Alternative titles; symbols
SNOMEDCT: 71003000; ORPHA: 231662, 631; DO: 0060873; MONDO: 0009876;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 17q23.3 | Growth hormone deficiency, isolated, type IA | 262400 | Autosomal recessive | 3 | GH1 | 139250 |
A number sign (#) is used with this entry because isolated growth hormone deficiency type IA (IGHD1A) is caused by homozygous or compound heterozygous mutation in the GH1 gene (139250) on chromosome 17q23.
Isolated growth hormone deficiency type IA (IGHD1A) is an autosomal recessive disorder characterized by severe growth failure (SDS less than -4.5) by 6 months of age, undetectable growth hormone (GH) concentrations, and a tendency to develop antibodies despite an initial good response to rhGH treatment (summary by Alatzoglou et al., 2014).
Genetic Heterogeneity of Isolated Growth Hormone Deficiency
See IGHD1B (617281) and IGHD2 (173100), both caused by mutation in the GH1 gene; IGHD3 (307200), caused by mutation in the BTK gene (300300); and IGHD4 (618157), caused by mutation in the GHRHR gene (139191).
Isolated growth hormone deficiency-5 (IGHD5) has been reclassified as combined pituitary hormone deficiency-7 (CPHD7; 618160).
In an early classification of IGHD (Phillips and Cogan, 1994), 4 forms of IGHD were based on ihheritance pattern. IGHD IA and IB (612781) were both inherited in an autosomal recessive manner. Both IGHD IA and IB were caused by mutations in the GH1 gene; IGHD IB could also be caused by mutation in the GHRHR gene (139191). IGHD II (173100) had an autosomal dominant mode of inheritance and was caused by mutation in GH1. IGHD III (307200) was an X-linked disorder that was often associated with agammaglobulinemia, suggesting a contiguous gene syndrome.
Proportionate short stature, accompanied by a decreased growth velocity, is the most important clinical finding to support the diagnosis of growth hormone deficiency (GHD) (Phillips, 1995; Rimoin and Phillips, 1997). Delayed bone maturation and the absence of bone dysplasias and chronic diseases are additional criteria. Adequate function of the GH pathway is needed throughout childhood to maintain normal growth. While most newborns with GHD have normal lengths and weights, those with complete absence of GH due to GH gene deletions can have birth lengths that are shorter than expected for their birth weights. The low linear growth of infants with congenital GHD becomes progressively retarded with age and some may have micropenis or fasting hypoglycemia. In those with IGHD, skeletal maturation is usually delayed in proportion to height retardation. Other frequent findings include truncal obesity, a facial appearance that is younger than that expected for their chronologic age, delayed secondary dentition, and a high-pitched voice. Puberty may be delayed until the late teens, but normal fertility usually occurs. The skin of adults with GHD appears fine and wrinkled, similar to that seen in premature aging. Concomitant or combined deficiencies of other pituitary hormones (luteinizing hormone (LH; 152780); follicle-stimulating hormone (FSH; 136530); thyroid-stimulating hormone (TSH; 188540); and/or ACTH; 202200) in addition to GH is called combined pituitary hormone deficiency (CPHD; see 613038) or panhypopituitary dwarfism. The combination of GH and these additional hormone deficiencies often causes more severe retardation of growth and skeletal maturation and spontaneous puberty may not occur.
Mullis (2007) stated that IGHD IA was first described by Illig (1970) in 3 Swiss children with unusually severe growth impairment and apparent deficiency of growth hormone.
Illig and Prader (1972) observed a possibly distinct form of IGHD. All features are more severe than in the majority of cases and there may be an exaggerated tendency to develop antibodies to administered growth hormone, which vitiates therapy. The patients may be somewhat short at birth, dwarfism is more extreme than in other cases, hypoglycemia is a conspicuous feature, and the facial features ('baby doll facies') are exaggerated. It may be that the cases of the more usual hGH deficiency have some growth hormone whereas these have none.
Moe (1968) reported brother and sister with hypoglycemia and presumed isolated somatotropin deficiency. The father had diabetes insipidus.
