Introduction

Gitelman syndrome (GS) is a rare genetic condition which is caused by an autosomal recessive gene mutation. This is a renal condition, characterised by salts not being absorbed effectively by the kidney. The gene that is mutated is the SLC12A3 gene, which codes for a sodium chloride cotransporter known as the thiazide-sensitive sodium chloride cotransporter (NCC). The TRPM6 gene that codes for a magnesium channel is also mutated. These gene mutations prevent electrolytes from being absorbed by tubular reabsorption. This process involves the kidney reabsorbing electrolytes and solutes into the bloodstream.¹ 

GS is autosomal recessive so, for it to be passed on from parents to their children, both parents need to be carriers of the mutated allele and pass it to their offspring. In Europe, there is a prevalence of about one percent of heterozygotes (carriers) of the SLC12A3 gene, and GS is estimated to be affecting about 1 in 40,000 caucasians. Symptoms, for the most part, are not typically present before six years of age, therefore, a diagnosis is usually made when affected people reach adolescence or adulthood.² 

It is very important to understand the symptoms present in children, because they may appear to be asymptomatic initially, and the growth and development process can be significantly affected. In this article, the causes of GS and explores the impact on child growth and development. Management strategies will also be mentioned.

Pathophysiology of Gitelman syndrome

Gitelman syndrome mainly affects the kidney’s distal convoluted tubule (DCT) which results in salt transport being affected. The SLC12A3 gene mutation leads to sodium chloride not being reabsorbed into the loop of Henle and the DCT. Salt is therefore lost in urine and dehydration can also occur. Channels that are responsible for magnesium and potassium reabsorption are also affected, therefore causing hypomagnesemia and hypokalaemia.³ 

Hypomagnesemia in GS cases can affect calcium metabolism. Hypocalciuria is a common symptom of GS – when urine calcium concentrations are abnormally low. When sodium levels in cells decrease, this causes calcium ions to exit from the cells through the sodium-calcium exchange system. To compensate for this loss of calcium ions inside the cells, calcium will enter the cells through other channels, known as the TRPV5 channels. Lower magnesium reabsorption also leads to calcium ions being reabsorbed via these channels. Both mechanisms result in lower calcium ion concentrations in the urine thus causing hypocalciuria. There is some evidence to suggest that sodium chloride transport increases in the loop of Henle to compensate for the initial loss of sodium ions.⁴ This causes voltage to increase in this region, which facilitates reabsorption of calcium ions. There are therefore a multitude of ways in which calcium metabolism is affected by GS.

Clinical symptoms in children with Gitelman syndrome

There are many symptoms associated with GS in children affected by this syndrome. The general symptoms include muscle cramps, as well tiredness, and general weakness. Abnormal blood pressure is also very common and this can be variable with many patients having increased blood pressure and some patients having characteristically low blood pressure.¹ 

Nausea and diarrhoea are more general symptoms that occur in children affected by GS.⁵ There are also growth-specific symptoms with many children displaying growth restrictions and a delayed onset of puberty, this is due to low magnesium and potassium ion levels for the most part. The growth delay can lead children to struggle in their adult life. Delayed puberty can lead to physical impairments as well as affecting the lives of those with GS in social scenarios, particularly as they get older.²

Impact of Gitelman syndrome on growth and development

Gitelman syndrome has the potential to impair the growth and development of children affected by this rare disease. Low potassium levels because of hypokalaemia have been linked to low growth hormone levels. Human growth hormone is very important regarding growth and development in humans and hypokalaemia due to GS can lead to lower than anticipated final growth in children.⁶ 

Hypomagnesemia has been more closely linked to lower epidermal growth factor (EGF) levels and EGF gene mutations can also cause lower TRPM6 expression. EGF is very important in cell differentiation thus GS impairs growth in more than one way.⁷ 

Hypercalciuria that commonly occurs in GS affected individuals, results in disrupted bone mineralisation – demonstrated in mouse models.⁸ This can eventually inhibit correct skeletal growth. 

