A prospective study of brachytelephalangic chondrodysplasia punctata: identification of arylsulfatase E mutations, functional analysis of novel missense alleles, and determination of potential phenocopies

Abstract

Brachytelephalangic chondrodysplasia punctata (BCP) describes a group of heterogeneous conditions with overlapping phenotypes. X-linked recessive BCP (CDPX1) (OMIM no. 302950), originally recognized by Sheffield et al., 1 is a panethnic congenital rare disorder that affects males. The most characteristic clinical features are as follows: 2,3 (i) Chondrodysplasia punctata, or stippled epiphyses, observed on X-ray. These minimally involve the ankle and distal phalanges but can also include long bones, vertebrae, hips, costochondral junctions, hyoid bone, and tracheal and bronchial cartilage. Chondrodysplasia punctata can be observed initially in the second trimester of pregnancy by ultrasound but tends to improve or disappear by age 2-3 years. (ii) Brachytelephalangy, or shortening of the distal phalanges. A characteristic finding on X-ray is an inverted triangle appearance of the distal phalanges, with punctata on either side. (iii) Nasomaxillary hypoplasia, referring to absence or hypoplasia of the anterior nasal spine, causing a flat nasal base, reduced nasal tip protrusion, shortened columella, and vertical grooves within the alae nasi. (iv) Proportionate short stature. Another commonly observed characteristic is mixed conductive and sensorineural hearing loss. Most children have normal intellect and life span, but comorbidities can be present, including compression of the cervical spinal cord associated with cervical vertebral abnormalities or stenosis of the upper and lower airways that result from extensive calcifications within the tracheal and bronchial cartilage. 3,4 Intrafamilial differences in disease severity have also been documented. 3 The only known genetic cause of CDPX1 is defects in arylsulfatase E (ARSE). The ARSE gene is located at Xp22.3, within a cluster of contiguous arylsulfatase genes that share high sequence homology, escape X inactivation, and have pseudogenes on the Y chromosome. 5 There are 17 sulfatases in the human genome; all share extensive sequence homology and contain a highly conserved cysteine that undergoes a unique posttranslational modification essential for their catalytic activity. 6-8 ARSE is localized to the Golgi membranes, 9 and its transcript has been identified in multiple tissues. 5 Its protein product is a 589-amino-acid and 60 kD precursor, which is subject Purpose: The only known genetic cause of brachytelephalangic chondrodysplasia punctata is X-linked chondrodysplasia punctata 1 (CDPX1), which results from a deficiency of arylsulfatase E (ARSE). Historically, ARSE mutations have been identified in only 50% of male patients, and it was proposed that the remainder might represent phenocopies due to maternal-fetal vitamin K deficiency and maternal autoimmune diseases. Methods:To further evaluate causes of brachytelephalangic chondrodysplasia punctata, we established a Collaboration Education and Test Translation program for CDPX1 from 2008 to 2010. Of the 29 male probands identified, 17 had ARSE mutations that included 10 novel missense alleles and one single-cod...

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

“…Some cases were described with only shortened distal phalanges and mild midfacial hypoplasia [ 1 ]. Delayed motor and cognitive development are reporeted in 19–33 % and 16–20 % of cases, respectively [ 3 , 6 ]. Also, fertility is normal.…”

“…In addition to genetic cause, important maternal etiological factors have been linked to the phenotype (warfarine exposure, vitamin K deficiency, maternal autoimmune disease), but still around 40 % of male patients with brachytelephalangic chondrodysplasia punctata do not have detectable ARSE mutations or known maternal etiological factors [ 3 , 6 ]. Further understanding of mechanism behind ARSE function might prove useful in identifying other potential candidates in the same disturbed pathway that, when defective, would lead to the similar phenotype of brachytelephalangic chondrodysplasia punctata.…”

“…The ARSE gene is located at Xp22.33, within a cluster of contiguous arylsulfatase genes, that share high sequence homology, escape X inactivation, and have pseudogenes on the Y chromosome [ 5 ]. ARSE is localized to the Golgi membranes and its transcript has been identified in multiple tissues [ 6 ]. Most affected males have minimal morbidity with normal intellect and life span and skeletal findings typically diminishing by adulthood.…”

“…By now around 140 male patients with a clinical phenotype had been reported, but genetic cause has been confirmed in less than half. In 60–75 % of CDPX1 cases, reported genetic cause is detected by sequence analysis of ARSE gene, in further 25 % of patients Xp deletions or rearrangements are identified on classical chromosome studies [ 6 ]. Smaller deletions can be evaluated by array CGH.…”

Maternal SLE and brachytelephalangic chondrodysplasia punctata in a patient with unrelated de novo RAF1 and SIX2 variants

“…However, 8 years later, the same group reported a female with the same condition and raised the possibility that BCDP is genetically heterogeneous (Peter et al, 1997). Further reports showed that 58% of the males with this phenotype carry pathogenic variants in the ARSE located at Xp22.33 (Matos‐Miranda et al, 2013), and the rest are probably the result of an evolving group of genetic aetiologies including Keutel syndrome (MIM# 245150), VKORC1 ‐related warfarin resistance (MIM# 122700) and other conditions yet to be identified. The possibility of maternal autoimmune condition was raised as an acquired cause but has not been investigated in the era of next generation gene sequencing (Chitayat et al, 2008).…”