From Israel, Laron et al. (1985) reported 4 cases of isolated growth hormone deficiency in which studies with a cDNA probe for chorionic somatomammotropin (150200) showed homozygosity for deletion of the growth hormone gene (the hGH-N gene). Yet, in all 4 cases, there was good growth response to human pituitary hormone. One family originated from Iraq, 2 from Yemen, and 1 from Iran. The reason for the discrepancy with the findings in patients from Switzerland, Argentina, and Japan studied by Phillips et al. (1981) and others was not clear. A heterogeneous response to growth hormone therapy, in terms of development of anti-human growth hormone antibodies, was documented by Matsuda et al. (1987) in their study of 4 Japanese patients with autosomal recessive growth hormone deficiency.
Pena-Almazan et al. (2001) evaluated 46 infants with congenital GHD followed in a single regional medical center. All were born full-term and had peak GH of less than 10 microg/liter after provocative stimulation. Length standard deviation score at birth was normal but subsequently showed deceleration, at 6 months and 12 months of age, before GH treatment. The majority were delivered vaginally (83%), and delivery was uncomplicated in 61%. Perinatal morbidities were found in 72% of infants and included jaundice in 17, hypoglycemia with or without seizure in 14, and hypoxemia in 5. Multiple pituitary hormone deficiencies were found in 85% of the subjects. Organic lesions were documented in all 22 subjects who had magnetic resonance imaging and in 4 of 11 subjects who had computed tomography scan. In the patients studied, GHD did not adversely affect fetal growth but was essential for normal linear growth during early infancy. The authors concluded that congenital developmental abnormalities in the hypothalamic-pituitary region are the most common cause of GHD and are best diagnosed by an MRI study.
Mullis (2007) reviewed the classification of IGHD. He noted that the development of anti-GH antibodies is an inconsistent finding in IGHD IA patients despite having identical molecular defects (homozygosity for GH1 gene deletions).
Hernandez et al. (2007) reviewed the clinical, biochemical, and molecular features described in individuals with IGHD.
Growth Hormone Replacement Therapy
The advent of transgenic technology provided the methods for production of pharmaceuticals by isolation of the proteins of interest from the blood of transgenic animals. The mammary gland has been investigated as a bioreactor since milk is easily collected from lactating animals and protein production can reach as high as 1 kg per day in cattle and 200 g per day in goats. Mammary-specific promoters have been used in transgenic animals to limit transgene expression to the mammary gland. Archer et al. (1994) used gene therapy techniques to target a foreign gene to a single organ. They directly infused replication-defective retroviruses encoding the human growth hormone gene into the mammary gland of goats via the teat canal during a period of hormone-induced mammogenesis. This resulted in the secretion of human GH into the milk when lactation commenced on day 14 of the regime.
The treatment of GH deficiency is replacement using exogenous, biosynthetic GH. Factors important in the clinical response include the etiology and severity of deficiency, age of onset, and duration of replacement, as well as the sex of the affected individual. Blethen et al. (1997) determined near-adult heights (AH) in 121 children (72 males and 49 females) with GHD who were prepubertal when they began treatment with recombinant DNA-derived preparations of human GH. AH as an SD score was -0.7 +/- 1.2 (mean +/- SD), and was significantly greater than the pretreatment height SD score (-3.1 +/- 1.2), the predicted AH SD score (-2.2 +/- 1.2; Bayley-Pinneau method), and the height SD score at the start of puberty (-1.9 +/- 1.3). Statistically significant variables were duration of treatment with GH, sex (males were taller than females, as expected for the normal population), age (younger children had a greater AH), height at the start of GH, and growth rate during first year of GH. Bone age delay (chronologic age minus bone age) had a negative impact on the AH SD score. Blethen et al. (1997) concluded that early diagnosis of GHD and continuous treatment with larger doses of GH to near AH should improve the outcome in children with short stature due to GHD.
Cassorla et al. (1997) studied the effect of delaying epiphyseal fusion on the growth of GH-deficient children. Patients treated with GH and a luteinizing hormone-releasing hormone (LHRH; 152760) analog had suppression of their pituitary-gonadal axis and a marked delay in bone age progression. After 3 years of treatment, Cassorla et al. (1997) observed a greater gain in height prediction in these patients than in patients treated with GH and placebo. The authors concluded that delaying epiphyseal fusion with an LHRH analog in pubertal GH-deficient children treated with GH increases height prediction and may increase final height compared to treatment with GH alone.
