12th April 2024

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

• Akhtar, F. and Bokhari, S., 2022. Down Syndrome. [online] Ncbi.nlm.nih.gov. Available at: https://www.ncbi.nlm.nih.gov/books/NBK526016/
• Allen, M. and Sharma, S., 2022. Noonan Syndrome. [online] Ncbi.nlm.nih.gov. Available at: https://www.ncbi.nlm.nih.gov/books/NBK532269/
• Chaudhry, H. and Singh, G., 2022. Cushing Syndrome. [online] Ncbi.nlm.nih.gov. Available at: https://www.ncbi.nlm.nih.gov/books/NBK470218/
• Gutierrez, M. and Mendez, M., 2022. Prader-Willi Syndrome. [online] Ncbi.nlm.nih.gov. Available at: https://www.ncbi.nlm.nih.gov/books/NBK553161/
• Kikkeri, N. and Nagalli, S., 2022. Turner Syndrome. [online] Ncbi.nlm.nih.gov. Available at: https://www.ncbi.nlm.nih.gov/books/NBK554621/
• Longmore, J., Wilkinson, I., Baldwin Andrew and Wallin Elizabeth., 2014. Oxford handbook of clinical medicine. 9th ed. Oxford: Oxford University Press, pp.212-213, pp.216-217, pp.224-225
• Patil, N., Rehman, A. and Jialal, I., 2022. Hypothyroidism. [online] Ncbi.nlm.nih.gov. Available at: <https://www.ncbi.nlm.nih.gov/books/NBK519536/>