Don’t miss the clues to endocrinopathy in NF1 nor the complexity of pain 

Dr Alexa Burgess has a child with NF1, she is a NF patient advocate and a member of the NF Community Advisory Panel at CTF Australia. She is also a scientist with a strong background and interest in research.  

Alexa had the opportunity to listen to several 2026 NF Conference presentations online which met her interest to stay informed as a NF-patient advocate and parent and we thank her for the recommendation to cover two inspiring presentations with a focus on endocrine issues during child development in NF1 and better pain care for all patients with NF in this series.

Endocrinology has a role to play in paediatric NF1 care and treatment 

The presentation by Dr Clement Cheung from The Children’s Hospital in Los Angeles was part of the ‘Clinical Care Program’, a session organised by NF specialist clinicians for clinicians at various stages of their career. As a paediatrician and endocrinologist, Dr Cheung sees patients with NF1 among other young patients with growth and developmental concerns related to endocrine disturbances.

The most relevant issues driven by hormonal imbalances during childhood in NF1 are pubertal abnormalities and impaired growth. According to Dr Cheung, these endocrine problems are more common than we think and NF1 specialist are urged to keep an eye out for any signs of unusual sex and growth hormone influences. In his words, ‘too early, too slow or too much’ can foreshadow puberty disorders and short stature, endocrinopathies which can be successfully treated if detected early. Dr Cheung’s strongest advice to the NF1 specialist audience was ‘if in doubt, refer to an endocrinologist’ - a phrase which reverberated far beyond his talk at the conference.

Benchmark events during puberty

As reiterated by Dr Cheung, girls normally start puberty around 10 years of age. The following events are included:

• Thelarche: The developments of breasts typically starts around 10 years of age and it can take several years for the breasts to fully develop.
• Pubarche: The growth of pubic and underarm hair typically starts about 6 months later.
• Menarche: The start of menstrual periods about 2 years later, with the first menstrual bleeding typically occurring around 12-13 years of age.
• A growth spurt starts around the time of thelarche at 10 years of age and can continue throughout puberty until about 14 years of age.

Boys show the first physical signs of puberty around 11 years of age, a year later than girls. It involves different events:

• The first sign is enlargement of the testicles at 11 years of age.
• The growth of pubic hair typically starts around 12 years of age followed by underarm hair growth.
• Then penile growth generally starts around 13 years of age followed by a voice change and facial hair growth between 13-15 years of age.
• A growth spurt in boys typically occurs later in puberty than in girls, starting around 12 and continuing until around 15 years of age.

Puberty-related disorders of note in NF1

• Central Precocious Puberty (CPP)

The most common deviation from the normal puberty timeline in NF1 is referred to as CPP. This condition reflects a premature activation of the neuroendocrine HPG-axis, which starts centrally, in the brain, with activation of the hypothalamus (H), which stimulates the pituitary gland (P) and gonads (G) to initiate the development of secondary sex characteristics. ‘Precocious’ refers to an unusually early start to puberty with breast development before 8 years of age in girls and testicle growth before 9 years of age in boys.

All children with NF1 have a slightly increased risk of CPP and it is 10 times more common for girls than boys with NF1 to be affected by CPP. Though rare in boys with NF1, if affected by CPP, it does come with a considerably higher chance of an optical pathway glioma (OPG) and MRI screening for a potentially undiagnosed OPG is advised.

• Rapid Pubertal Tempo

The pace of puberty development is as important as the age of onset. Regular screening in children with NF1 benefits from monitoring the signs of puberty progression by palpation and visualisation. Even if puberty onset seems typical, rapid advancement within 1 year instead of about 2 can speed up bone age and compromise adult height. Again, early detection allows for timely intervention.  

• Delayed Puberty 

Delayed puberty appears rare in NF1, but is also less often looked for by frontline NF1 specialists. If observed, it is likely caused by tumour damage or other trauma to the hypothalamus inhibiting HPG-signalling (secondary hypogonadism). A study from 2003 showed that among 123 women with NF1, 16% had delayed menarche (1st menstrual period beyond the age of 14 years) versus 3.4% in controls. More recently, central hypogonadism was reported in 1.1% of 181 children with NF1. While indeed sporadic, early recognition is critical for managing underlying endocrine dysfunction.  

