children

Case Report Caudal Regression Syndrome

Ranjit I. Kylat * and Mohammad Bader

Department of Pediatrics, University of Arizona, College of Medicine, Tucson, AZ 85724, USA; [email protected] * Correspondence: [email protected]

 Received: 17 August 2020; Accepted: 29 October 2020; Published: 4 November 2020 

Abstract: Caudal Regression Syndrome (CRS) or Caudal dysgenesis syndrome (CDS) is characterized by maldevelopment of the caudal half of the body with variable involvement of the gastrointestinal, genitourinary, skeletal, and nervous systems. CRS affects 1–3 newborn infants per 100,000 live births. The prevalence in infants of diabetic mothers is reported at 1 in 350 live births which includes all the variants. A related condition is sirenomelia sequence or mermaid syndrome or symmelia and is characterized by fusion of the legs and a variable combination of the other abnormalities. The Currarino triad is a related anomaly that includes anorectal atresia, coccygeal and partial sacral agenesis, and a pre-sacral lesion such as anterior meningocele, lipoma or dermoid cyst. A multidisciplinary management approach is needed that includes rehabilitative services, and patients need a staged surgical approach.

Keywords: caudal dysgenesis syndrome; caudal regression syndrome; sirenomelia

1. Introduction Caudal Regression Syndrome (CRS) or Caudal dysgenesis syndrome (CDS) is a rare disorder and characterized by maldevelopment of the caudal half of the body with variable involvement of the gastrointestinal, genitourinary, skeletal and nervous systems [1–4]. It includes a wide range of congenital anomalies affecting the caudal spine and spinal cord, the hindgut, the urogenital system and the lower limbs, and the spectrum of its severity is variable. CRS is reported to affect 1–3 newborn infants per 100,000 live births among the general population. The prevalence rate is much higher in infants of diabetic mothers. A multidisciplinary management approach is needed, and many patients need a staged surgical approach. Herein, we describe a patient with CRS.

2. Case Presentation This 30-week gestation female infant was born via vaginal delivery to a healthy non-diabetic 18-year-old primigravida female. Prenatal ultrasound revealed relatively hypoplastic lower limbs with bilateral clubfoot and low vertebral and sacral anomalies. There was also polyhydramnios and there was suspicion of a form of CRS based on lower limb and vertebral anomalies. Prenatal laboratory tests, including cell-free fetal DNA, were all normal except for her rubella nonimmune status. The family declined to pursue amniocentesis. There was no exposure to teratogens, illicit drugs or alcohol. There was no significant family history forthcoming and no consanguinity. There were no glycemic abnormalities during pregnancy. Her mother was admitted a week prior to birth for preterm labor and received two doses of betamethasone and appropriate antibiotics.

