Milan Bayer

Mutations in the mineralocorticoid receptor gene cause autosomal dominant pseudohypoaldosteronism type I.

Pseudohypoaldosteronism type I (PHA1) is characterized by neonatal renal salt wasting with dehydration, hypotension, hyperkalaemia and metabolic acidosis, despite elevated aldosterone levels. Two forms of PHA1 exist. An autosomal recessive form features severe disease with manifestations persisting into adulthood. This form is caused by loss-of-function mutations in genes encoding subunits of the amiloride-sensitive epithelial sodium channel (ENaC; refs 2,3 ). Autosomal dominant or sporadic PHA1 is a milder disease that remits with age. Among six dominant and seven sporadic PHA1 kindreds, we have found no ENaC gene mutations, implicating mutations in other genes. As ENaC activity in the kidney is regulated by the steroid hormone aldosterone acting through the mineralocorticoid receptor, we have screened the mineralocorticoid receptor gene (MLR) for variants and have identified heterozygous mutations in one sporadic and four dominant kindreds. These include two frameshift mutations (one a de novo mutation), two premature termination codons and one splice donor mutation. These mutations segregate with PHA1 and are not found in unaffected subjects. These findings demonstrate that heterozygous MLR mutations cause PHA1, underscore the important role of mineralocorticoid receptor function in regulation of salt and blood pressure homeostasis in humans and motivate further study of this gene for a potential role in blood pressure variation.

Vitamin D Status in Central Europe

Little published information is available regarding epidemiological data on vitamin D status in the large geographical region of Central Europe (CE). We searched the journal literature with regard to 25(OH)D concentrations among community-dwelling or healthy people living in CE. 25(OH)D concentrations varied by age, season, study sample size, and methodological approach [i.e., 25(OH)D assay used]. Concentrations of 25(OH)D in CE appeared lower than 30 ng/mL, and the magnitude of hypovitaminosis D was similar to that reported in Western Europe. While most of the studies reviewed were cross-sectional studies, a longitudinal study was also included to obtain information on seasonal variability. The longitudinal study reported wintertime 25(OH)D values close to 21–23 ng/mL for all studied age groups, with a significant increase of 25(OH)D in August reaching 42 ng/mL for those aged 0–9 years, but only 21 ng/mL for the elderly aged 80–89 years. The decrease in 25(OH)D with respect to age was attributed to decreased time spent in the sun and decreased vitamin D production efficiency. Based on the literature review on vitamin D status in the CE populations, it can be concluded that 25(OH)vitamin D levels are on average below the 30 ng/mL level.

Transient hyperphosphatasaemia of infancy and early childhood--clinical and laboratory data of 52 patients.

In their article, Carrol and Coakley thoroughly analysed 21 patients with transient hyperphosphatasaemia (TH) of infancy and early childhood. 1 We would like to add our experience with TH. Between 1987 and 2001, we have diagnosed TH in 52 patients (33 boys and 19 girls), using the criteria devised by Kraut et al . 2 Transient hyperphosphatasaemia was detected in patients with a wide variety of clinical disorders, gastrointestinal infections being the most frequent (18 patients), followed by bronchitis/bronchopneumonia (nine patients), anaemia (six patients) and history of prematurity (five patients). In the remaining 14 patients, the following diagnoses were established: urinary tract infection, history of rickets, cervical lymphadenitis, hypercalciuria, breath-holding spells, epilepsy, Quincke’s oedema, breast milk jaundice, juvenile idiopathic arthritis, hyperinsulinaemia, coeliac disease. There was no relationship between the course and severity of these disease states and alkaline phosphatase (ALP) activity. The mean age of the patients at the time of TH was 17 months ± 14 SD (range 1–60 months; median 13 months). The ALP values ranged between 15 and 127 μ kat/L (mean 36 μ kat/L ± 23 SD; median 31 μ kat/L), which was 2.5–20-fold above the age-related upper reference range. The ALP values returned to within normal limits in 12–343 days (mean 71 days ± 69 SD; median 52 days). However, exact maximal ALP levels and the duration of TH are difficult to establish because of the accidental detection of this state. The median age in our patients supports previous observations of TH preponderance between the first and second year of life. 1,3 We observed a marked seasonal clustering in September through November (Fig. 1), which is in accordance with previous reports. 1,3,4 As TH is presumed to be of infectious origin and infections tend to be more frequent during the autumn months, this could explain the seasonal occurrence. 1

Foramina parietalia permagna: report of nine cases in one family.

