A Syrian patient with Steel syndrome due to compound heterozygous COL27A1 mutations with colobomata of the eye

Abstract

The joint occurrence of short stature, congenital dislocation of the hip, carpal coalition, dislocation of the radial head, cavus deformity, scoliosis, and vertebral anomalies was first described in 1993 by Steel et al. (OMIM #615155) in 23 children from Puerto Rico. The condition is caused by a deficient matrix protein, collagen type XXVII alpha 1 chain, due to bi‐allelic loss of function mutations in the gene COL27A1. Outside of Puerto Rico, only four families have been described, in three of which the patients also had hearing loss. However, structural eye defects have not yet been reported in conjunction with this rare autosomal recessive syndrome. Here, we describe a 9‐year‐old girl born to nonconsanguineous Syrian parents with the characteristic features of Steel syndrome, including short stature, massive malalignment of large joints, kyphoscoliosis, hearing loss, and typical facial dysmorphism. However, she was also born with bilateral colobomata of the irides and choroido‐retinae with unilateral affection of the macula. Whole exome sequencing identified two pathogenic compound heterozygous variants in COL27A1: c.93del, p.(Phe32Leufs*71) and c.3075del, p.(Lys1026Argfs*33). There was no discernible alternative cause for the colobomata. Our findings might indicate an association of this exceptionally rare disorder caused by COL27A1 mutations with developmental defects of the eye from the anophthalmia/microphthalmia/coloboma spectrum.

Biallelic novel mutations of the COL27A1 gene in a patient with Steel syndrome

“…He showed kyphoscoliosis with L1 hypoplasia, radial head dislocation, acetabular and proximal femoral dysplasia, genu valgum, patellar dislocation, external torsional deformity of the lower extremities with marked out-toeing, and multiple sites of the carpal coalition. These findings have more or less been described in previous reports 1 – 5 , 8 , 9 , 12 . Although hip dislocation has been reported in most previous reports 6 – 10 , 12 , 13 , the present boy had acetabular and proximal femoral dysplasia but no dislocation, as found in some individuals previously 4 , 5 .…”

Functional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1 pathogenic alleles worldwide

“…We now also report three unrelated probands from Turkey with homozygous novel pathogenic variants (c.2683G>A:p.(Gly895Arg), c.4976_4980delGAGGA:p.(Gly1660Aspfs*3), and c.63-4_69del:p.(Gly22Serfs*6)]) in COL27A1 . These three individuals, in addition to recent case reports of unrelated patients with skeletal dysplasia within the spectrum of STLS, were found to have biallelic rare protein altering variants in COL27A1 consistent with an AR disease trait [ 7 – 11 ] (Fig. 1f ).…”

“…The two additional variants reported here are predicted to introduce frameshift or splice changes that result in the introduction of early termination codons that lead to nonsense mediated processing and clearance of the mutant transcripts, effectively resulting in loss-of-function (LoF) alleles with consequent loss of the COL27A1 protein. These two Turkish probands, in addition to the cases reported by Kotabagi et al [ 8 ] and Pölsler et al [ 11 ] are interesting as they reveal distinctions in the role and importance of collagen XXVII in human versus other mammalian skeletal systems. A previously reported mouse model of Col27a1 deficiency exhibited severe skeletal abnormalities with chondrodysplasia and perinatal death due to lung defects [ 29 ].…”

“…In blue, the three different pathogenic alleles identified in homozygosity in unrelated Turkish families reported here. In gray, previously reported disease associated variants in other populations [ 7 – 11 ]. Different disease-causing alleles homozygosed by consanguinity in the Turkish population and other populations around the world supports the Clan Genomics hypothesis.…”

“…Since our initial report, additional cases have been published linking novel rare recessive alleles in COL27A1 with osteochondrodysplastic phenotypes, mainly in consanguineous pedigrees [ 7 – 11 ]. Patients presented with clinical findings overlapping those of the reported Puerto Rican patients with STLS, but also with additional features not previously recognized in STLS, namely congenital hearing loss and speech delay [ 7 – 11 ]. We now report on the biology of this disease through an in vivo mouse model of the most common disease-causing allele and the worldwide allelic architecture in clinical populations.…”