Molecular defects in the growth hormone-IGF axis
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《美国医学杂志》
Division of Endocrinology, Department of Pediatrics, CS Mott Childrens Hospital, University of Michigan Health System, Ann Arbor, USA
Abstract
Many previously uncharacterized cases of poor growth in children, i.e. idiopathic short stature, are now attributable to genetic defects in the GH-IGF-1 axis. This paper will provide an overview of the clinical findings of patients identified with various genetic defects of the GH/IGF-1 axis with an emphasis on the more recently described syndromes.
Keywords: Growth hormone; Genetic defects; Mutations
Abbreviations
AR Autosomal recessive
AD Autosomal dominant
GHD Growth hormone deficiency
GHR Growth hormone receptor
GHRH Growth hormone releasing hormone
GHBP Growth hormone binding protein
HESX1 paired-like homeobox gene expressed in embryonic
stem cells
JAK2 Janus kinase 2
LHX-3,4 LIM-type homeodomain protein
PROP1 prophet of pit 1
POUF1 Pit-1, Oct-1; Oct-2; Unc-86
STAT Signal transducer and activator of transcription
The GH/IGF-1 axis plays an essential and central role in statural growth. Whereas abnormalities such as mutations in the GH gene locus are well established causes of genetic defects in this axis, a more thorough understanding of the different components of this axis has allowed for the identification of newer molecular defects in this axis. Hence as the physiology of the GH-IGF-1 axis is further elucidated, many previously uncharacterized cases of poor growth in children, i.e. idiopathic short stature, are now attributable to genetic defects in the GH-IGF-1 axis. This paper will provide an overview of the clinical findings of patients identified with various genetic defects of the axis with an emphasis on the more recently described syndromes.
Growth hormone secretion from the anterior pituitary gland is pulsatile, controlled by the stimulatory effects of GH-releasing hormone and the inhibitory effects of somatostatin, which are both released by the hypothalamus. Growth hormone, once released into circulation, binds to the extracellular component of the growth hormone receptor and induces receptor dimerization and/or a conformational change of pre-dimerized receptor complexes. This sequence of events results in phosphorylation of the Janus kinase 2 (JAK2) molecules, which in turn phosphorylates the intracellular portion of the growth hormone receptor, and also undergoes further tyrosine autophosphorylation. The formation of the JAK2 kinase-GH receptor complex leads to activation of the STAT pathway. STAT 1, STAT3, and STAT5 are cytoplasmic proteins that form homodimers and heterodimers, translocate to the nucleus, and bind to response elements on DNA to stimulate transcription of genes. Stat5b has been directly implicated in the GH-induced production of IGF-1. IGF-1 mediates many of the anabolic actions of growth hormone. IGF-1 binds to the IGF1 receptor, which mediates IGF actions on all cell types.[1]
HYPOTHALAMIC-PITUITARY DEFECTS
The graded expression of transcription factors leads to development of the anterior pituitary and its distinct cell types.[2] Several mutations in pituitary-specific transcription factors have been identified leading to growth hormone deficiency.
Septo-optic dysplasia is a condition of abnormal brain development, in which there is optic nerve hypoplasia, agenesis or hypoplasia of the septum pellucidum and/or corpus callosum, and hypothalamic-pituitary deficiencies, including isolated growth hormone deficiency (IGHD), or growth hormone deficiency in combination with TSH, ACTH, and gonadotropin deficiency.
HESX1 is a paired-like homeodomain transcription factor expressed in the developing pituitary gland. Mutations in this gene leading to decreased activity have been found in two siblings with panhypopituitarism, absent septum pellucidum, optic nerve hypoplasia, and agenesis of the corpus callosum, implicating a role for HESX1 in mediating forebrain development.[3], [4] Another mutation in HESX1 was recently discovered, in a patient with septo-optic dysplasia and isolated growth hormone deficiency.[5] Experimental evidence suggests that this particular mutation results in the production of an altered HESX1 protein with enhanced DNA binding activity that abrogates the transcriptional activity of PROP1, another transcription factor necessary for pituitary development.
