Somatic mosaicism in a mother of two children with Pitt-Hopkins syndrome.

Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder characterized by intellectual disability, unusual face and breathing abnormalities and can be caused by haploinsufficiency of TCF4. The majority of cases are sporadic. Somatic mosaicism was reported infrequently. We report on a proband with typical manifestations of PTHS and his younger brother with a less striking phenotype. In both, a heterozygous frameshift mutation (c.1901_1909delinsA, p.Ala634AspfsX67) was found in exon 19 of TCF4. The same mutation was found at low levels in DNA extracted from the mother's blood, urine and saliva. This report of familial recurrence with somatic mosaicism in a healthy mother has important consequences for genetic counseling. We suggest careful studies in parents of other patients with PTHS to determine the frequency of germline and somatic mosaicism for TCF4 mutations.

Hyperpnea-induced bronchoconstriction and urinary CC16 levels in athletes.

PURPOSE: Exercise-induced bronchoconstriction (EIB) is a common condition in both individuals with asthma and otherwise healthy elite athletes. Although excessive water loss by peripheral airways during hyperpnea is regarded as the initial trigger for EIB, the cascade of events that follows remains unclear. Our goal was to establish whether transient disruption of the airway epithelial barrier occurs after a short period of hyperpnea of dry air in athletes with EIB. METHODS: Urinary concentration of the pneumoprotein Clara cell (CC16) was used as an assumed biomarker of lung epithelial cell damage or dysfunction. Samples were collected at baseline and for 90 min after an 8-min eucapnic voluntary hyperpnea (EVH) test in 50 female individuals (28 athletes and 22 untrained). RESULTS: Nineteen subjects (10 athletes) demonstrated a sustained bronchoconstriction after EVH (mean±SE forced expiratory volume in the first second (FEV1) fall from baseline=23.4%±2.6%). The remaining subjects had a negative challenge result with an FEV1 fall of 5.9%±0.6%. An increase (P<0.001) in urinary CC16 concentration was noticed after EVH in all but one subject, with no group difference (median CC16 increase before to after challenge: athletes EVH 0.083 ng·µmol, athletes EVH 0.223 ng·µmol, untrained EVH 0.074 ng·µmol, untrained EVH 0.571 ng·µmol; P>0.05). CONCLUSIONS: Urinary levels of CC16 are increased after EVH in all individuals (trained and untrained, with and without EIB) suggestive of dehydration-induced perturbation of the distal respiratory epithelium during episodes of hyperventilation.

Renal denervation enhances the phosphaturic effect of parathyroid hormone.

Hyperventilation/hypocapnia increases renal phosphate reabsorption and decreases the phosphaturic effect of parathyroid hormone (PTH). Recent studies suggest that the blunted phosphaturic effect of PTH in hyperventilated/hypocapnic rats may be mediated by the stimulation of renal beta-adrenoreceptors. In the present study, no differences in plasma catecholamine levels were detected in hyperventilated/hypocapnic rats as compared to hyperventilated/normocapnic rats. Therefore, studies were performed to determine the role of the renal nerves in the blunted phosphaturic effect of PTH in hyperventilated/hypocapnic rats. In clearance experiments in acutely thyroparathyroidectomized male Sprague-Dawley rats, PTH infusion increased the fractional excretion of phosphate (FEPi) in the denervated left kidney of hyperventilated/hypocapnic rats (n = 8), from 2.4 +/- 1.1 to 18.6 +/- 2.7%, as compared to 1.0 +/- 0.3 to 9.1 +/- 2.1% in the contralateral innervated kidney. Denervation of the left kidney in hyperventilated/normocapnic rats (n = 8) also significantly increased the phosphaturic response to PTH by 2.5 +/- 1.5 to 26.9 +/- 3.0% as compared to 0.9 +/- 0.5 to 18.6 +/- 2.6% in the contralateral innervated kidney. The phosphaturic responses to PTH were similar when comparing the denervated kidney in hyperventilated/hypocapnic rats with the innervated kidney of hyperventilated/normocapnic rats. Thus, renal denervation enhanced the phosphaturic effect of PTH in both hyperventilated/hypocapnic and hyperventilated/normocapnic rats. These results suggest that renal nerves play a role in the modulation of the phosphaturic effect of PTH.