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Isolated growth hormone deficiency (type II)
This condition results from the pituitary gland not producing enough growth hormone, which is crucial for normal growth during childhood. It primarily affects children, causing slower-than-expected growth and reduced adult height.
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Overview
Isolated growth hormone deficiency (type II), often referred to as IGHD Type II, is a genetic condition where the body does not produce enough growth hormone. Growth hormone is a protein made by the pituitary gland, a small gland located at the base of the brain. This hormone is vital for normal growth and development in children, especially for increasing height and developing bones [PMID:33678096].
Individuals with IGHD Type II typically experience slower growth rates from early childhood, leading to a shorter adult height if left untreated. The condition is termed 'isolated' because, in this specific type, the deficiency primarily affects growth hormone production, without significantly impacting other hormones produced by the pituitary gland. The exact prevalence of all types of growth hormone deficiency is estimated to be between 1 in 4,000 and 1 in 10,000 live births.
Symptoms & clinical features
The primary symptom of isolated growth hormone deficiency (type II) is significantly slower growth compared to other children of the same age and sex. This slow growth often becomes noticeable within the first few years of life. Children with the condition may appear smaller than their peers and have proportionate body features, meaning their body parts are in the correct ratio to each other, just smaller overall [PMID:33678096].
Other potential signs can include a more rounded face, a higher-pitched voice, and sometimes an accumulation of fat around the abdominal area. Puberty may also be delayed in some individuals. It's important to note that these symptoms can vary in severity between affected individuals.
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Affected organs
The main organ affected in isolated growth hormone deficiency (type II) is the pituitary gland, specifically its anterior (front) part, which is responsible for producing and releasing growth hormone. While the pituitary gland itself may appear structurally normal in many cases, its function is impaired regarding growth hormone synthesis or secretion.
Indirectly, the skeletal system is significantly impacted, as growth hormone is crucial for the development and lengthening of bones, particularly in the arms and legs. Other body tissues, including muscle, also rely on adequate growth hormone for their normal development and maintenance. The overall effect is on the child's growth and eventual adult height.
Risks & severity
The severity of isolated growth hormone deficiency (type II) can vary. Without treatment, individuals typically reach an adult height significantly below the average range. The specific adult height attained depends on the degree of growth hormone deficiency and how early treatment begins.
While the primary concern is growth, research suggests that long-term growth hormone deficiency, if untreated, may be associated with other health considerations in adulthood, such as changes in body composition (e.g., higher body fat, lower muscle mass) and potential effects on bone density and cardiovascular health [PMID:28751523]. However, these are often managed through ongoing care. The age of onset for noticeable growth issues is typically in early childhood.
Genetic causes
Isolated growth hormone deficiency (type II) is caused by pathogenic variants in the GH1 gene. This gene provides the instructions for making growth hormone, which is also known as somatotropin. Growth hormone is a protein vital for growth and development, acting on various tissues throughout the body to promote cell growth and division, particularly in bone and cartilage.
Pathogenic variants in GH1 can lead to the production of a non-functional or abnormally structured growth hormone protein, or they can disrupt the process by which the hormone is made or secreted. When the growth hormone is faulty or insufficient, the body cannot achieve its full growth potential, resulting in the characteristic short stature seen in this condition. Type II specifically refers to a form that has a particular inheritance pattern.
- GH1 growth hormone 1The GH1 gene encodes growth hormone, a crucial protein produced in the pituitary gland that regulates normal growth, development, and metabolic processes throughout the body.
Inheritance pattern
Isolated growth hormone deficiency (type II) is inherited in an autosomal dominant pattern. This means that a person only needs one copy of the altered GH1 gene in each cell to develop the condition. If a parent has the condition, there is a 50% chance that each child they have will also inherit the altered gene and therefore be affected. This likelihood applies to every pregnancy, regardless of whether previous children have inherited the gene or not.
