American Journal of Medical Genetics 3:217-223 (1979)

The Association of Waardenburg Syndrome and Hirschsprung Megacolon Gilbert S. Omenn and Victor A. McKusick Division of Medical Genetics, Department of Medicine, University of Washington, Seattle (G.S.O.) and Johns Hopkins University, Baltimore (V.A.M.)

W e describe four patients with Waardenburg syndrome and Hirschsprung agang- Iioiiic megacolon. In view of pathophysiologic relationships and animal studies, we conclude that the association of these two uncommon disorders is patho- physiologically significant.

Key words: Waardenburg syndrome, Hirschsprung megacolon, deafness

INTRODUCTION

Like many other autosomal dominant disorders, the Waardenburg syndrome is char- acterized by highly variable expressivity and incomplete penetrance. The main manifesta- tions are lateral displacement of the medial canthi; hypopigmentation of the hair, skin, fundus, and irides; heterochromia; and impaired hearing, with deafness in about 20% of heterozygotes [Waardenburg, 195 1 ; Fraser, 19761 . Waardenburg syndrome with deafness occurs with a frequency of 2 cases per 100,000 general population and represents 2 4 % of cases of profound childhood deafness [Fraser, 1976; Brown and Chung, 19671 ; cases have been reported from many populations throughout the world [Fraser, 1976; Tsafrir, 1974; Hageman and Delleman, 19771.

We have noted individual patients who had Waardenburg syndrome together with Hirschsprung aganglionic megacolon [Omenn, cited in Passage, [ 19721 ; McKusick, 19731 and have sought to elicit from colleagues additional cases of this association. We report here four families in which megacolon and Waardenburg syndrome have been associated and sug- gest that the association is not fortuitous.

METHODS

We have reviewed records at the University of Washington and the Johns Hopkins Hospital, placed notices in the “New England Journal of Medicine” [McKusick, 19731 and in bulletins that reach professionals dealing with the deaf, and contacted a number of col- leagues in the fields of birth defects, pediatric surgery, and deafness. Primary data on the

Rcccivcd for publication October 2 3 , 1978; revision received November 9, 1978.

Address reprint requests t o Dr. G. S. Omenn, Office of Science and Technology Policy, Executive Office of thc President, Washington, DC 20500.

0148-7299/79/0303-0217$01.70 0 1979 Alan R. Liss, Inc.

2 18 Omenn and McKusick

probands to be reported here were reviewed in detail, and family members were examined personally by the authors in Case 1 and Case 2.

associated with deafness without positive evidence of Waardenburg syndrome. Among those set aside are four unrelated cases from Edinburgh [Skinner and Irvine, 19731, including one probably due to streptomycin; two from London [Bodian and Carter, 19631 ;one from Vancouver (RB Lowry, personal communication); one from Philadelphia (CE Koop, personal communication); two from Buffalo (JE Allen, personal communication), one of which was probably due to streptomycin; and two noted by Fraser [ 19761 , one of which was probably secondary to streptomycin while the other involved heterochromia of the irides without any other personal or familial evidence of Waardenburg syndrome. It is pos- sible that this last case (Case 66 , p 106) does represent an additional example of the joint association of Waardenburg syndrome and Hirschsprung disease.

We have excluded from analysis a number of cases in which Hirschsprung disease was

REPORTS OF PATIENTS

Case 1

Shortly after she left the hospital, obstipation was noted, and a clinical and radiographic diagnosis of tlirschsprung megacolon was made at Johns Hopkins Hospital. At 1 year she underwent signioid resection because of persistent constipation with overflow diarrhea. At 4 years profound bilateral sensorineural deafness was recognized in association with hetero- chromia irides, choroidal mottling, vitiligo, prominent nasal root, and synophrys. The presence of a white forelock was recorded during infancy by one observer, but measurements of inter-inner canthal-to-interpupillary distance were in the normal range at 4 years [Gold- berg, 1966, Case 11 . The proband was an only child, and there was no information about any relatives except the mother, who was reported to have been unaffected, but never to have had a detailed examination.

This black girl was born in 1960 at term after a normal first pregnancy for her mother.

