Partial deletion of the short arm of chromosome No. 4(4p-): Clinical studies in five unrelated patients

792

November, 1970 T h e Journal of P E D I A T R I C S

Partial deletion o/the short arm of chromosome No 4(4t,-). Clinical ,t,di , i , unrelated patients Five patients are described with a partial deletion of the short arm of a chromosome No. 4, which was identified auloradiographically. The 4p- syndrome can be distinguished from the cri du chat (Sp-) syndrome by the absence of a catlike cry and the presence of a lower birth weight, more marked psychomotor retardation, a fiat beaked nose with a fish-shaped mouth, seizures, cleft palate, eoloboma of the iris, preauricular or sacral dimple or sinus, hypospadias, midline scalp defect, underdeveloped dermal ridges on palm and sole, lower finger ridge count, and delayed bone maturation.

Orlando J. Miller, M.D., * W. Roy Breg, M.D., Dorothy Warburton, Ph.D., Dorothy A. Miller, Ph.D., Adriana deCapoa, M.D., Penelope W. Allderdice, Ph.D., Jessica Davis, M.D., Harold P. Klinger, M.D., Ph.D., Eve McGilvray, M.D., and Fred H. Allen, Jr., M.D. NEW

YORK,

N.

Y., AND NEW

HAVEN

I N 1965, Wolf and associates I described a patient with a partial deletion of the short From the Departments of Obstetrics and Gynecology, Human Genetics and Development, and Pediatric Pathology, Columbia University College of Physicians and Surgeons; Department of Pediatrics, Yale University, and Southbury Training School; Departments of Genetics and Pediatrics, Albert Einstein College of Medicine and the New York Blood Center. Supported in part by Grants Nos. HD 00516, HD 00339, GM 11556, HE 08630, and HE 09011 from the National Institutes of Health and by Grant No. 12 HS from the Children's Bureau. O. ]. M. and H. P. K. are Health Research Council o[ r address: Columbia Physicians and Surgeons, 630 N. Y. 10032.

Career Sdentlsts of the the City of New York. UMverslty College of W. 168th St., New York,

Vol. 77, No. 5, pp. 792-801

AND SOUTHBURY,

CONN.

arm of a group B chromosome in whom the clinical findings were somewhat different from those reported by Lejeune and associates ~ in the cri du chat syndrome. They showed, using terminal labeling with tritiated thymidine, that this deleted chromosome was late replicating, in contrast to the early replication of the deleted chromosome which had been found in two patients with the cri du chat syndrome, 8 and suggested that a chromosome No. 4, not 5, was deleted in this case. Since that time 9 additional cases have been reported in which replication studies have shown that part of the short a r m of of a chromosome No. 4 had been

Volume 77 Number 5

Deletion o[ short arm o/ chromosome No. 4

deleted. 4"~ I n addition, several other cases with a group B short a r m deletion have been described which clinically resemble those with deletions of chromosome No. 4, t h o u g h definitive replication studies have not been performed. 1~ T h e clinical findings in these cases are summarized in a recent review, s W e wish to report three new patients with a partial deletion of the short a r m of chromosome No. 4 a n d additional i n f o r m a t i o n a b o u t Patients 4 a n d 11, which were the subject of a brief earlier report. 4 I n all five of the patients, the deleted chromosome has been identified a u t o r a d i o g r a p h i c a l l y as a No. 4. CASE REPORTS

Most clinical and family data are presented in tabular form (Tables I to I I I ) ; this information has not been repeated in the case reports. Patient 4.* (KR261252,t Fig. 1, a ) The mother of the proband had four previous pregnancies leading respectively to a stillborn male child, an abortion at 2 months, a male child who died at age 4 years from endocardial fibroelastosis, and a normal girl. A paternal first cousin had mental retardation, hypopituitary dwarfism, and status epileptieus, from which he died at age 19.la Chromosome studies were made at age 11, during a clinical search at Southbury Training School for older patients with a Bp- deletion. His head circumference at age 12 was 47 cm. with a cephalic index of 0.76. Radiologic abnormalities included bilateral abnormally placed calcaneii slightly underdeveloped in the anterior portion, bilateral underdeveloped ilia, and valgus deformity of each hip. There was delayed ossification of the os pubis. Now age 17, he stares vacantly, is fairly unresponsive to any stimuli, makes few purposeful movements, and does not vocalize or respond to words or sounds. His height cannot be measured accurately because of spastic diplegia. There is a patch of alopecia at the crown; the mother states that he was born with a midline scalp defect. The patient has scoliosis and first-degree hypospadias (previously reported absent). He has reached *Cases numbered according to order among all group B deletions studied in our laboratory. "~Case initials ( K R ) , date of birth by day (26), month (12), and year (52), as recommended by the World Health Organization.

