Frequent COL4 mutations in familial microhematuria accompanied by later-onset Alport nephropathy due to focal segmental glomerulosclerosis.

Familial microscopic hematuria (FMH) is associated with a genetically heterogeneous group of conditions including the collagen-IV nephropathies, the heritable C3/CFHR5 nephropathy and the glomerulopathy with fibronectin deposits. The clinical course varies widely, ranging from isolated benign familial hematuria to end-stage renal disease (ESRD) later in life. We investigated 24 families using next generation sequencing (NGS) for 5 genes: COL4A3, COL4A4, COL4A5, CFHR5 and FN1. In 17 families (71%), we found 15 pathogenic mutations in COL4A3/A4/A5, 9 of them novel. In 5 families patients inherited classical AS with hemizygous X-linked COL4A5 mutations. Even more patients developed later-onset Alport-related nephropathy having inherited heterozygous COL4A3/A4 mutations that cause thin basement membranes. Amongst 62 heterozygous or hemizygous patients, 8 (13%) reached ESRD, while 25% of patients with heterozygous COL4A3/A4 mutations, aged >50-years, reached ESRD. In conclusion, COL4A mutations comprise a frequent cause of FMH. Heterozygous COL4A3/A4 mutations predispose to renal function impairment, supporting that thin basement membrane nephropathy is not always benign. The molecular diagnosis is essential for differentiating the X-linked from the autosomal recessive and dominant inheritance. Finally, NGS technology is established as the gold standard for the diagnosis of FMH and associated collagen-IV glomerulopathies, frequently averting the need for invasive renal biopsies.

Psychomotor development in congenital hypothyroidism. The Greek screening programme.

In 1979 a national screening programme for congenital hypothyroidism (CH) was introduced in Greece. Treatment with L-thyroxine was started immediately after confirmation of the diagnosis, at a median age of 28 days. A standardized development test (Griffiths) was given to a group of CH infants and to healthy controls at the ages of 5-7, 11-13, 17-19, and 23-25 months. Thirty-three infants with CH were also studied at the age of 35-37 months. The mean developmental quotient of CH infants was 103.8 +/- 12.0, 100.9 +/- 10.1, 103.3 +/- 7.1 and 99.8 +/- 10.2 from the ages of 5-7 to 23-25 months, and was not statistically different from those of the controls. Statistical analysis showed no significant differences between athyreotic children and those with an ectopic gland. Our findings show that the prognosis for psychomotor development of children with CH is quite good, provided that treatment starts in the first 6 weeks of life.