Rappaport et al. (1997) assessed the efficacy of GH therapy in GHD children treated before the age of 3 years. Their 5-year height gain was negatively correlated with the height SD score at the start of treatment; the first-year height gain was the most predictive parameter. There was no significant influence of intrauterine growth retardation, body mass index and age at the start of treatment, or parental target height. Rappaport et al. (1997) concluded that the rapid and almost complete return to normal height obtained in the study supported GH treatment in early diagnosed GH-deficient children. They considered the GH dosage used to be the minimum to obtain satisfactory catch-up growth. In addition, the dosage allowed growth at a rate normal for age in patients diagnosed before growth retardation.
De Boer and van der Veen (1997) advocated retesting all patients with childhood-onset GHD once they have reached their final height. This retesting identifies patients who have so-called transient GHD and who are therefore not at risk to develop the adult GHD syndrome, as well as those patients most likely to develop the adult GHD syndrome if GH treatment is stopped at final height and who could benefit from continued GH treatment in adulthood.
Tobiume et al. (1997) found that serum bone alkaline phosphatase (B-ALP) levels are a useful marker for bone formation in GH-deficient children undergoing GH therapy, and that B-ALP appeared to be a useful marker for predicting growth responses to long-term GH therapy.
Cuneo et al. (1998) reported the results of an Australian multicenter, randomized, double-blind, placebo-controlled trial of the effects of recombinant human GH treatment in adults with GH deficiency. Patients were randomly assigned to receive either GH or placebo. GH treatment in adults with GH deficiency produced the following results: prominent increases in serum IGF1 (147440) at the doses employed, in some cases to supraphysiologic levels; modest decreases in total and low density lipoprotein cholesterol, together with substantial reductions in total-body and truncal fat mass consistent with an improved cardiovascular risk profile; substantial increases in lean tissue mass; and modest improvements in perceived quality of life. The excessive IGF1 response and side-effect profile suggested that lower doses of GH may be required for prolonged GH treatment in adults with severe GH deficiency.
Maghnie et al. (1999) reevaluated GH secretion after completion of GH treatment at a mean age of 19.2 +/- 3.2 years in 35 young adults with childhood-onset GHD. A high proportion of children with IGHD and normal or small pituitary showed normalization of GH secretion at the completion of GH treatment, whereas GHD was permanent in all patients with pituitary hypoplasia, pituitary stalk agenesis, and posterior pituitary ectopia. IGF1 and IGFBP3 (146732) determinations shortly after GH withdrawal had limited value in the diagnosis of childhood-onset GHD associated with congenital hypothalamic pituitary abnormalities, but became accurate after 6 to 12 months. The authors concluded that patients with GHD and congenital hypothalamic pituitary abnormalities do not require further investigation of GH secretion, whereas patients with IGHD and normal or small pituitary gland should be retested well before the attainment of adult height.
It had been suggested that GH treatment may increase the risk of developing leukemia, in part because Fanconi anemia (227650), which is associated with an increased risk of leukemia, is also associated with GH deficiency and can present as short stature without skeletal or hematologic abnormalities in childhood. Nishi et al. (1999) collected data from more than 32,000 patients from the Foundation for Growth Science in Japan, which had monitored the safety and efficacy of GH treatment in GH-deficient patients since 1975. New leukemia was observed in 14 patients, and myelodysplastic syndrome (MDS; see 600049) in 1 patient. Leukemia developed in 9 of these patients during GH treatment and in 6 after the cessation of GH treatment. Six patients had known risk factors for leukemia, such as Fanconi anemia and previous radiation or chemotherapy. The incidence of leukemia of patient-years of GH therapy and patient-years of risk in GH-treated patients without risk factors was 3.0 per 100,000 and 3.9 per 100,000, respectively, a figure similar to the incidence in the general population aged zero to 15 years. The authors concluded that the incidence of leukemia in GH-treated patients without risk factors is not greater than that in the general population aged zero to 15 years, and a possible increased occurrence of leukemia with GH treatment appears to be limited to patients with risk factors.
