An update on clinical presentation and responses to therapy of patients with hereditary hypophosphatemic rickets with hypercalciuria (HHRH).

Pathogenic variants in solute carrier family 34, member 3 (SLC34A3), the gene encoding the sodium-dependent phosphate cotransporter 2c (NPT2c), cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH). Here, we report a pooled analysis of clinical and laboratory records of 304 individuals from 145 kindreds, including 20 previously unreported HHRH kindreds, in which two novel SLC34A3 pathogenic variants were identified. Compound heterozygous/homozygous carriers show above 90% penetrance for kidney and bone phenotypes. The biochemical phenotype for heterozygous carriers is intermediate with decreased serum phosphate, tubular reabsorption of phosphate (TRP (%)), fibroblast growth factor 23, and intact parathyroid hormone, but increased serum 1,25-dihydroxy vitamin D, and urine calcium excretion causing idiopathic hypercalciuria in 38%, with bone phenotypes still observed in 23% of patients. Oral phosphate supplementation is the current standard of care, which typically normalizes serum phosphate. However, although in more than half of individuals this therapy achieves correction of hypophosphatemia it fails to resolve the other outcomes. The American College of Medical Genetics and Genomics score correlated with functional analysis of frequent SLC34A3 pathogenic variants in vitro and baseline disease severity. The number of mutant alleles and baseline TRP (%) were identified as predictors for kidney and bone phenotypes, baseline TRP (%) furthermore predicted response to therapy. Certain SLC34A3/NPT2c pathogenic variants can be identified with partial responses to therapy, whereas with some overlap, others present only with kidney phenotypes and a third group present only with bone phenotypes. Thus, our report highlights important novel clinical aspects of HHRH and heterozygous carriers, raises awareness to this rare group of disorders and can be a foundation for future studies urgently needed to guide therapy of HHRH.

[Pulmonary air-leakage in newborn infants]. / Pulmonal luftlekkasje hos nyfødte.

BACKGROUND: Pulmonary air-leakage (PAL), especially pneumothorax, is a potentially severe complication of pulmonary disease in newborn infants. It is often related to therapeutic procedures such as resuscitation and mechanical ventilation. MATERIAL AND METHODS: This is a prospective study of infants with PAL who were born in the period 1989-2006 and were hospitalised in an intensive care unit. RESULTS: PAL occurred in 54 of 39,101 (1.4 per 1000) live-born infants; 34/54 (63%) were boys and 34/54 (63%) were born at term. 38/54 (70%) PAL cases had asphyxia and different pulmonary diseases, 16/54 (30%) PAL-incidences occurred spontaneously and 23/54 (43%) were diagnosed < 1 hour after birth. PAL occurred during resuscitation for perinatal asphyxia or initiation of mechanical ventilation in 18/54 (33%) patients, during CPAP-treatment in 12/54 (22%), and during mechanical ventilation after the start-up phase in 8/54 (15%) patients. Of 271 infants treated with mechanical ventilation, 144 (53%) were preterm infants with RDS. 64/114 (born 1992-2006) of these received a porcine surfactant and 3/64 (5%) developed PAL. The remaining 50 ventilated RDS-patients born in the same time period had a milder disease; 3/50 (6%) of these developed PAL (p > 0.05). INTERPRETATION: PAL often occurred spontaneously and shortly after birth in connection with resuscitation and stabilization for respirator treatment. The risk for PAL in mechanically ventilated infants was lower once the start-up process had been completed. In infants who had received porcine surfactant for RDS the incidence of PAL during mechanical ventilation was low.