Ring chromosome 14 as a distinct clinical

syndrome: a case report

Rong Li, Zheng-Yan Zhao, Li-Ying Sun and Xing-Bao Chen

Hangzhou, China

Author Affiliations: Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China (Li R, Zhao ZY, Sun LY and Chen XB)

Corresponding Author: Rong Li, MD, Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China (Tel: 86-571- 87061007 ext 2428; Fax: 86-571-87033296; Email: chebk@zju.edu.cn)

Background: The clinical features of ring chromo-some 14 and its possible relationship with severe growth retardation were studied.

Methods: Chromosome high-resolution G banding analysis on cultures at 550 band level of skin biopsy specimen and peripheral blood lymphocytes in patients with mental retardation at this hospital revealed a case of mosaicism of ring chromosome 14 (p11.2; q32.3), chromosome monosomy 14. The reported cases of ring 14 were analyzed.

Results: Ring chromosome 14 was detected in a 18-month-old female infant with severe growth retardation, seizure and minor abnormal craniofacial features including scaphocephaly and microcephalic, low-set ears, elongated face, short palpebral fissures, prominent nasal bridge, micrognathia, high palate, and short neck. Cells from skin fibroblasts showed that 50% cell line with 46, XX, r(14) and 50% with 45, XX, -14, had a 46, XX, r(14) (p11.2-q32.2)/45, XX, -14 karyotype.

Conclusions: Patients with ring 14 are characterized by mental retardation, seizures, microcephaly, low set ears, short palpebral fissure, depressed nasal bridge, shot neck, and retinal pigmentation. The seizure was a unique feature of ring chromosome 14; mental retardation, severe seizure, and abnormal facial features should be evaluated cytogenetically to rule out the appearance of ring chromosome 14. The amount of genetic material can be deleted from chromosome 14. The ring instability leading to aneusomy and the position effect of a telomere on ring chromosome determine the physical abnormalities and manifestations of ring chromosome 14. The structural and behavioral instability of a ring chromosome give rise to high proportion of secondary aneuploid, resulting in more severe growth retardation.

Key words: chromosomal anomaly; ring chromosome 14; seizure; psychomotor developmental delay

                    World J Pediatr 2006;1:72-75

Introduction

More than 40 patients with ring chromosome 14 have been reported since the description by Gilgenkrantz et al in 1971.[1-3] Cases of ring 14 chromosome have been associated with a special clinical syndrome. The typical manifestations of the disease include mental deficiency, seizures, retinal dysplasia, and few minor facial anomalies. Postnatal growth retardation was seen in nearly 50% of the reported cases.[3-5] We present a female infant with extreme somatic retardation and mild psychomotor retardation, in whom mosaicism of ring chromosome 14 and chromosome monosomy 14 were found.

Case report

The patient was an 18-month-old female infant who was referred to this hospital at age of one month old because of prematurity, small for gestational age (SGA) and dysmorphism. She was born normally at term after an uncomplicated pregnancy to a 26-year-old mother and unrelated 29-year-old father. Her birth weight (2.24 kg), length (47 cm), and head circumference (OFC) (32 cm) were corrected for gestational age at the <5th, 10th, and 5th, respectively. There was no prenatal exposure to alcohol, drug or tobacco. The infant had poor weight gain, slow linear growth, and slow head growth. Epilepsy was not found up to 5 months. Tonic clonic episode involved the upper and lower extremities, lasting 2-3 seconds.

She had scaphocephaly and microcephalic, low-set ears, elongated face, short palpebral fissures, prominent nasal bridge, micrognathia, high palate, and short neck on physical examination. Transverse palmar crease was seen on her left palm. Her fingers look slender and tapered, and she had dry skin, excessive skin folds, yellowish brown scaly areas on both legs and her back.

Routine laboratory tests showed normal serum and urine metabolic levels. At 3-month-old, magnetic resonance imaging of the brain revealed hypoplasia of the corpus callosum. Ocular examination showed nothing retinal pigmentation. No defect of the heart and other organs was detected.

Her family history was not exceptional; her parent had a normal phenotype.

Chromosome high-resolution G banding in cultures of skin biopsy and peripheral blood lymphocytes revealed a 46, XX, r(14) (p11.2-q32.2)/45, XX, -14 karyotype. The breakpoints were at bands p11.2 and q32.3. Fifty-two cells were analyzed (32 fibroblasts and 20 lymphocytes); 18 fibroblasts and 15 lymphocytes had a chromosome constitution 46, XX, r(14). Fourteen fibroblasts and 5 lymphocytes had 45 chromosomes and lacked the ring (Fig.). Normal cell line was not observed in the cultures. The karyotypes of the parents were normal.