Impaired growth issues in NF1

• Short stature

Short stature is common in children with NF1 and it can persist into adulthood if untreated. It is worth knowing here that final heights of teenagers with NF1 across the board are shorter than expected compared to the general population and may not always be perceived as problematic. Nevertheless, height measures in NF1 as indicators of ‘where the child is at’, can be best followed using NF1-specific growth curves available for boys and girls. This to avoid an underestimate of growth abnormalities using typical childhood growth percentiles charts.

Equally relevant is the importance of additional monitoring of growth velocity. It indicates where ‘the child is heading’, and is a crucial component of comprehensive growth assessment and a better indicator of neuroendocrine dysfunction along the HP-growth axis. As a reference, the typical growth velocity in children 4-10 years of age (before puberty onset) is 5-6 cm per year. Any subtle indication of gradually lower outcomes over time may be a sign of growth impairment.

• Growth Hormone Deficiency (GHD)

GHD is the second most common endocrinopathy in NF1 and tends to surface before or during puberty. The likelihood of GHD in NF1 children is above average compared to the general population, irrespective of the presence of a tumour on the optical pathway or not. However, an OPG further increases the chance of a child with NF1 being affected by GHD.

A diagnosis of GHD is tricky to confirm. The importance of continuous growth velocity measurements during puberty to detect any deviations from the expected growth trend is emphasised as a feasible approach by both carers and health care professionals to catch this abnormality as early as possible.

Adequate clinical testing for GHD requires referral to an endocrinologist. Although growth hormone (GH) is lacking, GHD testing should not be focused on GH measures alone. Its fluctuation with peak levels during the night complicates a meaningful outcome measure. It is better to test IGF-1 (a hormone regulated by GH), but ultimately dynamic testing with a GH-stimulation test is most useful to diagnose GHD.

A big challenge is to detect GHD in a child with NF1 and CPP. A premature growth spurt driven by CPP can mask reduced growth velocity caused by GHD, suggesting the child is following a normal growth trajectory. The presence of an OPG in a child with simultaneous CPP and GHD further enhances this chance, requiring frontline NF1 specialists to carefully watch the signs of GHD no matter what the growth charts indicate in a child with NF1 and CPP.

• Growth Hormone Excess (GHE)

Children with NF1 displaying accelerated growth and tall stature can produce too much GH. Enhanced growth axis activity can be transient but is most often related to the presence of an optic pathway glioma. GHE can be masked by a simultaneous manifestation of CPP and initial excess of GH can progress into a lack of GH over time. To cover all instances, the advice would be to carefully consider longitudinal growth monitoring, especially in tall children with NF1 lacking secondary sex characteristics.  

There are several explanations for neuroendocrine dysfunction in children with NF1. It appears that the endocrinopathies discussed can occur in all children with NF1, but they develop considerably more frequently in children with NF1 and an OPG. This would suggest that the gliomas interfere and disrupt proper functioning of the HPG and HP-growth axis. More research into the underlying biology of endocrinopathy in NF1 is needed.

Until we know more about their causes in general as well as specifically in children with NF1, clinical alertness to endocrinopathies is important. Early detection of a hormone deficit or excess can create a window of opportunity to intervene.

Dr Cheung has also seen that the early signs of hormonal disturbances impacting growth and puberty can precede the (earlier than usual) detection of glioma growth in children with NF1. His presentation hopefully serves as an eyeopener to many NF1 specialists and health care professionals, and have endocrinology added to the multidisciplinary approach to NF1 diagnosis, treatment and care.

New insights into pain and what this means for NF 

A special conference session was focussed on NF-related pain acknowledging its significant burden on a patient’s quality of life. To say the least, pain is complicated and one of the speakers in this session, Dr Deepak Ravindran from Teesside University in the UK, was invited to deconstruct this complexity as a start to better, more comprehensive pain care.  

