Growth Hormone Deficiency

Introduction

Growth hormone deficiency (GHD) is a rare paediatric disorder, affecting 1:4000-1:10,000 people globally.¹

Anatomy and physiology

Growth hormone (GH) is produced by the anterior pituitary gland in response to GH-releasing hormone (GHRH) from the hypothalamus (Figure 1). Binding of GH to its receptors causes the liver to produce insulin-like growth factor 1 (IGF1). IGF1 then mediates growth-promoting functions of GH.

Aetiology

GHD can be idiopathic, congenital or acquired.

Congenital

Congenital causes may include:

• Genetic mutation
• Structural brain malformation

Acquired

Acquired causes may include:

• Hypothalamic-pituitary tumour (e.g. craniopharyngioma)
• Cranial radiotherapy
• Traumatic brain injury (including peri- and postnatal)
• CNS infection
• Sarcoidosis
• Tuberculosis
• Abuse or neglect ^2,4,5

Risk factors

Risk factors for GHD include:

• Family history of GHD
• Deficiency of other pituitary hormones (e.g. TSH, prolactin)
• Hypothalamic-pituitary tumour
• Radiotherapy – particularly for CNS tumours and haematological malignancies²

Clinical features

History

Typical symptoms of GHD include:

• Short stature
• Suboptimal growth velocity (significant if the rate has decreased by 10%)⁵
• Absent or limited growth spurt
• Delayed puberty²
• Increased weight-to-height ratio
• Poor muscle tone (motor delay may result)

Less common symptoms may include:

• Signs of raised intracranial pressure (e.g. headache, vomiting)
• Visual disturbance (e.g. bitemporal hemianopia)
• Hyperphagia
• Temperature dysregulation
• Sleep disorder
• Behavioural problems²

Clinical examination

In the context of suspected GHD, a thorough top-to-toe paediatric examination is necessary, including a paediatric growth assessment.

Typical clinical findings include:

• Short stature – greater than 2 standard deviations below the mean
• High BMI or central obesity

Less common clinical findings include:

• Neonatal abnormalities (e.g. hypoglycaemia, prolonged jaundice, small penis)
• Characteristic facial appearance (e.g. facial hypoplasia, delayed dentition, frontal bossing, cleft lip and palate)⁵
• Fine hair
• Limited nail growth
• Small penis +/- undescended testes (if associated with LH deficiency)
• Visual disturbance²

Differential diagnoses

The clinical presentation of GHD is similar to the following conditions (Table 1).

Table 1. Differential diagnoses of paediatric GHD

Investigations

There is no gold standard test for GHD – the diagnosis must consider all clinical findings and investigations.

Bedside investigations

Relevant bedside investigations in the context of suspected GHD, include:

• Serial height and weight measurements- this may be done using a paediatric growth chart
• Capillary blood glucose (DM may cause short stature)

Laboratory investigations

Relevant laboratory investigations in the context of suspected GHD, include:

• TFTs
• Plasma cortisol level
• Coeliac (TTG) antibodies⁵
• Serum IGF1: low in GHD, hypothyroidism, malnutrition and chronic diseases
• GH provocation test – GH level measured after clonidine or arginine is administered which stimulates GH secretion
• Random GH (neonates only)
• Levels of other pituitary hormones (e.g. prolactin, gonadotropin, ACTH)^2,4

Imaging

Relevant image studies in the context of suspected GHD, include:

• Wrist X-ray – to determine bone age and compare to chronological age
• MRI brain – pituitary gland pathology must be ruled out in all patients with GHD^2,4

Management

Medical management

The mainstay of medical management is GH replacement with regular monitoring:

• SC recombinant human GH before bed (mimics normal GH secretion)
• The dose should be altered based on growth response and serum IGF1
• Treatment is continued until the final height or fusion of growth plates is achieved
• Height increase during the first year of treatment is used to predict treatment response^2,8

Early GH replacement is associated with a better growth response and prognosis.

If there is widespread pituitary dysfunction, additional pituitary hormone replacement may be necessary:

• Levothyroxine for hypothyroidism
• Corticosteroids for ACTH deficiency
• Oestrogen or testosterone for gonadotrophin deficiency

Surgical management

In certain causes of GHD, surgical management may be considered:

• Urgent neurosurgical opinion if CNS tumour is found on imaging.²
• Management may include a surgical biopsy with or without resection.⁹

Referrals

The following referrals may be considered in the management of GHD:

• Ophthalmology referral if eye abnormalities or visual disturbance
• Social services referral if abuse-related – psychosocial GHD is reversible and does not respond well to GH replacement²

Complications

If GHD is untreated, the following complications may occur:

• Ongoing short stature and failure to meet the expected adult height
• Osteoporosis
• Coronary artery disease
• Type 2 diabetes mellitus
• Poor quality of life – low libido, lethargy, social isolation²

There are also several adverse effects associated with GH replacement:

• Headaches and idiopathic intracranial hypertension
• Slipped capital femoral epiphysis
• Exacerbation of pre-existing scoliosis⁸

Patients are routinely monitored for these complications following initiation of treatment. These issues may be related to the rapid growth associated with GH replacement. If complications occur, GH therapy may be stopped and restarted at a reduced dose.

Key points

• GHD is a rare condition, usually associated with short stature.
• Risk factors include family history and additional pituitary hormone deficiencies.
• There is no gold standard test for GHD- diagnosis is dependent on clinical findings and investigations.
• GHD is primarily managed by GH replacement unless there is an underlying pathology warranting surgical treatment.
• The prognosis of GHD is good if hormone replacement therapy is initiated early.

References

1. Stanley T. Diagnosis of Growth Hormone Deficiency in Childhood. Published in 2013. [LINK]
2. BMJ Best Practice. Growth Hormone Deficiency in Children. Published in 2020. [LINK]
3. Witkowska-Sidek E and Ruminska M et al. The associations between the growth hormone/insulin-like growth factor-1 axis, adiponectin, resistin and metabolic profile in children with growth hormone deficiency before and during growth hormone treatment. Published in 2018. [LINK]
4. Chinoy A and Murray P. Diagnosis of growth hormone deficiency in the paediatric and transitional age. Published in 2016. [LINK]
5. National Organization for Rare Disorders (NORD). Growth Hormone Deficiency. Published in 2016 [LINK]
6. Fideleff H. Burden of Growth Hormone Deficiency and Excess in Children. Published in 2016 [LINK]
7. Davis T. Examination: the child with short stature. Published in 2014.
8. Rogol A and Richmond E. UpToDate: Treatment of growth hormone deficiency in children. Published in 2019. [LINK]
9. Chamberlain M and Silbergeld D. BMJ Best Practice: Published in 2018. [LINK]

Reviewer

Dr Kiran Kumar

Paediatric Endocrinologist

Editor

Hannah Thomas