PROP1 is thought to be involved in the differentiation of somatotropes, thyrotropes, lactotropes, and gonadotropes. Mutations in PROP1 leading to reduced DNA-binding and transcriptional activity have been identified in patients with combined pituitary hormone deficiency. These patients have a deficiency of TSH, GH, and prolactin, LH and FSH.[6] Patients with a demonstrated gonadotropin deficiency may present with failure to enter puberty spontaneously whereas other patients do enter puberty but have a subsequent loss of gonadotropin secretion. Although PROP1 is directly implicated in the differentiation of only 4 out of the five anterior pituitary cell types, some patients have also been described with ACTH deficiency. PROP1 mutations are believed to relatively common (32-50%) genetic causes of combined pituitary hormone deficiency.[7]
POU1F1 (also known as Pit1 or GHF-1) is another pituitary transcription factor that is responsible for the determination of lactotropes, somatotropes, and thyrotropes. It activates GH and prolactin gene expression, and can bind to and transactivate the TSH-B promoter. Accordingly, patients with POU1F1 mutations demonstrate GH, prolactin and variable TSH deficiencies.[8] It can be inherited in an autosomal dominant or recessive manner, but POU1F1(Pit-1) mutations are not a common cause of combined pituitary hormone deficiencies.
Rathke's pouch initially forms but fails to grow in LHX3-knockout mice.[7] Humans have been found to have mutations in the LHX3 gene, a LIM-type homeodomain protein, and demonstrate complete deficits of GH, PRL, TSH, and gonadotropins in addition to a rigid cervical spine leading to limited head rotation. LHX4 is a related protein which similar to LHX3 regulates proliferation and differentiation of pituitary lineages. A patient has been identified with a dominant mutation in this protein demonstrating deficiencies of GH, TSH, and ACTH, a small sella turcica, a hypoplastic anterior hypophysis, an ectopic posterior hypophysis, and a deformation of the cerebellar tonsil into a pointed configuration.[9]
Finally, Rieger syndrome is a condition with abnormal development of the anterior chamber of the eye, dental hypoplasia, and a protuberant umbilicus associated with growth hormone deficiency. All mutations in RIEG (Pitx2) found thus far have been heterozygous, with an autosomal dominant inheritance.[10]
To date, no mutations of the GHRH gene have been found, although mutations have been found in the GH-releasing hormone receptor. A number of kindreds have been found with a homozygous mutation of the GHRHR. These patients have undetectable GH concentrations that do not rise with growth hormone stimulation tests, nor with the administration of GHRH.[11],[12],[13],[14] table1
Idiopathic growth hormone deficiency
The gene which encodes growth hormone, GH1, is located on chromosome 17q23, and is part of a cluster of 5 related genes. Several growth hormone defects with various mendelian patterns of inheritance have been identified. Type 1A growth hormone deficiency leads to loss of pituitary GH secretion and is mostly due to deletions of the GH gene, although some patients have been found with point mutations. Inheritance is autosomal recessive and patients demonstrate severe growth hormone deficiency. These patients are at risk for development of significant levels of anti-GH antibodies after starting treatment, though this phenomenon is being described with less frequency with the use of the newer preparations of GH.[15], [16]
Type 1B GHD patients produce low levels of growth hormone and similar to Type 1A, Type 1B is inherited in an autosomal recessive fashion. Mutations in the GH1 gene have been found in some patients but other patients do not have any alterations in their GH1. These patients may present with partial or severe GHD, but respond well to growth hormone therapy since they do not generally develop significant levels of anti-GH antibodies.[17]
Autosomal dominant transmission is present in type II GHD, through a postulated mechanism of abnormal molecules acting in a dominant negative manner. Finally, type III GHD has X-linked transmission in association with hypogammaglobulinemia. No GH1 gene mutations have been identified with this disorder.[18]
Growth hormone insensitivity
