Letter to the Editor: “Forty-One Individuals With Mutations in the AVP-NPII Gene Associated With Familial Neurohypophyseal Diabetes Insipidus.”

Dear Editor,

We welcome with great interest the paper by García-Castaño et al, reporting Autosomal dominant Neurohypophyseal Diabetes Insipidus (adNDI) in 15 families from Spain (1). We would like to highlight some key points for readers mainly related to the fact that, despite the wide range of mutations reported, patients with aFNDI have remarkably similar but also very different presentations.

adNDI is a rare cause of central diabetes insipidus (CDI) and in our previous study of 79 patients, 6% were found to be familial (2). We recently reported the clinical, neuroimaging and molecular analyzes of 22 members of 13 Italian families carrying vasopressin-neurophysin-II (AVP-NPII) gene mutations, including 8 mutations reported by others and 2 new missense mutations in Exon 2, p.Cys58Ser and p.Ala72Glu (3); one is a single heterozygous missense mutation with a variation of G-C transversion in nucleotide position 173 (c.173 G>C) and replacement of cysteine with serine and the second determines a variation from C-A-A in nucleotide position 215 (c.215 C>A). Furthermore, in our study published in 2015 (4), one patient showed a deletion from the nucleotide position 52 to 54 (c.52_54delTCC) which produced the deletion of a serine residue in position 18 (p. Ser18del) of the AVP preprohormone signal peptide (4).

The discovery of p.Ser18del was first reported by our group before the cases published by Tian D et al (5) and Toustrup et al (6). Moreover, unlike the patients with p. Ser18del reported by Toustrup et al (6). and García-Castaño who were diagnosed with partial CDI at the age of 5 and 6 (1), polyuria and polydipsia started at the age of 8 months in our patient, who showed severe dehydration and failure to thrive with a serum osmolality of 405 mOsm/kg after 4 hours of dehydration test; the hyperintensity of the small posterior pituitary gland was documented by magnetic resonance imaging and the molecular diagnosis was established at 48 months. This confirms that this variant may result in an early-onset phenotype, although age of onset was reported late in carriers with mutations in the signal peptide and in infants in those with mutations in the AVP carrier neurophysin II (7). Finally, the p.Ala19Val mutation, involved in the abnormal processing of the prehormone, described by García-Castaño in a girl with the onset of polyuria at the age of 6 (1), was identified by our group in a girl at the age of 2 years and in her father at the age of 1 year (3).

The p.Gly54Arg missense mutation, reported by Garcia in 2 probands diagnosed respectively at the age of 9 months and 43 years (1), was detected by our group in 2 siblings with onset of the disease at the age of 17 months and 19 months, respectively (3), while all our patients carrying p. Ala19Thr mutations showed a late onset of the disease, similar to those reported by García-Castaño (1) and literature (8). The recurrent AVP-NPII mutation causing aFNDI is associated with several published times of disease-onset, suggesting the lack of a clear genotype-phenotype relationship. This could be explained on the one hand, by the fact that the condition occurs with high if not complete penetrance, and on the other because the time interval described between the onset of symptoms and the time of diagnosis is extremely variable between reports.

Additional Information

Disclosure Summary: The authors report no competing interests.

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