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W2411712128 abstract "Review ArticleThe Genetics of the Human Growth Hormone Axis and Associated Dwarfing Disorders Thaddeus E. Kelly, MD, PhD Ramla Al-Saif, MD Najya Attia, MD Abdullah Al-Ashwal, and MD Nadia SakatiMD Thaddeus E. Kelly Address reprint requests and correspondence to Dr. Kelly: Division of Medical Genetics, University of Virginia School of Medicine, Charlottesville, VA, 22908 USA. From the Division of Medical Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh Search for more papers by this author , Ramla Al-Saif From the University of Virginia School of Medicine, Charlottesville, and the Division of Endocrinology and Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh Search for more papers by this author , Najya Attia From the University of Virginia School of Medicine, Charlottesville, and the Division of Endocrinology and Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh Search for more papers by this author , Abdullah Al-Ashwal From the University of Virginia School of Medicine, Charlottesville, and the Division of Endocrinology and Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh Search for more papers by this author , and Nadia Sakati From the University of Virginia School of Medicine, Charlottesville, and the Division of Endocrinology and Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh Search for more papers by this author Published Online:1 Jul 1996https://doi.org/10.5144/0256-4947.1996.430SectionsPDF ToolsAdd to favoritesDownload citationTrack citations ShareShare onFacebookTwitterLinked InRedditEmail AboutIntroductionGenetic studies have proven to be a power tool in the dissection of normal physiological processes. By the analysis of errors in a biological process, one can begin to understand how this process normally functions. The understanding of the cascade of blood coagulation has been greatly advanced by studies of the numerous genetic forms of coagulation defects. It is now possible to identify the majority of the components involved in the hormonal regulation of linear growth in humans. This review will present an overview of these discrete genetic components and provide illustrative cases from King Faisal Specialist Hospital and Research Centre (KFSH&RC) which involve mutations of these genes.Table 1 is a listing of the components of the growth hormone axis, giving the sites of production and action of these components.Table 1. Components of the human growth hormone axis.Table 1. Components of the human growth hormone axis.GROWTH HORMONE RELEASING FACTOR (GHRF)The gene for GHRF is located on chromosome #20. It contains five exons and codes for a mature peptide of .44 amino acids.1 GHRF was first appreciated clinically when patients developed acromegaly or gigantism as a result of tumors of the pancreas or hypothalamus that produced excessive amounts of this factor.23Thorner et al. treated a series of patients with isolated growth hormone deficiency (IGHD) with GHRF. About half of these patients responded with growth rates that were comparable to those seen in children with IGHD treated with growth hormone.4 Most patients with IGHD probably do not have a genetic defect as the cause of their dwarfism. Many of these patients are felt to have sustained a variety of CNS insults resulting in IGHD. From the studies of Thorner et al., it would appear that more often the CNS pathology involves the hypothalamus rather than the pituitary gland.4,5 It can be expected that mutations of the gene coding for GHRF will be found among a small percentage of patients with IGHD, but to date, none have been described.GROWTH HORMONE RELEASING FACTOR RECEPTOR (GHRFR)The product of the GHRFR gene is a 423 amino acid protein that, like many hormone receptors, is a G-protein.6 The locus for the gene is located in band p1.4-1.5 of chromosome 7.7 Obviously, children with IGHD who respond to GHRF do not have a defect in the receptor. Among those who do not respond, one might expect that a defect in the receptor is only rarely the causative mutation. To date, no cases of IGHD have been described as a result of mutations of the GHRFR gene. However, the mouse mutation designated as “little” was shown by Lin et al. to be a point mutation in the GHRFR.8 In addition to dwarfism, the homozygously affected mouse is characterized by a hypoplastic anterior pituitary gland.GROWTH HORMONE (GH)The growth hormone gene is located on chromosome 17 at band q2.3.9 The gene contains 5 exons and codes for a protein with 191 amino acids. Because of its small size, the GH gene is ideally suited for mutation analysis in patients with IGHD and considerable information has accumulated from these genetic analyses. It is estimated that worldwide about 15% of patients with IGHD are affected as a result of mutations of the GH gene.10 An unknown, but probably small, number might be the result of GHRF and GHRFR mutations. Despite the small size of the GH gene, a number of different types of