Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities.

Hypertension affects one billion people and is a principal reversible risk factor for cardiovascular disease. Pseudohypoaldosteronism type II (PHAII), a rare Mendelian syndrome featuring hypertension, hyperkalaemia and metabolic acidosis, has revealed previously unrecognized physiology orchestrating the balance between renal salt reabsorption and K(+) and H(+) excretion. Here we used exome sequencing to identify mutations in kelch-like 3 (KLHL3) or cullin 3 (CUL3) in PHAII patients from 41 unrelated families. KLHL3 mutations are either recessive or dominant, whereas CUL3 mutations are dominant and predominantly de novo. CUL3 and BTB-domain-containing kelch proteins such as KLHL3 are components of cullin-RING E3 ligase complexes that ubiquitinate substrates bound to kelch propeller domains. Dominant KLHL3 mutations are clustered in short segments within the kelch propeller and BTB domains implicated in substrate and cullin binding, respectively. Diverse CUL3 mutations all result in skipping of exon 9, producing an in-frame deletion. Because dominant KLHL3 and CUL3 mutations both phenocopy recessive loss-of-function KLHL3 mutations, they may abrogate ubiquitination of KLHL3 substrates. Disease features are reversed by thiazide diuretics, which inhibit the Na-Cl cotransporter in the distal nephron of the kidney; KLHL3 and CUL3 are expressed in this location, suggesting a mechanistic link between KLHL3 and CUL3 mutations, increased Na-Cl reabsorption, and disease pathogenesis. These findings demonstrate the utility of exome sequencing in disease gene identification despite the combined complexities of locus heterogeneity, mixed models of transmission and frequent de novo mutation, and establish a fundamental role for KLHL3 and CUL3 in blood pressure, K(+) and pH homeostasis.

Etiology of hypertension in children and adolescents.

While most hypertension in children has been previously considered secondary to renal, cardiovascular or endocrine etiology, a substantial number of children aged 6 to 20 years are now diagnosed with primary or essential hypertension. Hypertension in children and adolescents seems to be increasing over the past two decades. This is attributed at least in part to an increased prevalence of overweight in this population. Essential hypertension in childhood is a diagnosis arrived at by excluding the known causes of secondary hypertension. This paper will discuss the etiology of hypertension in children and adolescents.

Pamidronate Rescue Therapy for Hypercalcemia in a Child With Williams Syndrome.

A 15-month-old male infant diagnosed with Williams Syndrome (WS) was admitted with severe hypercalcemia and nephrocalcinosis. Intravenous hydration and furosemide failed to yield an appreciable and sustainable fall in serum calcium, while the injection of pamidronate achieved a significant decrease in serum calcium in a short period of time. This bisphosphonate could be considered as a second-line treatment for refractory hypercalcemia in WS.

Severe hypoalphalipoproteinaemia in a child with acute post-streptococcal glomerulonephritis (APSGN).

We describe a child with acute post-streptococcal glomerulonephritis (APSGN), who developed a very low plasma high-density lipoprotein cholesterol (α-lipoprotein) in association with transient but massive proteinuria. The hypoalphalipoproteinaemia resolved spontaneously concomitant with the remission in proteinuria and the patient had a complete clinical recovery. Urinary loss of apolipoprotein A1 may have contributed to the hypoalphalipoproteinaemia. To our knowledge, this has not been reported previously in APSGN.

Renal venous thrombosis in a newborn with prothrombotic risk factors.

Renal venous thrombosis (RVT) is a rare but a well recognized entity in children and neonates. The clinical signs of neonatal RVT include hypertension, enlarged kidney(s), hematuria, renal insufficiency, proteinuria, thrombocytopenia, or all. Persisting impairment of kidney function and hypertension are serious and common complications in patients with RVT. Risk factors for the development of RVT include maternal diabetes mellitus, pathologic states associated with thrombosis (e.g., shock, dehydration, perinatal asphyxia, polycythemia), and sepsis. Inherited prothrombotic abnormalities have been described in some reports of RVT. We report the case of a male newborn with left RVT and associated homozygosity for both factor V Leiden (G1691A) and methylenetetrahydrofolate reductase C677T mutations in addition to elevated serum lipoprotein (a). The patient was treated with heparin. We believe our case to be the first reported case in the English medical literature of such an association between neonatal RVT and homozygosity for both factor V Leiden and methylenetetrahydrofolate reductase. This case and other studies clearly demonstrate that neonatal RVT should be evaluated for thrombophilia conditions.

A novel PCLN-1 gene mutation in familial hypomagnesemia with hypercalciuria and atypical phenotype.

Familial hypomagnesemic hypercalciuria and nephrocalcinosis (FHHNC [MIM 248250]) is a rare renal tubular disorder characterized by impaired reabsorption of magnesium and calcium in the thick ascending limb of Henle's loop (tALH), causing renal magnesium wasting and hypercalciuria. Patients with FHHNC usually present with recurrent urinary tract infections, polyuria, nephrolithiasis (NL) and nephrocalcinosis (NC) with many progressing to chronic renal failure (CRF). We have shown recently that loss of function mutations in paracellin-1 PCLN-1/claudin-16, a renal tight junction protein located in the TAL, are causative of FHHNC. We present clinical and molecular studies on a highly inbred family with FHHNC in association with an unusual phenotype in that all affected members were extremely short. Affected individuals were found to be homozygous for marker D3S1314 on chromosome 3q. Sequencing of the PCLN-1/claudin-16 gene revealed a previously unknown point mutation at S235Y on exon 4 on the 4th transmembrane domain, providing additional evidence that inactivating mutations in the PCLN-1/claudin-16 gene result in FHHNC.