RESEARCH LETTER

An Unusual Phenotypic Presentation of Trisomy 18Sonal Patel,† Malektaj Yazdani,‡ Brian Barkemeyer, and Yves Lacassie*Department of Pediatrics, LSU Health Sciences Center, New Orleans, Louisiana

Received 31 July 2009; Accepted 29 August 2009

TO THE EDITOR:

Trisomy 18 syndrome, also known as Edwards syndrome, was

initially described in 1960 by Edwards and colleagues. The same

year, David Smith and colleagues reported the first patient in North

America [Edwards et al., 1960; Smith et al., 1960]. With an inci-

dence of 1 in 6,000–8,000 live births, it is the second most common

trisomy after trisomy 21 [Carey, 2005; Jones, 2006; Crider et al.,

2008]. The disease is associated with a high rate of intrauterine

demise, with only 5% of the babies surviving until birth. Of the

survivors, there is a predilection for females [Crider et al., 2008].

Thereafter, 5–10% of newborns live beyond their first year of life,

95% succumbing in the first 6 months [Carey, 2005]. Race has no

bearing [Jones, 2006].

With increasing frequency trisomy 18 is prenatally diagnosed by

amniocentesis or chorionic villi sampling (CVS) based on increased

suspicion due to advanced maternal age or abnormalities on fetal

ultrasound such as intrauterine growth restriction, polyhydram-

nios, heart defects, clenched fists, limb anomalies, or myelome-

ningocele [Tanigawa et al., 2007]. Diagnosis of trisomy 18 at birth is

straightforward in most cases with characteristic features. These

newborns present with intrauterine growth restriction, character-

istic facies with small narrow cranium with prominent occiput, low

-set posteriorly rotated ears, micrognathia, and a small mouth. The

sternum is short and the extremities are also classic exhibiting

clenched hands with overlying fingers which show arches in most

fingertips and rocker bottom feet. Congenital heart defects (most

commonly ventricular septal defect (VSD), atrial septal defect

(ASD), patent ductus arteriosus (PDA) and coarctation of the

aorta) are found in over 90% of the patients. Other findings include

renal anomalies, brain malformations, vertebral and eye anomalies

[Jones 2006].

This report will detail a premature newborn with uncommon

findings of trisomy 18 precluding easy clinical diagnosis. Further-

more, the unexpected premature delivery during overnight hours at

a different hospital than originally planned, with no available

prenatal records and incomplete information provided initially by

the family impeded the medical team from establishing the etio-

logical diagnosis in the most timely fashion.

The patient was born to a 19-year-old African-American,

primigravida, healthy, nonconsanguineous mother and a 23-year-

old African-American father with a history of a maternal aunt with

three interrupted pregnancies due to multiple congenital anoma-

lies (MCA). Prenatal history revealed that ultrasound at 24 weeks

gestational age (WGA) showed MCA and polyhydramnios.

Amniocentesis performed at 25 WGA showed chromosomal

abnormality and a suspicion of neural tube defect due to positive

acetylcholinesterase. More detailed information was unavailable

due to the birth circumstances and mother’s post-ictal and post-

anesthesia state. Fetal echocardiogram showed hypoplastic right

ventricle. The baby was born via emergency cesarean due to

maternal eclampsia (systolic BP 200 mmHg. with seizure activity)

at 32 weeks gestation. Birth weight was 1,076 g (<3rd centile),

length was 35 cm (<3rd centile), and head circumference was

27 cm (3–10th centile). Apgar scores were 1, 3, and 8 at 1, 5, and

10 min, respectively. MCA were noted immediately. The newborn

was intubated and transferred to the NICU. Abnormal findings on

physical exam included a wide open anterior fontanelle, low set

ears, apparent hypertelorism and possible microphthalmia, wide

flat nasal bridge, micrognathia and a short neck (Fig. 1a,b). There

was a higher insertion of the three vessel umbilical cord (Fig. 1a).

The penis was small and unusually rotated, testes were palpable

but undescended, and anus was posteriorly displaced (Fig. 1g). A

meningomyelocele was located at the lumbar region (Fig. 1h).

Several gross skeletal anomalies were remarkable. Both lower

extremities were deviated, femurs, tibiae and fibulae were elon-

gated, bilateral club feet (Fig. 1e) and minor syndactyly of the

second and third left toes were observed (Fig. 1f). In the upper

†First Year Fellow in Neonatal-Perinatal Medicine; 3rd year fellow at Tuft

University in Boston.‡Director NICU at East Jefferson General Hospital.

*Correspondence to:

Yves Lacassie, M.D., FACMG, Division of Genetics, Department of

Pediatrics, LSUHSC and Children’s Hospital, 200 Henry Clay, New

Orleans, LA 70118. E-mail: ylacas@lsuhsc.edu

Published online 22 December 2009 in Wiley InterScience

(www.interscience.wiley.com)

DOI 10.1002/ajmg.a.33173

How to Cite this Article:Patel S, Yazdani M, Barkemeyer B, Lacassie Y.

