Pathophysiology of endocrine disorders

Loss of neurofibromin protein function leads to hyperactivation of the proto-oncogene RAS, as well as enhanced activity of RAS downstream effectors. RAS signaling pathway controls cell proliferation. Neurofibromin also positively regulates the generation of intracellular cyclic adenosine monophosphate (cAMP) in the brain. cAMP and the transcriptor factor known as cAMP response element-binding protein (CREB) are key regulators of hypothalamic-pituitary axis development.¹¹

In the absence of organic or medical causes, NF1-associated pituitary hormone deficiencies may be explained by the loss of normal neurofibromin function and subsequent cAMP signaling impairment.¹²

Nonetheless, OPG is the most frequent underlying cause of endocrinological disturbances.¹¹ In a study by Sani et al., at least one endocrinopathy was found in 55.6% of children with NF1 and OPG during a mean follow-up of 9.1 ± 3.4 years.⁸ None of the patients with OPG limited to the optic nerve developed endocrinopathy during follow-up, while 57.1% and 72.7% of patients with OPG involving the optic chiasm and hypothalamus developed endocrinopathy, respectively.

In the study by Santoro et al., OPG was diagnosed earlier in 26.7% of children with endocrine disorders compared to those without endocrine dysfunctions.⁶

Auxological features, growth, and puberty in NF1 children

Short stature and macrocephaly have long been acknowledged as clinical features of children with NF1.

Disease-specific growth charts for NF1 have been developed by Clementi et al. in 1999 (Figures 1, 2, 3 e 4).¹³ These charts are useful to determine the main growth profile differences in these patients compared to the healthy population, understand the pathogenesis of the condition, and allow the detection of a secondary growth disorder if present.¹³

Figure 1 NF1 height charts (from Clementi et al.)(13) 

Figure 2 NF1 weight charts (from Clementi et al.)(13) 

Figure 3 NF1 head circumference growth charts (from Clementi et al.)(13) 

Figure 4 NF1 height growth velocity charts (from Clementi et al.)(13) 

The growth profile of these children seems similar to their peers up to the age of seven years in girls and 12 in boys. Subsequently, the 50^th centile tends to overlap with the 25^th centile of healthy children, and the 3^rd centile is significantly lower in NF1 subjects.¹³ Pubertal spurt occurs one year earlier compared to healthy controls and is mildly reduced in boys but not in girls. The study by Carmi D et al. showed the same pattern: a poor pubertal growth velocity (GV) and peak height velocity, particularly in boys, resulting in a significant and gradual reduction in the relative height for age during puberty.¹⁰ Most patients did not attain their expected height and ended up with a shorter standard deviation score (SDS) compared to their initial height SDS.

Short stature (height below -2 SDS) occurs in 13-24% of prepubertal children and in more than 40% of adults.^10,14 Its etiology is probably multifactorial. It can be due to abnormal skeletal development, use of psychostimulant medications, short familial stature, hypothyroidism, precocious puberty, or GH deficiency (see below).

Head circumference (HC) is larger in NF1 patients during the whole growth period and in adulthood.¹³ The disproportion between head size and height increases with age, mainly in boys.¹³ A retrospective study in 80 Finnish NF1 children investigated the incidence and diagnostic accuracy of elevated HC to height ratio (HCHR). At a median age of NF1 diagnosis of 3.6 years, 53.8% of children showed elevated HCHR. Considering the seven diagnostic criteria for NF1, elevated HCHR was the second most common clinical manifestation after CALM (cit in Bizzarri C et al).¹¹ Macrocephaly typically requires no particular follow-up.³

A disproportionate growth of the extremities, including leg-length discrepancy, is generally associated with plexiform neurofibromas, causing local bone growth acceleration and soft-tissue hypertrophy.³

Endocrine disorders in NF1 children

Central precocious puberty

Central precocious puberty (CPP) is the most common endocrine manifestation of NF1 in childhood.^9,11 Its prevalence is higher than in the general population (~3-6% vs. 0.5%) and mainly affects boys.^09,10,15 The condition is suspected due to the occurrence of breast budding (Tanner stage II) before the age of eight years in girls and testicular volume of at least 4 mL before the age of nine years in boys and is typically accompanied by GV acceleration.

