The 'D' (13-15) Trisomy Syndrome: an Analysis of 7 Examples G

Arch Dis Child: first published as 10.1136/adc.41.217.250 on 1 June 1966. Downloaded from

Arch. Dis. Childh., 1966, 41, 250.

The 'D' (13-15) Trisomy Syndrome: An Analysis of 7 Examples G. J. A. I. SNODGRASS, L. J. BUTLER, N. E. FRANCE, L. CROME, and A. RUSSELL From Queen Elizabeth Hospital for Children, London E.2, and Queen Mary's Hospital for Children, Carshalton

The identification of an additional chromosome in cleavage, such as characterize some examples of the group D (13-15) in a child with multiple congenital 'D' trisomy syndrome, and median facial anomalies anomalies was first made in 1960 by Patau, Smith, (DeMyer, Zeman, and Palmer, 1964). The primary Therman, Inhorn, and Wagner (the Wisconsin embryological defect appears to involve the prechor- group). The principal anomalies noted in this case dal mesoderm upon which induction of forebrain were cleft lip and palate, polydactyly, microphthal- development seems to depend, as suggested by mia with hypoplasia of the optic nerves, simian Adelmann (1936) in his observations on cyclopia, palmar creases, retroflexible thumbs, and ventricular and from which certain midline facial structures septal defect. The publication of further cases with derive. additional anomalies amply demonstrated that a new, The facial and even ocular abnormalities occur- specific, and easily recognizable clinical syndrome ring in conjunction with the prosencephalic state had been established (Therman, Patau, Smith, and may be associated rather than primary phenomena, DeMars, 1961; Ellis and Marwood, 1961; Atkins and may thus parallel the severity of the underlying and Rosenthal, 1961; Lubs, Koenig, and Brandt, brain defect rather than the trisomic state per se. copyright. 1961). Smith, Patau, Therman, Inhorn, and De- Bearing in mind their common embryonic Mars of the Wisconsin group had by 1963 accumu- origin, the median facial anomalies should be lated 7 personal cases, the largest series so far considered as part of a malformation complex of published. The condition seems to be less common varying severity, consisting of orbital hypotelorism than 'E' or 'G' trisomy syndromes; the authors have usually accompanied by severe ocular abnormalities; been able to find only 33 published examples, almost hypoplasia or aplasia of the crista galli, other com- all in the form of single case reports. ponents of the ethmoid bone and the nasal septum; http://adc.bmj.com/ Our clinical, necropsy, and cytogenetic findings in and aplasia or hypoplasia of the median philtrum, the 7 cases in this report have been analysed to usually in association with median cleft lip, and illustrate the spectrum of anomalies which can palate. Aberrant development of the embryonic now be accepted as characteristic. The neuro- median fronto-nasal process forms the basis of this pathological studies of 4 of these cases focus malformation complex. attention upon the failure of prosencephalic According to severity, several gradations of this (forebrain) cleavage and its possible relationship fundamental malformation complex are seen in with the defects ofmidline cranio-facial development clinical practice, ranging from the mild to the on September 25, 2021 by guest. Protected underlying the two main facial categories observed. severe. (1) Orbital hypotelorism associated with bilateral cleft lip and well-developed nasal tip. Anomalies Evident on External Examination The philtrum is present. (2) A complex consisting (Table I) of moderate orbital hypotelorism, absence of the philtrum with median hare-lip, and hypoplasia or Cranio-facial. Analysis of the present cases aplasia of the nasal septum with a flattened nasal tip. and those in the literature shows that two basic The nasal cavity communicates with the pharynx, categories of facies occur. and a cleft palate is usual. (3) Cebocephaly, where there is severe orbital hypotelorism and a proboscis Category 1: Facies associated with defects of in the usual situation of the nose, having a single prosencephalic cleavage. There is a striking associa- aperture, which may or may not communicate with tion between certain defects of prosencephalic the pharynx. (4) Ethmocephaly, where the orbits Received September 22, 1965. are just separate and also having a proboscis. (5) 250 Arch Dis Child: first published as 10.1136/adc.41.217.250 on 1 June 1966. Downloaded from

