Case history
James, aged 14 years and 3 months, has been referred by his general practitioner with concerns about his growth.
James is the eldest child of professional parents and has become concerned that his friends and his 12-year-old sister are now taller than he is.
- Medical history: Mild asthma.
- Plays football for local club – trains a couple of times a week and plays matches on Sundays and sometimes mid-week.
- General health: No signs or symptoms of malabsorption.
- Appetite variable – can sometimes be a picky eater.
- Medication – Salbutamol as needed (takes <1 a week)
- No significant family medical history.
Question 1.
What other information would you want to ascertain?
Previous growth pattern/centile
Child health records show previous measurements above the 50th centile. Now on 25th centile, within target height range (9th – 91st centile)
Parental heights and timing of puberty
James’s father is 175.5 cm tall and his mother is 162.5 cm.
James’s mother experienced menarche at age 13 years and his father remembers having his growth spurt later than some of his friends.
Constitutional delay of growth and puberty (CDGP) more frequently presents in boys and there is often a history of delayed puberty in the parents. Recent studies suggest that the history of the same-sex parent is more relevant.
Normal sense of smell?
Anosmia can indicate Kallmann’s syndrome
Height: 160.2 cm 25th centile)
Weight: 44.2 kg (<25th centile)
BMI: 17.22 kg/m2
Pubertal assessment with consent and chaperone.
Tanner staging Pubic Hair 2, Genitalia 1, Testicular volumes 3 mL bilaterally.
Interpretation
Puberty development is just outside normal limits; 95% of boys will have started puberty by age 14 years. Ascertain how concerned James and family are – waiting another 6 months may be psychologically very difficult. Ensure James’s expectations are realistic.
Even if James did not want to consider treatment now, it would be prudent to organise baseline investigations to exclude underlying pathology.
Neurological examination to rule out central cause.
Question 2.
What are the differential diagnoses?
- Constitutional delay of growth and puberty
- Hypogonadotrophic hypogonadism (may be permanent, eg, Kallmann’s syndrome or transient, eg, from systemic illness such as inflammatory bowel disease)
- Primary gonadal failure
- Poor nutrition
- Possible growth hormone (GH) deficiency
Question 3.
Which baseline investigations would you now undertake?
- Full blood count
- ESR
- Na, K, Cl, HCO3
- Ca, phosphate
- Creatinine
- Alkaline phosphatase
- Tissue transglutaminase immunoglobulin A (for coeliac disease)
- Free T4, total T, TSH
- IGF-1
- Bone age X-ray
This will exclude systemic illness such as coeliac disease or inflammatory bowel disease.
A bone age can be reassuring for some families that growth is “stored” and may be useful for height prediction.
Reassure and plan a review in 6 months.
Assess psychological effect of delayed puberty and delayed growth spurt.
Explain that the puberty growth spurt will not start for at least 12 months (when testicular volume is 8–10 mL)
Explain that treatment with testosterone is a future option without adverse effects.
Next steps
A short course of testosterone (intramuscular 50–125 mg/month for 3–6 months) can then be given to “kick-start” puberty and stimulate growth.
GH stimulation test?
With height between the 25th and 50th centiles, GH deficiency would be very unlikely. There is no real evidence of growth failure so this would not be organized at this point. James’s height is still within target range and height velocity (HV) is appropriate for a prepubertal boy, and GH tests are not pleasant. If a GH stimulation test is performed, it should be preceded by sex steroid priming, ie, diethylstilbestrol 1 mg twice daily for the 2 days prior to the test.
LHRH test?
A LHRH (luteinising hormone releasing hormone) test can be done but is unlikely to be able to help differentiate between constitutional delay of growth and puberty and hypogonadotrophic hypogonadism at this stage. Organising the test may also delay the initiation of testosterone therapy, so discussion with James and parents about the value of this versus a short course of testosterone is important.
HCG stimulation test?
A human chorionic gonadotrophin (HCG) stimulation test not a suitable option at this stage as there is no evidence of, or risk factors for, gonadal failure.
Management plan
- Discuss normal growth and puberty in boys and reassure James that this is most likely to be simply delayed and there are options available to help him catch up with his peers.
- Discuss that slowing of growth is often seen peri-pubertally – but equally James is just growing at a rate that is normal during childhood and this looks as though it is slowing because the centile charts show the pubertal spurt.
- Explain that the puberty growth spurt occurs rather late in boys, ie, well after puberty has started. Discuss the differences in boys and girls. James’s sister will have had her growth spurt, as girls have theirs at the beginning of puberty. Reassure James that his growth spurt will come.
- As seen in the diagram, the growth spurt usually occurs once testicular volumes reach 10–12 mL. The height gain expected during puberty is around 20–25 cm which will bring James comfortably into his target range.
- Highlight the importance of adequate calorie intake to fuel both the exercise and pubertal growth.
During the discussion it is clear that James is finding his situation very difficult. He is being teased at school and he is very concerned that he will lose his place in the football team as he is unable to match the physical strength and speed of his peers. He and his parents are clear he wants treatment.