In some cases, the condition can arise from a new (de novo) pathogenic variant in the GH1 gene that occurs for the first time in an individual, with no family history of the condition. In such situations, the risk for future siblings of the affected individual is typically low, but the affected individual would then have a 50% chance of passing it on to their own children.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
Diagnosis of isolated growth hormone deficiency (type II) typically begins with clinical observations, such as significantly slow growth rate and short stature, followed by a series of tests. These usually include blood tests to measure growth hormone levels after stimulation and to check for other hormone deficiencies. Imaging, such as an MRI scan of the pituitary gland, may be performed to rule out structural abnormalities.
Confirmation of IGHD Type II involves genetic testing to identify a pathogenic variant in the GH1 gene. This testing is usually arranged by a paediatric endocrinologist or a clinical geneticist. In the UK, genetic testing for growth hormone deficiency falls under the NHS Genomic Medicine Service, and there are specific R-codes for this testing, such as R301 Growth failure. A referral to a clinical genetics service can facilitate access to these diagnostic pathways.
Management & lifestyle
The primary management for isolated growth hormone deficiency (type II) is treatment with synthetic growth hormone. This is typically administered via daily injections, usually until the child reaches their final adult height or no longer responds to treatment. The aim is to normalise the child's growth rate and help them achieve a more typical adult height [PMID:33678096]. The treatment plan is individualised and overseen by a paediatric endocrinologist.
Regular monitoring of growth, hormone levels, and general health is crucial throughout treatment. The NHS provides comprehensive care, including specialist paediatric endocrinology clinics, where treatment decisions are made and reviewed. Genetic counsellors can also provide support and information regarding the genetic aspects of the condition and its implications for family members. Long-term follow-up into adulthood may be recommended to monitor for any lasting effects or potential adult growth hormone deficiency, though this is less common with isolated deficiencies.
UK care pathway
In the UK, individuals suspected of having isolated growth hormone deficiency (type II) are generally referred to a paediatric endocrinologist. If a genetic cause is suspected, a referral to a clinical genetics service is typically made. Genetic testing for this condition, often under NHS Genomic Medicine Service R-codes like R301 Growth failure, is available to confirm the diagnosis.
Clinical geneticists and genetic counsellors provide essential support, explaining inheritance patterns, recurrence risks, and coordinating further family testing if appropriate. They also help navigate the care pathway within the NHS, ensuring access to relevant specialists and ongoing management.
Frequently asked questions
What is growth hormone?
Growth hormone is a natural protein produced by the pituitary gland in your brain. It plays a vital role in childhood growth, helping bones and tissues develop. It also has important functions in metabolism throughout life.
How is isolated growth hormone deficiency (type II) diagnosed?
Diagnosis typically involves measuring your child's growth, conducting blood tests to check hormone levels after stimulation, and sometimes an MRI scan of the pituitary gland. Genetic testing for changes in the GH1 gene confirms the diagnosis.
Can isolated growth hormone deficiency (type II) be treated?
Yes, the primary treatment is synthetic growth hormone given by daily injections. This treatment aims to help the child grow at a more typical rate and reach a more usual adult height. Treatment plans are tailored by a specialist doctor.
If I have this condition, will my children get it?
Because isolated growth hormone deficiency (type II) is inherited in an autosomal dominant pattern, there is a 50% chance for each child of an affected parent to inherit the altered gene and develop the condition. Genetic counselling can provide more personalised information.
Does this condition affect other aspects of health besides growth?
The main impact is on growth and adult height. While untreated, long-term growth hormone deficiency can be associated with some metabolic and bone health changes, these are typically monitored and managed as part of ongoing care.
References
- 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
- Ariyasu D, Yoshida H, Hasegawa Y. Endoplasmic Reticulum (ER) Stress and Endocrine Disorders. International journal of molecular sciences. 2017. PMID: 28208663
- 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
- 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
- Gucev Z, Tasic V, Saranac L. A novel GH1 mutation in a family with isolated growth hormone deficiency type II. Hormone research in paediatrics. 2012. PMID: 22188748
- Boguszewski CL, Boguszewski MCDS, de Herder WW. From dwarves to giants: South American's contribution to the history of growth hormone and related disorders. Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society. 2020. PMID: 31864177
- 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