PARTIAL
18 MONOSOMY
IN THE
CYCLOPS
MALFORMATION
H. M. Nitowsky, M.D., N. Sindhvananda, M.D., U. R. Konigsberg, Ph.D.,
and T. Weinberg, M.D.
Departments of Pediatrics and Pathology, the Sinai Hospital and the Johns Hopkins University School of Medicine, Baltimore, Maryland
(Submitted June 1; accepted for publication July 29, 1965.)
This study was supported by grants from the National Institutes of Health (A-494), the Association
for the Aid of Crippled Children, and the National Association for Retarded Children.
N. S. is Trainee under Training Grant No. 2A-5271 from the National Institutes of Health.
ADDRESS: (H.M.N.) Sinai Hospital, Belvedere and Greenspring Avenues, Baltimore, Maryland 21215.
PEDIATRICS, VOL. 37, No. 2, FEBRUARY 1966
260
T
HE holoprosencephalies comprise ateratologic series characterized by median facio-cerebral dysplasia.1’2 Because of the presence of D-trisomy in some mem-bers of this series, it has been assumed that facio-cerebral malformations are strongly associated with or even causally related to the trisomy. That such is not necessarily
the case is evident from the description of
two groups of patients with cebocephaly,
which are similar in respect to facio-cere-bral malformations, such as hypotelorism, arhinia, and alobar holoprosencephaly, but which differ in respect to extracephalic anomalies and karyotype.3 In the group with apparently normal karyotype, few or trivial extracephalic mafformations occur.
Interest arises in the cyclops malforma-tion, which, aside from the ocular abnor-malities, shows cerebral abnormalities very
similar to those found in cebocephaly. The
present report describes the morphologic and cytologic findings in a newborn infant
with cyclops but without malformation in-volving other systems. A cytologic abnor-mality was observed which involved a deletion of the short arms of one of the E chromosomes, which on the basis of size and autoradiographic studies has been identified as a number 18 chromosome. The findings in this case are unlike those report-ed in several other cases of partial mono-somy 18, and illustrate the phenotypic
vari-ability which can be observed in associa-tion with apparently similar chromosomal aberrations.
CASE REPORT
This Negro female infant was delivered by elective cesarean section at 38 weeks gestation because of previous section in 1947 for contracted inlet and uterine iner-tia. The pregnancy was uncomplicated and
delivery was uneventful. At birth, the in-fant showed a cyclops malformation with the following features: There was a central-ly placed orbital fossa containing a fused, elongated eyeball with double corneas and pupils. There was a tubular appendage with an external orifice resembling the nose situated at the base of the forehead just above the eye. The head was small, and the palatal arch was high. The heart sounds were faint with a rate of 30/min. No mur-mur was heard. Expansion of the chest was limited with poor air exchange by ausculta-tion. Muscle tone was poor. The external genitalia were normal for a female infant.
The remainder of the physical findings
were unremarkable. The Apgar Score at 1 minute was 5; ineffective respirations con-tinued for 20 minutes at which time the in-fant expired.
The family includes a 39-year-old father,
in good health. The mother is 42 years old
and has a history of three previous
preg-nancies, with a living 19-year-old son and 17-year-old daughter, both in good health.
A pair of liveborn twins delivered in 1946
Fi;. 1. A-P and lateral views showing tubal appendage resembling the nose and fused eyeball with
double corneas and pupils.
AUTOPSY FINDINGS
The body was that of a female infant weighing 2,000 gm and measuring 46.0 cm in total length, 32.0 cm in crown-rump length. The occipito-frontal circumference was 27.0 cm. The striking abnormality was confined to the ocular region (Fig. 1). There was a centrally placed eye which, on closer inspection, appeared to be a fusion of two globes. One could see two irises, two pupils, and two corneas. A whitish band measuring 1.0 X 0.3 cm ran between the two corneas. The whole eye measured 2.8 X 1.5 cm. The diameter of each cornea measured 0.8 cm. The eyelid of this “eye” was diamond shaped and appeared to be composed of two lateral halves of normal eyelids which had fused together. Another anomaly was seen just superior to the eye and this consisted of a tubular appendage which was covered by skin and measured 2.5 X 1.0 cm. It was attached to the glabel-la. In the center of this appendage there was an opening measuring 0.2 cm in
no faix cerebri, nor a sagittal sinus. The
cerebral veins appeared to run parallel to
the anterior-posterior aspect draining into
the occipital region, being curved under
the occipital areas, apparently emptying
into the deep veins which ran parallel to the Galenic system.