mutations have been described in the GH gene. These mutations are associated with several different clinical phenotypes.Autosomal Recessively Inherited IGHDIt has long been recognized that dwarfism consistent with the phenotype of IGHD occurs in siblings of normal-statured parents and with increased frequency in populations where consanguinity is frequent. Analysis of the GH gene has revealed a surprising array of different mutations and phenotypes.IGHD Type 1AThe first studies of the GH gene in families with autosomal recessive IGHD use a GH cDNA and Southern blotting techniques to examine the gross structure of the GH gene in affected children.10,12 This kind of analysis will reveal major alterations in the structure of the GH gene. Most of the initial abnormalities found were complete deletions of the GH gene. Patients with these deletions demonstrate neonatal hypoglycemia, micropenis in males and as older children without treatment, have a cherub-like face and usually appear younger than their age. Mutations which result in complete lack of gene product protein are referred to as CRM-negative mutations (CRM = cross-reacting material). Assays for GH (as is true with most hormones) often use a radioimmunoassay. The assays require the presence of enough of the protein structure to allow antibody recognition to be detected by the assay. With complete deletion of the GH gene, CRM negative, treatment with GH introduces a foreign protein into the body which may elicit an antibody response. Development of antibodies during treatment of these children eventually leads to lack of any stimulation of growth with GH administration. The term “Illig-type GH deficiency” is used to describe this form of GH mutation.13 Currently, there is no satisfactory explanation for the finding that some children with deletion of the GH gene develop neutralizing antibodies, while others with apparently the same kind of deletion do not.14 There is no obvious way to differentiate these two groups other than to administer GH and observe the response in the growth rate over a period of time.Clinical CasesShown in the pedigree in Figure 1 is a family with IGHD type IA secondary to homozygous deletion of the GH gene evaluated and managed through the Pediatric Endocrine clinic at KFSH&RC.Figure 1. Pedigree of a family with homozygous deletion of the GH gene.Download FigureThe female shown as IV-1 in the pedigree was the first-born of first-cousin parents. When she was initially seen and evaluated, a diagnosis of GH deficiency was made, but she was too old to justify treatment with GH. She had experienced recurrent hypoglycemia as an infant. At 20 years of age, her height was only 114 cm and her weight 25 kg. She was sexually mature, Tanner stage V, and her X-rays showed closure of the epiphyses. Her TSH and free T4 were normal, but with an exercise test, she had undetectable levels of serum GH; her serum IGF-1 levels were quite low. A younger brother with similar laboratory values was treated with GH and at 17 years of age had reached a height of 147 cm. An unaffected male in the family, IV-7, measured 170 cm at 17 years of age.The youngest member of this family, IV-9, was diagnosed in early infancy with IGHD. He had documented hypoglycemia at three months of age and his growth rate dropped dramatically after three months of age. He was begun on thrice weekly injections of GH as an infant. At five years, he weighed 8.9 kg and his height was 77 cm. By 10 years of age, he stood 120 cm tall and had a bone age of eight years. He continues to receive GH therapy and enjoys an excellent growth rate.The affected children in this family experienced infantile hypoglycemia. Their physical appearance was characterized by frontal bossing, depressed nasal bridge, a nasal quality to their speech, micropenis and a general appearance younger than their actual age. These changes disappeared over the period of GH replacement therapy. Many children with homozygous deletions of the GH gene will develop antibodies to GH with replacement therapy, the so-called “Illig form of IGHD.” The antibodies will inactivate any GH administered and further treatment requires the use of IGF-1. Fortunately, this family does not represent the Illig form of IGHD and they were able to receive GH over an extended period without the development of neutralizing antibodies.IGHD Type BThis type of GH deficiency results from less striking mutations of the GH gene. Often, these take the form of a single nucleotide substitution which results in a change in one of the amino acids of the GH peptide. Depending on the stability of the mutated GH, assays may reveal low but detectable levels of GH in serum.15 However, with a variety of stimuli, the GH level usually does not increase.Clinical CasesShown in the pedigree in Figure 2 is a family with IGHD type IB secondary to a point mutation in the GH gene evaluated and managed through the Pediatric Endocrine Clinic at KFSH&RC.Figure 2. Pedigree of a family with homozygous point