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Show Congenital Mydriasis Associated With Megacystis Microcolon Intestinal Hypoperistalsis Syndrome Collin McClelland, MD, Ryan D. Walsh, MD, Kudakwashe R. Chikwava, MBChB, Mark P. Johnson, MD, MS, Peter Mattei, MD, FACS, FAAP, Grant T. Liu, MD Abstract: We report a case of congenital mydriasis in a neonate with megacystis microcolon intestinal hypoperistal-sis syndrome (MMIHS). Pilocarpine testing and gastrointesti-nal pathology in our patient suggest that the mydriasis is due to an underlying smooth muscle myopathy of the iris sphincter muscle. These findings may have important implications regarding the pathogenesis of MMIHS. Journal of Neuro-Ophthalmology 2013;33:271-275 doi: 10.1097/WNO.0b013e31828b7d65 © 2013 by North American Neuro-Ophthalmology Society Megacystis microcolon intestinal hypoperistalsis syn-drome (MMIHS) is a rare congenital disease affecting smooth muscle peristalsis in the gastrointestinal (GI) tract and urinary bladder. Although the literature is full of hypotheses regarding the etiology of MMIHS, there is still no established pathophysiology. A mouse model lacking the a3 subunit of the nicotinic acetylcholine receptor (nAChR) has demon-strated phenotypic features of MMIHS, including megacystis, distended bowel, postnatal growth deficiency, and death within the first week of life (1). The mouse model also exhibited marked pupillary mydriasis, but at the time, mydriasis had not been reported in humans with MMIHS. A report of an infant with MMIHS and bilateral mydriasis further supports the theory that MMIHS is caused by a genetic defect in the nAChR a3 subunit (2). We report the second case of bilateral mydriasis associated with MMIHS and present the results of pilocarpine testing that, along with the histopathology of the excised intestine, suggest an underlying smooth muscle myop-athy in MMIHS. CASE REPORT A 23-year-old otherwise healthy Caucasian woman with no family history of consanguinity presented to our institution after an abnormal routine fetal ultrasound during an uncomplicated second pregnancy. Her first pregnancy was complicated by mild pre-eclampsia but resulted in a healthy baby boy. A high-resolution ultrasound at 28 weeks of gestational age showed a female fetus at the 95th percentile weight for her age and a markedly distended urinary bladder. Fetal magnetic resonance imaging (MRI) (Fig. 1) confirmed the ultrasound findings and also demonstrated a small sig-moid and descending colon raising suspicion for MMIHS. The child was born at 35 weeks gestational age through elective cesarean section and appeared neurologically normal except for mydriatic pupils bilaterally. She failed to tolerate any feeds, necessitating parenteral nutrition through a cen-tral venous line. Prenatal and postnatal testing for infectious teratogens, including toxoplasmosis, rubella, cytomegalovi-rus, and herpes (TORCH infections), were negative. At 8 weeks of age, it was recommended that she undergo extensive abdominal surgery. At operation, she was found to have intestinal malrotation with midgut volvulus (pre-sumably having occurred in utero), multiple small intestinal atresias, and a microcolon. Several atresias were repaired, and nonviable intestine was resected (Fig. 2A), leaving approximately 65 cm of small bowel, an intact ileocecal valve, and a complete colon. A gastrostomy tube was placed. Post-operatively, feeding attempts remained unsuccessful. A second Department of Ophthalmology and Visual Sciences (CM), Wash-ington University, St Louis, Missouri; Departments of Ophthalmology and Neurology (RDW), The Medical College of Wisconsin, Mil-waukee, Wisconsin; The Neuro-Ophthalmology Service (GTL); Department of Pathology (KRC); Center for Fetal Diagnosis and Treatment (MPJ); Division of General, Thoracic and Fetal Surgery in the Department of Surgery (PM), The Children's Hospital of Phila-delphia and The Perelman School of Medicine, University of