The No. 17–18 (E) trisomy syndrome

T h e J o u r n a l o[ P E D I A T R I C S

605

The No. 17-18 (E) trisomy syndrome Studies

on

cytogenetic~, dermatoglypbics, paternal age, and linkage

Three patients are described with trisomy 17-18 syndrome. One had a mongoloid sister suggesting the presence in her [amily o[ a genetic tendency to nondisjunction ("sticky genes"). Another o[ the patients had 46 chromosomes with a translocation revealing that the trisomy syndrome may result [rom triplication of the long arras of chromosome 17 or 18. However, most cases o] the syndrome have 47 chromosomes and parental age analysis indicates that maternal, rather than paternal, nondisjunction is the principal cause o/the trisomy 17-18 syndrome. The tendency to plain dermal arches on the fingers and toes provides a potent and simple diagnostic tool.

Frederick Hecht, M.D.,* Jean S. Bryant, B.A., Arno G. Motulsky, M.D.,** and Eloise R. Giblett, M.D.** SEATTLE~

WASH.

A U T O S O 2VI A L

trisomy occurs in m a n b u t

has not yet been discovered in any other mammal. In man 3 different autosomal trisomy syndromes have been well delineated: the D (No. 13-15) trisomy syndrome, the E ( N o . 17-18) trisomy syndrome, and Down's syndrome (trisomy 21). The syndrome resulting f r o m trisomy 17-18 was described simultaneously by Edwards and colleagues 1 and Patau and associates 2 in 1960. From the From the Departments o[ Medicine, Pediatrics, and Genetics, University o[ Washington, and Children's Orthopedic Hospital, Seattle, Wash. These investigations were aided by grants [rom the United States Public Health Service (H3091 and H5780) and the National Foundation ( C l 2 ) X-Research Fellow 'in Medical Genetics o[ the National Foundation. Present address, Division of Medical Genetics, University o[ Washington Medical School, Seattle 5, Wash. "~eReciplents o[ United States Public Health Service Grants H 3091 and H 5780, respectively.

beginning there has been some question as to the identity of the extra chromosome. Edwards interpreted it as chromosome No. 17, whereas Patau considered it No. 18. Subsequent workers ~, ~ have also been divided in their opinions. We will, therefore, use the term trisomy 17-18. We have recently studied 3 infants with trisomy 17-18 syndrome. This report presents the clinical histories, chromosomal findings, dermal patterns, and linkage data. D a t a were also gathered concerning the incidence, parental age effect, and sex ratio in trisomy 17-18.

CASE HISTORIES Case 1. This girl was born in Yakima, Wash., on June 6, 1962, to a healthy 17-year-old mother and 23-year-old father, both of Caucasian origin, neither of whom had received therapeutic or extensive diagnostic x-ray. They have a normal

60 6

Hecht

October 1963

et al.

Fig. I. Patient 1 at 2 months of age. Upper left, note especially hirsute forehead and small chin. Upper right, high-arched palate. Middle left, note opisthotonic position and small pelvis. Middle right, posterior protrusion of heel by x-ray. Lower left, enlarged clitoris and lack of complete hip abduction. Lower right, short upper lip and marasmic appearance. daughter 16 months old. No miscarriages had occurred. This pregnancy was generally unremarkable, although the obstetrician had difficulty hearing the fetal heart sounds an d feeling fetal movement. Pregnancy ended after 42 weeks in a spontaneous short labor. At delivery the cord was found wrapped once about the baby's neck. Resuscitation was difficult; oxygen was given by intermittent positive pressure for 15 minutes. The placenta was tiny, the size of a man's palm. .~ T h e baby weighed 1,490 grams at birth. She was referred at 28 days to the Children's Orthopedic Hospital in Seattle because of heart disease and clitoral enlargement. When examined at 2 months of age she appeared poorly nourished with loose-fitting skin (Fig. 1). The head circumference was 34.5 cm. The occiput was unusually prominent. Between the anterior and posterior fontanels there was a small 'third fontanel. There was hypertrichosis over the forehead. The

eyes and nose appeared normal. The upper lip was short, the palate high arched, and the chin small. The ears were low set and posteriorly rotated. The sternum was short (5 cm.) and the pelvis small (21 cm. in circumference). There was a small diastasis recti. The clitoris was enlarged, being 1 88 cm. long and ~ cm. wide.

MONGOLS IM I TRISOMY 17-IB

~---~NormoDmale ( ~ Nortool femole

O Abnormol femole A

Miscorriage, sex unkown

Fig. 2. Pedigree in Case 2.

Propositus

Volume 63 Number 4 part 1

Trisomy 17-18 syndrome

60 7

Fig. 3. Patient 2 at birth. Note the short upper lip, small sternum, widely separated nipples, and long abdomen.

The urethral meatus was normally situated. The hips could not be fully abducted (Fig. 1). The hands were often clenched with the index finger overlapping the third finger and fifth finger overlapping the fourth. The heels projected ~ cm. posteriorly. T h e halluces were 88 cm. shorter than the second toes. There was increased tone and she often lay in opisthotonus. Her M o r o reflex was incomplete. Sucking reflex and cry were strong. She did not follow a light although her pupils reacted to it. Because of heart failure she was given digitalis. She had several bouts of pneumonia, each of which temporarily caused reappearance of heart failure. The hospital course was complicated by the slow, gradual progression of left upper lobe emphysema and several episodes of apnea. A mild Pseudomonas conjunctivitis cleared promptly with antibiotics. At 98 days of age her head circumference was 34.5 cm. and her weight 2,380 grams. At 141 days of age death occurred from pneumonia. Permission for autopsy was not granted. The family history revealed that a maternal aunt died at 2 months of age in 1957 with a congenitally malformed heart. No autopsy was performed on her. However, the death certificate

lists "leprechaunism." T o the family she looked "exactly like" our patient. Laboratory data. Chest x-rays confirmed the progression of left upper lobe emphysema with shift of the mediastinal structures to the righl. Chest films also showed cardiomegaIy. Electrocardiograms revealed right ventricular overload. A right heart catheterization indicated a large left-to-right shunt at the ventricular level. An angiocardiogram also showed decreased circulation to the left lung. O n barium enema the colonic splenic flexure and descending colon appeared more medial than usual. Bone age, spine, and skull films were within normal limits. An intravenous pyelogram was abandoned after an episode of apnea. The hematocrit, hemoglobin, leukocyte count, blood smear, serum calcium, phosphorus, transaminases, and urea nitrogen were within normal limits. The urine contained clumped white cells and quantitative urine cultures grew out coliform organisms in significant numbers. Case 2. This patient was born on Oct. 4, 1962, in Seattle to a 42-year-old Alaskan Indian woman and a 46-year-old Caucasian man. The mother had tuberculosis of the right hip at 6 years of age with arthrodesis of that joint and

