American Journal of Medical Genetics 39155-160 (1991)
Partial Deletion of Chromosome 6p: Delineation of the Syndrome Catherine G. Palmer, Patricia Bader, Marilyn L. Slovak, David E. Comings, and Mark J. Pettenati Indiana University School of Medicine, Indianapolis (C.G.P.); Parkview Memorial Hospital, Fort Wayne, IN (P.B.); City of Hope National Medical Center, Duarte, C A (M.L.S.,D.E.C.); Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, NC (M.J.P.)
Here we summarize the clinical findings of five new patients and nine patients reported in the literature with deletions of the short arm of chromosome 6. The del(6p) syndrome appears to include the following clinical findings: mental retardation, microcephaly, abnormal sutures, broad nasal bridge, various eye and ear abnormalities, a short neck with excess skin folds, and a normal birth weight and length.
KEY WORDS: chromosome deletion, deletion 6p, clinical findings, partial monosomy 6p, multiple congenital anomalies/mental retardation (MCAMR) syndrome
sures, a small pinched nose with anteverted nostrils, a depressed nasal bridge, and a cleft in the chin. At birth, the patient had severe congenital subglottic tracheal stenosis and a congenital heart defect, including patent ductus arteriosus and a n atrial septal defect. She had pectus excavatum and a prominent abdomen. Cutis marmorata was present, and she was slightly hypotonic. During a hospital stay, a tracheostomy was performed and she had three cardiac arrests, but recovered sumciently to be discharged, after which she was later lost to follow-up.
Patient 2 (Fig. la) This boy was born to a 29 year old woman who had been exposed to trichlorethane during her pregnancy. His birth weight was 3,374 g (50th centile), birth length was 48.5 cm (25th centile), and OFC of 35.5 cm (75th centile). Apgar scores were 919 a t birth. The infant had respiratory distress for 18 hours. He was noted to have INTRODUCTION asymmetrical hydrocephalus, observed on ultrasound to Clinical reports of individuals with deletions of 6p are be minimal on the right and moderate on the left. A CT limited. They include patients with ring 6 [Chitayat et scan was performed after the head ultrasound which al., 19871, segregants from inversion of chromosome 6 showed prominent anterior horns. He had a round face [Magenis et al., 1978; Schroer et al., 19801 and seven with malar hypoplasia, highly arched palate, a poorly reports of partial deletions of 6p [Ouchi and Kasai, 1982; demarcated flattened philtrum, downturned corners of Reid et al., 1983; Sachs, 1983; Van Swaay et al., 1988; the mouth, prominent bulging eyes, hypertelorism, and Jalal et al., 1989; Kelly et al., 1989;Zurcher et al., 19901. downslanting palpebral fissures. There was a short naWe report the clinical and cytogenetic findings of five sal bridge and apparently low-set ears. The fontanelles additional patients with del(6Np23) and compare their were exceptionally wide with the sutures widely sepafindings to those of nine cases of del(6p) and 15 cases of rated. There was neck webbing and mildly redundant skin. He had a ventricular septal defect. The nipples ring 6 in the literature. were widely spaced, and he had a pectus excavatum. He CLINICAL HISTORIES had hepatosplenomegaly (the liver measured 6 cm bePatient 1 low the right costal margin) and mild thrombocytoA 3 month old girl was born at 37 weeks gestation with penia. There was a micropenis (1cm < 10th centile), but a weight of 2,794 g (50 centile), length of 50 cm (>75 both testes were in the scrotum. centile), OFC of 32 cm (25 centile), and Apgar scores of Patient 3 718 a t 1 and 5 mintues, respectively. She also had ridging of the coronal suture, narrow forehead, wide occiput, This boy was born a t term to a 23 year old mother after bulging eyes with slightly upslanting palpebral fis- a n uncomplicated pregnancy. Weight was 4,120 g (90th centile); length, 54 cm (90th centile), and OFC, 36 cm Received for publication March 26, 1990; revision received July (90th centile). At delivery, he developed respiratory 16, 1990. distress and cyanosis. Physical examination showed Address reprint requests to C.G. Palmer, PhD, Department of Medical Genetics, Indiana University School of Medicine, 975 marked trigonocephaly with prominent occipital and parietal areas of the skull, a narrow bifrontal diameter, West Walnut Street, Indianapolis, IN 46202-5251. 0 1991 Wiley-Liss, Inc.
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Fig. 1. a: Patient 2 a t 13.5 months showing pectus excavatum and unusual facies. b: Facial features of patient 4 with repaired bilateral cleft lip, flat broad nasal bridge, large protruding ears, and right internal strabismus. c: Microcephalic del(6p) female with “recessed’ eyes, micrognathia, and accessory nipple (patient 5).
and low anterior and posterior hairlines. There were skin folds over the forehead and a capillary hemangioma over the glabella and right eyebrow. The anterior fontanelle was normal; a small posterior fontanel was palpable. The neck was apparently short with redundant nuchal skin. The patient had blepharophimosis and scattered Brushfield spots. The base of the nose was broad with a prominent bridge and a short upturned tip. There was a short philtrum, flared columella, and a thin upper lip. The ears were apparently low set and posteriorly angulated with small tragi, dimpled lobes, and overfolded helices, There was marked micrognathia. The nipples were widely spaced and hypoplastic. Cardiovascular studies demonstrated a double outlet right ventricle, bicuspid aortic valve, and interrupted aortic arch. He had second-degreehypospadias. There was bilateral fifth finger clinodactyly. The toe nails were hypoplastic, and there was an increased space between the first and second toes and a longitudinal sole crease. The patient was hospitalized three times for pneumonia and once for heart failure. Linear growth and weight gain have been normal, but the patient was noted to have a head circumference at the 5th centile a t 6 months. He has psychomotor retardation and generalized hypotonia.
