Growth Hormone (GH) and Growth Hormone Deficiency (GHD):
GH is secreted from adenohypophysis present on the somatotrophs. It is also known as Somatotropin and exerts a myriad of pleiotropic effect via a number of intracellular signalling pathways. It blocks insulin action, promotes lipolysis and impedes lipogenesis. Its deficiency causes GHD.
GHD is a rare disorder characterized by the inadequate secretion of GH from the anterior pituitary gland, a small gland at the base of the brain which is responsible for the secretion of several other hormones as well.
GHD can either be present from birth known as congenital which can result from genetic mutations, structural defects in the brain, can also be acquired later in life as a result of trauma, infection, radiation therapy, or tumour growth within the brain known as acquired GHD. There’s a third group also which has no known or diagnosable cause known as idiopathic.
Childhood-onset GHD may result from any of the above three reasons: congenital, acquired, or idiopathic. It results in growth retardation/short stature, maturation delays that are reflected by the delay of lengthening of the bones of the extremities, which does not commensurate with the chronological age of the child. Whereas, Adult-onset GHD is most often acquired from a pituitary tumour or trauma to the brain but may also be idiopathic.
Types and Modes of Inheritance of GHD:
GHD can be inherited by various modes i.e. Autosomal Dominant, Autosomal Recessive, and X- linked recessive. The incidence of GHD is estimated to be in 1/4,000 – 1/10,000 live births and nearly ~3-30% cases had genetic origins.
GHD is mainly of two types: IGHD (Isolated Growth Hormone Deficiency) and CPHD (Combined Pituitary Hormone Deficiency). IGHD can result from mutations in GH1, GHRHR genes whereas CPHD is caused by the defects in transcription factor (TF) like PROP1, POU1F1 and HESX1.
Isolated Growth Hormone Deficiency (IGHD):
IGHD is caused by the severe shortage or absence of GH. Because, they do not have an adequate amount of GH, people with IGHD commonly experience a failure to grow at the expected rate and have unusually short stature. This condition is usually apparent by early childhood.
There are mainly four types of IGHD differentiated by the severity of the condition, the gene involved, and the inheritance pattern.
IGHD type IA is caused by the absence of GH and is the most severe of all the types. In patients with type IA, growth failure is evident in infancy as the affected neonates are shorter than a normal person, at birth.
Patients with IGHD type IB produce very low levels of GH. As a result, type IB is characterized by the short stature, but this growth failure is typically not as severe as in the type IA. Growth failure in patients with type IB is usually apparent in early to mid-childhood.
Individuals with IGHD type II have very low levels of GH and short stature that varies in severity. Growth failure in these individuals is usually evident in early to mid-childhood. It is estimated that nearly half of the individuals with type II have pituitary hypoplasia.
IGHD type III is similar to type II. In which affected individuals have very low levels of GH and short stature that varies in severity. Growth failure in type III is also usually evident in early to mid-childhood. People with type III may also have a weakened immune system and are prone to frequent infections. They produce very few B-cells, which are specialized white blood cells that help protect the body against infection (agammaglobulinemia).
The occurrence of IGHD is estimated to be 1 in ~ 4,000 to 10,000 individuals worldwide.
The causes of IGHD vary and, in most cases, the aetiology is unknown. Mutation in the genes encoded by GH1 and GHRHR are some of the main causes of IGHD. Additionally, mutations that occur in some genes encoding pituitary transcription factors such as HESX1 and LHX4 have also known to cause IGHD.
IGHD types IA and II are caused by mutations in the GH1 gene, type IB is caused by mutations in either the GH1 or GHRHR gene, and type III is caused by mutations in the BTK gene.
The GH1 gene provides instructions for making the GH protein. Mutations in the GH1 gene impair the production of GH. Without sufficient GH, the body fails to grow at its normal rate, results in slow growth and short stature as seen in IGHD type IA, IB, and II.
The GHRHR gene encodes growth hormone releasing hormone receptor. This receptor binds to a molecule called growth hormone releasing hormone (GHRH). The binding of GHRH to the receptor triggers the production of GH and its release from the pituitary gland. Mutations in the GHRHR gene vitiate the production of GH and as a repercussion delay in growth. Decreased GH activity due to GHRHR gene mutations is responsible for many cases of IGHD type IB.