Discussion

In this 18-month-old infant with de vono ring chromosome 14, both peripheral lymphocytes and skin fibroblast cultures were mosaic with two cell lines: one contained ring chromosome 14 and the other was monosomic for chromosome 14. A 45, XX, -14 pattern was found in 50% of the cell lines. Such a high proportion of the monosomy 14 cell line was not reported previously. Growth retardation was significant in this patient.

Morphologic features of ring chromosome 14 included scaphocephaly, microcephalic low-set ears, elongated face, short palpebral fissures, prominent nasal bridge, micrognathia, high palate, short neck, and delayed development.

As other specific chromosome abnormalities, manifestations of individual cases varied. In patients with r(14), common clinical manifestations included delayed development, intrauterine and postnatal growth retardation, microcephaly, dolichocephaly, high forehead, narrow palpebral fissures, epicanthus, broad nasal bridge, high arched palate, short neck, hypotonia, seizures, and retinal abnormalities. Other associated abnormalities were cutaneous pigment change and focal cerebral atrophy.[1-3]

In some reports, mild-to-moderate mental retar-dation was present in the patients except 3. Two exceptions were mothers with the disorder, who were patients with ring 14 syndrome. In both families, the inheritance of ring 14 was demonstrated, and two of them showed intelligence at the lower end of the normal range.[1,2] Major congenital malformation was relatively uncommon in ring 14, except one patient with congenital heart defects,[6] instead seizure and retinal pigment were the findings which were closely relevant to the reported cases. All patients described in the literatures with two exceptions[1,7] demonstrated epileptic seizure. In most cases, the onset of seizure tended to appear at age of 6 to 10 months. In our case, ocular manifestations such as pigmentation of the retinal and macular area, pale optic fundus and aplasia of the retina have been described in sporadic reports.[6,8-12] The lesions of the central nervous system include hydrocephaly, cerebellar hypoplasia,[6,9,10,13-15] corpus callosum hypoplasia,[16] cortical atrophy of the cerebrum,[12] and porencephaly.[7]

Ring chromosomes are specific deletion chromo-somes. The classic mechanism of ring formation is breakage in both arms of a chromosome followed by fusion of the two broken arms and loss of the distal segments. Therefore, phenotypic abnormalities associated with partial deletions can be found in patients with ring chromosomes.[17] It is reported that the manifestations of ring chromosome 14 contribute to the terminal deletion of long arm, most probably distal to band 14q32.[7] It is speculated that the amount of genetic material deleted from chromosome 14 determines the degree of physical abnormalities and mental retardation. Ring chromosome is subjected to various difficulties at mitosis. The normal occurrence of sister chromatid exchanges in a ring constantly produces secondary aneuploid cells with serious genetic imbalance that are less likely to survive. The process leads to death of cells and subsequent growth deficiency in patients with ring chromosome constitutions.[18] Growth failure is present significantly in more patients with a "labile" ring than in those with a "stable" ring, indicating that a correlation may exist between ring instability and growth failure.[19] In our case, the mosaicism associated with instability of a ring chromosome gave rise to cells with loss of 50% ring chromosomes, causing more severe growth retardation.

It has been noticed that a striking difference exists in the occurrence of seizure and retinitis pigmentosa between ring 14 syndrome and linear terminal deletion of 14q with similar breakpoints. But 4 cases reported elsewhere showed that r(14) with complete ring without major band deletion[12,13] presented seizure.[20,21]

It is believed that ring chromosome 14 has some other genetic factors to cause special clinical features. A telomere position effect in ring chromosome may result in reversible silence of nearby gene(s). In the novel spatial configuration that occurs in a ring chromosome 14, the telomere of the p-arm may cause a decrease in the expression of gene(s) on the adjacent 14q-arm.[3, 21-23]

The varying clinical presentations of r(14) of published cases may be explained by varied breakpoints, the different amount of deletion genetic material, and mitotic instability of ring chromosome, which result in different degrees of aneuploidy and a telomere position effect.

Ethical approval: This study was approved by the data inspectorate of China and by the local committee for medical research ethics.

Competing interest: None declared.

Contributors: LR wrote the first draft of this paper. All authors contributed to the intellectual content and approved the final version. ZZY is the guarantor.