Examination of the skull revealed no
evi-dence of a cribriform plate, and the olfac-tory bulbs and tracts were not identified.
Neither was the optic chiasm as such
iden-tifiable. The sella turcica was deep and the
posterior clinoids and clivus or dorsum
sellae appeared elevated. A tiny
infundibu-lum was identified. The oculo-motor nerves were present on both sides. However, the
fourth and sixth nerves were not specifically identified. The seventh, eighth, and ninth nerves were identified in their usual positions. The pons appeared normal. The cerebellum was intact. However, the
cerebellar veins appeared to drain through
emissaries. The basal portion of the tempo-ro-occipital area showed no abnormal flat-tening. There was no abnormal molding or elongation of the cerebellar tonsils. There
was no gross evidence of platybasia or a Klippel-Feil lesion. The temporal bones
ap-peared to be normally formed and the
spheno-parietal sinuses were apparently
in-tact. The right and left carotid arteries had
an apparent origin from the left side. The optic chiasm was not identified as such.
The infundibulum was of normal size. The cerebral peduncles were rudimentary. The cerebellum was normal and the medulla intact. The cisterna magna, in respect to the medulla and the cerebellar tonsils, ap-peared to be normal.
Special radiologic studies were performed through the courtesy of Dr. James F.
Bosma, Chief of the Oral and Pharyngeal
Development Section of the National Insti-tute of Dental Research, of the National Institutes of Health at Bethesda. A summa-tion of the report follows: Examination of a
plain lateral film and five sagittal and
para-sagittal laminograms at 0.5 cm intervals revealed a small cranium and a mass pro-truding through the partially excised vertex
area. The clivus appeared normal in size
and contour. The spheno-occipital synchon-drosis was of normal size and shape. The pituitary fossa was odd in shape and was enlarged, possibly artificially. In the eth-moid areas and the general transverse area
of the optic foramina there was a
distinc-tive down-bulging of the cranial vault. The orbits were small. The hard palate was of normal radiographic contour but was ex-ceptional in position in that its dorsal por-lion approximated the above-noted evagi-nation in the ethmoid area. Further studies of four coronal laminograms at 0.5 cm in-tervals revealed a partially bifid orbit and general narrowing of the upper face com-pared with the lower. In the 8.0 cm film, there was demonstrated a median keel pro-truding downward into the oral cavity from the palatal area and lesser protuberances downward on either side of it. The man-dible had a median cleft. Dr. Bosma’s in-terpretation was that this case does not represent a simple or typical cyclops, but rather an intergrade between cyclops and ethnocephaly.
CYTOLOGIC STUDIES
Chromosome analyses were based on the study of cell cultures derived from amnion
and from a skin biopsy obtained prior to
death with a motor-driven punch drill.4 The techniques of chromosome analysis de-veloped in this laboratory were used throughout. Analyses of chromosomes from the peripheral blood of both parents were carried out using a modification of the technique of Moorhead et al.6 In addi-tion, analyses were carried out on cell cul-tures derived from a skin biopsy from the mother.
The autoradiographic technique employed was a modification of that described by Schmid.7 Tritiated thymidine (specific ac-tivity, 1.9 C/mM) was added to replicate plates in a final concentration of 1 ‘tC/ml 6
hours prior to fixing, and coichicine was added 3 hours before termination of the
culture period. After fixation and air
A
ARTICLES
acetic orcein and photographs of the meta-phase plates were taken. The slides were then coated with Kodak NTB3 emulsion diluted 1:1 and warmed to 50#{176}C. The coated slides were kept at room tempera-ture in bakelite boxes containing silica gel. After 3 days, the slides were developed in Kodak D19 for 1 minute and fixed. Follow-ing this they were dehydrated, cleared, and mounted under a coverslip. Those meta-phase plates which showed evidence of ra-dioactivity from incorporated H3-thymi-dine were rephotographed and analyzed.
