PITUITARY DWARFISM IN THE R271W PIT-1 GENE MUTATION

The Pit-1 gene encodes the POU-domain transcription factor Pit-1 which is important for the differentiation of the anterior pituitary and re gulation of the PRL, GH and TSH genes. As a member of the POU domain t ranscription factors, Pit-1 contains a DNA-binding region, consisting of a POU-specific domain and a POU homeodomain. Mutation of the Pit-1 gene causes hypoplasia of the pituitary gland and deficiencies of GH, PRL and TSH. In a DNA sample from a 3-month-old girl with severe growt h deficiency from birth, single stranded conformational polymorphism a nalysis of the Pit-1 gene identified a gel shift in exon 6. DNA-sequen cing disclosed a single base mutation in codon 271 (CGG to TGG) that c hanges arginine to tryptophan (R271W) in the POU homeodomain. The pati ent presented distinct facial features with prominent forehead, marked mid-facial hypoplasia with depressed nasal bridge, deep-set eyes and a short nose with anteverted nostrils. MRI examination showed a hypopl astic pituitary gland. Low serum GH did not respond to insulin-arginin e provocation or GHRH tests. PRL levels below the detection limit did not increase in response to a TRH test. T4 and free T4 was below detec tion limit (< 20 nmol/l and < 4 pmol/l). TSH was 2.0 mU/l and showed a blunt response to 6.0 mU/l following TRH test. TBG was normal. In spi te of inappropriately low TSH and very low T4, T3 was in the low norma l range (1.4-1.6 nmol/l) and she was clinically euthyroid. The thyroid function tests are consistent with increased monodeiodination activit y and increased conversion of T4 to T3, possibly related to the Pit-1 gene mutation. GH and T4 treatment resulted in catch-up growth continu ed during 5 years of therapy. Conclusion Reports of nine other cases o f R271W mutations of different populations as well as the present Norw egian patient suggest codon 271 of exon 6 to be a ''hot spot'' for Pit -1 mutations. To enable rapid and simple detection of this type of de novo mutation we have designed a specific amplification-created-restri ction-site assay to check for the R271W mutation in patients suspected to have this rare form of genetic defect in growth hormone production .