Severe Clinical Phenotype Due to an InterstitialDeletion of the Short Arm of Chromosome 1:A Brief Review

David W. Stockton,1 Helen L. Ross,1,2 Carlos A. Bacino,1 Carolyn A. Altman,3 Lisa G. Shaffer,1 andJames R. Lupski1,3*1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas2Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas3Department of Pediatrics, Baylor College of Medicine, Houston, Texas

We report on a newborn girl with mal-formed ears, bilateral cleft lip and cleft pal-ate, complex congenital heart disease, ab-sent left thumb, and rib abnormalities. Cy-togenetic analysis demonstrated a de novointerstitial deletion of the short arm of chro-mosome 1 [46,XX,del(1)(p21p22.3)]. Reportsof interstitial deletions on the short arm ofchromosome 1 are rare. However, whencomparing this patient’s phenotype to oth-ers with deletions of 1p, we found that thecurrent case was much more severely af-fected than previously reported cases. Am.J. Med. Genet. 71:189–193, 1997.© 1997 Wiley-Liss, Inc.

KEY WORDS: chromosome 1p; chromosomeabnormality; chromosomedeletion; multiple congenitalanomaly (MCA) syndrome;congenital heart disease;monosomy 1p

INTRODUCTION

Interstitial deletions of the short arm of chromosome1 are reported rarely [Howard and Porteus, 1990].Most deletions of chromosome 1 reported occur in thelong arm or in the distal or terminal bands of the shortarm. Many of the previous cases of interstitial dele-tions of 1p were identified in older children or adultswith developmental delay. None of the patients had assevere a phenotype as reported here. The prominentfindings in our case consisted of facial clefting, verte-bral anomalies, absent thumb, and complex cardiacanomalies including a hypoplastic left heart.

CLINICAL REPORT

The patient was a 39-week-gestation female, born toa 30-year-old G4P2→3Ab1 Caucasian mother and 37-year-old non-consanguineous Caucasian father (Fig. 1).There were no prenatal drug, alcohol, tobacco, medica-tion, or infectious exposures, or illnesses. The preg-nancy was complicated by decreased fetal movement,growth retardation, and oligohydramnios. Birth was byvaginal delivery induced because of decreased fetalmovement and oligohydramnios.

The Apgar scores were 4 and 8 at one and 5 minutes,respectively. Birth weight was 2,200 g (<10th centileand 50th centile for 34 weeks gestation), length was40.5 cm (<10th centile and 50th centile for 29 weeksgestation), and OFC was 30 cm (<10th centile and 50thcentile for 32 weeks gestation). There was a three ves-sel cord. The patient developed bradycardia and de-creased respiratory effort requiring intubation andsubsequent transfer to a tertiary care facility.

On examination the infant was found to have awidely separated sagittal suture, a 4 cm by 5 cm ante-rior fontanel, posteriorly rotated ears with over-foldedhelices, with right ear length of 3 cm (3rd centile) andleft ear length of 2.75 cm (<3rd centile). The eyes hadno colobomas. Inner canthal distance was 2 cm (50thcentile) and outer canthal distance was 6.25 cm (50thcentile). The nose had a broad flat root. There was abilateral cleft lip and palate, short neck with posteri-orly redundant skin, and hypoplastic and invertednipples with an inter-nipple distance of 7.25 cm (25thcentile). Lungs were being ventilated. Heart soundswere normal and no murmurs were auscultated. Ab-dominal examination was unremarkable. Genitaliaand anus were normal. The left thumb was absent; theother digits were normal. The right thumb was smalland thin; the other digits were long and slender. Thenails were hypoplastic. There was bilateral radial de-viation at the wrists consistent with radial hypoplasia.Skin was unremarkable.

A chest radiograph showed decreased lung volume,rib anomalies of the upper left thoracic cage, and two‘‘butterfly’’ vertebrae at T3 and T4. Head ultrasound

*Correspondence to: Dr. James R. Lupski, Department of Mo-lecular and Human Genetics, Baylor College of Medicine, OneBaylor Plaza, Room 609E, Houston, TX 77030-3498.

