Rare Diseases Symptoms Automatic Extraction

Suppression of severe achondroplasia with developmental delay and acanthosis nigricans by the p.Thr651Pro mutation.

[achondroplasia]

Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN) is an extremely rare severe skeletal dysplasia characterized by significant developmental delay, brain structural abnormalities, hearing loss, and acanthosis nigricans. The disorder is the result of a single missense mutation at codon 650 (p.Lys650Met) in the fibroblast growth factor receptor 3 gene (FGFR3). We describe a child who initially presented with a mild achondroplasia or hypochondroplasia like phenotype. Molecular analysis of the FGFR3 gene showed the common SADDAN mutation and a second novel mutation at codon 651 (p.Thr651Pro). Both mutations were shown to occur on the same allele (cis) and de novo. Transient transfection studies with FGFR3 double mutant constructs show that the p.Thr651Pro mutation causes a dramatic decrease in constitutive receptor kinase activity than that observed by the p.Lys650Met mutation. Our data suggest that the molecular effect by the p.Thr651Pro is to elicit a conformational change that decreases the FGFR3 tyrosine kinase activity, which is constitutively activated by the SADDAN mutation. Due to the inheritance of both a gain-of-function and a loss-of-function mutation, we conclude that a reduction of constitutive activation caused the milder skeletal phenotype. Although the occurrence of double mutations are expected to be rare, the presence of other FGFR3 modifiers may be responsible for some of the clinically discrepant skeletal dysplasia cases.

Diseases presenting "developmental delay" symptom

  • 22q11.2 deletion syndrome
  • achondroplasia
  • alexander disease
  • alpha-thalassemia
  • aniridia
  • canavan disease
  • child syndrome
  • classical phenylketonuria
  • coats disease
  • cohen syndrome
  • congenital diaphragmatic hernia
  • congenital toxoplasmosis
  • cowden syndrome
  • gm1 gangliosidosis
  • harlequin ichthyosis
  • hirschsprung disease
  • holt-oram syndrome
  • homocystinuria without methylmalonic aciduria
  • kabuki syndrome
  • kallmann syndrome
  • krabbe disease
  • lamellar ichthyosis
  • monosomy 21
  • neonatal adrenoleukodystrophy
  • phenylketonuria
  • primary hyperoxaluria type 1
  • proteus syndrome
  • pyruvate dehydrogenase deficiency
  • sneddon syndrome
  • triple a syndrome
  • wolf-hirschhorn syndrome
  • zellweger syndrome

This symptom has already been validated