Penn-sylvania, Philadelphia, Pennsylvania. The authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the full text and PDF versions of this article on the journal's Web site (www. jneuro-ophthalmology.com). Address correspondence to Grant T. Liu, MD, Division of Neuro-ophthalmology, Department of Neurology, University of Pennsylvania School of Medicine, 3400 Spruce Street, Philadelphia, PA 19104; E-mail: gliu@mail.med.upenn.edu McClelland et al: J Neuro-Ophthalmol 2013; 33: 271-275 271 Clinical Observation Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. laparotomy was required 6 weeks after the first and revealed extensive adhesions and an intra-abdominal abscess. She has since remained dependent on parenteral nutrition and is being considered for bowel transplantation. Pathology of the resected small intestine (Fig. 2B, C) showed the circular layer of the muscularis propria to be markedly thicker than the focally discontinuous longitudi-nal layer of the muscularis propria. No aganglionic segments were seen, and the number of ganglion cells appeared nor-mal (Fig. 2D). Trichrome stains showed increased fibrous tissue in the submucosa and longitudinal layer of muscularis propria (Fig. 2E). Desmin and smooth muscle actin stains highlighted thinning and discontinuity of the longitudinal layer of the muscularis propria. A c-Kit stain demonstrated the presence of interstitial cells of Cajal. Neuro-ophthalmic evaluation at 3.5 months of age demonstrated intermittent fixation and following of a toy with both eyes. Motility appeared full with normal alignment on Hirschberg testing. There was no nystagmus. Facial grimacing was normal and symmetric. Corneal sensation was normal with cotton swab testing. Portable slit-lamp examination did not show cataract formation or iris trans-illumination but was remarkable for bilateral 7-mm non-reactive pupils with diffusely hypotrophic appearing irides with diminished surface crypts. There were spoke-like remnants of iris vessels spanning from the iris collarette across a hypotrophic pupillary ruff to the anterior lens surface. Fundus examination was normal in both eyes. One week later, pupillary testing was performed by placing 2 sets of 0.125% pilocarpine drops 5 minutes apart in both eyes. After 30 minutes, there was no significant change between the pre-drop (Fig. 3A) and the post-drop pupillary appearance (Fig. 3B). Next, an additional 2 sets of 1% pilocarpine drops were placed 5 minutes apart in both eyes. After 30 minutes, there was again no significant change in the pupillary examination (Fig. 3C). MRI of the brain and orbits was unremarkable, and an electroen-cephalogram (EEG) revealed no epileptiform activity. DISCUSSION MMIHS classically presents at birth in female infants (M:F = 1:2.3), with abdominal distension, an enlarged nonobstructed bladder, and a microcolon related to GI hypo-peristalsis (3-5). The majority of MMIHS patients fail enteric feeds and succumb to complications of chronic parenteral nutrition in the first year of life (3,6). GI promotility medi-cations (3) and numerous surgical interventions (2,3,5-7) often fail due to severe GI hypoperistalsis. A review of GI histopathology in MMIHS found that 72 of 93 cases showed a normal quantity and morphology of ganglion cells in excised intestinal segments (3). As in our case, the intestinal longitudinal muscle layer typically shows thinning and fibro-sis on light microscopy (8), whereas electron microscopy has disclosed myopathic changes including vacuolar degeneration of smooth muscle cells (8-11). Not observed in our case, excised bowel in MMIHS may show deficient immunohisto-chemical staining for a-smooth muscle actin (10,12). Numerous hypotheses for the pathogenesis of MMIHS have been proposed, including inflammatory (13), drug-induced teratogenesis (14), hormonal (15), neurogenic (1,2,16,17), and myogenic (8,10,12,18) causes. Over time, 2 leading theories for the pathogenesis of MMIHS have emerged: a smooth