The 'D' (13-15) Trisomy Syndrome 251 TABLE I External Anomalies

Case No. 1 2 3 4 5 6 7 FOsency

Sex M M M F M M F 5 M/2 F Caucasian/negro C C N C N C C 5 C/2 N Maternal age (yr.). 42 39 36 40 27 26 30 Mean 34-3 Patemal age (yr.) 35 38 32 63 26 27 34 Mean 36-4 Gestation (wk.) 38 40 38 40 37 0 34 Mean 37-8 Birth Weight (g.) 1,899 3,628 2,721 2,211 2,466 0 1,474 Mean 2,400 Age at death. 7 dy. 23 dy. 2 yr. li hr. 20 wk. 1 yr. 3 dy. 3 mth. 5 mth. Necropsy performed + + + 5/7 Cranio-facial Category. 2 1 2 1 2 2 Trigonocephaly + 1/7 Receding forehead + 5/7 Orbital hypotelorism 1 3/7 Microphthalmia + 3/7 Other optic defects 5/7 Minor abnormality of ears + + 4/7 Large fleshy nose . + + 4/7 Long upper lip + 4/7 Absent philtrum anlage. + + 1/7 Cleft lip 3/7 Cleft palate + + 3/7 Moderate micrognathia. + -~~~~~~+ + + + 6/7 Limbs + + Spade-like hands. 0 +0 + 5/5 Flexion deformity fingers 4/7 Overriding index fingers. + + 5/7 Retro-flexible thumbs + 5/7 Bilateral polydactyly hands + 5/7 Horizontal palmar crease + 6/7 copyright. Fleshy oblong soles + + 0 + 4/5 Protuberant heels. 5/7 Talipes calcaneo-valgus. + + + 2/7 Prehensile hallux. + + 5/5 Polydactyly feet. 0 + + + 1/7 Cleft between first and second toes + 3/7 Vertical skin crease between first and second toes + 0 6/6 Transverse hyperconvexity of nails 5/5 Flexion deformity of large joints + 3/7 + + Abdomen and Genitalia 0 Para-umbilical defects 3/7 http://adc.bmj.com/ Hypoplastic penis and scrotum. 2/5 Cryptorchidism + 3/5 Miscellaneous Redundant skin folds 5/7 Aplasia of skin of scalp. 2/7 Haemangiomata. 1/7 Hypertonicity 0 4/5 Myoclonic attacks + 3/7 Apparent deafness 0 3/3 Presumed or obvious mental defect + 5/5 Apnoeic attacks 6/7 on September 25, 2021 by guest. Protected

+ = present; - = absent; 0 = no information.

Cyclopia, where there is a single partially divided development, the forehead did not recede. Case 2 eye in a single centrally situated orbit, and a had similar features except that the philtrum was proboscis which is usually abnormally situated. present, though underdeveloped, together with The last four are associated with a holospheric bilateral cleft lip and cleft palate. Case 4 had brain; the first is usually associated with arrhinence- extremely severe prosencephalic defect with orbital phaly alone. hypotelorism, microphthalmia, and a flattened nasal Cases 2, 4, and 7, all with a prosencephalic tip. Unfortunately a detailed description of the cleavage defect, fell into this cranio-facial Category 1. nasal structure was not available, though the flatten- Case 7 showed all the features of the malformation ing suggested hypoplasia of the nasal septum. complex with severe microphthalmia (Fig. 1), There was no cleft lip or palate, but the latter was though surprisingly, in view of the poor frontal lobe high and arched. The mouth was unduly small and

3 Arch Dis Child: first published as 10.1136/adc.41.217.250 on 1 June 1966. Downloaded from

252 Snodgrass, Butler, France, Crome, and Russell

FIG. 1.-Case 7, with Category FIG. 2.-Case 6, with Category FIG. ?.-Case 1: note the redundant 1 facies. The facial malforma- 2 facies after surgical repair of the skin folds of the face, large bulbous tion complex with absence of the hare-lip. nose, and long upper lip. philtrum anlage. the gums irregular. The pattern of the oral and mild microcephaly was evident. A striking structures corresponded with that found in ceboce- feature was the large nose with broad well-developed phaly where, in the almost total absence of the bones bridge and bulbous fleshy tip (Fig. 6). There was mild diminution derived from the median frontal process, fusion of no obvious hypotelorism, though copyright. the lateral maxillary processes occurs without cleft of the interpupillary distance was not excluded, and lip or palate. Although the mouth appears intact severe optic defects were not present. The upper in cebocephaly and its close relation cyclopia, the lip was long and overhung the lower which tended philtrum is in fact absent, thus producing the to be slightly everted (Figs. 2 and 3). The mouth extremely small mouth. The brain defect in Case 4 was rather large and turned downwards at the was similar to that in cebocephaly, but as the nasal corners, in contrast to the small mouth of Category 1. septum was present the facies may be considered as All patients in this category had mild micrognathia transitional between cebocephaly and the malforma- and 2 showed minor ear abnormalities. http://adc.bmj.com/ tion complex already described. Ears. The ears were considered low set in 2 Category 2: Facies not associated with a prosen- patients (Cases 3 and 5), with the upper edge of the cephalic defect. Multiple minor anomalies are a pinna lower than the outer canthus of the eye. feature of this group. Bilateral cleft lip and palate Primitive helical development was found in 3 may be present in addition but are not part of a while the remaining 3 malformation complex. In these patients (Cases 2, 4, and 5), median facial on September 25, 2021 by guest. Protected ears. These findings contrast with the patients prosencephalic cleavage, and usually fusion had normal review of the Wisconsin group (Smith et al., 1963) in of maxillary processes with the lateral and medial which all cases had some ear abnormality where this nasal processes, have proceeded normally. The was specifically mentioned. Atresia of the external latter did not occur, however, in Case 6, which had auditory meatus, common in 'E' trisomy syndrome, bilateral cleft lip and palate, but following surgical and in this has been reported only once (Conen, Phillips, repair closely resembled the other patients Mauntner, 1962). Indeed, features of the first arch category (Fig. 2). syndrome as delineated by McKenzie (1958) are not Although these patients bore little resemblance to in this those of Category 1, they closely resembled each usual syndrome. other. Their features were coarse, with loose- fitting leathery skin, producing redundant folds in Eyes. Ocular anomalies are frequent. Yanoff, the mandibular and peri-orbital regions (Fig. 3 and Frayer, and Scheie (1963), who reported one case 4), and conferring a grotesque appearance, accentu- and reviewed 12 others from the literature, conclud- ated when crying. The forehead receded (Fig. 5) ed that microphthalmia, coloboma, and cataract Arch Dis Child: first published as 10.1136/adc.41.217.250 on 1 June 1966. Downloaded from

