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
.