Autosomal recessive Warburg syndrome

eye and brain anomalies."

Two siblings are reported who appear to have an autosomal recessive disorder o f eye and central

nervous sytem anomalies. The findings in fourteen previously described and similarly affected patients

are summarized. Ocular anomalies include microphthalmos, megalocornea, the Peter anomaly,

cataract, coloboma, persistent hyperplastic primary vitreous, and retinal detachment with retinal

dysplasia. Central nervous system malformations include agyria-pachygyria, cerebellar dysplasia,

encephalocele, Dandy-Walker cyst, and hydrocephalus. We suggest that this disorder be known as

Warburg syndrome. (J PEDtATR 102:542, 1983}

Roberta A. Pagon, M.D., Sterling K. Clarren, M.D.,

D. Frank Milam, Jr., M.D., and Anita E. Hendrickson M.D. Seattle, Wash.

IN 1971 WARBURG POSTULATED tha t the associat ion o f

hydrocepha lus , mic roph tha lmos , and congeni ta l re t inal

n o n a t t a c h m e n t was a nosologic en t i ty with a possible

gene t ic cause? W e desc r ibe two af fec ted sibl ings and review 14 s imilar pa t ients f rom the l i te ra ture , to es tabl ish

tha t this is an au tosomal recessive d i sorder and to define

the spe c t r um of eye and cent ra l nervous sys tem ( C N S )

anomal ies seen. A l though we have previously used the

m n e m o n i c H A R D + E (Hydrocepha lus , Agyr ia , Re t ina l

Dysplasia , Encepha loce le ) 2 to des igna te this d isorder , we

believe tha t this a c r onym is now too restr ic t ive, cons ider ing

the s pec t r um of eye and C N S anomal i e s present . W e

sugges t ins tead tha t this d i sorder be known as W a r b u r g

s y n d r o m e ?

C A S E R E P O R T S

Patient 1, This case has been reported in detail? The patient was delivered at 45 weeks' gestation by cesarean section for massive hydrocephalus, with occipitofrontal circumference 50 cm (greater than the ninety-eighth percentile). He died at 34 days of age from progressive hydrocephalus; weight was 3.6 kg, and length was 57 cm. Central corneal opacities were diagnosed as the

From the Departments o f Pediatrics and Ophthalmology, Chil- dren %' Orthopedic Hospital and Medical Center and University o f Washington School o f Medicine.

Supported by a grant from Fight for Sight, Inc.

Reprint requests: Roberta A. Pagon, M.D., Division o f Medical Genetics, Children's Orthopedic Hospital and Medical Center, P.O. Box C5371, Seattle, WA 98105.

Peter anomaly and prevented a view of the fundus. At autopsy the brain was hydrocephalic and the cortical surface was smooth. The cerebral cortex lacked any cytoarchitectural differentiation into the usuaI laminations. The cerebellar folia, dentate nucleus, ports, and inferior olivary nuclei were hypoplastic.

Only one eye was available for postmortem examination. In the central cornea there was contact of the intact anterior lens capsule to the posterior cornea (Peter anomaly). Although the stroma and epithelium were intact, the Descemet membrane and the endothe- [ium were discontinuous, with numerous small proliferative nests at that site. The iris was hypoplastic, consisting of one layer of pigment epithelium and one layer of stroma. The peripheral cornea was clear, and there were no iridocorneal adhesions. The anterior chamber angle was closed. There was a fibrous cataract. The posterior lens capsule was invaded by the hyatoid vessels of the persistent hyperplastic primary vitreous. There was a total retinal detachment, with retinal rosettes throughout. The chorio- capillaris was normal. The number of fibers in the optic nerve was reduced.

See related articles, pp. 547, 552, and 559.