608

H e c h t et al.

recurrent pulmonary tuberculosis leading to a thoracoplasty in 1950. This was her sixth pregnancy. She has a 9-year-old boy by a previous marriage. By her present husband she had in succession a spontaneous abortion, a normal girl now 5, a spontaneous abortion, and a girl who died at 8 months of age (Fig. 2). T h e latter had clinically well-documented mongolism. Her findings included braehycephaly, mongoloid facies, epicanthal folds, atrial septal defect, umbilical hernia, unilateral simian crease, wide interval between first and second toes, marked hypotonia, retarded development, and characteristic mongoloid hip measurements on x-ray of the pelvis. Our patient was conceived within weeks of the mongoloid sibling's death. Pregnancy was punctuated by 2 hospital admissions for dehydration due to hyperemesis gravidarum. Psychiatric consultants found the pregnant woman moderately depressed. She felt the child she was

October 1963

carrying would replace her dead (mongoloid) child. The patient, a girl, was born after a spontaneous 4 ~ hour labor. The Apgar score was 6 with heart rate over 100 at 1 minute. Resuscitation was moderately difficult. Birth weight was 3,310 grams, length 49 cm., head circumference 33 cm., and chest 33 cm. She was immediately noted to have multiple anomalies and within several hours of birth a clinical diagnosis of trisomy 17-18 syndrome was entertained. The child had poor tone, poor sucking reflex, and no Moro reflex. A third fontanel 1 cm. in diameter was located between the usual anterior and posterior fontanels. There was hypertrichosis over the forehead. T h e eyes were roving and showed an inferior medial coloboma of the left iris and bilateral eolobomas of the choroid involving the inferior fundus and disk, but probably sparing the macula. Nose and mouth were

Fig. 4. The hand of Patient 2 with tight fist, overriding index finger, and hypoplastic nails.

Volume 63 Number 4 part 1

Trisomy 17-18 syndrome

609

Fig. 5. Excised transilluminated diaphragm from Case 3. Arrows indicate area of eventration. normal, but the chin was rather small. T h e were small (measuring 2 ~ cm. from top to tom) and posteriorly rotated. T h e s t e r n u m very short ( 4 ~ cm.). T h e chest was short the a b d o m e n long. T h e nipples were in the

ears botwas and an-

terior axillary line (Fig. 3). T h e r e was excessive loose skin over the nape of the neck a n d hypertrichosis over the lower back. T h e r e was u l n a r deviation of b o t h hands, a simian line on the right, and tightly clenched fists with index finger

,;,

A:

c:

I

2

9

x-6-12

Fig. 6. Karyotype of Patient 1 with trisomy 17-18 syndrome due to a translocation. Total chromosome number is 46. Bottom arrow indicates missing chromosome in the D group. Top arrow points to translocation chromosome. (From Hecht et al., Lancet 1: 114, 1962).

6 10

H e c h t et al.

October 1963

overlapping the third finger. The fingernails were hypoplastic (Fig. 4). The perineum was very short, barely separating the vagina from the rectum. There was posterior protrusion of the heels. The halluces were short and intermittently dorsiflexed. The placenta, membranes, and cord weighed 620 grams and appeared grossly and histologically normal.5 During the first day of life the patient was given digitalis because of cardiac failure. However, She has remained slightly cyanotic. The precise nature of her cardiac malformation is not known. One bout of conjunctivitis resolved with antibiotic therapy. At g weeks she regained her birth weight, but appeared malnourished. Her head circumference was 35 cm., and length 50 cm. Her hips could not be fully abducted. At 16 weeks of age her weight was down to 2.8 kilograms. Head and chest circumference had not changed. Her length was 57 cm. Laboratory data. ttematocrit, peripheral blood smear, reticulocyte count, and routine urinalysis were normal. A lumbar puncture yielded clear cerebrospinal fluid with normal values for glucose and protein. Electrocardiograms disclosed right ventricular hypertrophy. Chest x-rays showed a fracture of the right clavicle, a short sternum with irregular ossification centers, cardiomegaly, and probable eventration of the right diaphragm. Skull, spine, and hip films were normal as was an intravenous pyelogram. Osseous maturation was considered normal by x-ray.

A:

1

2

Case 3. This patient, a Negro girl, was born on Dec. t, 1962, in Seattle to a 38-year-old father and a 35-year-old woman. The mother's 5 previous pregnancies had produced a normally formed boy who died at 4 days of age, and then 4 normal boys. The mother's x-ray experience is limited to 5 chest films. Pregnancy this time was complicated by hydramnios. Delivery was by elective cesarean section because of 2 previous sections. This baby was of 41I/2 weeks' gestation, weighing 2,280 grams at birth. The placenta weighed 530 grams and was not described further. Resuscitation was exceedingly difficult, with Apgar score 1 at 1 minute, 5 at 5 minutes, and 8 at 15 minutes. The infant was noted to have malformed feet. Her head circumference was 34.5 cm., chest 30.5 cm., and length 45 cm. She had an incomplete Moro reflex, pqor suck reflex, and fair cry. Her tone was normal to increased. The head did not show occipital prominence, but there was hypertrichosis over the forehead. Ears were low set, pixie-like, and pinned back. The eyes appeared somewha t small, but otherwise normal. Nose and mouth were normal. Chin was small. Neck was short but without significant redundant skin. The chest was remarkable for the short sternum and widespread nipples. The heart, lungs, and abdomen were unremarkable. The pelvis was small. The labia minora appeared enlarged to some observers but were considered within normal limits by others. The hips could not be fully abducted. The feet

3

C:

Fig. 7. Karyotype of Patient 2 with 47 ,chromosomes and trisomy 17-18 indicated by arrow.

