Premaxillary Agenesis, Ocular Hypotelorism

Holoprosencephaly, and Extracranial Anomalies

In An Infant With a Normal Karyogram

URSULA ROWLATT, D.M. (Oxon.)

SAMUEL PRUZANSKY, D.D.S.Chicago, Illinows 60680

This four-day-old male infant with Aoloprosencephaly and facial dysmorphia resembledother cases in that he had several severe extracranial malformations but unusual in that suchinfants often have an abnormal chromosome pattern, most frequently a trisomy 13. Ourpatient had a normal keryogram. He differed also in having a lobar rather than an alobartype of holoprosencephaly, which is the more usual form in association with this degreeof facial anomaly. A syrechia between the lips on one side and segmented double spinalcord (diastematomyelia) are rare lesions in this or any other condition. This infant illustratesthe principle that holoprosencephaly and facial dysmorphia together are a symptomcomplex that may be part of another syndrome rather than a disease in its own right.

Clinical History

This 2510 gm male infant was born to a

gravida 2, para 1, 27-year-old woman at 40

weeks gestation following an uneventful preg-

nancy. A normal female infant had been de-

livered at term, eight years before and was

alive and well. There was no history of con-

genital malformations on either side of the

family. The infant breathed well at birth with

Apgar scores of 9 at one and five minutes.

On examination, the skin was pink, but the

extremities were bluish. There was microceph-

aly, a short neck, a round full face with mild

orbital hypotelorism, a flat hypoplastic nose,

premaxillary agenesis, a soft tissue bridge be-

tween the upper and lower lips adjacent to

the left side of the midline facial cleft, a skin

dimple on the under surface of the chin in the

midline and absent external ears (Figures 1

through 3). A shallow external auditory mea-

tus, measuring 3.0 mm on the right and 2.0

mm on the left, was present on both sides.

Both orifices were low-set. There was a 1.5

Dr. Rowlatt is Associate Professor, Department ofPathology, University of Illinois Medical Center, Chi-cago, IL 60680. Dr. Pruzansky is Director, Center forCraniofacial Anomalies, University of Illinois MedicalCenter.

This investigation was supported in part by grantsfrom the National Institutes of Health (DE 02872) andMaternal and Child Health Services, Department ofHealth, Education and Welfare.

mm raised sessile nodule 1.0 cm below and

slightly posterior to the right meatus and a

3.0 mm plaque-like mass 2.0 cm posterior to

the left meatus. On cutting the synechia,

which interrupted the vermilion border of

both lips, a central palatine septum, and a

complete cleft palate were seen. The premax-

illa was absent as were the incisors (Figure 4).

The tongue was normal posteriorly but hy-

poplastic towards the tip. Deep skin grooves

were seen on the cheeks beneath the eyes; the

skin of the rest of the face was thick and

doughy. There was a simian palmar crease on

the right, and the left forefinger could not be

straightened at the proximal interphalangeal

joint. The penis was small. Both testes were

undescended, and the anus was imperforate

(Figure 5). Both feet and all toes were normal

except for puffiness of the subcutaneous tissue

of the dorsum of the feet.

Frequent suctioning of mucus from the

mouth was needed to maintain an airway,

and oxygen was given by face mask to correct

attacks of cyanosis on exertion. The infant

was given intravenous infusions but nothing

by mouth. Frequent twitching of hands and

feet together with eye rolling was noted

throughout the infant's life. Meconium was

passed through the urethral orifice on the

third day of life and the abdomen became

distended. At no time were the heart sounds

abnormal nor were murmurs heard. He de-

197

198 __Cleft Palate Journal, July 1980, Vol. 17 No. 3

FIGURE 1. Four-day-old male infant. Note orbital

hypotelorism, median facial cleft with absent prolabium,soft tissue bridge between medial margin of left cleft lipand lower lip, and micropenis.

veloped bradycardia the next day and died

later that night at the age of four days. A

karyogram obtained from a blood sample

showed the 46 XY pattern of a normal male

infant.

