Phenotype analysis impacts testing strategy in patients with Currarino syndrome

Abstract

Currarino syndrome (OMIM 175450) presents with sacral, anorectal, and intraspinal anomalies and presacral meningocele or teratoma. Autosomal dominant loss-of-function mutations in the MNX1 gene cause nearly all familial and 30% of sporadic cases. Less frequently, a complex phenotype of Currarino syndrome can be caused by microdeletions of 7q containing MNX1. Here, we report one familial and three sporadic cases of Currarino syndrome. To determine the most efficient genetic testing approach for these patients, we have compared results from MNX1 sequencing, chromosomal microarray, and performed a literature search with analysis of genotype-phenotype correlation. Based on the relationship between the type of mutation (intragenic MNX1 mutations vs 7q microdeletion) and the presence of intellectual disability, growth retardation, facial dysmorphism, and associated malformations, we propose a testing algorithm. Patients with the classic Currarino triad of malformations but normal growth, intellect, and facial appearance should have MNX1 sequencing first, and only in the event of a normal result should the clinician proceed with chromosomal microarray testing. In contrast, if growth delay and/or facial dysmorphy and/or intellectual disability are present, chromosomal microarray should be the first method of choice for genetic testing.

Spectrum ofMNX1Pathogenic Variants and Associated Clinical Features in Korean Patients with Currarino Syndrome

“…Large deletions or chromosome rearrangement involving 7q36 are related with holoprosencephaly (HPE) and CS due to haploinsufficiency of sonic hedgehog ( SHH ) and MNX1 . Some previous studies reported patients with a deletion or chromosome rearrangement involving 7q36 [ 3 4 14 17 27 28 29 30 31 32 33 34 ]. In these patients, microcephaly was the predominant craniofacial finding of HPE, and hypotelorism, ptosis, and midface hypoplasia were commonly associated.…”

“…Moreover, patient 16 also exhibited multiple associated anomalies including ptosis, bifid uvula, choanal atresia, laryngomalacia, Sprengel's deformity (congenital elevation of the scapula), cardiac anomalies, and umbilical hernia. According to the diagnostic algorithm proposed by Cuturilo et al [ 4 ], patients with CS exhibiting growth delay and/or developmental delay and/or facial dysmorphic features should be evaluated by a chromosomal microarray. Large deletions and complex rearrangements involving the 7q36 region have been identified in many previous reports [ 3 4 14 17 27 28 29 30 31 32 33 34 ].…”

“…The most frequent type of sacral agenesis is hemisacrum, which is a pathognomonic sign of CS and is also known as “scimitar sacrum” because of peculiar radiological findings such as sickle-shaped or crescent-shaped sacral deformities. Besides these major signs, developmental delays, neural tube defects, sensorineural deafness, and other features such as depressed nasal bridge, joint hyperextensibility, cataracts, ptosis, microcephaly, and facial dysmorphism have been reported in patients with CS [ 2 3 4 ]. Phenotypic variability has also been observed in these patients, with some of the major signs not being observed in incomplete cases [ 5 6 7 8 9 10 11 12 ].…”

How to Explore Fetal Sacral Agenesis Without Open Dysraphism: Key Prenatal Imaging and Clinical Implications

“…Generally, distal vertebrae (S4 and S5) are presented as nonsegmented hemivertebrae. In Currarino syndrome, hemiagenesis or partial unilateral agenesis below S2 is typical (Figures and ) . This rare syndrome is a congenital disorder characterized by partial sacral agenesis, anorectal malformation, and a presacral mass.…”

“…In Currarino syndrome, hemiagenesis or partial unilateral agenesis below S2 is typical ( Figures 6 and 7). 20,21 This rare syndrome is a congenital disorder characterized by partial sacral agenesis, anorectal malformation, and a presacral mass. In type 2, sacral agenesis is partial, bilateral, and symmetric ( Figure 6).…”