muscle myopathy related to abnormal expression of smooth muscle actin and a neurogenic distur-bance caused by a mutation in the a3 subunit of the nAChR in parasympathetic ganglia. Anatomical studies of chickens and guinea pigs have found that the a3 subunit of the nAChR to be prevalent in autonomic ganglia (19,20), and humans with antibodies to the a3 subunit of the nAChR demonstrate widespread autonomic dysfunction correlating with antibody levels (21). Xu et al (1) reported a mouse model lacking the a3 subunit of the nAChR that shares some similarities with human MMIHS, including megacystis, distended bowel, postnatal growth deficiency, and premature death leading to the theory that MMIHS is caused by an a3 nAChR subunit mutation. Subsequent in situ hybridization studies have shown decreased expression of the nAChR a3 subunit in MMIHS intestinal specimens (16). Other features of the nAChR a3 subunit knockout murine model including bilateral pupillary mydriasis were not associated with MMIHS until a report described pupillary mydriasis in association with MMIHS (2). We considered a variety of causes of neonatal pupillary dilation in our patient (Table 1). She received no sympatho-mimetic medications or eye drops. The iris was hypotrophic, FIG. 1. Sagittal T1 magnetic resonance imaging shows a massively enlarged fetal bladder (straight arrow) com-pared with the normal maternal bladder (arrowhead). 272 McClelland et al: J Neuro-Ophthalmol 2013; 33: 271-275 Clinical Observation Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. but structurally complete, making aniridia unlikely. Nor-mal alignment, full motility, and an absence of ptosis excluded bilateral third nerve palsies. A normal EEG and MRI, lack of fluctuation in pupil size, and absence of seizure-like activity excluded seizure-associated mydriasis. Although congenital, bilateral tonic pupils can occur and have been reported in association with neuroblastoma (22), congenital tonic pupils should exhibit supersensitivity to dilute pilocarpine (0.1%) drops. After a lack of pupillary response to 1% pilocarpine and a careful evaluation failed to reveal an alternative explanation, the diagnosis of congenital mydriasis (CM) associated with MMIHS was made. CM is defined as congenital pupillary dilation (.6 mm in diameter), grossly normal iris structure, and diminished accommodation in some cases (23,24). The pathophysiology underlying iris dysgenesis in CM remains unclear and likely reflects many different etiologies. A high frequency of hypotrophic irides and persistent pupillary membranes are observed in CM cases (23,25-28). Other systemic diseases associated with CM include Waardenburg syndrome, isolated patent ductus arteriosus (25,26,28-30), and the recently described multisystemic smooth muscle dys-function syndrome (MSMDS) (31,32).MSMDS is a systemic disorder of smooth muscle function affecting vascular, GI, genitourinary, pulmonary, and iris smooth muscle that has been associated with mutations of the smooth muscle-specific contractile protein alpha actin (ACTA2) (31,32). Although similarities exist between MMIHS and MSMDS, many fea-tures of MSMDS, such as thoracic aortic aneurysms, periven-tricular white matter changes on MRI, and central nervous system moyamoya-like vascular abnormalities, are not char-acteristic of MMIHS and were not seen in our patient (31). Our patient's lack of pupillary constriction to 1% pilocar-pine suggests that CM in MMIHS is caused by a structural FIG. 2. A. Resected maldeveloped small intestine demonstrates areas of atresia (arrow). B. Segment of resected intestine reveals circular layer (CL) of the muscularis propria to be markedly thicker than the longitudinal layer (LL) of the muscularis propria (hematoxylin and eosin, ·100). C. There is focal discontinuity (between arrows) within the LL of the muscularis propria (hematoxylin and eosin, ·100). D. There are normal quantity and morphology of ganglion cells (arrows) within the resected