The only other significant finding was cryptorchidism. Patient 2. This was the sister of patient 1 and the last child of

her unrelated parents. Birth weight at 40 weeks' gestation was 3700 gm, birth Icngth was 52 cm, and occipitofrontaI circumfer- ence 33.8 cm (fiftieth percentile). She had a 2 cm skin-covered occipital encephalocele. Noncommunicating hydrocephalus that required shunting developed after excision of the encephalocele at 2V2 months of age. She had microphthalmia of the right eye (corneal diameter 8.0 mm) and megalocornea of the left eye

5 4 2 T h e d o u r n a l o f P E D I A T R l C S

Volume 102 Warburg syndrome 5 4 3 .Number 4

(corneal diameter l l.0 mm). lntraocular tensions were normal. The corneae were clear. Initial clinical evaluation at 2 days of age showed a white retrolental mass in the right eye and an attached retina in the left eye, with absence of the choroidal pattern in the posterior pole. By 3 months of age the right retina had detached. She had no psychomotor development beyond that of a newborn infant, and died at one year of age, with increasing spasticity and progressive manltlOn.

On postmortem examination the cerebellum was pachygyric. The cortex was arranged in four rather than six lamellae. The cerebrum, diencephalon, midbrain, and cerebellum all deviated caudally toward the occipital defect. The malformation of the midbrain had obstructed the aqueduct of Silvius, resulting in hydrocephalus.

The eye examination disclosed persistence of hyperplastic primary vitreous, with a dysplastic gliotic retina in the right eye and a long-standing retinal detachment with retinal folding into pseudorosettes in the left eye. The entire posterior pole of the left eye lacked a definable choriocapillaris, whereas the right eye had a completely normal choroid. No ganglion cell layer was identified in either eye, and the optic nerves were small, with decreased axonal fibers. Both corneae were completely normal, and the anterior chamber angles were closed, although the trabeculae appeared normal.

D I S C U S S I O N

The brother and sister described here had similar early

developmental defects of the eye and brain without any

other major congenital anomalies on postmortem examina-

tion. The boy died at 34 days, but his sister survived for a

year, with profound mental retardation. The original

clinical presentations of these two infants were so disparate

that one would not have considered them to have the same

disorder had they not been siblings. We have summarized

the ophthalmologic findings and C N S malformations (Ta-

ble) in our patients and in 14 others from the literature, 4-~3

to clarify the phenotypic spectrum of this disorder.

Although the developmental defects of the eye and brain

are severe and unusual, this disorder may be underdiag-

nosed because of the deceptive phenotypic variability of

the malformations. We included only those patients who

had both typical eye and brain anomalies and no other

major malformations. The karyotype, if examined, was

normal. We included sporadic cases if the eye or brain

anomalies were well described 5-~'~~ and if no other

cause had been established. Several probable cases were

not included, because there was no postmortem examina- tional. 14 or the description was incomplete. 15' t6

Eye anomalies. Virtually every ocular structure can be

affected in this disorder (Table). Microphthalmia was a

common but not invariable finding and did not correlate

with the severity of other eye defects. Although no patient

had unilateral or bilateral anophthalmia, it would not be

unusual to see this as an extreme manifestation of

microphthalmia. Asymmetry in size of the two eyes of one

patient occurred occasionally (patients 2, 6, 15); the

megalocornea observed may be a manifestation of the

tendency for anterior chamber anomalies.

The Peter anomaly, a class of developmental defects of

the cornea that produce clinically apparent corneal opaci-

ties, occurred in one third of the patients. The term is

applied to two different developmental defects: (1) a defect

of the deepest stromal layers of the cornea and the

Descemet membrane, producing corneal opacities with or

without adhesions or remnants of adhesions to the iris ~6

(patient 8); and ( 2 ) c e n t r a l keratolenticular adhesion

(patient 1). The "corneal opacities" observed in other

patients (4, 5, 9) may have been caused by similar

developmental defects.

Cataract has been noted, and at least two causes appear

probable: keratolenticular adhesion in patients with the

Peter anomaly, and invasion of the posterior lens capsule

by the vessels of the persistent hyperplastic primary

vitreous.

Immature angle configuration with uninterrupted endo-

thelium extending into the anterior chamber angle and an

undeveloped trabecular meshwork was observed in 11 of

the 12 patients with adequate histologic examination. In

patient 2 there was megalocornea, immature angle config-

uration, and normal intraocular pressure. Only patient 15

was known to have increased intraocular pressure.