79 3

puberty; some facial and pubic hair is present. Abnormalities of the feet include pes planus and a down-pointed heel with malrotation of the front of the foot. Patient 11. (PM290664, Fig. I, b) An older brother and a younger brother and sister are clinically normal. Chromosome studies were performed at one year of age, at which time he weighed 5.7 Kg. and was 62 cm. long. The head was 40 cm. in circumference with a prominent glabella, a triangular-shaped skull, and a hemangioma of the forehead. At age 3 ~ years, the head circumference was 43.5, the cephalic index 0.79, the body length 76 cm., and weight 7.1 Kg. The optic fundi appeared normal. He had 7 upper and 6 lower teeth, external rotation of the legs, and some eversion of the feet, but no limitation of motion of his joints. The child made only very gross , generalized movements, and did not respond to loud sounds. No meaningful vocalization occurred. Patient 19. (RF281059, Fig. 1, c). An older brother is clinically normal. A maternal halfsister was clinically diagnosed as having Down's syndrome and died at 5 months of age from a congenital heart defect. At ten months of age the proband underwent repair of a patent ductus arteriosus and bilateral inguinal hernias. He was examined in a neurology clinic at one year. His height and weight were less than the third percentile and his head circumference was only 41 cm., with an increased anteroposterior diameter and bilateral temporal flattening. In the second year of life two generalized seizures occurred, associated with high fever. At 18 months an electroencephalogram was reported as abnormal, with excessive high-voltage slow waves that appeared through the tracing paroxysmally at times, many as irregular 3 to 4 per second high-v01tage spike waves. At age six years the child was studied at Mansfield Training School, Connecticut, as a suspected case of the cri du chat syndrome. His head circumference was 46 cm., the face narrow, and the glabella not prominent. He could sit and propel himself around on his knees, using his arms alone. He understood a few words, made some sounds, and was minimally responsive. Seizures still occurred with fever; he was maintained on diphenylhydantoin and phenobarbital. At 6 ~ years there was marked delay in appearance of ossification center of the carpals, tarsals, and the os pubis. Secondary ossification centers vzere present in the distal portion of the

79 4

M i l l e r et al.

The Journal o] Pediatrics November 1970

Fig. 1. Patients with 4p- syndrome, a, Patient 4, I 1 ~ years; b, Patient 11, 1 year; c, Patient 19, 8 ~ years; d, Patient 24, 6 months; e, Patient 28, 5 months.

Volume 77 Number 5

Deletion of short arm o[ chromosome No. 4

795

retardation was profound, with no head control or response to light and sound. The muscle tone was poor in the upper extremities and normal in the lower extremities. Seizures first occurred at age five months, at the time of a fever. At age one year her head circumference was 38 cm., and her length was 59 cm. The ears were obliquely placed and the temporal nmsctes were hypoplastic. No teeth were present. The epicanthus persisted on the right but had disapptared on the left. The occiput was rounded and the nipples were quite hypoplastic and set far apart. There was no heart murmur. The patient was profoundly retarded. No definite response to sound or light could be elicited. She responded to painful stimuli with minimal generalized motion and a weak cry. Seizures occurred about once a day despite regular administration of phenobarbital. She died at age 18 months during a prolonged seizure.

