ESPE Abstracts

Background: Mutations in the gene encoding the natriuretic peptide receptor-2 gene (NPR2) are responsible for monogenic growth disorders. Loss-of-function variants cause extreme short stature and skeletal dysplasia. Gain-of-function mutations cause tall stature with - in some cases - macrodactyly of the great toes, a Marfanoid habitus, arachnodactyly and scoliosis. We describe a novel gain-of-function mutation in exon 8 of NPR2 in a family with tall stature and macrodactyly of the great toes.

Methods: History, clinical characteristics and investigations were collected from 3 patients, a mother and her two daughters. Fibroblasts from the mother, the previously described activating NPR2 mutation patient with tall stature and a healthy volunteer with normal stature were obtained.

Results: Mother's height is 188.1 cm (+2.77 SD). She underwent epiphysiodesis to her great toes twice. At age 14 years she started treatment for 2 years with supraphysiological doses of estrogens in an attempt to reduce adult height. Menarche was at age 15. She has long thumbs with a positive thumb sign, minor ankle valgus, no scoliosis and no joint hypermobility. The eldest daughter is 6 years old. Her height is 132.6 cm (+1.96 SD), weight for height is -1.81 SD and sitting height to height ratio is -0.50 SD. She is known with pes planovalgus. She underwent epiphysiodesis of both great toes when she was 5 years old. The youngest daughter is 4 years old. Her height is 110.2 cm (+1.30 SD), weight for height is -1.42 SD and sitting height to height ratio is -0.66 SD. She has a history of minor gross motor developmental and speech delay. Both girls have markedly long great toes, ankle valgus and long thumbs with a positive thumb sign. Skeletal surveys showed pseudoepiphyses of the mid- and proximal phalanges of all fingers and both great toes, and mesomelia. Bone age was according to calendar age in both girls. The father of the girls is 178 cm, which results in a target height of 175 cm (+0.68 SD). Sequence analysis identified a novel heterozygous variant c.1444_1449del (p.Met482_Leu483del) in the NPR2 gene of mother and her both daughters.

Conclusion: This case serie adds to the phenotypic spectrum of growth disorders associated with NPR2 mutations, in particular gain-of-function variants. Functional tests of this variant to analyse the in vitro effect on cGMP and protein function are currently performed.