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Submitted on July 2, 2004
Accepted on January 19, 2005
Paediatric Endocrinology, University Children's Hospital, Inselspital, CH-3010 Bern, Switzerland; National Institute for Medical Research, Mill Hill, London NW7 1AA, United Kingdom; Hôpital Robert Debré, Department of Paediatric Endocrinology and Diabetology, 48, Boulevard Sérurier, F-75019 Paris, France; University-Children's Hospital and Growth Research Center, D-72076 Tübingen, Germany
* To whom correspondence should be addressed. E-mail: primus.mullis{at}insel.ch.
Four distinct familial types of isolated growth hormone deficiency (IGHD) have been described so far, of which type II, IGHD II, is the autosomal dominant inherited form. It is mainly caused by mutations within the first 6 base pairs of intervening sequence 3 (5'IVS-3). However other splice site - and missense mutations have been reported. Based on in vitro experiments and transgenic animal data there is strong evidence that there is a wide variability in phenotype in terms of the severity of GHD. Therefore, we studied a total of fifty-seven subjects belonging to 19 families suffering from different splice site- as well as missense mutations within the GH-1 gene. The subjects presenting with a 5'IVS-3 + 1 / + 2bp splice site mutation leading to a skipping of exon 3 were found to be more likely to present in the follow-up with other pituitary hormone deficiencies. In addition, although the patients with missense mutations have previously been reported to be less affected, a number of patients presenting with the P89L missense GH form, showed some pituitary hormone impairment. The development of multiple hormonal deficiencies is not age dependent and there is a clear variability in onset, severity and progression, even within the same families. The message of clinical importance from these studies is that the pituitary endocrine status of all such patients should continue to be monitored closely over the years, as further hormonal deficiencies may evolve with time.
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