The diagnosis of growth hormone insensitivity due to mutations in the growth hormone receptor gene is considered when patients demonstrate elevated GH levels and low IGF-1 levels. Because the growth hormone binding protein (GHBP) is the cleaved extracellular portion of the growth hormone receptor, patients with mutations in the growth hormone receptor that results in decrease synthesis of the receptor protein can demonstrate low GHBP levels in circulation. However, mutations in the growth hormone receptor gene that selectively involve the transmembrane or intracellular domains may demonstrate normal or even enhanced circulating levels of GHBP. For example, a patient with a mutation inhibiting dimerization of the receptor had normal GHBP levels because the receptor had a normal GH-binding site.[19] Another set of affected individuals had a mutation of the transmembrane domain of the receptor, leading to a truncated growth hormone product that is postulated to be more easily released from the cell membrane and elevated GHBP levels were noted.[20]
The activation of the growth hormone receptor by the binding of GH culminates in the activation of the STAT pathway. The interactions of the STAT proteins with their cognate gene targets in the nucleus is thought to be essential for the actions of GH. Recently a STAT5b homozygous gene mutation was identified in a patient with intrauterine growth retardation and growth failure with a near normal GH peak on provocative tests, low IGF1 and low IGFBP3. The proband failed to respond to growth hormone therapy, and, also had a history of immunodeficiency and lymphoid interstitial pneumonia, which is of interest given the proposed role of STAT5b in the activation of T cells.[21]
One patient has been identified with an IGF-1 mutation. This patient had evidence of intrauterine growth retardation, postnatal growth failure, sensorineural deafness, and mental retardation. This patient was homozygous for a deletional mutation. He was treated with recombinant IGF-1 with an improvement in his growth velocity in the first year of therapy.[22]
Mutations in the receptor for IGF-1 were recently discovered in two different patients. In one individual a compound heterozygous mutation was discovered in the IGF-1 receptor. This patient had intrauterine growth retardation, short stature, high growth hormone levels with provocative testing, and high IGF-1 levels. Another patient was also diagnosed with a compound heterozygous mutation in the IGF-1 receptor gene, also with intrauterine growth retardation, short stature, microcephaly, developmental delay and other dysmorphic features.[23]
As we learn more about the molecular mechanisms involved in the GH-IGF-1 pathway, previous cases of 'idiopathic short stature' will be attributable to a known genetic cause.
Acknowledgements
Supported in part by grant from the NIH (DK49845 [RKM].
References
1. Sperling M. Pediatric Endocrinology. 2nd edn. Philadelphia; Saunders. xvii 2002: 796.
2. Rosenfeld MG et al. Multistep signaling and transcriptional requirements for pituitary organogenesis in vivo. Recent Prog Horm Res 2000; 55: 1-13
3. Dattani MT et al. Mutations in the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse. Nat Genet 1998; 19(2): 125-133.
4. Thomas PQ et al. Heterozygous HESX1 mutations associated with isolated congenital pituitary hypoplasia and septo-optic dysplasia. Hum Mol Genet 2001; 10(1): 39-45.
5. Cohen RN et al. Enhanced repression by HESX1 as a cause of hypopituitarism and septooptic dysplasia. J Clin Endocrinol Metab 2003; 88(10): 4832-4839.
6. Wu W et al. Mutations in PROP1 cause familial combined pituitary hormone deficiency. Nat Genet 1998; 18(2): 147-149.
7. Deladoey J et al. 'Hot spot' in the PROP1 gene responsible for combined pituitary hormone deficiency. J Clin Endocrinol Metab 1999; 84(5): 1645-50.
8. Hendriks-Stegeman BI et al. Combined pituitary hormone deficiency caused by compound heterozygosity for two novel mutations in the POU domain of the Pit1/POU1F1 gene. J Clin Endocrinol Metab 2001; 86(4): 1545-1550.
9. Machinis K et al. Syndromic short stature in patients with a germline mutation in the LIM homeobox LHX4. Am J Hum Genet 2001; 69(5): 961-968.
10. Sadeghi-Nejad, A. and B. Senior, Autosomal dominant transmission of isolated growth hormone deficiency in iris-dental dysplasia (Rieger's syndrome). J Pediatr 1974; 85(5): 644-648.
11. Wajnrajch MP et al. Nonsense mutation in the human growth hormone-releasing hormone receptor causes growth failure analogous to the little (lit) mouse. Nat Genet 1996; 12(1): 88-90.
12. Netchine I et al. Extensive phenotypic analysis of a family with growth hormone (GH) deficiency caused by a mutation in the GH-releasing hormone receptor gene. J Clin Endocrinol Metab, 1998; 83(2): 432-436.