The 'D' (13-15) Trisomy Syndrome 253

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254 Snodgrass, Butler, France, Crome, and Russell They resembled the hands seen in Potter's syndrome (Cases 1 and 2), and has been noted twice previously of bilateral renal agenesis. Single flexion creases of (Miller et al., 1963; Warburg and Mikkelson, 1963). the fifth finger, common in 'E' trisomy syndrome, Capillary haemangiomata of the neck, glabella were not seen. The soles tended to be unduly region, and lower back, reported as common by fleshy and oblong in most cases. A vertical skin Smith (1963), were found only once. crease between the first and second toes, similar to that found in 'G' trisomy was frequent, while, in Dermatoglyphs. Adequate palm and foot addition, a small cleft existed between these toes in prints were obtained in 2 patients (Cases 3 and 5). three cases. Protuberant heels were common and Both had markedly distal axial triradii, with an 'atd' the hallux was prehensile in 5 cases. angle in excess of 90° and horizontal palmar creases. The arch-fibular-S pattern, said by Uchida and Abdomen. The only anomalies noted were Soltan (1963) to be typical of the plantar pattern, midline defects of the upper abdominal wall ranging was absent in both. from devarication of the recti (Case 1) and umbilical herniation (Case 5), to exomphalos in Case 7 and Miscellaneous. Generalized hypertonicity was thus conforming with Smith's (1963) findings. The marked in 3 patients (Cases 3, 4, and 5) and is a infra-umbilical portion of the abdominal wall feature of the syndrome. Myoclonic attacks, derives from a secondary sheet of mesoderm which apparent deafness, and severe mental retardation grows into the anterior portion of the cloacal were clinical features of the longest-lived cases but membrane, and no anomalies of this region have could not be assessed in the remainder. These been reported in 'D' trisomy syndrome. findings are in accordance with other published reports. Mental retardation is probably invariable Genitalia. External genital anomalies are fre- for it has been found in all cases old enough to be quent in published cases and appear to be confined assessed, while patients dying at an earlier stage have to males. In Cases 1, 2, and 6 the testes were frequently been found to have brain abnormalities situated in the inguinal canals. Cases 2 and 6 had a incompatible with normal mental development, as in hypoplastic scrotum abnormally attached to the this report. Apnoeic attacks of unknown aetiology copyright. ventral surface of a small penis, an anomaly first occurred in 4 patients. noted by the Wisconsin group. Both females had normal external genitalia. Anomalies of Internal Structures (Table II) Skin. Aplasia of the skin of the scalp (Fig. 7) Cardiovascular anomalies were found in 4 of the 5 simulating ulceration was present in 2 patients cases in which necropsy was performed; in each a

high ventricular septal defect was associated with http://adc.bmj.com/ wide patency of the ductus arteriosus. A ventricular septal defect was the clinical diagnosis in Case 6. In addition to these lesions in Case 4, the aorta arose entirely from a conspicuously hypertrophied right ventricle, and there was a severely stenosed bicuspid pulmonary valve. Cardiac abnormalities have been a consistent feature of this syndrome, with high ventricular septal defect as the commonest lesion. on September 25, 2021 by guest. Protected Dextroposition of the heart was considered to be the next most frequent anomaly by Smith (1963), though this has usually been a clinical interpretation and not a prominent feature at necropsy. Other cardiac lesions reported have been fibroelastosis (Patau et al., 1960), Fallot's tetralogy (Townes et al., 1962), atrial septal defect (Patau, Therman, Smith, and Inhorn, 1961; Neimann, Pierson, Gilgenkrantz, Olive, and Kahn, 1964), and bicuspid aortic valve (Smith et al., 1963). A clinical diagnosis of atrial septal defect and anomalous pulmonary venous drainage was made in one case (Lubs et al., 1961), FIG. 7.-Case 1, with aplasia of the skin of the scalp. but no necropsy was performed. Arch Dis Child: first published as 10.1136/adc.41.217.250 on 1 June 1966. Downloaded from

The 'D' (13-15) Trisomy Syndrome 255 TABLE II Necropsy Findings

Case No. Observed Frequency 1 2 4 5 7 Cardiovascular system Atrial septal defect .- . - + 1/5 Ventricular septal defect ..+ + + _ + 4/5 Patent ductus arteriosus ..+ + + _ + 4/5 Bicuspid pulmonary valve ... + _ _ 1/5 Pulmonary stenosis.. . _ _ + 1/5 Dextroposition of aortic valve .. . + _ _ 1/5 Single umbilical artery. . _ + _ _ _ 1/5 Urogenital system Hydronephrosis .+ _ _ - 1/5 Renal hyperlobation . + + _ - 2/5 Cysts of kidneys + + + _ 3/5 Septate uterus . + - 1/2 Granulosaballen of hypoplastic ovaries .. + 1/2 Alimentary system Universal mesentery. + _ + + 3/5 Meckel's diverticulum . . . + 1/5 Aberrant splenic tissue . + - _ _ 1/5 Skeletal system Lacunar skull + - - - - 1/5 Central nervous system Whole brain weight (g.) .. 317 429 90 490 176 Weight of brain-stem and cerebellum (g.) 19 29 NI NI 15 Holospheric brain . . . + _ + 2/5 Aplasia/hypoplasia of corpus callosum . + + - + 3/5 Absence of septum pellucidum . . . + - + 2/5 Rhinencephalic dysgenesis . . + + - + 3/5 Aplasia/hypoplasia of optic nerves . + _ - + 2/5 Unpaired diencephalon (partial). . . _ + + 2/5 Absent or third ventricle ._ + - + 2/5

rudimentary copyright. Hypoplasia of cerebellar vermis ..+ 1 _ _ 1/5

NI = no information.

