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Growth hormone insensitivity (Laron)
This condition is characterised by short stature and distinctive facial features, resulting from the body's inability to utilise growth hormone effectively. It affects individuals from birth and is caused by specific genetic changes.
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Overview
Growth hormone insensitivity, also known as Laron syndrome, is a rare inherited condition that primarily affects a person's growth. Despite having normal or even high levels of growth hormone (GH) in the bloodstream, the body does not respond to it as it should [PMID:33678079]. This lack of response means that the signals usually sent by growth hormone to stimulate growth and development are not received or processed correctly by the body's cells.
The condition is present from birth, and its effects on growth become apparent early in childhood. Individuals with Laron syndrome typically have severely reduced stature, often referred to as proportionate dwarfism, meaning their body proportions are generally maintained, but their overall height is much shorter than average for their age and sex. The exact prevalence of Laron syndrome is not well established, but it is considered a very rare condition globally.
Symptoms & clinical features
The primary symptom of growth hormone insensitivity (Laron) is significantly short stature, which becomes noticeable in infancy or early childhood. Affected individuals typically have heights well below the average for their age [PMID:33678079]. In addition to short stature, several other features are often associated with the condition.
Characteristic facial features may include a prominent forehead, a small jaw, and a saddle-shaped nose. Other common symptoms can involve obesity, particularly around the trunk, and reduced muscle strength. Some individuals may also experience episodes of low blood sugar (hypoglycaemia) in infancy and early childhood, which can be a serious concern. Bone density may also be affected, leading to an increased risk of bone fractures in some cases.
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Affected organs
Growth hormone insensitivity primarily impacts the skeletal system, leading to the characteristic short stature due to impaired bone growth. The condition also affects metabolic processes throughout the body, as growth hormone plays a crucial role in regulating metabolism.
Other organ systems that can be indirectly affected include the muscles, contributing to reduced muscle mass and strength, and potentially the brain, particularly in early life if severe hypoglycaemia occurs. The liver is also involved as it is the primary site where insulin-like growth factor 1 (IGF-1) is produced in response to growth hormone signalling; in Laron syndrome, IGF-1 levels are typically very low.
Risks & severity
The severity of growth hormone insensitivity (Laron) can vary, but individuals generally experience severe short stature. The condition is associated with a lifelong impact on growth and metabolism. While severe short stature is the most consistent feature, the extent of other metabolic complications can differ among affected individuals.
Some research suggests that individuals with Laron syndrome may have a lower risk of developing certain age-related diseases, such as cancer and type 2 diabetes, although more studies are needed to fully understand these potential long-term health implications [PMID:24075117]. However, the initial risks in infancy, particularly relating to severe hypoglycaemia, require careful monitoring and management.
Genetic causes
Growth hormone insensitivity (Laron) is caused by genetic changes (pathogenic variants) in the GHR gene. This gene provides instructions for making the growth hormone receptor protein. The growth hormone receptor is found on the surface of many cells throughout the body and is essential for receiving signals from growth hormone.
When growth hormone binds to its receptor, it triggers a cascade of events inside the cell that leads to growth and metabolic regulation. Pathogenic variants in GHR disrupt the normal function of this receptor, meaning that even if growth hormone is present in sufficient amounts, the cells cannot properly 'hear' its message. This inability to respond to growth hormone leads to the characteristic features of Laron syndrome.
- GHR growth hormone receptorThe GHR gene provides instructions for the growth hormone receptor, a protein vital for cell growth, division, and metabolism, primarily by interacting with growth hormone.
Inheritance pattern
Growth hormone insensitivity (Laron) is inherited in an autosomal recessive pattern. This means that a person must inherit two copies of the altered GHR gene - one from each parent - to develop the condition. Individuals who inherit only one copy of the altered gene are known as carriers.
Carriers typically do not show any symptoms of growth hormone insensitivity because they have one working copy of the GHR gene, which is usually sufficient to produce enough functional receptor protein. When two carriers have children, there is a 25% chance with each pregnancy that the child will inherit two altered copies and develop the condition, a 50% chance the child will be a carrier, and a 25% chance the child will inherit two normal copies of the gene.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
Diagnosis & testing
Diagnosis of growth hormone insensitivity (Laron) is typically suspected based on clinical features, particularly severe short stature, and characteristic physical findings. Blood tests usually show normal or elevated levels of growth hormone (GH) but very low levels of insulin-like growth factor 1 (IGF-1), which is produced in response to GH signalling.