intestine (hematoxylin and eosin, ·200). E. Increased blue staining of fibrous tissue is present in the LL of the muscularis propria (trichrome, ·40). McClelland et al: J Neuro-Ophthalmol 2013; 33: 271-275 273 Clinical Observation Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. iris abnormality such as a smooth muscle myopathy, although the possibility exists that the myopathic and neurogenic theories for MMIHS may not be mutually exclusive. Graf and Jungherr (26) theorized that CM could arise from "orthograde transsynaptic dysgenesis" of the iris musculature due to a "lack of sensibility of the cholinergic receptors." In accord with this theory, a genetic mutation causing dysfunction of the nAChR a3 subunit in both sympathetic and parasympathetic ganglia could lead to a secondary myopathy of smooth muscle through-out the GI tract, bladder, and, rarely, the iris smooth muscle structures as exhibited in the a3 nAChR knockout mouse model (1). Further discussion is available (see Supple-mental Digital Content, http://links.lww.com/WNO/A67). ACKNOWLEDGMENT The authors thank Taryn M. Edwards, MSN, CRNP, NNP-BC, for her assistance in reviewing the details of the patient's hospital course. REFERENCES 1. Xu W, Gelber S, Orr-Urtreger A, Armstrong D, Lewis RA, Ou CN, Patrick J, Role L, De Biasi M, Beaudet AL. Megacystis, mydriasis, and ion channel defect in mice lacking the alpha3 neuronal nicotinic acetylcholine receptor. Proc Natl Acad Sci U S A. 1999;96:5746-5751. 2. Narayanan M, Murphy MS, Ainsworth JR, Arul GS. Mydriasis in association with MMIHS in a female infant: evidence for involvement of the neuronal nicotinic acetylcholine receptor. J Pediatr Surg. 2007;42:1288-1290. 3. Puri P, Shinkai M. Megacystis microcolon intestinal hypoperistalsis syndrome. Semin Pediatr Surg. 2005;14:58-63. 4. Berdon WE, Baker DH, Blanc WA, Gay B, Santulli TV, Donovan C. Megacystis-microcolon-intestinal hypoperistalsis syndrome: a new cause of intestinal obstruction in the newborn. Report of radiologic findings in five newborn girls. AJR Am J Roentgenol. 1976;126:957-964. 5. Kohler M, Pease PW, Upadhyay V. Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) in siblings: case report and review of the literature. Eur J Pediatr Surg. 2004;14:362-367. 6. Anneren G, Meurling S, Olsen L. Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS), an autosomal recessive disorder: clinical reports and review of the literature. Am J Med Genet. 1991;41:251-254. 7. Melek M, Edirne Y, Beger B, Cetin M. Megacystis-microcolon-intestinal hypoperistalsis syndrome: a case report. Gastroenterol Res Pract. 2009;2009:282753. 8. Puri P, Lake BD, Gorman F, O'Donnell B, Nixon HH. Megacystis-microcolon- intestinal hypoperistalsis syndrome: a visceral myopathy. J Pediatr Surg. 1983;18:64-69. 9. Farrell SA. Intrauterine death in megacystis-microcolon-intestinal hypoperistalsis syndrome. J Med Genet. 1988;25:350-351. 10. Rolle U, O'Briain S, Pearl RH, Puri P. Megacystis-microcolon-intestinal hypoperistalsis syndrome: evidence of intestinal myopathy. Pediatr Surg Int. 2002;18:2-5. 11. Young ID, McKeever PA, Brown LA, Lang GD. Prenatal diagnosis of the megacystis-microcolon-intestinal hypoperistalsis syndrome. J Med Genet. 1989;26:403-406. 12. Piotrowska AP, Rolle U, Chertin B, De Caluwe D, Bianchi A, Puri P. Alterations in smooth muscle contractile and cytoskeleton proteins and interstitial cells of Cajal in megacystis microcolon intestinal hypoperistalsis syndrome. J Pediatr Surg. 2003;38:749-755. 13. Srikanth MS, Ford EG, Isaacs H Jr, Mahour GH. Megacystis microcolon intestinal hypoperistalsis syndrome: late sequelae and possible pathogenesis. J Pediatr Surg. 1993;28:957-959. 14. Dogruyol H, Gunay U, Esmer A, Kahveci R. Megacystis-microcolon- intestinal hypoperistalsis syndrome in a newborn after clomiphene ingestion during pregnancy. Z Kinderchir. 1987;42:321-323. 15. Jona JZ, Werlin SL. The megacystis microcolon intestinal hypoperistalsis syndrome: report of a case. J Pediatr Surg. 1981;16:749-751. 