Hirschsprung's Disease and Waardenburg's Syndrome

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PEDIATRICS Vol. 63 No. 5 May 1979 803

under

conditions that produced symptoms,

prolactin levels were depressed in the presence of

anxiety, pain, and fatigue, confirming the

impres-sion that prolactin inhibition was the problem.

In the absence of breast distention, the

symp-toms of continual milk leakage (case 3), excessive

nocturnal milk leakage (cases 1 and 4), and milk

ejection at the conclusion of the feeding (case 4)

represent inappropriate and excessive oxytocin

release. The postfeeding milk ejection in case 4

was of sufficient intensity on several occasions to

cause milk leakage to the floor. Cobo” has shown

a dose-effect relationship between circulating

oxytocin and milk-ejecting activity.

The recovery of reflex signs in these cases is of

interest because the process of reflex regulation

can be observed. These cases provide evidence

that the neurotransmitter dopamine plays a role

in the regulation of oxytocin release as well as

prolactin inhibition. Patients 1 and 4 responded

to chlorpromazine not only with breast fullness,

but

with less nocturnal milk leakage. Four weeks

later, the response in patient 4 to four days of

chlorpromazine therapy was cessation of

noctur-nal milk leakage. After seven weeks, this patient

experienced engorgement with no milk leakage in

response to 25 mg of chlorpromazine. With

dopamine blocked by chlorpromazine, oxytocin

was inhibited. With increased catecholamine

synthesis, oxytocin release was exacerbated.

Alco-hol causes an increase in brain catecholamine

synthesis.’2 Alcoholic intake of one drink

exacer-bated nocturnal milk leakage in patient 4. There

is also a nocturnal rise in brain catecholamine

‘ 2 Excessive nocturnal milk leakage

recurred in patient 4 during an episode of pain

immediately after she ended a course of

chlorpro-mazine therapy, both factors increasing central

dopamine. Chlorpromazine has been reported to

inhibit posterior pituitary hormone release.’

Moon and Turner’ ‘ demonstrated in an

experi-mental model that reserpine, a drug that depletes

catecholamine stores in the brain, acts as a

lactogen and inhibits oxytocin release.

Increased lactational sufficiency accompanied

the return of reflex signs. An increase of reflex

signs was accompanied by shifts in the slope of

the infants’ weight curves (cases 1, 3, and 4).

Weight gain in all infants became appropriate for

height. From the maternal point of view, these

patients experienced good outcomes, with

increased maternal confidence and enjoyment of

the infant.

1200

East Genesee Street Sijraciise,

NY

13210

CAROL E. WEICHERT, M.D.

REFERENCES

1. Jacobs LS, Daughaday WH: Physiologic regulation of

prolactin secretion in man, in Josimovich JB, Reynolds M, Cobo E (eds): Lactogenic Hormones, Fetal Nutrition and Lactation. New York, John Wiley & Sons Inc, 1974.

2. Tyson JE, Hwang P, Guyda H, et al: Studies of prolactin secretion in human pregnancy. Am I Obstet Gym’-co! 113:14, 1972.

3. Tindall JS, Knaggs GS: Pathways in the forebrain of the

rabbit concerned with the release of prolactin. I Endocrinol 52:253, 1972.

4. Tindal JS, Knaggs GS: Determination of the detailed

hypothalamic route of the milk-ejection reflex in

the guinea pig. I Endocrinol 50:135, 1971.

5. Cross BA: Neural control of lactation, in Kon 5K, Cowie AT (eds): Milk: The Mammary Gland and its

Secre-hon-i. New York, Academic Press Inc, 1961.

6. Cross BA: Neural control of oxytocin secretion, in

Martini LM, Ganong WF (eds):

Neuroendocrinolo-gy. New York, Academic Press, Inc, 1969.

7. Maclean PD, Ploog DV: Cerebral representation of

penile erection. I Neurophysiol 25:29, 1962. 8. Reichlin 5: Neuroendocrinologv, in Williams RH (ed):

Textbook of Endocrinology. Philadelphia, %VB

Satin-ders Co, 1974.

9. Zacur HA, Foster GV, Tyson JE: Multifactorial

regula-tion of prolactin secretion. L.ancet 1:410, 1976. 10. Friesen HG, Fourmier P, Desjardins P: Pituitary

prolac-tin in pregnancy and normal lactation. Clin Obstet Gynecol 16:25, 1973.

11. Cobo E: Neuroendocrine control of milk ejection in

women, in Josimovich JB, Reynolds M, Cobo E

(

eds): Lactogenic Hormones, Fetal Nutrition and

Lactation. New York, John Wiley & Sons Inc.

1974.

12. Melinon KL: Catecholamines amid the adrenal medulla, in Williams RH (ed): Textbook of Endocrinology.

Philadelphia, WB Saunders Co, 1974.

13. Goodman LS, Gilman A (ed): The Pharmacological Basis of Therapeutics, ed 5. New York, Macmillan Co.

1975, p 162.

14. Moon RC, Turner CW: Effect of reserpine on oxytocin

and lactogen discharge in lactating rats. Proc Soc

Exp Biol 101:332, 1959.

