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11th April 2024

Disorders of Growth

Normal growth

Physiology of growth hormone

Released in a pulsatile manner, the production of HGH is controlled in a negative feedback loop, which can be influenced by behavioural factors such as sleep, stress and exercise. Growth hormone-releasing hormone (produced in the hypothalamus) and ghrelin (produced from the stomach when hungry) are the main stimulants that act on the somatotrophs located in the anterior pituitary, resulting in the production/secretion of HGH. Increased HGH levels, in turn, stimulate hepatocytes to produce insulin-like growth factor (IGF-1) which directly reduces the release of HGH and indirectly via somatostatin. HGH also self-regulates its release by inhibiting the production of GHRH.

HGH can directly and indirectly stimulate growth. HGH activates mitogen-activated protein kinases (MAPK), initiating a cascade of protein activations that eventually result in increased gene transcription, replication and cellular division. Indirectly, IGF activates tyrosine kinase-mediated pathways, inhibiting cell apoptosis and increasing cellular division.

Physiology of the thyroid hormones

Thyroid hormones have a wide range of effects across multiple organs and tissues in the body. Production of thyroid hormones starts with the release of thyrotropin-releasing hormone from the periventricular nucleus of the hypothalamus. TRH binds to G-protein coupled receptors in cells located in the anterior pituitary gland, activating a complex signalling cascade that ends with the activation of protein kinase C, which stimulates thyroid-stimulating hormone production. TSH is released into the blood, where it will bind to G-protein coupled receptors of thyroid follicular cells, initiating the production of thyroglobulins. It also activates protein kinase A, an important enzyme responsible for mediating iodide uptake and oxidation in thyroglobulins via NaI symporters and thyroid peroxidase, respectively. Coupling reactions occur between MIT and DIT, producing T3 and T4, which are released into the circulation in a 20:80 ratio.

Only a small proportion of thyroid hormone remains unbound (~0.2%). The rest react to and are carried by transporter proteins such as thyroxine-binding globulin and albumin. When required, T3/T4 dissociate themselves from their transporter protein and enter the targeted cells either by diffusion or surface carrier proteins. Like most hormones associated with hypothalamus-pituitary axis, the concentration of thyroid hormones is controlled by a negative feedback loop. High concentrations of T3/T4 inhibit the release of TRH and TSH. External influences can affect this system; hormones such as somatostatin and glucocorticoids can inhibit TSH production, while environmental factors such as stress and exercise can increase TRH release.

Physiology of glucocorticoids

Glucocorticoids are one of three steroids produced in the adrenal glands (zona fasciculata). The process starts with the release of corticotrophin-releasing hormone from the hypothalamus. This stimulates the production of adrenocorticotropic hormone (ACTH) from the anterior pituitary gland. ACTH has a dual function; it binds to melanocortin 2 receptors, initiating signalling cascades for steroid production (in the mitochondria) and increasing the cholesterol availability, activating HMG CoA reductase and activating hormone-sensitive lipase. Dependent on the enzymes exposed, the cholesterol can be converted into mineralocorticoids, glucocorticoids or sex hormones. Important enzymes involved in the production of glucocorticoids are cholesterol desmolase, 17a-hydroxylase, 21-hydroxylase and 11-beta-hydroxylase. The final product, cortisone, is an inactive steroid that is converted to cortisol (active form) in the liver by 11-beta hydroxysteroid dehydrogenase type 1. The release of glucocorticoids follows a pulsatile circadian pattern, with the highest concentrations found in the morning. High levels of glucocorticoids inhibit the release of CRH and ACTH, while environmental factors such as stress can stimulate release.

Cortisol has several functions within the body. It increases glucose and free fatty acids availability by activating hormone sensitive lipase (HSL), encouraging glucose production and inhibiting insulin. It plays an important role in the immune system, increasing the presence of white cells through accelerating proliferation and maturation and reducing migration and apoptosis. Though glucocorticoids have no direct effects on cell growth, the concentration of the hormone can impact the production of growth hormone via the hypothalamus-pituitary-axis, with high concentrations ultimately inhibiting its secretion.

