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.