mutation of the GH gene.Download FigureThe second-born son, IV-2, in this sibship of five brothers, was born following a normal pregnancy and delivery with a birth weight of 3.3 kg. No problems were remarked upon until the family noticed poor growth at six months of age. He was referred to KFSH&RC at 10 months of age for evaluation. When first seen, his height was only 57.5 cm and his weight was 5.3 kg. The upper/lower segment ratio was 1.4. The father's height was 162 cm, the mother's height was 155 cm, yielding a predicted adult height of 165 cm. He had a prominent forehead, depressed nasal bridge, micropenis, and an undescended right testis. Levels of TSH, Cortisol, FSH and LH were normal, but following an insulin/arginine infusion, serum GH was undetectable.The patient was started on GH replacement therapy at 15 months of age and demonstrated an immediate increase in his growth rate. By nine years of age, his height had reached the 5th percentile and remained parallel to this curve over the ensuing five years.Two of the three subsequently born sons in the family, IV-3 and IV-5, presented virtually identically to their older brother. A decreased growth rate was apparent by six months of age and their facial features and micropenis were quite similar to that seen in their older brother. Treatment with GH also resulted in a similar increase in their growth rates. DNA analysis from this family showed that the males with IGHD were homozygous for a point mutation in the GH gene. Their response to GH administration is shown in Table 2.Table 2. Response to GH therapy in a family with IGHD.Table 2. Response to GH therapy in a family with IGHD.Kowarski SyndromeThis term has been applied to a specific type of GH mutation about which there is continued controversy.16 It is reasonable to expect that there are single nucleotide, or point, mutations in the GH gene which result in a GH peptide that is recognized by RIA measurement, but which has lost much of its biological activity. This condition has been called “immunoreactive GH, biologically inactive GH.” Patients would be expected to have normal or elevated levels of serum GH, short stature, delayed bone age and low levels of IGF-1. Treatment with GH would be expected to increase the growth rate. It has been speculated that many children with idiopathic short stature might fit this syndrome. Despite a vigorous search by numerous investigators, it currently seems that while this syndrome does occur, it is probably quite rare.Autosomal Dominantly Inherited IGHDIt has long been recognized that many forms of dwarfism are autosomal dominantly inherited. Most of these conditions involve skeletal dysplasias such as achondroplasia. As parents of children with autosomal recessive dwarfism secondary to deletion of the GH gene are of normal stature, despite being carriers of the deletion, one would not expect that a mutation of the GH could result in a form of autosomal dominant GH deficiency.17 The GH peptide complexes into dimers and tetramers and binds with GH binding proteins for serum transport. Single nucleotide mutations resulting in a change in a single amino acid have been shown to interfere with this tertiary structure of the GH molecule, leading to more rapid clearance and shortened half-life. Phillips and Cogan have described a dominantly inherited form of IGHD, called IGHD type II, in which a slice site mutation resulted in a truncated peptide that affected dimerization of the truncated peptide with the normal product made from the single normal copy of the GH gene.15 Affected children are less striking during infancy than IGHD type I, but it becomes apparent later that they have a dramatically reduced growth rate, with retarded bone age and low serum levels of GH and IGF-1. These patients respond to GH replacement therapy with a much improved growth rate.GROWTH HORMONE RECEPTOR (GROWTH HORMONE-BINDING PROTEIN)In 1966, Laron et al. described a syndrome of familial dwarfism with high plasma concentration of GH.18 Clinically, these children appeared to have GH deficiency, in that they had delayed bone ages and a retarded growth rate. However, these children did not experience an increased growth rate when they were administered GH. Later, it was appreciated that these children were deficient in IGF-1.19 The basic defect was recognized to be homozygous mutations of the growth hormone receptor (GHR). Most reported cases have come from the Middle East and Ecuador and are often the products of consanguineous marriages. While homozygosity for the same mutation is seen secondary to consanguinity, a variety of different types of mutations have been seen around the world.The growth hormone receptor gene is located at band 5p13.1 and contains nine exons.20 Interestingly, the gene for prolactin lies close to the gene for GH on chromosome 17 and the prolactin receptor lies close to the GHR on chromosome 5. These observations suggest that both GH and prolactin as well as their receptors arose by gene