|Year : 2017 | Volume
| Issue : 5 | Page : 163-168
Rahul Gupta, Dinesh Kumar Barolia, Ramesh Tanger, Lila Dhar Agrawal, Arun Kumar Gupta, Ram Babu Goyal
Department of Paediatric Surgery, SMS Medical College, Jaipur, Rajasthan, India
|Date of Submission||01-Mar-2017|
|Date of Decision||13-Apr-2017|
|Date of Acceptance||23-May-2017|
|Date of Web Publication||9-Oct-2017|
202 A, A3 Block, Kamal Apartment 2, Banipark, Jaipur, Rajasthan
Source of Support: None, Conflict of Interest: None
Introduction: Shah-Waardenburg syndrome (SWS) is WS associated with Hirschsprung's disease. It is very rare with <80 cases reported in the literature.
Aim: The aim of this study was to describe our experience with SWS.
Methods: The records of patients admitted to our tertiary care pediatric surgical institute between 2011 and 2015 were retrospectively reviewed. All patients with histopathological diagnosis of Hirschsprung's disease were studied. SWS was identified as per the diagnostic criteria proposed by the Waardenburg consortium.
Results: There were 202 patients diagnosed with Hirschsprung's disease during 5 years. We identified three male patients fulfilling the diagnostic criteria for WS (white forelock with the involvement of eyebrows and eyelashes, pigmentary disturbances of the iris, and broad high nasal root). All presented in the neonatal period with clinical and radiological features of small bowel obstruction. Family history (sibling) of SWS was seen in one of the neonates. Exploration revealed distended jejunal and ileal loops in all of them; colon contracted and unused (microcolon). Multiple seromuscular biopsies were performed from colon in all 3 neonates. Initial ileostomy was performed in case 2 and case 3. In case 1, the right transverse colostomy was done primarily as total colonic aganglionosis (TCA) was not expected (absence of transition zone in the early neonatal period) and also frozen section facilities were not available. It was followed by ileostomy (second surgery) about 15 cm proximal to the ileocecal junction as colostomy was not functioning adequately. The histopathology of gut biopsies revealed aganglionosis in the entire colon, confirming the diagnosis of TCA in all the cases. Out of three patients in our study, two neonates died in the postoperative period, while third case succumbed due to severe episodes of ileostomy diarrhea.
Conclusion: A patient of WS presenting with neonatal intestinal obstruction or constipation since birth should be evaluated on the lines of SWS . Patients with SWS have a higher incidence of TCA or long-segment Hirschsprung's disease. In SWS when transition zone is not clear, an ileostomy would be preferable in view of nonavailability of frozen section.
Keywords: Blue eyes, broad high nasal root, Hirschsprung's disease, Shah-Waardenburg syndrome, total colonic aganglionosis, white forelock
|How to cite this article:|
Gupta R, Barolia DK, Tanger R, Agrawal LD, Gupta AK, Goyal RB. Shah-Waardenburg syndrome. Formos J Surg 2017;50:163-8
| Introduction|| |
Waardenburg Syndrome (WS) is a group of genetic conditions of neural crest cell development that clinically manifests with varying degrees of pigmentary anomalies, sensorineural deafness, and minor defects in structures arising from the neural crest. The phenotypic appearance of WS or auditory-pigmentary syndrome is very prominent. It is named after the Dutch Ophthalmologist, Petrus Johannes Waardenburg.
Shah-WS (SWS) is WS associated with Hirschsprung's disease. SWS is very rare with <80 cases reported in the literature. The presentation is usually in the neonatal period with delayed passage of meconium (beyond 48 h) or with features of neonatal small bowel obstruction or constipation since birth although cases presenting beyond the neonatal period have been reported., To the best of our knowledge, only few cases of SWS with total colonic aganglionosis (TCA) as its component have been reported in the literature till date. We describe our experience with SWS, management of this rare entity, and discuss pertinent literature.
| Methods|| |
The records of patients admitted to our tertiary care pediatric surgical institute between January 2011 and December 2015 were retrospectively reviewed. All patients with histopathological diagnosis of Hirschsprung's disease were studied. SWS was identified by the presence of its various components as per the diagnostic criteria proposed by the Waardenburg consortium. The clinical, operative records and other details of patients with SWS were carefully analyzed. Charts were reviewed according to age, sex, chief complaints, duration of illness, and family history. All possible radiologic investigations were carefully reviewed. Operative records with establishment of preoperative diagnosis, intraoperative findings, and level of aganglionosis, operative procedures, postoperative records, and complications were studied.