Guyda (1999) comprehensively reviewed the treatment protocols for children with GHD as well as the administration of GH for other non-GHD conditions in childhood and adolescence. Protocols for idiopathic short stature (ISS), intrauterine growth retardation, chronic renal failure, and genetic disorders such as Turner syndrome were included. Information on the current worldwide distribution of GH use in almost 100,000 children was included, along with the long-term response and final heights attained in different disorders. Information on the psychosocial outcomes was also included.
In humans, hypopituitarism and GHD are believed to constitute risk factors for cardiovascular disease and, therefore, early death. However, patients with a PROP1 (601538) gene mutation, presenting with a combined pituitary-derived hormonal deficiency (262600), can survive to a very advanced age, apparently longer than normal individuals in the same population. Besson et al. (2003) analyzed the impact of untreated GHD on life span. Hereditary dwarfism was recognized in 11 subjects. Genetic analysis revealed an underlying deletion spanning 6.7 kb of genomic DNA encompassing the GH1 gene that caused isolated GHD. These patients were never treated for their hormonal deficiency and thus provided a unique opportunity to compare their life span and cause of death directly with those of their unaffected brothers and sisters as well as with the normal population. Although the cause of death did not vary between the 2 groups, median life span in the GH-deficient group was significantly shorter than that of unaffected brothers and sisters (males, 56 vs 75 years, P less than 0.0001; females, 46 vs 80 years, P less than 0.0001). The authors concluded that GH treatment in adult patients suffering from either childhood- or adult-onset GHD is crucially important.
Hartman et al. (2008) investigated if improvements in aerobic exercise capacity in adults with GHD treated with GH are related to changes in physical activity or the GH dosing regimen. They found that GH replacement therapy in GH-deficient adults improved maximal oxygen consumption similarly with both individualized dosing and fixed body weight-based regimens, without any influence of physical activity.
Growth Hormone-Releasing Peptides
GH-releasing peptides (GHRPs) are small synthetic peptides that are relatively specific stimulators of GH secretion (Mericq et al., 1998). GHRPs have no structural similarity to GHRH (139190); they bind to entirely different receptors and exhibit a strong synergy with GHRH in the release of GH. Chapman et al. (1997) found that oral administration of the GHRP6 mimetic MK-677 at both 10 and 50 mg/day increased serum IGF1 and 24-hour mean GH concentrations in 9 severely GH-deficient men aged 17 to 34 years who had been treated for GH deficiency with GH during childhood. In 6 prepubertal children with GHD and growth failure, Mericq et al. (1998) found that repeated administration of GHRP2 was able to produce a rise in nocturnal GH that was sustained after several months of treatment, although the effect of each injection of GHRP2 on GH secretion was relatively brief. Serum levels of IGF1 and IGFBP3 did not increase. Mericq et al. (1998) concluded that GHRP2 is well tolerated and able to stimulate GH secretion, and that formulations or routes of administration that allow for a longer duration of action would likely be needed to use GHRP2 in therapy.
Cardiovascular Effects of Growth Hormone Therapy
To determine the effects of recombinant human GH replacement therapy on cardiac mass and function, Shulman et al. (2003) analyzed comprehensive echocardiograms of 10 children with classical GH deficiency before and during the first year of therapy and correlated the findings with linear growth response. They concluded that cardiac growth impeded by GH deficiency can be improved by GH replacement therapy. While body size and cardiac mass both increased during the first year of treatment, there was an increase in left ventricular mass normalized for changes in body size, implying a quantitatively more significant effect of GH replacement therapy on the heart.
Colao et al. (2005) investigated the risk of early atherosclerosis in adolescents with GHD during GH replacement and withdrawal. Among 23 adolescents diagnosed with GHD during childhood, 8 were found to be non-GHD at retesting 1 to 3 months after cessation of GH replacement therapy. Intima-medial thickness (IMT) at the common carotid arteries was similar in GHD subjects and in controls, but was higher in patients determined to be non-GHD. In GHD adolescents, 6 months of GH treatment withdrawal and 6 months of GH treatment reinstitution modified IGF1 levels, lipid profile, and insulin resistance but not IMT or systolic and diastolic peak velocities at the common carotid arteries. Colao et al. (2005) concluded that increased IMT in the adult GHD population begins later in life or after a longer period of GH deprivation than that studied, and that adolescents with idiopathic GHD should be retested for GHD after completion of growth, as continued GH replacement in non-GHD subjects could negatively affect endothelial properties.
