Trichorhinophalangeal Syndrome Type I: A Patient with Two Novel and Different Mutations in the TRPS1 Gene

Background. Trichorhinophalangeal syndrome (TRPS) is an autosomal dominant skeletal dysplasia caused by defects involving the TRPS1 gene. Three types (TRPSs I, II, and III) have been described, exhibiting the common triad of hair, craniofacial, and skeletal abnormalities. TRPS II includes the additional characteristics of mental retardation and multiple exostoses. Case Report. We describe a sporadic case of TRPS type I in a child with two novel nonsense pathogenic mutations in the TRPS1 gene, both in heterozygosity—c.1198C>T (p. Gln400X) and c.2086C>T (p.Arg696X). None of these mutations were found in her parents. Clinical presentation included typical hair and facial features, as well as slight skeletal abnormalities. Discussion. There is a wide variability in clinical expression of TRPS I. Manifestations of the disease can be subtle, yet skeletal anomalies imply that TRPS I is more than an esthetic problem. Clinical and genetic diagnosis allows adequate followup and timely therapeutic procedures. When a single mutation was sufficient for the onset of the disease, our patient presented two different ones. 1. Introduction Trichorhinophalangeal syndrome (TRPS) is a rare skeletal dysplasia of autosomal dominant inheritance, caused by a defect in the TRPS1 gene. This gene, located on chromosome 8 (8q24.1) [1], encodes a transcriptional repressor involved in hair development and chondrocyte modulation [2]. Key clinical features of the syndrome include fine, slowly growing hair, a high frontal hairline, and rarefaction of the lateral eyebrows; craniofacial peculiarities with a typical pear-shaped nose, long and flat philtrum, thin upper lip, receding chin, and protruding ears; phalangeal cone-shaped epiphyses—resulting in brachydactyly or clinodactyly—and other orthopedic abnormalities, such as hip malformation and short stature [3–6]. Three types of trichorhinophalangeal syndrome have been described: TRPS I (Online Mendelian Inheritance in Man [OMIM] 190350), TRPS II (OMIM 150230), and TRPS III (OMIM 190351) [7, 8]. TRPS I, first described by Giedion, in 1966 [3], may be caused by several deletions or mutations in the TRPS1 gene [4, 7]. TRPS II, or Langer-Giedion syndrome, is a contiguous gene syndrome due to loss of functional copies of both the TRPS1 and EXT1 genes. It differs from TRPS I by the presence of mental retardation and multiple cartilaginous exostoses, in addition to the TRPS phenotype [9]. TRPS III has similar clinical features to TRPS I but presents with severe brachydactyly (due to short metacarpals) and growth retardation [4]. So far, a few