A novel variant in MAP3K7 associated with an expanded cardiospondylocarpofacial syndrome phenotype

Abstract

The transforming growth factor-β-activated kinase 1 (TAK1) encoded by mitogen-activated protein kinase kinase kinase 7 (MAP3K7) is widely expressed and participates in multiple molecular and cellular processes, including growth, differentiation, inflammation, and apoptosis. Pathogenic variants in MAP3K7 have recently been associated with two disorders: cardiospondylocarpofacial syndrome (CSCFS) and frontometaphyseal dysplasia 2 (FMD2). To date, all small in-frame deletions and splice variants in MAP3K7 have been associated with CSCFS, whereas missense variants have been reported in both CSCFS and FMD2. Here, we present a patient with a novel heterozygous likely pathogenic variant, c.125_127del, p.(Val42del), in MAP3K7, only the sixth variant associated with CSCFS to be described in the literature. Although this patient has a phenotype that is most consistent with that of CSCFS, including valvular heart disease, short stature, fusions of the spine and bones of the hands and feet, and certain facial dysmorphisms, he interestingly has some features reported previously in FMD2 but not CSCFS. These include flexion contractures of the elbow and widely spaced first and second toes, highlighting new points of overlap between these two syndromes. We additionally point out features in the patient presented here that are rare but recurrent among CSCFS patients previously reported in the literature, as well as a new distinctive cutaneous finding not previously reported.

Expanding the phenotypic spectrum of cardiospondylocarpofacial syndrome: From a detailed clinical and radiological observation of a boy with a novel missense variant in MAP3K7

“…We have evaluated carpal radiographs of previously reported cases of CSCF: the same fusion of the capitate and hamate and/or fusion of the triquetrum and lunate as in the present case were noted (AbuBakr et al, 2020;Forney et al, 1966;Le Goff et al, 2016). In addition, some previously reported adult cases also exhibited fusion of the trapezium and scaphoid (AbuBakr et al, 2020;Forney et al, 1966;Le Goff et al, 2016). This pattern (first, capitate-hamate; second, triquetrum-lunate; third, trapezium-scaphoid) could therefore represent how carpal bone fusion occurs in this disorder.…”

“…According to the case report of Patient 7, she was originally suspected of having a hereditary connective tissue disorder as a result of her combination of connective tissue abnormalities, and was subsequently suspected of having RASopathy, so gene panel analysis of cohesinopathy and RASopathy was performed (Morlino et al, 2018). Patient 8 was also clinically diagnosed with Noonan syndrome (AbuBakr et al, 2020). At least three cases, including the present case, showed phenotypes overlapping with these connective tissue disorders or Noonan syndrome.…”

“…Pathogenic variants of MAP3K7 are also identified in patients with frontometaphyseal dysplasia (FMD OMIM#617137) (Costantini et al, 2018; Wade et al, 2016; Wade et al, 2017) and in large cohorts of patients with developmental disorders (Deciphering Developmental Disorders Study, 2017; Haghighi et al, 2018; Harripaul et al, 2018). To date, eight individuals with CSCF from six families with MAP3K7 heterozygous pathogenic variants have been reported (AbuBakr et al, 2020; Le Goff et al, 2016; Morlino et al, 2018). All of the previously reported individuals had variants in the kinase domain of TAK1 (AbuBakr et al, 2020; Le Goff et al, 2016; Morlino et al, 2018).…”

“…To date, eight individuals with CSCF from six families with MAP3K7 heterozygous pathogenic variants have been reported (AbuBakr et al, 2020; Le Goff et al, 2016; Morlino et al, 2018). All of the previously reported individuals had variants in the kinase domain of TAK1 (AbuBakr et al, 2020; Le Goff et al, 2016; Morlino et al, 2018). TAK1 is a serine–threonine protein kinase and a member of the mitogen‐activated protein kinase kinase kinase family (MAPKKK) (Yamaguchi et al, 1995).…”

“…Cardiospondylocarpofacial syndrome (CSCF; OMIM#157800) caused by pathogenic variants in MAP3K7 , which encodes transforming growth factor‐β activated kinase 1 (TAK1), is an autosomal dominant disorder characterized by growth impairment, failure to thrive, multiple valvular disease, cardiac septal defects, cryptorchidism, hearing impairment, skeletal features such as joint hypermobility, vertebral fusions, carpal and tarsal fusions, brachydactyly, and facial features including a prominent forehead, hypertelorism, downslanting palpebral fissures, ptosis, upturned nares, full cheeks, a long philtrum, dental crowding, and ear deformities (AbuBakr et al, 2020; Le Goff et al, 2016; Morlino et al, 2018). Pathogenic variants of MAP3K7 are also identified in patients with frontometaphyseal dysplasia (FMD OMIM#617137) (Costantini et al, 2018; Wade et al, 2016; Wade et al, 2017) and in large cohorts of patients with developmental disorders (Deciphering Developmental Disorders Study, 2017; Haghighi et al, 2018; Harripaul et al, 2018).…”