PEDIATRIC DENTISTRY/Copyright -~ 1981 byThe American Academy of Pedodontics/Vol. 3, No. 4 CASE

Ring chromosome 5 with dental anomalies

Katherine Kula, DMD Shivanand Patil, PhDJames Hanson, MD Arthur Nowak, DMD Hans Zellweger, MD

AbstractAlthough ring chromosomes are observed in ahnost all

autosomal groups in man, they are rare. We describe a malepatient exldbiting cd du chat syndrome in whichcytogenetic studies demonstrate the presonse of a ringchromosome 5. Deletion o£ the ring chromosome 5 is foundbetween the p15 and q35 bands. Dental, medical andcytogenetic findings are compared to other ring chromosome5 cases descMbed in literature.

IntroduetionCri du chat syndrome, first described in 1963,~ is

characterized by a shrill high cry similar to that of ayoung cat. The cry is attributed to a hypotonic, dys-morphic larynx noted in some patients. ~ The cry maynot be pathognomonic of the syndrome since it is ab-sent in some patients and is reported in other chromo-somal abnormalities?

The following traits may be found during infancy:~,~

microcephaly, round facies, apparent ocular hypertel-orism, downward slant of palpebral fissures, epican-

thal folds, low-set posteriorly angt}.lated ears, preauri-cular tags, micrognathia/retrognathia, prominentnasal bridge, muscular hypotonia, congenital defectsof heart and genitourinary tract, abnormal dermato-glyphic findings, short metacarpals or metatarsals,and "dysmorphic" hips. Various characteristicschange with age. The faces becomes thin and asym-metric?.7 Hypotonia disappearg,8 and hyperactive re-flexes develop? The cry usually disappears or changeschaxacter,ml Hypertelorism and micrognathia are notas apparent. Older patients may exhibit prematuregreying, optic atrophy, strabismus, scoliosis, smallwings of the ilia, large frontal sinuses, and awkward,shuffling gaits.7 Almost all cases exhibit severe mental,growth, and motor retardation. ~° Breg et alJ reportdental malocclusions in adults consisting of micro-gnathia, flaring of anterior teeth, overbite, openbiteand local malalignments. Analysis of patients’ picturesindicates Breg probably used the term overbite to de-scribe marked overjet. The presence of high archedpalate is variableY Premature eruption of second per-

manent molars is reported in one case2Although some patients survive to adulthood),~

most patients die in infancy due to severe respiratoryand feeding problems2

Diagnosis is based on clinical features, abnormalcrying during infancy, chromosomal studies, and der-matoglyphic features. Diagnosis based soley on clini-cal features is difficult in some cases due to phenoty-pic variability and to characteristics changing withage. Clinical features are used, however, as indicationsfor confLrmatory chromosomal studiesY

Cri du chat syndrome is usually attributed to a par-tial deletion, either terminal or interstitial, of theshort arm of chromosome 57 in the area of p14 to p15band?~ The most commonly reported cause is de novodeletion occurring in approximately 85 percent of thecases,m~ There are eight reported cases of ring chromo-some 5.u,l~

Ring chromosomes result when deletions occur atthe proximal and distal ends of the chromosome andthe two broken ends fuse.1~ Rings may not be presentin all cells of affected individuals, may break intosmaller pieces (ring products), or may contain morethan one centromereY Rings that look alike may notbe alike due to different amounts of chromosomaldeletions.~

Phenotype may be affected by the presence andstability of a ring,~ the translocation of chromosome5 segments to other chromosomes)~.~ the translocationof other chromosomes onto chromosome 5, ~ or byvarying amounts of deletion of chromosome 5. Pa-tients with ring chromosome 13, for example, appearto fall into three clinical syndromes with some over-lapping features depending on how much of the ring islost in the major cell line. ~ There is, however, little in-formation about ring chromosome 5. Clinical charac-teristics of patients with ring chromosome 5 are com-pared in this paper for better understanding of theinfluence of a chromosomal ring information oncri du chat.

PEDIATRIC DENTISTRY: Volume 3, Number 4 329

Case ReportMedical HistoryA 2310 gm white male was born to a 20-year-old

mother and 24-year-old father. Following a normalpregnancy, delivery took place several weeks laterthan the expected date of birth. A weak high-pitchedcry was noted shortly after birth.

The head circumference was 30 cm; fontanels andsutures, including a metopic suture, were open. Bodylength was 45 cm. The nasal bridge protruded signifi-cantly (Figure 1). Other dysmorphic facial features in-

Figure 1. Patient with ring 5chromosome disorder.

eluded: large, low-set ears, widened external ear ca-nals, retrognathia, downward slant of palpebral fis-sures, and ocular hypertelorism. Skeleti1 abnormali-ties included a widened anterior-posterior sliest diam-eter, short sternum, short fingers, and slight lumbarkyphosis. A sixth supernumerary lumbar vertebra wasnoted on x-ray. A small ventricular septal defect,noted at birth, spontaneously closed by three years ofage. Rectus diastus was present. The genitalia werenormal. Extremities were proportional with consider-able muscular hypertonia and hyperactive reflexes.Both palms showed a single upper transverse Palmercrease. The toenails were small and concave.