proximal phalanges. The feet pointed downward. Patient 24. (MB201067, Fig. 1, d). The mother had three previous pregnancies: Two resulted in abortions (the second a 5 month macerated fetus with congenital anomalies) and the third in the birth of a normal male. The mother noted that the proband had been hypoactive during pregnancy; at birth she had an Apgar score of 1. Initially the eyelids did not close over the ocular globes. At the present time she has severe psychomotor retardation, with almost no purposeful movement of the eyes, arms, hands, or body, and minimal response to external stimuli, though she cries in response to hunger or painful stimuli. The patient has microcephaly (head circumference 35 cm., cephalic index 0.66), an occipital protuberance, and an almost healed midline scalp defect about 3 x 1.5 cm. over the crown, with an underlying bony defect. There are temporal muscle hypoplasia and a cleft soft palate. The ear pinnae are large and ~aIrotated. There are two hemangiomas on the nape of the neck, a mongolian spot in the sacral area, and a large sacral dimple about 0.5 cm. in diameter. The infant has a loud, blowing systolic heart murmur and associated precordial thrill without cyanosis, clubbing, or signs of heart failure. The clitoris, which was hypertrophic at birth, is now normal. The third and fourth toes are bilaterally webbed. Patient 28. (ME200267, Fig. 1, e). An older sister and a younger brother are clinically normal. The infant was admitted to the hospital at three months of age for feeding difficulties; at this time she was studied for possible chromosomal abnormalities. She weighed 3,880 Gin., was 53 cm. in length, and the head circumference was 35 cm. Frontal bossing with a prominent glabella and a tiny capillary hemangioma on the forehead were present, along with umbilical hernia and valgus deformities of both feet. Psychomotor

CLINICAL SUMMARY T a b l e I summarizes the a n a m n e s t i c data on our patients and their parents. T a b l e I I lists the clinical features which are c o m m o n ly found in patients with a deletion of the short a r m of either chromosome No. 4 or 5. T a b l e I I I lists clinical features distinguishing the 4 p - from the 5 p - syndrome. O n l y published cases in which the deleted chromosome has been identified by replication pattern have been included, r-9, 15, 1~ References to the 5 p - cases identified in this way are listed in the a c c o m p a n y i n g p a p e r by Breg a n d associates? 4 DERMATOGLYPHIC

STUDIES

T h e prevlously u n p u b l i s h e d dermatoglyphic features of our patients are shown in

T a b l e I. A n a m n e s t i c a n d family d a t a Patient No. Data

4

Sex Date of birth Maternal age Paternal age Mother's karyotype Father's karyotype Gestation (wk.) Age a t ascertainment Fetus hypoactive during pregnancy

M 12/26/52 29 36 Normal 39 11 yr. ?

[

11 M 6/29/64 29 30 Normal Normal 43 1 yr. +

[

19 M 10/28/59 27 33 Normal ? 41 6 yr. ?

24 F 10/20/67 26 30 Normal Normal 40 Birth +

28 F 2/20/67 23 34 Normal Normal 41 3.5 too. +

796

Miller et al.

The lournal o[ Pediatrics November 1970

T a b l e s I V a n d V . I n P a t i e n t 11 e x a m i n a t i o n

apparent

at age one year showed extensive hypoplasia

s o m e u n d e r d e v e l o p m e n t of t h e d e r m a l r i d g e s

of t h e r i d g e s i n t h e h y p o t h e n a r a r e a o f t h e

in t h e h y p o t h e n a r a r e a , t h o u g h n o t as ex-

palmar;

t e n s i v e as t h a t o f P a t i e n t 11. P a t i e n t s 4 a n d

at

3~

years there

had

been no

change.

P a t i e n t s 24 a n d

28 h a d

T a b l e I I . C l i n i c a l f e a t u r e s c o m m o n to 4 p - a n d 5 p - s y n d r o m e s

Clinical [eatures Hypotonia a n d / o r poor muscular develop. Psychomotor retardation Microcephaly Hypertelorism Downward slant to palpebral fissures Epicanthus Strabismus Broad base of nose Narrow ear canals Low-set ears Micrognathia High-arched palate Heart defect Inguinal hernia Undescended testes Short metacarpals or metatarsals Foot deformities Simian crease

4

I

1l

Patient No. I 19 ]

24

I

Affected~total* in 4p5p(13 cases) (31 eases)

28

+ + + +

+ + + +

+ + + +

0 + + +

+ + + +

10/13 13/13 13/13 13/13

15/24 29/29 28/29 15/29t

Right 0 Div. 0 0 Slight Slight + 0 Bilat. 0 S!ight + 0

Bilat. 0 Div. + + Slight + + 0 0 + 0 0 +

Bilat. 0 Div. + 0 0 Slight + + Bilat. 0 + + +

0 Bilat. Div. + + 0 + Cleft + 0 0 + 0

Bilat. Bilat. Div. + + 0 0 0 0 0 0 + 0

6/10 6/11 7/12 9/10 4/6 7/11 7/10 4/11 5/13 3/9 4/6

13/24t 20/29t 12/19t 14/25 6/i4 13/24 15/30 10/18 3/17 3/19 3/9 12/15t 18/19 18/25

2/5 8/11 7/11

~Number with trait/number in which its presence or absence is stated in patients in whom the deleted chromosome has been identified by autoradiography. The 13 4p- patients include 8 published cases 1, 5-9 References to the 31 5p- patients are given in the companion paper by Breg and associates. 14 tIncldence changes with age.