Case 2

This boy of Welsh-Irish-English stock was born in 1969 after a normal pregnancy and delivery. He spent most of the first three months in hospitals for a series of four operations to correct Hirschsprung megacolon, which was documented histologically. Later his mother realized that he had failed to respond to voices in the hospital, and profound deafness was recognized at 6 months. He had a transient white forelock in infancy. At the University of Washington Hospital, at 2 1/2 years he was noted to have broad nasal root, lateral dystopia of the inner canthi, several strands of white hair in the midfrontal area, white eyelashes, a patch of white hair in the right eyebrow, hypoplasia of iris stroma with homogeneous deep blue color, and blotchy depigmentation of the skin. He was totally deaf. Neither parent (pedigree, Fig. 1 ) had any signs of Waardenburg syndrome, but his 5-year-old sister had widened inter-inner canthal distance without other signs. One paternal uncle had unilateral deafness and hyperplasia of the eyebrows without other signs of Waardenburg syndrome. His 7-year-old son had had hypopigmentation of the hair and eyelashes during the first year of life and on examination had a broad nasal root and increased inter-inner canthal distance for age ; audiograms were normal. The 8-year-old daughter appeared entirely normal, but the 3-year-old daughter had slightly increased inter-inner canthal distance. On recent follow-up, after six years, there are no additional signs of the disorder in these relatives. There are no cases of deafness in the rest of the family and no strikingly abnormal facial

Waardenburg Syndrome and Hirschsprung Megacolon 219

Case 1

"I' f,

Case 3

Case 2

5 f 2 + 8 7 3

Case 4

1m f

Dystopia canthorum

Examined, found

I3 megacolon B heterochromia irides

0 Deafness

Aganglionic

E! normal

Pig. 1. Pedigrees for the four probands with joint occurrence of Waardenburg syndrome and Hirsch- sprung aganglionic megacolon.

features in photographs of grandparents. This patient was noted as a personal communica- tion by Passarge [1972] .

Case 3 *

megacolon, on the basis of extreme abdominal distention. He had patches of whitish hair and heterochromia irides. He had a pull-through operation at 7 months. He has profound sensorineural deafness. His mother, now 23 years old, underwent a colectomy with rectal anastomosis at age 23 months; she is deaf, has a broad nasal root, and a history of white forelock. His maternal grandmother, now 52 years old, has had constipation and overflow diarrhea all her life, still requires 2-3 enemas per day, but has never had an operation for the aganglionic megacolon which has been demonstrated radiographically. She is deaf and still has remnants of a white forelock. None of these three affected individuals has any sibs. The great-grandmother, now 71 years old, was interviewed by telephone and she denied any signs of Waardenburg syndrome in herself, her husband, her four sibs, or her parents. How- ever, she and her mother have a history of onset of prominent graying of the hair in their twenties.

At birth this 4-year-old boy was judged by his great-grandmother to have Hirschsprung

Case 4 t

A young boy had typical Waardenburg syndrome and aganglionic megacolon. He has a sib with deafness but without other signs of Waardenburg syndrome, a paternal cousin with uncharactenzed deafness, and a maternal cousin with a white forelock. The status of these family members is uncertain.

*Case 3 was contributed by Dr. A. Besserrnan, Austin, Texas.

t Case 4 was contributed by Dr. A. Boque, Barcelona.

220 Omenn and McKusick

DISCUSSION

Waardenburg syndrome has such variable manifestations that diagnosis is often diffi- cult. Even in cases of profound childhood deafness with pigmentary anomalies, hetero- geneity of the Waardenburg syndrome may be indicated by individual patients or families without the characteristic lateral displacement of the inner canthi (type 11) [Arias, 1971 ; Hageman and Dellemann, 19771 . It is not clear whether this variability reflects multiple alleles or different major genes for the Waardenburg phenotype or factors in the genetic and environmental background. Conditions that are probably analogous to Waardenburg syn- drome have been recognized in several animal species, including cats, mice, dogs, rabbits, and mink [Bergsma and Brown, 1971; Brown and Chung, 1971; Mair, 19733. In mice [Deol, 1968 J several dominant mutations have been identified at different loci.

