Molecular Genetics In Endocrinology

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3.1. THE GROWTH HORMONE PATHWAY The growth hormone (GH) pathway is comprised of a series of interdependent genes whose products are required for normal growth (see Fig. 1). The GH pathway genes include ligands (GH and insulin-like growth factor 1 or IGF-1), transcription factors (PIT1 and PROP1), agonists (GH-releasing hormone or GHRH), antagonists (somatostatin), and receptors such as the GHRH receptor (GHRHR) and the GH receptor (GHR). These genes are expressed in different organs and tissues, including the hypothalamus, pituitary, liver, and bone (see Fig. 1). The effective and regulated expression of the GH pathway is essential for growth in stature as well as for homeostasis of carbohydrate, protein, and fat metabolism. Diseases caused by known gene defects in the GH pathway include combined pituitary hormone deficiency (CPHD) caused by defects in transcription factors such as HESX1, LHX3, PROP1 and PIT1, isolated growth hormone deficiency (IGHD) caused by defects in the GH gene (GH1) and in GHRHR, and GH-resistance syndromes caused by defects in GHR and IGF1.

3.2. ISOLATED GROWTH HORMONE DEFICIENCY Estimates of the frequency of GH deficiency (GHD) range from 1 in 4000 to 1 in 10,000 in various studies. Causes of GHD include central nervous system insults or defects such as cerebral edema, chromosome anomalies, histiocytosis, infections, radiation, septo-optic dysplasia, trauma, or tumors that affect the hypothalamus or pituitary. Although most individuals with GHD have no family history of GHD, estimates of the proportion of cases that have an affected parent, sibling, or child range from 3% to 30% in different studies. This familial clustering suggests that a significant proportion of GHD cases might have a genetic basis and that having an affected relative conveys substantially increased relative risk for all first degree relatives (13-14). Our current understanding of the genetics of familial defects in the GH pathway will be discussed in the following subsections.

3.3. CLINICAL FEATURES An intact GH pathway is needed throughout childhood to maintain normal growth. Concomitant or combined deficiencies of other pituitary hormones (LH, FSH, TSH, and/or ACTH), in addition to GH, is called combined pituitary hormone deficiency (CPHD) or pan-hypopituitary dwarfism. The combination of GH and these additional hormone deficiencies often causes more severe retardation of growth, and skeletal maturation and spontaneous puberty might not occur (13,14).

3.4. DIAGNOSIS Short stature, delayed growth, and delayed skeletal maturation occur with GH pathway defects.

Severe Igf Deficiency Pathophysiology

Fig. 1. The growth hormone pathway. For details, see text. GH: growth hormone; HESX1: homeobox gene expressed in ES cells; LHX3: lim homeobox gene 3; PROP1: prophet of PIT1; PIT1: pituitary-specific transcription factor 1; GHRH: growth hormone-releasing hormone; GHRHR: growth hormone-releasing hormone receptor; GHR: growth hormone receptor; IGF-1: insulin-like growth factor 1; IGF-1R: insulinlike growth factor 1 receptor.

Fig. 1. The growth hormone pathway. For details, see text. GH: growth hormone; HESX1: homeobox gene expressed in ES cells; LHX3: lim homeobox gene 3; PROP1: prophet of PIT1; PIT1: pituitary-specific transcription factor 1; GHRH: growth hormone-releasing hormone; GHRHR: growth hormone-releasing hormone receptor; GHR: growth hormone receptor; IGF-1: insulin-like growth factor 1; IGF-1R: insulinlike growth factor 1 receptor.

Because these signs can also be associated with systemic illnesses, individuals suspected of having GHD should be evaluated for systemic diseases before having complicated tests to detect GHD. GH stimulation testing is necessary to confirm the diagnosis of GHD, and peak GH levels of less than 7-10 ng/mL are considered abnormal. Testing for concomitant deficiencies of LH, FSH, TSH, and/or ACTH should be done when GHD is diagnosed to detect CPHD and provide a complete diagnosis and enable planning of optimal treatment (13,14).

3.5. TYPES OF FAMILIAL IGHD There are at least six different Mendelian disorders. These include four autosomal recessive disorders (IGHD IA and IB, bioinactive GH, and GHRHR defects; OMIM 262400, 139250, 262650, and 139191, respectively). In addition, there are autosomal dominant (IGHD II, OMIM 173100) and X-linked forms of IGHD (IGHD III, OMIM 307200) (Table 1).

3.5.1. Autosomal Recessive Isolated Growth Hormone Deficiency The most severe form of IGHD, called IGHD IA (OMIM 262400 and139250) has an autosomal recessive mode of inheritance. Affected neonates occasionally have mildly decreased birth lengths and hypoglycemia in infancy. All develop severe dwarfism by 6 mo of age. Although replacement therapy with recombinant human growth hormone (rhGH) gives a good initial growth response in individuals with IGHD IA, this response is often temporary because of formation of anti-GH antibodies, which, in sufficient titer, cause GH resistance and an arrest of the response to rhGH replacement.

Table 1

Selected Genetic Defects Causing Isolated Growth Hormone Deficiency

Table 1

Selected Genetic Defects Causing Isolated Growth Hormone Deficiency

Type of IGHD

Location

Nucleotide change

Effect

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