Sacral Agenesis

Sacral agenesis is a rare condition characterised by the absence of between two and all sacral vertebrae.
This condition most often occurs as a part of a group of various abnormalities of the lower limbs, bowel, genitourinary tract and caudal spine, the so called “caudal regression sequence.”
 

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Sacral agenesis is an unusual condition affecting about 1 in 100,000 children.

There are two pathogenic theories that are thought to be causes of sacral agenesis / caudal regression sequence. The first is a primary defect in the generation of the mesoderm. The second hypothesis postulates a vascular defect, which leaves the caudal part of the embryo without an adequate perfusion. 
This vascular insult occurs in the midposterior mesoderm before the fourth week of gestation, when the caudal structures of the embryo are forming. If the disturbance in the development of the axial mesoderm is extensive, this can involve also the neural ectoderm, leading to concomitant neural tube defects1.
 

Sacral agenesis/caudal regression sequence is associated with pre-existing maternal diabetes mellitus, in particular in those cases with uncontrolled glucose blood level in the pre-conceptional period. Pre-existing maternal diabetes mellitus is reported to be present in 16 to 49% of cases. It is also associated with the intake of teratogens and vitamin A during the third week of gestation that interfere with the developing notochord.
Some genetic anomalies are associated with sacral agenesis and in particular terminal deletion 7q chromosome and T gene at 6q272. HLXB9 homeobox gene mutations have been identified in some patients with sacral bony anomalies, anorectal malformation, and a presacral mass (Currarino Syndrome). Other genetic mutations reported are in the coding sequences of HOXD13 and CYP26A1³. 
 

Renshaw classified the spectrum of caudal regression sequence/sacral agenesis into five types:⁴

• Type I: total or partial unilateral sacral agenesis. 
• Type II: variable lumbar and total sacral agenesis; the ilia articulate with the sides of the lowest vertebra. 
• Type III: variable lumbar and total sacral agenesis; the ilia are fused with the caudal end plate of the lowest vertebra (amphiarthrosis).
• Type IV: fusion of soft tissues in both lower limbs
• Type V: fused bones of lower limbs.

Sacral agenesis is reported to be associated with urologic (renal ectopia or agenesis), gastrointestinal (imperforate anus, anorectal atresia), neural tube (tethered-cord, diastematomyelia, lipomyelomeningocele) or other musculoskeletal anomalies such as dysplastic vertebrae, scoliosis, hip dislocation and contracture, knee flexion contracture, narrow pelvis, syringomyelia, clubfoot and “frog leg”.
Sacral agenesis can also be a part of syndromes such as VACTERL association (Vertebral Anorectal, Cardiac, Tracheoesophageal, Renal, Limb anomalies) or Currarino syndrome, characterised by the presence of presacral mass, sacral bone defect and anorectal malformation, inherited as an autosomal dominant tract with mutation or deletion of the HLXB9 gene.^6-7
 

In rare cases, the neural tube defect is part of a single gene disease, including HOXD13, CYP26A1 and HLXB9 mutations or is a part of a syndrome (VACTERL or Currarino syndrome). 
Because of the strong association between sacral agenesis and maternal diabetes, prevention is essentially based on a good control of blood glucose level in women with diabetes during the periconceptional period.
 

In caudal regression sequence, the spinal defect is often large enough to be detected during a screening exam. Once referred, at expert ultrasound it is possible to recognise the complex spinal defect and other possible associated anomalies.
The diagnosis of isolated sacral agenesis is made by coronal scanning of the spinal column.  Normally, the two iliac wings are visible surrounding the sacral vertebrae. In the case of sacral agenesis, the iliac wings are generally dysplastic and the sacral vertebrae in the middle are not visible. 3D skeleton mode ultrasound is useful in diagnosing sacral agenesis.
Recognising of the extreme form of caudal regression sequence, sirenomelia, is simple. In this case, the soft tissues or even the bony segments of the lower limbs are fused to each other. Sirenomelia is often associated with bilateral renal agenesis and subsequent oligohydramnios (which can impede ultrasound examination.)
 