CPP has been mostly reported in NF1 children with OPG, but it is not always so.^9,15 In children without OPG, the occurrence of CPP may be incidental and idiopathic or result from NF1 itself, loss of normal neurofibromin function and impaired cAMP signaling, or mild cerebral abnormalities undetectable in magnetic resonance imaging, such as slow-growing hamartomas.^11,16

In the study by Sani et al., around 20% of children with NF1 and OPG had both CPP and GHD.⁸ The coexistence of CPP and GHD can mask linear growth acceleration, resulting in normal GV and making GHD diagnosis more challenging. On the contrary, if GV remains high with appropriate CPP treatment, excess of GH should be suspected and investigated (see below). Since most children with OPG are asymptomatic, NF1 children should be closely monitored for early puberty signs leading to OPG diagnosis.¹⁵

Gonadotropin-releasing hormone (GnRH) agonist therapy should be decided on a case-by-case basis, as some patients do not benefit from this treatment. Long-term follow-up is required, since patients with OPG and precocious puberty can progress to gonadotropin deficiency later in life.^8,14,17

Growth hormone deficiency

As previously mentioned, not only puberty but also growth is commonly affected in NF1 children, and disease-specific growth charts have been published. Although the associated mechanism is not clearly elucidated, growth hormone deficiency (GHD) is more common in patients with NF1 than in the general population. As with CPP, GHD is more frequent in the presence of intracranial tumors.¹¹ In some cases, GHD is correlated with the use of radiotherapy, surgery, or chemotherapy as cancer treatments.^6,9,11

The incidence of GHD is estimated to be 2.5%, with a mean age at diagnosis of nine years, but can be as high as 35% in NF1 children with OPG.^8,9

A clear decrease in GV should raise suspicion of GHD, as well when growth is below the 3^rd centile (particularly if perceived in disease-specific NF1 growth charts) and when the predicted adult height falls below the estimated mid parental height (mother’s height + father’s height + 13 cm in boys/2; mother’s height + father’s height - 13 cm in girls/2). In these cases, further research should be carried to rule out GHD.

Concerns have been raised about whether treatment with somatotropin can enhance tumor growth and/or increase malignancy risk, but no randomized clinical trials addressing these issues have been conducted so far.

GH receptor expression has been documented in plexiform neurofibromas. This finding could indirectly suggest that these tumors may respond to GH stimulation (Cunha et al., cit in Kyritsi EM et al.).¹² Nonetheless, no increase has been noted in plexiform neurofibroma growth rate during puberty, a period of spontaneous increase in GH secretion (Dagalakis et al., cit in Kyritsi EM et al.).¹²

Howell et al. investigated a cohort of 102 NF1 patients receiving somatotropin treatment and reported a reassuring safety profile.¹⁸ Most adverse events reported seemed related to progression of NF1 features. CALM and neurofibroma changes were reported in 13% of patients over a median follow-up of 2.7 years, a percentage expected for disease progression in NF1 children.¹⁸ In the study by Sani et al., although tumor progression was not affected by somatotropin treatment, scoliosis progression could occur, which should be taken into account when planning treatment.⁸ Treatment response, although favorable, was not as good as in patients with idiopathic GHD.¹⁸

According to the current evidence, it seems very unlikely that the use of somatotropin affects the course of the several NF1 manifestations, in particular the risk of tumor development. GH treatment in NF1 patients with GHD seems beneficial, as it is associated with improved growth rate and is well tolerated.^8,18

Published guidelines underline that somatotropin treatment should be reserved for children with poor GV and low GH stimulation documented through testing.³ According to the National Commission for the Normalization of Growth Hormone in Portugal, only one stimulation test with a peak of less than 7 g/L is required to initiate somatotropin treatment in children with short stature and auxologic criteria for somatotropin deficiency with an identified etiology (for example, OPG; unpublished data). In cases of idiopathic GHD, two stimulation tests are necessary.