A single umbilical artery was found only in Case 2; Anomalies of the internal genitalia have been the frequency of this lesion in the syndrome is reported in several cases, of which cryptorchidism unknown. and septate uterus appear to be frequent . A curious

A high incidence ofgenito-urinary anomalies typi- finding in Case 7 was that of hypoplastic ovaries http://adc.bmj.com/ fies this syndrome (Smith, 1963). Of our cases, 6 showing collections of granulosa cells (Granulo- had renal abnormalities of which pathological saballen) and reduced numbers of primordial information was obtained on 5. A hydronephrotic follicles. A similar observation has been made in kidney with associated hydroureter was removed at this syndrome by Mottet and Jensen (1965) and in operation from Case 3, and a similar lesion was the 'E' trisomy syndrome by Butler, Snodgrass, demonstrated radiologically in Case 6. Bilateral France, Sinclair, and Russell (1965). hydronephrosis and hydroureter was found in Case 1, The commonest gastro-intestinal lesion has been without demonstrable obstruction to the bladder described as a universal mesentery with malrotation on September 25, 2021 by guest. Protected neck or urethra. These particular lesions appear of the colon. This was the sole intestinal anomaly common in this syndrome. Renal microcysts were in two of the present cases, and one other had a found in 3 cases; Case 2 showed multiple small Meckel's diverticulum. Aberrant splenic tissue, a cortical cysts of the uncommon variety in which a frequent finding in Smith's review (1963), was found small glomerular tuft projects into the cavity of each in the pancreas of Case 2 only. The gall-bladder cyst, resembling those noted by Northcutt (1962). was normal at necropsy in all cases, in contrast to the Case 4 had small cysts lined by cuboidal or squamous findings of the Wisconsin group (1963). Apart epithelium, some surrounded by increased amounts from the cranio-facial region, skeletal anomalies of connective tissue. This appeared to be an were not found in this series, and appear to be rare. example of cystic dysplasia, as described previously in this syndrome by Mottet and Jensen (1965). Neuropathological findings. Four cases in Case 5 showed a number of similarly-sized cysts this series were subjected to full neuropathological thought to be of tubular origin. examination. Arch Dis Child: first published as 10.1136/adc.41.217.250 on 1 June 1966. Downloaded from

256 Snodgrass, Butler, France, Crome, and Russell

FIG. 8.-Case 1, a section of cerebellum showing nodules of ectopic cerebellar cortex in the white matter. (Haematoxylin and eosin. x 65.)

Case 1. The whole brain weighed 317 g. (normal from the posterior margin. The dorsal surface was 388 g.). The brain-stem together with the cerebellum smooth, sulcus formation being limited to a few grooves weighed 19 g. The only macroscopical abnormality was radiating for a short distance from the anterior toward copyright. underdevelopment of the cerebellar vermis so that the the posterior poles. Rudimentary Sylvian fissures were cisterna magna was abnormally large. All cranial nerves present. On the inferior surface hemispheral pairing were normal. Histologically excessive numbers of was indicated by a shallow midline groove extending ectopic neuronal cells were scattered diffusely and in from the anterior toward the posterior pole for 2 cm. focal clusters within the white matter of the frontal lobes. This abutted on a cystic cavity enclosed by a thick, bluish Many ectopic collections of granular and Purkinje cells membrane. Posteriorly a discoid pituitary was adherent were present in the cerebellar white matter (Fig. 8). to the cyst. Section of the cerebrum revealed a single ventricle (holosphere), with absence of the septum http://adc.bmj.com/ Case 2. The whole brain weighed 429 g. after fixation, pellucidum, fornices, and corpus callosum. The the cerebellum and brain-stem accounting for 29 g. choroid plexuses were absent. The olfactory and optic The main abnormalities were absence of both olfactory nerves were absent, but all other cranial nerves were bulbs and tracts, small optic nerves (especially the right), present. At the inferior margin of the cerebrum, the and a short corpus callosum, the splenium of which pallium was reflected upward and inwards ending in a reached about half-way along the thalamus. The rim encircling the single ventricle. The diencephalon cingulate sulcus was shorter than usual and the precuneus was unpaired and inserted into the pallium by its central On its dorsal had grown down to fill in the space normally occupied by portion and two lateral extensions. aspect on September 25, 2021 by guest. Protected the posterior part of the corpus callosum. Some there was an ependymal surface with a central depression distortion of the development of the gyri of the basal which represented the rudimentary third ventricle. surface of the brain had also occurred, the convolutions The aqueduct was pinpoint in size. The pons was small tending to be drawn inwards towards the retrosplenial but otherwise normal, and cerebellum, medulla, and region. fourth ventricle were normal.