Coloboma of the choroid or disc was seen in four

(patients 4, 5, 9, 15), and is presumed to be a typical

coloboma reflecting abnormal closure of the embryonic

fissure. Iris coloboma was not seen in any of the

patients.

Persistent hyperplastic primary vitreous is persistence of

the hyaloid vessels and gliosis of the retina with detach-

ment. A white retrolental mass and cataract secondary to

invasion of the posterior lens capsule are seen.

Retinal dysplasia refers to rosettes of poorly differenti-

ated neurosensory retina seen on microscopic examination.

Clinically, dysplastic retinae are pale and elevated or

detached. All patients had developmental anomalies of the

retina (retinal dysplasia or retinal detachment or persistent

hyperplastic primary vitreous) whether or not there were

other obvious ocular anomalies.

The optic nerve usually had a reduced number of axonal

fibers, presumably secondary to the paucity of retinal

ganglion cells in the dysplastic retinae. In at least one

patient there was complete aplasia of the optic nerves. 6

Although in some patients the eye anomalies may be

severe and obvious without detailed examination, in others

a complete examination as well as follow-up examinations

may show more subtle anomalies or a progression from

retinal nonattachment to complete retinal detachment, as

5 4 4 P a g o n et aI. The Journal o f Pediatrics

April 1983

Table. Ophtha lmic and C N S malformat ions in 16 patients with Warbu rg syndrome

Pagon et al.*

Patient t 2

Eye malformations Microphthalmia/ - + / ( + ) + / ( + ) -

(megalocornea) Peter anomaly/ + - (+) (+) - -

(corneal opacity) Angle anomalies + + + - + Cataract + + / - + + + + Coloboma . . . . + + - Persistent hyperplastic + + / - + + +

primary vitreous Retinal detachment/ + + + + +

retinal dysplasia CNS malformations

Absent laminar + + + + + structure

Agyria/pachygyria + + + + + + + Ventriculomegaly + + + + + + + Cerebellar dysplasia + + + + + + Enccphalocele - + + + - - Dandy-Walker cyst + + Hydrocephalus + + (?) (?) + (?) Occipitofrontal 50 33.8 34 37 28.5

circumference at birth (cm) Percentile >98 50 50 98 <3

Chemke Yanoff Winter et al. 4. Walker s et al. 6 and Garner 7

3 4 5 6 7 8

+

+

+

+

+

+

+

+

+

+

4O

>98

Chan et al. 8

9

+

(+)

+

+

+

+ +

+

+

+ +

+

+

(?) 33.5

50

Gerhard

et alfl*

t 0

(?), Possibly present. *Familial. #Patient 8. :~Paticnt 9. w 10~

in pat ient 2. Pos tmor tem examinat ion of the eyes is critical

for detect ing the full range of ocular involvement in these

patients.

Brain malformations. Cerebral cortical disorganizat ion

has been a constant feature of W a r b u r g syndrome. There

may be a complete failure of cerebral gyrat ion (agyria) or

a part ial failure leading to wide, coarse gyrae (pachygy-

ria). There is evidence tha t agyria occurs when there has

been interference with cerebral neuronal migra t ion during

the eleventh to th i r teenth fetal weeks. L7"~9 Pachygyr ia is a

cont inuum from agyria, and the two are frequently found

together.~7. ~8 An al ternate te rm for agyria is lissencephaly.

Al though lissencephaly is a neuropathologic term, it has

become linked with the "l issencephaly syndrome," a dis-

crete disorder featuring cerebral agyria and a character is-

tic face. 2~ 2, Agyria can be associated with other conditions,

such as Zellweger syndrome, 22 and may perhaps occur in

pat ients with a normal phenotype.

