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Scientific letter
Familial central diabetes insipidus
Diabetes insípida central familiar
M. Pilar Bahíllo-Curiesesa,
Corresponding author
pilarbahilloc@yahoo.es

Corresponding author.
, Marta Palomares-Cardadora, Alejandro García-Castañob,c,d
a Servicio de Pediatría, Endocrinología Pediátrica, Hospital Clínico Universitario, Valladolid, Spain
b Biocruces Bizkaia Research Institute, Barakaldo, Bizkaia, Spain
c Enfermedades raras Centro de Investigación Biomédica en Red (CIBERER), Spain
d Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain
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Urine output of 3&#46;5<span class="elsevierStyleHsp" style=""></span>ml&#47;kg&#47;h&#44; without nocturia&#46; No remarkable personal history except for primary nocturnal enuresis&#44; overweight&#44; and attention deficit hyperactivity disorder &#40;ADHD&#41; under treatment with methylphenidate&#46; Her father also suffers from polyuria-polydipsia&#44; with a reported daily fluid intake of 8<span class="elsevierStyleHsp" style=""></span>L&#44; which have not been studied due to his own refusal to undergo testing&#46; Her paternal grandfather was diagnosed with CDI &#40;normal cranial magnetic resonance imaging &#91;MRI&#93; findings&#41; and type 2 diabetes treated with insulin therapy at another center&#46; Normal physical examination&#46; Weight&#58; 31&#46;4<span class="elsevierStyleHsp" style=""></span>kg&#46; Height&#58;<span class="elsevierStyleHsp" style=""></span>122&#46;2<span class="elsevierStyleHsp" style=""></span>cm &#40;&#43;0&#46;73 standard deviation &#91;SD&#93;&#41;&#46; Body mass index &#40;BMI&#41;&#58; 21&#46;03<span class="elsevierStyleHsp" style=""></span>kg&#47;m<span class="elsevierStyleSup">2</span> &#40;&#43;1&#46;83<span class="elsevierStyleHsp" style=""></span>SD&#41;&#46; Tanner&#58; <span class="elsevierStyleSmallCaps">I</span>&#46; Plasma osmolarity&#58; 270&#46;7<span class="elsevierStyleHsp" style=""></span>mOsm&#47;kg&#46; Plasma sodium&#58; 141&#46;2<span class="elsevierStyleHsp" style=""></span>mEq&#47;L&#46; The remaining blood biochemistry and blood count parameters were normal&#46; Systematic urine analysis&#58; pH 6&#44; density 1007&#44; and no other positive findings&#46; 24<span class="elsevierStyleHsp" style=""></span>h urine test&#58; urine output 2600<span class="elsevierStyleHsp" style=""></span>ml &#40;1517<span class="elsevierStyleHsp" style=""></span>ml&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#47;day&#41;&#46; Osmolarity&#58; 209<span class="elsevierStyleHsp" style=""></span>mOsm&#47;kg&#46; Fractional excretion of sodium &#40;FE<span class="elsevierStyleInf">Na</span>&#41;&#58; 0&#46;6&#37;&#46; Fractional excretion of potassium &#40;FE<span class="elsevierStyleInf">K</span>&#41;&#58; 6&#37;&#46; Fractional excretion of chloride &#40;FE<span class="elsevierStyleInf">Cl</span>&#41;&#58; 0&#46;6&#37;&#46; Tubular reabsorption of phosphate &#40;TRP&#41;&#58; 89&#46;42&#37;&#46; Calciuria&#58;<span class="elsevierStyleHsp" style=""></span>2&#46;1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day&#46; Ca&#47;creatinine ratio&#58; 0&#46;13&#46; Negative protein&#47;creatinine ratio&#46; Given the suspected diagnosis of DI&#44; a fluid deprivation test was performed twice with normal results&#46; Because her symptomatology had worsened at the 8-year 9-month follow-up&#44; the fluid deprivation test was repeated once again&#44; obtaining an inconclusive result &#40;partial CDI vs&#46; long-standing polydipsia&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; A cranial MRI was also performed&#44; showing a normal pituitary gland in terms of size&#44; morphology&#44; and behavior following the administration of contrast medium&#44; although with a small&#44; non-compressive cyst in the pineal gland &#40;8<span class="elsevierStyleHsp" style=""></span>mm&#41; as a casual finding&#46; Ophthalmological study with normal findings&#46; Given her family history of polyuria-polydipsia and her persistent symptomatology&#44; a genetic study was requested for both her parents and herself&#44; observing a c&#46;55G&#62;A&#59;p&#46;Ala19Thr mutation in exon 1 &#40;father and daughter&#41; in the <span class="elsevierStyleItalic">AVP-NPII</span> gene&#46; After confirming the diagnosis of familial CDI&#44; treatment with desmopressin was started at a dose of 1&#46;4<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;kg&#47;day&#44; achieving an immediate improvement in the patient&#39;s symptomatology in the form of decreased polyuria and polydipsia throughout the day and night&#44; with a daily fluid intake of 2100<span class="elsevierStyleHsp" style=""></span>ml and a urine output of 1900<span class="elsevierStyleHsp" style=""></span>ml &#40;1&#46;7<span class="elsevierStyleHsp" style=""></span>ml&#47;kg&#47;day&#41;&#46; The