What are the potential causes and treatment options for a 12-year-old with Neurofibromatosis type 1 (NF1) who is falling off the growth chart?

Growth Failure in a 12-Year-Old with NF1

A 12-year-old with NF1 falling off the growth chart requires immediate evaluation for growth hormone deficiency (GHD), which occurs in 15-79% of short children with NF1 even without suprasellar lesions, followed by assessment for optic pathway gliomas, precocious puberty, and tumor-related complications. 1

Primary Endocrine Causes

Growth Hormone Deficiency

• GHD is relatively common in NF1 children with poor growth, occurring independently of organic pituitary damage. In one study, 15 of 19 (79%) short children with NF1 growing poorly had GHD (peak GH <5 ng/mL) despite absence of suprasellar abnormalities. 1
• Children with NF1 typically grow normally until puberty, after which height velocity decreases relative to peers, with 18-30% reaching true short stature (<3rd percentile) by late puberty. 2
• Final height in NF1 is significantly below genetic target and predicted adult height calculated before puberty. 2
• Evaluate GH secretion with stimulation testing in any NF1 child falling off growth curve without other clinical explanation. 1

Precocious Puberty

• Precocious puberty occurs in 2.4% of NF1 patients overall, with 22.6% of those with optic pathway tumors (OPT) developing precocious puberty. 3
• Age at onset ranges from 5.2-7.5 years in girls and 7.9-8.9 years in boys. 3
• Screen for early pubertal signs (Tanner staging) and obtain brain MRI to rule out OPT if precocious puberty suspected. 3
• GnRH agonist therapy should be considered individually, as untreated patients may have final height markedly below familial range. 3

Delayed Puberty

• Delayed menarche (>2 SD) occurs in 16% of NF1 girls versus 3.4% in controls, with mean age at menarche 13.0 years versus 12.4 years in general population. 2
• This can contribute to growth concerns during adolescence. 2

Tumor-Related Causes

Optic Pathway Gliomas

• OPGs occur in approximately 20% of NF1 patients, presenting at median age 4-5 years, with 15-20% progressing and requiring intervention. 4
• Obtain ophthalmologic examination by pediatric ophthalmologist or neuro-ophthalmologist to assess for visual compromise. 4
• If visual examination raises concerns, obtain brain MRI with orbits. 4
• Chiasmatic involvement can cause GHD through hypothalamic-pituitary axis disruption. 3

Plexiform Neurofibromas

• PNs occur in approximately 50% of NF1 patients, are likely congenital, and have faster growth in young children. 4
• Large PNs can cause compression symptoms, pain, and disfigurement affecting nutrition and mobility. 4
• Assess for symptomatic PNs that may impair feeding, swallowing, or physical activity. 5

Severe Complications

• Among the shortest patients (<10th percentile), there is high incidence of CNS tumors, huge plexiform neurofibromas, and severe scoliosis. 2
• Perform clinical evaluation for scoliosis with Adam's forward bend test. 4

Nutritional and Systemic Factors

Dysphagia and Malnutrition

• Head and neck plexiform neurofibromas can cause dysphagia, leading to malnutrition and dehydration. 5
• Obtain detailed history focusing on oropharyngeal dysphagia symptoms and perform nutritional assessment. 5
• Unrecognized dysphagia increases mortality risk from aspiration pneumonia. 5

Vitamin D Deficiency

• Consider checking serum vitamin D concentrations and supplementation in context of clinical presentation. 4

Diagnostic Algorithm

1. Measure height velocity and plot on growth chart to confirm deceleration
2. Perform comprehensive endocrine evaluation:
   • GH stimulation testing (peak GH <5 ng/mL indicates deficiency) 1
   • Tanner staging for pubertal assessment 3
   • Thyroid function tests
   • IGF-1 and IGFBP-3 levels
3. Obtain brain MRI to evaluate for OPG or other CNS tumors if not recently performed 4, 3
4. Ophthalmologic examination with visual acuity and visual fields 4
5. Assess for skeletal complications: scoliosis screening, consider DEXA scan 4
6. Nutritional assessment including vitamin D, evaluation for dysphagia 4, 5

Treatment Considerations

• GH replacement therapy is indicated for documented GHD and can result in final height within familial range when initiated appropriately. 6, 3
• GnRH agonist therapy for precocious puberty should be individualized based on age at onset and predicted final height trajectory. 3
• Refer to specialized NF1 clinic for multidisciplinary management including medical genetics, endocrinology, neurology, and oncology. 7

Critical Pitfall

The most common error is attributing short stature solely to NF1 itself without investigating treatable causes like GHD, which can occur even without visible suprasellar lesions on imaging. 1 This represents a missed opportunity for intervention that significantly impacts final adult height and quality of life.