Waardenburg syndrome is a genetic disease characterized by hearing loss and pigmentation abnormalities. Waardenburg syndrome type 4 is very rare, and children with Waardenburg syndrome type 4 present with intestinal aganglionosis. The associated findings and severity of Waardenburg syndrome type 4 may also differ significantly between cases. Intestinal insufficiency is probable and creates difficulties in terms of treatment; intestinal transplant may be required. In this case report, we present 4 cases of patients with Waardenburg syndrome who have intestinal issues, 2 of whom underwent small bowel transplant. Appropriate surgical and nutritional management should be provided for patients with Waardenburg syndrome type 4 who have gastrointestinal manifestations.
Key words : Intestinal rehabilitation, Shah-Waardenburg syndrome, Small bowel transplant
Waardenburg syndrome (WS) is characterized by pigmentation differences in the eyes, hair, and skin, as well as bilateral congenital hearing loss accompanied by developmental anomalies. Waardenburg syndrome is a rare genetic disorder that is seen equally in both sexes: its incidence rate varies between 1 in 20 000 and 1 in 40 000.1 Clinical findings may vary widely between patients within the same family and among families. Incomplete forms are frequently observed. Waardenburg syndrome type 4 (WS4) is very rare, with a frequency of < 1 in 1 000 000.2 Children with WS4 present with pronounced phenotypic features and intestinal aganglionosis. Waardenburg syndrome type 4 causes total aganglionic megacolon with or without small bowel involvement. Small bowel involvement cause the clinical scenario of intestinal pseudo-obstruction and/or short bowel syndrome. The associated findings and severity of WS4 may also differ significantly between cases. Intestinal insufficiency is probable and creates difficulties in terms of treatment; intestinal transplant may be required.3
In this case series, we present 4 patients with WS4 who had intestinal failure, 2 of whom underwent small bowel transplant (SBTx). Written informed consent was obtained from parents to grant permission for publication of the cases in this report.
A 3-year-old male patient, who had an ileostomy after a diagnosis of aganglionic megacolon, was sent to our center. The patient’s history revealed that the defecation problem began postpartum. A physical examination indicated that the patient had intellectual disability, bilateral hearing loss, and abdominal distension. His parents did not have a consanguineous marriage, and it was learned that a sibling with the same clinical findings had died. Radiographic examination revealed that the stomach and intestinal loops were dilated. On this basis, the patient was diagnosed with WS4. The patient, who could not be provided with enteral nutrition, was supported with parenteral nutrition. The patient underwent an isolated SBTx at the age of 4 years from a deceased adult donor. Because of the presence of a pseudo-obstruction, a gastrostomy tube was implanted after SBTx via a percutaneous endoscopy and was used until the patient was adapted to total oral feeding. At the time of this writing, the patient was 10 years old and was fully fed enterally. His anthropometric body measurements by height and weight are now within the normal range. Hearing assistance is provided with an external audio device (Figure 1a).
An 18-month-old girl with defecation problems since birth was referred to our center after a diagnosis of aganglionic megacolon. Her parents are first-degree relatives, and we learned that 2 deceased siblings had been diagnosed with WS. A physical examination revealed a white forelock, right external ear atresia (Figure 1b), bilateral poliosis in the eyelashes, hypertelorism, and bilateral hearing loss. Jejunostomy was performed at the end of the ganglionic segment, which was supported with histopathologic examination. The patient was diagnosed with WS4 on the basis of these findings, and a cochlear implantation was performed to improve the patient’s hearing. The case was followed up with partially parenteral nutrition and enteral nutrition. The clinical presentation was short bowel syndrome, and she was monitored for intestinal adaptation.
A history revealed that the patient’s development and nutrition was normal until the age of 1 year, when he was diagnosed with intestinal pseudo-obstruction with constipation and vomiting. After undergoing a jejunostomy, he was referred to our center at the age of 3 years. There was no consanguinity between his parents. A physical examination revealed a white forelock and a partial heterochromia of the iris. Tests revealed normal hearing, and genetic analysis detected WS4. A gastrostomy tube was implanted by percutaneous endoscopy, and enteral nutrition was given. The patient received total parenteral nutritional support before being adapted to oral nutrition during follow-up. At the time of this writing, the patient was 8 years old, was being followed-up in our outpatient clinic, and was receiving total enteral nutrition. The patient’s growth according to his age is below 3 percentiles.
This male patient was not able to defecate on the first postnatal day, developed abdominal distention, and underwent a jejunostomy. Histopathology of the small intestine revealed it to be total aganglionic. A physical examination revealed a white forelock, heterogeneity in the iris, and bilateral sensorineural hearing loss. There was consanguinity between the parents, and his 1 sibling is healthy. Genetic analysis detected WS4. The patient, who could not be fed enterally and was supported with parenteral nutrition, underwent an isolated SBTx at the age of 9 months from a deceased adult donor. The patient was able to receive nutrition enterally during the follow-up, but posttransplant lymphoproliferative disease developed 9 months postoperative. He died from sepsis 1 year after the transplant.
