American Journal of Medical Genetics 43:747-750 (1992)

Two Patients With Chromosome 6q Terminal Deletions With Breakpoints at q24.3 and q25.3 Jianguo Meng, Hiroko Fyjita, Noboru Nagahara, Akira Kashiwai, Yasushi Yoshioka, and Masahisa Funato Department of Human Development and Welfare, Osaka City University (J.M., HP.),Department of Surgery, Children’s Medical Center of Osaka City (N.N., A X . ) , and Department of Pediatrics, Yodogawa Christian Hospital (Y.Y., M P . ) , Osaka, Japan ~

~~

We report on 2 patients with de novo terminal deletion of 6q. The first was a 4-month-oldboy whose karyotype was 46, XY, del(6Mq24.3);the second a 2-year-oldgirl whose karyotype was 46, XX, del(6Mq25.3). The main anomalies in both patients included mental retardation, minor craniofacial and cerebral anomalies, and cardiac defects. The characteristic manifestations were imperforate anus in the first patient, and retinitis proliferans and a triatrial heart in the other. Comparison of clinical findings of our 2 patients with those of 18 previously reported patients with similar phenotypes suggests that terminal deletion of the 6q23 or 6q25 band is critical in producing the main anomalies of del(6q) syndrome. o 1992 wiley-Liss, Inc.

KEY WORDS 6q terminal deletion syndrome, imperforate anus, retinitis proliferans, triatrial heart INTRODUCTION Terminal deletion of 6q was first reported by Mikkelsen et al. 119731. Here, we report on 2 additional Japanese patients with terminal deletions of chromosome 6; one patient had a deletion from 6q24.3 t o qter, and the second patient had a deletion from 6q25.3 to qter. We compare the clinical findings in the 2 patients with those of previously reported patients and discuss the correlations between the portion deleted and the phenotypical abnormalities found. CLINICAL REPORTS Patient 1 Patient 1, a 4-month-old boy (Fig. 11, was the second son of a 25-year-old mother and 31-year-oldfather. Both Received for publication July 5,1991;revision received September 30, 1991. Address reprint requests to Dr. Hiroko Fbjita, Department of Human Development and Welfare, Osaka City University, Sugimotocho 3-3-138, Osaka 558, Japan.

0 1992 Wiley-Liss, Inc.

parents were normal. Their elder son also was healthy. The patient was born at 39 weeks of gestation. Delivery was normal, but the infant had asphyxia. The weight at birth was 2,220 g, length 44 cm, and head circumference (OFC)30.8 cm. Apgar scores were 7 and 9 at 1 and 5 minutes, respectively. At birth, the patient was found to have an imperforate anus, for which a transverse colostomy was done. The infant was examined a t 3 months after he had a seizure. His weight was 2,734 g, length 46.6 cm, and OFC 33.0 cm. Some of his sparse hair was white. He had downturned palpebral fissures, hypertelorism, anteverted nostrils, low nasal root, long upper lip, highly arched palate, cleft soft palate, large and apparently low-set ears, preauriclar tags, and micrognathia. The neck was short and webbed. The patient also had a broad chest, widely spaced nipples, cryptorchidism, stubby hands with proximally set thumbs, simian creases, rocker-bottom feet, and hypotonia. There was a skin tag in the processus xiphoideus of the sternum. Echocardiography showed a ventricular septa1defect and patent ductus arteriosus. CT scan of the brain showed absence of the corpus callosum. The results of routine laboratory tests were normal.

Patient 2 Patient 2, a 2-year-old girl (Fig. 21, was born at 41 weeks of gestation, the first child of healthy parents who were both 23 years old. The family history was unremarkable. The weight at birth was 1,800g. Immediately after birth, a grade 213 systolic murmur in the left second intercostal space was detected. A cleft soft palate and hypotonia were also noted at birth. At age 6 months, the patient was referred for chromosome studies because of syndromal mental retardation. Findings from a physical examination included trigonocephaly, a prominent forehead, long upper lip, epicanthus, high-arched palate, broad nasal root, large and apparently low-set ears, and micrognathia. In addition, a webbed neck, a shield chest, and widely spaced nipples were noted. The patient also had scoliosis, a small pelvis, and hypertrichosis. An ophthalmic examination showed bilateral retinitis proliferans, which was treated. Echocardiography indicated the presence of a

748

Meng et al. triatrial heart with a complete atrioventricularis communis, and pulmonary hypertension was detected by ultrasonography. CT scan of the brain showed asymmetric dilation of the lateral ventricles. In the most recent evaluation of the patient at age 2 years, her weight was 5.73 kg and height was 61.2 cm. Mental and developmental retardation were severe. The patient could not lift her head.

