Central diabetes insipidus (CDI) results from deficiency synthesis, release of arginine vasopressin (AVP), or both. Polyuria and polydipsia are important clues to the diagnosis; nonetheless, approximately 40% of the patients have symptoms other than polyuria and polydipsia at presentation [
The etiology of childhood CDI is heterogeneous. It can be familial (i.e., a genetic defect of AVP synthesis) or secondary to diseases that affect the hypothalamic-pituitary system, such as Langerhans cell histiocytosis (LCH), germinoma, craniopharyngioma, trauma related to surgery or accident, or cranial malformations. Hypothalamic magnetic resonance imaging (MRI) is necessary because it not only may lead to a diagnosis of CDI by lack of posterior pituitary bright spot on T1-weighted imaging, but also can reveal intracranial tumor or LCH with a thickened pituitary stalk. However, 20–50% of cases are considered idiopathic [
To date, diagnosis and differential diagnosis of childhood CDI in China are daunting, with lack of systematic follow-up. In our study, we analyzed the clinical, hormonal, and neuroradiological data at diagnosis and follow-up to illustrate the importance of regular follow-up and monitoring of pituitary function.
From 2012 to 2014, 43 patients (23 boys and 20 girls) ranging in age from 1.9 to 11.5 y were diagnosed with CDI at the Pediatric Endocrinology Department of Shandong Provincial Hospital. A family history, chief complaints, physical examinations, and laboratory and radiological evaluation were obtained at presentation. Diagnosis of CDI was based on a history of polyuria and polydipsia (urine volume > 1500 mL/kg/d at birth, 100–110 mL/kg/d at 2 y, and 40–50 mL/kg/d after 2 y [
The water deprivation test lasted 4 to 7 hours, in accordance with the standard protocol previously reported [
After the water deprivation test, DDAVP was administrated by subcutaneous injection (0.1
Complete CDI was defined as urine osmolality < 300 mOsm/kg after the water deprivation test with a >50% increase in response to DDAVP. Partial CDI and partial nephrogenic diabetes insipidus and defined as maximum urine osmolality between 300 and 800 mOsm/kg during the water deprivation test and <50% increase in response to DDAVP. Complete CDI, partial CDI, and partial nephrogenic diabetes insipidus were distinguished by abolishment of thirst, polyuria, and polydipsia, without development of hyponatremia, in response to a therapeutic trial with a standard dose of desmopressin [
Growth hormone deficiency was confirmed by provocative tests in all patients. Blood samples to measure growth hormone levels were obtained at baseline and at 30, 60, 90, and 120 min after the administration of arginine (0.5 g/kg, given intravenously over a period of 30 min) and levodopa (10 mg/kg, maximum 500 mg, given orally). Growth hormone deficiency was defined as growth hormone peak level < 10 ng/mL combined with a subnormal IG-1 (insulin-like growth factor 1) level for chronological age.
Thyroid-stimulating hormone (TSH) deficiency was defined as free thyroxine (FT4) < 12.0 pmol/L with a low or low-to-normal serum concentration of TSH.
Plasma ACTH and serum cortisol were measured in the morning (08:00 a.m.). ACTH deficiency was defined by either a morning serum cortisol concentration < 138 nmol/L or a peak serum cortisol concentration < 550 nmol/L during insulin-induced hypoglycemia, in concert with an inappropriately low plasma ACTH concentration.
Follicle-stimulating hormone/luteinizing hormone (FSH/LH) deficiency was diagnosed in 2 patients who had absent/delayed pubertal development. Serum FSH and LH were measured at 0 minutes and 30, 60, and 90 min after administration of gonadotropin-releasing hormone. Low serum testosterone in boys or estradiol in girls, combined with a blunted LH/FSH response to gonadotropin-releasing hormone, was diagnostic for FSH/LH deficiency.
All patients underwent hypothalamic-pituitary MRI scans, without and then with contrast agent, using a 3.0 T magnetic resonance scanning machine (Siemens & Co., Germany), in accordance with standard protocol (3.0 mm slice thickness, coronal and sagittal orientation, 256 × 256 matrix size, T1-weighted imaging without and then with contrast agent). The contrast agent was intravenous gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA), 0.1 mmol/kg.
