Atypical Manifestations of Two Cases of Trisomy 9Syndrome: Rethinking Development Delay

Russell P. Saneto,1 Kimberly E. Applegate,2 and David G. Frankel2*1Departments of Pediatric Neurology and Neurology, Cleveland Clinic Foundation and Children’s Hospital,Cleveland, Ohio

2Department of Radiology, Cleveland Clinic Foundation and Children’s Hospital, Cleveland, Ohio

Trisomy 9 syndrome is characterized by‘‘bulbous’’ nose, microphthalmia, dislocatedlimbs, and other anomalies of skeletal, car-diac, genitourinary, and central nervoussystems. With the exception of one reportedcase study, all surviving infants have hadsevere mental impairment. The prospect ofsevere mental retardation often over-whelms parents who are faced with prena-tal diagnosis of trisomy 9. We report on twonew cases of mosaic trisomy 9, both of whomare only mildly developmentally delayed.One patient presented with the distinctivefacial appearance, large fontanels, and jointabnormalities. The other had none of thetypical congenital abnormalities. However,the patient was found to have a congenitalheart defect and hypoplastic left heart syn-drome, which to our knowledge has notbeen reported previously in the trisomy 9syndrome. When these two patients areadded to the published patients with thissyndrome, there appears to be a range ofmanifestations, especially with respect tomental status, which has not fully been rec-ognized. Am. J. Med. Gen. 80:42–45, 1998.© 1998 Wiley-Liss, Inc.

KEY WORDS: chromosome; trisomy 9; hy-poplastic left heart syn-drome; mosaicism; develop-ment

INTRODUCTION

Trisomy 9 syndrome is an uncommon disorder withless than 40 delivered infants analyzed and reported inthe literature. The cytogenetics of this syndrome com-prise complete trisomy 9 and mosaic trisomy 9 karyo-

types. Apparently, complete trisomy 9 was present inonly 15 infants, with males (n410) in greater fre-quency than females (n43). Mosaic trisomy 9 has beenfound in 24 infants, with females (n415) in greaterfrequency than males (n49) [Arnold et al., 1995; Wool-dridge and Zunich, 1995]. The gender of 2 patients wasunspecified [Arnold et al., 1995].

This syndrome is marked by severe mortality andmorbidity. Life span is typically measured in months,and multiple anomalies in multiple systems are char-acteristic of both types of trisomy 9. Shorter life spanand more severe anomalies are found in the completetrisomy form. The mean age of death in the completeform is less than 3 weeks, with a reported range of 10minutes to 107 days. The mosaic-type infant survivalaverages approximately 1 year, with the oldest knownsurvivor being 9 years of age at his death [Wooldridgeand Zunich, 1995; Haslem et al., 1973].

Multiple anomalies are found commonly, virtuallyall patients having one or more systems involved, withmost anomalies found in the cardiac, genitourinary,skeletal, and central nervous systems [Wooldridge andZunich, 1995; Arnold et al., 1995]. Although malforma-tions vary from individual to individual, some anoma-lies are common to all patients such as craniofacialanomalies in both sexes and male genital anomaliesand limb dislocations [Arnold et al., 1995]. The charac-teristic facial changes of trisomy 9 include microph-thalmia, deep-set eyes, ear anomalies, micrognathia,large anterior fontanels, and bulbous nose. All reportedmosaic males either had cryptorchidism or an abnor-mal penis [Arnold et al., 1995]. Except for one case[Frydman et al., 1981], all survivors had severe mentalimpairment.

We report on two new cases atypical for the trisomy9 syndrome. Both have only mild developmental de-lays; the one case without craniofacial anomalies hashypoplastic left heart syndrome (HLHS). To our knowl-edge, this is the first instance of absent craniofacialmalformations and HLHS in the trisomy 9 syndrome.

CLINICAL REPORTSPatient 1

A male infant was born spontaneously to a 36-year-old, G4P1A2 Caucasian mother at 38 weeks of gestation.

*Correspondence to: David G. Frankel, M.D., Section of Pediat-ric Radiology, Cleveland Clinic Foundation, 9500 Euclid Avenue,Cleveland, OH 44195.

Received 28 February 1998; Accepted 5 May 1998

American Journal of Medical Genetics 80:42–45 (1998)

© 1998 Wiley-Liss, Inc.

The parents were nonconsanguineous and in goodhealth. The pregnancy was uncomplicated. The infantrequired positive-pressure ventilation with a face maskand 100% oxygen for respiratory distress for severalminutes after birth. He quickly responded and at 5minutes had no further respiratory distress. Apgarscores were 1 at 1 minute and 8 at 5 minutes. He hadno minor anomalies (Fig. 1). Birth weight was 3.3 kg(75%), length 52 cm (>90%) and head circumference(OFE) 36 cm (>90%).