Table III. Clinical features distinguishing 4p- from 5p- syndrome

Clinical [eatures

4

11

Catlike cry in infancy Birth weight (Gin.) Ptosis Coloboma Scalp defect Beaky nose Carplike mouth Cleft palate Very simple ears Preauricular dimple or sinus Sacral dimple or sinus Hypospadias ( 1st degree) Delay in ossification of pelvis a n d / o r carpals Seizures Underdeveloped dermal ridges Low finger ridge count ( < 100) Oblique hall striations

0 t,980 0 0 + 0 + 0 + Bilat. + +

0 1,800 + 0 (? + + 0 + Unilat. + +

+ 0 0 + 0

? 0 + + +

~eaa. ~Mean. Only three had birth weight < 2~000 Gm.

Patient No. I 19 0 2,270 + 0 0 0 ~ + 0 + 0 + + + + 0 + 0

I ~ 24

I

28

Affected total i n 4p5p~ (I3 cases) (31 cases)

0 1,695 0 0 + + + Soft 0 0 + -

0 1,800 + 0 0 + + 0 + Bilat. 0 -

0/13 1,866" 5/11 2/12 3/12 8/12 9/11 7/13 9/11 5/10 7/10 8/8

28/30, 2,650t 1/21 0/19 0/18 1/23 3/20 0/20 0/21 0/15 1/14 0/I 0

? 0 + + +

? + + + +

5/6 9/13 10/12 6/7 3/5

0/16 1/15 0/17 4/19

Volume 77 Number 5

Deletion of short arm o/ chromosome No. 4

cantly longer than the m e a n relative length of the long arm found in patients with short arm deletions of chromosome 5, 0.2432 ~

19, the two oldest in our series, had no signs of ridge hypoplasia. A review of dermatoglyphics in both 4 p - and 5 p - syndromes has been publishedY CYTOLOGIC

797

GENETIC

STUDIES

MARKER

STUDIES

Various genetic markers were studied by F. H. Allen, L. K. Diamond, P. S. Gerald, and E. B. Robson. No evidence of a positive kind was found, but heterozygoslty, indicating that the given locus is not on the deleted segment in that individual, was demonstrated at the M N and H p loci in 4 of the 5 patients, at the R h locus in 3 of the 5 patients, at the G m locus in 2 of 4 patients studied, at the G c locus in 1 of 4 patients, at the Jk locus in 2 of 2 patients, at the Fy locus in 1 of 2 patients, and at the e~2cthrocyte acid phosphatase locus in 1 of 2 patients. Because not all 4 p - patients lack precisely the same segment of chromosome, demonstration that a locus is not on the deleted segment in a particular patient is not of general significance. However, the more cases in which this can be demonstrated, the more likely it is that the locus is not on the chromosome a r m being studied. Lack of heterozygosity when the genotypes of the parents could have led to heterozygous offspring was observed at the A B O locus in

T h e size of the deletion was variable. I n Patients 4, 11, 19, and 24 approximately one half of the short arm was deleted. I n Patient 28 about 10 per cent of a short a r m was absent? s, 19 Identification of the deleted chromosome was carried out by autoradiography and measurement. T h e techniques involved and m a n y of the results have been described elsewhere?G, 18 T h e deleted chromosome was a m e m b e r of the more heavily labeled pair of group B chromosomes in at least 95 per cent of the informatively labeled cells in each case. T h e relative length of the long arm of the deleted chromosome in each case was consistent with the conclusion that a chromosome No. 4 was deleted. However, while the mean relative length of our first two patients (4 and 11) was 0.254,16 in the other three patients it was somewhat shorter: 0.250 _+ .002 (Patient 19, 33 cells), 0.249 +_ .002 (Patient 24, 38 cells) and 0.251 _+ .004 (Patient 28, 17 cells). This is signifi-

Table IV. Digital dermatoglyphics

Patient No.