Images were interpreted by 2 independent observers without prior knowledge of the patients, noting posterior pituitary bright spot, pituitary height, and thickness of the pituitary stalk. Pituitary height was compared to the normal value for age, gender, and development [
The thickness of the pituitary stalk was characterized as mild (3.0–4.5 mm), moderate (4.6–6.5 mm), or severe (>6.5 mm) [
Based on the hypothalamic-pituitary MRI, patients were considered TPS− or TPS+ (diameter of pituitary stalk ≤ 3 mm or >3 mm, resp.).
To rule out LCH, 27 patients with thickened pituitary stalk underwent skeletal surveys, lung computed tomography (CT) scan, whole-body nuclear medicine bone scanning, and skin histopathological test. To detect secretary germinoma, alpha-fetoprotein (AFP) and
During a 1.5-to-2 y follow-up, patients with idiopathic conditions were seen at 3–6-month intervals and given physical examination and tested for anterior and posterior pituitary function and also tumor markers (serum AFP and
IBM SPSS Statistics ver. 20.0 (SPSS, Armonk, NY, USA) software was used for all statistical analyses. Student’s unpaired
There were 16 and 27 patients in the TPS− and TPS+ groups, respectively. Of these 43 patients (23 boys, gender ratio: 1.15), the median age at CDI diagnosis was
Baseline data of all patients with CDI.
Total | TPS− | TPS+ |
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Subjects, |
43 | 16 | 27 | — | |
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Male/female, |
23/20 | 12/4 | 11/16 | — | |
Age at diagnosis, y | 7.47 ± 0.49 | 6.58 ± 0.67 | 8.01 ± 0.66 | 0.16 | |
Interval, months | 22.29 ± 3.67 | 18.86 ± 5.99 | 24.32 ± 4.69 | 0.48 | |
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Short stature, |
17 (39.5%) | 5 (31.3%) | 12 (44.4%) | 0.39 | |
Height SDS | –3.23 ± 0.24 | –3.48 ± 0.45 | –0.13 ± 0.29 | — | |
BMI, kg/m2 | 16.12 ± 0.29 | 15.98 ± 0.42 | 16.20 ± 0.39 | 0.7 | |
Urine 24 h, mL/kg | 202.7 ± 9.83 | 188.6 ± 12.99 | 211.0 ± 13.56 | 0.27 | |
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APD | 23 (53.5%) | 6 (37.5%) | 17 (63%) | 0.11 | |
IGHD | 15 | 6 (37.5%) | 9 (33.3%) | 0.36 | |
MPHD | 8 | 0 | 8 (29.6%) | 0.02 |
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GHD +1 | 5 | 0 | 5 | — | |
GHD +2 |
1 | 0 | 1 | — | |
GHD +3 |
2 | 0 | 2 | — | |
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Pituitary bright spot | Absent (100%) | Absent (100%) | Absent (100%) | — | |
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AP | Normal | 26 (60.5%) | 12 (75%) | 14 (51.9%) | 0.13 |
<Normal | 11 | 4 (25%) | 7 (25.9%) | 0.95 | |
Not visible | 6 | 0 | 6 (22.2%) | 0.04 |
AP: anterior pituitary; APD: anterior pituitary deficiency; GHD: growth hormone deficiency; IGHD: isolate growth hormone deficiency.
The most common symptoms or signs were polyuria/polydipsia (
Two patients with mental retardation had comorbidity including hydronephrosis and ureterectasia; their intervals between presentation and diagnoses were 72 months and 108 months. Both had a poor response to DDAVP therapy.
None of the subjects had a familial etiology, nor a history of surgery, infection, or trauma. All TPS− cases were idiopathic, whereas 11 TPS+ patients were etiologically diagnosed with germinoma (
Plasma and urine chemistry.