Nine members of a family with foramina parietalia permagna (FPP), inherited as an autosomal dominant trait are reported. Although usually benign, FPP may be associated with other malformations.

Quantitative ultrasonometry of the calcaneus in children with osteogenesis imperfecta

Aims:  Osteogenesis imperfecta (OI) is characterised by low bone density and increased bone fragility. The aim was to evaluate calcaneal quantitative ultrasonometry (QUS) parameters in children with OI and to look for relationship with the number of prevalent fractures.

Prospective Follow-up of Children with Transient Hyperphosphatasemia

were not detected. The estimate is based on the studies of Farkas and Levinel and Enzler2 who took radiographs of consecutive newborns and found a combined 18 clavicle fractures (2%) in 800 consecutive newborns. In our study3 of 626 newborns, Dr. Rosenfeld and I found 18 (2.6%) with clavicle fractures. Any conclusion that the authors draw relates to the 64 identified clavicle fractures, which represent the 10% of clavicle fractures that were probably most severe, and not to the 604+ clavicle fractures that were not detected. The 22 disease processes fall into two categories: (1) probably related to clavicle fracture and (2) possibly related to clavicle fractures, but I do not know why. I consider Erbs palsy to fall in the first category and all the others into the second. The presence of

TRANSIENT HYPERPHOSPHATASAEMIA AND MALABSORPTION SYNDROME

Transient hyperophosphatasaemia of infancy (THI) and early childhood is characterized by a temporary increase in serum alkaline phosphatase (AP) activity (mostly bone isoenzyme) without any clinical, radiological or biochemical signs of bone or liver pathology in children under 5 years of age.’q2 The distribution of THI should not exceed 4 months. The syndrome is benign. It is speculated that THI is in its tissue of origin or activation of normal amounts of circulating enzyme or impaired clearance of AP from the circulation.2 Although some authors have documented evidence for an infectious origin of THI3 and a tendency to cluster during the autumn and winter months has been de~c r ibed ,~ the exact aetiology of THI remains unclear. Between 50 and 75% of cases reported in the literature did have related failure to thrive or diarrhoea,’-5 so these symptoms are considered to be a common clinical association. Mild dyspeptic problems usually precede the detection of THI. No causal relationship has been discovered between THI and gastrointestinal disorders. We would like to draw readers attention to the possibility of coincident manifestation of two distinct conditions. We recently treated a patient aged 15 months who was admitted to our Department of Pediatrics because of failure to thrive and diarrhoea. Nothing important was in his personal history and he received regular vitamin D prophylaxis. No pathogen was found in the stool. Laboratory investigation revealed an enormous increase of serum AP activity, 20 times above the upper reference level, predominantly caused by the bone isoenzyme. All other biochemical parameters, including plasma and urinary concentrations of calcium and phosphate, as well as liver and kidney function tests, were within normal limits. There were no signs of rickets on X-ray of the wrist. These results were consistent with a diagnosis of THI, which was finally confirmed by a decrease of AP activity to normal values within 6 weeks. However, the patient’s height on the third percentile, iron deficiency anaemia and recurrent diarrhoea led us to perform a biopsy of small intestine mucosa biopsy. Analysis of the biopsy specimen showed partial villous atrophy with abnormal surface epithelium, strongly reduced activity of lactase, and raised intraepithelial lymphocyte count. Circulating IgA and IgG antiendomysium antibodies were present. According to previously published criteria: such findings were consistent with coeliac disease. After withdrawal of gluten from the diet we observed full clinical remission, and the boy started to gain weight. We concluded that gastrointestinal disturbance can often accompany THI, but this fact should not be overestimated to avoid delay of diagnosis and treatment of malabsorption syndrome. Therefore, when dealing with gastrointestinal disturbances accompanying THI, one should look after the nutritional status and anthropometric parameters of the child, in order to avoid underdiagnosis of malabsorption syndrome.