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On initial assessment infant was noted to have underdeveloped lower limbs, bilateral club Childrenfoot, imperforate 2020, 7, 211 anus and absent sacrum. (Figures1–3) Other abnormal features included low2 setof 7 ears, depressed nasal bridge and high arched palate. A three-vessel umbilical cord was present. T12-L1Spinal ultrasounddisc space. Renal (US) revealedUS showed absence multicystic of the dyplastic sacrum with right the , conus duplicated having a blunt right endand atleft the renal tip collectingat the T12-L1 system, disc and space. distended Renal US right showed ureter. multicystic Head US revealed dyplastic premature right kidney, gyral duplicated and sulcal right pattern and thatleft renalwas, collectinghowever, system,appropriate and distended for the gestational right ureter. age. Head Magnetic US revealed resonance premature imaging gyral (MRI) and of sulcal the patternspine at thata month was, however,of age revealed appropriate a rudimentary for the gestational sacrum, absence age. Magnetic of coccyx resonance and blunting imaging of spinal (MRI) cordof the at spine T 11 and at a features month ofsuggesting age revealed a type a 1 rudimentary CRS (Figure sacrum,4). An echocardiogram absence of coccyx revealed andblunting small mid- of muscularspinal cord VSD at Twith 11 andleft to features right shunting. suggesting A kary a typeotype 1 CRS and (Figure chromosomal4). An echocardiogrammicroarray did not revealed reveal anysmall abnormalities. mid-muscular She VSD underwent with left to a rightcolostomy shunting. and Amucus karyotype fistula and creation chromosomal within 2 microarray days when did a rectovaginalnot reveal any fistula abnormalities. was also Shenoticed. underwent Prophylactic a colostomy antibiotics and mucus was initiated fistula creation due to withinurinary 2 daystract whenanomalies. a rectovaginal Patient subsequently fistula was also required noticed. gastro Prophylacticstomy tube antibiotics for poor was oro-motor initiated duefunction. to urinary She tracthad serialanomalies. casting Patient of her subsequently feet for management required gastrostomy of talipes tubeequinovarus. for poor oro-motorSubsequently, function. she had She two had tenotomies.serial casting An of herMRI feet of forthe managementbrain and spine of talipes done at equinovarus. 3 years of age Subsequently, showed 11 shethoracic had twovertebrae tenotomies. with Anthe MRIconus of medullaris the brain andbeing spine truncated done atand 3 yearsnodular of ageat the showed level of 11 intrapedicular thoracic vertebrae T11. A with rudimentary the conus dysgeneticmedullaris beingsacrum truncated with a sagittal and nodular cleft in at the levelmedian of intrapedicularsacrum with rudimentary T11. A rudimentary apophysis dysgenetic of both sidessacrum of withthe pelvis a sagittal and a cleft thickened in the mediancauda equine sacrum was with detected. rudimentary There was apophysis a sagittal of cleft both in sides the thecal of the pelvissac extending and a thickened from the cauda level equineof the L4 was pedicle. detected. (Figure There 5) was On a neurodevelopmental sagittal cleft in the thecal assessment sac extending at 18 andfrom 24 the months level of she the had L4 pedicle. mild to (Figuremoderate5) On language, neurodevelopmental social, cognitive assessment and fine at motor 18 and deficits 24 months and moderateshe had mild to severe to moderate motor language,deficit especially social, cognitiverelated to andambulation. fine motor Her deficits last follow and moderate up was at to the severe age ofmotor 3 years. deficit especially related to ambulation. Her last follow up was at the age of 3 years.

(a) (b)

Figure 1. ImageImage depicting depicting club club foot, foot, ear, ear, and sacral region anomaly (a,b).

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((aa)) ((bb))

FigureFigure 2. 2. Plain PlainPlain (anteroposterior (anteroposterior (anteroposterior ( (a a)) )and and and lateral lateral lateral ( (b (b)))))) radiograph radiograph radiograph of of of chest chest chest and and and abdomen abdomen abdomen showing showing showing absent absent sacrum.sacrum. BothBoth Both thethe the umbilicalumbilical umbilical arterialarterial arterial andand and venousvenous venous cathcath catheterseterseters onon on thethe the laterallateral viewview werewere notnot appropriatelyappropriately positionedpositioned but but was was pulled pulled back back to to optimal optimal site. site.

Figure 3. Plain lateral radiograph of foot showing club foot. Figure 3. PlainPlain lateral lateral radiograph of foot showing club foot.

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FigureFigure 4. Sagittal 4. SagittalSagittal MR MR MRimages images images show show show vertebrae vertebrae vertebrae down down down to roto toughly ro roughlyughly L5 L5with L5 with with no nodeveloped no developed developed sacral sacral sacral elements. elements. elements. TheThe conus conus medullaris medullaris is high is high at T11, at T11, with with a truncated, a truncated, inferior inferior tip. tip.