13. Salvatori R et al. Familial dwarfism due to a novel mutation of the growth hormone-releasing hormone receptor gene. J Clin Endocrinol Metab 1999; 84(3): 917-923.
14. Baumann, G. and H. Maheshwari, The Dwarfs of Sindh: severe growth hormone (GH) deficiency caused by a mutation in the GH-releasing hormone receptor gene. Acta Pediatr Suppl 1997. 423: 33-38.
15. Cogan JD, Phillips JA. 3rd. Growth disorders caused by genetic defects in the growth hormone pathway. Adv Pediatr 1998; 45: 337-361.
16. Wagner JK et al. Prevalence of human GH-1 gene alterations in patients with isolated growth hormone deficiency. Pediatr Res 1998; 43(1): 105-110.
17. Lopez-Bermejo, A, Buckway CK, Rosenfeld, RG, Genetic defects of the growth hormone-insulin-like growth factor axis. Trends Endocrinol Metab 2000; 11(2): 39-49.
18. Fleisher TA et al. X-linked hypogammaglobulinemia and isolated growth hormone deficiency. N Engl J Med 1980; 302(26): 1429-1434.
19. Duquesnoy P et al. A single amino acid substitution in the exoplasmic domain of the human growth hormone (GH) receptor confers familial GH resistance (Laron syndrome) with positive GH-binding activity by abolishing receptor homodimerization. Embo J 1994; 13(6): 1386-1395.
20. Woods, KA et al. A homozygous splice site mutation affecting the intracellular domain of the growth hormone (GH) receptor resulting in Laron syndrome with elevated GH-binding protein. J Clin Endocrinol Metab 1996; 81(5): 1686-1690.
21. Kofoed EM et al. Growth hormone insensitivity associated with a STAT5b mutation. N Engl J Med 2003; 349(12): p. 1139-47.
22. Camacho-Hubner C et al. Effects of recombinant human insulin-like growth factor I (IGF-I) therapy on the growth hormone-IGF system of a patient with a partial IGF-I gene deletion. J Clin Endocrinol Metab 1999; 84(5): 1611-1616.
23. Abuzzahab MJ et al. IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation. N Engl J Med 2003; 349(23): 2211-2222.(Lee Joyce, Menon Ram K)
Abstract
Many previously uncharacterized cases of poor growth in children, i.e. idiopathic short stature, are now attributable to genetic defects in the GH-IGF-1 axis. This paper will provide an overview of the clinical findings of patients identified with various genetic defects of the GH/IGF-1 axis with an emphasis on the more recently described syndromes.
Keywords: Growth hormone; Genetic defects; Mutations
Abbreviations
AR Autosomal recessive
AD Autosomal dominant
GHD Growth hormone deficiency
GHR Growth hormone receptor
GHRH Growth hormone releasing hormone
GHBP Growth hormone binding protein
HESX1 paired-like homeobox gene expressed in embryonic
stem cells
JAK2 Janus kinase 2
LHX-3,4 LIM-type homeodomain protein
PROP1 prophet of pit 1
POUF1 Pit-1, Oct-1; Oct-2; Unc-86
STAT Signal transducer and activator of transcription
The GH/IGF-1 axis plays an essential and central role in statural growth. Whereas abnormalities such as mutations in the GH gene locus are well established causes of genetic defects in this axis, a more thorough understanding of the different components of this axis has allowed for the identification of newer molecular defects in this axis. Hence as the physiology of the GH-IGF-1 axis is further elucidated, many previously uncharacterized cases of poor growth in children, i.e. idiopathic short stature, are now attributable to genetic defects in the GH-IGF-1 axis. This paper will provide an overview of the clinical findings of patients identified with various genetic defects of the axis with an emphasis on the more recently described syndromes.