Post-mortem Examination

The body was that of a small-for-gesta-

tional age male infant weighing 2645 gm and

measuring 44.0 cm from crown to heel and

27.0 em from crown to rump. The biparietal

head circumference was 27.0 ecm. The anterior

fontanelle measured 1.0 X 1.0 cm, and the

posterior fontanelle was closed. Both anterior

fossae were shallow and continuous across the

midline. Neither crista galli nor cribiform

plates were present (Figure 6). The greater

wings of the sphenoid were poorly formed so

that the middle fossae were also smaller than

normal. The petrous temporal bones and ar-

cuate ridges were hypoplastic. The internal

auditory meatus was normal on both sides.

The posterior fossa was also shallow but not

as markedly so as the other fossae.

The brain was smaller than normal and

globular with fusion of the hemispheres an-

teriorly for 2.0 em. Gyral formation was sim-

ple. The Sylvian fissures were present but

shallow, and the temporal lobes were short

and rounded. There were no olfactory bulbs

or tracts, but the remainder of the cranial

nerves and the vessels at the base of the brain

were normal except for a single anterior cere-

bral artery which ran on the under surface of

the brain. On sectioning the brain coronally,

the first section passed through fused frontal

lobes in which the convolutions were sparse

superiorly and absent on the orbital surface

(Figure 7). Anteriorly, the lateral ventricles

communicated freely with each other and

with the third ventricle. Posteriorly, there was

a definite corpus callosum and fornix. No

caudate nucleus, putamen, globus pallidus,

nor internal capsule were seen on either side.

The thalami were fused anteriorly but not

posteriorly. The hypothalamus and pituitary

gland were normal. The brainstem and cere-

bellum were unremarkable except for small-

ness of the cerebral peduncles, basis pontis,

and pyramids.

Microscopy of the brain showed the follow-

ing features: richly cellular meninges with a

superficial, multicellular layer of arachnoid

cells, a cortical ribbon lacking horizontal lam-

ination, marked congestion of blood vessels in

the central white matter and hypocellular

subependymal germinal plates There was

striking hypoplasia of the corticospinal tracts

at all levels of the brainstem. A random sec-

tion through the mid-portion of the spinal

cord revealed a diastematomyelia that had

not been observed grossly. Both spinal cords

were encased in their own leptomeninges as

they lay side by side within a common dural

sheath. Both were dysplastic with no sugges-

tion of anterior or posterior horns. There was

a dilated, elongated, more or less central canal

in the slightly larger cord, and two periph-

erally placed canals were present in the

smaller cord (Figure 12).

The heart was enormously enlarged with

the base-apex axis pointing to the right (piv-

otal dextrocardia) (Figure 8). A huge right

atrial appendage was displaced to the left and

lay posterior to a single arterial trunk that

gave off the pulmonary arteries and brachi-

ocephalic vessels. Internal examination

showed that there was tricuspid atresia, a

Rowlatt and Pruzansky, PREMaAXILLARY AGENESIS, OCULAR HYPOTELORISM, HOLOPROSENCEPHALY 199

FIGURE 2. Close-up of face illustrating mongoloid slant of palpebral fissures, orbital hypotelorism, flattenednose, absent columella and prolabium, bilateral anotia with low-set atretic external auditory meati, and dimplebeneath chin. The denuded scalp in the right temporal area is an artifact.

FIGURE 3. Close-up of soft tissue adhesion (syn-

echia) between upper and lower lips.

large atrial, and a small ventricular septal

defect with an overriding truncus communis

(Figure 9). Meconium was emerging into the

posterior urethra just distal to the posterior

urethral folds through a 0.2 cm rectourethral

fistula with a ragged margin (Figure 10). Very

striking distension of the whole of the colon

and appendix was noted. There was a single

umbilical artery.

The bony interorbital distance measured 9

mm on the cephalometric radiograph (Figure

11). Unfortunately, control data matched for

age and sex and adjusted for head circumfer-

ence are not available. Morin et al. (1963)

provided normative values for four-month-old

infants (mean interorbital distance 14.7 #

1.84; range 12.1-18.7). Based on our experi-

ence with radiographs of infants of similar

age, the impression is gained that this patient

presents a moderate degree of hypotelorism.

The lateral cephalometric radiograph re-

200 Cleft Palate Journal, July 1980, Vol. 17 No. 3

FIGURE 4. Top: Dissection to illustrate cleft of pri-mary and secondary palates with missing premaxilla.Bottom: Mucosa dissected to illustrate missing incisors.

