Nephrogenic diabetes insipidus in a patient with L1 syndrome: A new report of a contiguous gene deletion syndrome including L1CAM and AVPR2

Abstract

We report on an infant boy with congenital hydrocephalus due to L1 syndrome and polyuria due to diabetes insipidus. We initially believed his excessive urine loss was from central diabetes insipidus and that the cerebral malformation caused a secondary insufficient pituitary vasopressin release. However, he failed to respond to treatment with a vasopressin analogue, which pointed to nephrogenic diabetes insipidus (NDI). L1 syndrome and X-linked NDI are distinct clinical disorders caused by mutations in the L1CAM and AVPR2 genes, respectively, located in adjacent positions in Xq28. In this boy we found a deletion of 61,577 basepairs encompassing the entire L1CAM and AVPR2 genes and extending into intron 7 of the ARHGAP4 gene. To our knowledge this is the first description of a patient with a deletion of these three genes. He is the second patient to be described with L1 syndrome and NDI. During follow-up he manifested complications from the hydrocephalus and NDI including global developmental delay and growth failure with low IGF-1 and hypothyroidism.

A novel contiguous gene deletion of AVPR2 and ARHGAP4 genes in male dizygotic twins with nephrogenic diabetes insipidus and intellectual disability

“…Recently, there have been seven reports of the contiguous deletion of AVPR2 and ARHGAP4 genes in eight unrelated NDI patients [Schoneberg et al, 1999;Demura et al, 2002;Schulz et al, 2002;Broides et al, 2006;Dong et al, 2006;Fujimoto et al, 2008;Knops et al, 2008]. Our patients had significant ID and short stature, which distinguished them from previous reports (Table II and Fig.…”

“…Intellectual disability was described in three patients [Schoneberg et al, 1999;Demura et al, 2002 (case 2); Knops et al, 2008]. Although the ID in one of these patients could be explained by loss of L1CAM [Knops et al, 2008], the ID in other two patients [Schoneberg et al, 1999;Demura et al, 2002 (case 2)] could not be easily explained.…”

“…It is adjacent to the well-characterized gene Arginine Vasopressin Receptor 2 (AVPR2; OMIM# 304800) mutations in which cause X-linked congenital nephrogenic diabetes insipidus (NDI) [Spanakis et al, 2008]. There have been seven previous reports of different patterns of contiguous deletions involving the AVPR2 and ARHGAP4 genes [Schoneberg et al, 1999;Demura et al, 2002;Schulz et al, 2002;Broides et al, 2006;Dong et al, 2006;Fujimoto et al, 2008;Knops et al, 2008]. We report the clinical and genetic characterization of NDI and ID in two male dizygotic twins with a novel contiguous gene deletion of the AVPR2 and ARHGAP4 genes at Xq28 and review the reported deletions encompassing ARHGAP4 to identify the putative clinical signs of ARHGAP4 deletions.…”

An updated and upgradedL1CAMmutation database

“…The database contains only a few large deletions or duplications that involve more than one exon (Tegay et al, 2007;Panayi et al, 2005a;Vits et al, 1994;Van Camp et al, 1993), and only one case of a deletion of the entire L1CAM gene (Knops et al, 2008). In the new L1CAM mutation database, you can screen for mutations per exon or intron and select for reported classification and type (Figure 1).…”

“…To date more than 200 different L1CAM mutations have been published: 130 of these were reviewed in 2001 (Weller and Gartner, 2001) and another 41 were published subsequently (Simonati et al, 2006;Senat et al, 2001;Sztriha et al, 2002;Rodriguez et al, 2003;Silan et al, 2005;Bott et al, 2004;Okamoto et al, 2004;Hubner et al, 2004;Moya et al, 2002;Panayi et al, 2005b;Tegay et al, 2007;Knops et al, 2008;Griseri et al, 2009;Nakakimura et al, 2008;Wilson et al, 2009;Kanemura et al, 2006;De Angelis et al, 2002;Piccione et al, 2009;Wilson et al, 2009). Moreover 52 novel mutations have been detected in our laboratory and were published recently Most mutations have been compiled in the L1CAM Mutation Database, originally constructed by Van Camp et al (Van Camp et al, 1996) and later continued by our group.…”