LETTERS FROM FAMILIES
Hi Linda!
     It's MW, mom to Alex (11 yr-trisomy 14 mosaic). Since I last sent you the saga of our endocrinology visit (and thanks again for your input). I wanted to let you know what we found out.
     The arginine/clonidine stimulation test showed Alex to be "significantly" growth hormone deficient. His bone age is currently lagging by 2 years and 3 months.
     The endocrinologist recommended GH therapy. He did preface the suggestion with "I can't guarantee anything...due to the trisomy condition". Covering his posterior I think. :-)
     The next step was to see if our insurance would take on the treatments. Yea!! It did. We just owe our $10.00 co-pay per prescription. The syringes etc. aren't covered but that's only $24.00 every 3 months. We were elated!!
     The paraphernalia has arrived. We go for our "teaching" in the clinic on Wed. Alex is looking forward to the possibility of growing but not the shots 6 times weekly. I think we're all excited/apprehensive.
     Alex started growth hormone on September 23. On October 31st we measured him on the doorpost at home. He had grown 5/8th's of an inch!! Alex was absolutely thrilled and we were singing and dancing!!
     Thanks for being here!

Several of our families are fortunate to have extended family support. The following correspondence is from a loving grandfather, an organic chemist, whose research facilitated the growth hormone treatment of his grandson, who happens to have Down syndrome.

Value of Growth Hormone Replacement Therapy
     This memo reviews the reasons for the use of human growth hormone (rhGH) in treatment of Down syndrome (DS). Two major objectives are addressed in this report. It should be understood that this is an analysis of the information available and does not constitute a recommendation for any specific product or treatment.
     OBJECTIVE ONE - Maintain the optimum physical development to insure they can gain maximum improvement from the impending medical breakthroughs especially in the areas of biochemical and genetic technology.
     First challenge - Insure the full growth of the head/brain from the onset of growth. 80% of the individuals with Down's syndrome arc microcephalic by the age of 5 years (1). The average DS head is 2 standard deviations below the size of a normal child's head (2). The recognition of this fact a special chart has been developed for the measurement of head circumference, for individuals with DS. This problem expresses itself in the size (weight) of the brain. Through 22 weeks of gestation children with DS have normal brain weights, but by birth they begin to demonstrate a trend toward lower values After 5 years DS brains are found to be 30% to 50% smaller than normal (2).
     OBJECTIVE FULFILLED - It has been demonstrated that treatment of a child starting from 2 months age can produce a normal size head circumference/brain in a DS individual insuring that microcephaly will not prevent him from taking full advantage of any future technological developments that will improve brain function.
     Second Challenge - The nerve density in the brains of DS individuals has been found to be significantly lower that normal. In studies taking an actual neuron density count in DS vs. normal individuals the following data was obtained from the hypothalamus (3):

Brain Area	Neurons per square millimeter
	Control	DS
Arcuate Nucleus	422	85
Ventromedial Nucleus	318	59