Patient 4 (Fig. lb) This girl seen first at 3 months was born to a 19 year old mother; birth weight was 3,510 g (75th centile); length, 51 cm (75th centile); and OFC, 35 cm (75th centile). Facial anomalies included bilateral cleft lip and palate, mild microcephaly, a flat broad nasal bridge, and micrognathia. The ears were apparently low set with overfolded helices. There was a large anterior fontanelle. She had a short neck with excess skin. Congenital heart defects included a patent ductus arteriosus and an atrial septa1 defect. She had a large cystic right kidney. At age 6 months, she was noted to be developmentally delayed. At 2 years, she has an unusual face with a right internal strabismus, prominent ears, repaired bilateral cleft lip and palate, and a pectus excavatum. Patient 5 (Fig. lc) The patient was first seen at age 18 years. She was severely retarded with microcephaly, deeply set eyes, micrognathia, maxillary protrusion and micrognathia, high arched palate, and bilateral brachydactyly of fingers 3-5 with relative protrusion of the second metacarpal. The second toes were extended and had been
Deletion 6p partly amputated. Her heart was normal. She had a n accessory nipple on the right breast. Her gait was clumsy with some toe-walking. The left foot turned in and the right out. At birth, she was reported to have had a low Apgar score, inwardly rotated hands, and foot deformities.
RESULTS All cases were analyzed from blood lymphocyte cultures and Giemsa-banded metaphase preparations (Fig. 2). Patient 1 was studied in 1983. After recognition of the del(61, cells were synchronized with methotrexate and the deletion defined as 6p23 -+ pter. Patient 2 was studied in cultures treated with ethidium bromide [Ikeuchi, 19841. The de1(6)(p23)was present in all cells studied. The patient was also studied at a second hospital with the same findings. Patients 3 and 4 also showed the terminal deletion a t 6p23. All deletions were considered to be terminal. Patient 5 showed a 6p23 deletion at the 400 band level of resolution. Both parents of all five patients were chromosomally normal. DISCUSSION The earliest report of a patient with an apparent deletion of 6p [DeGrouchy et al., 19681was later shown with banding to be a deleted chromosome 7 [DeGrouchy and Turleau, 19741. Ouchi and Kasai [19821first described a patient with a de1(6)(p23). This newborn infant had a large anterior and posterior fontanelle, prominent occiput, hypoplasia of the right ear lobe, atresia of right external acoustic meatus, apparently low-set ears, and a left accessory ear lobe, cleft lip and palate, micrognathia, short neck, excess nuchal skin, hypoplasia of the nipples, funnel chest, small external genitalia, clinodactyly of the fifth fingers, and hypotonia. After death a t 5 months, autopsy showed valvular abnormal-
157
ities of the heart, membranous ventricular septal defect, ovarian cysts, and right hydronephrosis. Another child with a del6(p24-+p25) was described in a n abstract in 1983 [Reid et al., 19831. She was born a t 33 weeks gestation with hydrocephalus and a Dandy Walker cyst, clinical features of hypertelorism, corneal opacities, apparently low-set ears, preauricular tag, micrognathia, an ectopic anus, and a heart murmur. Normal Hageman factor levels were present in the child, suggesting that the region necessary for its expression to be localized to 6p23-+p24. Sachs et al. [1983] also published a brief description of a patient with del(6Xp22.2) in a report dealing with the localization of HLA. Anomalies included microphthalmos, nystagmus, unilateral cleft palate, low backwardly angulated ears, short neck with nuchal folds, hypoplastic nails, and rocker-bottom feet with abnormal “implantation”of the toes, a ventricular septal defect, insufficient ossification of the skull, and a large medial defect of the maxilla. More recently, there have been three clinical descriptions of individuals with deletions of 6p [Van Swaay et al., 1988; Clement et al., 1989; Jalal et al., 1989; Zurcher et al., 19901. Common clinical features of the del(6p) patients include mental retardation, a flat broad nasal bridge, and ear abnormalities [Van Swaay et al., 1988; Jalal et al., 1989; Zurcher et al., 19901. Only one child was reported to have eye abnormalities, a heart defect, and chest abnormalities [Van Swaay et al., 19881. Although the clinical findings were not remarkably different, this was also the only individual described to have a n interstitial deletion [de1(6)(p22.2p25.2)1.Clement et al. [1989] briefly report a de1(6)(p22.2)ascertained prenatally in a 26 week fetus which subsequently was stillborn a t 32 weeks of gestation. At autopsy, this stillborn infant had holoprosencephaly, hydrocephalus, cranial facial hypoplasia, hydronephrosis and polycystic kid-
Fig. 2. Deletion 6 ~ 2 3 - 6pter in patients 1 (a),2 (b),3 (c), 4 (d),and 5 (e).
nb
=
newborn; s b =
9/9 10/11 517 7112 11/12 619 9/10 516 515
618
719 919
1771
1521
9Fl5M
1
i =
+
c
-
=
+ + + + +
+ + + + +
+ +
died; m
t t
+ + + -
mi
months.
