Balkan Journal of Medical Genetics

X-LINKED RECESSIVE FORM OF NEPHROGENIC DIABETES INSIPIDUS IN A 7-YEAR-OLD BOY
Janchevska A1,*, Tasic V1, Gucev Z1, Krstevska-Konstantinova M1, Cheong HI2,3,4
*Corresponding Author: Dr. Aleksandra Janchevska, Department of endocrinology and genetics, University Children’s Hospital Skopje, Medical Faculty, 1000 Skopje, Republic of Macedonia. Tel: +389-2-3147-474. Fax: +389-2-3129-027. E-mail: dr.sasha1969@yahoo.com
page: 81

DISCUSSION

Males of various age groups are affected with type 1 NDI [5,6]. In a study of 30 Dutch patients with NDI, 87.0% were diagnosed during the first 2.5 years of life [7]. Severity of the disorder differs from mild form with polyuria and polydipsia to severe dehydration crisis with anorexia, failure to thrive, fever and constipation. Females are usually healthy or asymptomatic carriers [7]. Recently, Hong et al. [8] reported one girl among 24 boys in a cohort of 25 children with NDI. It was explained that she was analyzed separately and inactivation and mosaicism of the X chromosome may influence clinical manifestations in female patients [8]. Our boy had a few episodes of mild dehydration during the first 3 years of life, but after that, he was well hydrated despite large amounts of excreted dilute urine. Most of the patients with NDI grow up below the 50th percentile at the growth curve, but gained weight after years of life with low body weight. The index patient had an appropriate weight (+0.85 SDS) at 75th percentile, and height (+0.15 SDS) at 50th percentile at the age of 7 years. Although the children with X-linked NDI were expected to be mentally retarded as a result of dehydration in early childhood, the majority have normal intelligence. Our patient also has normal intelligence. Children with NDI usually do not have urinary tract anomalies or infections. Van Lieburg et al. [7] reported two patients with severe hydronephrosis and small rupture of the urinary tract due to minor trauma and an additional two patients had episodes of acute urine retention. Urinary tract malformation or infection was not detected in our patient. The gene that encodes V2 receptors was mapped at chromosome Xq28 by Seibold et al. [9]. It spans 2.2 kB and contains three exons and two small introns (MIM 300538). The majority of mutations disable the receptor reaching the plasma membrane, but rarely, the receptor cannot bond with the vasopressin or may cause stop trig-gering the cAMP signal [10,11]. The AVPR2 gene mutations associated with Xlinked NDI was first detected by van den Ouweland et al. [12] in 1992. Thereafter, many mutational reports followed [13-17], and at the moment, a total of 254 different mutations in the AVPR2 gene are listed in an online database site, HGMG® Professional 2014.1 (http://www/hgmd.cf.ac/il/ ac/search.php), including 134 missense mutations, 21 non-sense mutations, 49 small deletions, 22 large deletions, 15 small insertions, five small indels, four complex rear-rangements and one large insertion/duplication. Molecular analyses of our patient showed two non synonymous (missense) variants. The first is a hemizygous c.317G>A variant in exon 2 of AVPR2 [p.Arg(CGT) 106His(CAT)], and the second is also a hemizygous c.857C>T variant in exon 2 of AVPR2 [p.Pro(CCC) 286Leu(CTC)]. Both variants have segregation in the family. They were inherited from his mother. She is an asymptomatic carrier. A hemizygous c.317G>A mutation (p.R106H) is not listed in the latest version of HGMG® Professional. However, a different mutation at this residue (R106C) was reported by Bichet et al. [14] in 1994. The second hemizygous c.857C>T mutation (p.P286L) was reported by Bichet et al. [10] in 1998. The in silico analyses showed abnormal scores only for the p.P286L mutation. Also, only the p.P286L mutation is known to have an evolutionary conserved residue. Although we could not perform functional studies, we indirectly confirmed that a non synonymous p.P286L mutation is pathogenic for our patient and resulted in NDI. Knowing the receptor action caused by an identified mutation in the AVPR2 gene or carrier, may help physicians to provide adequate care and treatment to patients with NDI [10,16,18,19]. The aim of treatment of NDI patients is to ensure proper fluid balance and to avoid mental retardation due to severe dehydration, especially in the neonatal period and early infancy. This would be achieved with high volumes of fluids and low salt food followed by hydrochlorothiazide or amiloride treatment. Indomethacin may also be useful [20-22]. In addition, a novel therapeutic approach of rescuing mutant AVPR2 using chemical or pharmaceutical chaperones has been studied [23-29].

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