Baseline | End of WD | End of DDAVP | ||
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Plasma Na |
Total | 144.3 ± 0.9 | 150.0 ± 0.9 | 139.9 ± 0.8 |
TPS− | 145.4 ± 1.4 | 151.1 ± 1.7 | 137.9 ± 0.8 | |
TPS+ | 143.6 ± 1.1 | 149.4 ± 0.9 | 141.1 ± 1.0 | |
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Serum osmolality | Total | 286.2 ± 1.6 | 297.5 ± 1.9 | 278.7 ± 1.3 |
TPS− | 287.5 ± 2.8 | 298.4 ± 3.8 | 275.4 ± 1.5 | |
TPS+ | 285.4 ± 1.9 | 297.0 ± 2.2 | 280.6 ± 1.8 | |
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Urinary osmolality | Total | 128.6 ± 6.8 | 179.1 ± 0.5 | 492 ± 18.6 |
TPS− | 122.2 ± 14.1 | 187.2 ± 23.3 | 491.6 ± 29.9 | |
TPS+ | 132.4 ± 6.9 | 174.3 ± 9.8 | 492.2 ± 24.1 | |
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Urinary specific gravity | 1.0 to 1.004 | 1.0 to 1.007 | 1.01 to 1.023 |
WD: water deprivation.
Urine volume of the 43 patients was
The posterior pituitary bright spot was absent on T1-weighted MRI in all 43 patients (100%). Of the 27 patients with abnormal pituitary stalk, hypothalamic-pituitary MRI revealed suprasellar mass in 9: germinoma (
Craniopharyngioma patients (
In summary, anterior pituitary size was reduced in patients with normal or abnormal pituitary stalk and was undetected by MRI in patients with severely thickened and invisible pituitary stalk.
Anterior pituitary function was assessed in 43 patients; 23 (53.5%) had at least 1 anterior pituitary hormone deficiency. Isolated growth hormone deficiency was the most frequent abnormality (
Among the 16 patients with normal pituitary stalk, 6 (37.5%) had isolated growth hormone deficiency, 4 with small and 2 with normal anterior pituitary.
Among the 17 patients with mildly thickened pituitary stalk, 6 showed isolated growth hormone deficiency, 3 of whom had decreased size of anterior pituitary. Anterior pituitary hormone function was normal in 11 patients. MPHD was found in 2 patients with a moderately thickened pituitary stalk, and 2 of 3 patients with severely thickened pituitary stalk developed growth hormone deficiency and TSH deficiency. All 4 patients with an invisible pituitary stalk had MPHD (Table
Pituitary function of 27 patients with abnormal pituitary stalk
Anterior pituitary | MPHD | |||
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Patients | Invisible | <Normal | ||
Mild | 17 | 0 | 3 | 0 |
Moderate | 3 | 0 | 3 | 2 (66.7%) |
Severe | 3 | 2 | 1 | 2 (66.7%) |
Invisible | 4 | 4 | 0 | 4 (100%) |
Five patients with germinoma were treated with chemotherapy and then radiotherapy. Four patients with craniopharyngioma underwent surgical excision and pituitary stalk was undetectable on MRI. All patients with tumor developed at least 3 pituitary hormone deficiencies. Two patients with LCH are monitored regularly, and one was found to have isolated growth hormone deficiency. One craniopharyngioma patient relapsed 1.5 years after surgery.
One idiopathic patient with a mildly thickened pituitary stalk (3.4 mm) was normal one year after diagnosis but still required DDAVP therapy. The pituitary stalk of one patient increased from 3.9 mm to 4.0 mm after 6 months. Others did not have any significant change and are still under follow-up.
We analyzed the clinical, biochemical, neuroradiological, and hormonal results from pediatric patients with CDI.
Polyuria and polydipsia are the most common manifestations of CDI. However, some patients were seen by the doctor because of slow growth. In addition, polyuria and polydipsia can be masked by ACTH deficiency [
In the present study, the mean age at diagnosis was
Polydipsia and polyuria exceeding 5 mL/kg/hour with urine specific gravity less than 1.01, plasma sodium level above 145 mmol/L, and dehydration are the hallmarks of diabetes insipidus in infants and children [
As a type of diabetes insipidus, it is important to differentiate CDI from nephrogenic diabetes insipidus and primary polydipsia, because inappropriate treatment can result in severe complications. Direct measurement of serum AVP is recommended for diagnosis [
The water deprivation test and DDAVP trial still are the gold standard for diagnosis/differential diagnosis of CDI. But the interpretation is more and more challenging. For example, we confirmed 42 complete CDI and 1 partial CDI using the protocol in our study, but this would have been 39 and 4, respectively, if we defined complete CDI as a ratio of urinary osmolality to plasma osmolality of ≤1.0 and partial CDI as >1.0 [
MRI is recommended as soon as CDI is diagnosed. One common finding in MRI is the absence of a physiological posterior bright spot (PBS) on sagittal T1-weighted imaging. Some earlier reports showed that absence of a PBS is not specific for CDI diagnosis, because individual CDI cases with persistent PBS have been reported [
A thickened pituitary stalk, isolated or with a mass, is another common finding on MRI, in 50–60% of the children. LCH, germinoma, and craniopharyngioma are the most common causes of thickened pituitary stalk, but neither the pattern nor the thickness of the pituitary stalk correlated with clinical features. Radiological features of craniopharyngioma are typical and easy to differentiate from LCH and germinoma [
A biopsy of the pituitary stalk can provide a definitive diagnosis. However, physicians in China are conservative on biopsy, due to the risk of surgery and because of the parents. In our study, 2 of the 5 germinoma patients were diagnosed through elevated plasma
Features of CDI patients.