Growth hormone secretion from the anterior pituitary gland is pulsatile, controlled by the stimulatory effects of GH-releasing hormone and the inhibitory effects of somatostatin, which are both released by the hypothalamus. Growth hormone, once released into circulation, binds to the extracellular component of the growth hormone receptor and induces receptor dimerization and/or a conformational change of pre-dimerized receptor complexes. This sequence of events results in phosphorylation of the Janus kinase 2 (JAK2) molecules, which in turn phosphorylates the intracellular portion of the growth hormone receptor, and also undergoes further tyrosine autophosphorylation. The formation of the JAK2 kinase-GH receptor complex leads to activation of the STAT pathway. STAT 1, STAT3, and STAT5 are cytoplasmic proteins that form homodimers and heterodimers, translocate to the nucleus, and bind to response elements on DNA to stimulate transcription of genes. Stat5b has been directly implicated in the GH-induced production of IGF-1. IGF-1 mediates many of the anabolic actions of growth hormone. IGF-1 binds to the IGF1 receptor, which mediates IGF actions on all cell types.[1]
HYPOTHALAMIC-PITUITARY DEFECTS
The graded expression of transcription factors leads to development of the anterior pituitary and its distinct cell types.[2] Several mutations in pituitary-specific transcription factors have been identified leading to growth hormone deficiency.
Septo-optic dysplasia is a condition of abnormal brain development, in which there is optic nerve hypoplasia, agenesis or hypoplasia of the septum pellucidum and/or corpus callosum, and hypothalamic-pituitary deficiencies, including isolated growth hormone deficiency (IGHD), or growth hormone deficiency in combination with TSH, ACTH, and gonadotropin deficiency.
HESX1 is a paired-like homeodomain transcription factor expressed in the developing pituitary gland. Mutations in this gene leading to decreased activity have been found in two siblings with panhypopituitarism, absent septum pellucidum, optic nerve hypoplasia, and agenesis of the corpus callosum, implicating a role for HESX1 in mediating forebrain development.[3], [4] Another mutation in HESX1 was recently discovered, in a patient with septo-optic dysplasia and isolated growth hormone deficiency.[5] Experimental evidence suggests that this particular mutation results in the production of an altered HESX1 protein with enhanced DNA binding activity that abrogates the transcriptional activity of PROP1, another transcription factor necessary for pituitary development.
PROP1 is thought to be involved in the differentiation of somatotropes, thyrotropes, lactotropes, and gonadotropes. Mutations in PROP1 leading to reduced DNA-binding and transcriptional activity have been identified in patients with combined pituitary hormone deficiency. These patients have a deficiency of TSH, GH, and prolactin, LH and FSH.[6] Patients with a demonstrated gonadotropin deficiency may present with failure to enter puberty spontaneously whereas other patients do enter puberty but have a subsequent loss of gonadotropin secretion. Although PROP1 is directly implicated in the differentiation of only 4 out of the five anterior pituitary cell types, some patients have also been described with ACTH deficiency. PROP1 mutations are believed to relatively common (32-50%) genetic causes of combined pituitary hormone deficiency.[7]
POU1F1 (also known as Pit1 or GHF-1) is another pituitary transcription factor that is responsible for the determination of lactotropes, somatotropes, and thyrotropes. It activates GH and prolactin gene expression, and can bind to and transactivate the TSH-B promoter. Accordingly, patients with POU1F1 mutations demonstrate GH, prolactin and variable TSH deficiencies.[8] It can be inherited in an autosomal dominant or recessive manner, but POU1F1(Pit-1) mutations are not a common cause of combined pituitary hormone deficiencies.