V

[ IV

Lefthand lie [ II

[

I

I

Righthand I III IV

[ el

[

.Totalridge count

V

24

UL 2-0

A 0-0

A 0-0

A 0-0

UL 9-0

DL 11-8

A 0-0

A 0-0

DL 12-7

UL 4-0

38

28

UL 10-0

UL 9-0

UL 4-0

UL 6-0

UL 14-0

DL 13-6

UL 5-0

A 0-0

W 3-8

W 7-7

76

Table V. Palmar dermatoglyphics

Patient ] No. Axial triradlus

ATD angle

Thenar

Interdigital patterns [ III [

II

4 II

L t t

R t t

L 53 ~

R 41 ~

L 0 0

R 0 0

L 0 0

R 0 0

L 0 0

19 24

t' t

ff t

61 ~

54 ~

0 Vest.

0 Vest.

0 0

0 0

Loop Loop

28

t.

t'

0

0

0

0

0

iI 0 0

IV

L Loop Loop

R Loop Loop

0 0 Whorl Loop

0 Loop

0

0.

0

798

Miller et al.

3 of the 5 patients, a t the Kell locus in 2 of the 5, and at the erythrocyte acid phosphatase locus in the only 1 tested. DISCUSSION

I t is evident from Table I I that the syndromes produced by deletions of the short arm of chromosomes Nos. 4 and 5 share many clinical features. T h e similarity of .the two syndromes, and the absence in our first two patients (4 and 11) of m a n y of the features found in other published cases with a deleted No. 4, led us to doubt at one time whether two clinical syndromes could be distinguished. ~ We no longer question the existence of a 4 p - syndrome, though we still feel that in some cases the diagnosis may be difficult on clinical grounds alone, particularly in older patients. Patients 4 and 19 in our series, for example, were found during a screen for patients with the cri du chat syndrome, while Patient 25 in our series of patients with the 5 p - syndrome ~a was found during a search for the 4 p - syndrome. The fact that consistent clinical differences between the syndromes produced by a latereplicating 4 p - chromosome and an early replicating 5 p - chromosome do exist is evidence that the pairing of the group B chromosomes on the basis of homologous replication patterns is correct. In very young infants the presence or absence of a catlike cry is a useful diagnostic feature. No patients with the 4 p - syndrome in whom the chromosome was identified autoradiographically have had a catlike cry. gubrt and associates 2~ reported such a cry in a patient thought to have a 4 p - deletion because the relative length of the long arm of this chromosome, 0.255, was comparable to that observed in autoradiographically proved cases. 16 This appears to rule out a simple deletion of chromosome No. 5. Confirmation by autoradiography would be desirable 2z in an attempt to rule out a pericentric inversion of chromosome No. 5. The clinical features listed by gubrt and associates are almost all found in both the 4 p and the 5 p - syndromes and do not provide a sufficient basis for differential diagnosis.

The Journal o[ Pediatrics November 1970

Information on additional clinical features listed in our Table I I I might resolve the problem. Almost all of those with a 5 p deletion have had a catlike cry, but the peculiar cry is not completely diagnostic of the cri du chat syndrome; Gendel and associates 22 have observed a case of apparent mosaic trisomy D with a cry said to be typical of the 5 p - syndrome. Although the two syndromes share many "nonspecific" features, which are helpful in recognizing a patient with either syndrome, it appears that differences of degree may exist for some of these features between the 4 p - and the 5 p - syndromes. T h e psychomotor retardation found in patients with a 4 p is more profound than that found in the 5 p syndrome. T h e birth weight of 13 patients with 4 p - averaged only 1,866 Gm., compared with 2,650 Gm. for 30 patients with 5 p - ; this might lead to a high neonatal death rate. T h e 4 p - syndrome appears to be much less common than the 5 p - syndrome; Wolf and Reinwein 23 have suggested this may be due to the early death of patients with 4p-. However, only one of our patients died, at 18 months of age; the others show no sign of imminent death, even at ages 10 and 17 years. There is, of course, no apriori reason to expect deletions of chromosomes Nos. 4 and 5 to be equally frequent at conception or any other age. Neither of them has been identified in aborted fetusesY 4 In 4 p - patients, the facies appears to have a characteristic appearance in infancy. Ptosis and coloboma are sometimes present; the nose is broad at the base, with a flattened, often beaked tip and sometimes triangular nares'. The upper lip is sometimes full a n d appears to be pulled up in the center and curled downward at the corners, so that the mouth is fish shaped and similar to that seen after repair of a cleft lip. One patient has had bilateral cleft lip and 7 a cleft palate. The eyebrows give the appearance of beginning over the center of the eye, because the hairs nearer the bridge of the nose slant upward and are sparse; the result is a startled expression. Genital anomalies appear to be common

