Brachytelephalangic chondrodysplasia punctata caused by new small hemizygous deletion in a boy presenting with hearing loss

Abstract

X-linked recessive type chondrodysplasia punctata (CDPX1) is a congenital disorder of cartilage and bone development with typical findings of stippled epyphises, nasomaxillary hypoplasia and short distal phalanges in a male patient. Disease is caused due to the loss of arylsulfatase E activity and only 55 patients with genetically confirmed disease have been reported so far. In 60–75 % of all patients the mutation in ARSE gene is detected by sequence analysis and in further 25 % of patients Xp deletions or rearrangements are causative and may be identified by classical chromosome studies. We report on a male patient refered to clinical geneticist for congenital hearing loss and mild dysplastic signs, both phenotypic features being relatively unspecific and non suggestive of CDPX1 in first instance. Array comparative genomic hybridisation showed approximatelly 3 kb big deletion, spaning intron and exon 7 of arylsulfatase E gene located in Xp22.33. This explained the cause of hearing loss, being present in 26–89 % od CDPX1 patients, as well as additional non prominent skeletal characteristics described by geneticist in our patient - mild midface hypoplasia and mild brachytelephalangy. Reported case introduces different presenting clinical phenotype for CDPX1, emphasizing different expressivity in this disorder.

Familial X/Y Translocation Encompassing <b><i>ARSE</i></b> in Two Moroccan Siblings with Sensorineural Deafness

“…One of the largest deletions including the OA1 locus has extended to 9.9 Mb and was described in a male with ichthyosis, Kallmann syndrome, ocular albinism, and CDPX1 [Meindl et al, 1993]. However, the smallest one involved was about 3 kb in a boy with CDPX1 and hearing loss [Vrečar et al, 2015]. The translocation in our proband removed 2 well-delineated genes, ARSE and SHOX , known to cause CPDX1 [Franco et al, 1995] and short stature/Leri-Weill syndrome [Shears et al, 1998], respectively .…”

“…Terminal deletions of Xp with variable sizes have been published in numerous studies. These are often isolated [Meindl et al, 1993;Boycott et al, 2003;Lonardo et al, 2007;Melichar et al, 2007;Ben Khelifa et al, 2013;Vrečar et al, 2015], sometimes resulting from t(X;Y) [Bukvic et al, 2010;Palka-Bayard-de-Volo et al, 2012]. One of the largest deletions including the OA1 locus has extended to 9.9 Mb and was described in a male with ichthyosis, Kallmann syndrome, ocular albinism, and CDPX1 [Meindl et al, 1993].…”

“…CDPX1 is an X-linked recessive disorder due to ARSE gene haploinsufficiency. This condition includes typically stippled epiphyses, nasomaxillary hypoplasia, and brachytelephalangy in a male [Vrečar et al, 2015]. Epiph- …”

“…Nevertheless, brachytelephalangy is the most persistent distinguishing sign for late-diagnosed cases [Maroteaux, 1989]. Hearing loss was the major clinical symptom in the 2 siblings and was described previously in isolated Xp deletions [Spranger et al, 1999;Lonardo et al, 2007;Melichar et al, 2007;Vrečar et al, 2015] as well as 25% of the CDPX1 cases [Nino et al, 2008]. So far, this is the first familial report of t(X;Y) associated with sensorineural deafness.…”

Uniparental disomy as a mechanism for X-linked chondrodysplasia punctata

“…CDPX1 is caused by loss of arylsulfatase E: an enzyme involved with hydrolysis of sulphate esters, important in bone and cartilage composition. This deficiency is due to pathogenic variants in ARSL gene at Xp22.3, which is detected by gene sequence analysis in up to 3/4 of patients and by chromosomal studies in 1/4 of patients, with detection of Xp deletions or rearrangements (Vrečar et al , 2015).…”