Rathke's pouch initially forms but fails to grow in LHX3-knockout mice.[7] Humans have been found to have mutations in the LHX3 gene, a LIM-type homeodomain protein, and demonstrate complete deficits of GH, PRL, TSH, and gonadotropins in addition to a rigid cervical spine leading to limited head rotation. LHX4 is a related protein which similar to LHX3 regulates proliferation and differentiation of pituitary lineages. A patient has been identified with a dominant mutation in this protein demonstrating deficiencies of GH, TSH, and ACTH, a small sella turcica, a hypoplastic anterior hypophysis, an ectopic posterior hypophysis, and a deformation of the cerebellar tonsil into a pointed configuration.[9]
Finally, Rieger syndrome is a condition with abnormal development of the anterior chamber of the eye, dental hypoplasia, and a protuberant umbilicus associated with growth hormone deficiency. All mutations in RIEG (Pitx2) found thus far have been heterozygous, with an autosomal dominant inheritance.[10]
To date, no mutations of the GHRH gene have been found, although mutations have been found in the GH-releasing hormone receptor. A number of kindreds have been found with a homozygous mutation of the GHRHR. These patients have undetectable GH concentrations that do not rise with growth hormone stimulation tests, nor with the administration of GHRH.[11],[12],[13],[14] table1
Idiopathic growth hormone deficiency
The gene which encodes growth hormone, GH1, is located on chromosome 17q23, and is part of a cluster of 5 related genes. Several growth hormone defects with various mendelian patterns of inheritance have been identified. Type 1A growth hormone deficiency leads to loss of pituitary GH secretion and is mostly due to deletions of the GH gene, although some patients have been found with point mutations. Inheritance is autosomal recessive and patients demonstrate severe growth hormone deficiency. These patients are at risk for development of significant levels of anti-GH antibodies after starting treatment, though this phenomenon is being described with less frequency with the use of the newer preparations of GH.[15], [16]
Type 1B GHD patients produce low levels of growth hormone and similar to Type 1A, Type 1B is inherited in an autosomal recessive fashion. Mutations in the GH1 gene have been found in some patients but other patients do not have any alterations in their GH1. These patients may present with partial or severe GHD, but respond well to growth hormone therapy since they do not generally develop significant levels of anti-GH antibodies.[17]
Autosomal dominant transmission is present in type II GHD, through a postulated mechanism of abnormal molecules acting in a dominant negative manner. Finally, type III GHD has X-linked transmission in association with hypogammaglobulinemia. No GH1 gene mutations have been identified with this disorder.[18]
Growth hormone insensitivity
The diagnosis of growth hormone insensitivity due to mutations in the growth hormone receptor gene is considered when patients demonstrate elevated GH levels and low IGF-1 levels. Because the growth hormone binding protein (GHBP) is the cleaved extracellular portion of the growth hormone receptor, patients with mutations in the growth hormone receptor that results in decrease synthesis of the receptor protein can demonstrate low GHBP levels in circulation. However, mutations in the growth hormone receptor gene that selectively involve the transmembrane or intracellular domains may demonstrate normal or even enhanced circulating levels of GHBP. For example, a patient with a mutation inhibiting dimerization of the receptor had normal GHBP levels because the receptor had a normal GH-binding site.[19] Another set of affected individuals had a mutation of the transmembrane domain of the receptor, leading to a truncated growth hormone product that is postulated to be more easily released from the cell membrane and elevated GHBP levels were noted.[20]
The activation of the growth hormone receptor by the binding of GH culminates in the activation of the STAT pathway. The interactions of the STAT proteins with their cognate gene targets in the nucleus is thought to be essential for the actions of GH. Recently a STAT5b homozygous gene mutation was identified in a patient with intrauterine growth retardation and growth failure with a near normal GH peak on provocative tests, low IGF1 and low IGFBP3. The proband failed to respond to growth hormone therapy, and, also had a history of immunodeficiency and lymphoid interstitial pneumonia, which is of interest given the proposed role of STAT5b in the activation of T cells.[21]
One patient has been identified with an IGF-1 mutation. This patient had evidence of intrauterine growth retardation, postnatal growth failure, sensorineural deafness, and mental retardation. This patient was homozygous for a deletional mutation. He was treated with recombinant IGF-1 with an improvement in his growth velocity in the first year of therapy.[22]
Mutations in the receptor for IGF-1 were recently discovered in two different patients. In one individual a compound heterozygous mutation was discovered in the IGF-1 receptor. This patient had intrauterine growth retardation, short stature, high growth hormone levels with provocative testing, and high IGF-1 levels. Another patient was also diagnosed with a compound heterozygous mutation in the IGF-1 receptor gene, also with intrauterine growth retardation, short stature, microcephaly, developmental delay and other dysmorphic features.[23]
As we learn more about the molecular mechanisms involved in the GH-IGF-1 pathway, previous cases of 'idiopathic short stature' will be attributable to a known genetic cause.
Acknowledgements
Supported in part by grant from the NIH (DK49845 [RKM].
References
1. Sperling M. Pediatric Endocrinology. 2nd edn. Philadelphia; Saunders. xvii 2002: 796.
2. Rosenfeld MG et al. Multistep signaling and transcriptional requirements for pituitary organogenesis in vivo. Recent Prog Horm Res 2000; 55: 1-13
3. Dattani MT et al. Mutations in the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse. Nat Genet 1998; 19(2): 125-133.