Hirschsprung’s

Disease

and

Waardenburg’s

Syndrome

There are several reports of an association of

congenital deafness with Hirschsprung’s

aganglionic megacolon.’ This patient is

de-scribed because she has Hirschspning’s disease in

association with Waardenburg’s syndrome. The

genetic mechanisms and a possible causal

rela-tionship are discussed.

at Viet Nam:AAP Sponsored on September 7, 2020 www.aappublications.org/news

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804 HIRSCHSPRUNG’S DISEASE CASE REPORT

A black girl was born at 37 weeks’ gestation, with a birth weight of 2,380 gm, following an uncomplicated pregnancy

and a breech delivery. Apgar scores were 2 at one minute

and 6 at five minutes, and the perinatal course was

uncom-plicated. On day 2, when no stools had been passed and

abdominal distention was noted, the infant was transferred to

Buffalo Children’s Hospital.

On arrival, the physical findings were remarkable for the presence of a white forelock, wide epicanthal distance, broad

nasal root, and marked abdominal distention. Plain

abdomi-nal roentgenograms and a barium enema were consistent with the clinical impression of Hirschsprung’s disease. A

full-thickness rectal biopsy specimen confirmed the

diagno-sis.

Waardenburg’s syndrome was suspected because of lateral displacement of the inner canthi (inner canthi at 90th

percentile with outer canthi at the 25th percentile) in

association with a white forelock. Hearing testing at 10 weeks of age showed absent acoustic reflexes to 1,000- and

2,000-Hz stimuli at 125 dB, indicating a mild to moderate

degree of hearing loss. This is consistent with the type II deafness described by Fisch.” No family members were found

to have features of Waardenburg’s syndrome or

Hirsch-sprung’s disease.

DISCUSSION

Hirschsprung’s disease is a disorder of intestinal

motility caused by absence of parasympathetic

ganglion cells from the submucosal and myenteric

plexuses of the

gut.

The diagnosis is made in about

one in 5,000 white children, in a sex ratio of five

males to one female for the short-segment type

and two males to one female for the rarer

long-segment type.2 ‘ Exact data on black

chil-dren are not available, but the prevalence is

estimated to be less than that for whites. Several

conditions are known or suspected to be

asso-ciated with an increased risk of Hirschsprung’s

disease, including Down’s syndrome,

neuroblasto-ma, and several disorders with genetic bases. The

family data on isolated Hirschsprung’s disease

indicate a polygenic mechanism of

determina-tion, although there is evidence that the most

severe type, total intestinal aganglionosis, may be

autosomal recessive.

Waardenburg’s syndrome is inherited via an

autosomal dominant mechanism with varying

penetrance. The white forelock, although the

most obvious feature, is present in only 17% of

patients. Other expressions of partial albinism,

including heterochromia of the iris, are also

frequently seen. The widened epicanthal distance

and broad nasal root are more common, seeii in

99% and 78% of patients, respectively. Twenty

percent of patients display congenital deafness.”

There are at least two and probably several

autosomal alleles that can give rise to this clinical

picture. Fraser7 estimates that one in 10,000

British children carry a gene that can cause the

syndrome. Thus, the chances of a random

coinci-dence of Hirschsprung’s disease and

Waarden-burg’s syndrome would be expected to be less

than one in 5 X 10 children.

McKusick’ seems to have been the first to

suspect an association between Waardenburg’s

syndrome and Hirschsprung’s disease, after

deal-ing with two patients in which they coexisted and

hearing of a third. Fraser7 reported an additional

case in his large survey of deaf children. Both of

these authors reviewed the relevant observations

in mice and other mammals. “Spotting” genes,

which result in the absence of identifiable

melan-ocytes in more or less widespread areas of the

coat, are often associated with deafness and, in

mice at least, with a cochlear abnormality similar

to that found in Waardenburg’s syndrome.8 The

5’ spotting gene in the mouse has been shown to

cause

megacolon when present in homozygous

form.” The melanocytes, parts of the acoustic

ganglion, and the cells of the myenteric plexus are

all believed to originate from the neural crest.5

Similarly, Hirschsprung’s aganglionic megacolon

is probably caused by a defect in migration of

neuroblasts before the 12th week of gestation.’#{176}

Several authors have reported cases of

Hirsch-sprung’s

disease coexisting with apparently

congenital deafness without the pigmentary

abnormalities or central deformity of

Waarden-burg’s syndrome.22 Some of these cases had

been treated in infancy with potentially ototoxic

antibiotics, but this would not account for the

deafness

in the three-generation pedigree of

Weinberg et al.12 It is therefore possible that

there exist one or more syndromes of congenital

deafness separate from Waardenburg’s syndrome

associated with Hirschsprung’s disease. An

alter-native, though less likely, possibility is that these

patients had the nondystopic form of

Waarden-burg’s syndrome with lack of penetrance of the

pigmentary anomalies.

It seems likely that the association between

Hirschsprung’s disease and Waardenburg’s

syn-drome

is a significant

one. The Waardenburg

gene, probably by its effect on the neural crest, is

likely to be one of several mutations that

substan-tially increase the risk of development of

Hirsch-sprung’s disease.

