, fatigue, muscle weakness and tetany, abdominal pain, vomiting, fever, and joint pain. Patients may suffer from chondrocalcinosis and paresthesias, usually in the face.⁴ Familial Mediterranean fever (FMF) (OMIM #249100) is also an autosomal recessive disorder characterized by recurrent attacks of pleuritis, febrile peritonitis, and synovitis. A FMF (MEFV) gene has been identified on the short arm of chromosome 16 and several mutations in this gene have been demonstrated in FMF patients.⁵ Because of the restricted expression of pyrin in innate immune cells, the major role of pyrin appears to be in the regulation of inflammation.⁶ In this case report, we report a patient with GS and FMF. To the best of our knowledge, this the first report of association between GS and FMF.

CASE REPORT

A 46-year-old man was admitted to our hospital 2 years ago with recurrent arthritis of right knee and heel pain. In his past history, he had abdominal pain 2–3 times a year without fever. His daughter had a diagnosis of FMF and was using colchicine. He had a C reactive protein (CRP) level as 53 mg/L and erythrocyte sedimentation rate (ESR) was 18 mm/h. Genetic evaluation revealed that he was heterozygous for E148Q mutation and HLA B27 test was negative. FMF was suspected and he was prescribed colchicine 3 times a day and methylprednisolone 4 mg/day. Two months later, he was admitted again with prickling in his hands, spasm, and muscle weakness in his arms. His neurologic examination was normal. Upon further evaluation, he had hypomagnesemia, hypokalemia, metabolic alkalosis, and elevated plasma renin levels with normal BP. Blood levels of magnesium were 1.33 mg/dL (1.6–2.6), potassium was 2.1 mmol/L (3.5–5.1), and chloride was 93 mmol/L (98–107). Plasma renin level was 43 ng/mL/h (0.2–1.6) and aldosterone was 140 pg/mL (3.5–30). Urine analysis was normal and there was no glucosuria or abnormal proteinuria. Twenty-four hour urinary level of sodium was 346.5 mmol (40–220), potassium was 159.95 mmol (25–125), calcium was 70 mg (100–300), magnesium was 245 mg/day (24–255), and chloride was 332.5 mmol/L (110–250) (volume 3200 cm³). The patient was diagnosed with GS based on clinical and biochemical features. He was given replacement treatment with magnesium and potassium. During follow-up, spironolactone of 100 mg was added to this treatment. The symptoms of the patient were resolved with potassium and magnesium supplementation. The informed consent form of the patient was taken.

DISCUSSION

The presentation of GS is quite heterogeneous in terms of age at the presentation, clinical features, and severity of biochemical abnormalities. Patients are mostly diagnosed in late childhood, after 6 years of age. They are also diagnosed in adulthood, especially during routine investigation or when evaluating the patient for cramps, fatigue, paresthesias, and tetany.² In GS, the degree of volume contraction and the stimulation of the renin–angiotensin–aldosterone axis mostly represent a milder phenotype, and plasma aldosterone levels might remain within normal range.⁷ Our patient showed biochemical abnormalities, including hypokalemia, metabolic alkalosis, hypomagnesemia, hypocalciuria, and increased plasma renin and aldosterone activity, strongly suggesting that GS is a disorder usually showing minor or mild symptoms and its long-term prognosis is also extremely good.⁴ Bettinelli et al.⁸ reported a 6-year-old girl followed for 14 years. When she was 20 years old, the growth of the patient was satisfactory and magnesium supplementation decreased the risk of symptoms such as fatigue. Improvement of biochemical abnormalities (long-term potassium and magnesium supplementation) in our patient also resulted in significant clinical improvement at the end of the follow-up of 2 years.

Genetic counseling is also important in GS. GS is inherited as autosomal recessive, so the recurrence risk of an affected child for parents is 25%. Clinical symptoms can appear later in life and adult patients with GS have a lower risk of having children with GS (∼1 in 400) if the patient and his/her partner are not consanguineous. The prognosis of the disease is good, so antenatal diagnosis is not recommended to the patients.⁷

MEFV gene encodes pyrin, a protein consisting of 781 amino acids. The association between the disease and many FMF gene mutations, such as M694V, M694I, and V726A, has been clearly defined. But, controversy still exists on the role of some amino acid substitutions, for instance, E148Q, where glutamine (Q) substitutes for glutamic acid (E). Formerly, this sequence variation was described as a disease-causing mutation with low penetrance and mild symptoms, but in some recent studies, a similar frequency of E148Q among patients and controls was found and therefore suggested that it is no more than a benign polymorphism.⁹ Our patient had also E148Q heterozygosity; however, he had recurrent arthritis especially in his right knee.

Coexistence of GS and FMF has not yet been reported. There can be an association between the genes (SLC12A3 and MEFV), because both of them are on chromosome 16 and both of the diseases affect renal processes. To the best of our knowledge, this is the first report of FMF and GS. Further studies are needed to identify if there is an association between these two genes.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.