References

Causes of excessive growth

Acromegaly

Acromegaly is an endocrine disorder characterised by the excess of growth hormone production. Typically caused by pituitary gland tumours or hyperplasia, it can also be a result of ectopic production from other sources, such as carcinoid tumours. Common signs and symptoms include excessive growth of hands (spade hands), feet and tongue, tired demeanour involving puffy facial features, coarsening of the face and supraorbital ridges, reduced libido, obstructive sleep apnoea and arthralgia. Gigantism, a form of acromegaly in children, occurs due to excessive growth before the completion of epiphyses fusion. Acromegaly increases the risk of colon cancer, IHD, CVA and diabetes.

Investigations

Serum IGF-1 is used as an initial screening test and is more reliable than GH as it can vary during the day. The oral glucose tolerance test (OGTT) is used to confirm after a positive screening test. It consists of fasting the patient overnight and giving glucose supplementation in the morning with serial GH measurements, as glucose should inhibit GH. A diagnosis is made if the glucose load does not suppress GH <1 microgram/litre. All these tests can be affected by puberty, pregnancy, anorexia, liver/renal diseases or diabetes.

An MRI scan of the pituitary and hypothalamus may demonstrate a tumour. Visual field testing allows assessment for any abnormalities and echocardiography for acromegaly-associated cardiomyopathies.

Management

The management consists of removing the tumour, with the majority having transsphenoidal surgery. Medical therapy can be undertaken with or without prior surgery and includes somatostatin analogues (octreotide/lanreotide) and GH antagonists (pegvisomant). In select patients with aggressive disease or when medication is ineffective, radiotherapy can also be considered.

Marfan syndrome

A genetic connective tissue disorder affecting the production of fibrillin. It follows an autosomal dominant pattern, affecting FBN1 gene on chromosome 15. Typical presentation includes excess long bone growth causing dolichostenomelia (disproportionate extremity to trunk length), joint laxity (pectus carinatum/excavatum, pes planus, acetabular protrusion/hip dislocations), arachnodactyly and ectopia lentis (upwards dislocated lens). Due to abnormal elastic fibre formation, patients are at increased risk of several cardiac pathologies, such as aortic regurgitation, mitral valve prolapse and dilatation/dissection of vessels. Management involves investigating and monitoring for cardiac pathologies with echocardiography, CT and MRI. Beta-blockers are used to reduce myocardial contractility and pulse pressure and lower the risk of aortic dilatation. Elective repair or replacement is also considered.

References

  • Adigun, O., Nguyen, M., Fox, T. and Anastasopoulou, C., 2022. Acromegaly. [online] Ncbi.nlm.nih.gov. Available at: <https://www.ncbi.nlm.nih.gov/books/NBK431086/>
  • Longmore, J., Wilkinson, I., Baldwin Andrew and Wallin Elizabeth., 2014. Oxford handbook of clinical medicine. 9th ed. Oxford: Oxford University Press, pp.230-231
  • Salik, I. and Rawla, P., 2022. Marfan Syndrome. [online] Ncbi.nlm.nih.gov. Available at: https://www.ncbi.nlm.nih.gov/books/NBK537339/
  • Longmore, J., Wilkinson, I., Baldwin Andrew and Wallin Elizabeth., 2014. Oxford handbook of clinical medicine. 9th ed. Oxford: Oxford University Press, p.720.

Causes of delayed growth

Growth hormone deficiency

Growth hormone is stimulated by GH-releasing hormone and is secreted by the anterior pituitary. Deficiency of this hormone can be due to trauma, surgery, radiotherapy, infections such as TB and pituitary adenomas causing hypopituitarism. It can cause growth delays in children and redistribution of fat, reduced muscle mass, increased fragility fractures and other psychosocial symptoms.

GH deficiency can be diagnosed using the insulin tolerance test. It consists of overnight fasting with later administration of insulin with measurements of glucose, GH and IGF-1 at intervals. Diagnosis is made when the peak GH level is measured below 3 mcg/l. Directly replacing growth hormone is the mainstay of treatment. Risks associated with the use of this drug include fluid retention, arthralgia and myalgia.