Volume 77 Number 5

Deletion o/ short arm o/ chromosome No. 4

799

Fig. 2. Ears from patients with 4p- syndrome, a, Patient 4; b, Patient 11; c, Patient 19; d, Patient 28.

in the 4p- syndrome. All the male patients have had hypospadias (some to a minimal extent), while none of the 10 male patients with a proved deletion of chromosome No. 5 have had hypospadias. Other anomalies such as undescended testes, enlarged clitoris, and premature pubarche have been found. 6 The high frequency of preauricular and sacral dimples or sinuses found in patients with a 4p- also serves to distinguish them from patients with the cri du chat syndrome in whom preauricular tags, but not sinuses, are sometimes found. The cartilage of the outer ear is extremely underdeveloped in many cases of the 4p- syndrome (Fig. 2).

Although the ears in the @ - and 5 p - syndromes have both been described as "simple," those in the 4p- syndrome are much more underdeveloped. The incidence of seizures appears to be much higher in patients with 4 p - than those with 5p-. Markedly delayed ossification of the carpals, tarsals, and pubic bones is another distinguishing feature found in the syndrome. A midline scalp defect, similar to that sometimes seen in trisomy 13, has been present in 3 patients with 4p-. In older patients the only remaining sign of this defect may be a small area of alopecia on the crown. W h e n this scalp defect occurs in

800

Miller et al.

conjunction with c o l o b o m a t a , cleft palate, a n d seizures, a very similar clinical picture to t h a t of trisomy 13 is p r o d u c e d . Polydactyly has not been r e p o r t e d in the 4 p syndrome, however. T h e high incidence of areas of hypoplasia of the d e r m a l ridges on the p a l m s a n d the feet is a n o t h e r feature of the 4 p - syndrome which has n o t been r e p o r t e d in the cri du c h a t syndrome. T h e most useful differences in d e r m a t o g l y p h i c p a t t e r n s between the two syndromes a p p e a r to be a lower ridge count ( m e a n of 69.8 for five cases) associated with a higher frequency of a r c h p a t t e r n s on the digits, a h i g h e r frequency of double loops on the thumbs, a n d a lower incidence of t ' a n d t h e n a r p a t t e r n s in 4 p - as c o m p a r e d to 5 p - . O b l i q u e ridges on the fingernails occur in m a n y of the patients with 4 p - a n d rarely in the individuals with 5 p - . T h e control frequency is unknown. A l t h o u g h we have no e x p l a n a t i o n for it, we w o u l d like to p o i n t o u t the extremely p o o r r e p r o d u c t i v e histories of the p a r e n t s of the 5 patients in o u r series. O f 14 pregnancies o t h e r t h a n those of the probands, 2 e n d e d in the birth of children with fatal congenital defects, 3 m o r e aborted, a n d 1 was stillborn. T h e defects were a p p a r e n t l y u n r e l a t e d to those of the p r o b a n d . T h e group B short a r m deletions are the first clear e x a m p l e of a situation which will p r o b a b l y arise often in h u m a n chromosome s t u d i e s - - t w o clinically similar syndromes, p r o d u c e d by two cytologically similar a b e r r a tions, w h i c h can only be distinguished by m e a n s o t h e r t h a n simple visual inspection of the chromosomes.

The Journal o[ Pediatrics November 1970

4.

5.

6.

7.

8.

9. 10.

11.

12.

13. 14.

15. .,

REFERENCES

I. Wolf, U., Relnwein, H., Porsch, R., Schr~Ster, R., and Baitsch, H. : Defizienz an den kurzen Armen Eines Chromosoms Nr. 4, Humangenetik h 397, 1965. 2. Lejeune, J., Lafourcade, J., de Grouchy, J., Berger, R., Gautier, M., Salmon, C., and Turpin, R.: Drlrtion partlelle du brag court du chromosome 5. Individualisation d'un nouvel ~tat morbide, Sere. Hop. Paris 40: !069, 1964. 3. German, J., Lejeune, J., Maclntyre, M. N., and de Grouchy, J.: Chromosomal autoradiog-

16.