Subsequent studies over seven years revealed severedevelopmental delay. The child sat at two years of ageand walked unsupported at five years of age. Therewas no language development although the patientdid make sounds. There was marked growth failure atseven years of age (height and weight below fifth per-centile). The child had a history of pneumonia andfailure to thrive.

Cytogenetic FindingsChromosome analysis was done on lymphocytes

and skin fibroblast cells using Giemsa and Quinacrinebanding procedures. One hundred metaphase cellsfrom the peripheral blood lymphocytes were analyzedover a seven-year span (Table 1). Eighty percent ofthe cells had 46 chromosomes with a ring 5 (45, + r), 11percent with 45 chromosomes with ring (44, + r) and 7percent without ring product (46,-r, + ring products).The presence of two double rings was noted in ten

cells. Nearly 70 percent of the skin fibroblasts showeda ring chromosome 5.

It appears that a small amount of chromosomalmaterial was lost from the clearly banded ringchromosome (Figure 2) at break points, 5pl5 and 5q35(long arm), as reported in other studies.18'20 Thus, thekaryotype was designated as 46,XY,r(5)(pl5q35).Both parents had normal karyotypes.

Dental FindingsAt the age of seven years and two months, the pa-

tient was first seen in the dental clinic at the Univer-sity Hospital School of the University of Iowa with ahistory of dental pain.

The patient was extremely uncooperative. Exami-nation revealed micrognathia (Figure 3), an ulceratedlesion on the maxillary lip, gingivitis, and poor oralhygiene. Occlusal examination indicated an openbiteof approximately 2 mm, an overjet of approximately15 mm with flaring anterior teeth, and a Class IImolar relationship. Multiple carious lesions of the pos-terior teeth with radiographic evidence of internalroot resorption were found. Class I incisal fractureswere present on the maxillary central incisors. Ra-diographically, there was an apparent lack of alveolarbone around both maxillary centrals. Fusion of themandibular left primary canine and lateral was noted,as was the absence of the left permanent lateral. Themandibular right primary molar was markedly small-er than the left, although no measurements weretaken. The patient's dental age as determined by cal-cification was 7.5 years. Eruption was within normallimits for a seven-year-old male. Hypomineralizationwas present on the maxillary primary canines andmandibular permanent left lateral incisor. The maxil-lary left first permanent molar was hypoplastic.

Due to the lack of patient cooperation, distance theparent traveled for treatment and, at that time, anuncertain medical condition, the patient was hospital-ized. Oral rehabilitation utilizing nitrous oxide, oxy-gen, and halothane anesthesia with nasoendotrachealintubation consisted of: examination, nine radio-graphs, oral prophylaxis, topical fluoride, three stain-less crowns, six amalgam restorations, one occlusalsealant and two extractions.

Although the parent was instructed in positioningbrushing, flossing, and the use of daily topical fluo-

Table 1. Chromosome data on blood and skin fibroblast cells.

Tissue

Blood

Skin

45,r

2

27

44, + r

11

5

45, + r

80

89

46,-r,+ ring

products

7

14

Number ofcells

analyzed

100

135

330 RING CHROMOSOME 5 WITH DENTAL ANOMALIES: Kula et al.

Figure 2. Ring chromosome5 with homologous chromo-some, r [5] (See cover photo)

ride, both before and after oral rehabilitation, the pa-tient exhibited poor oral hygiene with severe gingivitisat the postoperative appointment. A white 0.5 x 0.5cm lesion was found on the soft palate but the ulcer-ated lip lesion had healed.

Two months later, the patient was referred fromthe pediatric clinic with complaints of failure tothrive, bruxing and biting. The father asked that allteeth be extracted because he could not stand thenoise caused by the patient grinding his teeth.

An examination revealed poor oral hygiene, gener-alized severe gingivitis, mobility of the maxillary andmandibular centrals, radiographic evidence of widenedperiodontal ligaments around the mandibular rightcentral (Figure 4) and lack of bony support around themaxillary centrals (Figure 5). The pulp canals of themaxillary centrals were open whereas the root forma-tion of the mandibular centrals was complete. Our im-pression was that the mobility and widened periodon-tal ligaments of the anteriors and the status of theanterior root canals were probably due to a combina-tion of developmental status of the root canal, lack ofbony support around the maxillary anteriors, andpossible trauma from either falling or from a notedhabit of chewing his bed or other hard substances. Thefather could not remember the patient retraumatizinghis teeth since the oral rehabilitation. The white le-sion noted at the postoperative appointment was notpresent. Since there was no evidence of pain or oral le-sions, the parent was informed of our findings andagain instructed in oral hygiene. The patient was re-ferred back to the pediatric clinic for examination forother contributing factors. If none were found, extrac-tion of the maxillary incisors would be considered.Otherwise, observation was indicated.