Dr Ravindran has extensive expertise in pain medicine. He has even published a science-backed book, The Pain-Free Mindset, on a practical approach to manage chronic pain with careful considerations around lifestyle as an alternative to addictive pain medication.

As a clinical physician, Dr Ravindran primarily runs a general pain service. He is not a NF specialist but hopes sharing new insights into the complexity of pain can improve pain care in NF. 

Many NF-patients struggle with chronic pain: 35-53% in NF1, 47% in NF-SWN and more than 50% in SWN. While almost 1 in 2 patients across the spectrum of NF suffers from chronic pain, the mechanisms of pain may not always be the same. The 2 best known categories of pain are as follows:

1-Nociceptive pain

Pain experienced by NF patients in this category can most often be described as pain caused by acute local inflammation, skeletal compression or a tumour mass physically pressing on neural structures but not damaging the nerves at the pain site. It is referred to as a macro (or tissue) level pain. 

The feeling of pain arises from a cascade of events: noxious stimuli activate nociceptors in non-neural tissue at the pain site; nociceptors then transmit signals to the brain, which are registered as potentially harmful local signals and interpreted as pain by the brain.

2-Neuropathic pain

This type of pain in NF is caused by direct damage to the nerve. It most often arises as an unwanted consequence of surgery, an identifiable injury affecting the nervous system or a known cause of nervous system dysfunction.

Neuropathic pain can sometimes be perceived as unusual sensations such as burning, tingling and numbness.

Both nociceptive and neuropathic pain in NF can benefit from surgical intervention or be treated with pain medication for routine use (paracetamol, ibuprofen, non-steroidal anti-inflammatory drugs, opioids, and sometimes gabapentinoids specifically for nerve pain).

However, a clinical pain study from 2025 by Meller et al. showed that in a NF patient cohort, 20% of NF patients with chronic pain were neither suffering from nociceptive nor neuropathic pain.

It has also become clear from systemic reviews in the field of pain management, including NF care, that most standard pain medication given in pain clinics or clinical care settings are not as effective as we would hope. According to Dr Ravindran, the broad consensus is that ‘only 30% of patients experience about 30% of pain relief and they have about 30% of efficacy’. This suggests that only a fraction of NF patients with pain and taking pain medication experience relief of pain. And when pain relief is felt, the level of reprieve seems less than expected.

It led to the recognition of a new category of pain called nociplastic pain, which is included in the latest international pain management guidelines by IASP and WHO. 

3-Nociplastic pain

This type of pain is considered a micro-level pain. In NF specifically, a possible cause of nociplastic pain can be altered cell function as a result of the gene mutation underlying NF.  Changes in cell signalling pathways can influence the local environment of the site where pain is perceived.

Nociplastic pain emerges when the typical way that the body processes and feels pain becomes dysregulated. It reflects complex changes throughout the nervous system involving neuroinflammation, altered nociception, peripheral and central sensitisation, impaired pain inhibition and altered pain perception by the brain.

Because of this altered pain processing, nociplastic pain cannot be explained by a lesion or disease, but is nonetheless very real. Its hallmark is an amplified inflammatory loop which drives a self-perpetuating persistent type of pain. 

• Importantly, pain relief of nociplastic pain with standard medication is ineffective.

This new 3rd category of pain, nociplastic pain, makes pain even more intricate, complex and above all personal. Dr Ravindran argued that nociplastic pain responds better to lifestyle adjustments and mind-body therapies than standard pain relief medication. For example, brain training is believed to mitigate the contribution of a lowered threshold to pain caused by the lived experience of chronic pain over time.

Overall, it is likely that most NF patients (NF1, NF-SWN and SWN) suffer from a combination of all 3 types of pain. Living with chronic pain could be improved with a comprehensive pain care approach.

Dr Ravindran supports a more holistic treatment plan which can include pain medication and intervention where needed. If also informed by social determinants of health and awareness of modifiable lifestyle variables (diet, sleep, exercise and cognitive training), pain care may reset brain sensitisation and change the perception of pain for those living with the burden of chronic pain.