duplication, with subsequent gene divergence.Patients with the main features of Laron syndrome (short stature with delayed bone age, elevated levels of serum GH and low serum levels of IGF-1) could have a defect at several points in the GH axis. Type I Laron dwarfism is the term for patients with this phenotype who respond with increased growth to IGF-1 administration and in whom mutations of the GHR gene have been demonstrated. Laron dwarfism type II is used as the designation for a post-receptor defect in IGF-1 stimulation.21,22 Growth hormone binding protein (GHBP) is encoded by the GHR gene; alternative splicing of the GHR mRNA deletes exon 3 in giving rise to GHBP. Low levels of GHBP are found in type I Laron dwarfism and this has proven to be a valuable laboratory tool in the diagnosis of Laron dwarfism. A small number of patients have been described who fit the clinical phenotype of Laron dwarfism, except that GH and GHBP levels are normal, while IGF-1 is low. Such patients respond to IGF-1 administration with increased growth.Clinical CasesShown in Figure 3 is the pedigree including the first case of Laron dwarfism diagnosed at KFSH&RC. At seven years of age, this male, IV-9, was referred for evaluation of short stature. He had a history of poor growth since one year of age. When first seen, his height was 83 cm and his weight 10.5 kg. Thyroid function studies were normal. His serum GH levels were elevated on fasting, after exercise and following an arginine infusion. His IGF-1 level was markedly reduced. At 16 years of age, his height was 129 cm, weight 39.5 kg and his bone age was 21 years, with his sexual development at Tanner stage V. He was given a six-month trial of IGF-1 therapy, but there was no increase in height noted. At 21 years of age, his height was the same as it had been at 16 years of age. This patient illustrates the growth pattern of an untreated patient with Laron dwarfism; he had presented and been evaluated prior to the availability of IGF-1 therapy.Figure 3. Pedigree of a family with a single male affected with type 1 Laron dwarfism.Download FigureA female patient presented at eight years and nine months of age for evaluation of short stature at a time when her height was 84 cm, weight 14.1 kg, and bone age of 4.5 years. Her parents were first cousins, but there was no family history of other individuals with a similar degree of short stature. Thyroid function tests were normal, GH was elevated both on fasting and following clonidine stimulation. Her IGF-1 level was markedly reduced. She received IGF-1 and had an increase in her growth velocity from 3.8 cm/year to 8.8 cm/year.INSULIN-LIKE GROWTH FACTOR-1 (IGF-1)Insulin-like growth factor-1 is coded for by a gene on the long arm of chromosome 12, and the gene product contains only 70 amino acids.23,24 The presence of homozygous mutations at this locus would be expected to result in a form of dwarfism much like Laron dwarfism; GH levels would be high and IGF-1 levels would be absent. However, to date no such cases have been described. This suggests that complete deficiency of IGF-1 in utero may be lethal. This peptide has been used in the treatment of patients with Laron dwarfism, both types 1 and 2, with an increased growth rate. In fact, children with dwarfism involving any of the previous factors, whether genetically or nongenetically determined, would be expected to respond well to treatment with IGF-1. The availability of GH and extensive experience with treatment using this hormone has reduced the clinical use of IGF-1 to growth-retarded children with defects involving the GHR.INSULIN-LIKE GROWTH FACTOR RECEPTOR (IGF-1-R)In 1986, Franche et al. assigned the locus for IGF-l-R to 15q25-26 and Ullrich et al. published data on the structure of the receptor deduced from cloned cDNA for the receptor.25,26 The nascent peptide contains 1367 amino acids with a 30 amino acid signal peptide which is cleaved from the protein. The product is then cleaved further to yield alpha and beta subunits much like that for the insulin receptor.A patient with a deletion of the distal portion of chromosome 15q, and thus monosomy for the IGF-1-R gene, demonstrated intrauterine growth retardation (IUGR) and several birth defects.27 While this might suggest that mutations of the IGF-1-R might be the basis for a syndrome with IUGR, no such cases have been reported to date.INSULIN-LIKE GROWTH FACTOR BINDING PROTEIN (IGFBP)A series of proteins has been described as IGF binding proteins. IGFBP-1 and IGFBP-3 are both coded for by loci on chromosome #7. No mutations or diseases have been described involving these proteins. In Laron dwarfism, serum levels of IGFBP-1 are elevated; assay of this protein has been used as a parameter of responsiveness to IGF-1 therapy in patients with Laron dwarfism.OTHER SYNDROMES WITH GROWTH HORMONE DEFICIENCYPituitary-Specific Transcription Factor 1 (Pit 1)Pituitary-specific transcription factor (Pit 1) is responsible for pituitary development and hormone