(a) (a) (b) (b) (c) (c) (d) (d) (e) (e)

FigureFigure 5. ( a5. – (e(a):a–– MRIee):): MRI MRI of spine of of spine spine T1, T1, T2, T1, T2, T1 T2, T1FS T1 andFS FS and and T1 STIRT1 T1 STIR STIR images: images: images: The The Theconus conus conus medullaris medullaris medullaris is truncated is is truncated truncated and and and nodularnodular at the at thethe level levellevel of ofintrapedicularof intrapedicularintrapedicular T11 T11 T11 with with with ru rudimentarydimentary rudimentary dysgenetic dysgenetic dysgenetic sacrum sacrum sacrum and and and sagittal sagittal cleft cleft inin the in thethe medianmedian median sacrum sacrum sacrum with with rudimentarywith rudimentary rudimentary apophysis. apophysi apophysi Thickeneds. s.Thickened Thickened cauda cauda equine cauda equine is seen.equine FS—fatis isseen. seen. suppression. FS—fat FS—fat suppression.suppression.STIR—short STIR—short TSTIR—short 1 inversion T 1 T recovery.inversion 1 inversion recovery. recovery.

3. Discussion3. Discussion Discussion CRSCRS or CDSor CDS is also is is also also known known known as caudalas as caudal caudal dysplasia, dysplasia, dysplasia, sacral sacral sacral dysgenesis dysgenesis dysgenesis or regression,or or regression, regression, congenital congenital sacral sacral agenesis,agenesis, sacral sacral defect defect with with anterior anterior meningocele, meningocele, sacro-coccygeal sacro-coccygeal dysgenesis dysgenesis and and caudal caudal dysplasia dysplasia sequencesequence [1–4]. [1–4]. [1– A4]. relatedA Arelated related condition, condition, condition, sirenomelia sirenomelia sirenomelia sequence sequence sequence (mermaid (mermaid (mermaid syndrome) syndrome) syndrome) or orsymmelia, symmelia, or symmelia, was was thoughtthoughtwas thought to beto bea tomore a be more a moresevere severe severe form form formof CRS,of ofCRS, CRS, but but it but is it it arguedis is argued argued that that it is itit aisis distincta a distinct distinct entity entity entity [5,6]. [5 [5,6].,6]. Sirenomelia Sirenomelia Sirenomelia is is characterizedischaracterized characterized by by byfusion fusion fusion of oftheof the legs legs legs and and and a variable a avariable variable combination combination combination of theof the ofother theother abnormalities other abnormalities abnormalities [5,6]. [5,6]. The [The5 ,6]. prevalenceprevalenceThe prevalence of ofsirenomelia sirenomelia of sirenomelia is aboutis about is about1 in 1 100,000in 1 in100,000 100,000 live live births live births births [7]. [7]. The [7 ].The TheCurrarino Currarino Currarino triad triad triad or orsequence or sequence sequence is ais is a a related,related, yet yet distinct distinct condition condition and and includes includes anorectal anorectal atresia atresia or or ectopia, ectopia, coccygeal coccygeal and and partial partial sacral sacral agenesis,agenesis, and and and a pre-sacral a a pre-sacral mass mass mass lesion lesion lesion such such such as asanterior as anterior meningocele, meningocele, meningocele, lipoma lipoma lipoma or ordermoid or dermoid dermoid cyst cyst cyst [8,9]. [8,9]. [8 ,9]. TheThe prevalence prevalence of CRSof CRS in infantsin infants of diabeticof diabetic mothers mothers is documentedis documented at upat up to 1to in 1 350in 350 live live births births and and betweenbetween 20% 20%20% and andand 25% 25% 25% of of ofmothers mothers mothers of infantsofinfants infants with with with CDS CDS CDS have have have insulin-dependent insulin-depend insulin-dependent diabetesent diabetes mellitus mellitus mellitus [10,11 ]. [10,11].[10,11]. Family history and maternal diabetes mellitus are two of the risk factors for this disorder. TheFamily abnormalFamily history history embryologic and and maternal maternal development diabetes diabetes mellitus ofmellitus the ar caudale ar twoe two mesodermof theof the risk risk occursfactors factors withinfor for this this thedisorder. disorder. first 4 The weeks The abnormalabnormalof embryonic embryologic embryologic development development development [12]. Theof ofthe exact the caudal caudal pathogenesis mesoderm of occurs this occurs syndrome within within the is the poorlyfirst first 4 weeks understood,4 weeks of of embryonicembryonicand several development development etiologic factors [12]. [12]. haveThe The beenexact exact suggested. pathogenesis pathogenesis Maternal of ofthis exposurethis syndrome syndrome to cocaine is poorlyis poorly oralcohol understood, understood, consumption, and and severalseveral etiologic etiologic factors factors have have been been suggested. suggested. Matern Maternal exposureal exposure to cocaineto cocaine or alcoholor alcohol consumption, consumption, is knownis known to beto beassociated associated in somein some cases. cases. Other Other po stulatedpostulated mechanisms mechanisms includ include vasculare vascular steal steal theory theory