+
+ +
+
+
+ + +
+ + +
51 1751
3,510
4,120 [go] 54 [go]
3,374 1501 48.5 1251
2,794 1501 50 [751
F 6m
p23
4
M 6m
p23
3
M nb
p23
2
F 3m
P23
stillbirth; d
Microcephaly Mental retardation Abnormal sutures Eye abnormalities Flat broad nasal bridge Micrognathia Palatal abnormalities Ear abnormalities Abnormal genitalia Heart defect Short neck Pectus excavatum
Clinical findings Sex Age Birth weight (gm) [centilel Birth length (cm) [centilel
Breakpoints:
14
Total
This paper
t i
+
+
+
+
+
i
+
2,360 [I01
F d5m
+
+
t
+
+ +
no1
2,400
F 2,000 [501
F nb
+
+
+ +
-
+
+
-
t
M 3Y 3,960 [901 53.5 1751
p22.2 I p25.2
P24
p23
p22.2
Van Swaay [19881
Ouchi Sachs Reid [19821 119831 rig831
-
-
+ + -
+ + -
F 18y
p23
5
i
2,327 1901
F sb
p22.2
Clement f19891
+
+ +
F ~ O Y 3,070 [~OI 533 1951
p23
1
Kelly
$
+ +
Zurcher ~ 2 3
+
+
f
+ +
i
t
+ +
t
+
+
-
2Y 3,700 [851 53 [go1
F
P24
[19891 _ _ _ [19901
M M 2m 6~ 2,778 2,060 1251 131 53.3 42 1901 [31
p23
2
Jalal [19891
TABLE I. Comparison of the Common Clinical Findings in del(6p) and r(6) Patients
12 2 10 6
9 9
11 13 1
Ring 6 (15 cases) Chitayat 119871
Deletion 6p
neys, ascites, rocker-bottom feet, and cleft lip and palate. Parental karyotypes were normal in the above-described cases. Kelly et al. [19891provided the only report of a del 6p as a result of an unbalanced translocation. The clinical findings of this child are very similar to those of the del(6p) children. In the present report, four cytogenetic laboratories have independently identified a del(6p) in five patients referred for malformations and/or mental retardation. The common clinical findings of these five patients and the nine reported cases are summarized in Table I. The common deletion breakpoint is band p23 (9/14 cases), with the remaining five patients having breakpoints at p22.2 (three cases), p24 (two cases), and p25.2 (one case). Clinical features commonly reported in > 70% of the del(6p)cases include mental retardation, microcephaly, abnormal skull sutures, a flat broad nasal bridge, eye and ear abnormalities, pectus excavatum, and an apparently short neck with excess skin folds. Heart defects occur in 90% of the patients. Birth weight and length were generally normal. The only notable exception was the low birth weight and length associated with the del(6p) that was the result of an unbalanced translocation [Kelly et al., 19891. Clefts of the lip and/or palate were fairly common (4/12) with 3/12 cases described as having a highly arched palate. Although eye anomalies are fairly common in the del(6p) patients (9/9), there does not appear to be a single typical abnormality. The eye malformations included blepharophimosis, iris coloboma, microphthalmia, corneal opacification, Peters anomaly, optic atrophy, megalocornea, Brushfield spots, strabismus, nystagmus, and epicanthal folds. Ears were often described as low set, posteriorly angulated, and incompletely developed. There were also hypoplastic ear lobules, atresia of the external acoustic meatus, accessory ear lobes, and “crumpled” or folded ear lobes or incomplete outfolding of the ears. The heart defects varied and included atrial septal defect, ventricular septal defect, patent ductus, prominent pulmonary vessels on chest film, and abnormalities of the valves. Chest anomalies included hypoplasia of the nipples and pectus excavatum. Other reported abnormalities included umbilical hernia, short forehead, flat occiput, unusual hair pattern, ovarian cysts, and hydronephrosis. Hands were reported to demonstrate clinodactyly of the fifth finger and short terminal phalanges, in particular of the thumb, and several patients were reported to have nail dysplasia. Patients with ring 6 also lack a portion of 6p and therefore should have some clinical findings. The clinical findings in 15 cases of r(6) as summarized by Chitayat et al. [19871are also included in Table I for comparison. The common findings include hypertelorism, eye abnormalities, flat nasal bridge, and a short webbed neck. The frequent occurrence of eye abnormalities in patients with r(6) suggested to Chitayat et al. [19871 that a gene or genes located distally on 6p or 6q may influence the development of the iris. The clinical finding of eye abnormalities in the del(6p)patients appear to confirm the suggestion that such a gene is on distal 6p [Zurcher et al., 19901.