Volume 63 Number 4. part i

Trisomy 17-18 syndrome

6 11

Fig. 8. Dermal patterns of Patient 1. Continuous lines indicate dermal ridge patterns. Interrupted lines indicate flexion creases. Note the plain arches on all toes and all but the fifth fingers.

showed marked calcaneovalgus deformities. The hands showed ulnar deviation at the wrist. There was hollowing of the thenar eminences. T h e fists were clenched with flexion contracture of the fingers, second finger overriding the third and fifth overriding the fourth. The right index finger also showed a rotational deformity at the distal interphalangeal joint. The fingernails were hypoplastic. T h e r e was moderate lanugo hair over the back. She was put at 20 days of age in a hip spica cast, which was removed after 2 weeks in favor of leg and foot casts. A t 8 weeks of age she weighed only 2,800 grams. Head and chest measurements had not changed since birth. Her length was 49.5 cm. At 62 days of age she developed pneumonia and died following a series of apneic spells. Laboratory data. The hematocrit, reticulocyte count, white cell count and differential, platelet count, routine urinalysis, and blood urea nitrogen were within normal limits. X-rays showed a short sternum with a single epiphyseal center. Bone maturation appeared generally retarded (no dis-

tal femoral, proximal tibial, or carpal epiphyseal centers). All phalangeal bones were present. X-rays confirmed bilateral dislocation of the hips with no bon)~ acetabulum on the right. There was no eventration of the diaphragm noted by the x-ray. Skull and spine films and intravenous pyelogram were normal. Autopsy findings. ~ The heart was enlarged with a patent foramen ovale, a 5 ram. high ventricular septal defect, and a patent ductus arteriosus 7 mm. in diameter. The aortic valve was bicuspid. Both coronary ostia were located in one sinus of Valsalva. O n all 4 heart valves were fine beads which were histologically identical t o the valves. There was a shallow aneurysm of the ascending aorta. The lungs showed right lower lobe atelectasis and resolving patchy pneumonia. Alveolar septa in several areas appeared thick. One small artery in the lung showed eccentric patch of foamy, endothelial proliferation compatible with atherosclerosis. No other artery, pulmonary or systemic, appeared abnormal.

6 12

October 1963

Hecht et al.

35-

I~AII Births (USA, 1960) /

30-

t\J

t /

"s 2 5 -

\

..'~Mongolisrn 0038

,,\

I

'/,

t

~20-

I

..."" p-'"

'

-,,./

Cases)

"

i

I

~.

i

\ \

.."

" "

\/

15-

5-

10-14 15-19 20-24 25-29 30-34 35-39 4 0 - 4 4 45-49 50-54 Maternal

age

in 5 y e a r

periods

The diaphragm was eventrated (Fig. 5). A thick band of muscle stretched between lower sternum and central tendon to separate two thin aponeurotic domes covering anomalous knobs of liver. A 1 cm. plaque of pancreatic tissue was found in the jejunum 12 cm. below the ligament of Treitz. The kidney microscopically showed several large unstructured masses of nephrogenic cells beneath the capsule. The adrenal glands were small (combined weight 2.05 grams), but histologically normal. Ectopic chromaffin tissue and a massive neural plexus rich in ganglion cells were located adjacent to the vagina. The thymus was small (2,2 g r a m s ) a n d involuted. A small amount of thymus tissue found just below the thyroid contained a single normalappearing parathyroid. The left submandibular gland was extensively infiltrated with mononuclear cells. The calvarium showed irregularly alternating areas with and without diploic marrow space. The entire brain weighed 470 grams prior to fixation. The cerebellum, however, appeared small and with the brain stem weighed only 26 grams. There was marked medial displacement of the right olfactory nerve. The pituitary appeared grossly and microscopically normal. Dissection of the left thenar area disclosed

"X'By Dr. Michael K. Reedy, Department of Pathology, University of Washington Medical School

Fig. 9. Percentage distribution of maternal ages in trisomy 17-18 syndrome, mongolism,14 and the United States Population. 11

absence of the abductor pollicis, flexor pollicis brevis, and opponens pollicis, all normally innervated by the median nerve. The adductor pollicis, which is usually supplied by the ulnar nerve, was present. RESULTS

Cytogeneties. Buccal mucosa smears in all 3 cases showed a n o r m a l female c h r o m a t i n positive pattern. C h r o m o s o m a l studies of p e r i p h e r a l blood leukocytes were carried out by a modification of the m e t h o d of M o o r h e a d a n d co-workersY T h e chromosomal findings in Case 1 have been reported in a p r e l i m i n a r y c o m m u n i c a tion. r T h e karyotype in this case (Fig. 6) revealed the absence of a chromosome in the 13-15 (the D ) group and the presence of an additional large chromosome which we have designated D / E . I t appears to have been formed by a translocation of the long arms of a No. 17 or 18 chromosome (one of the E group) onto one of the D group chromosomes. T h e chromosomes of this child's parents are n o r m a l b o t h as to total n u m b e r and karyotype ( T a b l e I ) . T h e c h r o m o s o m e counts in Cases 2 a n d 3 showed a m o d a l n u m b e r of 47 with an e x t r a chromosome in the 17-18 group (Fig. 7). T h e n o n m o d a l cells were inconsistent in their chromosome complements.