The BTK gene encodes Bruton tyrosine kinase (BTK), which is essential for the development and the maturation of immune system cells called B lymphocytes. The BTK protein transmits important chemical signals that instruct B cells to mature and produce antibodies. It is unknown how mutations in the BTK gene contribute to the short stature in patients with IGHD type III.
Some patients with IGHD do not have mutations in the GH1, GHRHR, or BTK genes. In these individuals, the cause of the condition is unknown. When this condition does not have an identified genetic cause, it is known as idiopathic IGHD.
IGHD can be inherited as an autosomal recessive (Type 1A and Type IB IGHD), autosomal dominant (Type II IGHD) or X-linked recessive (Type III IGHD). GH1 is the definitive gene involved in the synthesis of pituitary GH.
Isolated growth hormone deficiency can have different inheritance patterns depending on the type of the condition.
IGHD types IA and IB are inherited in an autosomal recessive pattern, which means both alleles of the GH1 or GHRHR gene are mutated. The parents of an individual with an autosomal recessive condition carry one allele of the mutated gene, but they typically do not show signs and symptoms of the condition.
IGHD type II can be inherited in an autosomal dominant pattern, which means a mutation in a single allele of the GH1 gene is sufficient to cause the disorder. This condition can also result from new mutations in the GH1 gene and occur in people with no history of the disorder in their family.
IGHD type III, caused by mutations in the BTK gene, is inherited in an X-linked recessive pattern. The BTK gene is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation would have to occur in both copies of the gene to cause the disorder. Because it is unlikely that females will have two altered copies of this gene, males are affected by X-linked recessive disorders much more frequently than their females counterpart. A typical characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.
· Severe short stature
· Undetectable serum GH concentration
· Anti-GH Abs on treatment
Less severe than IA
· Low but detectable serum GH concentration
· No anti-GH Abs on treatment
· Variability in height deficit
· GH deficiency with agammaglobulinemia
Table 1: Summary of IGHD types, inheritance, phenotype and genes involved (Alatzoglou, K. S. & Dattani, M. T. 2010).
GHRH (Growth Hormone Releasing Hormone):
GHRH is secreted by the hypothalamus and plays a fundamental role in GH secretion, expression, as well as in the differentiation and proliferation of pituitary somatotrophs. This myriad of actions is mediated through G-protein coupled receptors (GPCR). GHRH binds to the GHRHR which consist of 13 exons and encodes a 423 amino acids long protein, which is a member of the secretin/VIP (Vasoactive Intestinal Polypeptide)/glucagon receptor superfamily.
As their name implies, G protein-coupled receptors (GPCRs) are receptors that are closely associated with a member of the guanosine nucleotide binding protein (G protein) family. Three essential components define signal transduction through GPCRs: a plasma membrane receptor with seven transmembrane helical segments, a G protein that cycle between active (GTP-bound) and inactive (GDP-bound) forms, and an effector enzyme (or ion channel) in the plasma membrane that is regulated by the activated G protein. The G protein, stimulated by the activated receptor, exchanges bound GDP for GTP, then dissociates from the occupied receptor and binds to the nearby effector enzyme, altering its activity. The activated enzyme then generates a second messenger that affects downstream targets.
Figure 4a & 4b: GPCR signalling pathway and cAMP production respectively. (Lehninger 6th Edition
Figure 5: The 13 exons of GHRHR (Alatzoglou, K. S. & Dattani, M. T. 2010).
GHRHR promotes intracellular cyclic AMP (cAMP) production by adenylate cyclase which further promotes the activation of protein kinase A (PKA) and PKA mediated phosphorylation, which results in cellular proliferation and GH secretion. cAMP is recognized as an important mediator of GHRH action. A recessive mutation within the GHRHR has been documented and several other recessive mutations have now been identified in the human homologue of the gene. These mutations are scattered throughout the gene, affecting both the ability of GHRH to bind the GHRHR and also the ability to transactivate the receptor.