After several hours, it was noticed that he was duskyand tachypneic. Oxygen saturation was below 70% on100% FiO2. Doppler echocardiogram demonstratedHLHS with a hypoplastic ascending aorta, atretic mi-tral and aortic valve, and a very small ventricle. Inaddition, he had a large atrial septal defect and patentductus arterosis. He underwent cardiovascular stabili-zation and a septic workup. Antibiotics were startedbut were discontinued when cultures were negative forbacterial growth. His initial head ultrasound study wasread as normal; however, kidney ultrasound studyshowed mild bilateral pyelocaliectasis and ureterecta-sis. Subsequently, he underwent a modified Norwoodstage I procedure performed on day 3 of life. Repeatultrasonography of the kidneys showed normal sizewithout hydronephrosis. The patient’s only complica-tion during his hospital stay was the need of photo-therapy for hyperbilirubinemia. The patient was dis-charged from the hospital on day 16 of life.

Upon analysis, both parents had normal chromo-somes. The patient’s karyotype derived from PHA-stimulated lymphocytes was found mosaic for trisomy9. Approximately 82% of his cells had the extra 9 chro-mosome while 18% of his cells were normal [47, XY,+der(9)? Inv(9) (q11q34.3) [33]/46, XY [7]]. The extrachromosome appeared to have a paracentric inversionof the long arm (Fig. 2). This did not appear to be asimple inversion since the overall chromosome lengthwas slightly shorter than the normal chromosome 9and the amount of centeromeric heterochromatin wasexcessive. Results of neonatal screening for thyroidfunction, galactosemia, and phenylketonuria were nor-mal.

Subsequent well-child visits showed the patient tohave initial feeding problems manifested by very slowweight gain and persistent but mild motor develop-mental delay. Formula change to higher caloric densityformula and more frequent feeds ameliorated theweight gain problem. By 3 months the patient was coo-ing, focusing, and following, responding to voice, andwas beginning to lift his head from a prone position. Atthe 4-month exam, it was noted that his left testiclehad not descended. At age 5 months, the patient un-derwent a modified Glenn procedure for the secondstage of cardiovascular repair of his HLHS. The patienttolerated the surgery well and was discharged from thehospital within 1 week of surgery.

At his 7-month exam the patient was noted to bemildly hypotonic in his lower limbs. He was able to rollfront to back and lift his chest off the ground when inthe prone position. By 8 months, he was able to saymama and dada. At his 13-month exam he still did notsit without support and could not come to a sittingposition from either the abdomen or from his back. Hespoke three to four single words, and he was describedas a curious and alert child who was constantly explor-ing his environment. At his 16-month exam, he wasable to sit without support, standing briefly on his own,and creeping. He was babbling, with his mother beingable to understand a few words, and he understood andfollowed simple one-word commands. At 18 months hewas beginning to pull to a standing position. Morewords could be understood by someone other than hismother, and he was still able to follow simple com-mands. At 21 months he was able to pull to a standingposition easily and crawl up stairs. He was respondingto a greeting with ‘‘hi’’ and just beginning to use pro-nouns such as ‘‘my’’ for objects he was using or withwhich he was playing. His 21-month status corre-sponded to that of 9 months in gross and fine motor

Fig. 1. Patient 1 with mosaic trisomy 9 at age 22 months.

Fig. 2. Three sets of homologue 9’s are shown from the trisomic cellline. The rightmost group is C-banded. The arrows indicate the abnor-mal 9.

Developmental Delay in Trisomy 9 Syndrome 43

development. Although he was pulling to a standingposition, he was not walking on his own. His cognitionwas approximately 16-month level, with use of four tosix words and following simple commands.

Patient 2

A girl was born at 33 weeks of gestation to a 39-year-old G1P, Caucasian woman by C-section. C-section wasdue to transverse position of the fetus. Patient wasdiagnosed in utero by chorionic villi sampling to betrisomy 9, as 36 out of 36 metaphase cells were 47,XX+9. A postnatal chromosome analysis of peripheralblood showed 3 of 100 cells to be trisomic for chromo-some 9. The parents were nonconsanguineous and ingood health. Birth weight was 1.88 kg (50%), and Ap-gar scores were 8 at 1 minute and 8 at 5 minutes.

