Duplication of PTHLH causes osteochondroplasia with a combined brachydactyly type E/A1 phenotype with disturbed bone maturation and rhizomelia

Abstract

Parathyroid hormone-like hormone (PTHLH, MIM 168470) plays an important role in endochondral bone development and prevents chondrocytes from differentiating. Disease-causing variants and haploinsufficiency of PTHLH are known to cause brachydactyly type E and short stature. So far, three large duplications encompassing several genes including PTHLH associating with enchondromatas and acro-osteolysis have been described in the literature. Here, we report on a three-generation pedigree with short humerus, curved radius, and a specific type of severe brachydactyly with features of types E and A1 but without the enchondromatas and the acro-osteolysis. Microarray-based comparative genomic hybridization (array-CGH) revealed a 70-kb duplication on chromosome 12p11.22 encompassing only PTHLH. Our data extend the phenotypic spectrum associated with copy number variations of PTHLH, and this family is to our knowledge the first description harboring a microduplication encompassing only PTHLH. 3 with severely retarded ossification of epiphyses, pelvis, hands, and feet, Jansen metaphyseal chondrodysplasia (MIM 156400) 4 that is caused by constitutively active heterozygous variants and characterized by generalized osteopenia, and lethal Blomstrand chondrodysplasia (BOCD, MIM 215045) 5 that is caused by inactivating loss-of-function variants and characterized by severe defects in endochondral bone formation.Here, we report on a family that presented with autosomal dominant inheritance of short humerus, curved radius, and brachydactyly. 6 Initially, several candidate genes for brachydactyly type A1 (BDA1) including IHH and GDF5 were excluded via Sanger sequencing and a 105K microarray-based comparative genomic hybridization (array-CGH) was normal. Therefore, no molecular diagnosis could be established at the time. 6 To exclude smaller copy number variations we recently performed high-resolution array-CGH (1 M) and identified a 70-kb duplication encompassing only PTHLH. Mouse studies show that overexpression of PTHLH in proliferating chondrocytes results in chondrodysplasia and delayed endochondral bone formation. 7 So far, three larger duplications encompassing a total of 5 to 12 genes have been described at the PTHLH locus. All three duplications are associated with enchondromatas and acro-osteolysis

Disruption of the PTHLH regulatory landscape results in features consistent with hyperparathyroid disease

“…These conditions include Jansen type metaphyseal dysplasia or neonatal onset hyperparathyroidism, which show cortical thinning, metaphyseal dysplasia, and pathological fractures on plain X‐rays (Al‐Khalaf, Ismail, Soliman, Cole, & Ben‐Omran, ; Charrow & Poznanski, ). Similar findings have also been observed in individuals with PTHLH duplications (Collinson et al, ; Flöttmann et al, ; Gray et al, ).…”

“…Several different groups have reported skeletal anomalies caused by the duplication of PTHLH . The smallest duplication reported that only contained PTHLH and no other known genes has been found to result in short humeri, curved radii, and brachydactyly (Flöttmann et al, ). Larger reported duplications by two other groups which also included additional genes had more severe presentations with the presence of acro‐osteolysis and enchondromatas (Collinson et al, ; Gray et al, ).…”

“…Loss of function mutations in PTHLH results in brachydactyly type E2, an autosomal dominant condition characterized by shortening of the metacarpals, metatarsals, and phalanges of the hands and feet (Klopocki et al, ). Duplication of PTHLH results in short humeri, curved radii, and brachydactyly (Flöttmann et al, ).…”

A Comparison of Gene Expression Profiles between Glucocorticoid Responder and Non-Responder Bovine Trabecular Meshwork Cells Using RNA Sequencing

“…PTHLH regulates endochondral bone development and epithelial mesenchymal interaction. Flöttmann et al reported that duplication of PTHLH causes osteochondroplasia [74]. Since Borras and colleagues suggest that the pathological changes in the POAG TM resembles calcification [75], a down-regulation of PTHLH in the non-responder group may help to explain why their TM is less effected by DEX.…”

Diagnosis and management of pseudohypoparathyroidism and related disorders: first international consensus statement

“…A high incidence of carpal tunnel syndrome has been observed in patients with PHP1A and PPHP (67% of patients with PHP1A reported symptoms versus 15% of the general population) 253 . Additional skeletal features have been described in different disorders of the PTH-PTHrP pathway, such as Madelung deformity 72,128 , spinal stenosis 203,[254][255][256][257] , acroosteolysis, cortical irregularity of long bones and metadiaphyseal enchondromata or short humerus and curved radius 258 , as well as other craniofacial peculiarities (typical pear-shaped nose, long and flat philtrum, thin upper lip and receding chin) and phalangeal cone-shaped epiphyses, resulting in clinodactyly 259 . Depending on the functional consequences, the patient might require corrective orthopaedic surgery.…”