expression in mammals. The locus for the Pit-1 gene is on chromosome #3.29 It is now recognized that growth hormone factor-1 (GHF-1) represents the same gene and gene product as Pit 1. The development and expression of specific cell types of the anterior pituitary are regulated by Pit 1. Mutations in the Pit-1 gene are associated with deficiency of GH, prolactin and TSH. Proper treatment requires replacement of both GH and thyroid hormone. In most families reported with thyroid, prolactin and GH deficiency secondary to Pit-1 mutations, the disorder has been autosomal recessively inherited.30 This is the case of the family reported below from KFSH&RC. An interesting family was reported by de Zegher et al., in which a point mutation in codon 271 of the gene coding for Pit 1 was present in single dose (heterozygosity) in mother and child.31 The mother, who was not on thyroid replacement, delivered an infant with a striking delay of respiratory, cardiovascular, neurological and bone maturation. While there was improvement with thyroid replacement therapy, the infant did not fully recover loss of neurological function. This case argues for the important role of thyroid hormone during in utero development.Shown in Figure 4 is a family with hypothyroidism and GHD secondary to the homozygous expression of a point mutation in the Pit-1 gene evaluated and managed at KFSH&RC.Figure 4. Pedigree of a family with homozygous point mutation of the Pit-1 gene.Download FigureThe first affected child in the family, II-3, was seen at four months of age because of constipation, inactivity and anemia. Hypothyroidism was recognized, TSH was undetectable and therapy with thyroxin was begun. The sister, II-4, was recognized to be hypothyroid at one week of age and the brother, II-5, was investigated at an early age based on the family history. All three siblings had undetectable levels of serum GH following provocative stimulation. The brother, evaluated last, also had low levels of serum IGF-1.All three children were treated initially for hypothyroidism and later, GH replacement therapy was started.Hanhart SyndromeHanhart described familial panhypopituitarism in an inbred population in Switzerland, as well as on the Island of Veglia in the Adriatic.32 The disorder has also been extensively analyzed in the Hutterites, an inbred religious isolate in the United States.33 While Hanhart syndrome and Pit-1 deficiency represent autosomal recessive inheritance of multiple pituitary hormones, the two conditions are distinct. Pit-1 mutations lead only to GH, prolactin and TSH deficiency. Hanhart syndrome results in panhypopituitarism and each of the tropic hormones disappears in a typical time sequence. GH and gonadotropin deficiency occur in the first decade of life; loss of TSH function occurs in the second decade; finally, ACTH deficiency occurs in the third decade.34 The gene for Hanhart syndrome has not been mapped. Therefore, there is no information on the molecular pathology in this disorder.Fleisher SyndromeIn 1980, Fleisher et al. described the family shown in Figure 5.35 The four males had immunodeficiency characterized by deficiency of all immunoglobulin isotypes, as well as circulating B lymphocytes. Short stature, delayed puberty and delayed bone age were shown to be due to deficiency of GH. Following Fleisher's report, additional isolated and familial cases have been reported. Recognizing that the immunodeficiency seen in Fleisher syndrome is quite similar to Bruton agammaglobulinemia, Duriez et al. suggested that the defect in Fleisher syndrome is in the BTK gene, the gene responsible for Bruton syndrome.36 As is seen in Bruton syndrome, mothers who are carriers for Fleisher syndrome do not show random inactivation of the X chromosomes in their circulating B lymphocytes, but do show random inactivation among their T lymphocytes. This difference can be used to detect carriers among the females in families in which either Bruton or Fleisher syndrome has occurred.Figure 5. Pedigree of the family reported by Fleisher with x-linked immunodeficiency and isolated GH deficiency.Download FigureGH Deficiency With Large Sella TurcicaIn 1978, Parks et al. described three siblings with an apparent autosomal recessive form of combined GH and TSH deficiency.37 Replacement of both hormones was required to achieve an increased growth rate. The large sella turcica found in the siblings was thought to distinguish this family from patients with Hanhart syndrome.GH Deficiency With Small Sella TurcicaIn 1969, Ferrier and Stone described two sisters with an apparent autosomal recessive form of panhypopituitarism.38 The clinical features were severe growth retardation from infancy, recurrent hypoglycemia, markedly delayed bone age and a very small sella turcica. They showed deficiency of GH, TSH and ACTH.PYGMIESPygmies have long held a fascination among investigators and clinicians interested in short stature. Studies among the pygmies of central Africa have failed to identify a