The patient displayed a constant chro-mosome number of 46 in all acceptable metaphase figures from skin and amnion cultures, except for an occasional aneu-ploid cell (Table I). All complete cells con-tained an abnormal chromosome and lacked a morphologically normal chromosome of group 16-18. In constructing the karyotype (Fig. 2), the abnormal chromosome was as-signed to the number 18 position, because it seemed to match best the long arm of the smallest and least metacentric member of the group. The missing short arm of this chromosome could not be seen either on the acrocentric chromosomes or elsewhere in the set in any of the karyotypes con-structed. Cytologic studies on the father and mother showed each to have 46 chro-mosomes with a normal karotype (Table I and Fig. 3). Karyotype analysis on the small percentage of aneuploid cells showed no consistent abnormality.
Of 49 metaphase plates examined in the autoradiographic study, only 29 showed ev-idence of H3-thymidine incorporation, and 25 were found suitable for DNA replication
TABLE I
I)ISTRIBUTION OF CHROMOSOME NUMBERS IN
PATIENT AND PARENTS
(‘hromoao ,,ze Vu ruber
.Suhj’et Speeuuen
-<4.
--4.5 4ti 4
Total
Inlant K Skin
Aninion
.
.
.1
2
35
41
. .
. 36
43
Father Blood 2 1 :34 1 :38
Mother : Blood 2 3 44 3 52
Skin 2 2 53 .. 37
B
FIG. 2. Kaeyotype of the propositus prepared from chromosomes obtained by amnion (A) and skin (B) cultures. Note loss of short arms in one
mem-ber of pair 18.
studies. In 8 of the suitable plates, there was differential uptake of the label by the group E chromosomes. As a rule, chromo-somes 17 and 18 can be readily distin-guished morphologically on the basis of size and centromere position. In our anal-yses the number 17 chromosome incorpo-rated earliest, the number 18 chromosome next, and the number 16 last. In all cases the abnormal telocentric chromosome matched the number 18 chromosome on the
basis of its incorporation of H3-thymidine
I
I;
III
41
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into mirror image hemispheres. Thus in arhinencephaly the cerebrum may be a sphere with a single ventricle (alobar holo-prosencephaly), two partially separated hemispheres, or two well-formed hemi-spheres that lack normal olfactory and optic structures. Not only are the olfactory bulbs and tracts usually missing, but the optic nerves and eyes are often hypoplas-tic.
The most severely malformed member of this spectrum of abnormalities is generally considered to be cyclopia, which is charac-terized by a single-chambered median eye, together with a single chambered prosen-cephalon. As an indication of their close re-lationship, cyclopia and cebocephaly have occurred in the same sibship.9
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B
Fic. 3. Normal karyotype of mother (A) and father (B) of propositus prepared from chromosomes
obtained by leukocyte culture of peripheral blood.
COMMENT
A
In 1882 Kundrat described under the term arhinencephaly a series of malforma-tions characterized by median dysplasia of the face and aplasia of the olfactory bulbs and tracts.8 Since not all rhinencephalic structures are missing in this condition, the term is actually a misnomer.1 Nevertheless, arhinencephaly is commonly used to des-ignate the neurologic features of a teratism that when fully expressed consists of anom-alous development of the nose, mouth, eyes, or ears, defective evagination of ol-factory and optic structures, and impaired midline cleavage of the embryonic forebrain
B
Fic. 4. Karyotype of propositus prepared from
chromosomes obtained by skin culture before (A)
and after (B) autoradiographs were prepared.
Tritiated thvmidine was added 6 hours prior to fixing. Note the two earlier replicating number 17 chromosomes, the later replicating number 18,
The causes of holoprosencephaly in man are unknown. It has been reported in asso-ciation with diabetes mellitus,’#{176} syphilis,1 and possibly toxoplasmosis.11 Intrauterine infections, such as cytomegalic inclusion disease, may severely damage the olfactory system, but postmortem studies have not provided evidence of an inflammatory process in holoprosencephaly. This malfor-mation is genetically determined in a strain of guinea pigs,12 and in sheep its occur-rence has been related to the ingestion of a plant toxin. Although usually sporadic, the occasional familial occurrence of this malformation in humans is of interest in
this regard.