most relevant changes at an analytical level after 8 months of treatment were a plasma osmolarity of 272&#46;47<span class="elsevierStyleHsp" style=""></span>mOsm&#47;kg and plasma sodium levels of 141&#46;14<span class="elsevierStyleHsp" style=""></span>mEq&#47;L&#46; The systematic urine analysis revealed a pH of 5&#44; a urine density of 1020&#44; and a urinary osmolarity of 819<span class="elsevierStyleHsp" style=""></span>mOsm&#47;kg &#40;after taking her morning dose of desmopressin&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">This case demonstrates the usefulness of genetic testing for the diagnosis of this condition in children with a suspected familial CDI&#46; Because there is no clear genotype-phenotype relationship in this condition&#44; there is significant intra-familial variability in the age of onset of the symptoms &#40;usually between one and six years&#41; and their severity&#44; and&#44; thus&#44; it seems that other genetic and&#47;or environmental factors may be involved&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">1&#44;2</span></a> Although the fluid deprivation test is useful for screening this disease&#44; its normality does not allow for ruling it out in patients with significant suspicion for this disease due to its gradual and progressive onset initially manifesting as partial DI&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">1&#44;3</span></a> Similarly&#44; some studies indicate that the absence of hyperintensity in a cranial MRI in cases of familial CDI is closely related to the lack of functional activity at the level of the posterior pituitary lobe and that this finding supports the diagnosis&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">4</span></a> In our case&#44; and in view of the father&#39;s refusal to undergo the fluid deprivation test&#44; we directly proceeded to carry out genetic testing&#46; The mutation found in both the index case and the progenitor &#40;c&#46;55G&#62;A&#59;p&#46;Ala19Thr in exon 1 of the <span class="elsevierStyleItalic">AVP-NPII</span> gene&#41; has already been described as pathogenic in the literature&#44; although there are few references available in this respect&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">5</span></a> The diagnostic certainty provided by the genetic test is crucial to start treatment early and offer genetic counseling to family members&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">1&#44;2</span></a></p></span>"
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">2nd&#58; 7 years</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="4" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">3rd&#58; 8 years and 8 months</th></tr><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">pOsm mOsm&#47;kg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Pl Na&#43; mEq&#47;l&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">uOsm mOsm&#47;kg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">UD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">pOsm mOsm&#47;kg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Pl Na&#43; mEq&#47;l&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">uOsm mOsm&#47;kg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">UD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">pOsm mOsm&#47;kg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Pl Na&#43; mEq&#47;l&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">uOsm mOsm&#47;kg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">UD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Basal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">275&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">142&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">410&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1005&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">267&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">137&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">116&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1005&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">275&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">142&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">140&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1005&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">234&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">225&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1006&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">614&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">318&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">140&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">1009&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">7<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
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