Results of baseline tests:
| Test | Result | Comment |
|---|---|---|
| Full blood count | Normal | |
| Renal profile | Normal | |
| Liver function test | Normal | Low albumin can indicate inflammatory bowel disease |
| FT4 | 11.7 pmol/L | Normal |
| TSH | 2.1 mU/L | Normal |
| CRP ESR |
<1 2 mm/hr |
Normal – elevated levels seen in chronic inflammatory conditions |
| IGF-1 | 22.9 nmol/L | Normal level for puberty stage |
| Bone profile | Normal | |
| Coeliac screen | Negative | |
| LH | 2.2 iu/L | Normal prepubertal level |
| FSH | 2.7 iu/L | Normal prepubertal level |
| Testosterone | 0.8 nmol/L | Normal prepubertal level 9 am sample |
| Prolactin | 142 mU/L | Normal |
| Bone age | 12 yr 1 month | 2-year delay |
| ACTH & Cortisol | Not done | Not clinically indicated |
| IGFBP3 | Not done | Not clinically indicated |
| Genetic studies | Not sent | Not indicated at present. Consider if discordant pubertal progression or persistent hypogonadotrophic hypogonadism |
Management plan
Short course of testosterone – consider both routes and allergies.
Some available preparations contain arachis oil, and should be used with caution in those with peanut allergy (and soy allergy, due to cross reactivity). The arachis oil does not contain peanut protein and therefore most individuals with peanut allergy will tolerate the preparation, unless their sensitivity is very high.
Advantages and disadvantages of testosterone preparations
| Route | Advantages | Disadvantages |
|---|---|---|
| Intramuscular |
|
|
| Transdermal |
|
|
| Oral |
|
|
James was keen to have a short course of testosterone.
In practice the majority of centres prescribe intramuscular preparations as it is easier to ensure correct dosage and concordance. This makes it clearer when evaluating response. James was prescribed testosterone 75 mg once a month for four doses.
An appointment was made for review in 6 months.
Age: 14 years 9 months
Height: 163.3 cm
Weight: 47.4 kg
HV: 6.19 cm/yr
BMI: 17.7 kg/m2
Tanner stage: Pubic Hair 3, Genitalia, 2 Testicular volumes 4–6 mL
Question 4.
Is this what you would expect? What is the definitive diagnosis?
The increase in HV, penile growth and increase in pubic hair is due to exogenous testosterone.
Once puberty begins there is an increase in testicular volume due to LH and FSH release from the pituitary gland. The increased testicular volume is mainly due to increase in number and size of Sertoli cells. An increase in testicular size is not seen in hypogonadotrophic hypogonadism.
What will you do next?
LHRH test?
James may have hypogonadotrophic hypogonadism and an LHRH test will help confirm whether there is gonadotropin deficiency. In approximately 10% of boys, hypogonadotropic hypogonadism resolves following the introduction of sex steroids. So further investigation can be deferred and done alongside other investigations if there is no further pubertal progression following a second course of testosterone.
HCG test?
A HCG test is not indicated – the basal investigations do not suggest primary gonadal failure and if there is ongoing hypogonadotrophic hypogonadism then the results of a standard HCG test may not be reliable
Second course of testosterone?
A small proportion of boys require a second course of testosterone to stimulate the start of puberty. Another course of 3–6 months is usually given. If this is required, causes of systemic illness should be investigated again.
GH test?
There is still no clear evidence of true growth failure – but this may be considered if James or parents are concerned. An increase in HV following testosterone therapy strongly argues against a diagnosis of GH deficiency.
Management plan
On discussion James wanted to pursue treatment with testosterone rather than delay and have further investigations. He and parents were reassured that his growth spurt would occur once puberty commenced and did not want any GH tests.
James’ next review was in 6 months following another four injections of testosterone 75 mg.
Age: 15 years 3 months
Height: 167.2 cm
Weight: 52 kg
HV: 7.83 cm/yr
BMI: 18.6 kg/m2
Tanner stage: Pubic Hair 3; Genitalia 3; testicular volume 8 mL on left, 10 mL on right
The increase in HV and further development of his genitalia and pubic hair is likely to be partly due to the testosterone injections.
However, the increase in testicular volume indicates that James is now in puberty.
James is still frustrated that he is not yet catching up with his friends.
It is important to manage the expectations of James and his parents and not give unrealistic predictions of his adult height. It is likely that he has inherited more of his mother’s growth genes than his father’s.
Boys with constitutional delay of growth and puberty do not reach their mid-parental height centile.
Remind the parents that boys have their peak height velocity (growth spurt) later than girls. This would be expected once testicular volumes are around 10–12 mL – so would not be expected yet but will happen.
It may also be reassuring for James to understand that having a late puberty will have no impact on his gender identity or sexual orientation.
James was offered a further appointment for review in 9 months’ time, but if he and his parents are happy with his growth and have no further concerns they can cancel this.
- Brook GD, Dattani MT. 2012. The management of Puberty Disorders. In Brook CG, Dattani MT (eds), Handbook of Pediatric Endocrinology, second edition. John Wiley & Sons Ltd, 120–126.
- Tanner JM, Whitehouse RH, Marubini E, Resele LF. The adolescent growth spurt of boys and girls of the Harpenden Growth Study. Ann Hum Biol 1976; 3: 109–126
- Wei C, Crowne EC. Recent advances in the understanding and management of delayed puberty Ach Dis Child 2016; 101: 481–488
- Pyra E & Schwarz W. Puberty: Normal, Delayed and Precocious. 2019. In Llahana S, Folin C, Yedinak C, Grossman A Davies K & Keil MF (eds), Advanced practice in Endocrinology Nursing. Springer Nature Switzerland, 70–76.
- Busch AS, Hagen CP, Juul A. Heritability of pubertal timing: detailed evaluation of specific milestones in healthy boys and girls. Eur J Endocrinol 2020; 183: 13–20