16. Richardson CE, Morgan JM, Jasani B, Green JT, Rhodes J, Williams GT, Lindstrom J, Wonnacott S, Thomas GA, Smith V. Megacystis-microcolon-intestinal hypoperistalsis syndrome and the absence of the alpha3 nicotinic acetylcholine receptor subunit. Gastroenterology. 2001;121:350-357. TABLE 1. Causes of bilateral pupillary dilation in a neonate Pharmacologic Tonic pupils Idiopathic Neuroblastoma Bilateral third nerve palsies Aniridia Ictal pupillary dilation Congenital mydriasis Isolated Megacystis microcolon intestinal hypoperistalsis syndrome MSMDS Patent ductus arteriosus associated without other MSMDS features MSMDS, multisystemic smooth muscle dysfunction syndrome. FIG. 3. A. Pupillary appearance before pilocarpine admin-istration shows 7-mm pupils bilaterally. Thirty minutes after the application of 2 sets of 0.125% pilocarpine drops (B) and 1% pilocarpine drops (C), there is no change in the size of the pupils. 274 McClelland et al: J Neuro-Ophthalmol 2013; 33: 271-275 Clinical Observation Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. 17. Szigeti R, Chumpitazi BP, Finegold MJ, Ranganathan S, Craigen WJ, Carter BA, Tatevian N. Absent smooth muscle actin immunoreactivity of the small bowel muscularis propria circular layer in association with chromosome 15q11 deletion in megacystis-microcolon-intestinal hypoperistalsis syndrome. Pediatr Dev Pathol. 2010;13:322-325. 18. Ciftci AO, Cook RC, van Velzen D. Megacystis microcolon intestinal hypoperistalsis syndrome: evidence of a primary myocellular defect of contractile fiber synthesis. J Pediatr Surg. 1996;31:1706-1711. 19. Kirchgessner AL, Liu MT. Immunohistochemical localization of nicotinic acetylcholine receptors in the guinea pig bowel and pancreas. J Comp Neurol. 1998;390:497-514. 20. Role LW, Berg DK. Nicotinic receptors in the development and modulation of CNS synapses. Neuron. 1996;16:1077-1085. 21. Winston N, Vernino S. Recent advances in autoimmune autonomic ganglionopathy. Curr Opin Neurol. 2010;23:514-518. 22. Lambert SR, Yang LL, Stone C. Tonic pupil associated with congenital neuroblastoma, Hirschsprung disease, and central hypoventilation syndrome. Am J Ophthalmol. 2000;130:238-240. 23. Lindberg K, Brunvand L. Congenital mydriasis combined with aneurysmal dilatation of a persistent ductus arteriosus Botalli: a rare syndrome. Acta Ophthalmol Scand. 2005;83:508-509. 24. Caccamise WC, Townes PL. Bilateral congenital mydriasis. Am J Ophthalmol. 1976;81:515-517. 25. Buys Y, Buncic JR, Enzenauer RW, Mednick E, O'Keefe M. Congenital aplasia of the iris sphincter and dilator muscles. Can J Ophthalmol. 1993;28:72-75. 26. Graf MH, Jungherr A. Clinicopathologic reports, case reports, and small case series: congenital mydriasis, failure of accommodation, and patent ductus arteriosus. Arch Ophthalmol. 2002;120:509-510. 27. Li G, Polomeno RC. Congenital mydriasis: spontaneous resolution in one of two cases. Can J Ophthalmol. 2005;40:204-207. 28. Richardson P, Schulenburg WE. Bilateral congenital mydriasis. Br J Ophthalmol. 1992;76:632-633. 29. Laor N, Korczyn AD. Waardenburg syndrome with a fixed dilated pupil. Br J Ophthalmol. 1978;62:491-494. 30. Suzuki T, Obara Y, Fujita T, Shoji E. Unilateral congenital mydriasis. Br J Ophthalmol. 1994;78:420. 31. Milewicz DM, Ostergaard JR, Ala-Kokko LM, Khan N, Grange DK, Mendoza-Londono R, Bradley TJ, Olney AH, Ades L, Maher JF, Guo D, Buja LM, Kim D, Hyland JC, Regalado ES. De novo ACTA2 mutation causes a novel syndrome of multisystemic smooth muscle dysfunction. Am J Med Genet A. 2010;152A:2437-2443. 32. Moller HU, Fledelius HC, Milewicz DM, Regalado ES, Ostergaard JR. Eye features in three Danish patients with multisystemic smooth muscle dysfunction syndrome. Br J Ophthalmol. 2012;96:1227-1231. McClelland et al: J Neuro-Ophthalmol 2013; 33: 271-275 275 Clinical Observation Copyright © North American Neuro-Ophthalmology Society. 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