Volume 63 Number 4 part 1

Dermatoglyphics. The fingerprint patterns in the 3 cases and their families are summarized in Table II. All 3 patients showed the predominance of plain arches usually seen in trisomy 17-18. 8 Since plain arches have no triradii and therefore no ridge count, the total ridge counts in the patients were extremely low. In contrast, their families had normal fingerprint patterns and normal total ridge counts. The toes in these 3 patients evidenced the same tendency to simple arches as the fingers (Fig. 8). All 3 patients had simple arches on every toe, as did an unpublished case of trisomy 17-18 studied by Dr. James R. Miller in Vancouver, B. C. Other findings of diagnostic interest include the short incurving fifth finger with a single flexion crease in 2 of our patients. This finding was also apparent in 8 of 13 cases studied by Uchida, Patau, and Smith2 A transverse palmar (simian) line was present on the right in Case 1 and bilaterally in Cases 2 and 3. Linkage studies. Blood grouping as well as haptoglobin and transferrin typing were done in Cases 1 and 2 (Table V). The results are compatible with the averred paternity. There is no evidence for linkage with the triplicated chromosomes. To test for linkage with the hemoglobin loci, blood was obtained from Patient 2 at 14 days and from Patient 3 at 4 days of age. The hemolysates were examined by starch gel electrophoresis and column chromatography using techniques described separately. 9 No hemoglobin abnormalities were found. Incidence. The 3 patients in this report were born in the state of Washington within 6 months. Two of the cases (Patients 2 and 3) were born at the University Hospital 59 days and 150 births apart. On this obstetrical service there have been 999 deliveries in the year (July, 1962, through June, 1963) since surveillance for this condition began. The assumption of no missed cases of trisomy 17-18 syndrome gives a highly tentative incidence figure of about 1 in 500 live births.

Trisomy 17-18 syndrome

6 13

Parental age studies.* Previous reports 4, 10 have suggested that infants with trisomy 17-18 syndrome tend to be born to older mothers. The maternal ages in 37 cases and in the control population (United States Census, 1960) 11 were arranged in 5 year groups (Table I I I ) and plotted (Fig. 9). All 37 cases showed the characteristic clinical picture of trisomy 17-18 syndrome with chromosomal confirmation in 36 of the cases. T h e single case 4 included without chromosomal analysis had typical dermal patterns with 10 plain digital arches, s Of the 36 karyotyped cases 2 had translocations, 12 and 1 was a mosaic la with trisomy 17-18 and normal cells. The maternal age curve for trisomy 17-18 syndrome (Fig. 10) cannot be strictly compared to that for mongolism since the later curve comes from Great Britain? * T o our knowledge no extensive recent North American data on maternal age in mongolism are available. Since older husbands naturally tend to have older wives, the apparent increase in maternal age in trisomy 17-18 syndrome might merely reflect a rise i n paternal age. The mean paternal-maternal age difference was compared, therefore, with that in the United States (Table I V ) . Only cases of trisomy 17-18 with 47 chromosomes were included. One case from Table I I I had to be omitted because paternal age was not specified. Both paternal age and maternal age are increased. The mean paternal age in trisomy 17-18 is 36.0 years compared to 29.9 years for the general population. T h e mean maternal age in trisomy 17-18 is 34.3 years as compared to 26.4 years for the general population. Most importantly, the mean paternalmaternal age difference in these 32 cases of trisomy 17-18 is only 1.7 years compared to the national mean paternal-maternal difference of 3.5 years. This comparison is highly significant as shown in the equation found on top of page 614.

~In this and subsequent sections of this report only cases oJ[ trisomy 17-18 syndrome published prior to Dec. 1, 1962, are considered.

6 14

October 1963

H e c h t et al.

3.5--1.7

Population mean--sample mean -

-

Standard error of sample mean

0.6

3.0

)

The hands in trisomy 17-18 syndrome are extraordinary (Fig. 4). T h e fists are tightly clenched with the index finger overlapping the third. The skin creases and dermal patterns also make the hands a diagnostic centerpoint. Anomalies in the perineal area are common. Case 2 was lacking a perineal body so that the anus lay within the fourchette. The clitoris was enlarged in Case 1 (Fig. 1). Previous cases have also been reported with an enlarged clitoris 16 a n d anal anomalies? Hip abnormalities are also common in trisomy 17-18. Hip abduction was limited without dislocation in Cases 1 and 2. The hips were dislocated in Case 3. Aside from the small size of the pelvis, measurements of the acetabular and iliac angles in the three patients showed no alternation of diagnostic value. Microcephaly was not present. The head size at birth was small, but it was in proportion to the small body size. Neither head nor body grew significantly. There was hydramnios in our Case 3 and in all 5 cases for which information was available in the literature?~ 17 T h e occurrence of hydramnios unaccompanied by fetal intestinal obstruction suggests severe cenfral nervous system deficit in utero and is consistent with the marked developmental retardation seen after birth. The trisomy 17-18 syndrome like mongolism seems to result uniformly in mental retarda-

with 31 degrees of freedom, P = 0.01--0.002. The more narrow difference in age between fathers and mothers together with the marked parental age effect strongly supports an etiologically significant increase in maternal rather than paternal age in trisomy 17-18. Sex ratio. Patients 2 and 3, both of whom had trisomy 17-18 with 47 chromosomes, were females. T a k e n alone this would hardly be noteworthy. However, a tally of all known cases of trisomy 17-18 syndrome in August, 1962, is disclosed a predominance of females: 22 girls in contrast to 9 males. Taken with our 2 cases, 2 and 3, this makes 24 females and 9 males. The probability of this excess of females occurring by chance is between 1:50 and 1:100 (X~ = 5.94 and P = 0.010.02). DISCUSSION The anomalies. The patients showed the typical features of the trisomy 17-18 syndrome with prominent occiput, low-set malformed ears, high palate, short upper lip, small chin, short sternum, tiny pelvis, typical hand posture, and rockerbottom feet. They also had a third fontanel which is commonly observed in mongolism. The forehead and back especially were covered by profuse fine hair (Figs. 1 and 3). The appearance of malnutrition was not present at birth but developed with time (compare Figs. 1 and 3). Table I. Peripheral blood--leukocyte cultures

Chromosome No.

