Currarino syndrome: a comprehensive genetic review of a rare congenital disorder

Abstract

Background The triad of a presacral mass, sacral agenesis and an anorectal anomaly constitutes the rare Currarino syndrome (CS), which is caused by dorsal–ventral patterning defects during embryonic development. The major causative CS gene is MNX1, encoding a homeobox protein. Main body In the majority of patients, CS occurs as an autosomal dominant trait; however, a female predominance observed, implies that CS may underlie an additional mode(s) of inheritance. Often, the diagnosis of CS is established solely by clinical findings, impacting a detailed analysis of the disease. Our combined data, evaluating more than 60 studies reporting patients with CS-associated mutations, revealed a slightly higher incidence rate in females with a female-to-male ratio of 1.39:1. Overall, MNX1 mutation analysis was successful in only 57.4% of all CS patients investigated, with no mutation detected in 7.7% of the familial and 68% of the sporadic patients. Our studies failed to detect the presence of an expressed MNX1 isoform that might explain at least some of these mutation-negative cases. Conclusion Aside from MNX1, other genes or regulatory regions may contribute to CS and we discuss several cytogenetic studies and whole-exome sequencing data that have implicated further loci/genes in its etiology.

Presacral mature cystic teratoma associated with Currarino syndrome in an adolescent with androgen insensitivity: illustrative case

“…3 There is an estimated incidence of 1 in 40,000 births, with a slight female predominance of 1.39:1; however, the actual incidence may be more common because it is thought that many cases go undiagnosed. 2,4 The pathogenesis of Currarino syndrome is commonly due to abnormal separation of the ectoderm and endoderm during development that causes a connection between the spinal column and bowel due to failed anterior vertebral fusion. 6 In over half of cases, Currarino syndrome is caused by a mutation in the MNX1 gene on chromosome 7q36.…”

“…3 Currarino syndrome has a female predominance (1.39:1) and has a familial autosomal dominant inheritance with associated MNX1 gene mutations. 4 Associated mass lesions are identified on investigation of common symptoms, such as chronic constipation, sacrococcygeal/perianal pain, and urinary incontinence, but they may also be found incidentally on imaging. It is extremely rare to find a presacral mass in an adolescent or adult because most cases present in the first decade of life.…”

The Role of De Novo Variants in Formation of Human Anorectal Malformations

“…Currarino syndrome (CS; OMIM #176450) is characterized by the triad of a presacral mass, sacral anomalies and ARM [ 21 ]. Heterozygous variants in MNX1 have been identified in 92% of familial and 32% of sporadic cases [ 22 ]. The fraction of de novo MNX1 variants has not been systematically studied, but there are frequent reports of de novo occurrence [ 23 , 24 , 25 , 26 ].…”

“…Since CS presents with variable expressivity and pathogenic variants may have a reduced penetrance, it is not surprising that completely asymptomatic individuals with pathogenic MNX1 variants have been reported [ 27 ]. However, even if a patient appears to represent a sporadic case, screening of the parents for features of CS and genetic testing of the parents in the case of identification of a MNX1 variant in the patient is recommended [ 22 ].…”

Transcription Factor Hb9 Is Expressed in Glial Cell Lineages in the Developing Mouse Spinal Cord

“…However, differentiation of MN progenitors within the spinal cord into somatic and visceral MNs remains constant ( Arber et al, 1999 ; Stifani, 2014 ). Mutations in the human HB9 gene cause disruptions in dorsal-ventral patterning resulting in a congenital malformation, characterized by significant sacral defects, called Currarino syndrome ( Dworschak et al, 2021 ).…”