Child With Velocardiofacial Syndrome and del(4)(q34.2): Another Critical Region Associated With aVelocardiofacial Syndrome–Like Phenotype

Chun-Hui Tsai, Daniel L. Van Dyke, and Gerald L. Feldman*Department of Medical Genetics, Henry Ford Hospital, Detroit, Michigan

We report on a child with congenital heartdisease (atrial septal defect, ventricularseptal defect, pulmonic stenosis), submuco-sal cleft palate, hypernasal speech, learningdifficulties, and right fifth finger anomalymanifestations, consistent with velocardio-facial syndrome (VCFS); however, cytoge-netic analysis demonstrated a small termi-nal deletion of the segment 4q34.2 to 4qter.Fluorescent in situ hybridization did notidentify a deletion of the critical region as-sociated with VCFS. In previously reported4q deletions with a breakpoint distal to4q34.2, no cardiac defects or cleft of palatewere reported. Our patient has a deletion of4q34.2 to 4qter and has palate and cardiacinvolvement and minor learning difficul-ties, which implies that genes involved inheart and palate development lie distal to4q34.2, and that the critical region for moresevere mental retardation on 4q may resideproximal to 4q34.2. These results suggestthat a distal 4q deletion can lead to a phe-notype similar to VCFS and emphasizes theimportance of searching for other karyo-type abnormalities when a VCFS-like phe-notype is present and a 22q deletion is notidentified. Am. J. Med. Genet. 82:336–339,1999. © 1999 Wiley-Liss, Inc.

KEY WORDS: VCFS-like syndrome; 4q34.2deletion; cleft palate

INTRODUCTION

Deletion of chromosome region 4q31→qter has beencharacterized as a distinctive malformation syndrome(4q- syndrome), comprising variable mental andgrowth deficiency, cleft palate, limb anomalies, cardiac

and genitourinary defects [Towens et al., 1979]. Dele-tions involving bands distal to 4q33-4q35 are less com-mon, and these patients present with less characteris-tic physical anomalies and milder mental retardation.Lin et al. [1988] suggested that loss of q31-q33 wascritical for the more severe phenotype. We report on achild with congenital heart disease (atrial septal defect[ASD], ventricular septal defect [VSD], pulmonic ste-nosis), submucosal cleft palate, hypernasal speech, mi-nor learning difficulties, and fifth finger anomaly whohas a deletion of 4q34.2→qter. The phenotype was con-sistent with velocardiofacial syndrome (VCFS) al-though no 22q deletion was present. Twenty patientsreported with deletions from 4q33 to 4q35→qter arereviewed.

CLINICAL REPORT

The propositus was born to a G1 19-year-old motherat term by vaginal delivery. The pregnancy was com-plicated by premature contractions at 6 months of ges-tation. There were no known prenatal teratogen expo-sures. Results of multiple ultrasound examinationswere reportedly normal. Birth weight was 4,365 g (98thcentile); birth length was 53cm (95th centile). Therewas no history of perinatal distress. A partially dupli-cated left fifth finger was present. A VSD, ASD, andpulmonic stenosis were diagnosed at age one month.The VSD was repaired at 2 months and a balloon val-vulotomy was done for the pulmonary stenosis when hewas 6 months old. The distal fifth phalanx was re-moved because of a duplicated dysplastic nail. The pa-tient has a history of asthma and repeated ear infec-tions, which required placement of ventilation tubes.He had a tonsillectomy because of sleep apnea.

His psychomotor development was mildly delayed.He walked at 14 months and spoke in sentences at 2years. However, articulation and phonation problemswere present and speech therapy was initiated at 3years. At the current age of 6, he is performing at ap-proximately a 5-year-old level.

The index case was born to nonconsanguinous par-ents of Polish, German, and French descent. He has a3-year-old brother with spinal muscular atrophy, typeII, with homozygous deletions of exons 7 and 8 in theSurvival Motor Neuron (SMN) gene.

*Correspondence to: Gerald L. Feldman, M.D., Ph.D., Depart-ment of Medical Genetics, Henry Ford Hospital, 2799 W. GrandBlvd., Detroit, MI 48202.

Received 28 August 1998; Accepted 29 October 1998

American Journal of Medical Genetics 82:336–339 (1999)

© 1999 Wiley-Liss, Inc.

At age 6 he weighed 33.1 kg (above the 95th centile),was 124 cm tall (above the 95th centile), and had ahead circumference of 54 cm (25th–50th centile). Healso had a broad and flat nasal bridge (Fig. 1), a bifiduvula, a high-arched palate with a submucosal cleft,and partial deficiencies of the left fifth finger. Therewas a mild component of hypernasality in his speech.

CYTOGENETICS

Cytogenetic studies were performed on cells derivedfrom a culture of PHA-stimulated peripheral blood leu-kocytes. Routine methods were employed for cell cul-ture, harvesting, slide preparation, and GTG banding.A terminal deletion of the long arm of chromosome 4,interpreted as 46,XY,del(4)(q34.2), was identified in 13/13 cells analyzed (Fig. 2). The parental chromosomeswere normal.

Fluorescent in situ hybridization (FISH) was per-formed using the probe D22S75 localized to 22q11.2(Oncor, Inc., Gaithersburg, MD). A microdeletion inthis region has been associated with DiGeorge syn-drome and VCFS. Ten metaphase cells were analyzed.Two hybridization signals were seen in all cells, indi-cating no deletion of the critical region. No hybridiza-tion signal was seen on any other chromosome, rulingout a translocation involving 22q11.2.

