We, the investigators at the University of Texas Health Science Center at San Antonio, want
to learn if height and IQ (intelligence quotient) scores are improved by growth hormone (GH)
treatment in children with chromosome 18 deletions and abnormal growth. Data from a previous
study showed that growth hormone improved height in all children with 18q- and growth
hormone deficiency. In addition, most of the study participants on growth hormone treatment
showed an increase in IQ scores.
Our hypothesis with reference to children with 18q deletions who have abnormal growth are:
- growth hormone will improve growth; and
- growth hormone will improve performance IQ (pIQ).
Therefore, our specific aims are to evaluate the impact of GH treatment on:
- linear growth in children with 18q deletions who have abnormal growth but who are not
classically growth hormone deficient; and
- pIQ in children with 18q deletions who have abnormal growth
GOALS AND METHODS:
We have already investigated the growth axis in 50 individuals with a cytogenetically and
molecularly confirmed 18q deletion by determining the height, growth velocity, insulin-like
growth factor 1 (IGF1), IGF binding protein 3 (IGFBP3), bone maturation and growth hormone
(GH) response to pituitary stimulants (clonidine and arginine). To summarize: children with
18q deletions are short: 64% have a height more than 2 S.D. below the mean. Affected
children also grow slowly: 68% have a growth velocity more than 1 S.D. below the mean. Half
of the individuals have delayed bone maturation. Growth factors are skewed downward: 72% of
the IGF1 values and 83% of the IGFBP3 values are below the average for normal children.
Similarly, 72% of the children failed to adequately respond to the GH stimulants. In the
total group of 50 children, 20 (40%) were classically GH DEFICIENT (height <-2 S.D.,
velocity <-1 S.D., bone age <-2 S.D., IGF1 < -1 S.D., IGFBP3 <-1 S.D., peak GH <10 ng/ml by
polyclonal GH assay) and are on GH treatment. Of the remaining 30 children, 28 have multiple
abnormalities of the growth axis, primarily growth velocity <-1 S.D. (ABNORMAL GROWTH), but
did not qualify for GH treatment according to criteria set by their private insurer. Almost
all of these children had abnormalities suggestive of hypothalamic dysfunction involving TSH
(thyroid stimulating hormone) and prolactin. None have CNS (central nervous system)
abnormalities of the pituitary on MRI. Thus we suspect that many of these children have
neurosecretory dysfunction. Parental heights are slightly above average (father (height
standard deviation score) HTZ = 0.3 +/- 1.2, mother HTZ = 0.1 +/- 1.1) and none of the
children are overweight.
Of 8 children with GHD (growth hormone deficiency) on prolonged GH treatment, growth rates
are comparable to those reported by the NCGS (National Collaborative Growth Study) for
idiopathic GHD at 1 and 2 years. The mean change in height over a 28-month period for the
treated group in our study was +1.8 S.D. while it was -0.25 S.D. in the untreated group
(p<0.001). No known complications of GH treatment were encountered. Furthermore, because of
an association between 18q deletion, hypomyelination and cognition, some non-statural
benefits of GH treatment were examined: specifically, the performance intelligence quotient
(pIQ) was measured using a detailed battery of neuropsychological instruments. The pIQ was
measured because many of the children are hearing impaired and a full scale IQ, which relies
on verbal skills, would underestimate their abilities. The GH-treated group was compared to
an untreated group. The GH-treated group (n=8) showed an increase in pIQ of 23 points (range
0 to +47) while the untreated group (n=6) showed no change (range -2 to +6)(p=0.003). Based
on these observations, we conclude that GHD children with 18q deletions respond favorably to
GH therapy in terms of both linear growth and pIQ. In contrast, children with 18q deletions
with abnormal growth who are not classically GH deficient, show little change in height S.D.
and pIQ over time. Therefore, we propose to study (NEW STUDY) whether children with 18q
deletions with abnormal growth can benefit from GH treatment. For purposes of this proposal,
abnormal growth is defined as a growth velocity <-1 S.D.
Initial auxology, endocrine testing, and neurocognitive evaluation will be performed at our
Center. Auxologic and neurocognitive testing will be repeated after 18 months of therapy at
our Center. These studies are done at our Center to assure consistency of evaluation, which
is a particular concern for the neurocognitive tests. Many of the children will also
participate in other studies in our Center (MRI imaging, psychological evaluations of family
function) that are not part of this application. Children begun on GH treatment will need to
be seen by a pediatric endocrinologist for dosage adjustment after 3, 6, 9 and 12 months.
The untreated children will also need to be seen by a pediatric endocrinologist for
auxologic studies at the same time points. We enrolled 20 children in this study. Few of the
children are located in any single geographic area; therefore, we will have 12-20 centers
seeing individual children. Rather than developing new forms, standard NCGS intake forms
will be used for the intermediate visits by the local pediatric endocrinologists.
Control Group: We have more than 20 previously studied children, 5.3 +/- 2.8 years of age,
who have abnormal growth and have never received GH. All have undergone extensive auxologic,
hormonal, neurocognitive and neuroimaging evaluations. These studies were done 15.4 +/- 9
months ago (range 11-28 months). We have already shown that, in the absence of intervention,
height S.D. and pIQ are stable over time; therefore, these children can serve as their own
We also have 20 children who are GH deficient and on treatment that are participants in
another study. These children were evaluated prior to the initiation of treatment. All are
scheduled to be re-evaluated at least twice in a five-year period. The data on the first 8
treated children were reported above. These children will serve as important "disease
NAME OF FDA APPROVED DRUG TO BE USED:
We are using Nutropin AQ in this study.
METHOD OF TREATMENT ASSIGNMENT:
All children who have previously been evaluated in our Center were offered the opportunity
to receive GH, subject to the following limitations:
- The prior evaluation must have occured at least 12 months preceding the anticipated
date of initiation of GH therapy.
- May not be on GH treatment or have been previously treated with GH
- Growth velocity <-1 S.D. with normal weight for length/height
- Must be willing to return to our Center for reevaluation of auxologic parameters and
neurocognitive testing prior to the initiation of GH therapy.
- Must be willing to administer GH on a daily basis for 12-15 months
- Must be willing to return to our Center for re-evaluation after 12-15 months of
The majority of the 20 patients for this study came from the group of children who have been
New children (families) being seen for their initial visit in our Center, will be offered
the opportunity to participate in the clinical trial if they have abnormal growth and are
not classically GHD. However, these children will be randomly assigned either to treatment
or non-treatment for the initial 12-month period. Both treated and untreated children
(families) must comply with limitations 2-6 above.
The minority of the 20 patients for this study came from the group of children who are new.
TYPE OF RANDOMIZATION:
Randomization applied only to children who are new to our Center. When the results of growth
factor and GH provocative testing are known, a two-step process will occur. Children, who
are GHD, will be started on GH and entered into an on-going study already underway in our
Center. They will not qualify for participation in the proposed NEW study. Children who have
abnormal growth will be assigned to either the treatment or non-treatment category, using an
adaptive randomization scheme to avoid imbalances in the numbers of subjects allocated to
the two groups.
PLANNED INTERIM ANALYSIS:
GH-treated children will be seen at 3, 6, 9 and 12 months by their local pediatric
endocrinologist for measurement of height and weight, review of medical history and dosage
adjustment. Untreated children will be seen at 3, 6, 9, and 12 months for measurement of
height and weight and review of medical history.
- Diagnosis of chromosome 18 deletion (cytogenetics report)
- Children with abnormal growth but who are not classically growth hormone deficient
- Children previously on growth hormone therapy