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Summarized here are some highlights of the joint meeting of ESPE and LWPES in Lyon, France, September, 2005.
Congenital Hyperinsulinism
The molecular basis of congenital hyperinsulinism in
infancy (CHI) was reviewed by de Lonlay et al (S7-30) from Paris. CHI is
characterized by severe dysregulation of insulin secretion that causes profound
hypoglycemia. It is associated with either focal or diffuse pathology of the
endocrine pancreas. These pancreatic anatomical forms of pathology require
major differences in the treatment of CHI.
Mutations in genes encoding the beta-cell sulfonylurea
receptor (SUR1) and the inward-rectifying potassium-channel (Kir6.2) have been
identified in CHI. These genes encode subunits of KATP channels which couple
glucose metabolism to insulin release. Hypoglycemia is related to homozygosity
of a paternally inherited mutation of one of these genes that results in
diffuse hyperplastic pancreatic pathology. The CHI is more complex in the
diffuse form which present as a heterogeneous disorder involving several
genes and various inheritances. Forms occurring in the CHI, resistant to
medical treatment, are mostly due to mutations of the KAPT channel with a
recessive inheritance and often require total pancreatectomy. Forms occurring
after the first month of life are mostly sensitive to medical treatment and may
be related to de novo or dominantly inherited mutations. Nonetheless
about half of the patients in the later group do not carry these mutations.
Focal lesions in CHI represent areas of adenomatosis
related to the loss of the maternal allele in the 11p15 region. It is mostly
sporadic. This somatic molecular event disrupts the balanced expression of
imprinted genes involved in the control of cell growth and lead to pancreatic
tumor development. This clinical form of CHI is potentially curable by limited
pancreatic resection. Until recently rather invasive techniques, with direct
pancreatic catheterization using transhepatic portal venous sampling, and
arterial calcium-stimulated venous sampling were used to aid the surgeon with
the localization and the extent of the pancreatectomy. In localizing pancreatic
focal lesions Otonkoski (S7-31) from Helsinki successfully used the PET
technique to detect neuroendocrine tumors using (18F)-DOPA uptake by the
hyperplatic islet cells. Very promising results were also obtained by several
other centers, including Blankenstein et al (P3-1260) from Berlin and Stanley
et al (S7-32 and P3-1262) from Philadelphia. All patients with positive PET
technique localization of a focal lesion had the tumor removed while preserving
the healthy portion of the pancreas and the hypoglycemia ceased. Stanley et al
described their experience in 217 cases with neonatal hypoglycemia over 6
years. They confirmed the accuracy of the PET scan technique performed before
surgery and recommended that candidates for surgery be referred to specialized
centers.
Growth Hormone Treatment
Simon et al (OR3-75) from Paris reported on the early
recombinant human growth hormone (rhGH) treatment started one year after
initiation of glucocorticoid therapy of children with juvenile rheumatoid
arthritis. This randomized-controlled study was carried out over 3 years in
prepubertal children receiving prednisone (0.6 ± 0.4 mg/kg/day) and rhGH (0.46
mg/kg/week). Growth was maintained at a normal rate for chronological age and
lean body mass was improved. However, there was no significant effect on fat
mass or bone mineralization. Although increased insulin resistance was expected
with rhGH therapy, glucose intolerance was mild and transient, occurring only
in pubertal patients. It was concluded that rhGH treatment was safe and
prevented growth retardation in these patients. However, higher steroid doses
may limit the beneficial effects of rhGH. Thus rhGH treatment may prove to be
more significant when given early as prevention of growth retardation. Further
studies that follow patients until final height is achieved and focus on muscle
mass and long-term function are in progress.
Mauras et al (P1-149)
from Jacksonville reported on the limited efficacy of rhGH treatment during the
so-called transition period in a well defined cohort: children with GH
deficiency (GHD). Subjects had been treated early and reached normal final
height, metabolic control, muscle strength, and bone mineral density (BMD). The
authors delved with the question of the timing of rhGH treatment: namely the
continuation or the temporary discontinuation throughout late adolescence to adulthood,
until the persistence of GHD could be re evaluated. A phase III double-blind,
randomized 2-year trial was performed. Subjects were classified in 3 groups:
persistently GHD randomized to either continued rhGH treatment or to placebo
injections, and GH sufficient on retesting considered controls and given no
treatment. After 2 years metabolic measures, cardiac function, BMD, and quality
of life were comparable in all 3 groups. It was concluded that GHD adolescents
in good metabolic control at time of epiphyseal fusion may safely discontinue
rhGH therapy for at least 2 years. If such an attitude is chosen, a careful
follow-up is needed to determine if and when rhGH is warranted. Such an
approach may help manage the so-called transition period before adulthood in
previously well treated GHD patients. (Refer to abstract on page 14.)
