Abnormalities either in the synthesis or the activity of GH can cause a wide variation in the clinical phenotype of the patient. General clinical features of IGHD deficiency include proportionate growth retardation accompanied by a decreased growth velocity, puppet-like facies, frontal bossing, thin hair, a high-pitched voice, moderate trunk obesity, delayed bone maturation and dentition. Patients with IGHD appear younger than their chronological age. Puberty may be delayed until late teens, but usually fertility is preserved.

To date, four Mendelian types of IGHD have been identified on the basis of the type of defect, mode of inheritance, and degree of deficiency.

1) Type 1 GH deficiency is an autosomal recessively inherited condition, which exists as either a complete, or as a partial loss of GH expression.

a) Type 1a deficiency is characterized by the complete absence of measurable GH. Infants born with a type 1a defect are generally of normal length and weight, suggesting that, in utero, GH is not an essential growth factor (22,23). Growth immediately after birth and during infancy may also be less dependent on circulating GH levels than during other phases of life. Patients with Type 1a deficiency initially respond to rhGH treatment well. However, about 1/3 of patients develop antibodies to GH which leads to markedly decreased final height as adults(109). The exact prevalence of Type 1a deficiency is not known, and most reported families are consanguineous (109). Mutations in Type 1a have been described in GH1 and GHRHR-including nonsense mutations, microdeletions/frame-shifts, and missense mutations.

b) Type 1b deficiency represents a state of partial-rather than an absolute-deficiency of GH, with measurable (but insufficient) serum GH. Therefore it is milder than Type 1a deficiency. Patients with Type 1b deficiency do not typically present with mid-facial hypoplasia or microphallus. They also have a good response to GH treatment without developing GH antibodies. Most cases of Type 1b GH deficiency are caused by missense and/or splice site mutations in the GH1 and GHRHR genes (39).2) Type 2 GH deficiency is an autosomal dominantly inherited disorder with reduced secretion of GH. Patients with Type 2 GHD usually do not have any pituitary abnormality (116). However, recently, it has been shown that their pituitary may become small over time (117). They have a good response to GH treatment. This type of GH deficiency is intuitively less clear, since autosomal dominant conditions generally occur as a result of either haploinsufficiency or secondary to dominant-negative activity. Haploinsufficiency, however, has not been demonstrated in the obligate heterozygote carriers of individuals harboring GH1 deletions, and is therefore an unlikely explanation. Dominant-negative activity is usually associated with multimeric proteins, also making this explanation less intuitive. Type 2 GHD appears to be the most common form of IGHD and many mutations have been identified in GH1 including splicing and missense mutations (24-31, 118). Recent studies suggest that GH1 may not be the only gene involved in Type 2 GHD. Screening 30 families with autosomal dominant IGHD did not show any GH1 mutations, raising the possibility of other gene(s) may be involved (119).

3) Type 3 growth hormone deficiency is inherited in an X-linked recessive manner. There are no candidate genes and no compelling explanations for this condition. There are no reported mutations of the GH-1 gene in Type 3 GHD. In addition to short stature, patients may also have agammaglobulinemia (109).

Table 6 summarizes phenotype of mutations involved in human pituitary transcription factors causing IGHD and MPHD and their mode of inheritance.