Severe Achondroplasia with Developmental Delay and Acanthosis Nigricans Syndrome

Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN) is an extremely uncommon genetic disorder that is characterized by abnormalities in the skeleton, brain, and skin. Those who suffer from the disorder frequently have shorter limbs and legs and are typically extremely short in stature. In addition to having a smaller thorax and shorter rib bones, and apnea, these individuals also have curved collarbones (Tavormina et al. 1999). SADDAN shares many characteristics with other skeletal disorders, particularly achondroplasia and thanatophoric dysplasia (Kumar et al. 2011). Achondroplasia is a form of dwarfism with slender limbs. This form of dwarfism is caused by the inability of the skeleton’s cartilage to ossify and transform into bone (Legare 1993). Acanthosis nigricans is a velvety skin discoloration that typically affects intertriginous regions. This hyperpigmentation has ill-defined borders, typically appears in skin fold regions like the back of the neck, axilla, and groin, and may also be associated with skin thickening. Acanthosis nigricans is most frequently linked to diabetes and insulin resistance, but it can occasionally indicate an internal malignancy. Those who have SADDAN frequently experience early onset of acanthosis nigricans in infancy or early childhood. Approximately 10% of those with achondroplasia have acanthosis nigricans (AN) (González-Saldivar et al. 2018; Smid et al. 2018).The disease was first identified in 1999, when a novel fibroblast growth factor receptor 3 (FGFR3) missense mutation causing Lys650Met substitution in the kinase domain of FGFR3 on chromosome (4p16.3) was found in four unrelated individuals with skeletal dysplasia. Three of the four individuals developed extensive areas of acanthosis nigricans beginning in infancy, suffered from severe neurological impairments, and survived past infancy without the use of protracted life-support measures. The phenotype caused by the Lys650Met mutation is referred to as “severe achondroplasia with developmental delay and acanthosis nigricans” (SADDAN), because it differs markedly from the phenotypes of other known FGFR3 mutations (Bellus et al. 1999).