Since recent cytologic studies have shown 13-15 trisomy in patients with alobar or lobar holoprosencephaly in association with extracephalic malformations, it was surprising indeed to find an entirely different chromosome abnormality in our patient with cyclops malformation. The ap-parent deletion of the short arms of a num-ber 18 chromosome was observed in vir-tually all metaphase figures from two different tissues, and therefore it appears unlikely to have resulted from an artifact of tissue culture. The recent preliminary note of an apparently identical finding in another case of cyclops1 lends support to the conclusion that the chromosomal abnor-mality may be a characteristic feature of this congenital malformation.
The presence of a normal karyotype in both parents suggests that the abnormal chromosome arose during gametogenesis or during an early cleavage division of the zy-gote. The patient’s abnormal phenotype would almost certainly rule out a balanced translocation; the abnormal karyotype more probably reflects a pure deletion or else a deletion and rearrangement involv-ing the short arms of one of the 17-18 chro-mosomes. On the basis of morphology, the abnormal chromosome resembles most closely the long arms of a number 18 chro-mosome. The radioautographic studies with tritiated thymidine indicate that it com-pletes its DNA replication later than two
other members of the 17-18 group. Previous studies of DNA synthesis in peripheral blood cultures from normal subjects have shown two distinct types of labeling pat-tern for the number 17-18 chromosomes. When they could be distinguished mor-phologically, the number 17 chromosomes have been found to replicate earlier than the number 18.15 Similar temporal differences in DNA replication of the num-ber 17 and 18 chromosomes in skin cell
cul-lures from normal subjects have been
ob-served in our laboratory.16 Hence, on the basis of tritiated thymidine incorporation as well as morphology, the abnormal chro-mosome can be identified as a number 18
with a deletion of the short arms.
The first description of a congenital ab-normality in humans related to a deletion of all or part of a chromosome involved cases with Turner’s syndrome. Although it had been assumed that autosomal deletions of human chromosomes would be non-viable, recent evidence suggests that this is not so. That small deficiencies are compat-ible with life and even with a normal phe-notype has been shown repeatedly in per-sons who are translocation carriers for the number 21 and other chromosomes, although these individuals do show a predisposition to transmit to their offspring a partial mono-somy or trisomy involving the translocated fragments.
In recent years, two distinct syndromes
have been described in which deleted
in-TABLE II
PARTIAL 18 MON0SOMY
Type of Abnormality Phenotype
I. Straight deletion
a) Short arms
1. de Grouchy, Lamy, Thieffry, 6-year-oldfemale; mother4l,father42; hypertelorisln, divergent squint,
Arthuis, and Salmon2’ epicanthic folds; chinodactyly of fifth fingers; bilateral syndactyly of
third and fourth toes; mental retardation.
. Btihler, Btihler, and Stalder’1 3-year-old female; mother 40, father 40; hypothyroid; mental and
growth retardation; slight epicanthic folds.
3. Van Dyke, Valdmanis, and 16-year-old female; mother 30, father 82; mental and growth retardation;
MannB strabismus, webbed neck, broad flattened nose; bilateral pes planus, external rotation both feet; poorly developed teeth.
4. Summitt24 44-yr-old female; mother J
,
father 26; Inental and growth retarda-tion; slight hypoplasia of supraorbital ridges; webbed iieck; shieldchest; incurved fifth fingers.
5. Nitowsky, Konigsberg, Levy, 16-year-old female; mother 37, father 56; mental and growth
retarda-Sindhvananda, and NitowskyB tion; pectus excavatum, atrial septal defect; webbed neck; macro-gnathia; kyphoskoliosis.
6. Faint and Lewis’4 Newborn female with cyclops malformation.
7. Present case Newborn female with cyclops malformation.
Also, other cases cited, not described
b) Long arms
1. de GrouchyB 1-year-old female; mother 7, father 40; mental and growth retarda-tion; small ears, arched palate, broad chest widely spaced IlippIeS
edema of feet; atresia middle ear; single palmar crease.
II. Ring chromosome
1. Wang, Melnyk, McDonald, Male; mother 23; mental retardation, deafness due to atresia of ear Uchida, Carr, and Goldberg27 canals; hypertelorism; bilateral epicanthus; bilateral syndactyly
second and third toes; minor motor seizures.
