Autosomal recessive familial neurohypophyseal diabetes insipidus: onset in early infancy.
BACKGROUND
Familial neurohypophyseal diabetes insipidus (FNDI), usually an autosomal dominant disorder, is caused by mutations in the arginine vasopressin (AVP)-neurophysin II preprohormone leading to aberrant preprohormone processing and gradual destruction of AVP-secreting cells. Patients typically present between 1 and 6 years of age with polyuria and polydipsia.


OBJECTIVE
Clinical, biochemical, and genetic studies of three new cases of autosomal recessive FNDI presenting in early infancy.


METHODS
Three Palestinian cousins presented with failure to thrive, vomiting, irritability, and fever. The parents were asymptomatic. Patients developed hypernatremia (154-163 mmol/l) and serum hyperosmolality (>320 mOsm/kg), while urine osmolality remained between 73 and 229 mOsm/kg. Plasma AVP levels were low, and the posterior pituitary bright spot was absent on magnetic resonance imaging (MRI). All patients responded to desmopressin.


RESULTS
Patients were homozygous and parents were heterozygous for microsatellite markers flanking the AVP gene. All patients were homozygous for the P26L (proline to leucine) substitution affecting mature AVP. A founder effect with the single original kindred carrying the P26L mutation was confirmed by microsatellite analysis, but patients in that family presented only at 2 years of age. In microsatellite analysis, the new kindred patients were not homozygous and did not share a single allele at the aquaporin 2 and vasopressin receptor-2 genes locuses.


CONCLUSIONS
This is the first description of autosomal recessive FNDI presenting in the neonatal period. The unusual early clinical and radiological (MRI) presentation argues against gradual destruction of AVP-secreting neurons as the pathophysiological mechanism. Factors beside allelism of AVP-related genes must influence the age of FNDI presentation given the founder effect demonstrated for the P26L mutation.
Abu Libdeh
Abdulsalam
A
Division of Pediatric Endocrinology, Department of Pediatrics, Hadassah Hebrew University Medical Center, PO Box 24035, 91240 Jerusalem, Israel.
Levy-Khademi
Floris
F
Abdulhadi-Atwan
Maha
M
Bosin
Emily
E
Korner
Mira
M
White
Perrin C
PC
Zangen
David H
DH
D000293:Adolescent; D017668:Age of Onset; D018912:Arabs / Q000235:genetics*; D001127:Arginine Vasopressin / Q000235:genetics*; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D020790:Diabetes Insipidus, Neurogenic / Q000235:genetics*; D005192:Family Health; D005260:Female; D005808:Genes, Recessive; D008040:Genetic Linkage; D006801:Humans; D006955:Hypernatremia / Q000235:genetics; D007223:Infant; D008297:Male; D018895:Microsatellite Repeats; D020125:Mutation, Missense; D010375:Pedigree
D001127:Arginine Vasopressin