Cutis marmorata telangiectatica congenita (CMTC) is a rare capillary malformation characterised by persistent reticulated marbled erythema. It tends to be associated with cutaneous atrophy, ulcerations and body asymmetry. CMTC is usually reported to be a benign condition; however, associated anomalies are not rare. Here, we have compiled information on published CMTC patients with the aim to evaluate the proposed diagnostic criteria by Kienast et al. and address the clinical manifestations, associated anomalies, differential diagnoses, management and prognosis. Our review is based on a search of the PubMed database which retrieved studies between 1922 and April 2019. The search yielded 148 original articles with a total of 485 patients. Of the identified patients, 24.5% had generalised CMTC, 66.8% had localised and 8.7% had a non-specified distribution of CMTC. Associated anomalies were observed in 42.5% of patients, predominantly body asymmetry and neurological defects like seizure and developmental delay. Fewer patients (10.1%) had ophthalmological defects, usually glaucoma. The major criterium "absence of venectasia" was not met in 20.4% of patients. We suggest that children with CMTC should be referred to an ophthalmologist for regular follow-up, and children with CMTC affecting the legs should be monitored for leg length discrepancy throughout the growth period. Furthermore, we suggest reconsideration of the major criterium "absence of venectasia" from the proposed diagnostic criteria, and instead include body asymmetry.

In human, mutations of the protocadherins FAT4 and DCHS1 result in Van Maldergem syndrome, which is characterised, in part, by craniofacial abnormalities. Here, we analyse the role of Dchs1-Fat4 signalling during osteoblast differentiation in mouse. We show that Fat4 and Dchs1 mutants mimic the craniofacial phenotype of the human syndrome and that Dchs1-Fat4 signalling is essential for osteoblast differentiation. In Dchs1/Fat4 mutants, proliferation of osteoprogenitors is increased and osteoblast differentiation is delayed. We show that loss of Dchs1-Fat4 signalling is linked to increased Yap-Tead activity and that Yap is expressed and required for proliferation in osteoprogenitors. In contrast, Taz is expressed in more-committed Runx2-expressing osteoblasts, Taz does not regulate osteoblast proliferation and Taz-Tead activity is unaffected in Dchs1/Fat4 mutants. Finally, we show that Yap and Taz differentially regulate the transcriptional activity of Runx2, and that the activity of Yap-Runx2 and Taz-Runx2 complexes is altered in Dchs1/Fat4 mutant osteoblasts. In conclusion, these data identify Dchs1-Fat4 as a signalling pathway in osteoblast differentiation, reveal its crucial role within the early Runx2 progenitors, and identify distinct requirements for Yap and Taz during osteoblast differentiation.

Biallelic variants in FAT4 are associated with the two disorders, Van Maldergem syndrome (VMS) (n = 11) and Hennekam syndrome (HS) (n= 40). Both conditions are characterized by a typical facial gestalt and mild to moderate intellectual disability, but differ in the occurrence of neonatal hypotonia and feeding problems, hearing loss, tracheal anomalies, and osteopenia in VMS, and lymphedema in HS. VMS can be caused by autosomal recessive variants in DCHS1 as well, and HS can also be caused by autosomal recessive variants in CCBE1 and ADAMTS3. Here we report two siblings with VMS and one girl with HS, all with FAT4 variants, and provide an overview of the clinical findings in all patients reported with FAT4 variants. Our comparison of the complete phenotypes of patients with VMS and HS indicates a resemblance of several signs, but differences in several other main signs and symptoms, each of marked importance for affected individuals.