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Estimated prevalence is 1-9/100,000. Recent data estimates a 1.39:1 female-to-male ratio.

The disease typically presents as a triad of features (all 3 occur in 20% of cases) including anorectal, sacral and presacral anomalies, sometimes accompanied by other pelvic malformations. It may be an emergency at birth or found later with milder symptoms. Around 1/3rd of the patients are asymptomatic and identified through an affected relative or coincidentally on scans. Presacral anomalies may present as a mass and include anterior meningocoele, teratomas (which may also be sacrococcygeal), enteric cysts or a combination of those. Local pressure may cause constipation, incontinence, peripheral or central neurological symptoms. There is a 1-2 % risk of malignant transformation with various tumour types reported. Sacral agenesis occurs as anterior sacral defects. The S1 vertebra is typically intact. It may result in sickle-shaped (scimitar) sacrum or complete sacral agenesis below S2. Bifid or pepperpot sacrum are less frequent. Spinal cord anomalies (tethering, lipoma, cysts) can occur. Tethered cord can cause bowel/ bladder control issues if untreated. Spinal canal defects (e.g. enterothecal fistula) can cause seeding of gut microorganisms resulting in meningitis. Uterine or external genital anomalies occur in 15% of cases. Structural renal tract issues include kidney or bladder anomalies. Asymmetry of the lower limbs has been reported.

MNX1 is the only confirmed causal gene to date. All mutational mechanisms have been observed (rearrangements, deletions and SNVs). Cases resulting from 7q36 deletion may be associated with extrapelvic malformations and/or intellectual delay if other genes are involved. Homozygous cases are rare and often lethal early in life. MNX1 is detectable in 57-65% of patients, most frequently in familial cases. The involvement of other genes of interest is ongoing. There is no direct phenotype-genotype correlation. The pathogenic mechanism is still unknown but likely due to MNX1 haploinsufficiency. A disruptive event is speculated to occur during the development of the notochord at Carnegies stage 12 (but has not been observed in humans to date). If the endodermal & ectodermal layers fail to separate, splitting of the notochord and fistula between the gut and the neural tissue may occur.

Diagnosis is based on clinical findings. Plain film X-Ray, CT or MRI are useful. MNX1 gene testing can be offered. No international criteria currently exist.

Differential diagnosis includes caudal regression syndrome, VACTERL association and sacrococcygeal teratoma.

Foetal ultrasound can reveal a presacral mass or sacral defects if present. Targeted foetal MRI can be considered. Testing for MNX1 can be considered.

Inheritance is autosomal dominant with reduced penetrance and variable expressivity. Genetic counseling and imaging screening can be offered to relatives. If there is an established MNX1 variant, cascade testing can be offered.

Management depends on presenting features. Surgical correction of anorectal malformations may be necessary. Conservative management (e.g. stool softening agents) and monitoring may be offered for milder cases. Monitoring of presacral mass is advised. Surgical management (coordinated by various surgical specialities) of presacral masses may be necessary. Cancer biomarkers for presacral teratomas are not well established. Sacral agenesis is managed clinically. If there is cord dysfunction, neurosurgery may be required. Caution is advised for spinal procedures, including anaesthesia. Spinal cord tethering may require early surgery to avoid complications. Follow up is important as the cord can retether.

Long term prognosis is good for the majority of patients. Urinary/bowel dysfunction may impact quality of life. Malignant transformation of presacral mass is rare.

Last update: April 2023 - Expert reviewer(s): Dr John COLEMAN - Pr Sally Ann LYNCH | ITHACA*

* European Reference Network