The patient was hospitalized for further examina-tion. His clinical notes indicated he ate and slept well.No oral or medical problems were noted. The physi-cian recommended that the patient receive institu-tional care.

DiscussionThe reported cases of ring chromosome 5 show

similar craniofacial features (Table 2). Microcephaly

Figure 3. Oral findings include rerognathia, flaring incisors,fusion, fractured maxillary central incisors, gingivitis, andulceration.

Figure 4. Mandibular per-iapical radiograph taken atpostoperative appointment.

Figure 5. Maxillary periapi-cal radiograph taken at post-operative appointment.

and epicanthic folds are common to all patients. Hy-pertelorism, dysmorphic ears, retrognathia, and anti-mongoloid slant are present in over half the patients.The presence of prominent nasal bridge and higharched palate is variable as reported in cri du chatpatients.

An abnormal cry is reported in all but two cases.Mental retardation is a consistent finding. Abnormaldermatoglyphics is reported in six of the nine cases,with no mention in the other three cases. Other abnor-malities are grouped under organ systems due to lackof specificity. Abnormalities of organ systems include:cardiac abnormalities (grade 3-4 systolic murmur,VSD, enlarged heart), three cases; urogenital abnor-malities (undescended testes, atrophied testes), twocases; skeletal abnormalities other than cranial (dys-

PEDIATRIC DENTISTRY: Volume 3, Number 4 331

Table 2. Clinical findings in patients with ring 5 chromosome.

Rohde & Steele Cousin Nakagome Chuang Bailon Suerinck PresentTomkins et al. et al. et al. et al. et al. et al. {1978) Case(1965) (1966) (1972) {1972) (1976) (1977) Case 1 Case2

Age Newborn 18 mons 4 yrs 4 mons 17 mons 15 ~ 1 mo 6 yrs 7 yrs Total

Craniofacial featuresMicrocephaly + + + + + + + + + 9/9Hypertelorism + + + + + ? + + + 8/9Epicanthic folds + + + + + + + + + 9/9Prominent nasal bridge + + ? ? ? + + 4/9Dysmorphic ears + ? + ? + + + 5/9High-arched palate + ? ? + ? + 3/9Retrognathia + + ? + + ? + + + 7/9Antimongoloid slant + + ? + + + ? + + 7/9

Abnormal cry + + ? + + + + + 7/9Abnormal dermatoglyphics + + + ? ? ? + + + 6/9Mental retardation + + + + + + + + + 9/9Cardiac abnormalities + ? + ? ? ? + 3/9Genital abnormalities ? ? + ? ? + 2/9Skeletal abnormalities + ? + ? + ? ? + 4/9Syndactyly + ? ? + ? + ? 3/9

+ - reported as present, - - reported as missing, ? - no mention.

plastic fingers, scoliosis, extra vertebra, dysplastichips, short sternum), four cases; and syndactyly, threecases. Thus, the most constant findings in ringchromosome 5 patients are craniofacial abnormalities,cry, mental retardation, and dermatoglyphics.

As a group, ring chromosome 5 patients cannot bedifferentiated into a separate syndrome from cri duchat patients. However, comparison of clinical find-ings (Table 2) and interpretation of the influence ring structure are complicated. Authors may have de-leted mention of various characteristics either becausethe characteristics were not present, were not consid-ered important, or were not observed althoughpresent. As previously discussed, various character-istics are modified with age. Therefore, the paucity ofreported phenotypic characteristics in the case of thefifteen-year-old male may be due to craniofacialgrowth. The phenotype may also be influenced by theamount of chromosomal deletion within a band.=

The influence of the ring chromosome on dentalcharacteristics is difficult to determine. Dental obser-vations of ring chromosome 5 patients are scant.Chuang et al.lg report delayed dentition in a 17-month-old. Steele et alY report the presence of ten teeth in aone-year-old patient. Dental age is normal in this case.Therefore, of interest in our case, is the presence of fu-sion, a missing permanent lateral incisor, discrepancyin size of mandibular first primary molars, mineraliza-tion, and lack of bone around the maxillary incisors.Fusion may be inherited as autosomal dominant withreduced penetrance,= although it has not been associ-ated with a particular chromosome. Paternal andmaternal dental histories are unknown in this case.