The prognosis is extremely variable and depends on the severity of vertebral anomalies and associated malformations. Children who survive usually have normal intelligence.

The best prognosis is associated with unilateral or partial bilateral sacral agenesis. In these cases orthopedic intervention is simpler and the column provides a stable midline, allowing a higher chance of ambulation. The prognosis is poor in those cases with total sacral agenesis; lethality is generally attributed to renal failure, in particular in sirenomelia, or to the pulmonary hypoplasia subsequent to oligohydramnios. For these cases postnatal treatment is only supportive, since the primary disease is irreversible.  
For the treatment of urinary disorders, surgical interventions such as trans-uretero-ureterostomy and cutaneous cystostomy, intermittent ureteral catheterisation and/or anticholinergic drug administration are usually required.^8-9 

Motor deficit may vary depending on the level of vertebral dysgenesis. The lumbar plexus is formed by the ventral rami of the L1-L4 nerves, including femoral and obturator nerves, while the sacral plexus is formed by the ventral rami of L4-S4. In sacral agenesis, this is commonly affected, causing an unopposed activity of the femoral and obturator nerves. This causes the typical abnormal posture of lower limbs (hip flexion and knee extension). The contractures of the knees are the most difficult orthopedic deformities to treat.¹⁰ 
 

Termination of pregnancy may be offered when the diagnosis of sacral agenesis / caudal regression sequence is made prior to viability. In future pregnancies, no modification of standard obstetric management is necessary, and delivery can occur vaginally at term.

1. Isik Kaygusuz E, Kurek Eken M, Sivrikoz ON, Cetiner H. Sirenomelia: a review of embryogenic theories and discussion of the differences from caudal regression syndrome. J Matern Fetal Neonatal Med. 2016 Mar;29(6):949-53. 
2. Ayub S, Gadji M, Krabchi K, Côté S, Gekas J, Maranda B, et al. Three new cases of terminal deletion of the long arm of chromosome 7 and literature review to correlate genotype and phenotype manifestations. Am J Med Genet A. 2016;170A:896–907.
3. Postma AV, Alders M, Sylva M, Bilardo CM, Pajkrt E, van Rijn RR, et al. Mutations in the T (brachyury) gene cause a novel syndrome consisting of sacral agenesis, abnormal ossification of the vertebral bodies and a persistent notochordal canal. J Med Genet. 2014;51:90–7.
4. Renshaw TS. Sacral agenesis. J Bone Amp Jt Surg. 1978 Apr 1;60(3):373.
5. Guille JT, Benevides R, DeAlba CC, Siriram V, Kumar SJ. Lumbosacral agenesis: a new classification correlating spinal deformity and ambulatory potential. J Bone Joint Surg Am. 2002 Jan;84-A(1):32-8.
6. Phillips WA, Cooperman DR, Lindquist TC, Sullivan RC, Millar EA. Orthopaedic management of lumbosacral agenesis: Long-term follow-up. J Bone Joint Surg Am. 1982; 64(9):1282-94.
7. White RI, Klauber GT. Sacral agenesis. Analysis of 22 cases. Urology. 1976 Dec;8(6):521-5.
8. Boemers TM, van Gool JD, de Jong TP, Bax KM. Urodynamic evaluation of children with the caudal regression syndrome (caudal dysplasia sequence). J Urol. 1994 Apr;151(4):1038-40.
9. Cho PS, Bauer SB, Pennison M, Rosoklija I, Bellows AL, Logvinenko T, Khoshbin S, Borer JG. Sacral agenesis and neurogenic bladder: Long-term outcomes of bladder and kidney function. J Pediatr Urol. 2016 Jun;12(3):158.e1-7. 
10. Balioğlu MB, Akman YE, Ucpunar H, Albayrak A, Kargın D, Atıcı Y, Büyük AF. Sacral agenesis: evaluation of accompanying pathologies in 38 cases, with analysis of long-term outcomes. Childs Nerv Syst. 2016 Sep;32(9):1693-702. 

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