Case 4. The whole brain weighed 90 g. and was Case 7. The brain was small (176 g.) and dome- mushroom-shaped, the stalk consisting of brain-stem shaped. The two cerebral hemispheres were separated prolonged anteriorly by the unpaired diencephalon and from each other by the longitudinal fissure. This the cap being the unpaired cerebrum. The stalk-like separation was incomplete inferiorly, where the sub- structure was inserted into the concave undersurface of callosal areas and posterior parts of the gyri recti were the cerebrum near its anterior extremity (Fig. 9). The fused across the midline. cerebrum measured 7 cm. in diameter. The only The corpus callosum, fornices, and septum pellucidum indication that separation into two hemispheres had were absent. A single ventricle was present, normal in occurred was a divergence of the posterior poles 2 - 5 cm. size posteriorly but grossly narrowed anteriorly (Fig. 10). Arch Dis Child: first published as 10.1136/adc.41.217.250 on 1 June 1966. Downloaded from

The 'D' (13-15) Trisomy Syndrome 257

O I 2 3 4 5 6 7 8 9 10 Cm. FIG. 9.-Case 4: brain showing extreme prosencephaly. The corpora striata and anterior portions of the thalami The cerebellum and brain-stem were normal and were fused in the midline. Posteriorly a small vertical weighed 15 g. slit indicated rudimentary diencephalic cleavage which was complete at the level of the pulvinaria. The hypo- Cytogenetic Findings (Table III) thalami were fused and the third ventricle was absent. Materials and methods. Using techniques des- The corpora mamillaria could not be identified. The cribed by Butler (1965; 1966, simplified skin and copyright. hippocampi were well formed and the fimbriae ascended peripheral blood techniques for use incytogenetic studies, normally to their insertion in the undersurface of the unpublished observations), chromosome preparations intercerebral mantle. All trace of these formations was were obtained as far as possible from cultures of both lost further anteriorly. peripheral blood and skin. The relative duration of http://adc.bmj.com/ on September 25, 2021 by guest. Protected

O 1 2 3 cm. 10- 65 FIG. 1O.-Case 7: coronal section of brain showing a single ventricular cavity, absence of the septum pellucidum, and replacement of the corpus callosum by a plate of grey and white matter. The third ventricle is represented by a short vertical slit. Arch Dis Child: first published as 10.1136/adc.41.217.250 on 1 June 1966. Downloaded from

258 Snodgrass, Butler, France, Crome, and Russell TABLE III Chromosome Counts and Karyotype Diagnoses

Chromosome Count Trisomic Case Tissue Photo- Karyo- Category No. ___48 48 Analysed Arrangement)

1 Blood 1 1 56 - - 30 25 Trisomy 13 { Blood 2 2 54 - - 22 22 Trisomy 13/14 + 2 Skin 3 2 54 - - 30 25 Trisomy 13/14 + 3 { Blood 1 1 53 -- 25 20 Trisomy 14 + Skin 2 1 51 - - 31 22 Trisomy 13 + 4 Skin 2 1 57 - - 25 23 Trisomy 13/14 + J Blood 3 2 51 - - 34 26 Trisomy 13/14 + Skin 3 1 56 - 4 27 21 Trisomy 13 + (Blood - 1 31 - - 17 10 Trisomy 13 Indeter- 6 minate Skin 2 1 78 - 1 56 38 Trisomy 13 + 7 Skin 3 1 51 1 - 30 25 Trisomy 13/14 + incubation with colchicine and other details ofprocessing No. 15, could be distinguished relatively easily from were adjusted so that the resulting material from all the other 5 chromosomes. A visual assessment was tissues sampled was morphologically similar when view- made of the possible trisomic arrangement in each ed by phase-contrast microscopy. By this means cell and the totals of all categories are shown in satellites can be compared in all tissues under similar conditions, while variations in apparent degrees of taleIV. From these observations it appeared contraction between homologous chromosomes can be that all cases, possibly one exception (Case 2), checked and any significant differences more easily represented regularwlth trisomy of chromosome 13. determined. Reassessment of each cell by measurement of the As far as possible, at least 50 cells were counted and long arms of all group 'D' chromosomes did not examined for each tissue, the material being sampled produce such a clearly defined result, indicating from more than one culture, and in most cases at least that, using long arm lengths alone, chromosomes 13 half of the cells counted were suitable for karyotype and 14 could not be separated with certainty. copyright. analysis by photograph. Cells were also selected for a Measurements of a normal control series have more detailed microscopical examination. Usually 6 shown that there is very little difference in the complete karyotypes, prepared from prints at a final magnification of 6-8,000, were examined in detail relative over-all lengths of 'D' chromosomes, but, on mainly to check that all groups other than group 13-15 average, No. 15 is the shortest. Chromosomes 13 were normal. The large acrocentric chromosomes were and 14 are approximately equal in length, but, by identified in the remaining photographs and arranged in virtue of centromeric position, No. 13 has the

pairs of descending order of size. greater arm ratio. However, because of satellite http://adc.bmj.com/ variation the short arms cannot always be clearly delineated and measurement becomes difficult. Results. Table III shows the chromosome Autoradiographic studies are helpful, and Yunis, counts obtained. Visual arrangement seemed to Hook, and Mayer (1964) have shown that the indicate that usually the shortest pair in group 'D', chromosome involved (designated D1) is late TABLE IV Identification of Additional Chromosomes on September 25, 2021 by guest. Protected

Trisomic Category Case No. Large 13 13/14 14 14/15 15 Small Total Tissue Unpaired Unpaired 1 - 13 9 3 - - - 25 Blood 2 2 1 - 17 1 1 22 Blood 2{- 13 2 8 1 1 - 25 Skin 1 5 10 3 1 - 20 Blood 3 ii 20 1 - 1 - - - 22 Skin 4 1 6 12 4 - - - 23 Skin 5 i 8 4 10 - 3 - 26 Blood 5 - 16 1 3 - 1 - 21 Skin 6 f1 8 - 1 - - - 10 Blood 6 6 8 17 3 2 2 - 38 Skin 7 - 9 - 16 - - - 25 Skin Total 10 104 51 59 23 9 1 257 Arch Dis Child: first published as 10.1136/adc.41.217.250 on 1 June 1966. Downloaded from