studied histologically at the turn of the century [Alexander, 19001, has a variable clinical and histologic picture, due to either of two autosomal dominant genes. Unilateral and bi- lateral hearing loss occurs. Using cochlear microphonic recordings, Brown and Chung [1971] were able to determine the phenotypes of kittens as young as 2 days old and then follow the development of hearing and histologic features. Some “deaf white cats” actually hear up to the age of a few weeks or months with a progressive pattern of decreasing response, while others never have any detectable cochlear microphonic response ; in parallel, the spiral ganglion and cochlea may be intact, be affected only in one part of one turn, or be severely affected. Observations on the histogenesis of inner ear degeneration in the deaf white cat [Bosher and Hallpike, 1966; Mair, 19731 indicate that degeneration of the inner ear mechanism occurs after the first days of extrauterine life, possibly because of abnormal regulation of the constitution of the endolymphatic fluid. If the factors that permit reten- tion of hearing were determined, it might become possible to prevent deafness in those pre- disposed by the Waardenburg allele. These persons have no abnormalities of the osseous structures of the middle or inner ear; some degenerative process affects the organ of Corti at a cellular level.

These pleiotropic effects of single genes may be explained by effects on the neural crest cells involved in the origin of all the tissues affected in Waardenburg syndrome [Weston, 19691 . The neural crest forms lateral to the closing neural tube in early embryogenesis. Its cells migrate extensively to produce all melanocytes (except some neuroectodermal cells in the eye), the adrenal medulla, sympathetic ganglia, sensory components of the spinal and cranial nerves, and membranous bones of the face and palate. The cochlea is served both by sensory cranial nerves and by postganglionic autonomic fibers that innervate the stria vas- cularis of the cochlea [Ross, 19691 . Degeneration of the stria vascularis has been demon- strated in deaf white mink [Sugiura and Hildring, 19701, In a histologic study of a person affected with Waardenburg syndrome, Fisch [I9591 reported absence of the organ of Corti, atrophy of the stria vascularis, and collapse of Reissner’s membrane, all consistent with neural crest defects.

Since the destination of neural crest cells includes the visceral ganglia in the gastroin- testonal tract, these ganglia could be involved in association with widespread pigmentary anomalies in any hereditary defects affecting the neural crest cells. A number of interesting hereditary syndromes have been described in the mouse [Bielschowsky and Schofield, 1960; Lane, 19661 . Homozygotes for the recessive allele piebald have spotting of the skin and a 10% incidence of aganglionic megacolon. Homozygotes for piebald-lethal are black- eyed, white-coated mice with a 100% incidence of megacolon, with onset ranging from 1 to 1 5 months. Compound heterozygotes biebaldlpiebald-lethal) are spotted and also have

The deaf, blue-eyed, white cat, noted by Bree [ 18291 and by Darwin [ 18921 and

Waardenburg Syndrome and Hirschsprung Megacolon 22 1

roughly a 10% incidence of megacolon. At another locus the allele lethal-spotting has a 100% incidence of megacolon together with a less severe pigment deficiency of skin and hair. Apparently, studies of hearing are lacking in these mice. In the cat, where dominant alleles produce hearing loss and pigmentary anomalies, megacolon or abnormality of other parts of the gastrointestinal tract has not been reported.

Against this background of embryologic relationships and seemingly analogous cate- gories of auditory/pigmentary/ganglionic anomalies in animals, the association of Hirsch- sprung aganglionic megacolon with the Waardenburg syndrome in man is not surprising. We shall attempt now to assess the significance of the association.

Hirschsprung megacolon is believed to be inherited on a multifactorial basis, quite likely involving heterogeneity of genetic predispositions. The incidence in populations of Western European origin is about 0.02% with a sex ratio of 4M:lF. The longer the agang- lionic segment the higher the recurrence risk for first-degree relatives [Bodian and Carter, 1963; Passarge, 19671 . The highest recurrence risk is 18%, for brothers of female probands with long-segment disease [Passarge, 19721 . Aganglionosis represents a failure of migration or survival of neuroblasts which originate from the vagus and migrate caudally, beginning in the fifth and sixth weeks of embryonic life [Yntema and Hammond, 1954; Okamoto and Ueda, 1967; Okamoto et al, 1967; Meier-Ruge, 19741. If neuroblasts fail to migrate to the intestinal wall in the seventh week, aganglionosis of the entire colon and segments of the ileum will result; impairment of migration in the eighth week affects the colon only; im- pairment in the ninth week affects the entire descending colon and rectosigmoid, while similar faulty development in the 10th to 12th week will affect only the rectosigmoid. In mice that develop aganglionic megacolon (piebald-lethal homozygotes) the process is basically normal, except that neuroblasts appear to migrate at a slower than normal rate, becoming out of phase with the rapid elongation of the gut [Webster, 19731 . The sacral parasympathetic extramural innervation is accentuated in congenital intestinal agang- lionosis, contributing to the permanent state of contraction of the aganglionic segment [Meier-Ruge, 19741 . Adrenergic nerves are present in relative profusion and disarray within the muscle layers, instead of forming a network around ganglion cells [Touloukina et al, 19751.