2. Genest, Leclerc, and Augur28 3-year-old female; hypertelorism; atresia of middle ear; club feet.
3. Lucas, Kemp, Ellis, and Mar- I-year-old female; mild mental retardation, microcephialy; mild
hypo-shall29 plasia of mandible; cleft palate; congenital hip dislocation. (Mosaic.)
4. deGrouchy, L#{233}v#{233}que,De- 5-year-old female; mother 27, father 37; mental retardation; slight bauchez, Lamy, and Marie30 hypertelorism, bilateral epicanthus; low set hair line; widely spaced
nipples; webbed neck; generalized hypotonia.
5. Gropp, Jussen and Ofteringer3’ 17-month-old male; mother 26, father 27; mental and growth
retar(1a-tion; dolichocephalic skull with synostosis of sutures; low set ears; high arched palate; micrognathia; short blunt hands, rocker bottom feet, heart murmur (?V.S.D.) left hydronephrosis with bilateral megoureter.
volving a number 4-5 and 13-15 was partial trisomy for the short arm of
found in one of the parents, which in the 4515bo
unbalanced form had produced an abnor- In contrast to these findings, the cases
arm of 17-18 do not constitute a distinct clinical entity. Aside from the two cases with cyclops deformity, the group of pa-tients with an apparently similar cytologic abnormality present variable clinical findings (Table II), although retardation of growth and mental development appears to be one common feature. Perhaps this by itself indicates heterogeneity in the type of underlying cytologic abnormality, because of differences in the specific chromosome involved or in the extent of the deletion. Nevertheless, it is surprising how relatively mild the abnormalities are in the cases with deletion of the short arms of a 17-18 in comparison with the 4-5 deletion. In the patients with deletion involving the 17-18 chromosome, viability with relatively mini-mal clinical abnormality may possibly be explained by the distribution of heterochro-matin and euchromatin. Since the cen-tromere region often consists mainly of het-erochromatin, it is possible that a large portion of the chromosome fragment which has been deleted is ordinarily heterochro-matic with relatively little active genie ma-terial.
Ring chromosomes arising through loss of both distal ends of the chromosome fol-lowing breakage or faulty replication are representative of the types of structural changes classified as deletions, although deletions are more frequently encountered in linear form. With the exception of ring X chromosomes in certain stocks of Drosophi-la, ring chromosomes have always been re-garded as rather unstable aberrations undergoing either numerical or structural changes, or elimination during mitotic cycles. Ring formation with assumed dele-tion has occurred predominantly in diploid cells and has involved those chromosomes for which trisomy occasionally occurs, namely 13-15, 17-18, 21-22, and the sex chromosomes. The phenotypes associated with ring chromosomes involving 17-18 are summarized in Table II. As in the case of simple deletions, no characteristic feature, aside from mental retardation, has been observed with this cytologic abnormality.
An individual with a balanced
chromo-some translocation can give rise to off-spring with partial monosomy as well as par-tial trisomy. In addition, there can be a mixture of the two, so that the infant has a deletion of part of one chromosome (partial monosomy) and a duplication of part of another (partial trisomy). It is not surpris-ing that the clinical signs in such cases are hard to predict. Reciprocal translocations of portions of the number 18 chromosome have heretofore involved either the acro-centric chromosomes or the 18 itself. In the present case, it appears that no appreciable amount of chromosome material from a number 18 has been translocated to any of the other chromosomes. Theoretically, a small translocated fragment might be hid-den on one of the larger autosomes, but this seems unlikely. On the other hand, the
p05-sibility of an 18/X translocation cannot be dismissed so easily.23 While deletions of a portion of the X have been recorded in
hu-mans, translocations of portions of the au-tosomes to the X have not been recognized in man.
Autosomal deletions have been used in some experimental organisms to assign genes to particular chromosomes. However, no satisfactory information has been ob-tained as yet from the human cases with deletions which have been investigated. While it may not reveal the pathogenesis of this unusual teratism, the association of a short arm deletion of an 18 chromosome with the cyclops malformation may assist in the studies of gene localization on the chromosomes of man.
SUMMARY
14. Faint, S., and Lewis, F. J. W.: Presumptive with cyclops malformation and suggest the presence of a characteristic chromosomal
defect in this unusual teratism. On the other hand, the different abnormalities in other cases of partial monosomy 18 illus-trates the phenotypic variability which can be observed in association with apparently similar chromosomal aberrations.
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