The study was conducted in accordance with the Declaration of Helsinki and was approved by the local ethics committee of the institute. Informed written consent was obtained from all patients prior to their enrollment in this study.
| Results|| |
There were 202 patients diagnosed with Hirschsprung's disease during 5 years. We identified three male patients fulfilling the diagnostic criteria for WS [white forelock with involvement of eyebrows and eyelashes, pigmentary disturbances of the iris and broad high nasal root as seen in [Figure 1] and [Figure 2]. The results of the study are described in [Table 1] and [Table 2]. All the three patients were male neonates having low birth weight. Bilious vomiting was the chief complaint with all of them. Additional complaints were either constipation since birth or failure to pass meconium. Out of the three, two patients were in sepsis at the time of presentation. Family history (sibling) of SWS was seen in one of the neonates; his father was having features of WS [Figure 1]. All had clinical and radiological features [Figure 2] and [Figure 3] of small bowel obstruction. Operative intervention was carried out in all patients. Exploration revealed distended jejunal and ileal loops in all of them; colon contracted and unused (microcolon). Multiple seromuscular biopsies were performed from colon in all 3 neonates. Initial ileostomy approximately 15 cm proximal to the ileocecal junction was performed in case 2 and case 3. In case1, the right transverse colostomy was done primarily as TCA was not expected (absence of transition zone in the early neonatal period) and also frozen section facilities were not available. It was followed by ileostomy (second surgery) about 15 cm proximal to the ileocecal junction as colostomy was not functioning adequately. The histopathology of gut biopsies revealed aganglionosis in the entire colon, confirming the diagnosis of TCA in all the cases. Out of 3 patients in our study, case 1 died postoperatively due to complications of sclerema neonatorum (within 1st postoperative week), while case 2 died due to complications of sepsis (9th postoperative day). Case 3 was discharged with ileostomy and was planning Martin modification of Duhamel procedure in the patient, but the patient suffered severe episodes of ileostomy diarrhea and was admitted to a private clinic for the treatment. He succumbed due to dyselectrolytemia and severe dehydration, before reaching infancy.
|Figure 1: Clinical photographs showing white forelock and partial albinism in the patient, (a and b) blue eyes and white eyebrows and eyelashes, (c) while his father has heterochromia irides in the left eye and a broad nasal root (d)|
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|Figure 2: Clinical photographs showing white forelock, blue eyes, white eyebrows and eyelashes, broad nasal root, and partial albinism in the patient, (a) abdominal radiographs revealing dilated small bowel loops with few air-fluid levels and absence of any colonic gas shadow (b)|
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|Figure 3: The abdominal radiographs of the neonate revealing dilated small bowel loops but no air-fluid levels, (a) barium enema showed a microcolon with no obvious transitional zone (b)|
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|Table 2: Management and outcome of patients with Shah-Waardenburg syndrome|
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| Discussion|| |
WS is rare with predicted incidence of 1/40,000 live births. The clinical features in WS may vary among affected individuals, even among people in the same family. According to the diagnostic criteria proposed by the Waardenburg consortium, a patient must have two major or one major plus two minor criteria to be diagnosed as WS type I., Major criteria are white forelock, pigmentary disturbances of the iris, congenital sensorineural hearing loss, affected first-degree relative, and dystopia canthorum; minor criteria are broad/high nasal root, hypoplasia of alae nasi, synophrys or medial eyebrow flaring, skin hypopigmentation, and premature graying of hair (before age 30).,