159
There are a number of genes localized to the p arm of chromosome 6. Early reports on del(6p)were concerned with the localization ofHLA [Magenis et al., 1978;Sachs et al., 19831. The HLA region is localized to 6~21.3. Loci of particular interest to the del(6p) patients are the fragile sites, fra(6Xp23) rare, folic-acid type, fra(6) ( ~ 2 5 . 1common, ) aphidocolin type, and fra(6)(p22)common aphidocolin type. Nine of the deletions in these patients occur at 6p23, the site of the rare fragile sites, and three at p22.2, with one having a second breakpoint at 6~25.2.In addition, all the deletion 6p cases arose de novo. This suggests a possible relationship of fragile sites to the occurrence of deletions previously proposed [Malthy and Higgins, 1987; Stallard et al., 1987; Voullair et al., 1987; Pettenati et al., 1988;Palmeret al., 19901. In addition, ring 6 breakpoints are most frequently located at 6p24 or 6p25 [Kini et al., 1979; Nishi et al., 1982; Peeden et al., 1983; Levin et al., 1986; Chitayat et al., 19871,with only one reported breakpoint at 6p23 or 24 [Carnevale et al., 19791.The origin of rings and deletions may differ with the more frequent occurrence of breaks leading to ring formation occurring during association of telomeres at meiotic prophase. The existence of true terminal deletions has often been questioned since the telomere, a structural component of each end of the chromosome, is necessary to prevent stickiness of chromosomes after breakage. Recent in situ evidence of the location of human telomeric repeat sequences interstitially in chromosome 2 at 2qll-q14 has raised the possibility that fragile sites may represent the location of interstitial telomeres [Hastie and Allshire, 19891.These authors also enumerate common properties of internal telomeric repeats and fragile sites such as recombogenicity, location of repeating stretches of C and T residues, and fragility and suggest that at least some fragile sites may be structurally similar to telomeres. If true, these observations could provide an explanation for the stability of terminal deletions and the location of such deletions at fragile sites as seen in the cases of the de1(6)(p23).
REFERENCES Carnevale A, Blanco B, Castillo V, Dominguez D (1979): Ringchromosome 6 in a child with minimal abnormalities. Am J Med Genet 4:271-277. Chitayat D, Hahm S, Iqbal MA, Nitowsky HM (1987): Ring chromosome 6: Report of a patient and literature review. Am J Med Genet 26:145-151. DeGrouchy J , Turleau C (1974):Tentative localization of a Hageman (Factor XII) locus on 7q, probably the 7q35 band. Hum Genet 24:197-200. DeGrouchy J, Veslot J, Bonnette J , Roidot M (1968): A case of ?6p chromosomal aberration. Am J Dis Child 115:93-99. Hastie ND, Allshire RC (19891: Human telomeres: Fusion and interstitial sites. TIG 5:326-330. Ikeuchi T (1984): Inhibitory effect of ethidium bromide on mitotic chromosomal condensation and its application to high-resolution chromosome banding. Cytogenet Cell Genet 38:56-61. Jalal SM, Macias VR, Roop H, Morgan F, King P (1989):Two rare cases of 6p partial deletion. Clin Genet 36:196-199. Kelly PC, Blake WW, Davis J R (1989): Tandem Y/6 translocation with partial deletion 6(p23+ pter). Clin Genet 36:204-207. Kini KR, Van Dyke DL, Weiss L, Logan MS (1979):Ring chromosome 6: Case report and review of literature. Hum Genet 50:145-149.
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Levin H, Ritch R, Barathur R, Dunn MW, Teekhasaenee C, Margolis S (1986): Brief clinical report: Aniridia, congenital glaucoma, and hydrocephalus in a male infant with ring chromosome 6. Am J Med Genet 26:281-287. Magenis RE, Chamberlin J, Overton K, Lovrien E (1978): Linkage relationships of HLA and a familial chromosome 6 inversion (pter- p23::q23-p23::q23+ qter): Lack of dose effect in duplication-deficient offspring. Cytogenet Cell Genet 22418-420. Maltby EL, Higgins S (1987):Folate sensitive fragile site a t 10q23 and its expression as a deletion. J Med Genet 24:299. Nishi Y, Yoshimura 0, Ohama K, Usui T (1982):Ring chromosome 6: Case report and review. Am J Med Genet 12:109-114. Ouchi K, Kasai R (1982): A case of partial monosomy 6p. Jpn J Hum Genet 27214. Palmer CG, Heerema NA, Bull M (1990): Deletions in chromosome 2 and fragile sites. Am J Med Genet 36214-218. Peeden J N , Scarbrough P, Taysi K, Wilroy RS, Finley S, Luthardt F, Martens P, Howard-Peebles PN (1983): Ring chromosome 6: Variability in phenotypic expression. Am J Med Genet 16563-573. Pettenati MJ, McNay JW, Hayworth R, Sherman SL (1988):Support-
ing evidence of a role for common fragile sites in constitutional abnormalities. Am J Hum Genet 43:A177. Reid CS, Stamberg J , Phillips JA (1983):Monosomy for distal segment 6p: Clinical description and use in localizing a region important for expression of Hageman factor. Pediatr Res 17:A217. Sachs ES, Hoogeboom AJ, Niermeijer MF, Schreuder GM (1983):Clinical evidence for localisation of HLA proximal of chromosome 6p22. Lancet 1:659. Schroer R J , Culp DM, Stevenson RE, Potts WE, Taylor HA, Simensen RJ (1980): Duplication-deletion syndrome in a family with pericentric inversion of chromosome 6. Clin Genet 18:83-87. Stallard R, Dickerman L, Johnson W (19871: A fragile site on 2p promoting dup(Z)(pll+pter). Am J Hum Genet 41:A146. Van Swaay E , Beverstock GC, VandeKamp JJ (1988):A patient with an interstitial deletion of the short arm of chromosome 6. Clin Genet 33:95-101. Voullaire LE, Webb GC, Leversha MA (1987): Chromosome deletion at l l q 2 3 in a n abnormal child from a family with inherited fragility at llq23. Hum Genet 76:202-204. Zurcher VL, Golden WL, Zinn AB (1990): Distal deletion of the short arm of chromosome 6. Am J Med Genet 35:261-265.