Stewart and Prescott~ assume that identical geneticcontrol determines the size of contralateral teeth andthat asymmetry is attributed to environmental influ-ences. Thus, one can do no more than speculate thatcontralateral tooth size asymmetry in this patient isdue to genotypic variation. This patient exhibitsretrognathia and overjet as previously reported in cridu chat patientsY The incisal fractures are related totrauma either from a chewing habit or the decreasedmotor ability of the patient. The handicapped condi-tion of the child and reduced parental interest con-tribute to poor oral health of the patient. Additionalstudies are needed to understand the influence of thechromosomal ring structure on dental phenotype.

This work was supposed by a grant from the Office for MaternalChild Health, Bureau of Community Health Services, Departmentof Health and Human Services, Project Number 327.

The authors thank Kay Nielsen, Vicky Yang, and Judy Heilman fortechnical assistance, and Dr. Herman Wyandt, I~.vision of MedicalGenetics, University of Virginia Medical Center, Charlottesville,Virginia for some of the data on skin fibroblast cells.

Dr. Kula is assistant professor, department of l~iiatric dentistry,University of Maryland, Baltimore, Maryland 21201. Drs. Patil,Hanson and Zellweger are in the division of medical genetics, Uni-versity of Iowa Hospital and Clinics, Iowa City, Iowa. Dr. Nowak isprofessor, department of pedodontics, University of Iowa, IowaCity, Iowa 52242. Requests for reprints should be ~nt to Dr. Kula.

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332 RING CHROMOSOME 5 WITH DENTAL ANOMALIES: Kula et al.

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791, 1970.8. Malnardi, P., Vianello, M., and Bonioli, E. Considerazioni su

cinque casi di sindrome di cri du chat, Miner Pediatr, 28:2389-2400, 1976.

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11.Bailon, A., DaSilva, J., and Schuh, B. Cri du chat: clinical andcytogenetic findings in two older patients, J Med Soc N J, 74:431-432, 1977.

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14.DeCapoa, A., Warburton, D., Breg, W., Miller, D., and Muller,O. Translocation heterozygosis: a cause of five cases of the cri duchat syndrome and two cases with a duplication of chromosomenumber 5 in three families, Am J Human Genet, 19:586-603,1967.

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16.Cousin, J., Boutu, F., Savary, J., Jacqueloat, N., Deminatti, M.,and Fournier, A. Maladie du cri du chat par chromosome 5 enanneau, Arch Fr Pediatr, 29:896-897, 1972.

17.Steele, M., Breg, W., Eidelman, A., Lion, D., and Terzakis, T. AB-group ring chromosome with mosaicism in a newborn with cridu chat syndrome, Cytogenet, 5:419-429, 1966.

18.Nakagome, Y., Inuma, K., and Taniguchi, K. Points of exchangein a human No. 5 ring chromosome, Cytogenet Cell Genet, 12:35-39, 1973.

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20.Suerinck, E., Noel, B., and Rethore, M. Ring chromosome 5 intwo malformed boys with cri du chat syndrome, Clin Genet, 14:125-129, 1978.

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with multiple congenital malformations, Ann Genet, 16:157-166,1973.

24.Jackson, L. and Barr, M. A 45,XY,5-15-,t(Sq15q) cri du chatchild, J Med Genet, 7:161-163, 1970.

25.S/lengo, M. and Andria, G. Partial monosemy 22 as a result of anunbalanced translocation 5:22 in a patient with cri du chat syn-drome, Human Genet, 34:319-322, 1976.

26.McDermott, C., Poulding, R., and Creery, D. Cri du chat syn-drome in a child with 46,XX,der(5),t(4;5)(q32;p14) pat type, Human Genet, 39:109-112, 1977.

27.Vigietti, P., Chessa, L., Bruni, L., Ferrante, E., and Callapiccoh,B. Translocation Y/5 resulting in cri du chat syndrome, ClinGenet, 12:319-322, 1977.

28.Stewart, R. and Prescott, G. Oral-Facial Genetics, St. Louis: C.V. Mosby Co., 1976, p 680.

Quotable QuoteIn a message of solace to consumers and industry alike, the Food and Drug Administration (FDA) has con-

cluded that most common food additives are harmless. A review of 415 natural and artificial additives generallyregarded as safe turned up few surprises. Only salt was targeted for restriction or possible removal from the foodsupply, because of its potential for increasing hypertension.

The review, conducted by the Federation of American Societies for Experimental Biology, suggests that addi-tional study be made of more than a dozen additives, including caffeine, on which there was considerable disagree-ment. Additional information on BHA and BHT, two widely used preservatives, was also sought, as were data onthe long-term effects of vitamin additives such as iron, zinc, vitamin A and vitamin D -- each consumed in ever-larger quantities.

From: Smith, R. J. Most additives areharmless. Science, 211:260, January 1981.

PEDIATRIC DENTISTRY: Volume 3, Number 4 333