Cytogenetic Findings Cytogenetic analysis of cultured peripheral lymphocytes was performed with a standard high-resolution GTG banding pattern. Patient 1had a karyotype of 46, XY, del(6) (~24.31, and patient 2 had a karyotype of 46, XX, del(6) (q25.3).The partial karyotypes from different cells of patients 1 and 2 are shown in Figure 3. Prometaphase chromosome studies of all of the parents gave normal results. DISCUSSION Terminal deletions of 6q are rare. Including the 2 patients presented here, a total of 20 individuals have been reported with terminal deletions of 6q. Table I compares the main clinical manifestations in our 2 patients with those of 18 previously reported patients. Depending on the breakpoints, patients with deletions of terminal 6q were divided into 4 groups: (1)2 patients with a 6q21 to qter deletion [Chery et al., 1989;lto et al., 19891 and one patient with a 6q22.1 to qter deletion [Dallapiccola et al., 19781; (2) 4 patients with a 6q23 to qter deletion [Kueppers et al., 1977; Fryns et al., 1986; Goldberg et al., 1980; Shen-Schwarz et al., 19891;(3) our patient 1with a 6q24.3 to qter deletion and our patient 2

1

Fig. 1. Patient 1 at age 4 months.

’ ii

6q24 3

6q25 3

I

I

6

Fig. 2. Patient 2 at age 2 years.

Fig. 3. High-resolution GTG banding pattern showing terminal deletions of the long arm of chromosome 6. (1)Deletion 46, XY, del(6) (q24.3) in patient 1. (2) Deletion 46, XX, del(6) (q25.3) in patient 2.

Terminal Deletion 6q

749

TABLE I. Clinical Findings in Patients with Deletion of Terminal 6q

Group 1 Breakpoint q21 or q221 Sex (&,PI 36 Mental retardation 3 Main abnormalities 3 Microcephaly Retinal abnormalities 0 Strabismus 1 Hypertelorism 2 Epicanthic folds 0 Downturned palpebral fissures 2 Broad, prominent nasal bridge 2 Malformed ears 3 Apparently low-set ears 3 2 Long philtrum High arched palate 2 Cleft palate, cleft lip 1 Downturned mouth 3 Micrognathia or retrognathia 2 1 Short neck Abnominal wall, genital hernias 0 Cryptorchidism 1 Hand and foot abnormalities 2 2 Abnormal palmar crease 3 Hypotonia 1 Joint myotonia Abnormalities of internal organs 0 Respiratory tract abnormalities 1 Digestive tract abnormalities Urinary abnormalities 0 2 Congenital heart defect Cerebral abnormalities 1 Seizures 1

2 q23

q24.3"

3819 4

16 1

2 0 0 0 4 0 2 3 3 2 0 2 1 3 2 1 1 3 1 1

1 1

1

2 1 1 2 1 2

3 q25.3b 19 1

4 q25 - q26 4659 1 6 1 9 9 2 ~

0 0 1

1 0 0 1 1 1 1 1 1 1 0 1 1 1

1 0 1 1 1 1 1

1 0 0 1 1 1 1

5 4 4 1 4 6 8 4 4 7 4 5 3

0

0 0 0 1 1 1

1 1 1 4 1 3

0 1

1 1 1 1 1 1 1

1 0 1 1 1

9 2 6 1 5 1

8 8

Total

Frequency, %

12889 20120

1:0.66 100

2 2 2 0 1 1 1 0 0 1 1 0 0 1 1 0 0 0 0 1 0

18/20 5/20 9/20 5/20 12/20 6/20 15/20 16/20 13/20 11/20 8/20 5/20 9/20 14/20 14/20 5/20 7/12 14/20 9/20 12/20 7/20

90 25 45 25 60 30 75 80 65 55 40 25 45 70 70 25 58 70 45 60 35

0 0 0 1 0 1

3/20 4/20 2/20 11/20 5/20 9/20

15 20 10 55 25 45

"Patient 1. bPatient 2.