Partial Deletion of Chromosome 6p: Delineation of the Syndrome Catherine G. Palmer, Patricia Bader, Marilyn L. Slovak, David E. Comings, and Mark J. Pettenati Indiana University School of Medicine, Indianapolis (C.G.P.); Parkview Memorial Hospital, Fort Wayne, IN (P.B.); City of Hope National Medical Center, Duarte, C A (M.L.S.,D.E.C.); Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, NC (M.J.P.)
Here we summarize the clinical findings of five new patients and nine patients reported in the literature with deletions of the short arm of chromosome 6. The del(6p) syndrome appears to include the following clinical findings: mental retardation, microcephaly, abnormal sutures, broad nasal bridge, various eye and ear abnormalities, a short neck with excess skin folds, and a normal birth weight and length.
KEY WORDS: chromosome deletion, deletion 6p, clinical findings, partial monosomy 6p, multiple congenital anomalies/mental retardation (MCAMR) syndrome
sures, a small pinched nose with anteverted nostrils, a depressed nasal bridge, and a cleft in the chin. At birth, the patient had severe congenital subglottic tracheal stenosis and a congenital heart defect, including patent ductus arteriosus and a n atrial septal defect. She had pectus excavatum and a prominent abdomen. Cutis marmorata was present, and she was slightly hypotonic. During a hospital stay, a tracheostomy was performed and she had three cardiac arrests, but recovered sumciently to be discharged, after which she was later lost to follow-up.
Patient 2 (Fig. la) This boy was born to a 29 year old woman who had been exposed to trichlorethane during her pregnancy. His birth weight was 3,374 g (50th centile), birth length was 48.5 cm (25th centile), and OFC of 35.5 cm (75th centile). Apgar scores were 919 a t birth. The infant had respiratory distress for 18 hours. He was noted to have INTRODUCTION asymmetrical hydrocephalus, observed on ultrasound to Clinical reports of individuals with deletions of 6p are be minimal on the right and moderate on the left. A CT limited. They include patients with ring 6 [Chitayat et scan was performed after the head ultrasound which al., 19871, segregants from inversion of chromosome 6 showed prominent anterior horns. He had a round face [Magenis et al., 1978; Schroer et al., 19801 and seven with malar hypoplasia, highly arched palate, a poorly reports of partial deletions of 6p [Ouchi and Kasai, 1982; demarcated flattened philtrum, downturned corners of Reid et al., 1983; Sachs, 1983; Van Swaay et al., 1988; the mouth, prominent bulging eyes, hypertelorism, and Jalal et al., 1989; Kelly et al., 1989;Zurcher et al., 19901. downslanting palpebral fissures. There was a short naWe report the clinical and cytogenetic findings of five sal bridge and apparently low-set ears. The fontanelles additional patients with del(6Np23) and compare their were exceptionally wide with the sutures widely sepafindings to those of nine cases of del(6p) and 15 cases of rated. There was neck webbing and mildly redundant skin. He had a ventricular septal defect. The nipples ring 6 in the literature. were widely spaced, and he had a pectus excavatum. He CLINICAL HISTORIES had hepatosplenomegaly (the liver measured 6 cm bePatient 1 low the right costal margin) and mild thrombocytoA 3 month old girl was born at 37 weeks gestation with penia. There was a micropenis (1cm < 10th centile), but a weight of 2,794 g (50 centile), length of 50 cm (>75 both testes were in the scrotum. centile), OFC of 32 cm (25 centile), and Apgar scores of Patient 3 718 a t 1 and 5 mintues, respectively. She also had ridging of the coronal suture, narrow forehead, wide occiput, This boy was born a t term to a 23 year old mother after bulging eyes with slightly upslanting palpebral fis- a n uncomplicated pregnancy. Weight was 4,120 g (90th centile); length, 54 cm (90th centile), and OFC, 36 cm Received for publication March 26, 1990; revision received July (90th centile). At delivery, he developed respiratory 16, 1990. distress and cyanosis. Physical examination showed Address reprint requests to C.G. Palmer, PhD, Department of Medical Genetics, Indiana University School of Medicine, 975 marked trigonocephaly with prominent occipital and parietal areas of the skull, a narrow bifrontal diameter, West Walnut Street, Indianapolis, IN 46202-5251. 0 1991 Wiley-Liss, Inc.
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Fig. 1. a: Patient 2 a t 13.5 months showing pectus excavatum and unusual facies. b: Facial features of patient 4 with repaired bilateral cleft lip, flat broad nasal bridge, large protruding ears, and right internal strabismus. c: Microcephalic del(6p) female with “recessed’ eyes, micrognathia, and accessory nipple (patient 5).
and low anterior and posterior hairlines. There were skin folds over the forehead and a capillary hemangioma over the glabella and right eyebrow. The anterior fontanelle was normal; a small posterior fontanel was palpable. The neck was apparently short with redundant nuchal skin. The patient had blepharophimosis and scattered Brushfield spots. The base of the nose was broad with a prominent bridge and a short upturned tip. There was a short philtrum, flared columella, and a thin upper lip. The ears were apparently low set and posteriorly angulated with small tragi, dimpled lobes, and overfolded helices, There was marked micrognathia. The nipples were widely spaced and hypoplastic. Cardiovascular studies demonstrated a double outlet right ventricle, bicuspid aortic valve, and interrupted aortic arch. He had second-degreehypospadias. There was bilateral fifth finger clinodactyly. The toe nails were hypoplastic, and there was an increased space between the first and second toes and a longitudinal sole crease. The patient was hospitalized three times for pneumonia and once for heart failure. Linear growth and weight gain have been normal, but the patient was noted to have a head circumference at the 5th centile a t 6 months. He has psychomotor retardation and generalized hypotonia.
