Spondyloepimetaphyseal dysplasia type Isidor-Toutain (RPL13-SEMD) is an autosomal dominant skeletal dysplasia caused by heterozygous pathogenic variants in the RPL13 gene, encoding the ribosomal protein eL13. To date, 13 pathogenic variants in RPL13 have been reported, all clustering within intron 5 and exon 6, suggesting this hotspot region is critical for the function of ribosomes in skeletal tissues. Here, we present clinical and radiological characteristics of seven individuals, five children and two adults, from four unrelated families with RPL13-SEMD caused by two novel variants (c.477+5G>C and c.539_541del) and two previously reported variants (c.477+1G>C and c.548G>A) in RPL13. RNA analysis demonstrated that c.477+5G>C leads to a 54-nucleotide extension of exon 5, resulting in an 18-amino acid insertion. The phenotypic spectrum ranged from mild manifestations, such as Blount-like tibial deformity without significant short stature or Perthes-like femoral epiphyseal changes, to severe skeletal deformities with disproportionate short stature, accompanied by extraskeletal features (e.g., penoscrotal hypospadias, coccygeal abnormalities). For the first time, we describe Blount-like tibial deformity as a feature of this dysplasia, which resolves with age. Our study provides additional insights into the clinical, radiological, and genotypic features of RPL13-SEMD through detailed analysis of patients and their affected relatives.

Growth retardation for more than 2 SD below the average population or presumed familial target height is classified as a short stature and may be a clinical manifestation of a large number of disorders. The use of the latest methods of molecular genetic analysis in recent years has allowed for a better understanding of the pathogenesis of inherited forms of a short stature. One of the recently discovered mechanisms of this pathology was monoallelic mutations in RPL13 gene, leading to the development of Isidor-Toutain type spondyloepimetaphyseal dysplasia (SEDM). Characteristic phenotypic features for this form are normal birth length, early postnatal growth deficiency, platyspondyly, proximal femoral epiphyseal changes, coxa vara, genu varum. This study presents the clinical and radiological characteristics of the first patient in the Russian -Federation with SEMD caused by a mutation in RPL13 gene. Задержка роста более 2 SD ниже среднего популяционного или предполагаемого семейного целевого роста классифицируется как низкорослость и может быть клиническим проявлением большого числа заболеваний. Использование в последние годы новейших методик молекулярно-генетического анализа позволило лучше понять патогенез наследственных форм низкорослости. Одними из недавно открытых механизмов развития данной патологии являются гетерозиготные патогенные варианты в гене RPL13, ассоциированные со спондилоэпиметафизарной дисплазией (СЭД) тип Исидора-Туте. Характерными фенотипическими особенностями для данной формы являются нормальные показатели роста при рождении, выраженная постнатальная задержка роста, платиспондилия, эпифизарные дефекты проксимального отдела бедренной кости, coxa vara, genu varum. В настоящем исследовании представлены клинико-рентгенологические характеристики первого в Российской Федерации пациента со СЭД, вызванной мутацией в гене RPL13.

We describe the case of a seven-year-old female patient who presented in our service with severe developmental delay, intellectual disability, facial dysmorphism, and femur fracture, observed in the context of very low bone mineral density. Array-based single nucleotide polymorphism (SNP array) analysis identified a 113 kb duplication involving the morbid OMIM genes: ANKRD11 (exon1), RPL13, and PGN genes. ANKRD11 deletions are frequently described in association with KBG syndrome, the duplications being less frequent (one case described before). The exome sequencing was negative for pathogenic variants or of uncertain significance in genes possibly associated with this phenotype. The patient presented subtle signs of KBG syndrome. It is known that the phenotype of KBG syndrome has a wide clinical spectrum, this syndrome being often underdiagnosed due to overlapping features with other conditions, also characterized by multiple congenital anomalies and intellectual disability. The particularity of this case is represented by the very low bone mineral density in a patient with 16q24.3 duplication. ANKRD11 haploinsufficiency is known to be associated with skeletal involvement, such as short stature, or delayed bone age. An effect on bone density has been observed only in experimental studies on mice with induced missense mutations in the ANKRD11 gene. This CNV also involved the duplication of the very conserved RPL13 gene, which could have a role for the skeletal phenotype of this patient, knowing the high level of gene expression in bone tissue and also the association with spondyloepimetaphyseal dysplasia Isidor Toutain type, in case of splicing mutations.