FIGURE 5. Micropenis and imperforate anus.

vealed the frontal eminence to be relatively

sunken and the anterior cranial base

shortened in length. The film also confirmed

the shallowness of the middle and posterior

cranial fossae.

Radiography of the skeleton showed that

there was a hemivertebra between T; and T4

and that the remaining thoracic vertebrae

were formed of atypical, bony masses with

poor alignment of twelve pairs of ribs

SUMMARY OF INTERNAL MALFORMATIONS

Internal malformations included lobar hol-

oprosencephaly (absent olfactory bulbs and

tracts, anterior fusion of cerebral hemispheres,

common lateral and third ventricles, hypo-

plastic corticospinal tracts, poorly formed

caudate nucleus, putamen and globus palli-

dus, fused thalami anteriorly), focal diaste-

matomyelia, thoracic hemivertebra, isolated

dextrocardia with tricuspid atresia and over-

riding truncus communis, imperforate anus

with rectourethral fistula, and single umbili-

cal artery.

Discussion

There is a copious literature on the associ-

ation of holoprosencephaly and facial dys-

FIGURE 6. Exposed cranial fossa reveals absence ofcrista galli and cribiform plates. Anterior fossae are smalland shallow, and middle fossae are also reduced in size.The posterior fossa was shallow but not as markedly asthe other fossae.

Rowlatt and Pruzansky, PrEMAXIELLARY AGENESIS, OCULAR HYPOTELORISM, HOLOPROSENCEPHALY

FIGURE 7. Coronal sections through brain. Top leftand middle left illustrate fused frontal lobes with absentconvolutions on orbital surface. Bottom left, lateral ven-tricles communicate freely with each other. Top right,corpus callosum and fornix are visible. Middle right, thecerebral hemispheres are not fused at this level; note thesmall cerebral peduncles. Bottom right illustrates normalcerebellum, basis pontis, and pyramids.

morphia, the most helpful accounts being

those of DeMyer and Zeman (1963), DeMyer

et al. (1964), Cohenet al. (1971), and Cohen

and Hohl (1976).

The term "holoprosencephaly" was sug-

gested by DeMyer and Zeman (1963) to de-

scribe a brain in which there is incomplete

division into two cerebral hemispheres, a sin-

gle central ventricle, and absent olfactory

bulbs and tracts. They described an alobar

form in which a small monoventricular brain

has no lobes or hemispheres, a semilobar form

in which division is restricted to the posterior

part of the brain, and a lobar form with a

distinct interhemispheric fissure, which is ab-

sent only anteriorly, where the frontal lobes

are fused. They extended the observations

made by others that these lesions are associ-

ated with anomalies of the midface of varying

degrees of severity from cyclopia through eth-

mocephaly, cebocephaly, and premaxillary

201

agenesis to double cleft lip and palate. De-

Myer et al. (1964) suggested that the degree

of severity of lesions in these two systems is

sufficiently close to merit the aphorism "the

face predicts the brain." Subsequent experi-

ence has shown that there are many excep-

tions to this statement. However, the associa-

tion of premaxillary agenesis, hypotelorism,

and holoprosencephaly is sufficiently constant

to permit appearance to be used reliably to

predict poor psychomotor development and

death in infancy (DeMyer, 1975).

An exception to the foregoing conclusion is

contained in the report by Ben-Hur et al.

(1978) of a 12-year-old boy with median cleft

lip, missing columella, prolabium and pre-

maxilla, and orbital hypotelorism. Pneumo-

encephalography performed at the age of two

months was within normal limits. At the age

of eleven months, an electroencephalogram

showed a generally normal pattern except for

a few spikes in the temporal region. At age

12, the bony interorbital distance measured

<15 mm (normal values according to Morin

et al. (1963), mean 23.05 + 2.35; range 17.0-

FIGURE 8. Enlarged heart with the base-apex point-

ing to the right (pivotal dextrocardia). Huge right atrialappendage displaced to left and posterior to a singlearterial trunk.

202 Cleft Palate Journal, July 1980, Vol. 17 No. 3

FIGURE 9. Internal examination of heart revealed large atrial and small ventricular septal defect with overriding

truncus communis.

