Cardiospondylocarpofacial syndrome (CSCFS) is an extremely rare autosomal dominant disorder resulting from variant in the MAP3K7 gene, which encodes the transforming growth factor-β-activated kinase 1 (TAK1). Only 26 cases of CSCFS have been reported worldwide. The main manifestations are growth retardation, hypotonia, dysmorphic facial features, skeletal and limb abnormalities, cardiac septal defects with valve dysplasia, cardiomyopathy, and deafness with inner ear malformations. In this study, we recruited an unrelated Chinese family with a patient diagnosed with CSCFS. Whole exome sequencing revealed a novel heterozygous variant, c.142G > A[p. (Gly48Arg)], in the MAP3K7 gene. The variant was confirmed by Sanger sequencing to be absent in other family members and is de novo. The patient described here has a similar dysmorphology profile to that associated with CSCFS. Compared with reported cases of CSCFS, our patient presented with new complications of short tongue tie, brain abnormalities including asymmetrical cerebral hemispheres with widening of the right frontotemporal exoptic hiatus, intestinal obstruction and intussusception. In addition, scoliosis, vertebral abnormalities, carpal/tarsal fusion, pectus excavatum, and cervical spine fusion were not found in our patient. The molecular diagnosis in this patient extends the known genetic spectrum of CSCFS. Furthermore, the specific manifestations in this case offer valuable additional clinical details regarding the syndrome.

Cardiospondylocarpofacial syndrome (CSCF) is a rare congenital disorder characterized by growth impairment, polyvalvular heart diseases, and skeletal anomalies caused by a mutation in the mitogen-activated protein three kinase seven (MAP3K7) gene. It encodes transforming growth factor-β activated kinase1 (TAK1), a member of the mitogen-activated protein kinase (MAPK) family, and is responsible for abnormal skeletal and cardiac morphogenesis. We report a case of CSCF syndrome with a novel variant of the MAP3K7 gene c.710 C>T (p.F237s) in a newborn who has severe dilated cardiomyopathy (DCM) and congenital heart disease (CHD) and presented with acute heart failure (HF). DCM has not been reported before with CSCF. This case emphasizes the role of genetic testing in diagnosing the syndromic neonate with DCM.

Cardiospondylocarpofacial syndrome (CSCFS) is a congenital malformation characterized by growth retardation, facial features, short toes with carpal and tarsal fusion, extensive posterior neck vertebral fusion, congenital heart disease, and deafness. Here, we report a severe case of CSCFS with a novel variant, p.Thr187Ile, in MAP3K7. Thr187 is the main phosphorylation site for TGF-beta-activated kinase 1 encoded by MAP3K7, and this variant may cause significant abnormalities in downstream signaling.

Here we present the case of a patient with a novel de novo, likely pathogenic, heterozygous MAP3K7 variant (c.528dupT, p.G177WfsX5) causing cardiospondylocarpofacial syndrome (CSCFS). The variant, which falls in exon 6, is the first frameshift or non-sense mutation to be connected to CSCFS and presents with a phenotype that shares features with other MAP3K7-linked pathologies, including frontometaphyseal dysplasia 2 (FMD2) and the syndrome arising from an interstitial 6q15 deletions which envelop the gene. Other known mutations associated with CSCFS are plotted in black text (1,2,3).