single gene or single hormonal deficiency responsible for the short stature of this population. Merimee et al. have shown that growth rates and levels of GH and IGF-1 in pygmies are normal until the age of puberty.39 At puberty, however, they fail to show an increase in growth rate or IGF-1 levels. These changes are sufficient to account for the shortened adult height. In areas where the pygmies overlap and marry with populations of normal adult height, one would expect to see a Mendelian pattern of inheritance emerge if a single gene disorder were responsible for the short stature of pygmies. This has not been observed and the pattern has been more suggestive of a multifactorial basis for the short stature of pygmies.GENETIC PRINCIPLES ILLUSTRATEDIn a busy clinical setting where children with short stature with genetic forms of hormonal deficiency are recognized, many of the basic principles of clinical genetics are observed. This truism certainly holds for the Pediatric Endocrine Clinic at KFSH&RC.Genetic heterogeneity is defined as the presence of the same clinical phenotype occurring as a result of mutations at two different genes. The phenotype of short stature, delayed bone age, micropenis, prominent forehead with depressed nasal bridge, tendency towards hypoglycemia and doll-like appearance can occur as a result of mutations at several different genes in the GH axis.Pleiotropism refers to the multiple clinical consequences that can result from mutation at a single gene. Mutations at the Pit-1 gene produce deficiency of three different hormones: GH, TSH and prolactin.Consanguinity increases the likelihood for an autosomal recessive disorder and when it occurs, this produces homozygosity for a mutation. When the son and daughter of brothers marry, a first-cousin marriage common in Saudi Arabia, there is a one in 64 chance of a child being homozygous and affected by an autosomal, recessive disorder for which one of the common great-grandparents is a carrier. Each of us is a carrier for six to seven different autosomal recessive disorders, but consanguinity greatly increases the likelihood that husband and wife will be carriers for the same disease.Founder effect occurs when a small group of people establishes a population that remains isolated over many generations. The isolation refers to selection of marriage partners; thus, isolation may occur geographically or culturally. After founder effect has been in effect for many generations, that population becomes recognized by the autosomal recessive diseases which occur at high frequency in that population. In the United States, founder effect is recognized in the Old Order Amish, the Mennonites, the Hutterites, and to a lesser degree, in the Mormons. In Saudi Arabia, certain geographical areas or large tribal groups are recognized to have certain recessive growth disorders or inborn errors of metabolism.As a result of founder effect and consanguinity, practically all of the children with mutation at a specific gene locus will be homozygous for the same mutation. This results in a highly reproducible phenotype and physicians familiar with that phenotype become highly proficient at clinical diagnosis. In outbred populations such as the United States, the same disorder will be seen much less frequently, and because an affected child is as likely to have received different mutations at the same locus from each parent, there is a greater degree of variability in the phenotype despite a similar molecular defect. All of this makes clinical diagnosis that much more difficult.While the current information about the genetics of the components of the GH axis are impressive, it is obvious that there are many unanswered questions about the regulation of linear growth in humans. The interaction of a hormone with its receptor on a target cell sets in motion a series of biochemical changes which eventually act to direct the target cell to respond to the hormonal signal. Equally fascinating and not understood are the controls and significance of the pulse release of hormones and the release of hormones in step with a circadian rhythm. Genetic defects in these processes will likely play a major role in unraveling these complicated, but normal, physiological systems.Children who are recognized to be short or to have a slowed growth rate (falling on their growth chart) deserve evaluation of a possible hormonal basis at a young age. While most children who are short do not have a specific endocrinopathy, evaluation is usually straightforward. Most importantly, endocrinopathies represent the most likely basis for successful treatment of short stature, but such treatment can only be successful when diagnosis and treatment are undertaken at an early age.ADDENDUMIn 1996, Wahnrajch et a" @default.
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W2411712128 title "The Genetics of the Human Growth Hormone Axis and Associated Dwarfing Disorders" @default.
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