Patient 4 (Fig. lb) This girl seen first at 3 months was born to a 19 year old mother; birth weight was 3,510 g (75th centile); length, 51 cm (75th centile); and OFC, 35 cm (75th centile). Facial anomalies included bilateral cleft lip and palate, mild microcephaly, a flat broad nasal bridge, and micrognathia. The ears were apparently low set with overfolded helices. There was a large anterior fontanelle. She had a short neck with excess skin. Congenital heart defects included a patent ductus arteriosus and an atrial septa1 defect. She had a large cystic right kidney. At age 6 months, she was noted to be developmentally delayed. At 2 years, she has an unusual face with a right internal strabismus, prominent ears, repaired bilateral cleft lip and palate, and a pectus excavatum. Patient 5 (Fig. lc) The patient was first seen at age 18 years. She was severely retarded with microcephaly, deeply set eyes, micrognathia, maxillary protrusion and micrognathia, high arched palate, and bilateral brachydactyly of fingers 3-5 with relative protrusion of the second metacarpal. The second toes were extended and had been
Deletion 6p partly amputated. Her heart was normal. She had a n accessory nipple on the right breast. Her gait was clumsy with some toe-walking. The left foot turned in and the right out. At birth, she was reported to have had a low Apgar score, inwardly rotated hands, and foot deformities.
RESULTS All cases were analyzed from blood lymphocyte cultures and Giemsa-banded metaphase preparations (Fig. 2). Patient 1 was studied in 1983. After recognition of the del(61, cells were synchronized with methotrexate and the deletion defined as 6p23 -+ pter. Patient 2 was studied in cultures treated with ethidium bromide [Ikeuchi, 19841. The de1(6)(p23)was present in all cells studied. The patient was also studied at a second hospital with the same findings. Patients 3 and 4 also showed the terminal deletion a t 6p23. All deletions were considered to be terminal. Patient 5 showed a 6p23 deletion at the 400 band level of resolution. Both parents of all five patients were chromosomally normal. DISCUSSION The earliest report of a patient with an apparent deletion of 6p [DeGrouchy et al., 19681was later shown with banding to be a deleted chromosome 7 [DeGrouchy and Turleau, 19741. Ouchi and Kasai [19821first described a patient with a de1(6)(p23). This newborn infant had a large anterior and posterior fontanelle, prominent occiput, hypoplasia of the right ear lobe, atresia of right external acoustic meatus, apparently low-set ears, and a left accessory ear lobe, cleft lip and palate, micrognathia, short neck, excess nuchal skin, hypoplasia of the nipples, funnel chest, small external genitalia, clinodactyly of the fifth fingers, and hypotonia. After death a t 5 months, autopsy showed valvular abnormal-
157
ities of the heart, membranous ventricular septal defect, ovarian cysts, and right hydronephrosis. Another child with a del6(p24-+p25) was described in a n abstract in 1983 [Reid et al., 19831. She was born a t 33 weeks gestation with hydrocephalus and a Dandy Walker cyst, clinical features of hypertelorism, corneal opacities, apparently low-set ears, preauricular tag, micrognathia, an ectopic anus, and a heart murmur. Normal Hageman factor levels were present in the child, suggesting that the region necessary for its expression to be localized to 6p23-+p24. Sachs et al. [1983] also published a brief description of a patient with del(6Xp22.2) in a report dealing with the localization of HLA. Anomalies included microphthalmos, nystagmus, unilateral cleft palate, low backwardly angulated ears, short neck with nuchal folds, hypoplastic nails, and rocker-bottom feet with abnormal “implantation”of the toes, a ventricular septal defect, insufficient ossification of the skull, and a large medial defect of the maxilla. More recently, there have been three clinical descriptions of individuals with deletions of 6p [Van Swaay et al., 1988; Clement et al., 1989; Jalal et al., 1989; Zurcher et al., 19901. Common clinical features of the del(6p) patients include mental retardation, a flat broad nasal bridge, and ear abnormalities [Van Swaay et al., 1988; Jalal et al., 1989; Zurcher et al., 19901. Only one child was reported to have eye abnormalities, a heart defect, and chest abnormalities [Van Swaay et al., 19881. Although the clinical findings were not remarkably different, this was also the only individual described to have a n interstitial deletion [de1(6)(p22.2p25.2)1.Clement et al. [1989] briefly report a de1(6)(p22.2)ascertained prenatally in a 26 week fetus which subsequently was stillborn a t 32 weeks of gestation. At autopsy, this stillborn infant had holoprosencephaly, hydrocephalus, cranial facial hypoplasia, hydronephrosis and polycystic kid-
Fig. 2. Deletion 6 ~ 2 3 - 6pter in patients 1 (a),2 (b),3 (c), 4 (d),and 5 (e).
nb
=
newborn; s b =
9/9 10/11 517 7112 11/12 619 9/10 516 515
618
719 919
1771
1521
9Fl5M
1
i =
+
c
-
=
+ + + + +
+ + + + +
+ +
died; m
t t
+ + + -
mi
months.
