Four siblings with distal renal tubular acidosis and nephrocalcinosis, neurobehavioral impairment, short stature, and distinctive facial appearance: A possible new autosomal recessive syndrome

Abstract

We report on four siblings (three males, one female) born to first cousin Arab parents with the constellation of distal renal tubular acidosis (RTA), small kidneys, nephrocalcinosis, neurobehavioral impairment, short stature, and distinctive facial features. They presented with early developmental delay with subsequent severe mental, behavioral and social impairment and autistic-like features. Their facial features are unique with prominent cheeks, well-defined philtrum, large bulbous nose, V-shaped upper lip border, full lower lip, open mouth with protruded tongue, and pits on the ear lobule. All had proteinuria, hypercalciuria, hypercalcemia, and normal anion-gap metabolic acidosis. Renal ultrasound examinations revealed small kidneys, with varying degrees of hyperechogenicity and nephrocalcinosis. Additional findings included dilated ventricles and cerebral demyelination on brain imaging studies. Other than distal RTA, common causes of nephrocalcinosis were excluded. The constellation of features in this family currently likely represents a possibly new autosomal recessive syndrome providing further evidence of heterogeneity of nephrocalcinosis syndromes.

Hypercalcemic Disorders in Children

“…Distal renal tubular acidosis has been reported to be associated with hypercalcemia . In addition, Bartter syndrome type 1 (neonatal), which is characterized by metabolic alkalosis, renal hypokalemia, and secondary hyperaldosteronism, and is due to mutations in the sodium‐potassium‐chloride co‐transporter‐2 gene ( SLC12A1 ), has also been reported to be associated with hypercalcemia, hypercalciuria, and nephrocalcinosis.…”

“…Distal renal tubular acidosis has been reported to be associated with hypercalcemia. (61) In addition, Bartter syndrome type 1 (neonatal), which is characterized by metabolic alkalosis, renal hypokalemia, and secondary hyperaldosteronism, (62) and is due to mutations in the sodium-potassium-chloride co-transporter-2 gene (SLC12A1), has also been reported to be associated with hypercalcemia, hypercalciuria, and nephrocalcinosis. (62)(63)(64) However, the hypercalcemia was associated with increased circulating PTH concentrations, which may be explained by an inappropriate response to hypocalcemia secondary to hypercalciuria (63) and is consistent with marginally increased circulating PTH concentrations that have been reported in other, older children with Bartter syndrome.…”

Renal tubular acidosis in pediatrics: A review article

“…Most common association is with Sjogren's syndrome and with kidney stones. 12 3-Hereditary played a role in most RTA as they arose from hereditary hypercalciuria complication. Hypocitraturia in most cases was due to potassium depletion and renal failure, but few were reported to occur as a primary defect in hereditary RTA.…”

“…In a case series of Faqeih the renal tubular acidosis was associated with neurobehavioral impairment, nephrocalcinosis, facial features, small kidneys and short stature, but no genes are detected. 12 Nephrocalcinosis is calcium deposition in renal medulla. Types include organic, iatrogenic and hereditary, and usually asymptomatic, if symptomatic, patients will present with inability to gain weight, blood in the urine and abdominal pain.…”

“…It is associated with tubular acidosis, bratter and lowe syndromes, medullary sponge kidney, policalicosis, hypervitaminosis D, hyperoxaluria, hypercalcuria, hypercalcemia and hypoparathyroidism. 12,13 Hemoglobinopathies due to mutations in gene SLC4A1 encoding AE1, band 3, are causes of hereditary RTA. Patients with homozygous G701D/G701D or heterozygous SAO/G701D had reticulocytosis, which means compensated haemolysis.…”