17.

raphy in the cri du chat syndrome, Cytogenetics 3: 347, 1964. Miller, O. J., Breg, W. R., Warburton, D., Miller, D. A., de Capoa, A., and Chutorian, A. M.: Deleted /ate-replicating chromosome 4/5, Lancet 2: 105, 1966. Carneiro Le~o, J., Bargman, G. L., Neu, R. L., Kajii, T., and Gardner, L. I.: New syndrome associated with partial deletion of short arms of chromosome No. 4, J. A. M. A. 202: 434, 1967. Van Kempen, C., and Jongbloet, P. H.: Partial deletion of the short arm of a chromosome No. 4. Wolf's syndrome, Mschr. Kindergeneesk. 35: 252, 1967. Pfeiffer, R. A.: Neue Dokumentation zur Abgrenzung eines Syndroms der Deletion des Kurzen Arms eines Chromosoms Nr. 4, Z. Kinderheilk. 102: 49, 1968. Arias, D., Passarge, E., Engle, M. A., and German, J.: Human chromosomal deletion: Two patients with the 4p- syndrome, J. PzDrAT. 76: 82, 1970. Passarge, E., Altrogge, H. C., and Rildiger, R. A.: Human chromosomal deficiency: The 4p- syndrome, Humangenetik. In press. Hirschhorn, K., Cooper, H. L., and Firschein, I. L.: Deletion of short arms of chromosomes 4-5 in a child with defects of midline fusion, Humangenetik h 479, 1965. Sidbury, J. B., Jr., Schmickel, R. D., and Gray, M.: Findings in a patient with apparent deletion of short arms on one of the B group chromosomes, J. PEmAT. 65: 1098, 1964. (Abst.) Giorgl, P. L., Cecearelli, M., and Paci, A.: Su un easo di sindrome del "cri du chat" con peculiari anomalie fenotipiche, Minerva Pedlar. 17: 1972, 1965. Joseph, C., and Yannet, H.: Congenital idiocy, sexual infantilism and dwarfism, Yale J. Biol. Med. 24: 257, 1952. Breg, W. R., Steele, M. W., Miller, O. J., Warburton, D., de Capoa, A., and Allderdice, P. W.: The cri du chat syndrome in adolescents and adults: Clinical and other findings in 13 older patients with partial deletion of the short arm of chromosome No. 5(5p-), J. PZDIAT. 77: 782, 1970. Miller, O. J., Breg, W. R., Warburton, D., Miller, D. A., Firschein, I. L., and Hirschhorn, K.: Alternative DNA replication patterns associated with long arm length of chromosomes 4 and 5 in the cri du chat syndrome, Cytogenetics 5: 137, 1966. Warburton, D., Miller, D. A., Miller, O. J., Breg, W. R., de Capoa, A., and Shaw, M. W.: Distinction between chromosome 4 and chromosome 5 by replication pattern and length of long and short arms, Amer. J. Hum. Genet. 19: 399, 1967. Warburton, D., and Miller, O. J.: Dermatoglyphlc features of patients with a partial short arm deletion of a B-group chromosome, Ann. Hum. Genet. 31: 189, 1967.

Volume 77 Number 5

Deletion of short arm o/ chromosome No. 4

18. Miller, D. A., Warburton, D., and Miller, O. J.: Clustering in deleted short-arm length among 25 cases with a Bp- chromosome, Cytogenetics 8: 109, 1969. 19. Warburton, D., Miller, D. A., Miller, O. J., Allderdice, P. W., and de Capoa, A.: Detection of minute deletions in human karyotypes, Cytogenetics 8: 97, 1969. 20. ~ubrt, I., Blehov~, B., and Sedl~6kov~, E.: Mewing cry in a child with the partial deletion of the short arm of chromosome No. 4, Humangenetik 8: 242, 1969. 21. Ridler, M. A. C., and Faunch, J. A.: Long

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arm measurements of chromosomes 4 and 5 with special reference to the cri du chat syndrome, Ann. Hum. Genet. 32: 375, 1969. 22. Gendel, E., Zelson, C., Allderdice, P. W., and Miller, O. J.: A misleading cri, In preparation. 23. Wolf, U., and Reinwein, H.: Klinische und cytogenetische Differentialdiagnose der defizienzenan den Kurzen Armen der B-Chromosomen, Z. Kinderheilk. 98: 235, 1967. 24. Geneva Conference: Standardization of procedures for chromosome studies in abortion, Bull. W H O 34: 765, 1966.