Iris pigmentary abnormality may constitute two eyes with different color or iris bicolor (heterochromia irides) or characteristic brilliant blue iris. Hair hypopigmentation constitute white forelock or white hairs at other sites on the body. Dystopia canthorum is lateral displacement of inner canthi., There are four subtypes of WS. WS type II lacks dystopia canthorum of WS type I. Type III, also called Klein–WS (rarest form), and has associated limb abnormalities. Type IV WS or SWS or Waardenburg-Hirschsprung disease is an extremely rare variant of WS with <80 cases reported in literature. It is named after Shah et al. Shah who described 12 newborns with WS associated with long-segment Hirschsprung's disease in 1981.,
Neurocristopathy is a diverse class of pathologies (spectrum of disorders) that may arise from defects in the development of tissues containing cells commonly derived from the embryonic neural crest cell lineage. Neural crest cells are transient and multipotent progenitors that give rise to various cell types, including neural, enteric nervous system, sympathetic ganglia, and sensory components of the spinal and cranial nerves, endocrine, inner ear, pigment (melanocytes), craniofacial, and conotruncal cardiac cells. The aberrations of neural crest cell occur in growth, migration, and differentiation. The term “neurocristopathy” was coined by Bolande in 1974., Neurocristopathy is divided into 2 types: (1) simple type - single pathological process (unifocal, localized) which may be (a) nonneoplastic dysgenetic (Hirschsprung's disease, albinism, mandibulofacial dysostosis, otocephaly, congenital central hypoventilation syndrome [CCHS], WS) and (b) neoplastic (neuroblastoma, pheochromocytoma, medullary carcinoma thyroid, carcinoid tumors, nonchromaffin paraganglioma) and (2) complex type - multifocal disease (syndromic forms, more complex and associations of simple types) which may be (a) nonneoplastic dysgenetic (CCHS with Hirschsprung's disease [Haddad syndrome], CHARGE syndrome, and SWS) and (b) neoplastic (neurofibromatosis, multiple endocrine neoplasia [MEN] type 1, MEN type 2A, MEN type 2B, neurocutaneous melanosis, familial neuroblastoma with Hirschsprung's disease).,, Thus, Hirschsprung disease is a neurocristopathy of the enteric nervous systems and SWS is a complex nonneoplastic neurocristopathy (involving melanocytes and the neuroblasts which contribute the enteric ganglion cells). Bowel involvement in SWS is characteristic in the form of aganglionosis in the myenteric and submucous plexus with variable length of the involved intestines.,, Patients with SWS have a higher incidence of TCA with or without small bowel involvement., The bowel involvement may be long-segment, or short-segment or even limited to persistent constipation., WS usually have the characteristic hair and skin changes and also sensorineural hearing loss. In case of mild variety, symptoms may be masked and it may go undiagnosed until a family member is diagnosed and all family members are examined. In our study, pigmentary abnormality of iris and white forelock were present in all the cases. Audiologic evaluation (brainstem evoked response audiometry) during neonatal screening is performed for assessment of sensorineural hearing loss.,
SWS is heterogeneous, ascribed to either of three genes.(i) SOX10 (22q13.1), dominant trait, encoding the SRY-bOX10 transcription factor; (ii) endothelin3/EDN3 (20q13.2-q13.3), recessive trait, encoding the endothelin 3 peptide; (iii) endothelin-B receptor (EDNRB) (13q22), dominant or recessive trait) encoding its receptor.,, These genes regulate the proliferation, migration, and differentiation of the neural crest cells. SOX10 mutations account for about 50% case of SWS.,, Regarding EDNRB gene, a nonsense mutation at codon 253 has been identified (CGA→TGA, Arg→STOP) which leads to a premature end of the translation of EDNRB at exon 3, and it is predicted to produce a truncated and nonfunctional EDNRB., There is 50% risk of having affected children in succeeding pregnancy; hence, genetic counseling for parents is paramount. Periconceptional folic acid supplementation has been recommended for women at increased risk of having a child with WS.
