Renal genetic testing confirms diagnosis, guides management
Renal genetics, a nascent but growing field, is offering hope to patients with inherited kidney diseases, particularly in cases with no family history, or a confusing family history, that can be challenging to diagnose.
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Medical geneticist and nephrologist Xiangling Wang, MD, PhD, a staff physician and Director of the Renal Genetics Clinic in Cleveland Clinic’s Center for Personalized Genetic Healthcare and in the Department of Kidney Medicine, and colleagues reported one such case in Kidney International. They describe for the first time the management and outcome of pregnancy in a patient with CASR-activated mutations.
A 25-year-old female presented to the Renal Genetics Clinic at 20 weeks of gestation due to refractory and severe but also asymptomatic hypocalcemia, a condition characterized by a deficiency of calcium in the bloodstream. The hypocalcemia was detected during a routine prenatal workup. At this time, she was prescribed a standard regimen of calcium and calcitriol, but at four months the hypocalcemia persisted, prompting a referral to Dr. Wang’s clinic.
The patient reported no past medical or surgical history and was not on any other medications, except prenatal vitamins. Her maternal family history was positive for hyperparathyroidism, which can cause hypercalcemia, higher than normal calcium in the blood, but not low as seen in the patient. Regardless of her persistent hypocalcemia, the patient did not have any symptoms commonly associated with hypocalcemia, such as muscle twitching and spasms, and her physical exam was normal.
Her laboratory findings revealed a different story. They were remarkable for persistent hypocalcemia, low PTH, hyperphosphatemia, hypomagnesemia and hypercalciuria. And a renal ultrasound showed bilateral renal calculi.
Dr. Wang and colleagues suspected the patient’s mutation was associated with the calcium-sensing receptor (CASR) gene, encoded by chromosome 3q21,1, a key regulator of systemic calcium homeostatic, which enables pathologies like autosomal dominant hypocalcemia (ADH).
Indeed, the genetic testing revealed a mutation of c.398A>T,pGlu133Val of the CASR gene, consistent with the ADH diagnosis. This specific mutation has not been widely reported. And, in this case, would have been difficult to make a diagnosis without the expertise of Renal Genetics Clinic, as it was a de novo (not inherited from parents) mutation and its significance was previously unknown.
Dr. Wang worked closely with colleagues in maternal fetal medicine and endocrinology to manage the patient’s care throughout the rest of her pregnancy. “Because hypocalcemia-related fetal complications can be associated with intrauterine growth restriction, low neonatal bone mass and stillbirths, careful management across our teams was very important,” says Dr. Wang.
In the case of asymptomatic hypocalcemia, her care teams discontinued supplemental calcium and vitamin D, which could have exacerbated underlying dysfunction and promoted hypercalciuria and nephrolithiasis. Although, calcium supplements may be warranted in symptomatic patients in tandem with close monitoring of urinary calcium excretion and should be discontinued when symptoms dissipate.
Additionally, use of thiazides are not recommended in pregnancy because they can cross the placenta and are associated with neonatal jaundice and thrombocytopenia.
The patient’s asymptomatic hypocalcemia persisted throughout her pregnancy, but there were no related perinatal or neonatal outcomes. She passed renal calculi during delivery; however, recurrent calculi with obstructive features were later discovered during post-delivery follow-up, necessitating laser lithotripsy and left ureteral stent insertion.
Several months later, laboratory findings from her 8-month-old son were consistent with hypocalcemia at 8.2 mg/dL and low PTH at 14 pg/ml, indicating he may share the same variant in the CASR gene; although, genetic testing has not been completed. Thus far, he has also been asymptomatic and is meeting developmental growth milestones.
The patient was prescribed thiazide to manage hypercalciuria, and Dr. Wang reports she was doing well at her one-year follow-up appointment.
“This case highlights the strengths of precision medicine with genetics evaluation in the diagnosis and management of patients. It’s one example of a patient diagnosed and collaboratively managed in our Renal Genetics Clinic in partnership with other Cleveland Clinic specialists,” concludes Dr. Wang.
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