Hypothyroidism

Hypothyroidism is the result of a low level of thyroid hormones in circulation. The causes of hypothyroidism can be acquired or inherited. Worldwide, the most common cause of hypothyroidism is a result of malnutrition, leading to iodine deficiency. In the UK, autoimmune diseases such as Hashimoto’s disease are the leading cause of hypothyroidism. Other causes include postpartum thyroiditis, De Quervain disease, medications (amiodarone, phenytoin, lithium), iatrogenic (surgical/radiotherapy) and tumours. The pathophysiology of hypothyroidism can be divided into two main groups: primary and secondary. Primary causes are when the ability to produce thyroid hormones from the thyroid gland itself is affected, while secondary causes are when the hypothalamus-pituitary gland is affected. Typical signs and symptoms are a result of low metabolism and low cell turnover. Low metabolism can lead to fatigue, weight gain, sensitivity to cold, reduced reflexes and bradycardia. Low cell turnover results in brittle hair and thin skin. Autoimmune conditions can lead to thyroid enlargement (goitres).

Investigations

Diagnosis of hypothyroidism is when T4 levels are <12pmol/L. Differentiating the type of hypothyroidism relies on TSH levels. Primary causes are due to low production from the thyroid glands, resulting in high TSH levels to try and stimulate more production. Secondary causes are a result of a reduction or blockage of stimulation of the thyroid gland and so will typically have low TSH levels. Subclinical hypothyroidism has the potential to lead to hypothyroidism and will typically have high TSH levels with compensated T4 levels. Thyroid autoantibodies, including anti-thyroid peroxidase and anti-thyroglobulin antibodies, suggest Hashimoto thyroiditis. Adrenal insufficiency should be investigated concurrently with hypothyroidism due to the potential of exacerbation with levothyroxine treatment if left untreated.

Management

Management of hypothyroidism mainly involves the use of levothyroxine as hormone replacement. Initial doses should be around 1.6mcg/kg; however, if the patient is elderly or has a history of cardiac diseases, lower doses should be used due to the risk of developing angina or AF.

Cushing’s syndrome

Cushing syndrome is an umbrella term for the body being exposed to excessive cortisol. The causes of Cushing Syndrome can be divided into three groups: ACTH-dependent, ACTH-independent and exogenous sources. ACTH-dependent sources can be central causes, such as ACTH-secreting pituitary tumours (Cushing’s disease) or peripheral from non-pituitary tumours. ACTH-independent would be from sources that are overproducing cortisol without the influence of ACTH, such as adrenal hyperplasia or tumours. The most common cause of Cushing’s syndrome would be from exogenous sources such as steroidal use.

A typical presentation of Cushing’s syndrome would involve excessive central fat deposition leading to buffalo hump (behind the neck), moon facies and purple abdominal striae. Peripheral limbs would be less affected, leading to thin limbs with proximal muscle weakness. Common complications include depression, bruising, osteopenia/osteoporosis, recurrent infection, infertility, reduced libido, and hirsutism in women. Though Cushing syndrome in adulthood has no impact on growth, high cortisol levels are known to suppress the secretion of growth hormone and could affect growth if present in childhood.

Investigations

When Cushing syndrome is suspected, two different tests are used to confirm the diagnosis. The initial investigations involve a 24-hour urine-free cortisol test measuring total cortisol. The other test is the 48-hour low-dose dexamethasone suppression test, where those with Cushing syndrome would have a high cortisol result.

The high-dose dexamethasone suppression test allows localisation of the abnormality. After this dose is administered, a low cortisol would indicate Cushing disease. A result showing high cortisol and low ACTH localises to the adrenal glands as it is non-ACTH dependent. A high cortisol with a high ACTH indicates ectopic ACTH. Dexamethasone suppression tests can be affected by illness/stress, obesity, alcohol, exogenous steroids, increased oestrogen and malnutrition.

Management

Treatment is dependent on the cause of Cushing Syndrome and may involve removal of the source of stimulation (adrenal/ectopic tumours), radiotherapy if surgery is unsuccessful or not possible and medications such as somatostatin analogues (pasireotide), dopamine agonists (cabergoline), cortisol antagonists (mifepristone).