Received 8 August 1996; Accepted 5 January 1997

American Journal of Medical Genetics 71:189–193 (1997)

© 1997 Wiley-Liss, Inc.

findings were unremarkable. Renal ultrasonographydemonstrated small kidneys with a normal contour,echogenicity, and position. An electrocardiogramshowed a normal sinus rhythm, indeterminate axis,right ventricular hypertrophy, and ST elevation consis-tent with early repolarization. An echocardiogramdemonstrated interrupted aortic arch type B with flowto the descending aorta dependent on a patent ductusarteriosus. Mild to moderate hypoplasia of the subaor-tic region, aortic annulus, and transverse arch werenoted. There was functionally a single right ventricle: aright ventricular dominant, intermediate type of atrio-ventricular canal defect with a hypoplastic mitral valvestraddling the interventricular septum and markedlyhypoplastic left ventricle. There was a moderate pri-mum atrial septal defect, a small inlet ventricular sep-tal defect, and a moderate secundum atrial septal de-fect. The pulmonary veins drained normally to the leftatrium, but there was interruption of the hepatic seg-ment of the inferior vena cava with probable azygouscontinuation (Fig. 2).

The initial impression was that the patient likelyhad a chromosomal abnormality and her findings ap-peared most consistent with trisomy 13. Chromosomeanalysis of 28 G-banded cells documented a46,XX,del(1)(p21p22.3) karyotype (Fig. 3). Parentalchromosomes were normal.

Because of her irreparable cardiac anomalies andchromosomal deletion a recommendation was made forconservative management. The patient was dischargedfrom the hospital at 6 days of life and died at age 44days. No autopsy was obtained.

DISCUSSION

Chromosome 1 is the largest human chromosome,containing approximately 8% of the genome (VirtualGenome Center at http://alces.med.umn.edu/tables/

hum-chr.html). Given its size, one would expect a largenumber of reports of deletions but, in fact, there is onlya small number [Howard and Porteus, 1990]. Most re-ports are either of long arm deletions or deletions of theterminal short arm. A MEDLINE search for case re-ports of chromosome 1 short arm interstitial deletionsidentified only 12 cases and one of these involved atranslocation between chromosomes 1 and 2 (Fig. 4).

The first reported case of a cytogenetic abnormalityon the short arm of chromosome 1 was by Aarskog in1968. This was likely a terminal deletion but, since itwas identified prior to the availability of chromosomebanding technology, it is not certain. The first report ofan interstitial deletion on the short arm of chromosome1 was by Bene et al. in 1979 (H in Fig. 4). Most reportedcases are of children or adults with psychomotor retar-dation and multiple minor anomalies [Bene et al.,1979; Petersen and Warburg, 1987; Lai et al., 1991;Yoshino et al., 1991; Mattia et al., 1992; Barton et al.,1995]. Table I shows a compilation of the anomaliesreported. Comparison of the cases is complicated by thevarying detail of clinical descriptions and the relativeimprecision of the deletion breakpoints based on differ-ing chromosome lengths. The deletion reported by Mat-tia (M in Fig. 4) [Mattia et al., 1992] shows a largeamount of overlap with our patient but the breakpointswere disputed and reassigned by Kohler (G in Fig. 4)[Kohler, 1993] to a region with no overlap to our pa-tient.

There are six reported cases with breakpoints over-lapping those of our patient [Ikeuchi et al., 1982; Hertzand Jensen, 1985; Petersen and Warburg, 1987; Lai etal., 1991; Tabata et al., 1991; Mattia et al., 1992]. Thereport with the closest breakpoints is a translocation

Fig. 1. Photographs of the patient at 6 days of life. A: General, demon-strating the patient’s bilateral facial cleft and malformed ears. B: Righthand, demonstrating the hypoplastic nails, long slender fingers and abnor-mal thumb. C. Absent left thumb.

Fig. 2. Sketch of the patient’s cardiac anatomy. (Note: RA, right atrium;RV, right ventricle; LA, left atrium; LV, left ventricle; Ao, aorta; PA, pul-monary artery; PDA, patent ductus arteriosus).