4. Thomas PQ et al. Heterozygous HESX1 mutations associated with isolated congenital pituitary hypoplasia and septo-optic dysplasia. Hum Mol Genet 2001; 10(1): 39-45.
5. Cohen RN et al. Enhanced repression by HESX1 as a cause of hypopituitarism and septooptic dysplasia. J Clin Endocrinol Metab 2003; 88(10): 4832-4839.
6. Wu W et al. Mutations in PROP1 cause familial combined pituitary hormone deficiency. Nat Genet 1998; 18(2): 147-149.
7. Deladoey J et al. 'Hot spot' in the PROP1 gene responsible for combined pituitary hormone deficiency. J Clin Endocrinol Metab 1999; 84(5): 1645-50.
8. Hendriks-Stegeman BI et al. Combined pituitary hormone deficiency caused by compound heterozygosity for two novel mutations in the POU domain of the Pit1/POU1F1 gene. J Clin Endocrinol Metab 2001; 86(4): 1545-1550.
9. Machinis K et al. Syndromic short stature in patients with a germline mutation in the LIM homeobox LHX4. Am J Hum Genet 2001; 69(5): 961-968.
10. Sadeghi-Nejad, A. and B. Senior, Autosomal dominant transmission of isolated growth hormone deficiency in iris-dental dysplasia (Rieger's syndrome). J Pediatr 1974; 85(5): 644-648.
11. Wajnrajch MP et al. Nonsense mutation in the human growth hormone-releasing hormone receptor causes growth failure analogous to the little (lit) mouse. Nat Genet 1996; 12(1): 88-90.
12. Netchine I et al. Extensive phenotypic analysis of a family with growth hormone (GH) deficiency caused by a mutation in the GH-releasing hormone receptor gene. J Clin Endocrinol Metab, 1998; 83(2): 432-436.
13. Salvatori R et al. Familial dwarfism due to a novel mutation of the growth hormone-releasing hormone receptor gene. J Clin Endocrinol Metab 1999; 84(3): 917-923.
14. Baumann, G. and H. Maheshwari, The Dwarfs of Sindh: severe growth hormone (GH) deficiency caused by a mutation in the GH-releasing hormone receptor gene. Acta Pediatr Suppl 1997. 423: 33-38.
15. Cogan JD, Phillips JA. 3rd. Growth disorders caused by genetic defects in the growth hormone pathway. Adv Pediatr 1998; 45: 337-361.
16. Wagner JK et al. Prevalence of human GH-1 gene alterations in patients with isolated growth hormone deficiency. Pediatr Res 1998; 43(1): 105-110.
17. Lopez-Bermejo, A, Buckway CK, Rosenfeld, RG, Genetic defects of the growth hormone-insulin-like growth factor axis. Trends Endocrinol Metab 2000; 11(2): 39-49.
18. Fleisher TA et al. X-linked hypogammaglobulinemia and isolated growth hormone deficiency. N Engl J Med 1980; 302(26): 1429-1434.
19. Duquesnoy P et al. A single amino acid substitution in the exoplasmic domain of the human growth hormone (GH) receptor confers familial GH resistance (Laron syndrome) with positive GH-binding activity by abolishing receptor homodimerization. Embo J 1994; 13(6): 1386-1395.
20. Woods, KA et al. A homozygous splice site mutation affecting the intracellular domain of the growth hormone (GH) receptor resulting in Laron syndrome with elevated GH-binding protein. J Clin Endocrinol Metab 1996; 81(5): 1686-1690.
21. Kofoed EM et al. Growth hormone insensitivity associated with a STAT5b mutation. N Engl J Med 2003; 349(12): p. 1139-47.
22. Camacho-Hubner C et al. Effects of recombinant human insulin-like growth factor I (IGF-I) therapy on the growth hormone-IGF system of a patient with a partial IGF-I gene deletion. J Clin Endocrinol Metab 1999; 84(5): 1611-1616.
23. Abuzzahab MJ et al. IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation. N Engl J Med 2003; 349(23): 2211-2222.(Lee Joyce, Menon Ram K)