References

1   Matalon R, Supple P, Wyandt H, Rosenthal IM. Transmission of ring 14 chromosome from mother to two sons. Am J Med Genet 1990;36:381-385.

2   Zelante L, Torricelli F, Calvano S, Mingarelli R, Dallapiccola B. Ring chromosome 14 syndrome. Report of two cases, including extended evaluation of a previously reported patient and review. Ann Genet 1991;34:93-97.

3   van Karnebeek CD, Quik S, Sluijter S, Hulsbeek MM, Hoovers JM, Hennekam RC. Further delineation of the chromosome 14q terminal deletion syndrome. Am J Med Genet 2002;110: 65-72.

4   Meschede D, Exeler R, Wittwer B, Horst J. Submicroscopic deletion in 14q32.3 through a de novo tandem translocation between 14q and 21p. Am J Med Genet 1998;80:443-447.

5   Krawczun M, Melink G, Cervenka J. Ring chromosome 14 and immunoglobulin locus. Am J Med Genet 1984;17:465-469.

6   Amarose AP, Dorus E, Huttenlocher PR, Csaszar S. A ring 14 chromosome with deleted short arm. Hum Genet 1980;54: 145-147. 

7   Fryns JP, Kubien E, Kleczkowska A, Nawrocka-Kanska B, Van den Berghe H. Ring chromosome 14: a distinct clinical entity. J Genet Hum 1983;31:367-375.

8   Howard PJ, Clark D, Dearlove J. Retinal/macular pigmentation in conjunction with ring 14 chromosome. Hum Genet 1988;80: 140-142.

9   Portoian-Shuhaiber S, Al-Awadi S, Farag TI, Sundareshan TS, Jindal HR, Al-Rashied AA. Clinical findings in an Arab boy with ring (14) (mos 46, XY, r(14)/45, XY, -14). Ann Genet 1986;29:122-124.

10 Vekemans M, Watters G, Tsipouras P, Bourrouilh H. Ring chromosome 14 identified by banding techniques. Am J Hum Genet 1978;31:115A.

11 Iselius L, Ritzen M, Bui TH, Olsson K, Eklof O. Ring chromosome 14 in a mentally retarded girl. Acta Pediatr Scand 1980;69:803-806.

12 Lippe BM, Sparkes RS. Ring 14 chromosome: association with seizures. Am J Med Genet 1981;9:301-305.

13 Riley SB, Buckton KE, Ratcliffe SG, Syme J. Inheritance of a ring 14 chromosome. J Med Genet 1980;18:209-213.

14 Triolo O, Serra A, Bova R, Carlo Stella N, Caruso P. Infant male with ring chromosome 14. Ann Genet 1981;24:236-238.

15 Schmidt R, Eviatar L, Nitowsky HM, Wong M, Miranda S. Ring chromosome 14: a distinct clinical entity. J Med Genet 1981;18:304-307.

16 Ono J, Nishiike K, Imai K, Otani K, Okada S. Ring chromosome 14 complicated with complex partial seizures and hypoplastic corpus callosum. Pediatr Neurol 1999;20:70-72.

17 Kosztolanyi G. Does "ring syndrome" exist? An analysis of 207 case reports on patients with a ring autosome. Hum Genet 1987;75:174-179.

18 Kjessler B, Gustavson KH, Wigertz A. Apparently non-deleted ring-1 chromosome and extreme growth failure in a mentally retarded girl. Clin Genet 1978;14:8-15.

19 Kosztolanyi G, Pap M. Severe growth failure associated with atrophic intestinal mucosa and ring chromosome 15. Acta Pediatr Scand 1986;75:326-331.

20 Kristensen I, Wieg C, Friedrich UK. The ring chromosome 14 syndrome. Ugeskr Laeger 1992;154:3248-3249.

21 Sigurdardottir S, Goodman BK, Rutberg J, Thomas GH, Jabs EW, Geraghty MT. Clinical, cytogenetic, and fluorescence in situ hybridization findings in two cases of "complete ring" syndrome. Am J Med Genet 1999;87:384-390.

22 Wintle RF, Costa T, Haslam RH, Teshima IE, Cox DW. Molecular analysis redefines three human chromosome 14 deletions. Hum Genet 1995;95:495-500.

23 Yen FS, Podruch PE, Weisskopf B. A terminal deletion (14) (q31.1) in a child with microcephaly, narrow palate, gingival hypertrophy, protuberant ears, and mild mental retardation. J Med Genet 1989;26:130-133.

Received August 2, 2005; Accepted after revision November 30, 2005