A definitive diagnosis is confirmed through genetic testing, which identifies pathogenic variants in the GHR gene. Genetic testing for growth disorders, including GHR variants, can be accessed via the NHS Genomic Medicine Service. Referrals to clinical genetics services for assessment and genetic testing are typically made by paediatricians or endocrinologists following initial clinical and biochemical investigations. The relevant NHS Genomic Medicine Service R-code would guide the specific genetic testing panel.
Management & lifestyle
The management of growth hormone insensitivity (Laron) focuses on supporting growth and addressing associated metabolic concerns. Treatment often involves injections of recombinant human insulin-like growth factor 1 (rhIGF-1), which can bypass the non-functional growth hormone receptor and directly promote growth [PMID:33678079]. The response to rhIGF-1 can vary among individuals.
Ongoing monitoring by an endocrinologist is crucial to assess growth, manage metabolic issues like hypoglycaemia, and address potential complications. Individuals and families are typically supported by a multidisciplinary team within the NHS, which may include paediatricians, endocrinologists, dietitians, and genetic counsellors. Regular assessments help to tailor treatment plans and provide comprehensive care.
UK care pathway
In the UK, individuals suspected of having growth hormone insensitivity (Laron) would typically enter the NHS Genomic Medicine Service pathway following referral from a specialist, such as a paediatrician or endocrinologist. These specialists can refer patients to clinical genetics services for evaluation and consideration of genetic testing.
Genetic testing for conditions like Laron syndrome is guided by NHS Genomic Medicine Service R-codes, which ensure appropriate and effective testing. Genetic counsellors play a vital role in this pathway, providing information about the condition, inheritance patterns, and supporting families through the testing process and its implications.
Frequently asked questions
What is the difference between growth hormone insensitivity and growth hormone deficiency?
In growth hormone insensitivity, the body makes enough growth hormone but cannot use it properly. In contrast, with growth hormone deficiency, the body does not produce enough growth hormone. Both lead to short stature but have different underlying causes and treatments.
Can growth hormone insensitivity be treated?
Yes, growth hormone insensitivity can be treated with injections of recombinant human insulin-like growth factor 1 (rhIGF-1). This medication helps to bypass the faulty growth hormone receptor and directly stimulates growth, though individual responses can vary.
If I am a carrier for growth hormone insensitivity, will I have symptoms?
No, if you are a carrier for growth hormone insensitivity, you typically will not have symptoms of the condition. Carriers have one working copy of the GHR gene, which is usually sufficient for normal growth and health.
How is growth hormone insensitivity inherited?
It is inherited in an autosomal recessive pattern. This means a child must inherit a faulty copy of the GHR gene from both parents to develop the condition. Parents who each carry one faulty copy typically do not have the condition themselves but can pass it on.
Is growth hormone insensitivity the same as dwarfism?
Growth hormone insensitivity (Laron) is a specific genetic cause of proportionate dwarfism, meaning individuals are significantly shorter than average but their body parts are in proportion. There are many different causes of dwarfism, and Laron syndrome is one of them.
References
- Villela TR, Freire BL, Braga NTP. Growth Hormone insensitivity (Laron syndrome): Report of a new family and review of Brazilian patients. Genetics and molecular biology. 2020. PMID: 31429861
- Cotta OR, Santarpia L, Curtò L. Primary growth hormone insensitivity (Laron syndrome) and acquired hypothyroidism: a case report. Journal of medical case reports. 2011. PMID: 21745362
- Rosenbloom AL. A half-century of studies of growth hormone insensitivity/Laron syndrome: A historical perspective. Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society. 2016. PMID: 26276451
- Savage MO, Blum WF, Ranke MB. Clinical features and endocrine status in patients with growth hormone insensitivity (Laron syndrome). The Journal of clinical endocrinology and metabolism. 1993. PMID: 7505286
- Baumann G. Growth hormone binding protein. The soluble growth hormone receptor. Minerva endocrinologica. 2002. PMID: 12511849
- Baumbach L, Schiavi A, Bartlett R. Clinical, biochemical, and molecular investigations of a genetic isolate of growth hormone insensitivity (Laron's syndrome). The Journal of clinical endocrinology and metabolism. 1997. PMID: 9024234
- Yordam N, Kandemir N, Erkul I. Review of Turkish patients with growth hormone insensitivity (Laron type). European journal of endocrinology. 1995. PMID: 7581982
- Laron Z. Growth hormone insensitivity (Laron syndrome). Reviews in endocrine & metabolic disorders. 2002. PMID: 12424436