RIN2 syndrome: Expanding the clinical phenotype

Abstract

Biallelic defects in the RIN2 gene, encoding the Ras and Rab interactor 2 protein, are associated with a rare autosomal recessive connective tissue disorder, with only nine patients from four independent families reported to date. The condition was initially termed MACS syndrome (macrocephaly, alopecia, cutis laxa, and scoliosis), based on the clinical features of the first identified family; however, with the expansion of the clinical phenotype in additional families, it was subsequently coined RIN2 syndrome. Hallmark features of this condition include dysmorphic facial features with striking, progressive facial coarsening, sparse hair, normal to enlarged occipitofrontal circumference, soft redundant and/or hyperextensible skin, and scoliosis. Patients with RIN2 syndrome present phenotypic overlap with other conditions, including EDS (especially the dermatosparaxis and kyphoscoliosis subtypes). Here, we describe a 10th patient, the first patient of Caucasian origin and the oldest reported patient so far, who harbors the previously identified homozygous RIN2 mutation c.1878dupC (p. (Ile627Hisfs*7)). Besides the hallmark features, this patient also presents problems not previously associated with RIN2 syndrome, including cervical vertebral fusion, mild hearing loss, and colonic fibrosis. We provide an overview of the clinical findings in all reported patients with RIN2 mutations and summarize some of the possible pathogenic mechanisms that may underlie this condition. © 2016 Wiley Periodicals, Inc.

KIF16B is a candidate gene for a novel autosomal‐recessive intellectual disability syndrome

“…We found variants in the following genes: MPEG1 , AFMID , RIN2 , FBXW2 , and KIF16B . RIN2 is known to cause MACS (macrocephaly, alopecia, cutis laxa, and scoliosis) syndrome, which does not match the two siblings' phenotype (Rosato et al, ). Only the KIF16B variant (NM_024704.4:c.3611T > G:p.Phe1204Cys) was in the autozygous regions and could explain their phenotype.…”

Biallelicframeshift mutation in RIN2 in a patient with intellectual disability and cataract, without RIN2 syndrome

“…With great interest we have read the article by Aslanger et al () and Rosato et al () describing RIN2 syndrome (Aslanger et al, ; Rosato et al, ). RIN2 syndrome was previously known as MACS syndrome, since the first patients had Macrocephaly, Alopecia, Cutis Laxa, and Scoliosis.…”

“…So far, five families have been reported (Albrecht et al, ; Aslanger et al, ; Basel‐Vanagaite et al, ; Rosato et al, ; Syx et al, ) and since the features of the MACS acronym are not present in all patients, several authors proposed to change the name in RIN2 syndrome (Aslanger et al, ; Rosato et al, ; Syx et al, ). Overlapping clinical features are progressive coarsening facial features, scoliosis, joint hypermobility, and skin abnormalities, which have characteristics of both cutis laxa and Ehlers‐Danlos syndrome (EDS) (Rosato et al, ). In 2009, RIN2 deficiency was reported as the underlying cause of RIN2 syndrome (Basel‐Vanagaite et al, ).…”

“…The biallelic RIN2 mutations found in RIN2 syndrome, so far, were all frameshift mutations in exon 8 or 9 (Albrecht et al, ; Aslanger et al, ; Basel‐Vanagaite et al, ; Rosato et al, ; Syx et al, ) and were located in or just after the RIN homology domain, lacking the carboxyl‐terminal vacuolar protein sorting 9 (Vps9) and Ras association (RA) domains. Both the reported mutations and the frameshift mutation in our patient are predicted to lead to the absence of a functioning protein due to nonsense‐mediated decay (NMD).…”

“…Our patient thus has no MACS syndrome and his phenotype does also not fit the broader clinical spectrum underlying RIN2 syndrome. Three recently reported patients with a mutation in RIN2 had mild ID (Rosato et al, ), the other patients had normal intelligence. It is unlikely that the exon 2 mutation in RIN2 in our patient explains his mild ID and congenital cataract, because his sister who is heterozygous carrier is similarly affected.…”