. Subject Case 1 Patient Mother Father

<45 1 4 ,

f

46

I

47

1 1

40* 48

1

2

46

1

I

48

I

>48

I

Total

41 50 50

Case 2 Patient

1

2

46

Mother Father

1 1

48 46

1 2

50 50 50

4

46

50

Case 3

Patient

*Italics indicate modal number of chromosomes.,

Cells karyotyped

Volume 63 Number 4 part 1

tion. This retardation cannot usually be accounted for by microcephaly or by malformations of the brain. Only a minority of patients with trisomy 17-18 have had central nervous system anomalies and these have not been major,l, ~0, 17, is Other clinical features of trisomy 17-18 syndrome are well analyzed by Smith and collaborators ~~ and by Rosenfield and coauthors. 19 Trisomy 17-18 and mongolism in sisters. Patient 2 with trisomy 17-18 had a sister with mongolism (Fig. 2). To account for 2 such occurrences in the same family, one might point out that (1) the mother was in her forties and that (2) she had a long history of p u l m o n a r y and hip tuberculosis, which probably led to considerable diagnostic x-ray including the gonads. Both elevated maternal age and x-ray exposure might have predisposed to a higher probability of nondisjunction. However, the effect of x-ray exposure on the rate of nondisjunction in man is still under debate. ~~ Another possibility, a genetic predisposition to nondisjunction, needs to be considered. For instance, patients with double trisomy have been found. Thus, Table I V includes a child with both trisomy 17-18 and X X X 2' and a child with trisomy 17-18 and trisomy 21. 22 Stronger evidence for a genetic predisposition to nondisjunction comes from families containing several aneuploid individuals such as the family described by Miller and associates, 2a with an X X X X Y male and two 21-trisomic mongols. In a survey of mental defectives Wright and coworkers x* found 10 individuals with X X Y Klinefelter's syndrome. Two of the 10 had a mongoloid sibling. Genes which cause aberrant chromosomal behavior have been demonstrated in plants 2~ and in certain animals. 2~ In corn, for example, Beadle 25 demonstrated "a gene for sticky chromosomes," which disrupts meiosis and mitosis to produce nondisjunction, translocation, and chromosome fragmentation. Dermatoglyphics. The dermal patterns in mongolism are abnormal and quite characteristic. Since dermal patterns are influenced by a large number of genes presumably lo-

Trisomy 17-18 syndrome

6 15

cated on different chromosomes, we might expect to find dermatoglyphic derangements in autosomal trisomies other than mongolism. This has now been demonstrated in trisomy 17-18 by Uchida, Patau, and Smith. s T h e 3 cases here reported confirm and extend their findings. The tendency to digital arches provides a useful criterion for diagnosis of the trisomy 17-18 syndrome. All 3 of our patients and 17 out of 18 cases of Uchida, Patau, and Smith's experience showed 6 or more plain digital arches. Less than 2 per cent of normal persons have 6 or more plain digital archesY 7 No disease except trisomy 17-18 has been found associated with this increase in digital arches. One case of X X X X Y syndrome was reported with 9 digital arches, but this tendency to arches appears inherited since his father also had 4 arches. 28 We have studied 2 patients with X X X X Y syndrome. The first (seen through the courtesy of Dr. Horace Thuline at the Rainier State School, Buckley, Washington) showed only 1 digital arch. The second case (seen through the courtesy of Dr. Ralph Hayden at the Fircrest School, Seattle, Washington) had no digital arches. Dermal prints in infants, especially those with trisomy 17-18, are admittedly not technically easy, but they can be obtained rapidly and inexpensively with less equipment and training than chromosomal studies. A number of infants have clinical findings suggesting the trisomy 17-18 syndrome without a .detectable chromosomal abnormality. Our first clue to several such phenocopies came from their normal dermal patterns. Cytogenetics. Patient 1 clinically showed the full-blown trisomy 17-18 syndrome. However, on karyotyping she proved to have 46 chromosomes including a D / E translocation. This interpretation of the kaI~/otype seems reasonable in view of her clinical picture and dermatoglyphics. The translocation chromosome could be definitely identified in every cell karyotyped. It is the same size as chromosome 3, but is less metacentric. The parents of this patient had normalappearing chromosomes in their leukocytes,

6 16

October 1963

H e c h t et al.

Table II. Dermal patterns on fingertips Left 5 U/R ~

Subject

4 U/R

Patient 1 Mother Father Sister

0/(4) t 0/20 0/10 0/( 13 )

Patient 2 Mother Father Sister

0/0 0/10 0/17 (10)/(18)

Patient 3 Mother

0/0 0/16

0/0

14/16 0/17 (10)/15

3 U/R 0/0

2 U/R 0/0

1

U/R 0/0

15/15 0/16 0/19

16/8 8/12 15/(12)

0/16 0/14 (11)/19

0/0 18/16 0/16 22/(23)

0/O 0/8 0/17 0/20

O/0 1/0 0/16 14/(19)

0/0 18/8 0/19

0/0 0/20

0/0 0/tl

O/0 26/14

O/20

(12)/0 16/19

e'U ~ Ulnar ridge count; R ~--- Radial ridge count. tParentheses indicate probable ridge count.

so tile child's translocation is thought probably to have arisen de novo during gametogenesis. Gonadal mosaicism in one of the parents cannot be ruled out. If they were to have a second child possessing the translocation chromosome, parental gonadal mosaicism would be likely. O n e other case of trisomy 17-18 syndrome due to a translocation has been reported. *~ I n that case the child clearly received the translocation chromosome from the mother who was carrying the translocation but was genetically balanced. This translocation, like ours, was between chromosomes of the D and Table I I I . Distribution of births by maternal age % distribution Maternal age (in years) at birth of child

Below 15 15 to 19 20 to 24 25 to 29 30 to 34 35 to 39 40 to 44 45 to 49 50 to 54 Total

Trisomy 17-18 All births 1,038 cases in popu- of monsyndrome lationt golism$ % No. of distri- % distri- % districases ~ bution bution bution

0 2 7 4 5 8 9 2 0 37

0.0 5.4 18.9 10.8 13.5 21.6 24.4 5.4 0.0 100.0

0.1 13.8 33.5 25.7 16.2 8.5 2.1 0.1 0.0 100.0

0.0 1.0 6.1 10.8 14.1 27.3 31.9 8.8 0.0 100.0

'~'Refs. 1-4, 10, 12, 13, 16-18, 22, 34, 35 and present report. ~Unlted States Census, 1960.1. ~.Series from Brltain. .4