DAVID BRANSKI,

M.D.

Division of Gastroenterology

NICHOLAS

R.

DENNIS,

M.B.,

M.R.C.P.

Division of Genetics

J

OHN

M.

NEALE,

M.D.

LEE

J.

BROOKS,

M.D.

Department of Pediatrics, Buffalo Children’s Hospital

Buffalo

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FIG 1. Plain film of markedly distended abdomen with no air beyond stomach. Stomach is displaced upward toward left.

PEDIATRICS Vol. 63 No. 5 May 1979

805

ADDRESS FOR REPRINTS: (L.J.B.) Department of

Pedi-atrics, Buffalo Children’s Hospital, 219 Bryant Street, Buffa-lo, NY 14222.

REFERENCES

1. McKusick VA: Congenital deafness and Hirschsprung’s disease. N EngI I Med 288:691, 1968.

2. Lowry RB: Hirschsprung’s disease and congenital deaf-ness. I ,1ed Genet 12:114, 1975.

3. Fisch L: Deafness as part of an hereditary syndrome. I Larijiigol Otol 75:355, 1959.

4. Passarge E: Genetic heterogeneity and recurrence risk of congenital intestinal aganglionosis. Birth Defects

8, No. 2 (pt 13):63-67, March 1972.

5. MacKinnon AE, Cohen SJ: Total intestinal

agangliono-sis: An autosomal recessive condition? Arc/i Dis C/mild 52:898, 1977.

6. Smith D’sV: Recognizable Patterns of Human Malforma-tiOfl, ed 2. Philadelphia, \\‘B Saunders Co. 1976, pp

124- 125.

7. Fraser C R: The Gooses of Profound Deafness in Child-1100(1. Baltimore, Johns Hopkins Press, 1976, pp 90- 132.

8. Deol MS: The relationship between abnormalities of

pigmentation and of the inner ear. Proc R Soc Loud Biol 175:201, 1970.

9. Lane PW: Association of megacolon with two recessive

spotting genes in the mouse. I Hered 57:29, 1966.

10. Okamoto E, Ueda T: Embryogenesis of intramural

ganglion of the gut and its relation to

Hirsch-sprung’s disease. I Pediatr Surg 2:437, 1967. 1 1. Skinner R, Irvine D: Hirschsprung’s disease and

congen-ital deafness. I .‘sf(’(l Genet 10:337, 1973.

12. \Veinberg AC, Currarino C, Besserman AM:

Hirsch-spnmng’s disease and congenital deafness: Familial association. Human Genet 38: 157, 1977.

ACKNOWLEDGMENT

Dr. Dennis is the recipient of a Buawell Fellowship from the Anthony C. and Bertha H. Buswell Research Foundation,

School of Medicine, State University of New York at

Buffalo.

Dr. V. A. N’lcKusick provided helpful comments on this case.

Megacystis-M

icrocolon-lntestinal

Hypoperistalsis

Syndrome

The syndrome of megacystis-m

icrocolon-intes-tinal hypoperistalsis has been reported in a total

of seven female infants. Massive abdominal

distention secondary to a distended urinary

blad-The opinions and assertions herein contained are those of

the authors amid do not necessarily represent those of the

Department of the Army or the Department of Defense.

der was the major presenting characteristic.

lutes-tinal hypoperistalsis, apparent in the early

neonatal period, persists without improvement.

Exploratory laparotomy reveals malrotation and

malfixation of a small microcolon. No anatomic

cause of intestinal or bladder obstruction can be

found. Intestinal and/or rectal biopsy specimens

contain abundant ganglion cells and nerve fibers.

The outcome has been uniformly fatal, with

survival in the reported cases ranging from two

days to 34 months.

CASE REPORT

The patient was a 3,020-gm, full-term, Polynesian female infant. Pregnancy, labor, and deliver were reported to be uneventful. There was no mention of oligohdramnios.

During the first 24 hours of life, progressive abdominal

distention and bilious vomiting were noted (Fig 1). Barium

enema examination revealed an extremely thin microcolon outlining a large, rounded, midline mass (Fig 2). On the

second hospital day the infant was transferred to Tripler Army Medical Center (TAMC) for evaluation and treat-ment.

Upon arrival at TAMC, the infant’s abdomen appeared markedly distended. Large, firm renal masses were readily

palpable in both flanks. Catheterization of the bladder produced 450 ml of clear urine with a specific gravity of 1.()03. In the next hour, another 150 ml of urine was obtained by means of the urinary catheter. Renal angiograms revealed severe bilateral hydronephrosis. A retrograde cvstogram

confirmed the large, flaccid urinary bladder (Fig :3) without ureteral reflux. Decompression of the bladder relieved the abdominal distention, producing a prune-belly appearance.

Contrast study of the tipper gastrointestinal tract showed

minimal movement of contrast material over an I 1-day

period (Figs 4, 5). Exploratory laparotomy disclosed

malro-tation with diffuse peritoneal adhesions compressing the

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1979;63;803

Pediatrics

David Brancki, Nicholas R. Dennis, John M. Neale and Lee J. Brooks