ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: Eur J Pediatr 2017; 176:873-879

Achondroplasia (ACH) is the most common genetic form of disproportionate short stature, occurring in 1:15,000 –1:40,000 live births [28]. Most patients have a gain of function mutation in the transmembrane domain of the fibroblast growth factor receptor 3 (FGFR3), leading to prolonged intracellular MAPK signaling. FGFR3 works as a negative regulator of bone development. FGFR3 over-activation alters the terminal chondrocyte differentiation into hypertrophic chondrocytes, shortening the proliferation phase. ACH involves long bones, vertebrae and base of skull, resulting in short-limbed severe short stature, relative macrocephaly with prominent forehead, midface hypoplasia, lumbar lordosis, trident configuration of hands and hydrocephalus, secondary to foramen magnum narrowing. ACH patients have severe growth retardation and experience decreased pubertal growth spurt, ultimately leading to extremely short adult height which on average is 130 (118–145) cm in males and 120 (112–136) cm in females.

Currently, few therapeutic options are available and effective treatment is still lacking. Limb lengthening remains the most effective measure to increase final height in ACH patients. However, this surgical procedure is associated with many co-morbidities, including stiffness of the Achilles tendon, recurrent fractures, asymmetry of the legs, focal bacterial infection, and pain. A recent paper reported that the overall height increase obtained with limb lengthening ranges from 6 to 12 cm [29]. Several trials have evaluated the effect of GH treatment in ACH children, and a recent meta-analysis reported a change in mean height SDS from -5.0 to -4.0 during 5-years GH treatment [28]. However, the data are limited by small sample sizes, poor study design, and lack of intention-to-treat analyses.

Here, Harada et al. report a retrospective study showing that the increase in adult height attributable to GH therapy was on average 3.5 cm in males and 2.8 cm in females, slightly improving the effect obtained by limb lengthening alone. The wide individual variability in the response to therapy suggests that other factors such as genetic background, dose, age at start, adherence and duration of treatment may influence the long-term response. Unfortunately, study limitations such as the retrospective design, the small number of patients and the heterogeneous treatment regimens make this study inconclusive. Although ACH is an approved indication for GH therapy in Japan, there is no robust evidence that this treatment is worthwhile. As the pathogenesis of ACH is related to defects in enchondral ossification due to FGFR3 gain of function mutations, future targeted treatments might rely on the use of inhibitors of receptor signaling, antibody blockade of receptor activation, and negative interference with FGFR3 downstream pathways [30].

28. Miccoli M, Bertelloni S, Massart F. Height Outcome of Recombinant Human Growth Hormone Treatment in Achondroplasia Children: A Meta-Analysis. Horm Res Paediatr. 2016;86:27-34.

29. Kim SJ, Pierce W, Sabharwal S. The etiology of short stature affects the clinical outcome of lower limb lengthening using external fixation. A systematic review of 18 trials involving 547 patients. Acta Orthop. 2014;85:181-6.

30. Legeai-Mallet L. C-Type Natriuretic Peptide Analog as Therapy for Achondroplasia. Endocr Dev. 2016;30:98-105.