DISCUSSION

Deletions of chromosome 4q31→qter have been char-acterized as a distinctive syndrome (4q- syndrome)

comprising variable mental and growth deficiency,cleft palate, limb anomalies, and cardiac and genitouri-nary defects. Patients with more distal deletions, in-volving 4q33-qter breakpoints, were less severely af-fected because they had neither major malformations(congenital heart defect, cleft palate) nor severe mentalretardation [Stamberg et al., 1982; Lin et al., 1988].

We reviewed 20 patients with deletions involving4q33 to 4q35 (Table I). Six had a cardiac anomaly andsix had a cleft palate. Manifestations common to pa-tients with q34-qter deletions include a high-archedpalate, frontal bossing, upper lip abnormalities (promi-nent and/or thin upper lips), abnormal ears (cup-shaped pinnae with bilateral double tragus and/or pos-teriorly rotated ears), normal growth parameters, anda history of learning disabilities and/or mental retar-dation [Lin et al., 1988; Descartes et al., 1996; Caliebeet al., 1997]. Four of the five patients with q34→qterdeletion had mental retardation, (one had mild delay),and the fifth patient was too young for assessment.Among the 11 patients with 4q33→qter deletion, sixhad mental/psychomotor retardation, one had an IQ of83–88 but was described as much slower than the sibs[Mitchell et al., 1981], one was described as normal atage 9 months [Menko et al.,1992], one died in infancy[Grammatico et al., 1997], one was described at 17weeks with normal development [Tomkins et al., 1982,case 2], and one patient died at age 34 days [Ho and Ng,1993]. The patient with a q33-qter deletion reported byHo and Ng [1993] had anomalies suggestive of VCFS.All interstitial q33-q35 deletion patients reviewed havemental delay (one is mildly delayed). Among the fivereported cases with the breakpoint distal to 4q34.2,none had a cardiac defect or cleft palate.

Lin et al. [1988] and Mitchell et al. [1981] comparedphenotypes between deletions of 4q31→qter and4q33→qter and reported that the severity of the phe-notype, including the degree of malformations andmental retardation, correlated well with the quantityof missing chromosomal material. Sarda et al. [1991]

Fig. 1. Patient at age 6. Note flat and broad nasal bridge but otherwiselack of minor facial anomalies.

Fig. 2. GTG-banded 4th chromosomes of the patient. Normal homo-logue (left) and deletion 4q34.2 (right)

Velocardiofacial Syndrome–Like Phenotype 337

reviewed and compared phenotypes of patients withinterstitial deletions or terminal deletions involving4q33 or distal regions and suggested that q31-q33 wasthe critical region for the more severe phenotype. Ourpatient has a deletion of 4q34.2 to 4qter and has asubmucous cleft palate and cardiac involvement as wellas minor learning difficulties, which implies that genesinvolving the development of the heart and palate re-sides in or distal to 4q34.2. These results also suggestthat the critical region for more severe mental retar-dation on 4q may reside proximal to 4q34.2. A compari-son of our patient and the reported cases is listed inTable I.

Approximately 85–90% of DiGeorge syndrome pa-tients, 68% of VCFS patients, and 29% of patients withsporadic nonsyndromic conotruncal cardiac defectshave a deletion of 22q11 [Thomas and Graham, 1997].A DiGeorge-like phenotype has been reported in pa-tients with deletions of chromosome 4q21.3-q25 [Fuku-shima et al., 1992], 8p21 [Devriendt et al., 1995], 10p13[Lynch et al., 1995], 17p13 [Greenberg et al., 1988] andunbalanced translocations involving numerous otherchromosomes [Garza et al., 1995; Summar et al., 1995;Thomas and Graham, 1997]. The findings in our pa-tient suggest that a distal 4q deletion may lead to asyndrome similar to VCFS and emphasizes the impor-tance of searching for other karyotype abnormalities

when a VCFS-like phenotype is present and a 22q de-letion is not identified.

ACKNOWLEDGMENTS

We thank Anne Wiktor for technical assistance inperforming the FISH studies.

REFERENCES

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TABLE I. Distal Deletion of Long Arm of Chromosome 4: Comparison of the Breakpointsin Previous Reports and the Present Patient

Breakpoints q33-qter q33-q35 q34-qter q34.2-qter

No. of cases 11a 4b 5c 1 (Present case)Development

Growth retardation 5 — 1 —Mental retardation 6 4 4 1

Craniofacial findingsAbnormal skull 3 1 — —Upslanting palpebral fissures 5 2 2 —Upper lip anomaly — — 4 —Epicanthic folds 4 — 1 —Abnormal nasal bridge 8 — 3 1Small/short nose 4 — 3 —Low set/abnormal ears 5 2 4 —High arched palate 5 — 4 1Cleft lip/palate 5 1 — 1Micrognathia 11 — — —

SkeletalAbnormal fifth finger 5 1 — 1Tapering of fingers 1 — — —Abnormal toes 7 1 1 —

Cardiac defectCoarctation of aorta 1 — — —Aortic stenosis 2 — — —VSD — — — 1ASD 1 1 — 1AV canal 1 — — —Pulmonic stenosis 2 — — 1Arrhythmia 1 — — —

GenitourinaryHypoplastic labia majora 1 — — —Cryptorchidism 1 1 — —

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338 Tsai et al.

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