Hirschprung's Disease and Thoracic Limb Amputation by Amniotic Bands in a Patient With Down Syndrome: A Case Report

The male patient was first evaluated at the Down clinic at the age of 3 months. He was born from the second pregnancy of a 28‐year‐old mother and a 32‐year‐old father, both non‐consanguineous and originally from Guadalajara, Jalisco, Mexico. The mother had a history of endometriosis and ovarian cysts. She previously experienced a spontaneous abortion at 5 weeks of gestation. There was no family history of DS. During the fifth week of pregnancy, she was diagnosed with a urinary tract infection and was treated with a course of oral antibiotics (unspecified). Concurrently, she developed transvaginal bleeding, for which progesterone therapy was administered. Additionally, hyperglycemia was identified and managed with dietary adjustments. At the sixth month of pregnancy, an ultrasound revealed an amputation of the forearm in the fetus. The infant was delivered at 38 weeks of gestation via cesarean section due to pelvic presentation. Birth metrics included a weight of 2540 g, a length of 48 cm, and APGAR scores of 9/9. The Silverman index was 0.

Rosario Hernández‐Ramírez: investigation, writing – review and editing. María de la Luz Ayala‐Madrigal: methodology, writing – review and editing. Laura Macias Trinidad: conceptualization, investigation. Guadalupe Delia Luna Romero: conceptualization, investigation. César Eduardo Monterrubio Ledezma: conceptualization, investigation, methodology, writing – review and editing.

The authors have nothing to report.

Auditory evaluation at 8 months revealed right normoacusia and moderate left conductive hypoacusia. Ophthalmological assessment revealed convergent strabismus and nystagmus. A visual potential study conducted at 10 months demonstrated bilateral permeable visual pathways, with an axonal lesion observed on the right side. The patient has been receiving regular outpatient follow‐up from the pediatric surgery, gastroenterology, genetics, physical medicine and rehabilitation services. Currently, he is 3 years and 10 months old and is undergoing the adaptation process for an arm prosthesis.