with a 6q25.3 to qter deletion together with 9 similar previously reported cases [Mikkelsen and Dyggve, 1973; MilogeviE and KaliEanin, 1975;Bartoshesky et al., 1978; Liberfarb et al., 1978; Rivas et al., 1986; Stevens et al., 1988 (2 cases); Oliveira-Duarte et al., 1990 (2 cases)]; and (4) 2 patients with a 6q26 to qter deletion [Hagemeijer et al., 1977;McLeod et al., 19901. The sex ratio was 12 males:8 females. Most of these patients were born a t term. The deaths of 3 patients, one female and 2 male, were reported. Two of the patients died in infancy because of the cerebral anomaly and congenital heart defects [Shen-Schwarzet al., 19891,or a perforating duodenal ulcer [Ito et al., 19891. One patient died at age 52 years because of mucopurulent tracheobronchitis [Mikkelsen and Dyggve, 19731. In all groups, mental retardation, growth deficiency, microcephaly, broad nasal bridge, epicanthus, apparently low-set ears, short neck, cryptorchidism, abnormal hands and feet, and hypotonia were common manifestations. In groups 2 and 3, internal defects were the most frequent findings. These defects are discussed below. Congenital heart defects. Found in both of our patients and in most of the patients of groups 2 and 3. Patient 2 had a triatrial heart, which is rare and to our knowledge not reported before in association with 6q deletions. Most of the heart anomalies were ventricular

septa1defects and patent ductus arteriosus. Other kinds of reported cardiac defects included a partial anomalous pulmonary venous return [Goldberg et al., 19801,a double outlet right ventricles [Liberfarb et al., 19781, and atrioventricular canal [Shen-Schwarz et al., 19891. Retinitisproliferans. Found in our patient 2 and in 3 other patients with deletions of distal bands 6q25 or 6q26, including bilateral oval areas of macular degeneration [Hagemeijer et al., 19771, a crescent-shape hypopigmented area traversing the macula [Rivas et al., 19861,and a nonspecific retinal abnormality [McLeod et al., 19901. Recently, a genetic cone dystrophy was tentatively assigned to 6q27 to qter [Rivas et al., 1986; Tranebjaerg et al., 19861. This suggests that deficiency of the distal portion of 6q is associated with retinal abnormalities. Imperforate anus. Found in our patient 1. McLeod et al. [1990] reported a 2-year-old patient with an interstitial deletion of 6q23 to 6q25, who had anus defect and extreme hyperextensibility of the skin. Other abnormalities of the digestive system included bilateral diaphragmatic hernias [Shen-Schwarz et al., 19891 and hemangioendothelioma of the liver [Ito et al., 19891. Brain anomalies. Found in both of our patients. The corpus callosum was absent in patient 1,and there was asymmetric dilation of the lateral ventricles in patient 2. Other reported cerebral malformations included

750

Meng et al.

pseudocystic cavities in the brain [Rivas et al., 1986; Chery et al., 19891, agenesis of the corpus callosum, a large nuchal cyst, and absence of olfactory bulbs [ShenSchwarz et al., 19891. Respiratory disease. Found in 3 patients. Two of these patients with terminal deletions of 6q23 had laryngeal stenosis [Kueppers et al., 19771 and pulmonary hypoplasia [Shen-Schwarz et al., 19891. The remaining patient with terminal deletion of 6q25 had choanal atresia [Liberfarb et al., 19781. Urological anomalies. Found in 2 patients with terminal deletions of 6q25; the anomalies were bladder neck obstruction, cystic kidneys [MiloSeviE and KaliEanin, 19751,and renal dysplasia [Shen-Schwarzet al., 19891. Cervical cystic hygroma was found in one patient with a distal 6q23 deletion [Fryns et al., 19861. Thirteen patients had de nouo terminal deletions of 6q and 7 had additional chromosome aberrations. Four of these were associated with de nouo translocations: t(6;15) (q25;q12) [Mikkelsen and Dyggve, 19731, t(X;6) (p21;q26) [Hagemeijer et al., 19771, t(5;6) (q22;q23.3) [F’ryns et al., 19861, and t(6;7) (q25;q22) [Stevens et al., 19881. The 3 other patients had relatives with abnormalities: one patient had monosomy of 6q23 to qter resulting from a balanced translocation of iris(3;6) (p13;q21q27)in both her mother and maternal grandmother [Kueppers et al., 19771. Two of these patients, who were half-sisters, had a distal deletion of 6q25 inherited because of maternal translocation t(6;17) (q25;q25) [Oliveira-Duarte et al., 19901. Finally, the relationships between chromosome aberrations and the phenotypic anomalies in all groups were clear. Karyotype-phenotype comparison suggested that the breakpoints occurred most frequently at positions 6q23 and 6q25 (groups 2 and 3). Distal deletion of 6q26 (group 4) may cause minor congenital anomalies, including retinal abnormalies. Distal deletion of 6q23 or 6q25 may produce various major manifestations such as malformations of the eye, internal organs, and brain. Therefore, based on these typical clinical findings, we conclude that distal deletion of band q23 or q25 may possibly constitute 6q terminal deletion syndrome.