Male predominance was seen in our cases with SWS and it has been observed by other authors also.,,,,,, All our patients presented in neonatal period and were low birth weight. Furthermore, in Hirschsprung's disease, males are 3.5–4.0 times more likely to be affected than females. However, WS equally affects both sexes and all races. Familial SWS has been reported earlier also.,
The differential diagnoses of aganglionosis (gastrointestinal features in WS) are ileal atresia, neonatal small left colon syndrome, meconium ileus, meconium plug syndrome, and intestinal neuronal dysplasias. The differential diagnosis of white forelock and skin patches is Vitiligo, Piebaldism, Rozycki syndrome, Vogt–Koyanagi–Harada syndrome, Tietze syndrome, and tuberous sclerosis.
Referral to pediatric surgical center should be done at the earliest as typical radiological features; including air-fluid levels and the presence of dilated colonic loops are usually absent, when associated with TCA. Contrast enema may show microcolon in cases with TCA. Initial surgical management in SWS is confirmation of diagnosis by routine seromuscular colonic biopsy and stoma formation depending on the involvement of the colon as per frozen section biopsy report (not available at our institute).,, Appendix biopsy helps in supplementing the diagnosis of TCA. It must be sent to histopathological evaluation along with other seromuscular colonic biopsy specimens. In case of involvement of the entire colon with contracted and unused microcolon (TCA) and when transition zone is not clear, an ileostomy would be preferable in case of nonavailability of frozen section. Ileostomy in TCA should be fashioned at least 10–15 cm proximal to the ileocecal valve. This is supported by other study also. As level of aganglionosis is variable and may extend into proximal jejunoileum (extensive small bowel aganglionosis), enterostomy (higher diversion) is decided on case-to-case basis., Pathology of ileum in our cases could not be checked as frozen section facility was not available at our institute. Second, there was absence of transition zone (absent in the early neonatal period). Third, there was unfavorable outcome in our patients. Thus, initial treatment is usually directed on the lines of TCA or long-segment Hirschsprung's disease.
The definitive treatment of aganglionosis is performed at a later date according to the level of involvement. Colonic patch graft procedure as proposed by Kimura et al., an extended myectomy–myotomy advocated by Ziegler et al., modified Duhamel and ileoanal pull-through with Soave technique have been described for TCA and extensive small bowel aganglionosis.,
Outcomes for TCA (without WS) presenting in neonatal age tend to be poor with high mortality rate in our region. In addition, there was delayed referral and also delayed diagnosis in two of our cases which resulted in their mortality. Improper referral facilities in rural Indian setup, lack of knowledge among clinicians about the disease entity are the cause of delayed diagnosis. Mortality is also very high in patients of SWS with TCA or long-segment Hirschsprung's disease., Higher incidence of malnourishment and enterocolitis complicates SWS.,, Short bowel syndrome and complications related to total parenteral nutrition are seen with higher diversion.,,, Prognosis was also poor in our series owing to delayed presentation, sepsis, and sclerema in our two cases. Mutational analysis (not done in our cases due to resource limitations) is crucial for gaining a better understanding of its pathogenesis, development of new strategies for the prevention and treatment.
Our recommendations are:
- Suspect SWS in case of WS presenting with delayed passage of meconium or neonatal intestinal obstruction or constipation
- Pediatric surgical opinion must be sought early to prevent delay in diagnosis and morbidity associated with it
- When entire colon is contracted and unused, an ileostomy (at least 10–15 cm proximal to the ileocecal valve) should be preferred if frozen section facility is unavailable as neonates with SWS have a higher incidence of TCA
- Appendix must be sent to histopathological evaluation along with other seromuscular colonic biopsy specimens
- Prognosis must be explained to the parents as there is high mortality associated with this entity
- Family members must be evaluated for WS.
| Conclusion|| |
Clinicians, especially pediatricians and pediatric surgeons should have high index of suspicion for SWS in any case of WS presenting with neonatal intestinal obstruction or constipation since birth. With delay in diagnosis, prognosis is poor. Timely and appropriate referral is paramount. Patients with SWS have a higher incidence of long-segment Hirschsprung's disease or TCA as observed in all the cases in our study. In SWS when transition zone is not clear, an ileostomy would be preferable in case of nonavailability of frozen section. Parents and siblings of the patient should be examined for signs of WS.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]