Two cases of Legg–Perthes and intellectual disability in Tricho–Rhino–Phalangeal syndrome type 1 associated with novel TRPS1 mutations

Abstract

Tricho-Rhino-Phalangeal syndrome is a rare autosomal dominant genetic disorder caused by mutations in the TRPS1 gene. This malformation syndrome is characterized by distinctive craniofacial features including sparse scalp hair, bulbous tip of the nose, long flat philtrum, thin upper vermilion border, and protruding ears. Skeletal abnormalities include cone-shaped epiphyses at the phalanges, hip malformations, and short stature. In this report, we describe two patients with the physical manifestations and genotype of TRPS type I but with learning/intellectual disability not typically described as part of the syndrome. The first patient has a novel heterozygous two-base-pair deletion of nucleotides at 3198-3199 (c.3198-3199delAT) in the TRPS1 gene causing a translational frameshift and subsequent alternate stop codon. The second patient has a 3.08 million base-pair interstitial deletion at 8q23.3 (113,735,487-116,818,578), which includes the TRPS1 gene and CSMD3. Our patients have characteristic craniofacial features, Legg-Perthes syndrome, various skeletal abnormalities including cone shaped epiphyses, anxiety (first patient), and intellectual disability, presenting unusual phenotypes that add to the clinical spectrum of the disease.

Genetics of Legg-Calvé-Perthes Disease: A Review Study

“…The first patient had a novel heterozygous mutation that involved the deletion of two base pairs (c.3198-3199delAT) in the TRPS1 gene, which led to a translational frameshift and premature termination codons. The other patient had a deletion of 3.08 million base-pair at 8q23.3, which contains the TRPS1 gene and CSMD3 [48].…”

Clinical and genetic characteristics of Legg-Calve-Perthes disease

“…These studies raise the possibility of a strong genetic component in the etiology of LCPD. Furthermore, the occurrence of LCPD-like hip changes in a few inherited dysplasias of the skeleton, such as trichorhinophalangeal syndrome [52][53][54] and Floating-Harbor syndrome, [55] also suggests the presence of major genetic defects underlying LCPD. In the succeeding section, genetic factors associated with the pathogenesis of LCPD will be discussed.…”