ACKNOWLEDGMENTS We thank Mrs. N. Totuka and Mrs. F. Ishii, Mitsubishi Yuka Bio-Clinical Laboratories Inc., for their helpful technical assistance in cell culturing. We also thank Dr. J.M. Opitz, professor at Shodair Children’s Hospital, and Dr. A. Niikawa, professor at Nagasaki

University School of Medicine, for their review of this manuscript.

REFERENCES Bartoshesky L, Lewis MB, Pashayan HM (1978): Developmental abnormalities associated with long arm deletion of chromosome No. 6. Clin Genet 13:68-71. Chery M, Formiga LdeF, Mujica P, Andre M, Stehelin D, Dozier C, Gilgenkrantz S (1989): Interstitial deletion of the long arm of chromosome 6. Ann Genet 32:82-86. Dallapiccola B, Bricarelli FD, Quartino AR, Mazzilli MC, Chisci R, Gandini E (1978):Delineation of syndromesdue to partial 6q imbalances: Trisomy 6q2l+qter and monosomy 6q221-qter in two unrelated patients. Acta Genet Med Gemellol 2757-66. Fryns J-P, Bettens W, Van den Berghe H (1986):Distal deletion of the long arm of chromosome 6: A specific phenotype? Am J Med Genet 24:175-178. Goldberg R, Fish B, Ship A, Shprintzen FLJ (1980):Deletion of a portion of the long arm of chromosome 6. Am J Med Genet 5:73-80. Hagemeijer A, Hoovers J, Smit EME, Bootsma D (1977): Replication pattern of the X chromosomes in three Xiautosomal translocations. Cytogenet Cell Genet 18:333-348. Ito H, Yamasaki T, Okamoto 0, Tahara E (1989): Infantile hemangioendothelioma of the liver in patient with interstitial deletion of chromosome 6q: Report of an autopsy case. Am J Med Genet 34:325-329. Kueppers F, Dewald G, Gordon H, Pineda A (1977): Exclusion of the HLA locus from a large portion of the long arm of chromosome 6. Hum Hered 27:242-246. Liberfarb RM, Atkins L, Holmes LB (1978): Chromosome 6q- and associated malformations. Ann Genet 21:223-225. McLeod DR, Fowlow SB, Robertson A, Samcoe D, Burgess I, Hoo JJ (1990): Chromosome 6q deletions: A report of two additional cases and a review of the literature. Am J Med Genet 35:79-84. Mikkelsen M, Dyggve H (1973): (6;15)’Pranslocationwith loss of chromosome material in the patient and various chromosome aberrations in family members. Humangenetik 18:195-202. MiloseviE J, KaliEanin P (1975): Long arm deletion ofchromosome No. 6 in a mentally retarded boy with multiple physical malformations.J Ment Defic Res 19:139-144. Oliveira-Duarte M-H, Martelli-Soares LR, Sarquis-Cintra T, Machado ML, Lison MP (1990):Distal monosomy of the long arm of chromosome 6 (6q25-6qter) inherited by maternal translocation t(6q;17q). Ann Genet 33:56-59. Rivas F, Ruiz C, Rivera H, Moller M, Serrano-Lucas JI, Cantu JM (1986): De novo del(6Kq25) associated with macular degeneration. Ann Genet 29:42-44. Shen-Schwarz S, Hill LM, Surti U, Marchese S (1989): Deletion of terminal portion of 6q: Report of a case with unusual malformations. Am J Med Genet 32:81-86. Stevens CA, Fineman RM, Breg WR, Silken AB (1988): Report of two cases of distal deletion of the long arm of chromosome 6. Am J Med Genet 292307-814. ’Pranebjaerg L, Sjo 0,Warburg M (1986): Retinal cone dysfunction with a de novo balanced translocation 1;6 (q44;q27). Ophthalmic Paediatrics Genetics 7:167-173.

Two patients with chromosome 6q terminal deletions with breakpoints at q24.3 and q25.3.

We report on 2 patients with de novo terminal deletion of 6q. The first was a 4-month-old boy whose karyotype was 46,XY,del(6)(q24.3); the second a 2-...
428KB Sizes 0 Downloads 0 Views