Classically, familial IGHD has been classified into four types depending on the inheritance pattern: autosomal recessive (types IA, OMIM 262400 and IB, OMIM 612781), autosomal dominant (type II, OMIM 173100), and X- linked (type III, OMIM 307200). Mutations in GH1 can cause IGHD types IA, IB, and II, while IGHD type IB can also be caused by mutations in growth hormone- releasing hormone receptor (GHRHR). In relation to IGHD type III, a X- linked GHD associated with agammaglobulinemia has been described: although the BTK (Bruton tyrosine kinase) gene, a key regulator of B cell development, has been associated with this condition, its genetic aetiology remains unknown. Additionally, homozygous and heterozygous mutations in the GHSR, also known as ghrelin receptor, have been associated with partial IGHD (OMIM 615925). On neuroimaging, regardless of the genetic defect, patients have normal or hypoplastic anterior pituitary with a normally sited posterior pituitary ‘bright’ signal.
This traditional classification was made before the exact genetic defects were known. In this chapter, we have chosen to focus on the most well characterized genetic defects and mentioned the former classification for completeness.
GH1
Mutations in the GH1 (growth hormone 1) gene are an excellent example of how different genetic defects and modes of inheritance lead to distinct phenotypes. Homozygous deletions of the GH1 gene locus ranging from 6.7 to 45 kB lead to severe forms of IGHD. Patients usually present within the first 6 months of life with typical clinical features associated with complete GH deficiency: severe growth failure (height standard deviation score (SDS) and point mutations have also been reported to cause this phenotype, known as IGHD type IA. In contrast, other homozygous mutations— splice- site, frameshift, or nonsense— cause a less severe phenotype also with marked short stature, delayed bone age, and low GH concentrations but with a good response to r- hGH without neutralizing antibody formation. This form is known as IGHD type IB.
In the autosomal dominant mode of inheritance, known as IGHD type II, patients present with low but usually detectable GH, a variable height deficit and time of presentation and they may or may not have anterior pituitary hypoplasia on magnetic resonance imaging (MRI) (38– 50%) [18]. These patients may develop additional pituitary hormone deficiencies (ACTH, prolactin, TSH, and/ or gonadotropin deficiencies) needing lifelong follow- up. Most mutations have been shown to affect the correct splicing of GH1, including single base mutations in the first six nucleotides of intron- 3, mutations in the exonic splice enhancers ESE1 and ESE2 or disruption of sequences downstream of the consensus splicing sites that affect intronic splice enhancers. The result is the skipping of exon 3 and the production of a 17.5 kDa isoform that exerts a dominant- negative effect on the secretion of the 22 KDa molecule. In trans genic mice studies the overexpression of 17.5 kD isoform showed defective GH secretory vesicles with anterior pituitary hypoplasia, loss of somatotropes, and invasion by macrophages. The most severely affected animal developed other anterior pituitary cell line deficiencies. There are also missense mutations with complex mechanisms of action which disturb GH secretion or reduce the binding affinity for the GH receptor.
GHRHR
The GHRHR gene encodes a G- protein coupled receptor. Its expression is upregulated by POU class 1 homeobox 1 (POU1F1, formerly called PIT1) and is required for the proliferation of somatotropes. Patients with pathogenic variants in this gene present with early and severe growth failure, typical facial features, and have a good response to r- hGH therapy; other clinical findings such as neonatal hypoglycaemia and micropenis are absent [20]. On MRI, most patients have anterior pituitary hypoplasia with a normally placed posterior pituitary signal; however, there are some reports of a normal- sized anterior pituitary. These patients are also classified as having IGHD type IB (OMIM 612781). Homozygous or compound heterozygous mutations have been reported (missense, nonsense, splice- site, deletions, or regulatory mutations) and patients are usually of consanguineous pedigrees or certain ethnic backgrounds— Indian subcontinent and Brazil. There is a report of a heterozygous mutation in the signal peptide leading to a dominant form of inheritance with variable penetrance.