The 'D' (13-15) Trisomy Syndrom32 259 replicating in the lower half of the long arms and on carriers, and all 5 had a high frequency of arch morphological grounds appears to be No. 13. patterns on the finger tips together with ears of Only one patient (Case 2) did not fit into this unusual shape. These observations indicate that consistent pattern. In most cells the short arms of satellites could be gene bearing, though partial one chromosome were exaggerated, and satellites, trisomy by virtue of a small duplication or insertion though present, were not always clearly differenti- could not be ruled out. All cases with enlarged ated. Measurements of long arms indicated that satellites recorded in this laboratory have been the chromosome could not be matched with others. clinically abnormal while none of the clinically One possible explanation could be that the position normal individuals possessed such satellites. of the centromere had been altered by an asymmetri- cal pericentric inversion. By abnormal pairing this could have contributed to non-disjunction during gametogenesis. In six patients very prominent satellites were observed on at least one group 'D' chromosome (Fig. 11). A random selection of subjects with normal karyotypes and a series of patients with 'E' trisomy syndrome, 13 of whom have been published previously (Butler et al., 1965), have been used to test satellite prominence. In the former, only 19 out of 125 (15%) had at least one group 'D' chromosome prominently satellited, and in the latter 3 out of 18 (16 5%). This indicates that the frequency of satellite prominence is abnormally high in this series and could be an important factor in relation to chromosome pairing and non-disjunction. Alterna- tively, prominent satellites could represent an copyright. abnormality at the cellular level due to the trisomic state. In 'D' trisomy patients, Huehns, Lutzner, and Hecht (1964) have observed unusual nodular projections of the nuclei of neutrophils which were Feulgen-positive and sometimes pedunculated; these were distinct from the neutrophil drumsticks described by Davidson and Smith (1954). There http://adc.bmj.com/ could be a direct relation between these anomalous formations and the enlargement of satellites described here. Prominent satellites in otherwise normal karyotypes have been described in association with Marfan's syndrome (Tjio, Puck, and Robinson, 1959; McKusick, 1960); other reports, however (Handmaker, 1963; Filippone and Martinelli, 1962), FIG. 11.-The 'D' group chromosomesfrom a karyotype of on September 25, 2021 by guest. Protected have been inconsistent and two examples studied in each patient showing prominent satellites in Cases 2-7. this laboratory had normal satellites. However, 2 patients with some features of the 'D' trisomy syndrome showed abnormally large satellites on one Obstetric Factors of the large acrocentrics in a 46 count. Similarly, Pregnancy and delivery were normal in the 6 cases an infant with ovarian hypoplasia, cleft palate, and where information was available. There had been other anomalies had both a ring-X chromosome and no irradiation of the mother during the putative a 'D' group chromosome with short arms of period of conception or during pregnancy. There abnormal length and very large satellites. was no instance of polyhydramnios. Delivery was Jacobson, Tischler, and Miller (1964) have achieved between 37 and 40 weeks of gestation in 5 reported the familial transmission of a group 'D' of 6 cases, no information being available on Case 6. chromosome with apparently enlarged satellites: No special resuscitation was required for any of 4 of 5 members with mental retardation were them. The birth weight ranged from 1,474 g. to Arch Dis Child: first published as 10.1136/adc.41.217.250 on 1 June 1966. Downloaded from