Patient | Cause of CDI | Age, y |
Gender | PSD | AP, mm |
Signs and symptoms | PHD | |
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1 | Germinoma | 9.2 | F | 17 | I | Polyuria, polydipsia, short stature, and anorexia | Trial diagnostic radiation | GH + TSH |
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2 | Germinoma | 2.7 | F | 6.5 | <N | Polyuria, polydipsia, and short stature | Trial diagnostic chemotherapy | GH + TSH |
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3 | Germinoma | 4.9 | F | 6.7 | <N | Polyuria, polydipsia, short stature, and vomit | Plasma |
GH + TSH + ACTH, PRL |
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4 | Germinoma | 7.6 | F | 5.5 | <N | Polyuria, polydipsia, short stature, and anorexia | Plasma |
GH + TSH |
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5 | Germinoma | 9 | M | 6.7 | I | Short stature, polyuria, and polydipsia | Trial diagnostic radiation | GH |
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6 | Craniopharyngioma | 11.5 | F | I | I | Short stature and headache | Histological examination after surgery | GH + TSH + ACTH + GnRH |
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7 | Craniopharyngioma | 7.9 | M | I | I | Short stature and headache | Histological examination after surgery | GH + TSH + ACTH + GnRH, PRL |
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8 | Craniopharyngioma | 3 | M | I | I | Short stature, polyuria, and polydipsia | Histological examination after surgery | GH + TSH |
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9 | Craniopharyngioma | 5.9 | M | I | I | Short stature, polyuria, polydipsia, and headache | Histological examination after surgery | GH + TSH |
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10 | LCH | 10.6 | F | 5.5 | <N | Polyuria and polydipsia | Trial diagnostic chemotherapy | No |
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11 | LCH | 3.5 | F | 3.9 | N | Polyuria, polydipsia, short stature, and rash | Skin biopsy | GH |
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12–27 | Idiopathic | <4.5 |
<N |
GH |
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To 6.5 |
<N |
GH |
AP: anterior pituitary; GH: growth hormone; I: invisible; N: normal; PHD: pituitary hormone deficiency; PSD: pituitary stalk diameter.
The height of the pituitary gland on MRI can be normal, low, or high. Maghnie et al. [
Dysfunction of the anterior pituitary can be determined at diagnosis and during the follow-up period of CDI. In the present study, 53.5% of the patients had anterior pituitary hormone deficiency when CDI was diagnosed, which was lower than the 80% reported by Liu et al. [
In our study here, the probability of developing MPHD was associated with thickness of the pituitary stalk. In addition, our study found higher prevalence of MPHD in cases with intracranial tumor compared with LCH. Marchand et al. [
The natural history of CDI in terms of etiology is hard to determine. Clinical, radiological, and endocrinological investigations must be performed at diagnosis and follow-up. During follow-ups that ranged from 4.1 to 14.3 years of 43 idiopathic CDI patients (mean age: 7.4 y), 3 patients had LCH and one patient developed Hodgkin’s lymphoma 8.5 to 10 years after CDI onset [
In this study, we have demonstrated the limitations in the diagnosis and follow-up of childhood CDI in China. These limitations are important to note, and the attention of parents and physicians given to the associated symptoms, signs, and diagnostic tests should be improved to prevent delay in diagnosis. As soon as there is a diagnosis of CDI, regular and long-term clinical follow-ups are required that include imaging and tests for tumor markers and pituitary function.
The authors declare that they have no competing interests.