PITUITARY DWARFISM I
GROWTH HORMONE DEFICIENCY, ISOLATED, AUTOSOMAL RECESSIVE
PRIMORDIAL DWARFISM
ILLIG-TYPE GROWTH HORMONE DEFICIENCY
IGHD IA
IGHD1A
SEXUAL ATELEIOTIC DWARFISM
Congenital isolated growth hormone deficiency type IA
Congenital IGHD type IA
Congenital isolated GH deficiency type IA
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 ... 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.
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 ... 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 173110 and 601538) 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 patients studied, GHD did not adversely affect fetal growth but is 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 for individuals with IGHD.
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 ... 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.