Growth hormone excess

Somatotropin excess has also been described in NF1 patients. To date, there are no reports of somatotropin excess without imagiological evidence of OPG.^7,11,19 The estimated incidence of somatotropin excess in children with NF1-OPG is 5-11%.^6-8

Growth hormone excess is usually suspected by excessive/accelerated linear growth, with high levels of insulin growth factor 1 (IGF-1) and IgF-binding protein 3 and lack of GH suppression to levels <1 ng/mL after oral glucose tolerance test (OGTT) confirming the diagnosis. IGF-1 concentrations must be compared with age- and sex-dependent normative data.¹⁴ As there are no normative data in children, the diagnostic threshold of GH levels suppressibility during OGTT, especially during puberty, has not been clearly established.¹⁴ In the study by Cambasio et al., all patients studied for GHE and OPG had IGF-1 and IGFBP-3 levels above the 97^th percentile. ⁷ Lack of GH suppression on OGTT was demonstrated in five of seven patients.

The mechanism underlying GH excess is still unclear. Infiltration of the somatostatinergic pathway by the tumor, presumably resulting in reduced somatostatin tone and overproduction of GHRH-mediated pituitary GH, has been proposed by Manski et al. (cit in Cambiaso P et al).^7,14

In the study by Cambasio P et al., increased GV was the only sign of OPG in one patient, showing that it should be considered in the differential diagnosis of OPG and reinforcing the need for frequent and accurate auxologic evaluation in NF1 children.⁷ Because CPP is more frequent in this patient population, it is usually considered first in the differential diagnosis, often neglecting GH excess.¹⁹ However, CPP and GH excess may coexist. Therefore, when puberty is biochemically and clinically suppressed with GnRH agonist therapy and persistently high levels of IGF-1 are observed, particularly if combined with tall stature and growth acceleration, additional studies should be conducted to rule out GH excess.¹⁴

Concerns have been raised that endogenous GH excess may increase the risk of cancer in NF1 children and induce preexisting tumor growth, namely OPG.^14,19Josefson et al. suggested that medical treatment of GH excess with somatostatin analogs (SSa) or GH receptor antagonists should be provided to reduce tumor growth and long-term detrimental systemic effects related to uncontrolled GH excess (gigantism-related skeletal problems, hypertension, glucose intolerance, and cardiomegaly).¹⁹

GH excess may be a transient phenomenon that resolves without treatment.^7,14,19 In these cases, only short-term therapy with SSa may be required to reduce patient discomfort, treatment costs, and potential treatment side effects.

Pheochromocytoma

Pheochromocytoma (PHEO) is usually reported in NF1 adult patients with an estimated incidence of 0.1-5.7%. Its incidence in the pediatric population is unknown, but some cases have been reported in the literature.⁵ Classical symptoms include hypertension, headache, and hyperhidrosis (the three H’), with loss of circadian blood pressure rhythm characterized by a ‘non-dipping pattern’ as an early marker of future hypertension. Because not all NF1 patients with PHEO have hypertension, the lack of this sign should not be considered reassuring or taken as absence of the condition.¹¹

Most experts recommend screening for PHEO if there is an acute and dramatic increase in heart rate and/or blood pressure.³

Gynecomastia

An increased frequency of unilateral and bilateral prepubertal gynecomastia cases has been described in NF1 patients, with endocrine workup shown to be normal in all.¹¹ The management of gynecomastia in these patients should thus follow the same recommendations as for the general pediatric population.

Osteopenia and vitamin D deficiency

Childhood osteopenia is frequent in NF1, but the risk of fractures is only slightly increased. The etiology of osteopenia is unknown. It has been hypothesized that it may be related to decreased musculoskeletal strength and poor neuromuscular coordination, leading to decreased bone remodeling. ³ Children with NF1 have a high prevalence of insufficient serum (25-hydroxycholecalciferol) vitamin D levels.³ Periodic assessment of vitamin D levels, especially in the presence of risk factors (low sun exposure, use of antiepileptic drugs), is helpful in determining the need and dosing of vitamin D supplementation.