Spontaneous remission of diabetes insipidus in a man with short stature, panhypopituitarism
A man aged 27 years, 6 months was referred to the endocrine clinic for short stature and a bone age of 12 years, 6 months. The patients history was significant for a severe head injury from a motor vehicle accident in his native country of Cameroon when he was 13 years old. His recovery was complicated by polyuria, but he did not receive any therapy. Over time, his thirst and polyuria subsided, and he denied nocturia. After the accident, the patient did not grow any taller or develop axillary or pubic hair. He never received medical treatment for his lack of development and he was not taking any medications.
He immigrated to the United States when he was 21 years old. He took college courses but failed because of fatigue and poor concentration. He complained of headaches that occurred for the last year without vision abnormalities. His voice had not deepened, and he did not shave. He denied anosmia and noted occasional morning erections. On exam, he appeared to be a prepubertal man appearing younger than his stated age. His blood pressure sitting was 92 mm Hg/64 mm Hg with a pulse of 80 and, after standing, fell to 74 mm Hg/56 mm Hg with a pulse of 84. His height was 52 inches with a waist-to-floor height of 31 inches and a heightwaist ratio ≤0.5. His exam was significant for periorbital edema; gynecomastia without galactorrhea; absence of a thyroid cartilage prominence (Adams apple); normal thyroid; no beard, pubic or axillary hair; microphallus; small testes (Tanner stage 1); normal cranial nerves exam; normal visual fields on confrontation; and delayed relaxation of the bicep reflexes.
Lab testing showed a low free thyroxine 0.5 pg/dL (reference, 0.87-1.8), inappropriately normal thyroid-stimulating hormone 2.24 (reference, 0.35-5.5), growth hormone ≤0.1 ng/mL and low insulin-like growth factor I ≤6 ng/mL (reference, 114-492). His adrenocorticotropic hormone was 16 pg/mL (reference, 9-52) with a basal morning cortisol of 3 mcg/dL and a subnormal stimulation to 13 mcg/dL at 60 minutes after 250-mcg IV cosyntropin. His luteinizing hormone 0.1 mIU/mL and follicle-stimulating hormone ≤0.3 mIU/mL were low with a testosterone ≤10 ng/dL (reference, 241-827) and prolactin 8 ng/mL (reference, 2.1-17.7). His electrolytes were normal with a sodium 137 mmol/L, bicarbonate 27.7 mmol/L, chloride 97 mmol/L, potassium 4.3 mmol/L, creatinine 0.5 mg/dL and random glucose 65 mg/dL. The results of radiology studies showed the humeral epiphysis was not closed on chest X-ray and the spheno-occipital synchondrosis was unfused on CT, suggesting a delay of bone maturity (see figure 1). An MRI scan showed a small pituitary and the absence of both the infundibulum (pituitary stalk) and posterior pituitary bright spot in the sella (see figure 2).
Clinically, the patient was found to have a eunuchoid habitus with long limbs due to delayed pubertal closure of epiphyses of the long bone by sex hormones. This can be documented with either a measurement of the waist to floor ≤one-half height or arm span ≥2 cm longer than height. His physical exam suggested panhypopituitarism with deficiencies in thyroid hormone (delayed relations of deep tendon reflexes), adrenal hormone (low and orthostatic BP), GH (short stature) and hypogonadism (lack of secondary sex characteristics). Biochemically, panhypopituitarism was confirmed. He was started on levothyroxine 75 mcg and prednisone 2.5 mg daily, which was changed to hydrocortisone 10 mg in the morning and 5 mg in the afternoon to avoid glucocorticoid excess limitation on growth. A few weeks later, he was started on GH. After three years of GH therapy, his height increased from 51.97 inches to 57.01 inches, and then he was started on testosterone with deepening of his voice, growth of pubic and axillary hair and increased libido. Testosterone therapy was not started until after substantial growth with GH and thyroid hormone therapy to avoid early fusion of the epiphyses and reduction of his final height. After seven years of HT, he is continuing to grow (see figure 3), with a current height of 58.60 inches, he reports feeling well with good energy and libido. He denies severe headache, lightheadedness or hypothyroid symptoms.