HD is a gastrointestinal disorder characterized by a congenital absence of ganglion cells in the myenteric and submucosal tissues of the gastrointestinal tract. DS is the condition primarily associated with HD, and recent studies have reported that in the United States, 9% of pediatric patients with HD have DS; they are also 14% more likely to have necrotizing enterocolitis, and the mortality rate of patients with DS is four times higher than that of patients without DS. Mortality from enterocolitis due to HD in patients with DS increased by up to 83% [ 8 ]. Despite having both diagnoses, the patient probably survived owing to timely detection and treatment at birth, as early care is considered to have a better prognosis [ 9 , 10 ]. Hirschsprung‐associated enterocolitis, which this patient presented with acutely, is a potentially life‐threatening complication of HD. Historically, mortality rates reached as high as 20% to 30% in the 1970s; however, advances in early diagnosis and surgical management have reduced mortality to approximately 2% to 5% in recent years. Despite improved outcomes, recurrence occurs in up to 35% of cases [ 11 ]. Causes associated with HD include decreased availability of neuroblasts for migration to the enteric nervous system, abnormal neuroblasts, impaired synaptic nerve function, influence of related early germline genes on neuroblast migration, genetic mutations in developmental genes, and somatic mutations resulting from alterations in the local tissue microenvironment [ 3 , 8 ]. Among the etiological factors of HD, the migration of enteric neural crest cells (ENCCs) during embryogenesis is particularly critical. These precursor cells primarily originate from the vagal region of the neural tube and invade the foregut, subsequently migrating in a rostrocaudal direction along the gastrointestinal tract between embryonic weeks 4 and 7. These cells also migrate inward to form the myenteric and submucosal plexuses [ 12 ]. HD arises from the failure of these cells to colonize the fetal distal gut. This process requires the coordinated action of trophic factors, cell surface receptors, transcription factors, and signaling molecules [ 12 ]. Disruptions in these mechanisms, whether due to genetic mutations [ 11 ] or external influences, are strongly associated with the pathogenesis of HD. It is noteworthy that the antibiotic and progesterone treatment received by the mother coincided with the crucial period of ENCCs migration; however, the actual impact of this exposure remains unknown. Respecting genetic factors, a 12.5–13 Mb region on chromosome 21q22 has been identified as critical for the development of HD [ 8 ]. Although DSCAM (Down syndrome cell adhesion molecule), a gene located within this region, is known to play a role in the development of the human central and peripheral nervous systems and is associated with HD, the Clinical Genome Resource ( search.clinicalgenome.org/kb/gene‐dosage ) does not indicate that DSCAM exhibits triplosensitivity. Thus, an extra copy of the DSCAM gene has not been reported as a mechanism for human disease. Other genes have been associated with altered gene dosage of chromosome 21 in DS patients [ 3 , 8 ], such as RET (transmembrane receptor tyrosine kinase protooncogene, 10q11.21), EDNRB (gene for endothelin receptor non‐selective, 13q22), whose variations are significant in HD, and COL6A1 (collagen VI, 21q22.3), which participates in the development of the enteric nervous system at the level of the extracellular matrix. Supporting this latter association, a previous study [ 13 ] analyzed colon muscle containing myenteric ganglia from HD patients and healthy controls to investigate whether excess collagen VI contributes to HD risk. Results showed a twofold increase in collagen VI surrounding myenteric ganglia in HD patients and a threefold increase in those with HD and DS. In addition, this study described that elevated collagen VI levels reduce the speed of ENCCs migration based on mice experimental results [ 13 ]. ABS is caused by bridles or stretched bands found in the walls of the amniotic sac, where the fetus can be trapped and undergo amputations, disruptions, or asymmetric malformations, mainly in the extremities. The diagnosis can be made prenatally thanks to the findings of ultrasonography, as in the patient who was diagnosed in the second trimester of pregnancy when the affected limb was observed. Although the bands were not located at that time, it was not necessary to observe them for diagnosis [ 4 ]. In a study conducted in 2020, it was observed that the diagnosis of limb reduction transverse, as in our patient, was mostly due to ABS [ 14 ]. In addition, it has been seen in the literature that there are good bases of evidence for ABS being a cause of congenital limb deficiencies and being easily identified [ 15 ]. ABS is considered sporadic, so the risk of recurrence would be the same as in the general population, as well as DS, because it is a regular trisomy 21, there is no increased risk, and both pathologies would have a < 1% recurrence. However, other factors such as maternal age, risk of spontaneous abortion, and maternal medication intake should be evaluated for adequate genetic counseling [ 16 ]. In Mexico, a study involving 90,000 live births reported an incidence of ABS of 1 in 2000, with 44% of affected individuals being female and 38% male, suggesting that ABS is a relatively common condition [ 17 ]. Although ABS and DS have distinct etiologies and no evidence supports a direct association between them, which could indicate this is an incidental finding in our patient, the co‐occurrence of these two different congenital anomalies in the same patient warrants thorough clinical documentation. While limb amputation due to amniotic bands typically results from an isolated mechanically disruptive event, it can occasionally coexist with other malformations or syndromes. Given that no previously reported cases have presented with this specific combination of characteristics, this report highlights an unusual clinical coincidence. This presentation may represent a multifactorial coincidence, as each condition has a distinct origin: chromosomal for DS, neurogenic for HD (which has a known association with DS), and mechanically disruptive for amputation caused by ABS [ 9 , 18 ]. Alternatively, the increased susceptibility to malformations during embryonic development in individuals with DS could be a contributing factor [ 2 ]. Progesterone is routinely used in the first trimester to support the luteal phase and treat threatened miscarriage. The proband's mother was prescribed progesterone at 5 weeks of gestation due to transvaginal bleeding and a history of miscarriage. We hypothesize that progesterone use during this early stage of pregnancy might be linked to limb amputation associated with ABS, based on a recently observed novel association [ 4 , 19 ]; further research is needed to confirm this potential connection. Additionally, these events occurred during the critical period of migration of ENCCs related to HD [ 12 ]. In conclusion, based on the clinical, the laboratory tests, and imaging results, this report represents the first documented case of HD and thoracic limb amputation by ABS in this patient, who was confirmed to have DS with a karyotype 47,XY,+21.