Delayed puberty is also a common symptom of GS. This is due to GS leading to lower levels of sexual hormones, for example, in people assigned male at birth (AMAB) testosterone levels may be very low and this can coincide with low levels of calcium and potassium. Sexual development is typically slower and characteristics associated with puberty are abnormal.⁹ People assigned female at birth (AFAB) affected by GS tend to also have sex hormones abnormally low – this can affect the development of secondary characteristics such as an abnormal menstrual cycle.¹⁰ Due to low electrolyte levels such as potassium ions, motor and cognitive development is also impacted in children with GS. Some patients can display a cognitive delay of more than two years, as well as this other cognitive issues and symptoms such as seizures can occur.¹¹ It was previously mentioned that children have muscle weakness and tend to be more tired, and that leads to worse performance in an academic environment.

Diagnosis and monitoring in children

There are multiple ways to diagnose and manage GS symptoms in children. Blood tests are commonly used to test for hypokalaemia, and frequently a diagnosis is made starting the investigations from hypokalaemia, because these patients often don’t present many other symptoms.¹⁰ 

Blood tests are also useful for detecting magnesium levels, as well as bicarbonate levels. Bicarbonate levels in blood are typically increased in GS patients, due to metabolic acidosis, as it is used to correct this metabolic abnormality.¹ 

Urine tests are also used to test for GS, as sodium and chloride levels in urine are higher in individuals with GS. Genetic screening for homozygous SLC12A3 gene mutations to detect GS are also proven to help diagnosis and are very accurate.¹² 

As growth retardation commonly occurs in GS patients, by monitoring growth and the milestones in puberty, medical professionals can monitor GS progression and allow strategies to be implemented earlier.¹³

Management of Gitelman syndrome in children

There are strategies to manage GS symptoms in children. To compensate for the electrolytes that are lost because of GS, supplementation of electrolytes – magnesium ion supplements in cases of hypomagnesemia – can help restore the normal levels. This can also apply for electrolytes such as potassium ions.¹⁴ 

These electrolytes can also be replenished through dietary changes, such as eating foods rich in potassium – salmon – and foods rich in magnesium – seeds and nuts. Diets that are high in salt can ensure sodium levels are high enough and hydration will ensure water levels are at optimal levels.¹⁵ 

There are also diuretics which limit potassium loss in urine as well as oral supplements for magnesium and potassium, that can help normalise the electrolyte levels. In extreme cases growth hormone therapy can be undertaken, particularly for those with a very short stature. However, this is seen as a last resort for those affected.¹⁶

Prognosis and long-term outcomes

In order to ensure normality for the children diagnosed with GS, electrolyte imbalances can be managed through the strategies mentioned previously. Assuming treatment and protocol is thorough, many children can have a good quality of life with symptoms such as tiredness and dizziness resolving after electrolyte supplementation. There will, however, still be some challenges, due to the delayed puberty and growth retardation, as halts in growth and development are irreversible. This can be a long-term issue in children with GS as they grow.²

Support and resources for families

Multidisciplinary care is integral for those affected by GS. Nephrologists can work in conjunction with endocrinologists. This can help elucidate the effects GS mutations are having on the kidneys and how hormones are affecting growth and development. A dietician is also required to design diets that will ensure electrolyte supplementation and replenishment which is the most effective way to manage GS. Counselling for affected children and their families can help with difficulties they are facing, especially when children are entering school, as this is a key event in their lives. Special support for children affected with GS due to learning difficulties can help children prevent falling behind in their education, despite muscle weakness and tiredness leading to many children struggling to learn. Special strategies to assist those with cognitive issues also need to be more available for those struggling with GS.

Summary

GS is caused by rare mutations and it is a kidney disorder that causes major disruptions in electrolyte levels. This can eventually result in poor growth and development in children, although many do not present symptoms at very early stages in their life. Diagnosis is possible using genetic screening, urine and blood testing. Early diagnosis is crucial in improving patient outcomes. This will allow treatment strategies such as electrolyte supplementation to be implemented early. 

Although there is no cure, genetic screening can take place for those carrying the gene mutation or if a parent has the condition, to help couples with family planning. For those affected, treatment strategies are improving and if GS is treated promptly. The majority of patients will hopefully have a high quality of life despite the initial struggles this condition poses to the individual.