Photos courtesy of: Stephanie L. Lee, MD, PhD
Diabetes insipidus (DI) is a disorder in which large volumes of dilute hypotonic urine are excreted. Central DI is due to decreased vasopressin and most commonly occurs because of destruction of the long vasopressin-secreting neurons that originate in the paraventricular and supraoptic nuclei of the hypothalamus and transverse down through the pituitary stalk to terminate in the posterior pituitary. The most common causes of DI are trauma, pituitary surgery, accelerationdeacceleration head injury and subarachnoid hemorrhage. DI may result from metastatic tumor, large sella masses such as craniopharyngiomas and Rathke-cleft cysts but rarely by slow-growing anterior pituitary adenomas. DI may be caused by infiltrative diseases such as lymphocytic infundibulo-neurohypophysitis, Langerhans histiocytosis X and sarcoid. Other rare causes of DI reported in the literature are acute febrile illness, meningoencephalitis, electrical injury and herbicide (glufosinate) poisoning.
Although the DI after closed head injury of this man may be from direct injury to the pituitary, stalk or hypothalamus, it may be due to the accelerationdeacceleration tearing injury of the long vasopressin nerves and the venous plexus comprising the stalk. During a sudden deacceleration, the pituitary stalk is damaged when the brain shifts in the cerebral spinal fluid cushion, but the pituitary is fixed below within the skull by the bony cage of the sella and above by the dura. It is important to realize that both anterior and posterior pituitary dysfunction often occur in closed traumatic brain injury. In a study by Agha and colleagues, 21.6% developed DI immediately after the trauma and 6.9% had permanent DI after a median 17 months follow-up. CT or MRI in a large group of patients with posttraumatic hypopituitarism, including DI, reported hemorrhage in the hypothalamus or posterior pituitary in 55% of patients, and approximately 5% of patients had stalk resection or infarction of the posterior pituitary.
Similar to the course of postoperative injury to the vasopressin neurons, DI after head trauma follows a triphasic course. The first phase of DI of temporary antidiuretic hormone deficiency lasts for five to seven days and is initiated by a partial or complete pituitary stalk section with neuronal dysfunction due to axon shock and neuron dysfunction. The second phase of inappropriate antidiuresis lasts from two to 14 days and is caused by an uncontrolled release of vasopressin from the degenerating nerve terminals in the posterior pituitary. After the vasopressin stores are depleted, a third phase of DI develops if >80% to 90% of the vasopressin-secreting neuronal cell bodies in the hypothalamus have degenerated. The major determinant of whether DI is permanent is related to the location of the neuronal damage such that the closer the injury is to the cell bodies in the hypothalamus, the more likely the neurons will degenerate.
Occasionally, as illustrated by this patient, over time some patients resolve their symptoms of DI. This observation has not been systematically studied and is based on anecdotal experience and case reports. Presumably this patient had partial central DI, and over time some, ADH nerve terminals were able to form at the base of the hypothalamus, resulting in the resolution of DI symptoms and the development of an ectopic posterior pituitary. Although ectopic posterior pituitary located at the base of the hypothalamus has been reported in cases of congenital absence of the anterior pituitary, it is unlikely in this case, as his growth was normal until his head injury.
Subramanian Kannan, MD, is a PGY3 Resident in Internal Medicine at University of Connecticut Health Center, and Stephanie L. Lee, MD, PhD, is Associate Chief of the Section of Endocrinology, Diabetes and Nutrition, and Associate Professor of Medicine at Boston University Medical Center.
For more information:
- Agha A. J Clin Endocrinol Metab. 2004;89:5987-5992.
- Agha A. Eur J Endocrinol. 2005;152:371-377.
- Benvenga S. J Clin Endocrinol Metab. 2000;85:1353-1361.
- Schneider HJ. JAMA. 2007;298:1429-1438.