E groups, but differed by forming an unusually long acrocentric chromosome. Chromosomal fragments of differing sizes were also found in m o t h e r and child. Trisomy 17-18 syndrome due to translocation is similar to "translocation mongolism." I n both cases the patient with the translocation at present appears clinically indistinguishable f r o m the child with the trisomy syndrome and 47 chromosomes. Cytogenically, however, there is an important difference. Chromosome 21 is an acrocentric chromosome with tiny short arms, whereas chromosomes 17 and 18 have sizeable short arms. T h a t mongolism can result from a translocation tells us only that the minute short arms of chromosome 21 may not need to present in triplicate to cause mongolism. This could have been safely predicted. In other species the centromere and immediate paracentric segments carry little, if any genetic informationY 9 Thus the D / E translocation in Case 1 allows us to assess the relative roles of the short and the long arms in the production of the trisomy syndrome. The D / E translocation clearly incriminates the long arms and exonerates the short arms as responsible for the trisomy 17-18 syndrome. Linkage studies. Autosomal trisomy should facilitate the detection of linkage of autosomal genes to their visible carriers, the autosomes. Presently no autosomal gene can be assigned with complete certainty to a specific chromosome. I n 1962 it was suggested that a gene af-

Volume 63 Number 4 part I

Trisomy 17-18 syndrome

6 17

Right f

1 R/U

2 R/U

0/0 13/10 22/16 14/0

0/0 9/15 16/0 13/0

o/o

o/o

16/0 26/0 (21)/0 0/0 18/17

Table

3 R/U

4 R/U

5 R/U

Total ridge count

Total No. of arches

0/0 16/0 14/0 14/0

0/0 21/12 17/0 >14/0

(9)/0 21/0 13/9 (17)/0

(13) 169 151 >153

8 0 0 0

o/o

o/o

o/o

o

lO

0/2 17/13 (17)/14

0/0 t8/0 18/0

16/11 22/15 (23)/16

9/0 13/0 (20)/13

98 181 199

1 0 0

0/0 10/28

0/0 7/0

0/0 21/12

(12) 185

9 0

IV. Parental

age in trisomy

No.

Reference

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32

E d w a r d s et al. 1 C r a w f u r d a4 G a g n o n et al. 22 S m i t h et al. 1~ S m i t h et al. 1~ S m i t h et al. 1~ S m i t h et al. 1~ S m i t h et al. a~ S m i t h et al. 1~ S m i t h et al. 1~ U c h l d a et al. 4 U c h i d a et al. 4 U e h l d a et al. ~ U c h i d a et al. ~ U c h i d a et aI. ~ G e r m a n et al. la G e r m a n et al. is Voorhees et al? 6 Voorhees et al. 16 V o o r h e e s et al. 16 T o w n e s et al. 35 Gottlieb et al. s Gottlieb et alY Gottlieb et al. 3 K o e n i g et al. 17 K o e n i g et al. 1~ Weiss et al. a3 Weiss et al. 13 Weiss et al. la Weiss et al. la T h i s report T h i s report

0/0 19/0

17-18

Author's case No. (if any)

8 19 11 27 34 41 215 1 3 4 5 6 1 2 1 2 3 1 2 3 1 2 2 3 4 5 2 3

Age of father (years) 32 49 21 49 46 35 32 25 48 46 26 36 33 38 48 29 36 40 29 42 43 39 29 43 30 42 26 25 27 23 46 38

Age of mother (years) 31 40 20 46 46 37 30 21 39 43 26 36 36 33 40 31 37 40 29 33 42 36 27 43 40 42 26 24 24 23 42 35

Paternal-maternal age difference (years) 1 9 1 3 0 -2 2 4 9 3 0 0 -3 5 8 -2 -1 0 0 9 1 3 2 0 -10 0 0 1 3 0 4 3

M e a n (years)

36.0

34.3

1.7

S t a n d a r d error

+1.5

+1.3

+0.6

M e a n (years) U.S.A. 196011

29.9

26.4

3.5

6 18

Hecht

October 1963

et al.

T a b l e V. Blood, haptoglobin, a n d transferrin typing Subject

A

A1

B

M

N

S

s

+ + + -

+ +

-

+ + + + *

+ +

+ + + + +

+ + +

+

+ +

+ + +

+ +

+ + +

PI

D

Case 1

Patient ~ Mother Father Paternal grandmother Paternal grandfather

+ -

-

+

-

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

Case 2

Patient Mother Father

+

-

X'The Le (a + b +) phenotype indicates that this child is in transition to the Le (a -

fecting leukocyte alkaline phosphatase m i g h t reside on chromosome 21 since that enzyme a p p e a r s to be increased in mongolism (trisomy 21) a n d decreased in chronic myeloid leukemia (associated with a somatic deletion of chromosome 21).3~ I n trisomy 17-18 similar enzyme studies with carefully standardized techniques will be difficult since it is going to be h a r d to assemble a significant n u m ber of live individuals with trisomy 17-18 when the m e a n age at d e a t h is about 90 days? ~ Evidence against linkage can only be derived from the blood a n d serum group typing in Cases 1 a n d 2 with certain assumptions. F o r example, in Case 2, assuming m a t e r n a l nondisjunction in the first meiotic division without crossing-over, we can rule out the presence of h a p t o g l o b i n structural genes on the triplicated chromosome since the trisomic child obviously d i d not inherit both of the mother's h a p t o g l o b i n genes. U n f o r t u n a t e l y , in m a n nothing is known a b o u t the frequency of crossing-over or a b o u t the relative frequency of first versus second meiotic division nondisjunction. ( T h e evidence to d a t e indicates that nondisjunction in D r o s o p h i l a melanogaster occurs at the first meiotic division. 31) T h e derivation of linkage information from the d a t a in T a b l e V on Case 1 requires similar assumptions. F o r example, the child lacks the mother's s gene a n d the father's N gene, a n d the ] k a gene which both parents possess. Assuming that the translocation occurred d u r i n g first meiotic division without crossing-over, we can rule out entirely the presence of the M N S a n d

+ +

b +) phenotype.