To date, we have identified only four probands (six cases) of aganglionic megacolon in association with definite Waardenburg syndrome. In a number of large series (sources: Swenson et a1 [ 19731 ; E. Koop, personal communication; A.H. Bill, Jr., personal communi- cation) no cases of known Waardenburg syndrome have been recognized. However, it should be noted that the clinical signs of Waardenburg syndrome may well be missed during the preoperative workup and subsequent care of an infant or child with signs of megacolon. The relatively low frequency of deafness in Waardenburg syndrome, and the fact that hear- ing loss may not be recognized when very young children are treated for megacolon, make deafness a poor criterion for surgical series. Finally, the two conditions are not common. Waardenburg syndrome with deafness has an incidence in the general population of about 2 per 100,000 and Hirschsprung aganglionic megacolon has an incidence of about 2 per 10,000. Thus, the joint occurrence of these two conditions by chance would be only 4 per billion people. This incidence seems to be exceeded even by the few cases summarized here. The joint occurrence of these conditions in three generations of one family (Family 3) further indicates a significant association, at least in that family, compared with the risk of 3 4 % for first-degree relatives. The only condition in which a predisposition to Hirschsprung disease has been established previously is the Down syndrome. Of 1,696 cases of Hirschsprung disease,42 (2.5%) had Down syndrome [Passarge, 1972; Swenson et al, 1973; Tobon and Shuster, 19741 . Two patients had neuroblastomas and four had pheochromocytomas

222 Omenn and McKusick

[Passarge, 19721 , possibly consistent with the hypothesis here of relationships mediated by inherited properties of neural crest cells.

There are no data on the incidence of Hirschsprung disease in Down syndrome, but a simple estimate based upon the incidences of the two conditions (2/10,000 and 1/660, re- spectively) is about one case with Hirschsprung disease among 300 cases of Down syn- drome. It will be necessary to examine carefully large series of children who have under- gone surgical therapy for Hirschsprung megacolon for signs of Waardenburg syndrome, in order to assess further the relationship proposed here. Given the low incidence of diagnosed cases of Waardenburg syndrome, the relative risk for Hirschsprung disease may well be higher than for Down syndrome.

ACKNOWLEDGMENTS

We thank Drs. Besserman, Dorman, and Boque for information about Case 3 and Case 4 , and Drs. Allen, Bill, Brown, Chung, Fraser, Hageman, Koop, Lowry, Nance, Partington, and Passarge for checking their files on Waardenburg cases and/or Hirschsprung cases.

NOTE ADDED IN PROOF

We are now aware of four additional unrelated children with Waardenburg syn- drome in association with aganglionic megacolon (K.N. Shah, Bombay, India; personal communication, 1978). No family histories are available.

REFERENCES

Alexander G (1900): Zur vergleichenden, pathologischen Anatomie der Gehoerorganes. I. Gehoerorgan and Gehirn einer unvolkommen albinotischen, weissen Katze. Arch Ohrenh 50: 159-181.

Arias S (1971): Genetic heterogcneity in the Waardenburg syndrome. Birth Defects: Orig Art Ser 7(4):

Bergsma DR, Brown KS (1971): White fur, blue eyes, and deafness in the domestic cat. J Heredity

Bielschowsky M, Schofield GC (1960): Studies on the inheritance and neurohistology of megacolon in

Bodian M, Carter CO (1963): Family study of IIirschsprung’s disease. Ann Hum Genet 29:261-277. Bosher SK, Hallpike CS (1966): Observations of the histogenesis of the inner ear degeneration of the

deaf white cat and its possible relationship to the aetiology of certain unexplained varieties of human congenital deafness. J Laryngol 80:222-235.

87-101.

6 2 : 171-185.

mice. Proc Univ Otago Med Sch 38:14-15.

