‘If there were water we should stop and drink’: neurofibromatosis presenting with diabetes insipidus

Abstract

A 58-year-old right-handed woman presented to our institution with a 1-month history of polydipsia and polyuria. She had a remote history of neurofibroma excision by dermatology and, on examination, was noted to meet the clinical diagnostic criteria for neurofibromatosis type 1. Laboratory investigations revealed hypernatraemia and elevated serum osmolality, accompanied by reduced urinary osmolality. A subsequent water deprivation test confirmed central diabetes insipidus, which responded to treatment with desmopressin. MRI of the brain showed pituitary enlargement, which raised the possibility of an underlying pituitary adenoma or, alternatively, lymphocytic hypophysitis. Both conditions have rarely been described in neurofibromatosis.

Background

Neurofibromatosis type 1 (NF1) is a reasonably common genetic condition¹ associated with characteristic skin changes, and an increased frequency of benign, and malignant, tumours of the nervous system. We report a case of NF1 that presented with polyuria and polydipsia secondary to central diabetes insipidus.

Case presentation

A 58-year-old right-handed woman presented to our institution with a 1-month history of nausea, polydipsia and polyuria. She reported drinking approximately 5–6 L of water per day and was passing urine at least three times per night. Her weight was stable, and she had not experienced any recent head injury. Her only medication was metoclopramide (as required), which was first prescribed 3 weeks before her presentation. She had never been treated with lithium. Her medical history was significant for a cutaneous neurofibroma excised 12 years previously. She had never been seen by a neurologist. There was no family history of neurofibromatosis. On examination, she was found to have multiple neurofibromas, four café au lait spots, Lisch nodules and freckling of her left axilla. Her neurological examination, including visual fields, was normal.

Investigations

Laboratory investigations on admission (table 1) revealed hypernatraemia (sodium: 150 mmol/L) and elevated serum osmolality (302 mOsm/kg), accompanied by reduced urinary osmolality (82 mOsm/kg). Serum glucose was normal (5.6 mmol/L). Creatinine, serum ACE, thyroid and liver function tests were normal. CT of the brain was normal, aside from multiple cutaneous neurofibromas (figure 1). MRI of the brain (figures 2 and 3) showed global asymmetric enlargement of the pituitary gland, including stalk, 1.8 cm coronally, 0.8 cm vertically, 1.1 cm anteroposteriorly, with suprasellar extension posteriorly. There was heterogeneous enhancement of the gland on the postcontrast images, with smooth uniform enhancement of the pituitary stalk. The posterior pituitary bright spot was retained. A water deprivation test (table 2) was performed. The absence of antidiuretic hormone, in the setting of elevated serum osmolality, was suggestive of central diabetes insipidus. The diagnosis was confirmed when subsequent testing revealed a >50% rise in urine osmolality in response to desmopressin. Additional investigations (table 2) were performed to outrule another endocrinopathy.

Table 1.

Blood tests

Test	Result	Reference range
TSH	1.85	0.35–4.9 mIU/L
Prolactin	1015 ↑	109–577 mIU/L
IGF-1	148	46–238 ng/mL
FSH	38	26.7–133.4 IU/L
LH	20.3	5.2–62 mIU/L
ACTH	3.1	1.1–13.2 pmol/L
Cortisol (morning)	345	171–800 nmol/L
K+	3.5	3.5–5.5 mmol/L
Ca2+ (corrected)	2.4	2.1–2.55 mmol/L

ACTH, adrenocorticotropic hormone; FSH, follicle-stimulating hormone; IGF-1, insulin growth factor-1; LH, luteinising hormone; TSH, thyroid-stimulating hormone.

Figure 1.

CT of the brain demonstrating cutaneous neurofibromas. Nil pituitary abnormality identified.

Figure 2.

MRI of the brain: sagittal view showing global pituitary enlargement.

Figure 3.

MRI of the brain: coronal view showing global pituitary enlargement.

Table 2.

Water deprivation test

Test	Result	Reference range
Antidiuretic hormone	<0.5 ↓	4–14 ng/L
Serum osmolality	297	275–295 mOsm/kg
Urine osmolality	Pretest: 65 ↓ Post-test: 236 (>50% rise)	300–900 mOsm/kg

Treatment

Serum sodium normalised following the introduction of desmopressin.

Outcome and follow-up

Our patient improved both clinically and biochemically following treatment with desmopressin.

She was discharged home 1 week after her initial presentation. During her admission, she was formally given a diagnosis of NF1, as two of the seven clinical criteria were satisfied (table 1). Neuroradiology and neurosurgery services reviewed her MRI. Surveillance imaging was recommended, as it was unclear whether pituitary swelling represented a pituitary adenoma or lymphocytic hypophysitis. She continues to attend neurology and endocrinology clinics.