+
+ +
+
+
+ + +
+ + +
51 1751
3,510
4,120 [go] 54 [go]
3,374 1501 48.5 1251
2,794 1501 50 [751
F 6m
p23
4
M 6m
p23
3
M nb
p23
2
F 3m
P23
stillbirth; d
Microcephaly Mental retardation Abnormal sutures Eye abnormalities Flat broad nasal bridge Micrognathia Palatal abnormalities Ear abnormalities Abnormal genitalia Heart defect Short neck Pectus excavatum
Clinical findings Sex Age Birth weight (gm) [centilel Birth length (cm) [centilel
Breakpoints:
14
Total
This paper
t i
+
+
+
+
+
i
+
2,360 [I01
F d5m
+
+
t
+
+ +
no1
2,400
F 2,000 [501
F nb
+
+
+ +
-
+
+
-
t
M 3Y 3,960 [901 53.5 1751
p22.2 I p25.2
P24
p23
p22.2
Van Swaay [19881
Ouchi Sachs Reid [19821 119831 rig831
-
-
+ + -
+ + -
F 18y
p23
5
i
2,327 1901
F sb
p22.2
Clement f19891
+
+ +
F ~ O Y 3,070 [~OI 533 1951
p23
1
Kelly
$
+ +
Zurcher ~ 2 3
+
+
f
+ +
i
t
+ +
t
+
+
-
2Y 3,700 [851 53 [go1
F
P24
[19891 _ _ _ [19901
M M 2m 6~ 2,778 2,060 1251 131 53.3 42 1901 [31
p23
2
Jalal [19891
TABLE I. Comparison of the Common Clinical Findings in del(6p) and r(6) Patients
12 2 10 6
9 9
11 13 1
Ring 6 (15 cases) Chitayat 119871
Deletion 6p
neys, ascites, rocker-bottom feet, and cleft lip and palate. Parental karyotypes were normal in the above-described cases. Kelly et al. [19891provided the only report of a del 6p as a result of an unbalanced translocation. The clinical findings of this child are very similar to those of the del(6p) children. In the present report, four cytogenetic laboratories have independently identified a del(6p) in five patients referred for malformations and/or mental retardation. The common clinical findings of these five patients and the nine reported cases are summarized in Table I. The common deletion breakpoint is band p23 (9/14 cases), with the remaining five patients having breakpoints at p22.2 (three cases), p24 (two cases), and p25.2 (one case). Clinical features commonly reported in > 70% of the del(6p)cases include mental retardation, microcephaly, abnormal skull sutures, a flat broad nasal bridge, eye and ear abnormalities, pectus excavatum, and an apparently short neck with excess skin folds. Heart defects occur in 90% of the patients. Birth weight and length were generally normal. The only notable exception was the low birth weight and length associated with the del(6p) that was the result of an unbalanced translocation [Kelly et al., 19891. Clefts of the lip and/or palate were fairly common (4/12) with 3/12 cases described as having a highly arched palate. Although eye anomalies are fairly common in the del(6p) patients (9/9), there does not appear to be a single typical abnormality. The eye malformations included blepharophimosis, iris coloboma, microphthalmia, corneal opacification, Peters anomaly, optic atrophy, megalocornea, Brushfield spots, strabismus, nystagmus, and epicanthal folds. Ears were often described as low set, posteriorly angulated, and incompletely developed. There were also hypoplastic ear lobules, atresia of the external acoustic meatus, accessory ear lobes, and “crumpled” or folded ear lobes or incomplete outfolding of the ears. The heart defects varied and included atrial septal defect, ventricular septal defect, patent ductus, prominent pulmonary vessels on chest film, and abnormalities of the valves. Chest anomalies included hypoplasia of the nipples and pectus excavatum. Other reported abnormalities included umbilical hernia, short forehead, flat occiput, unusual hair pattern, ovarian cysts, and hydronephrosis. Hands were reported to demonstrate clinodactyly of the fifth finger and short terminal phalanges, in particular of the thumb, and several patients were reported to have nail dysplasia. Patients with ring 6 also lack a portion of 6p and therefore should have some clinical findings. The clinical findings in 15 cases of r(6) as summarized by Chitayat et al. [19871are also included in Table I for comparison. The common findings include hypertelorism, eye abnormalities, flat nasal bridge, and a short webbed neck. The frequent occurrence of eye abnormalities in patients with r(6) suggested to Chitayat et al. [19871 that a gene or genes located distally on 6p or 6q may influence the development of the iris. The clinical finding of eye abnormalities in the del(6p)patients appear to confirm the suggestion that such a gene is on distal 6p [Zurcher et al., 19901.