190 Stockton et al.

involving chromosomes 1 and 2, with loss of chromo-some 1 from bands p21-p22.2 (I in Fig. 4) [Hertz andJensen, 1985]. The phenotype of that patient includedbilateral colobomas of the iris which our patient did nothave. Their patient had ulnar deviation at the wristwhile our patient had radial deviation. Additionally,their patient had normal radiograph of the thorax, nocardiac defect and no finger anomalies.

There are seven manifestations that have been ob-served in more than two of these patients: malformedears (four patients), small ears (three), broad nasalbridge and tip (three), microretrognathia (four), shortneck (three), low hair line (three), and psychomotorretardation (four). However, with these six literaturereports there is no obvious proximal 1p deletion clinicalphenotype.

The rarity of reports of interstitial deletions of theshort arm of chromosome 1 may be attributable to ahigh rate of lethal outcomes resulting in spontaneouspregnancy loss. Others have attributed the apparentlethality directly to chromosome 1’s large size [Tabataet al., 1991]. This hypothesis may apply to completetrisomy or monosomy but should not apply to intersti-tial deletions. A deletion of chromosome 1 would notdelete any more DNA than an equal size deletion onany other chromosome. On every chromosome, thereare gene rich and gene poor regions; light staining re-gions on G-banding are usually more gene rich. Thereare no data suggesting chromosome 1 to be more generich than any other chromosome. Therefore, deletionsof the short arm of chromosome 1 would not be ex-pected to be more lethal than similar size deletions onother chromosomes. The question remains why consti-tutional deletions on the short arm of chromosome 1are so rarely reported.

One of the reports of constitutional 1p deletion (A inFig. 4) [Biegel et al., 1993] also developed neuroblas-toma and the deleted segment in this patient includesthe putative neuroblastoma locus. There are also manypublications of neoplasms associated with loss of het-erozygosity and cytogenetic abnormalities involving

Fig. 4. Idiogram of the short arm of chromosome 1 at the 550 bandstage of resolution showing the extent of our patient’s (F.) and the otherreported interstitial deletions. A. del(1)(p36.1p36.2) [Biegel et al., 1993], B.del(1)(p34.1p36.1) [Howard and Porteus, 1990], C. del(1)(p32.3p34.1)[Yoshino et al., 1991], D. del(1)(p32.1p32.3) [Barton et al., 1995], E.del(1)(p22.3p31.3) [Lai et al., 1991], F. del(1)(p21p22.3), our patient, G.del(1)(p32p34.3) [Kohler, 1993], H. del(1)(p22p32) [Bene et al., 1979], I.del(1)(p21p22.2) [Hertz and Jensen, 1985], J. del(1)(p22.1p32.1) [Ikeuchi etal., 1982], K. del(1)(p22.1p31.2) [Lai et al., 1991], L. del(1)(p22.1p31.2)[Petersen and Warburg, 1987], M. del(1)(p13.3p22.3) [Mattia et al., 1992],N. del(1)(p13.3p22.3) [Tabata et al., 1991].

Fig. 3. Idiogram of chromosome 1 and partial G-banded karyotype from this patient showing the deleted chromosome 1 (arrows).

Interstitial 1p Deletion 191

TABLE I. Comparison of Manifestations of our Patient and the Previously Reported Patients With Interstitial Deletions ofChromosome 1p*

del(

1)(p

36.1

p36.

2)

del(

1)(p

34.1

p36.

1)

del(

1)(p

32.3

p34.

1)

del(

1)(p

32.1

p32.

3)

del(

1)(p

22.3

p31.

3)

del(

1)(p

21p2

2.3)

del(

1)(p

22p3

2)

del(

1)(p

21p2

2.2)

del(

1)(p

22.1

p31.

2)

del(

1)(p

22.1

p31.

2)

del(

1)(p

13.3

p22.

3)

del(

1)(p

13.3

p22.