Pinto et al. (1997) investigated the pathogenesis of pituitary stalk interruption syndrome (PSIS), the identification of which by magnetic resonance imaging (MRI) is a clinical marker of permanent GHD. Pinto et al. (1997) classified 51 patients, 27 of them males, with GHD and PSIS according to whether the GHD was isolated (group 1; 16 cases) or associated with other anterior pituitary abnormalities (group 2; 35 cases). The 2 groups had similar characteristics: frequencies of perinatal abnormalities, ages at occurrence of first signs and at diagnosis, height, GH peak response to stimuli other than growth hormone-releasing hormone (GHRH; 139190). However, associated malformations were less frequent in group 1 (12%) than in group 2 (54%; P less than 0.01); hypoglycemia occurred in 25% of group 1 and 70% of group 2 (P less than 0.01); and the GH peak response to GHRH was less than 10 micro g/L in 0% of group 1 (4 cases evaluated) and 57% of group 2 (21 cases; P less than 0.05). Thirty-one cases (61%; 25 from group 2) had features suggesting an antenatal origin: familial recurrence (4 cases), microphallus (10 boys), and/or associated malformations (50%; 21 cases). Twenty-seven cases (53%; 22 from group 2) had features suggesting a hypothalamic origin. Pinto et al. (1997) concluded that most patients with GHD associated with multiple anterior pituitary abnormalities and PSIS have features suggesting an antenatal origin, and that the GH, GHRH receptor (139191), and PIT1 (173110) genes do not seem to be implicated in PSIS.
While short stature, delayed growth velocity, and delayed skeletal maturation are all seen with GH deficiency, none of these symptoms or signs is specific for GH deficiency. Therefore, patients should be evaluated for other, alternative systemic diseases before provocative tests to document GH deficiency are done. Provocative tests for GH deficiency include post-exercise, L-DOPA, insulin tolerance, arginine, insulin-arginine, clonidine, glucagon, and propranolol protocols. Inadequate GH peak responses (usually less than 7-10 ng/ml) differ from protocol to protocol. Importantly, additional testing for concomitant deficiencies of LH, FSH, TSH, and/or ACTH should be done to provide a complete diagnosis and thus enable planning of optimal treatment (Phillips, 1995; Rimoin and Phillips, 1997).
Rosenfeld (1997) suggested the following as guidelines for diagnosing GHD: severe growth retardation with height more than 3 standard deviations (SD) below the mean for age in the absence of an alternative explanation; moderate growth retardation with height 2 to 3 SD below the mean for age, plus growth deceleration with height velocity less than 25th percentile for age, in the absence of an alternative explanation; severe growth deceleration with height velocity less than 5th percentile for age, in the absence of an alternative explanation; a predisposing condition (e.g., cranial irradiation) plus growth deceleration; or other evidence of pituitary dysfunction (e.g., other pituitary deficiencies, neonatal hypoglycemia, microphallus). However, even in the appropriate clinical setting, the diagnosis of GHD remains problematic, largely because of the difficulty in measuring physiologic GH secretion. GH stimulation tests are widely used in the diagnosis of GHD, although they are associated with a high false positive rate.
Tillmann et al. (1997) compared alternative tests of the GH axis such as urinary GH excretion, serum IGF1, and IGFBP3 levels to GH stimulation tests in identifying children defined clinically as GH deficient. The best sensitivity for a single GH test was 85% at a peak GH cutoff level of 10 ng/mL, whereas the best specificity was 92% at 5 ng/mL. The sensitivities of IGF1, IGFBP3, and urinary GH, using a cutoff of -2 SD score, were poor at 34%, 22%, and 25%, respectively. The authors devised a scoring system based on the positive predictive value of each test, incorporating data from the urinary GH, IGF1, and IGFBP3 levels. A specificity of 94% could be achieved with a score of 10 or more, with a maximum of 17, and a sensitivity of 32%. The latter could not be improved above 81% with a score of 5 points or more and a specificity of 69%. A high score was highly indicative of GHD, but was achieved by few patients. A normal IGFBP3 level, however, did not exclude GHD, particularly in patients with radiation-induced GHD and those in puberty. A GH test with a peak level more than 10 ng/mL was the most useful single investigation to exclude a diagnosis of GHD.