159
There are a number of genes localized to the p arm of chromosome 6. Early reports on del(6p)were concerned with the localization ofHLA [Magenis et al., 1978;Sachs et al., 19831. The HLA region is localized to 6~21.3. Loci of particular interest to the del(6p) patients are the fragile sites, fra(6Xp23) rare, folic-acid type, fra(6) ( ~ 2 5 . 1common, ) aphidocolin type, and fra(6)(p22)common aphidocolin type. Nine of the deletions in these patients occur at 6p23, the site of the rare fragile sites, and three at p22.2, with one having a second breakpoint at 6~25.2.In addition, all the deletion 6p cases arose de novo. This suggests a possible relationship of fragile sites to the occurrence of deletions previously proposed [Malthy and Higgins, 1987; Stallard et al., 1987; Voullair et al., 1987; Pettenati et al., 1988;Palmeret al., 19901. In addition, ring 6 breakpoints are most frequently located at 6p24 or 6p25 [Kini et al., 1979; Nishi et al., 1982; Peeden et al., 1983; Levin et al., 1986; Chitayat et al., 19871,with only one reported breakpoint at 6p23 or 24 [Carnevale et al., 19791.The origin of rings and deletions may differ with the more frequent occurrence of breaks leading to ring formation occurring during association of telomeres at meiotic prophase. The existence of true terminal deletions has often been questioned since the telomere, a structural component of each end of the chromosome, is necessary to prevent stickiness of chromosomes after breakage. Recent in situ evidence of the location of human telomeric repeat sequences interstitially in chromosome 2 at 2qll-q14 has raised the possibility that fragile sites may represent the location of interstitial telomeres [Hastie and Allshire, 19891.These authors also enumerate common properties of internal telomeric repeats and fragile sites such as recombogenicity, location of repeating stretches of C and T residues, and fragility and suggest that at least some fragile sites may be structurally similar to telomeres. If true, these observations could provide an explanation for the stability of terminal deletions and the location of such deletions at fragile sites as seen in the cases of the de1(6)(p23).
REFERENCES Carnevale A, Blanco B, Castillo V, Dominguez D (1979): Ringchromosome 6 in a child with minimal abnormalities. Am J Med Genet 4:271-277. Chitayat D, Hahm S, Iqbal MA, Nitowsky HM (1987): Ring chromosome 6: Report of a patient and literature review. Am J Med Genet 26:145-151. DeGrouchy J , Turleau C (1974):Tentative localization of a Hageman (Factor XII) locus on 7q, probably the 7q35 band. Hum Genet 24:197-200. DeGrouchy J, Veslot J, Bonnette J , Roidot M (1968): A case of ?6p chromosomal aberration. Am J Dis Child 115:93-99. Hastie ND, Allshire RC (19891: Human telomeres: Fusion and interstitial sites. TIG 5:326-330. Ikeuchi T (1984): Inhibitory effect of ethidium bromide on mitotic chromosomal condensation and its application to high-resolution chromosome banding. Cytogenet Cell Genet 38:56-61. Jalal SM, Macias VR, Roop H, Morgan F, King P (1989):Two rare cases of 6p partial deletion. Clin Genet 36:196-199. Kelly PC, Blake WW, Davis J R (1989): Tandem Y/6 translocation with partial deletion 6(p23+ pter). Clin Genet 36:204-207. Kini KR, Van Dyke DL, Weiss L, Logan MS (1979):Ring chromosome 6: Case report and review of literature. Hum Genet 50:145-149.
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Levin H, Ritch R, Barathur R, Dunn MW, Teekhasaenee C, Margolis S (1986): Brief clinical report: Aniridia, congenital glaucoma, and hydrocephalus in a male infant with ring chromosome 6. Am J Med Genet 26:281-287. Magenis RE, Chamberlin J, Overton K, Lovrien E (1978): Linkage relationships of HLA and a familial chromosome 6 inversion (pter- p23::q23-p23::q23+ qter): Lack of dose effect in duplication-deficient offspring. Cytogenet Cell Genet 22418-420. Maltby EL, Higgins S (1987):Folate sensitive fragile site a t 10q23 and its expression as a deletion. J Med Genet 24:299. Nishi Y, Yoshimura 0, Ohama K, Usui T (1982):Ring chromosome 6: Case report and review. Am J Med Genet 12:109-114. Ouchi K, Kasai R (1982): A case of partial monosomy 6p. Jpn J Hum Genet 27214. Palmer CG, Heerema NA, Bull M (1990): Deletions in chromosome 2 and fragile sites. Am J Med Genet 36214-218. Peeden J N , Scarbrough P, Taysi K, Wilroy RS, Finley S, Luthardt F, Martens P, Howard-Peebles PN (1983): Ring chromosome 6: Variability in phenotypic expression. Am J Med Genet 16563-573. Pettenati MJ, McNay JW, Hayworth R, Sherman SL (1988):Support-
ing evidence of a role for common fragile sites in constitutional abnormalities. Am J Hum Genet 43:A177. Reid CS, Stamberg J , Phillips JA (1983):Monosomy for distal segment 6p: Clinical description and use in localizing a region important for expression of Hageman factor. Pediatr Res 17:A217. Sachs ES, Hoogeboom AJ, Niermeijer MF, Schreuder GM (1983):Clinical evidence for localisation of HLA proximal of chromosome 6p22. Lancet 1:659. Schroer R J , Culp DM, Stevenson RE, Potts WE, Taylor HA, Simensen RJ (1980): Duplication-deletion syndrome in a family with pericentric inversion of chromosome 6. Clin Genet 18:83-87. Stallard R, Dickerman L, Johnson W (19871: A fragile site on 2p promoting dup(Z)(pll+pter). Am J Hum Genet 41:A146. Van Swaay E , Beverstock GC, VandeKamp JJ (1988):A patient with an interstitial deletion of the short arm of chromosome 6. Clin Genet 33:95-101. Voullaire LE, Webb GC, Leversha MA (1987): Chromosome deletion at l l q 2 3 in a n abnormal child from a family with inherited fragility at llq23. Hum Genet 76:202-204. Zurcher VL, Golden WL, Zinn AB (1990): Distal deletion of the short arm of chromosome 6. Am J Med Genet 35:261-265.