Bree WT (1 829) : White cats with blue eyes always deaf. Loudon’s Magazine of Natural History 1 : 178. Brown KS, Chung CS (1967): Genetic studics of deafness at the Clarke School for the Deaf, Northamp-

ton, Mass. Report Proc Cong Education of the Deaf, Doc N o 106, 88th Cong, 2nd Session, Senate. Washington DC: US Government Printing Office, pp 643-648.

Brown KS, Chung CS (1971): Observations on the epidemiology, genetics and pathogenesis of deafness in children and lower mammals. Audiology 10:234-256.

Darwin C (1892): “The Variation of Animals and Plants Under Domestication.” 2nd Ed. New York: Appleton and Co, vo l2 , pp 322-323.

Deol MS (1968): Inherited diseases of the inner ear in man in the light of studies on the mouse. J Med Genet 5:137-158.

Fisch L (1959): Deafness as part of an hereditary syndrome. J Laryngol73:355-382. Fraser GR (1976): “The Causes of Profound Deafness in Childhood. A Study of 3535 Individuals With

Severe Hearing Loss Present at Birth or of Childhood Onset.” Baltimore: Johns Hopkins University Press, pp 90-132.

Goldberg MF (1966): Waardenburg’s syndrome with fundus and other anomalies. Arch Ophthalmol 76~797-810.

Waardenburg Syndrome a n d Hirschsprung Megacolon 223

Hageman MJ, Delleman JW (1977): Heterogeneity in Waardenburg syndrome: Am J Hum Genet 29:468485.

Lane PW (1966): Association of megacolon with two recessive spotting genes in the mouse. J Heredity 57: 29-3 1.

Mair IWS (1973): Hereditary deafness in the white cat. Acta Oto-laryngol, Suppl314. McKusick VA (1973): Congenital deafness and Hirschsprung’s disease (letter). N Engl J Med 288:691. Meier-Ruge W (1970): Hirschsprung’s disease: Its aetiology, pathogenesis and differential diagnosis.

Curr Top Pathol59:131-179. Okamoto E, Iwasaki T , Kakutani T , Ueda T (1967): Selective destruction of the myenteric plexus: Its

relation to Hirschsprung’s disease, achalasia of the esophagus, and hypertrophic pyloric stenosis. J Pediatr Surg 2:444-454.

Okamoto E, Ueda T (1967): Embryogenesis of intramural ganglia of the gut and its relation to Hirsch- sprung’s disease. J Pediatr Surg 2:437443.

Passarge E (1967): The genetics of Hirschsprung’s disease: Evidence for heterogeneous etiology and a study of sixty-three families. N Engl J Med 276:138-143.

Passarge E (1972): Genetic heterogeneity and recurrence of risk of congenital intestinal aganglionosis. Birth Defects: Orig Art Ser 8(2):63 -67.

Ross MS (1969): The general visceral efferent component of the eighth cranial nerve. J Comp Neurol 135:453-478.

Skinner R, Irvine D (1973): Hirschsprung’s disease and congenital deafness. J Med Genet 10:337-339. Sugiura A, Hildring DA (1970): Stria vascularis of deaf hedlund mink. Acta Otolaryngol69:160-171. Swenson 0, Sherman JO, Fisher JH (1973): Diagnosisof congenital megacolon: An analysis of 501

Tobon F, Shuster MM (1974): Megacolon: Special diagnostic and therapeutic features. Johns Hopkins

Touloukina RJ, Morgenroth VH 111, Roth RH (1975): Sympathetic neurotransmitter metabolism in

Tsafrir JS (1974) : “Light-Eyed Negrocs and the Klein-Waardenburg Syndrome.” London: Macmillan. Waardenburg PJ (195 1): A new syndrome combining developmental anomalies of the eyelids, eyebrows

patients. J Pediatr Surg 8587-594.

Med J 135:91-105.

Hirschsprung’s disease. J Pediatr Surg 10:593-598.

and nose root with pigmentary defects in the iris and head hair and with congenital deafness. Am J Hum Genet 3:195-253.

genital aganglionic megacolon. J Embryo1 Exp Morphol30:573-585. Webster W (1973): Embryogenesis of the enteric ganglia in normal mice and in mice that develop con-

Weston JA (1969): The migration and differentiation of neural crest cells. Adv Morphogenesis 8:41-114. Yntema CL, Hammond WS (1954): Origin of intrinsic ganglia of trunk viscera from vagal neural crest

in chick embryo. J Comp Neurol 100:515-542.

Edited by Rober t J . Gorlin