Mahajan and Lightman (2000) evaluated the GH-releasing effect of a combination of the hypothalamic secretagogue GHRH with a small dose of the synthetic peptide GHRP2 to diagnose GHD. They compared the GH response to ITT and GHRH/GHRP in a group of 36 adults (22 males and 14 females, aged 18 to 59 years) with hypothalamic/pituitary disease and in 30 healthy volunteers (15 males and 15 females, aged 22 to 66 years). The GHRH/GHRP test produced a measurable GH secretory response in normal, hypopituitary, and GH-deficient patients. The test had no detected side effects. Using the ITT as the 'gold standard' with a GH response of 9 mU/L as the cut-off to define GHD, they compared the clinical efficacy of these 2 tests. Choosing an arbitrary cut-off of 17 mU/L to define GHD in the GHRH/GHRP test, this new test proved to have 78.6% sensitivity and 100% specificity even when only the 30-minute datum point was used.
By magnetic resonance imaging (MRI), Chen et al. (1999) studied GH-deficient children showing ectopic posterior pituitary hyperintense signal (EPP). Patients were classified into 2 groups according to the presence (group 1; 14 patients) or absence (group 2; 11 patients) of pituitary stalk visibility after gadolinium injection. Most (12 of 14) patients in group 1 had isolated GH deficiency, whereas all but 1 patient in group 2 had multiple anterior pituitary hormone deficiency. The prevalence of a normally sized adenohypophysis was higher in group 1 than in group 2 (50% vs 9%; P less than 0.05). The authors concluded that in cases of GH deficiency associated with EPP, patients with no visible pituitary stalk on MRI after gadolinium injection present a more severe form of the disease in childhood that is associated with multiple anterior pituitary hormone deficiency, whereas visibility of the pituitary stalk is related to isolated GH deficiency.
Osorio et al. (2002) stated that the pathogenesis of pituitary stalk interruption and ectopic posterior lobe, frequently observed on MRI in patients with GHD, was controversial. They performed pituitary stimulation tests and MRI, and studied the GH1, GHRHR, and PROP1 (601538) genes, in 76 patients with IGHD or combined pituitary hormone deficiency (CPHD). Compared with the 62 patients without mutations, 14 patients with mutations had higher frequencies of consanguinity (P less than 0.001) and familial cases (P less than 0.05) and lower frequency of breech delivery or hypoxemia at birth (P less than 0.005). On MRI, all patients with mutations had an intact stalk, whereas it was interrupted or thin in 74% without mutations (P less than 0.001). The posterior pituitary lobe was in normal position in 92% of patients with mutations versus 13% without mutations (P less than 0.001). Among patients with combined pituitary hormone deficiency, hormonal deficiencies were of pituitary origin in all with PROP1 and PIT1 mutations and suggestive of hypothalamic origin in 81% without mutations. GH1, GHRHR (139191), and PROP1 mutations were associated with consanguineous parents, intact pituitary stalk, normal posterior lobe, and pituitary origin of hormonal deficiencies. Osorio et al. (2002) concluded that pituitary MRI and hormonal response to stimulation tests are useful in selection of patients and candidate genes to elucidate the etiologic diagnosis of GHD.
Based on a study of the GH-IGF axis in a large, genetically homogeneous population with a homozygous donor splice site mutation in intron 1 of the GHRHR gene (139191.0002), Aguiar-Oliveira et al. (1999) recommended that diagnostic tests used in the investigation of GHD should be tailored to the age of the individual. In particular, measurement of IGF1 in the ternary complex may prove useful in the diagnosis of GHD in children and older adults, whereas free ALS may be more relevant to younger adults.
