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Isolated growth hormone deficiency (type II)
This condition primarily affects a person's growth, resulting in shorter height than expected. It is caused by changes in a specific gene, and its effects can become apparent in childhood.
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Overview
Isolated growth hormone deficiency (GHD) refers to a condition where the body does not produce enough growth hormone (GH), a crucial substance for normal growth and development. Type II specifically refers to forms of GHD that are inherited in an autosomal dominant pattern. This means a single altered copy of a gene is sufficient to cause the condition.
Children with isolated GHD type II typically experience slow growth, leading to short stature. The severity can vary among individuals, even within the same family. Early diagnosis and management are important to support affected individuals.
Symptoms & clinical features
The primary symptom of isolated GHD type II is slow growth, which often becomes noticeable during infancy or early childhood. Children may fall below the expected height range for their age and sex on growth charts. While height is the main concern, body proportions usually remain normal.
Other potential, less common, features can include delayed bone age (bones appearing less mature than the child's actual age) and sometimes, in very young children, hypoglycaemia (low blood sugar). these symptoms can also be associated with other health conditions, so a thorough medical evaluation is essential to confirm a diagnosis.
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Affected organs
Isolated GHD type II primarily affects the pituitary gland, a small gland located at the base of the brain. The pituitary gland is responsible for producing and releasing growth hormone. In this condition, the pituitary gland either produces insufficient amounts of growth hormone or the growth hormone it produces does not function correctly, leading to systemic effects on growth, particularly of the bones and other tissues.
Risks & severity
The main risk associated with isolated GHD type II is significant short stature if left unmanaged. The severity of growth impairment can range from mild to severe, even among individuals with the same genetic alteration. The exact prevalence of all types of GHD combined is estimated to be between 1 in 4,000 and 1 in 10,000, but the specific prevalence for type II is not well established.
Symptoms typically become apparent in childhood as growth velocity slows. If the condition is suspected, early referral to an endocrinologist (a doctor specialising in hormones) can help in diagnosis and discussions around management options.
Genetic causes
Isolated growth hormone deficiency type II is most often caused by genetic alterations in the *GH1* gene [PMID:17961226]. The *GH1* gene contains instructions for making human growth hormone. This hormone is a protein that plays a vital role in stimulating growth during childhood and adolescence, influencing bone development, and affecting various metabolic processes in the body.
Pathogenic variants in the *GH1* gene can lead to insufficient production of growth hormone, or to the production of a growth hormone that does not function effectively [PMID:7862657]. This disruption in the normal growth hormone pathway prevents the body from growing to its full potential, resulting in the characteristic short stature observed in individuals with isolated GHD type II. Other genes can sometimes be implicated in other forms of GHD, but *GH1* is the primary cause for type II.
- GH1 growth hormone 1The GH1 gene encodes growth hormone, a crucial protein produced in the pituitary gland that is essential for normal growth, tissue development, and metabolic regulation.
Inheritance pattern
Isolated growth hormone deficiency type II follows an autosomal dominant inheritance pattern. This means that an individual only needs to inherit one altered copy of the *GH1* gene from one parent to develop the condition. If a parent has isolated GHD type II, there is a 50% chance with each pregnancy that their child will also inherit the altered gene and therefore be at risk of developing the condition.
Autosomal dominant conditions affect males and females equally. sometimes a new (de novo) genetic alteration can occur in an individual for the first time, without it being inherited from either parent.
Each child of an affected parent has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
Diagnosis of isolated GHD type II typically begins with a clinical assessment, including a detailed review of growth charts and medical history. Blood tests may be performed to measure levels of growth hormone and other related hormones, such as insulin-like growth factor 1 (IGF-1) [PMID:30613898]. Growth hormone stimulation tests, where medication is given to stimulate GH release, might also be used to assess the pituitary gland's function.
Confirmation of isolated GHD type II is achieved through genetic testing, which can identify specific alterations in the *GH1* gene. In the UK, genetic testing for GHD may be accessed via the NHS Genomic Medicine Service (GMS) pathways, often following referral from a paediatrician or endocrinologist. Relevant R-codes for GHD include R91 for Growth Hormone Deficiency and R90 for Short Stature, which would guide genetic testing panels.