IGF-I
Camacho-Hubner, Savage,
and Underwood (S10-40) from London and Chapel Hill updated their experience
with rh insulin-like growth factor (IGF)-I alone or combined with rhIGF binding
protein (BP)-3 in patients with GH insensivity (GHI) due to GH receptor
defects, to growth attenuating antibodies to GH, or to extreme insulin
resistance due to genetic defects. The doses of rhIGF-I ranged from 60 to 120
mg/kg/day. Height improved by 1.2 to 1.5 SD over 2 years of therapy; the best
responses occurred when the treatment was started at a young age. However
long-term responses varied among treated children and were not as well
sustained as the responses elicited with rhGH therapy in GHD children. Adverse
events were: coarsening of facial features, hypoglycemia in younger children,
lymphoid hyperplasia, and pseudotumor cerebri. The combined rhIGF-I and IGFBP-3
(0.5 to 2 mg/kg/day) given as a single injection, resulted in a prolonged half-life
of IGF-I, allowing once daily injection with appropriate tolerance and good
results. The only treatment available for patients with severe genetic insulin
resistance and genetic IGF defects is rhIGF-I. A multicenter open labelled
phase III study is in progress in children with GHI.
Genetics of GH Receptor
A recent issue of interest focuses on genetic factors
possibly influencing the growth response to rhGH therapy. A provocative, well
documented study of GH gene polymorphism and variations in growth in GH treated
children by Bougneres et al (S3-20) from Paris investigated the potential role
of the 2 forms of the GH receptor (GHR), the full length (fl) or the exon-3
deleted (d3) receptor, on the response to rhGH treatment. In transfection
experiments a 30% increase in the transduction in GH signalling had been
demonstrated in d3 homo or heterodimers of the GHR. This suggested that there
could be a potential genetic factor influencing the response to rhGH. An
advantage for the d3-allele carriers was shown in children with small for
gestational age or idiopathic short stature (ISS) who showed 1.7 to 2 times
greater growth acceleration as compared with those who did not have this GHR.
These results were confirmed in a cohort with complete GHD treated for 3 years
by Thomas-Teinturier (P1-152) from Paris.
Two other studies were at variance with these data. Blum et
al (OR3-71) from Lilly’s Genesis Program studied a large cohort of GHD children
treated with rhGH (0.2 + 0.06 mg/kg/week). This group evaluated the
first year of rhGH treatment response according to the exon-3 genotype and
reported a small but consistent (although not significant) increase in growth
parameters in the d3 groups. Ito et al (P1-150) from Japan evaluated Japanese
children with partial GHD and could not demonstrate a significantly increased
growth during the first rhGH treatment year in patients with 3d allele.
However, the initial finding by Bougneres remains an
important and provocative paper that will generate future studies to better
understand the large individual differences in growth response to rhGH. The
role of exon-3 genotype must be confirmed with strong methodological approaches
selecting groups according to etiology of short stature, rhGH dosage, duration
of treatment, and ethnicity before it can be applied as a genomic tool for
therapy.
Congenital Adrenal Hyperplasia
The presence of
testicular adrenal rest tumors in congenital adrenal hyperplasia (CAH) patients
is known to cause Leydig cell failure and impaired spermatogenesis. These rest
tumors are often unresponsive to intensified corticoid therapy. Bachelot et al
(OR 14-142) from Paris reported treatment of 3 adult patients with mitotane, an
adrenolytic agent, for 2 to 3 years and obtained a reduction in the testicular
rest tumor volume with an improved sperm count. This may represent a potent
tool to improve fertility of some poorly controlled CAH patients.
Ovarian Failure
The causes of premature ovarian failure (POF) are rarely
identified in adults. However Conway (S9-38) from London approached this issue
with data related to optimization of the substitutive estrogenic therapy in
adolescents. Age at onset of this treatment was critical for adult carotid
intima media thickness, predictive of vascular complications, and was inversely
correlated with the estrogen dosage. Appropriate uterine thickness for future
pregnancy was obtained if treatment was not delayed. Finally, better results in
assisted conception with donated oocytes were also obtained in women with early
ovarian failure who received treatement before the age of 14. These data may
also be relevant to patients with gonadal dysgenesis and those with ovarian
failure secondary to cancer therapy in pediatric practice.
Raphaël Rappaport, MD
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Current GGH - Vol. 24 No. 1
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