Al though the cerebral gyral anomalies in W a r b u r g

syndrome have been relatively constant , seemingly diverse

abnormali t ies have been found in the posterior fossa. These

have included cerebel lar hypoplasia, occipital encephalo-

cele, and Dandy-Walker cyst. Each of these anomalies has

an unclear origin, with nei ther the embryonic t iming or

pathway to mal format ion known, z3 These anomalies are

not presently thought to create an embryonic cont inuum,

yet their presence in pat ients with Warbu rg syndrome

indicates this as an avenue for future investigatio n .

When hydrocephalus has occurred, it has usually

resulted from mechanical obstruct ion in the posterior

fossa. In pat ient 1 the hydrocephalus was so extreme tha t

the smooth bra in surface and cortical disorganizat ion

could have been argued to be only secondary phenomena.

Even when spinal fluid flow has been normal , ventriculo-

megaly has been generally observed. This hydrocephalus

ex vacuo is related to general deficiency of cerebral tissue

ra ther than to increased in t racrania l pressure.

These severe aberra t ions in early brain development

have generally led to neonata l death. In all known longer

survivors there has been profound menta l re tardat ion.

Volume 102 Warburg syndrome 5 4 5 Number 4

SnelP ~

11

+

Whitley et alJ 1 L e v i n e 12 . K r a H s e 13

r

12 I 13 152 16~

+ + + + / ( + ) -

+ + + + + - + + - + - -

. . . . qt_

+ + + + + +

+ + + +

+ + + + + + + + + + +

+ + +

+ + + + + + --

47

>98

Only postmortem examination can reveal the full extent of

C N S malformations in this disorder, and even then the

phenotypic variability of the brain anomalies in Warburg

syndrome may be confusing.

Inheritance. Autosomal recessive inheritance of these

eye and brain anomalies appears likely. Seven of the 16

cases were familial. The parents in the report of Chemke et

al? were consanguineous. The male-female ratio was 6:9.

The seven patients who had karyotypes had normal chro-

mosomes.

C O N C L U S I O N

The overall pattern of complex ocular and brain anom-

alies cannot be summarized adequately with one or two

descriptive terms, and we suggest that this disorder be

known as Warburg syndrome, because Warburg was the

first to recognize the pattern of eye and brain anomalies

and to suggest a genetic cause. Although the developmen-

tal defects of the eye and brain are severe and distinctive,

this disorder may be underdiagnosed because of the large

number of different anomalies and the phenotypic variabil-

ity seen with almost any of the anomalies. The tendency to

consider major anomalies such as hydrocephalus, lissen-

cephaly, encephalocele, Dandy-Walker cyst, microphthal-

mia, Peter anomaly, and retinal dysplasia as specific

diagnoses might preclude the consideration in any given

patient that these anomalies are part of a broader pattern

of malformation. We believe that the minimal criteria for

making this diagnosis are developmental anomalies of the

retina and poor cortical and cerebellar differentiation with

ventriculomegaly. Postmortem examination of both the

brain and the eyes will usually be necessary for establish-

ing this diagnosis.

Differential diagnosis of Warburg syndrome includes

lissencephaly syndromC ~ 2~ and Meckel-Gruber syndrome,

an autosomal recessive disorder in which occipital enceph-

alocele and similar eye malformations occur with other

systemic anomalies, including polydactyly, polycystic kid-

neys, cleft lip and palate, congenital heart disease, and

genital ambiguity? 4 Patients in whom postmortem ocular

examination is not done may be considered to have isolated

Peter anomaly, an autosomal recessive disorder in which

there are no systemic malformations? 5 Retinal dysplasia

was once considered a diagnostic entity, but is now

recognized to have diverse causes, including such chromo-

somal disorders as trisomy 13 and triploidy, which should

be considered in patients with eye and brain anomalies.

Affected individuals have profound retardation if they

survive the neonatal period, and prenatal diagnosis does

not seem possible with currently available techniques, so

the recognition of this disorder is crucial in order to provide

accurate genetic counseling to families at risk.

We thank Maxine L. Covington, Beverlee M. Bowman, and Betsy Brown for editorial and secretarial assistance, and De Veta (Moe) Jennings for processing the histologic materials.

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