260 Snodgrass, Butler, France, Crome, and Russell 2,721 g. The mean maternal age was 34-3 years trisomy (Ishmael and Laurence, 1965). Available and the mean paternal age 36-4 years in this series. information concerning the brains ofother published Our information was, however, numerically insuffi- cases either does not permit -full classification or cient to permit conclusions as to the role played. implies that the prosencephalic state was absent. Of the 4 cases in this report subjected to detailed Sex and Race neuropathological examination, 2 are extreme A preponderance of female cases was noted by examples of the prosencephalic state, Case 4 Ferguson-Smith (1962) and Smith (1963), but males exhibiting the most severe degree and Case 7 being predominate in this series. Insufficient cases have less severe. Case 2 was an example of arrhinence- been reported as yet to form adequate conclusions. phaly, while Case 1 showed no macroscopical anomaly, but showed microscopical anomalies reminiscent of the retinal dysplasia described by Prognosis Sergovich, Madronich, Barr, Carr, and Langdon This is uniformly bad, but the duration of (1963). survival shows considerable variation from case to During early embryonic life certain inductor case. No patient with severe cerebral defect sur- substances elaborated by one primordial layer may vived longer than 1 month. Two patients lived for have a profound effect on the normal development more than 1 year (Table I), and both were in of adjacent layers. Teratogenic influences may cranio-facial Category 2. interfere with this process causing maldevelopment of structures of different primordial origin and Comment resulting in a malformation complex, composed of a Interference with the process of sagittal cleavage number of anomalies, apparently unrelated but of the prosencephalon, or forebrain, results in an possessing certain affinities. Such a process could abnormal union between the cerebral hemispheres be postulated to explain the undoubted association (DeMyer et al., 1964). In its extreme form this between aberrant development of the median facial leaves a prosencephalon with a single ventricle structures and of the forebrain (Yakovlev, 1959; (holosphere), callosal agenesis, absence of the DeMyer et al., 1964). During the fourth week of copyright. septum pellucidum, and varying degrees of fusion embryonic life the prechordal mesoderm in the of the basal ganglia. Less severe forms show either region ofthe dorsal lip ofthe foregut induces changes incomplete separation of the anterior portions of the in the rostral neuro-ectoderm to initiate develop- hemispheres, partial collosal agenesis, or union by a ment of the primitive prosencephalon, and, accord- plate of grey and white matter in the usual site of the ing to Yakovlev (1959), indirectly will determine its corpus callosum. Alternatively, these anomalies ultimate morphology. In addition, the prechordal may reflect failure of the development of midline mesoderm gives rise to the median facial bones so http://adc.bmj.com/ structures in the developing brain. Prosencephalic notably defective in the prosencephalic state. brains tend to be small with absence of the olfactory Abnormal disposition of this mesoderm has been nerves or more central parts of the rhinencephalon observed in experimentally induced cyclopia by in addition to absence ofthe corpus callosum. Thus Adelmann (1936). Thus teratogenic influence the prosencephalic state is sometimes regarded acting on this tissue before the seventh week of erroneously as synonymous with arrhinencephaly or embryonic life (i.e. before prosencephalic differ- callosal agenesis. Severe optic defects are almost entiation is complete) might be expected to result in invariably associated with the severe prosencephalic severe malformations of both forebrain and median on September 25, 2021 by guest. Protected state. A complete spectrum of prosencephalic facial structures, as is found in facial Category 1 of defects is possible in this syndrome from cyclopia to 'D' trisomy. A more belated influence would tend uncomplicated arrhinencephaly which is probably to produce no more than minor cranio-facial the commonest brain lesion encountered. anomalies, such as characterize facial Category 2 and Undoubted examples of the prosencephalic state not part of a malformation complex. in association with 'D' trisomy have been reported Extreme cranio-facial abnormalities such as by Biihler, Bodis, Rossier, and Stalder (1962), cyclopia, ethmocephaly, and cebocephaly are Smith et al. (1963), and Laurence (1964), while the probably invariably associated with holospheric case described by Miller et al. (1962, 1963) suggests brain, as is the absence of the median philtrum a defect more severe than arrhinencephaly alone. anlage. When the philtrum is present but the Uncomplicated arrhinencephaly has frequently been malformation complex coexists, the prosencephalic reported in association with this syndrome, and has defect is usually less severe. Trigonocephaly and also been described in a probable case of partial 'D' major degrees of orbital hypotelorism usually imply Arch Dis Child: first published as 10.1136/adc.41.217.250 on 1 June 1966. Downloaded from

