III. Discussion
Central diabetes insipidus (CDI) is a complex disorder characterized by excretion a large volume of dilute urine due to the defective production, transport, or secretion of arginine-vasopressin (AVP). This condition is mainly caused by hypothalamus dysfunction. polyuria, defined as urine volume > 2 L/m2/24h ⁓150 mL/kg/24h at birth, 100-110 mL/kg/24h up to 2 years of age, and 40-50 mL/kg/24h in older children and adult (6), occurs when more than 80-90% of AVP-secretory neurons foundaliy in supraoptic and paraventricular nuclei are damaged (7).
Congenital CDI is observed mainly in a neonate with brain malformations including inclusive of optic nerve hypoplasia, septo-optic dysplasia, HPE, and absence of the internal carotid. Moreover, CDI has been found in children and adolescents in the presence of inflammatory/autoimmune conditions, Langerhans histiocytosis (LCH), intracranial germ cell tumors, infectious, vascular disease, trauma, and sellar surgery as acquired etiologies (8).
HPE spectrum disorders, resulting from failed forebrain deviation observed in cases with midline brain malformation include corpus callosum agenesis, absent septum pellucidum, absent olfactory bulbs and tracts, and vermain hypoplasia. Associated findings with HPE include craniofacial dimorphism, neurologic issue, feeding problems, and endocrinopathies (9). It is etiologically heterogeneous and may be caused by maternal ingestion of massive doses of salicylate, maternal diabetes, poverty, and parental exposure to cytomegalovirus (8). Midline facial anomalies are typically related to the severity of the brain malformation (10). Olsen et al described eye malformation in 76.8% of patients, nose malformation in 69.5%, ear malformations in 50%, and oral cleft in 41.5%. These malformations arise at different stages during gestations (11).
A study on 68 patients with HPE showed 33 of 68 (49%) patients had at least one seizure, without a direct relationship with seizure prevalence and severity of HPE. In addition, 49 (72%) patients had at least a sodium balance problem in the form of DI (12). On the other hand, medical reports of 117 children with HPE by Hahn et al shows seizure are often present (13). Neurologic examination on a case of HPE revealed microcephaly with spastic quadriplegia (14).
In our case study early heart evaluation by echocardiography, revealed some structural defects as patent foramen oval (PFO) and patent ductus arteriosus (PDA). Comorbidity of HPE and congenital heart disease (CHD) in an individual with genetic variants in known HPE-related genes has been recently observed. Cardiac assessment in 434 individuals with HPE, showed 8% (n=33) identified CHD. 4 of 33 cases (12%) included PFO and two of these four cases of PFO had the finding of PDA.(15). more than any other birth anomalies, CHD is in communication with numerous genetic conditions. PDA in association with ventricular septal defects (VSD) and aortic coarctation, reported the most common cardiac anomalies in a case of Edward syndrome with central diabetes insipidus (16).
In our case study, polyuria provided an important clue for the diagnosis. In most cases of CDI, primary symptoms are persistence polyuria and polydipsia, young children may have severe dehydration, vomiting, constipation, fever, irritability, sleep disturbance, nocturia, failure to thrive, and growth retardation. Another prominent sign in our case was seizures, which may be caused due to hypernatremia or HPE-related (6). Investigation of CDI can be straightforward but underestimated polyuria by parents and poor accuracy of the biochemical test can lead to delayed diagnosis and incorrect management. when polyuria is confirmed, urinary osmolality measurement would be the second step. A random urine osmolality >700-900 milliosm/kg indicates the appropriate renal response to endogenous vasopressin, thereafter, in whom urine osmolality of <700-800 milliosm /kg, serum sodium (>143 mmol/kg) and plasma osmolality measurement could be suggestive of DI. The next investigation in water drinker patients with normal or low serum sodium is the water deprivation test and desmopressin (DDAVP) challenge. The administration of 5-10 µg of desmopressin intranasal will help differentiate CDI from NDI. A case report in 2018 shows intravenous vasopressin as a safe way to diagnosing neonatal CDI.3 for the first time.(17) Recently, Copeptin, the c-terminal segment of AVP precursor peptide, become available as an attractive new surrogate marker for diagnosis of DI (18). As germinoma is a tumor-inducing CDI, germ cell tumor markers can be useful for the early diagnosis of CDI (19). In addition, early signs of polyuria (heavy diaper) and refractory hypernatremia, in our study, DI diagnosis was based on high serum sodium level and low urine specific gravity and CDI confirmed by the effect of dDAVP on decreasing serum sodium levels.
It is important to note that the index patient progressed to hyponatremia soon after initiation of desmopressin. After discontinuation of desmopressin and adjustment of serum therapy, she no longer experienced remarkable changes in serum sodium level. This sudden progression to hyponatremia after administration of desmopressin may be explained by resetting of the osmostat. This condition is due to chronic effect of volume expansion on ADH release, as a result of which, a higher osmolality is recognized as normal (20, 21).
Primary imaging study due to persistent seizures made our differential diagnoses narrower, with CDI related to HPE. Magnetic resonance imaging (MRI) is a crucial neuroimaging for CDI and is a primary method for evaluating the sellar/suprasellar region with high contrast resolution and lack of invasiveness in pediatric patients with CDI. We can use computed tomography (CT) for providing complementary information when a detailed assessment of bone involvement is required (22).
The cardinal treatment approach for CDI is free access to water associated with a pharmacologic agent, Desmopressin. Desmopressin (dDAVP) is a synthetic AVP analog, administered orally, intranasally, or parenterally (23). Daily dosages for oral preparations (20-fold less potent than the intranasal form) vary from 100 to 1200 g in three doses, for the intranasal preparations, approximately 2.5-40 g (once or twice a day) and for parenteral use, a low dose should be used initially and increased as necessary. The intranasal formulation remains of benefit in patients that need an individualized administration of the dose (23, 24).
The management of CDI in infancy is very challenging because of different individual responses and limited treatment options (25). furthermore, ML Moritz and JC Ayus demonstrate that hypernatremia is in combination with a 15% mortality rate in children, which is estimated 15 times higher than the age-matched mortality in hospitalized children without hypernatremia (26). In a study on 4 cases of CDI (one of them was HPE), several episodes of hyponatremia (serum sodium<130 mmol/L) and hypernatremia (serum sodium>150 mmoL/L) were reported. Their results pointed that a combination of hydrochlorothiazide (HCTZ) with low solute feed resulted in less alteration in serum sodium than desmopressin (25, 27). the mechanism of HCTZ is not exactly known, several hypotheses suggest that after increased renal sodium excretion, extracellular volume contraction leads to decreased GFR and increased tubular sodium and water reabsorptions. In addition, renal solute load, point to all solutes of exogenous or dietary origin that require excretion by the kidney, help to decrease urine output (25). Limited researches report other treatment options in CDI with different mechanisms, like Carbamazepine , Chlorpropamide and Indapamide (28).
Danielle C.M et al demonstrated the challenges in a case of CDI; as they started intranasal desmopressin (0.2 ug/kg), oliguria several hours of anuria and a 25-point drop in sodium level within 15 hrs was ensued. Rapid reduction of hypernatremia can cause significant mortality and morbidity. This study recommends using low dose of intranasal desmopressin (0.05-0.1 ug/kg) if oral desmopressin is not well tolerated and also emphasizes the importance of dose titrations based on clinical and biochemical response (29). In our study, a persistent seizure occurred prior to CDI diagnosis. However, tonic-clonic movement and other neurological sequala were related to hypernatremia. It makes sense that electrolyte evaluation based on physical examinations (cleft lip and palate with polyuria) can help us to apply the best management.