Laron syndrome

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Laron syndrome is a rare form of short stature that results from the body's inability to use growth hormone, a substance produced by the brain's pituitary gland that helps promote growth. Affected individuals are close to normal size at birth, but they experience slow growth from early childhood that results in very short stature. If the condition is not treated, adult males typically reach a maximum height of about 4.5 feet; adult females may be just over 4 feet tall.

Other features of untreated Laron syndrome include reduced muscle strength and endurance, low blood glucose levels (hypoglycemia) in infancy, small genitals and delayed puberty, hair that is thin and fragile, and dental abnormalities. Many affected individuals have a distinctive facial appearance, including a protruding forehead, a sunken bridge of the nose (saddle nose), and a blue tint to the whites of the eyes (blue sclerae). Affected individuals have short limbs compared to the size of their torso, as well as small hands and feet. Adults with this condition tend to develop obesity. However, the signs and symptoms of Laron syndrome vary, even among affected members of the same family.

Studies suggest that people with Laron syndrome have a significantly reduced risk of cancer and type 2 diabetes. Affected individuals appear to develop these common diseases much less frequently than their unaffected relatives, despite having obesity (a risk factor for both cancer and type 2 diabetes). However, people with Laron syndrome do not seem to have an increased lifespan compared with their unaffected relatives.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Laron syndrome is caused by mutations in the GHR gene. This gene provides instructions for making a protein called the growth hormone receptor. The receptor is present on the outer membrane of cells throughout the body, particularly liver cells. As its name suggests, the growth hormone receptor attaches (binds) to growth hormone; the two proteins fit together like a key in a lock. When growth hormone is bound to its receptor, it triggers signaling that stimulates the growth and division of cells. This signaling also leads to the production, primarily by liver cells, of another important growth-promoting hormone called insulin-like growth factor I (IGF-I).

Growth hormone and IGF-I have a wide variety of effects on the growth and function of many parts of the body. For example, these hormones stimulate the growth and division of cells called chondrocytes, which play a critical role in producing new bone tissue. Growth hormone and IGF-I also influence metabolism, including how the body uses and stores carbohydrates, proteins, and fats from food.

Mutations in the GHR gene impair the receptor's ability to bind to growth hormone or to trigger signaling within cells. As a result, even when growth hormone is available, cells are unable to respond by producing IGF-I and stimulating growth and division. The cells' inability to react to growth hormone, which is described as growth hormone insensitivity, disrupts the normal growth and function of many different tissues. Short stature results when growth hormone cannot adequately stimulate the growth of bones. Changes in metabolism caused by insensitivity to growth hormone and the resulting shortage of IGF-I cause many of the other features of the condition, including obesity.

Researchers are working to determine how mutations in the GHR gene may protect people with Laron syndrome from developing cancer and type 2 diabetes. Studies suggest that insensitivity to growth hormone may help prevent the uncontrolled growth and division of cells that can lead to the development of cancerous tumors. Growth hormone insensitivity also appears to alter how the body responds to insulin, which is a hormone that regulates blood glucose levels. Resistance to the effects of insulin is a major risk factor for type 2 diabetes. People with Laron syndrome have the opposite situation, an increased sensitivity to insulin, which likely helps explain their reduced risk of this common disease.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

Most cases of Laron syndrome are inherited in an autosomal recessive pattern, which means both copies of the GHR gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Much less commonly, the condition has an autosomal dominant pattern of inheritance, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In most of these cases, an affected person has one parent with the condition.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

Laron syndrome is a rare disorder. About 350 people have been diagnosed with the condition worldwide. The largest single group of affected individuals (about 100 people) lives in an area of southern Ecuador.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Abnormal facial shape · Very frequent (99-80%)

An abnormal morphology (form) of the face or its components.

Abnormality of the endocrine system · Very frequent (99-80%)

An abnormality of the endocrine system.

Aplasia/Hypoplasia involving the nose · Very frequent (99-80%)

Underdevelopment or absence of the nose or parts thereof.

Delayed eruption of teeth · Very frequent (99-80%)

Delayed tooth eruption, which can be defined as tooth eruption more than 2 SD beyond the mean eruption age.

Delayed skeletal maturation · Very frequent (99-80%)

A decreased rate of skeletal maturation. Delayed skeletal maturation can be diagnosed on the basis of an estimation of the bone age from radiographs of specific bones in the human body.

High forehead · Very frequent (99-80%)

An abnormally increased height of the forehead.

Microdontia · Very frequent (99-80%)

Decreased size of the teeth, which can be defined as a mesiodistal tooth diameter (width) more than 2 SD below mean. Alternatively, an apparently decreased maximum width of tooth.

Micrognathia · Very frequent (99-80%)

Developmental hypoplasia of the mandible.

Other findings in the same source

From: Orphanet

Additional reported features include Severe short stature (Very frequent (99-80%)); Tooth agenesis (Very frequent (99-80%)); Truncal obesity (Very frequent (99-80%)); Hypoplastic nasal bridge (Very frequent (99-80%)); Abnormality of the elbow (Frequent (79-30%)); Brachydactyly (Frequent (79-30%)); Delayed puberty (Frequent (79-30%)); Hypoglycemia (Frequent (79-30%)); Motor delay (Frequent (79-30%)); Short toe (Frequent (79-30%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Laron syndrome is Endocrinology, with a endocrinologist as the relevant type of clinician. General physician / Family Medicine; paediatrician for children. Referral depends on symptoms.

Additional services that may be relevant, depending on the findings, include: Clinical Genetics.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Which hormone or metabolic finding is important in this case?
• How should test timing and current medicines be taken into account?
• What follow-up would show whether the care plan is working?

Treatment discussions and follow-up

Where the source describes treatments, these are an overview of possible care, not a prescription for an individual. Ask which option applies to the confirmed diagnosis, what benefit is expected, what adverse effects to watch for and how progress will be assessed. Availability, approvals and local practice can differ from the country described in the source.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.