Turner syndrome (45, XO)

Turner syndrome is a congenital condition caused by an absent or nonfunctioning sexual chromosome. The typical presentation involves short stature, a webbed neck and a shield chest (characterised as widely spaced nipples). Skeletal development is also affected, causing short 4th metacarpals/tarsals and Madelung deformities of the forearms and wrists. Patients are at increased risk of cardiovascular structural defects such as bicuspid aortic valve and coarctation of the aorta. Other complications associated with this syndrome include autoimmune diseases such as hypothyroidism, IBD, coeliacs and renal malformation such as horseshoe kidneys. Commonly, Turner syndrome is suspected in girls who have primary amenorrhoea, delayed/no puberty stage of growth and normal intelligence.

Investigations

Prenatal investigations include chorionic villus sampling or amniocentesis. Further karyotyping is performed to confirm the diagnosis.

Management

Hormone replacement therapy (GH and oestrogen) is often started at the time of puberty to encourage growth and minimise symptoms through increasing androgen levels.

Noonan syndrome

An autosomal dominant genetic condition, affecting the RAS/MAPK cell signalling pathway. This condition typically presents with short stature, macrocephaly, and widely set but low-set eyes. It is associated with intellectual and developmental delays, and the main cardiac pathology is pulmonary stenosis. Noonan syndrome also has other complications, such as cryptorchidism, leading to male infertility and deafness. Diagnosis is through molecular genetic testing.

Down syndrome

Down syndrome is a well-known and recognised genetically acquired condition. This is a result of the presence of an extra chromosome at Ch21, which resulted from either the failure to separate (most common), Robertsonian translocation or mosaicism (rare). The risk of Down’s increases with maternal age, with a risk of 1:800 at the age of 30 increasing significantly to 1:100 by 40.

People with Down’s have certain facial features such as almond-shaped eyes slanting upwards, flat face, protruding tongue and small ears. Due to anatomical variation, they are at an increased risk of developing otitis media, eardrum perforation and hearing loss. Down’s patients are predisposed to developing a wide variety of conditions including cardiac abnormalities (atrioventricular septal defect (most common), ventricular septal defect (2nd), atrial defect, tetralogy of Fallot, PDA), GI abnormalities (Hirschsprung disease, duodenal atresia, bowel stenosis, imperforate anus, Coeliac’s disease) and neurological abnormalities (hypotonia, seizures, early onset dementia, learning difficulties). As well as this. There is an increased risk of leukaemia and hypothyroidism.

Investigations

The likelihood of a neonate having Down syndrome can be identified through one of two national screening tools: the combined test and the quadruple test. If the risk is sufficient, diagnosis can be made via amniocentesis or chorionic villus sampling.

Pregnancy blood tests at 10 to 14 weeks may show a raised β-hCG, low plasma protein A and an increased nuchal translucency. A blood test performed at 14 to 20 weeks may show again a raised β-hCG and inhibin with a low AFP and unconjugated oestriol.

Prader-Willi syndrome

This condition is caused by the loss of gene expression present on chromosome 15. It is mostly acquired spontaneously but can be passed down from the paternal genes of the mother. On examination, the patient would have a short stature, almond-shaped eyes with a thin upper vermilion and narrow nasal bridge. Patients affected by this condition have a trend of failure to thrive, which progressively reaches the opposite spectrum of obesity (in mid-adulthood) secondary to hyperphagia. As well as this, it causes hypotonia with reduced muscles and strength, leading to poor suck reflex and motor developmental delay. During childhood, speech is commonly affected, and behavioural conditions such as OCD or anxiety may be present. Sexual development is also affected, causing hypogonadism in males due to cryptorchidism and hypoplasia of external genitalia, and late menarche in females. Investigations and diagnosis involve DNA methylation testing. Many patients are GH deficient and administration of this hormone aids physical and cognitive development.

References

Complete Guide to Clinical Genetics ST3 Application and Recruitment (2027)

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Complete Guide to Paediatric Surgery ST3 Application and Recruitment in United Kingdom (2026)

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