In this case report, we evaluated 4 patients with WS4 who presented with intestinal failure. Two of the patients underwent SBTx. One patient was 10 years old at the time of this writing and was receiving total enteral nutrition, but the other patient died 1 year after the transplant as a result of posttransplant lymphoproliferative disease. Another patient received a gastrostomy to treat intermittent pseudo-obstruction attacks and was being followed-up with total oral nutrition. The final patient, who was receiving partial parenteral and enteral nutrition, was being monitored for intestinal adaptation. Clinical findings in WS4 range from mild intestinal findings to intestinal failure. The literature reports that most WS4 cases with early intestinal findings require surgical intervention in the neonatal and early infancy periods, and mortality and complication rates are high.4,5 Transplant is a potential treatment for patients with WS4 who have intestinal failure. Intestinal failure is defined as the critical reduction of functional gut mass below the minimal amount necessary for adequate digestion and absorption to satisfy body nutrient and fluid requirements. The primary indications for intestinal transplant include frequent or life-threatening episodes of line sepsis, loss of venous access, parental nutrition-induced liver failure and frequent life-threatening episodes of dehydration or electrolyte imbalances, and the lack of effective intestinal rehabilitation, as in cases of motility or epithelial disorders.6 In addition to intestinal insufficiency, patients with at least 1 of these indications were evaluated for SBTx. In our country (Turkey), the organ donation rate for SBTx is inadequate for the pediatric population. Therefore, we had to perform SBTx from deceased adult donors in these cases.
Waardenburg syndrome is an auditory and pigmentation syndrome that occurs with genetically and clinically variable features. There may be many phenotypic findings in WS. These phenotypic features are classified as major and minor criteria. For diagnosis, at least 2 major criteria, or 1 major and 2 minor criteria, must be found.7 The diagnostic criteria of WS and the characteristics of our cases are shown in Table 1.
There are 4 types of WS. Type 1 (WS1) is the most common, in which all symptoms of the disease and dystopia canthorum are seen. There is no dystopia canthorum in WS type 2 (WS2). If the condition is accompanied by musculoskeletal pathologies, then it is defined as WS type 3 (WS3, Klein-Waardenburg syndrome). Type 4 (WS4, Shah-Waardenburg syndrome) is defined as congenital aganglionic megacolon (Hirschsprung disease) accompanying WS2.8 Waardenburg syndrome is usually inherited as an autosomal dominant gene. It is rarely caused by new mutations in the gene. Autosomal recessive inheritance can be observed in patients with WS2 or WS4. Mutations in the SRY-related HMG-BOX gene 10 transcription factor (SOX10), the endothelin 3 (EDN3) gene, or the endothelin receptor type B (EDNRB) gene may be the cause of WS4. These genes play a role in the formation and development of melanocytes, as well as many cells. Melanin, which contributes to skin, hair, and eye color and plays an important role in the normal function of the inner ear, is produced by melanocytes. The embryonic neural crest, which is the precursor of melanocyte cells, also contributes to the development of limb muscles, craniofacial bones, and enteric cells.9 Hirschsprung disease is associated with WS4 and is a direct result of the timeless arrest of vagal neural crest cell migration in the posterior intestine.10
Waardenburg syndrome type 4 is characterized by the comorbid presence of Hirschsprung disease, a congenital malformation that causes intestinal obstruction and severe constipation. Waardenburg syndrome type 4, which is generally diagnosed in the neonatal period, includes abdominal swelling, vomiting, delay in meconium passage after birth, and signs of intestinal obstruction. Patients with WS4 who have intestinal pseudo-obstruction can tolerate enteral feeding with gastrostomy, and gastrostomy can reduce complaints such as abdominal distension and vomiting.11 More seriously, WS4 can occur with neonatal enterocolitis. In older children, the symptoms are more chronic and include the inability to develop.12 Any child suspected of having WS4 should be referred to pediatric gastroenterology. The treatment and nutritional approach should be determined separately for each patient depending on the severity of the disease. The prognosis may be worse in rare and more severe subtypes of WS4. If patients with colonic aganglionosis, specifically with small bowel involvement, are not properly treated, then it can cause more complications and mortality in early infancy.
Waardenburg syndrome can be found in 2% of patients with congenital sensorineural deafness. Genetic screening may also be useful in identifying neonates with mild hearing loss.8,13 Early intervention with a cochlear implant or hearing aid can improve hearing problems and mental development.8 The intellectual disability of the patient in case 1 may have been prevented by the correction of the patient’s hearing problem at a younger age.
Consequently, medical and palliative surgical treatment should be the first options for patients with WS4. In the patients who do not respond to these treatments, SBTx may be an option. It is important that WS is diagnosed early, particularly to allow for early treatment of hearing loss to ensure speech and intellectual development. Genetic counseling should be provided to the family of a patient with WS.
DOI : 10.6002/ect.2020.0166
From the 1Department of Pediatric Gastroenterology, Hepatology, and Nutrition,
Izmir Katip Celebi University, SBU Tepecik Training and Research Hospital; the
2Department of Pediatrics, SBU Tepecik Training and Research Hospital; the
3Department of Pediatric Gastroenterology, Hepatology, and Nutrition, SBU
Tepecik Training and Research Hospital; the 4Department of Cardiovascular
Surgery, SBU Tepecik Training and Research Hospital; and the 5Department of
Organ Transplantation and General Surgery, SBU Tepecik Training and Research
Hospital, Izmir, Turkey
Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no potential declarations of interest.
Corresponding author: Yeliz Cagan Appak, Department of Pediatric Gastroenterology Hepatology and Nutrition, Izmir Katip Celebi University, SBU Tepecik Training and Research Hospital, Izmir, Turkey
Phone: +90 505 598 52 29
Figure 1. External Features of Patient 1 and Patient 2
Table 1. Waardenburg Syndrome Diagnostic Criteria and Findings