Initial evaluation after birth showed apparently low-set ears and, with the exception of anteverted nares,there was no additional documentation of facial abnor-malities. A 50% subluxation of the left hip was diag-nosed ultrasonographically. This was corrected with aPavlik harness. She was found to have malrotation ofthe bowel, an anal stricture, and reflux esophagitis.The anal stricture was corrected by dilation, and themalrotation was corrected with a Ladd procedure. Theinfant required a high calorie formula for feedings andgastrointestinal tube placement for supplementaryfeedings. Ultrasound findings of the head and kidneyswere normal.

At her 4-month exam the patient was able to respondto parents with a smile, follow to midline, and madehand-to-face movements. Her tone was considered nor-mal, and she was able to hold her head in the midline.At the 9 month exam, she was able to hold her head up,sit with support but not independently, and was rollingfrom front-to-back. She was also cooing at this time andfollowing past the midline. The 1-year exam showedher to be sitting independently, rolling over in bothdirections, and beginning to babble. By 15 months shewas pulling to a standing position and cruising. Herlanguage development was improving, as she was say-ing mama and dada. At 18 months she was able to sayfive words other than mama and dada. She was begin-ning to eat with a spoon, and pulling her shoes andsocks off. She was also walking independently. Thisexam showed a girl with the developmental maturity ingross and fine motor skills in the range of approxi-mately 12 months. However, her cognition as evi-denced by her use of words was in the range of age14–16 months.

DISCUSSION

Of the previous 39 reported cases of trisomy 9 syn-drome, 38 were severely mentally impaired. The singlecognitively normal infant was a girl who at age 24months had normal psychomotor development, al-though she had multiple other anomalies [Frydman etal., 1981]. Another infant was reported to have no grossexternal or internal congenital anomalies but died dueto congenital leukemia at 14 days of life [Djernes et al.,1976]. These latter two cases represent the phenotypic

exception in this syndrome. The last review of the tri-somy 9 syndrome indicated most of the infants haddefects that severely limit the developmental outcome,a life span of less than 1 year, and numerous anomaliesof various organ systems [Wooldridge and Zunich,1995]. Although 38 of 39 patients had severe mentalimpairment, only 35% showed gross central nervoussystem structural abnormalities [Wooldridge and Zu-nich, 1995]. The Dandy-Walker malformation was themost frequent anomaly but was only found in completetrisomy 9 patients. Other anomalies of the CNS in-cluded dilated ventricles, structural abnormalities ofthe lobes, and altered cellular structure.

Our two patients suggest that the range of motor andcognitive development is broader than previously re-ported for this syndrome. Currently, both have onlymild developmental delays and have lived beyond age18 months.

The male patient was found to have greater motordelay than cognitive function deficit. He had a normalface, a feature previously reported as universally ab-normal [Wooldridge and Zunich, 1995]. He also had aclassic HLHS [Lev, 1952; Noonan and Nadas, 1958]that was not reported previously in trisomy 9 cases.Williams et al. [1985] reported on an infant with asmall left ventricular cavity and an undivided truncusarteriosus but not true HLHS. Furthermore, our pa-tient was speaking three to four words at 13 monthsand many words at 20 months. This would make himonly mildly delayed. He does exhibit some motor delayin that he is only beginning to pull to a standing posi-tion and still only cruising at 20 months of age. Itshould be noted that he has also had two open heartsurgeries during this time, which may account for someof these delays.

Our female patient has a more typical phenotype ofthis syndrome [Arnold et al., 1995]. Except for gastro-intestinal defects [Levy et al., 1989], her other systemswere normal with no defects noted on ultrasound andother radiological testing of her brain, cardiovascular,skeletal (no absence of bones or joint dislocations), orgenitourinary system. This patient has motor and cog-nitive delay. At 18 months she was speaking threewords other than mama and dada and still not follow-ing simple commands. She was also just beginning tofurniture walk and standing on her own. Her develop-mental delay seems only mild to moderate.

Neither of these patients expresses the severity incognition previously described in most infants with tri-somy 9 syndrome. Of the previous 39 reported patients,only 1 had normal mental cognition [Frydman et al.,1981]. When confronted with this statistic, one set ofparents (Case 2) had a difficult time deciding whetherto terminate or continue the pregnancy. We feel thatwith the presentation of our two cases, the range ofmental development might be seen as a continuum,from normal to severely compromised. We realize that3 out of 41 cases is still a minority of the cases, but itspeaks of a range of mental acumen not previously re-ported (although formal neuropsychological testing hasnot been performed), and the developmental mile-

44 Saneto et al.

stones attained would indicate only a mild cognitivedelay.

ACKNOWLEDGMENTS

The authors wish to thank Dr. Gerald A. Hoeltge forkindly providing the photograph of the trisomy 9 chro-mosomes.

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