Management & lifestyle
Management of isolated GHD type II primarily involves treatment with recombinant human growth hormone (rhGH) to promote normal growth. This is typically given as daily injections under the skin. The goal of treatment is to achieve a more typical adult height. Response to treatment can vary, and it is usually continued until linear growth has ceased, typically in late adolescence.
Treatment decisions and monitoring are managed by a paediatric endocrinologist. Regular follow-up appointments are necessary to monitor growth, adjust hormone dosage, and assess for any potential side effects. Genetic counsellors can provide valuable support and information to families regarding the inheritance pattern and implications of the condition.
UK care pathway
In the UK, individuals suspected of having isolated growth hormone deficiency type II would typically be referred by their GP to a paediatrician or endocrinologist. If a genetic cause is suspected, they would then be referred to a clinical genetics service. These services work within the NHS Genomic Medicine Service (GMS) pathways, which use national testing directories and R-codes (such as R90 for Short Stature or R91 for Growth Hormone Deficiency) to guide appropriate genetic testing.
Genetic counsellors are also an integral part of this pathway, offering information, support, and guidance on the genetic aspects of the condition for affected individuals and their families.
Frequently asked questions
What is growth hormone and why is it important?
Growth hormone is a protein produced by the pituitary gland that is essential for normal growth and development, particularly during childhood and adolescence. It helps stimulate the growth of bones and tissues, and also plays a role in metabolism.
How is isolated GHD type II diagnosed?
Diagnosis typically involves checking growth charts, blood tests to measure hormone levels, and sometimes growth hormone stimulation tests. Genetic testing for changes in the *GH1* gene confirms isolated GHD type II.
Can isolated GHD type II be treated?
Yes, isolated GHD type II can often be managed with recombinant human growth hormone (rhGH) therapy. This involves regular injections to supplement the body's natural growth hormone, aiming to improve growth and adult height.
If I have isolated GHD type II, will my children inherit it?
Since isolated GHD type II is inherited in an autosomal dominant pattern, there is a 50% chance with each pregnancy that your child will inherit the altered gene and may develop the condition. Genetic counselling can provide more personalised information and support.
What kind of doctor treats isolated GHD type II?
A paediatric endocrinologist, a doctor specialising in hormonal disorders in children, typically manages the treatment and ongoing care for individuals with isolated GHD type II.
References
- Shariat N, Holladay CD, Cleary RK. Isolated growth hormone deficiency type II caused by a point mutation that alters both splice site strength and splicing enhancer function. Clinical genetics. 2008. PMID: 18554279
- Miletta MC, Flück CE, Mullis PE. Targeting GH-1 splicing as a novel pharmacological strategy for growth hormone deficiency type II. Biochemical pharmacology. 2017. PMID: 27457999
- Huang X, Chen H, Shangguan H. The clinical and genetic aspects of six individuals with GH1 variants and isolated growth hormone deficiency type II. Frontiers in endocrinology. 2024. PMID: 39435354
- Kannenberg K, Wittekindt NE, Tippmann S. Mutant and misfolded human growth hormone is rapidly degraded through the proteasomal degradation pathway in a cellular model for isolated growth hormone deficiency type II. Journal of neuroendocrinology. 2007. PMID: 17927666
- Hamid R, Phillips JA 3rd, Holladay C. A molecular basis for variation in clinical severity of isolated growth hormone deficiency type II. The Journal of clinical endocrinology and metabolism. 2009. PMID: 19837935
- Ariyasu D, Yoshida H, Hasegawa Y. Endoplasmic Reticulum (ER) Stress and Endocrine Disorders. International journal of molecular sciences. 2017. PMID: 28208663
- Ariyasu D, Kubo E, Higa D. Decreased Activity of the Ghrhr and Gh Promoters Causes Dominantly Inherited GH Deficiency in Humanized GH1 Mouse Models. Endocrinology. 2019. PMID: 31436800
- Solis AS, Peng R, Crawford JB. Growth hormone deficiency and splicing fidelity: two serine/arginine-rich proteins, ASF/SF2 and SC35, act antagonistically. The Journal of biological chemistry. 2008. PMID: 18586677