K i d d blood group genes on the long arms of the triplicated chromosome. Incidence. O u r estimate of one case of trisomy 17-18 p e r 500 live births is rough a n d tentative. I t is based on the 2 cases born at the University Hospital. These two children are of different racial origin. T h e m o t h e r of Case 2 is Alaskan I n d i a n a n d the father is Caucasian. T h e p a r e n t s of Case 3 are Negro. O u r estimate, therefore, depends on the assumption t h a t the frequency of trisomy 17-18, like mongolism, a2 does not differ significantly f r o m race to race. I t is obvious t h a t no precise estimate of the frequency of any condition can be based on two cases. O u r experience in Seattle, however, is in a g r e e m e n t with t h a t of U c h i d a a n d her colleagues in Winnipeg, Man., C a n ada, where they f o u n d trisomy 17-18 to be a "relatively c o m m o n . . . entity. ''4 T h e incidence of trisomy 17-18 w o u l d thus a p p e a r to be n e a r t h a t of mongolism, the incidence of which is between 1:600 to 1:800 live births. ~2 P a r e n t a l age studies. T h e elevated m a t e r nal age in trisomy 17-18 with 47 chromosomes implies t h a t nondisjunction here, as in mongolism, 14 is m a i n l y maternal. This m a y be related to the long storage of ooeytes. A f t e r first meiotic prophase is c o m p l e t e d in late fetal life, the oocyte waits for 12 to 50 years to c o m p l e t e the first meiotic division? a I n contrast, the spermatocyte races t h r o u g h all of meiosis in a relatively short time. O f the cases of trisomy 17-18 syndrome with c h r o m o s o m a l analysis, 33 of 36 (92 per

Volume

63 N u m b e r 4

part 1

K

k

Fy ~

Trisomy

17-18 syndrome

6 1 9

.lk ~

Jk b

Hpl

T/~

E

c

e

Le a

Le ~

Hp2

+

+

+

+

+

+

-

+

-

+

+

+

+

+

-

+

-

+

+

-

+

+

+

+

+

+

-

+

+

+

+

+

+

+

+

+

+

-

+

+

-

+

+

-

+

+

+

+

-

+

+

+

+

+

+

-

+

4--

+

-

+

+

+

+

+

-

+

+

+

-

-

+

-

+

+

cent) had 47 chromosomes with trisomy 1718. Nondisjunction seems, as in mongolism, to account for most cases of the trisomy 17-18 syndrome. The curve (Fig. 9) showing the distribution of cases of trisomy 17-18 syndrome according to maternal age is bimodal. T h e first peak is partially due to the presence of the young mothers (ages 15, 17, and 20 years) of afflicted babies who, on karyotyping showed mosaicism or translocation. Removing these 3 cases and considering only cases Of trisomy 17-18 with 47 chromosomes, a suggestion of bimodality remains. This may reflect those causes of disjunction, such as the genetic tendency to nondisjunction, which may operate independently of maternal age. Sex ratio. The ratio of girls with trisomy 17-18 syndrome to boys is 2.7: 1. This excess of females is perplexing. The girls with trisomy 17-18 do not survive longer than their unfortunate male counterparts. 15 Why should an excess of females be born with this autosomal trisomy? Trisomy 21 in man does not alter the sex ratio. Neither does autosomal trisomy in Drosophila. It is obvious that more cases are needed to establish this female preponderance beyond doubt, but the existing data point to an unusual interaction between this autosomal trisomy and sex determination. CONCLUSION Trisomy 17-18 syndrome is a well-demarcated clinical and cytogenetic entity. Three cases of the syndrome are presented. Atten-

+

+

+

+

+

tion is drawn to the common hip and perineal anomalies. One case was due to a translocation, whereas the other 2 showed trisomy 17-18 with 47 chromosomes. One of the latter children had a sibling with mongolism (maternal age 40), suggesting a similar etiology for both these autosomal trisomies. Analysis of parental ages in 32 cases of trisomy 17-18 with 47 chromosomes revealed an increase in both paternal (36.0 years) and maternal (34.3 years) ages." However, the mean paternal-maternal age difference was only 1.7 years in trisomy 17-18 as compared to 3.5 years in the control population (United States Census, 1960). This difference is highly significant (P<0.01) and indicates a primary increase in maternal age. Since the vast majority (92 per cent) of reported cases of the trisomy 17-18 syndrome have shown 47 chromosomes, maternal nondisjunction would seem to be the single most important cause of the syndrome. The existence of chromosomal mechanisms other than age-dependent nondisjunction is implied in the shape of the maternal age curve. One such mechanism is translocation, as seen in 1 of the cases in this report. From the cytology of this translocation it is concluded that the clinical trisomy syndrome may result from triplication of the long arms. Triplication of the short arms may not be necessary. In an attempt to link specific genes with the extra chromosome, hemoglobin electrophoresis, chromatography, and extensive

620

H e c h t et al.

blood a n d serum group typing were carried out in 2 patients a n d their families. No evidence for linkage could be demonstrated. T h e dermal patterns in trisomy 17-18 syndrome are characteristically abnormal. T w e n t y of 21 affected infants have shown 6 or more plain digital arches in the absence of a strong trend to plain arches in their families. T h e toes also reveal the same tendency to plain arches. O u r preliminary estimate of the frequency of trisomy 17-18 syndrome is about 1:500 live births. Unrecognized u n t i l 1960, trisomy 17-18 is emerging as an i m p o r t a n t disease of the newborn.

October 1963

10. 11.

12.

13.

14. 15. 16.

We are indebted to many physicians including Drs. M. Mulloy, J. Moon, G. Gentile, and E. Kaplan for their referral and clinical study of these patients; Dr. G. R. Fraser for help with the maternal age study; and Mr. David Arakaki for the chromosomal analysis in Case 1.