Written informed consent and permission have been obtained from the patient's parents for the use of information and photographs for the presentation of the case, in accordance with the journal's patient consent policy. This report does not contain any personal information that could lead to the identification of the patient.

Down Syndrome (DS) is the most frequent chromosomal alteration in live‐born children, with a prevalence of 3.7 per 10,000 births in Mexico [ 1 ]. DS causes intellectual disability and constitutes a risk factor for several diseases, such as congenital heart disease, leukemia, Alzheimer's disease, and Hirschsprung's disease (HD), with broad clinical variability due to an imbalance involving either complete or partial trisomy of chromosome 21q [ 2 ]. In patients with DS, there is a 100‐fold increased risk of developing gastrointestinal disorders, which is approximately 12% of all affected cases that present with HD, considered the most commonly associated chromosomal abnormality [ 3 ]. HD is caused by the absence of myenteric ganglion cells limiting peristalsis, leading to intestinal obstruction, abdominal distention, failure to evacuate the meconium, enterocolitis, and megacolon from the first days of life [ 3 ]. The amniotic band sequence (ABS) or Streeter's anomaly is an entrapment of fibrous bands on fetal structures, resulting in a set of congenital malformations or disruptions of primarily the limbs but also the bones, face, torso, and viscera. Its origin remains unclear, with several hypotheses, such as the alteration of the development of the embryonic disc and the most popular, the sequential mechanism of rupture of the amnion that leads to the entanglement of fetal structures by the mesodermal bands [ 4 , 5 ]. In most cases, the underlying cause was unknown. Some associated risk factors include maternal primiparity and the use of progestogens and beta‐blockers during the first trimester of pregnancy [ 6 ]. This sequence can be lethal; however, it is usually related only to limb malformations. The incidence in Latin America is one affected birth per 11,200 live births [ 7 ]. This report describes a case of DS with HD and an ABS.

The authors declare no conflicts of interest.

At birth, the infant was clinically diagnosed with DS and left radioulnar terminal transverse meromelia, characterized by amputation due to ABS (Figure  1 ). Despite this, the infant demonstrated adequate flexion and extension of the elbow. A cytogenetic analysis was performed on chromosome preparations from a peripheral blood sample. G‐banding was conducted, and the analysis of 20 metaphase cells revealed his karyotype was consistent with regular trisomy 21: 47,XY,+21[20]. Patient with Down syndrome at eight months‐old, (A) following surgical intervention for Hirschprung's disease, and (B) focus on left‐sided radio‐ulnar terminal transverse meromelia. At one month of life, the patient was admitted to the neonatal intensive care unit due to enterocolitis (grade 1B) and bicytopenia. Management included antibiotic therapy for enterocolitis and a transfusion of fresh frozen plasma to address thrombocytopenia (platelet count of 23,000). He also presented with jaundice with a total bilirubin of 16.5 mg/dL. During his hospital stay, a colonic biopsy was performed, showing the absence of ganglion cells in the submucosal and intermuscular nerve plexus, and a diagnosis of HD was established. Surgeries performed in association with HD included stoma, surgical cleaning for infection, placement of a Bogota bag, and VAC therapy. Ileostomy was performed in the right lower quadrant. In addition, congenital heart disease, patent foramen ovale, perimembranous ventricular septal defect, and persistent ductus arteriosus were diagnosed without requiring medication for treatment. The patient was also diagnosed with atrophy and total fibrosis of the testicular parenchyma, requiring a left orchiectomy.