     The hypothalamus controls the endocrine system, including the release of release of growth hormone releasing hormone (GHRH). In addition the neurons themselves are smaller and the dendritic trees extending from the neurons are thinner and reduced in number. In control brains, the Arcuate Nucleus (ARC) consisted of isomorphic, densely packed, spindle shaped neurons... In DS brains, the ARC was composed of loosely packed, small, spindle like neurons. In DS not only are the cortical neurons reduced in number, but the number of synaptic spines is also reduced and also very thin. In DS, there are few spines, and those that are present tend to be long with thin necks. Long thin necks have higher resistance to current flow than those that are short and stubby, leading to a greater voltage drop from the spine head to the dendrite shaft. The ontogenesis of spine formation DS suggests that before birth normal spines arc present but after birth there is an arrest of spine development that parallels cognitive dysfunction (2). With early growth and development, the normal dendritic tree continuously expands. In Down syndrome at 4 months of age, the neurons show a relatively expanded dendritic tree, but during the first year the dendrites stop growing and become atrophic relative to control neurons. (3) We have seen no data on the specific effect on rhGH on neuron/dendrite growth in humans, but studies have been undertaken with the Snell dwarf mouse where the pyramidal neurons located in layer V were found to have small perikarya (neuron structure) and short primary dendrites with sparse branchings. After administration of bovine growth hormone (bGH) and thyroxine (T4) during the first 20 days of post natal life, this retarded neuronal growth was restored to normal: neuronal perikarya were enlarged, and the dendrites were thicker, with denser branchings. (4)
     OBJECTIVE ADDRESSED - It is important to preserve the neuronal density and dendritic structure that is found in the neonatal DS brain. It would certainly be more desirable to expand these nerve structures, but if the objective is to maintain them from entering an atrophic stage rhGH appears to be our best available pharmaceutical treatment. It (rhGH) causes growth of all issues of the body that are capable of growing. It promotes both increase sizes of the cells and increased mitosis with increased numbers of cells. (5)
     FUTURE DEVELOPMENTS - In the mid 80s the development of recombinant chemistry combined with advance in analytical techniques ushered in a major new era in biochemistry. It allowed chemist to produce intricate DNA, RNA and protein molecules that had previously been too complex to even consider reproducing. The fruits of this technology explosion are now being felt throughout the medical world. Human growth hormone was one of the first products to arise from these developments, but now they extend far beyond the original replication of this simple 191 amino acid protein. Growth factors are being uncovered and reproduced specifically for blood, bone and nerve cell and structures. In nerve technology the most promising of these is a neuroimmunophilin discovered by Guilford Pharmaceutics Inc. and now being developed by Amgen Corp. Specifically it grows dendritic trees on neurons. (6,7) The commercial driving forces for this development, are Parkinson's and Alzheimer's disease, but if it is successful it will surely give equally positive results in DS. This technology explosion is just beginning and efforts in the field of genetics are also moving at an accelerated rate, e.g. geneticists are learning how to turn on and off specific genes. They also know that there are exactly 1005 genes in the 21st chromosome, and they believe less than 2% of them produce the DS phenotype. DS individuals should be prepared to benefit from the impending advances.
     OBJECTIVE TWO - Improve the health and quality of living of the DS individuals.
First, growth hormone increases the rate of protein synthesis in all cells of the body...It directly enhances transport of at least some and perhaps most amino acids through cell membranes to the interior of the cells. This increases the concentrations of amino acids in the cells and is presumed to be at least partly responsible for the increased protein synthesis. Even when amino acids are not increased, growth hormone still causes protein to be synthesized in increased amounts in the cells. This is believed to be partly due to a direct effect on the ribosomal machinery, making it produce greater numbers of protein molecules. Over more prolonged periods of time. growth hormone also stimulates the transcription process in the nucleus causing formation of increased quantities of RNA. This in turn promotes protein synthesis. (5)
     Growth takes place throughout the body, in bones, cartilage, muscles, and the nervous system. In a young DS child the change in muscle tone is truly dramatic, and a weak, listless child becomes a strong, alert active child in a matter of days.
     Second, growth hormone increases mobilization of fatty acids from adipose tissue, and increases the use of fatty acids for energy... In addition, in the tissues it enhances the conversion of fatty acids to acetyl-CoA with subsequent utilization of this product for energy. Therefore, under the influence of growth hormone, fat is utilized for energy in preference to both carbohydrate and proteins. (5)
     Finally, growth hormone has three major effects on cellular metabolism of glucose. These effects are a) decreased utilization of glucose for energy, b) marked enhancement of glycogen deposition in the cells, & c) diminished uptake of glucose & glycogen. (5)
     Thus in effect, growth hormone enhances the body protein, uses up the fat stores, and conserves carbohydrate. It is probable that the increased rate of growth results mainly from the increased rate of protein synthesis.
     We have seen the practical results of the rhGH hormone replacement program on Neal in his first year.

1. Head circumference grew dramatically moving him from microcephalic to normal in 4 weeks (grew 1 inch in 1 month).
2. Rapidly developed good muscle tone. His body firmed up and his physical strength was greatly improved.
3. Was reaching for, picking up and playing with toys at eight months.
4. Babbles and laughs constantly since six months.
5. It is obvious that any problems with the SAMe cycle did not prevent sufficient production of methionine which would have restricted the production of proteins.
6. Prior to the introduction of rhGH his urine frequently had the odor of maple syrup. Possibly unabsorbed branched chain amino acids or ketones formed by insufficient metabolism of food. It was stopped immediately when rhGH was administered.
7. Tooth buds all visible and in orderly array through the mouth, with four teeth fully erupted at twelve months.
8. Able to pull himself to standing position at twelve months, creeping at 12 months and standing momentarily.
9. Spoke first word at 13 months.

References

1. Wisniewski KE. Am J Genet Suppl 1990;7:274-281.
2. Wisniewski KE. Growth Hormone Treatment in Down's Syndrome, J Wiley & Sons 1993.
3. Wisniewski KE., Bobinski M. in The Morphogenesis of Down Syndrome. Wiley-Liss, Inc. 1991, 153-167.
4. Noguchi T, Sugisaki T. Tsukada Y. Neurchem Pathol 1984; 2:123-138.
5. Guyton AC. Human Physiology and Mechanism of Disease, WE Saunders Co. 1987.
6. http://www.mgipharma.com
7. http://www.amgen.com