REFERENCES

1. Edwards, J. H., Harnden, D. G., Cameron, A. H., Crosse, V. M., and Wolff, O. H.: A new trisomic syndrome, Lancet 1: 787, 1960. 2. Patau, K., Smith, D. W., Therman, E., Inhorn, S. L., and Wagner, H. P,: Multiple congenital anomaly caused by an extra autosome, Lancet 1: 790, 1960. 3. Gottlieb, M. I., Hirschhorn, K., Cooper, H. L., Lusskin, N., Moloshok, R. E., and Hodes, H. L.: Trisomy-17 syndrome, Am. J. Med. 33: 763, 1962. 4. Uchida, I. A., Bowman, J. M., and Wang, H. C.: The i8-trisomy syndrome, New England J. Med. 266: 1198, 1962. 5. Hecht, F.: The placenta in trisomy 18 syndrome, Obst. & Gynec. (in press). 6. Moorhead, P. S., Nowell, P. C., Mellman, W. J., Battips, D. M., and Hungerford, D. A.: Chromosome preparations of leukoeytes cultured from human peripheral blood, Exper. Cell Res. 20: 613, 1961. 7. Hecht, F., Bryant, J., Arakaki, D., Kaplan, E., and Gentile, G.: Trisomy 18 syndrome due to de novo translocation, Lancet, 1: 114, 1963. 8. Uchida, I. A., Patau, K., and Smith, D. W.: Dermal patterns of 18 and D1 trisomies, Am. J. Human Genet. 14: 345, 1962. 9. Huehna, E. R., Hecht, F., arid Motulsky, A.

17.

18.

19.

20. 21.

22.

23.

24.

25. 26.

G.: Hemoglobin anomalies in D1 trisomy syndrome (in preparation). Smith, D. W., Patau, K., Therman, E., and Inhorn, S. L.: The No. 18 trisomy syndrome, J. PEDIAT. 50: 513, 1962. Vital statistics of the United States, 1960. Natality characteristics, Washington, D. C., 1962, United States Government Printing Office, vol. 1, section 2. Brodie, I-I. R., and Dallaire, L.: The E syndrome (trisomy 17-18) resulting from a maternal chromosomal translocation, Canad. M. A. J. 87: 559, 1962. Weiss, L., DiGeorge, A. M., and Baird, H. W. III: Four infants with the trisomy 18 syndrome and one with trisomy 18 mosaicism, A. M. A. J. Dis. Child. 104: 533, 1962. Penrose, L. S.: Mongolism, Brit. M. Bull. 17: 184, 1961. Ferguson-Smith, M. A.: Abnormal sex ratio in the autosomal trisomy syndromes, Lancet 2: 357, 1962. Voorhees, M. L., Vaharu, T., and Gardner, L. I.: Trisomy 16-18 syndrome, Lancet 2: 992, 1962. Koenig, E. U., Lubs, H. A., Jr., and Brandt, I. K.: The relationship between congenital anomalies and autosomal chromosomal abnormalities, Yale J. Biol & Med. 35: 189, 1962. German, J. L., Rankin, J. K., Harrison, P. A., Donovan, D. J., Hogan, W. J., and Beam, A. G.: Autosomal trisomy of a group 16-18 chromosome, J. PEDIAT. 60: 503, 1962. Rosenfield, R. L., Breibart, S., Isaacs, H., Jr., Klevit, H. D., and Mellman, W. J.: Trisomy of chromosomes 13-15 and 17-18: Its association with infantile arteriosclerosis, Am. J. Med. Sc. 244: 763, 1962. Schull, W. J., and Neel, J. V.: Maternal radiation and mongolism, Lancet 1: 537, 1962. Uchida, I. A., Lewis, A. J., Bowman, J. M., and Wang, H. C.: A case of double trisomy: Trisomy No. 18 and triplo -X, J. PEDIAT. 60: 498, 1962. Gagnon, J., Katyk-Longtin, N., deGroot, J. A., and Barbeau, A.: Double trisomie autosomique ~t 48 chromosomes (21 + 18), Union m6d. Canada, 90: 1220, 1961. Miller, O. J., Breg, W. R., Schmickel, R. D., and Trotter, W.: A family with an XXXXY male, a leukemic male, and two 21-trisomic mongoloid females, Lancet 2: 78, 1961. Wright, S. W., Day, R. W., Mosier, H. D., Koons, A., and Mueller, H.: Klinefelter's syndrome, Down's syndrome (mongolism), and twinning in the same sibship. Chromosome studies in 2 families, J. PEDIAT.62: 217, 1963. Beadle, G. W.: A gene for sticky chromosomes in Zea mays, Zeitschr. f. Indukct. Abstamm. 63-64: 195, 1933. Sturtevant, A. H.: The claret mutant type of Drosophila simulans: A study of chromosome elimination and of cell-lineage, Zeitsehr. f. Wiss. Zooh 135: 323, 1929.

Volume63 Number4 part]

27. Poll, H.: Data tabulated, in Cummins, H., and Mideo, C.: Fingerprints, palms, and soles. An introduction to dermatoglyphics, New York, 1961, Dover Publications, Inc. 28. Fraccaro, M., Klinger, H. P., and Schutt, W.: A male with XXXXY sex chromosomes, Cytogenetics 1: 52, 1962. 29. Hannah, A.: Localization and function of heterochromatin ill Drosophila melanogaster, In Advances in genetics, Vol. IV, New York, 1951, Academic Press, Inc., p. 87. 30. Trubowitz, S., Kinman, D., and Masek, B.: The leukocyte alkaline phosphatase in mongolism, Lancet 2: 486, 1962.

Trisomy 17-18 syndrome

62 1

31. Merriam, J. R.: Personal communication. 32. Wagner, H. R.: Mongolism in Orientals, A. M. A. J. Dis. Child. 103: 706, 1962, 33. Ohno, S., Klinger, H. P., and Atkin, N. B.: Human O6genesls, Cytogenetics 1: 42, 1962. 34. Crawfurd, M. d'A.: Multiple congenital anomaly associated with an extra chromosome, Lancet 2: 22, 1961. 35. Townes, P. L., Manning, J. A., and DeHart, G. K., Jr.: Trisomy 18 (16-18) associated with congenital glaucoma and optic atrophy, J. PEDIAT.61: 755, 1962.