Children 2020, 7, 211 5 of 7 is known to be associated in some cases. Other postulated mechanisms include vascular steal theory or hypo-perfusion, fetal hypoxemia and amino acid imbalances. A primary deficiency of the caudal mesoderm is implicated in CRS. In Sirenomelia vascular steal could play a more important role due to the presence of an aberrant umbilical artery (persistent vitelline artery) and the single midline lower limb. Genetic mutations in combination with environmental factors may lead to an increased risk of CRS. Multiple genetic factors such as mutations in the VANGL1 gene on chromosome 1p13, the CELSR1 and the HLXB9 gene on chromosome 7q36 in cases of the Currarino syndrome, have been implicated [13–16]. The clinical manifestations of this patient included bilateral clubfoot, anorectal malformation, and renal abnormalities including duplication of the collecting systems. CRS is a varied combination of abnormalities involving the musculoskeletal, gastrointestinal, genito-urinary and central nervous systems. The common factor to these abnormalities relates to defects in the development of the caudal mesoderm and the structures that it ultimately forms. Common findings include flexion contractures of the knees and hips, pelvic deformity, syn- or poly-dactyly, anorectal malformations, abdominal wall defects, gut malrotation, intestinal atresia, renal agenesis or dysplasia, absent bladder, transposition of external genitalia, hypospadias, myelomeningocele and hydrocephalus. There are some differences in the classification of all CRS and sirenomelia. The Renshaw and Pang classification is used for the CRS, while the Pang, Kjaer and Stocker and Heifetz classification is used for sirenomelia [17–20]. Renshaw described CRS based on type of defect and articulation between bones. Type 1 has total or partial unilateral sacral agenesis; type II has variable lumbar and total sacral agenesis and the ilia articulates with the sides of the lowest vertebra; type III has variable lumbar and total sacral agenesis and the caudal end plate of the lowest vertebra rests above fused ilia or an iliac amphiarthrosis; type IV has fusion of soft tissues in both lower limbs; type V, also known as sirenomelia, has fused bones of lower limbs [20]. Stocker and Heifetz classified sirenomelia in 7 types: I would have all thigh and leg bones the type II has a single fibula, the type III has an absent fibulae, the type IV haspartially fused and fused fibulae, the type V has partially fused femurs along with absent fibulae, the type VI has a single and a single tibia, and type VII has a single femur and absent tibiae [19]. After the second MRI, the patient described above has a CRS type II and this is based on her severe sacral dysgenesis with hypoplasia of the fifth lumbar vertebra. Management of CRS is dependent on the specific anatomical abnormalities present in a given patient. This patient required surgical creation of a sigmoid colostomy, serial casting of her clubbed feet and bilateral tenotomy to release equinus contracture. Management of other CRS patients can include a wide variety of interventions to address the full spectrum of possible anatomical abnormalities. There are reports of the use of growth hormones with improved function by promoting distal innervation [21]. This spectrum of abnormalities across multiple organ systems although not an uncommon finding in cases of poorly controlled gestational diabetes, our patient presented with these malformations, consistent with CRS without a history of maternal diabetes. Understanding the varying complexity and multisystem involvement of this disease and rarity in nondiabetic mothers may allow for better multidisciplinary approach to management of such infants.

Author Contributions: R.I.K. designed, wrote the initial draft, revised and edited. M.B. did the revisions. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Acknowledgments: The institutional review and ethics board and the office for human research protections provided a waiver from a full review. Parental consent was obtained. Conflicts of Interest: The authors declare no conflict of interest. Children 2020, 7, 211 6 of 7

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