The biochemical diagnosis of GH deficiency has traditionally been based on provocative tests using a variety of GH stimulation agents. Estrogen administration increases GH responsiveness to provocative stimuli. It had been proposed that estrogen priming might reduce the percentage of false-positive GH deficiency diagnosis in prepubertal and early pubertal subjects. To evaluate the effect of estrogen administration on GH stimulation tests in both short normal and GHD patients and to compare the diagnostic efficiency of this approach with that of serum levels of IGF1 and IGFBP3, Martinez et al. (2000) studied the effect of estradiol on the GH-IGF axis in 15 prepubertal children with GH deficiency and 44 prepubertal or early pubertal children with idiopathic short stature. All received a daily dose of micronized estradiol or placebo for 3 days before a sequential arginine-clonidine test. The authors concluded that GH stimulation tests after estradiol priming had the highest diagnostic efficiency. They also suggested that the effect of estrogen priming on GH stimulated levels, by reducing the number of false nonresponders, might be useful to better discriminate between normal and abnormal GH status in children with idiopathic short stature.
The transmission pattern of IGHD1A in the family reported by Igarashi et al. (1993) was consistent with autosomal recessive inheritance.
For an extensive discussion of the molecular genetics of IGHD type 1A and a listing of allelic variants in the GH1 gene, see 139250.
Dattani (2005) reviewed the genetic causes and phenotypic features of IGHD and combined pituitary hormone deficiency (see 613038). The author noted that hormone abnormalities may evolve over time, necessitating frequent reevaluation, and that determining the genotype can aid in management, e.g., because it is well established that the enlarged anterior pituitary associated with PROP1 mutations will undergo spontaneous involution, invasive procedures can be avoided.
Hastings Gilford (1904) called dwarfs with normal body proportions ateleiotic ('not arrived at perfection'). He distinguished sexual and asexual types and referred to patients with the former type as 'Tom Thumb dwarfs.' The 2 types correspond to what are referred to here as pituitary dwarfism I and III (262600), respectively. The first type has an isolated deficiency of growth hormone, whereas the second has deficiency of all anterior pituitary hormones. The existence of an isolated growth hormone deficiency in recessively inherited sexual ateleiosis was demonstrated by Rimoin et al. (1966). (Merimee et al. (1975) reported autopsy studies in the original case on the basis of which Rimoin et al. (1966) delineated autosomal recessive isolated growth hormone deficiency.) Families of this type have been reported by McKusick (1955), von Verschuer and Conradi (1938), Dzierzynski (1938) and others.
Leisti et al. (1973) found growth hormone deficiency in a male with deletion of the short arm of chromosome 18. The association may be coincidence or may indicate that a locus controlling growth hormone synthesis is on the deleted segment (see 146390).
On the basis of a study of 140 cases of idiopathic growth hormone deficiency, Rona and Tanner (1977) favored a multifactorial hypothesis. They pointed to a high male-female ratio and a high frequency of breech delivery. They felt that birth trauma may be a significant factor. McKusick (1972) noted the association of osteogenesis imperfecta (see 166200) in 2 cases from his own experience. Birth trauma affecting the pituitary gland or hypothalamus may be particularly likely to happen when the baby has OI. He suggested the presence of a small deletion as an alternative explanation, since the genes encoding growth hormone and the alpha-1 chain of type I collagen (COL1A1; 120150) are closely linked on chromosome 17.
Potential for gene therapy in the type of growth hormone deficiency shown by Phillips et al. (1981) to have deletion of the growth hormone gene was reported by Palmiter et al. (1982). They fused to the structural gene for rat growth hormone a DNA fragment containing the promoter of the mouse metallothionein-I gene. The fused gene was then injected into the pronuclei of fertilized mouse eggs. Of 21 mice that developed from those eggs, 7 could be shown by Southern blot analysis to be carrying the fusion gene and 6 of the 7 grew appreciably larger than their littermates. In addition to correcting genetic diseases, the method has promise for accelerating animal growth and forming valuable gene products such as antihemophilic globulin (F8; 300841), where the protein requires special covalent modifications, such as proteolytic cleavage, glycosylation or gamma-carboxylation for activity or stability. The designation hpGRF-40 refers to a peptide with major growth factor-releasing function derived from pancreatic tumors causing acromegaly. It seemed likely that peptide(s) of similar or identical sequence are released from the hypothalamus to control the synthesis and secretion of pituitary growth hormone.
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