Discussion

NF1 was first described by Frederich von Recklinghausen in 1882.¹ It is an autosomal dominant condition with a prevalence of 1 in 2500 to 3000 people worldwide.¹ A germline mutation in the NF1 tumour suppressor gene on chromosome 17 results in typical skin changes and an increased frequency of benign and malignant tumours, particularly of the nervous system. Associated tumours include glioma of the optic nerve pathway, glioblastoma, malignant peripheral nerve sheath tumour, gastrointestinal stromal tumour, breast cancer, phaeochromocytoma, duodenal carcinoid tumour and rhabdomyosarcoma. Fifty per cent of individuals with NF1 have no family history of the disease, as in our patient.¹ These cases are attributed to de novo mutations. The diagnosis of NF1 is a clinical one, using established criteria (box 1). NF1 gene testing is reserved for unusual presentations or to inform reproductive decision-making.²

Box 1. Clinical criteria for diagnosis of neurofibromatosis type 1 (NF1).

• ≥6 Café au lait macules >5 mm in greatest diameter in prepubertal individuals and >15 mm in greatest diameter in postpubertal individuals.

• ≥2 Neurofibromas of any type or >1 plexiform neurofibroma.

• Freckling in the axillary or inguinal regions.

• Optic glioma.

• ≥2 Lisch nodules (iris hamartomas).

• A distinctive osseous lesion, such as sphenoid dysplasia or thinning of the long bone cortex, with or without pseudoarthrosis.

• A first-degree relative (parent, sibling or offspring) with NF1 according to the above criteria.

Pituitary abnormalities, including both pituitary adenoma and lymphocytic hypophysitis, have been rarely described in patients with NF1, although recognition is increasing.³ Attention to the suprasellar region, in addition to the brain tissue, and orbits, on brain imaging of patients with NF1 is advised. The presence of pituitary swelling in our patient adds to the evidence that the suprasellar fossa should be carefully reviewed when performing intracranial imaging of an NF1 carrier.

No single radiological feature distinguishes pituitary adenoma from lymphocytic hypophysitis so patients must have functional endocrine testing, imaging and be followed clinically if histology is not available. An asymmetrical, heterogenously enhancing lesion with maintained posterior pituitary bright spot supports pituitary adenoma; while stalk involvement and volume <6 cm³ would favour lymphocytic hypophysitis.⁴

One previous case of neurofibromatosis with lymphocytic hypophysitis, an autoimmune inflammation of pituitary tissue, has been reported.⁵ Presentation is typically with headache, hypopituitarism and central diabetes insipidus (CDI). In NF1, overexpression of the neurofibromin gene leads to suppression of Fas ligand, and subsequent lack of apoptosis of CD4 +T lymphocytes. This leads to an increased incidence of other autoimmune conditions including vitiligo, Hashimoto’s thyroiditis and Graves disease in patients with NF1.^{6 7} Our patient did not have headache or hypopituitarism on the testing performed and improved without immunotherapy. This case suggests that lymphocytic hypophysitis may be an additional autoimmune complication that can occur in NF1.

Diabetes insipidus is a rare complication of NF1. Only two cases have been previously reported. One of these patients also suffered from myelodysplastic syndrome secondary to monosomy 7, a condition that has also subsequently been linked to CDI.^8–10 CDI is a pathological deficiency in the secretion of antidiuretic hormone (ADH), resulting in failure to maintain optimal plasma osmolality.¹¹ Increased plasma osmolality above 280 mOsmol/kg is detected by osmoreceptors of the anterior hypothalamus, triggering ADH release into the circulation.¹¹ ADH acts on V2 receptors in the nephron, leading to reabsorption of free water.¹¹ ADH deficiency presents clinically with polyuria and polydipsia. It can be diagnosed by demonstrating low levels of antidiuretic hormone in the setting of elevated serum osmolality. Although plasma ADH levels can be measured, caution should be applied when interpreting the results of ADH immunoassays, as levels may be artefactually low due to instability ex vivo. In this case, we confirmed CDI by demonstrating a greater than 50% increase in urine osmolality postdesmopressin. Our case illustrates CDI in a patient with NF1 with polyuria, hypernatraemia and an enlarged pituitary. Patients with NF1 may be at increased risk of CDI due to a genetic increased risk of both tumours and deranged T lymphocyte function, within the nervous system.

Learning points.

• Neurofibromatosis type 1 (NF1) is a condition that is diagnosed on clinical examination. Although there is genetic linkage, a family history is not mandatory.

• Patients with NF1 are at increased risk of developing both benign and malignant tumours, among which pituitary adenoma should be considered.

• NF1 carriers are at increased risk of autoimmune conditions.

• Central diabetes insipidus is a rare complication of NF1.