The effect of growth hormone treatment in a child with tricho-rhino-phalangeal syndrome: A case report and review of the literature

Abstract

Tricho-rhino-phalangeal syndrome (TRPS) is characterized by craniofacial and skeletal malformations including short stature, cone-shaped phalangeal epiphyses and Perthes-like changes of the hip. We describe the response to growth hormone (GH) treatment in a boy with TRPS. The patient presented at age 3.5 years for evaluation of short stature (−3.2SD). On physical examination, the characteristic facial phenotype of TRPS was noted. Radiographs showed cone-shaped phalangeal epiphyses and bilateral small and fragmented femoral heads. The diagnosis was confirmed by Sanger sequencing of the TRPS1 gene. Two GH stimulation tests revealed GH deficiency, and GH treatment was initiated. Subsequently, growth velocity improved, as did the radiographic appearance of the femoral epiphyses, as seen on sequential pelvis radiographs.

This observation suggests the possibility of a beneficial effect of GH treatment on both height and epiphyses status in TRPS patient with GH deficiency. Further studies are needed to support the observation.

Introduction

Trichorhinophalangeal syndrome (TRPS) is a rare autosomal dominant malformation syndrome characterized by distinctive craniofacial and skeletal abnormalities (Maas et al., 2015). Craniofacial features include slowly growing scalp hair, laterally sparse eyebrows, bulbous tip of the nose, long flat philtrum, thin upper vermilion border and protruding ears (Maas et al., 2015). Skeletal abnormalities include cone-shaped epiphyses at the phalanges, hip dysplasia and short stature (de Barros and Kakehasi, 2016). Radiological features of the hip of TRPS patients include joint dysplasia, small and fragmented femoral heads resembling but not identical to Legg-Calve-Perthes disease, and reduced joint space. Systemic manifestations may also be present, such as congenital heart defects and renal anomalies, including unilateral and underdeveloped kidneys, vesicoureteral reflux and stenosis of the ureter-bladder junction (Vaccaro et al., 2009).

Two subtypes of TRPS have been described (Maas et al., 2015). Type I is the classical form and is due to a mutation in the TRPS1 gene that maps to 8q24. Type II is a contiguous gene deletion syndrome that involves TRPS1 and EXT1 genes, resulting in the additional finding of multiple cartilaginous exostoses and mild intellectual impairment. Some authors have proposed another subtype, TRPS type III, associated with more marked growth impairment and severe brachydactyly. However, the differences between TRPS type I and III are small and may represent a spectrum of severity (Maas et al., 2015).

TRPS1 is a transcription factor that regulates proliferation and apoptosis of chondrocyte through Stat3 signaling (Suemoto et al., 2007). TRPS1 deficiency has been postulated to impair chondrocyte differentiation in the growth plate and epithelial/mesenchymal cell interactions in developing hair follicles (Nishioka et al., 2008; Itoh et al., 2008). Moreover, patients with this syndrome may have growth hormone (GH) deficiency since this transcription factor has been found to be expressed in the pituitary and hypothalamus (Correa et al., 2018).

Linear growth is decreased in almost all TRPS patients, both prenatally and postnatally; adult height falls below −2 SD in about half the patients (Maas et al., 2015). Table 1 presents GH axis evaluation and the effect of GH treatment in children with TRPS who were described previously. Only children whose TRPS diagnosis was confirmed by DNA analysis were included in the table (Stagi et al., 2008; Sohn et al., 2012; Merjaneh et al., 2014; Marques et al., 2015; Riedl et al., 2004). GH deficiency (defined as low growth hormone concentrations in two stimulation tests) was found in some, but not all patients. The response to treatment was variable (Table 1).

We report a boy with TRPS type I and GH deficiency, and the effect of GH therapy on his linear growth and on the radiographic appearance of the femoral epiphyses.