3)

A B C D E F H I K L M N

Overweight − +Short stature + + +Microcephaly + + +Prominent occiput + − +Large anterior fontanel + +Frontal bossing, ridged metopic − +Face rounded − + +Narrow or long face − +Synophrys − +‘‘Coarse’’ face with freckles − +Microphthalmia + − +Hypertelorism + + −Narrow palpebral fissures + + −Upslanting palpebral fissures + + −Downslanting palpebral fissures − +Epicanthal folds + − +Long eyelashes + − +Colobomas − − + +‘‘Pupil abnormality’’ + −Absence of lens of eye + −‘‘Lowset’’ ears + + + − +Malformed ears + + + + + + +Small ears + + +Prominent ears + −Preauricular tags & pits + + −Bulbous nose + + − +Prominent nose − +Broad flat root of nose + + +Prominent nasal bridge and tip + − +Long philtrum + + + −Beaked upper lip + −Large, half open mouth + − + +Cleft lip and palate +High arched palate + + + + − +Flat palate − +Microdontia +Ridged tongue − +Microretrognathia − + + + + +Low hair line + + + +Short neck + + + + + +Widely spaced nipples + + + − + +Cyanotic heart disease + − + − − +Cryptorchidism +Long thin fingers + + + +Drumstick terminal phalanges + −Clinodactyly of 5th finger + − + +Proximal implantation of thumbs + − +Absent left thumb +Adducted thumb or thumbs − +Ulnar deviation of wrists − +Radial deviation of wrists + −Digitalized thumbs + +Toe anomalies + + − + +Prominent calcanei + +Equinovarus − +Skeletal anomalies + +Psychomotor retardation + + + + + + + + +Seizures − + +Hypertonic − +Hypotonic + + + +

*A [Biegel et al., 1993], B [Howard and Porteus, 1990], C [Yoshino et al., 1991], D [Barton et al., 1995], E [Lai et al., 1991], F Our patient, H [Bene etal., 1979], I [Hertz and Jensen, 1985], K [Lai et al., 1991], L [Petersen and Warburg, 1987], M [Mattia et al., 1992], and N [Tabata et al., 1991]. Columnheadings correspond to breakpoint labels in Figure 4. Note, G is missing from the table since this is only a redefinition of the breakpoints of M, and J ismissing because there is no clinical information in the report.

192 Stockton et al.

the short arm a chromosome 1 in somatic tissues [Par-miter and Nowell, 1993; Gibas et al., 1994; Ambros etal., 1996]. This may be a result of the size of the chro-mosome or it may imply there are important tumorsuppressor and/or oncogenes located there. Many of thetumor suppressor genes and oncogenes described per-form important cell cycle regulation functions or act astranscription factors. In non-neoplastic cells these areunder tight control and may only be transcribed duringa portion of embryogenesis. If there are many tran-scription factors and cell cycle regulatory genes onchromosome 1p this may lead to non-viability whenhaploinsufficient.

The syntenic mouse regions do not demonstrate anyimprinting. The few mouse genes mapped to the anala-gous deleted region of chromosome 1 in this patient donot obviously explain the phenotype. However, it is in-teresting to speculate how some may contribute to thispatient’s phenotype and to the lethality of interstitialdeletions on the short arm of chromosome 1. These in-clude Ps (polysyndactyly), Pxmp1 (peroxisomal mem-brane protein 1), Csf1 (macrophage colony stimulatingfactor 1), and Pmv19 (polytropic murine leukemia vi-rus-19).

A final conclusion for the severe phenotype seen inour patient compared to other patients having overlap-ping and larger deletions cannot be drawn. Many pos-sibilities exist including the uncovering of recessivemutations, imprinting in the deleted region and thecombined effect of genes at other loci independent ofthe deletion (multigenic affects). The spectrum ofanomalies observed with chromosome 1p interstitialdeletions and their varying outcomes is an importantissue that must be addressed when counseling thesefamilies.

ACKNOWLEDGMENTS

The authors thank the Kleberg Cytogenetics Labora-tory, Baylor College of Medicine for their expert cyto-genetics on this case, and Dr. David Adler for the chro-mosome 1 idiogram in Figure 4 from his World Wide

Web page http://www.pathology.washington.edu/cyto_page.html.

REFERENCES

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