The 'D' (13-15) Trisomy Syndrome 261 the presence of arrhinencephaly (Curranino and Ferguson-Smith, M. A. (1962). Abnormal sex ratio in the autosomal trisomy syndromes. ibid., 2, 357. Silverman, 1960), such as was found in Case 2 of our Filippone, C., and Martinelli, G. (1962). Contributo cariologico ed series. All these malformations are possible in 'D' elettroencefalografico allo studio della sindrome di Marfan. G. ital. Oftal., 15, 391. trisomy syndrome, cebocephaly having actually been Handmaker, S. D. (1963). The satellited chromosomes of man with reported once (Biihler et al., 1962), though cyclopia reference to the Marfan syndrome. Amer. J. hum. Genet., 15, 11. has not yet been reported. Huehns, E. R., Lutzner, M., and Hecht, F. (1964). Nuclear abnormalities of the neutrophils in D1 (13-15) trisomy syndrome. Lancet, 1, 589. Summary Ishmael, J., and Laurence, K. M. (1965). A probable case of incomplete trisomy of a chromosome of the 13-15 group. J. med. Genet., 2, 136. Clinical, pathological, and cytogenetic details of Jacobson, T. S., Tischler, B., and Miller, J. R. (1964). Enlarged seven examples of 'D' trisomy syndrome are chromosomal satellites associated with mental retardation and presented. Two major categories of facial appear- digital arches in three generations. Ann. hum. Genet., 28, 21. Laurence, K. M. (1964). Arrhinencephaly and trisomy of the 13-15 ance are defined based upon the presence or absence chromosomes. In the proceedings of the Paediatric Pathology of the prosencephalic state. Embryological factors Club, 9th Annual Meeting. Arch. Dis. Childh., 39, 302. Lubs, H. A., Koenig, E. U., and Brandt, I. K. (1961). Trisomy underlying these anomalies are discussed. 13-15: a clinical syndrome. Lancet, 2, 1001. All cases were straightforward examples of 'D' McKenzie, J. (1958). The first arch syndrome. Arch. Dis. Childh., 33, 477. trisomy, and detailed analysis suggests that the McKusick, V. A. (1960). Chromosomes in Marfan's syndrome. additional autosome is No. 13. Lancet, 1, 1194. Satellites were on at least one Miller, J. Q., Picard, E. H., Alkan, M. K., and Gerald, P. S. (1962). unduly prominent Neurologic manifestations of 13-15 trisomy. A chromosome 'D' group chromosome in 6 of the 7 cases. abnormality in arhinencephaly. Trans. Amer. neurol. Ass., 87, 51. -, , , Warner, S., and Gerald, P. S. (1963). A specific We are grateful to the following paediatricians for brain defect (arhinencephaly) in 13-15 trisomy. New Engi. J. Med., 268, 120. allowing us to study patients under their care: Drs. Mottet, N. K., and Jensen, H. (1965). The anomalous embryonic I. M. Anderson, R. J. K. Brown, P. Clay, R. H. Dobbs, development associated with trisomy 13-15. Amer. J. clin. J. N. O'Reilly, M. J. Wilmers. We are also indebted to Path., 43, 334. Professor N. H. Ashton and Mr. C. G. Keith for the Neimann, N., Pierson, M., Gilgenkrantz, S., Olive, D., and Kahn, C. ophthalmological findings, Dr. T. E. W. Goodier for the (1964). La trisomie 13-15. Arch. franc. Pediat., 21, 661. copyright. postmortem information in Case 2, Dr. J. Norman for Northcutt, R. C. (1962). Multiple congenital anomalies in a negro the in Case Professor L. S. infant with 13-15 trisomy. Sth. med. J. (Bgham, Ala.), 55, 385. neuropathological findings 2, Patau, K., Smith, D. W., Therman, E., Inhorn, S. L., and Wagner, Penrose for the dermatoglyphic findings in Cases 3 and 5, H. P. (1960). Multiple congenital anomaly caused by an extra and Mr. V. A. J. Swain who performed the nephrectomy autosome. Lancet, 1, 790. in Case 3. -, Therman, E., Smith, D. W., and Inhorn, S. L. (1961). Two new cases of Dl trisomy in man. Hereditas (Lund), 47, 239. REFERENCES Sergovich, F., Madronich, J. S., Barr, M. L., Carr, D. H., and Langdon, W. A. (1963). The D trisomy syndrome. A case Adelmann, H. B. (1936). Problem of cyclopia. Quart. Rev. Biol., report with a description of ocular pathology. Canad. med. 11, 161, 284. Ass. J., 89, 151. http://adc.bmj.com/ Atkins, L., and Rosenthal, M. K. (1961). Multiple congenital Smith, D. W. (1963). The No. 18 and Dl trisomy syndromes. abnormalities associated with chromosomal trisomy. New Pediat. Clin. N. Amer., 10, 389. Engl. J. Med., 265, 314. -, Patau, K., Therman, E., Inhorn, S. L., and DeMars, R. I. Buhler, E., Bodis, I., Rossier, R., and Stalder, G. (1962). Trisomie (1963). The Dl trisomy syndrome. J. Pediat., 62, 326. 13-15 mit Cebocephalie. Ann. paediat. (Basel), 199, 198. Therman, E., Patau, K., Smith, D. W., and DeMars, R. I. (1961). Butler, L. J. (1965). A micro-method for peripheral blood. The D trisomy syndrome and XO gonadal dysgenesis in two Hum. Chrom. Newsletter, 15, 5. sisters. Amer. J. hum. Genet., 13, 193. -, Snodgrass, G. J. A. I., France, N. E., Sinclair, L., and Russell, Tjio, J. H., Puck, T. T., and Robinson, A. (1959). The human A. (1965). The E (16-18) trisomy syndrome: an analysis of 13 chromosomal satellites in normal persons and in two patients cases. Arch. Dis. Childh., 40, 600. with Marfan's syndrome. Proc. nat. Acad. Sci. (Wash.), 46,532. Cogan, D. G., and Kuwabara, T. (1964). Ocular pathology of the Townes, P. L., DeHart, G. K., Jr., Hecht, F., and Manning, J. A. on September 25, 2021 by guest. Protected 13-15 trisomy syndrome. Arch. Ophthal., 72, 246. (1962). Trisomy 13-15 in a male infant. J. Pediat., 60, 528. Conen, P. E., Phillips, K. G., and Mauntner, L. S. (1962). Multiple Uchida, I. A., and Soltan, H. C. (1963). Evaluation of dermato- developmental anomalies and trisomy of a 13-15 group chromo- glyphics in medical genetics. Pediat. Clin. N. Amer., 10, 409. some (D syndrome). Canad. med. Ass. J7., 87, 709. Warburg, M., and Mikkelson, M. (1963). A case of 13-15 trisomy Curranino, G., and Silverman, F. N. (1960). Orbital hypotelorism, or Bartholin-Patau's syndrome. With a review of the ophthal- arhinencephaly, and trigonocephaly. Radiology, 74, 206. mological literature concerning cases with similar sympto- Davidson, W. M., and Smith, D. R. (1954). A morphological sex matology. Acta ophthal. (Kbh.), 41, 321. difference in the polymorphonuclear leucocytes. Brit. med. J., Yakovlev, I. (1959). Pathoarchictectonic studies of cerebral 2, 6. malformations. III. Arrhinencephalies (Holotelencephalies). DeMyer, W., Zeman, W., and Palmer, C. G. (1964). The face J. Neuropath. exp. Neurol., 18, 22. predicts the brain: diagnostic significance of median facial Yanoff, M., Frayer, W. C., and Scheie, H. G. (1963). Ocular anomalies for holoprosencephaly (arhinencephaly). Pediatrics, findings in a patient with 13-15 trisomy. Arch. Ophthal., 70, 34, 256. 372. Ellis, J. R., and Marwood, J. C. (1961). Autosomal trisomy Yunis, J. J., Hook, E. B., and Mayer, M. (1964). Deoxyribonucleic- syndromes. Lancet, 2, 263. acid replication pattern of trisomy D1. Lancet, 2, 935.