26.5). Chromosome studies were normal. Psy-

chomotor development was reported to be

normal. The authors conclude by suggesting

that the original spectrum of diagnostic facies

described by DeMyer and White (1964) be

expanded to include their patient without

holoprosencephaly. The report by Ben-Hur et

al. (1978) compels caution in reaching the

conclusion that the typical facial dysmorphia

combined with orbital hypotelorism inevita-

bly spells holoprosencephaly. The CT scan

affords a non-invasive procedure for validat-

ing the diagnosis, and, in rare instances, could

preclude a grim prognosis.

The infant reported herein is an example

of the classic association between face and

brain. In addition, microcephaly and abnor-

1. BLADDER mal ears are often present as in our case.

2. RECTUM However, a band between the lips is a most

3. VERUMONTANUM unusual lesion in this or in any other condi-4. RECTO-URETHRAL FISTULA tion. .It resembles the syuechlae betweeu the

jaws illustrated by Gorlin et al. (1976) in a5. PENILE URETHRA patient with the popliteal pterygium syn-FIGURE 10. Rectourethral fistula. drome. The way in which it is produced is

Rowlatt and Pruzansky, PREMAXILLARY AGENESIS, OCULAR HYPOTELORISM, HOLOPROSENCEPHALY 203

FIGURE 11. Measurements of bony interorbital distance obtained on cephalometric radiographs support diag-

nosis of orbital hypotelorism.

FIGURE 12. Photomicrograph

obscure. Based upon available literature, our

patient is also atypical in having a lobar

rather than an alobar form of holoprosence-

phaly-although we have two similar cases in

our files. Hypoplasia of the corticospinal

tracts is a well-known feature of holoprosen-

cephaly, but a segmental, double, dysplastic

spinal cord is unique in this condition. Ver-

tebral malformations often occur with dia-

stematomyelia as in our case (Friede, 1975).

In general, infants with premaxillary

agenesis and holoprosencephaly have normal

karyograms unless there are additional extra-

of diastematomyelia.

cranial malformations. If other lesions exist,

the most common chromosome anomaly is

trisomy 13. In fact, this type of facial clefting

is often found in patients with complete or

partial trisomy 13. Our infant is unusual in

that there are many, severe malformations of

several organ systems without a chromosome

anomaly.

Most cases of holoprosencephaly are spo-

radic, but families have been described in

which various craniofacial anomalies have oc-

curred in different generations. Dallaire et al.

(1971) reported 17 instances of face or brain

204 Cleft Palate Journal, July 1980, Vol. 17 No. 3

anomalies ranging from fusion of the eyelids

to alobar holoprosencephaly with premaxil-

lary agenesis in one family. Gorlin et al. (1976)

have collected similar pedigrees and have

drawn attention to minor lesions such as an-

osmia, hyposmia, mild ocular hypotelorism,

asymmetric nose, or a single permanent inci-

sor in some members of the family. A careful

search for such lesions has not been made in

the kindred of our patient. However, there is

no history of any overt craniofacial defects in

either of the parents or in their relatives.

The purpose of reporting this infant is to

draw attention again to the heterogeneity of

holoprosencephaly and facial dysmorphia as

stressed repeatedly by Cohen et al. (1971).

They regard the various forms of face-brain

lesions as a symptom-complex which may

occur in a number of different disorders. Ac-

cumulation of individual cases that demon-

strate variations on this dysmorphogenetic

theme may help to define the range of syn-

dromes of which holoprosencephaly-facial

dysmorphia forms a part.

References

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Conmen, M. M., Jr., Jirasek, J. E., Guzman, R. T.,GorLmm, R. J., and PETErRson, M. Q., Holoprosence-phaly and facial dysmorphia: nosology, etiology andpathogenesis, Birth Defects, Orig. Art. Series, 7, 125-135,1971.

Conxrn, M. M., Jr., and Hox1, T. H., Etiologic hetero-geneity in holoprosencephaly and facial dysmorphiawith comments on the facial bones and cranial base.In Development of the Basicranium, Bosma, J. F.(Editor). Bethesda, Maryland: U. S. Department ofHealth, Education and Welfare, 383-399, 1976.

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