2010. An unusual phenotypic presentation of

trisomy 18.

Am J Med Genet Part A 152A:218–221.

� 2009 Wiley-Liss, Inc. 218

extremities the humerii were elongated but both radial and ulnar

bones appeared hypoplastic. The thumbs were hypoplastic, espe-

cially on the left where only a rudimentary and necrotic thumb was

present (Fig. 1c); the right thumb was pedunculated (Fig. 1d). No

overriding of the fingers was observed.

Short sternum and 11 ribs were observed on the chest X-ray

(Fig. 2b,c). No vertebral anomalies were noted, however, the

lumbar spine had a mild convexity to the left and a partial sacral

agenesis was evident (Fig. 2c,d). The upper extremities demon-

strated radii aplasia and ulnae hypoplasia. The right hand showed

four metacarpal bones with five phalanges; while the left hand had

only four metacarpal bones and phalanges (Fig. 2b). The head of the

femur and greater trochanteric area had two small ossification

centers bilaterally (Fig. 2a). The acetabulum was dysplastic. The

FIG. 1. a: Whole body showing major findings including severe deviation of lower extremities, abnormal hands, high insertion of umbilical cord, short

neck and dysmorphic face with low-set ears. b: Face with wide flat nasal bridge, micrognathia, low set ears and short neck. c: Left hand with necrotic

thumb. d: Right hand with pedunculated thumb. e: Lower extremities deviation, reverse dislocation of the right knee and club feet. f: Minor syndactyly

of the 2nd and 3rd left toes. g: Small and unusually rotated penis. h: Posteriorly displaced anus and meningomyelocele. [Color figure can be viewed in

the online issue, which is available at www.interscience.wiley.com.]

PATEL ET AL. 219

distal right tibia and fibula were laterally subluxed (Fig. 2a,d).

There was reverse dislocation of the right knee (Fig. 2a,d). There

were dense ossification centers in both ankles (Fig. 2a). Both feet

had five metatarsals and phalanges and rocker-bottom feet was

observed on the left (Fig. 2a). Skull X-ray showed a widely open

sagittal suture. Ultrasounds of the head and abdomen were normal.

A postnatal echocardiogram demonstrated a very small right

ventricle with a large VSD and ASD.

After initial review of the physical and radiologic findings,

Roberts syndrome seemed a possibility. Subsequently, however,

early in the morning, prenatal records were obtained including

result of the chromosomal analysis showing a full regular trisomy

18. The baby survived for approximately 5 hr. Finger patterns

showed six arches out of eight fingers examined. Parents refused

autopsy. Postnatal microarray-based comparative genomic hybrid-

ization confirmed the diagnosis of trisomy 18 showing also a

FIG. 2. a: lower extremities showing striking deformities (see text). b: Upper extremities showing radial aplasia and ulnar hypoplasia and only four

fingers on the left hand. c: Only 11 ribs, minor left convexity of the lumbar spine, and partial sacral agenesis. d: Whole view of the body.

220 AMERICAN JOURNAL OF MEDICAL GENETICS PART A

deletion of three BAC clones from the Xq/Yq pseudoautosomal

region at Xq28/Yq12. This was considered a normal variant

[Ravnan et al., 2006; Repping et al., 2006].

This patient illustrates the occasional atypical presentation of a

classic syndrome [Becerra et al., 1992; Collinsworth and Lacassie,

2008]. When the most consistent, characteristic and well-known

manifestations of classic syndromes are absent and less common

features are present, the clinical diagnosis may become more

challenging. A young mother giving birth to a male infant, without

overriding fingers and nail hypoplasia, along with other uncom-

mon findings, such as radial hypoplasia with hypoplastic thumbs,

deformed lower extremities with hyperextended right knee, me-

ningomyelocele and unusually rotated penis made the diagnosis

more challenging. Most of these uncommon abnormalities have

been reported in trisomy 18, especially the neural tube defects. It is

well known that meningomyelocele is more common in chromo-

somal abnormalities with an incidence of 9–10% [Kennedy et al.,

1998; Sepulveda et al., 2004]. The diagnosis in this unusual patient

was further complicated because of the lack of medical records,

the emergency nature of the premature delivery, and maternal

condition after birth including general anesthesia and post-ictal

state.

ACKNOWLEDGMENTS

We appreciate the contribution of the family, Dr. Ian D. Krantz for

his willingness to do further studies to rule out other differential

diagnoses, Dr. Kenneth Ward for radiological interpretation, Sara

Alliman, MS, for helpful discussions and Kelly Allerton for editorial

assistance.

REFERENCES

Becerra M, Moya F, Lacassie Y, Stopa A, Craver R. 1992. Clinico-patho-logical conference: A preterm infant with multiple congenital anomalies.Am J Med Genet 44:503–507.

Carey JC. 2005. Trisomy 18 and trisomy 13 syndromes. In: Cassidy SB,Allanson JE, editors. Management of genetic syndromes. 2nd edition.New York: Wiley-Liss, Inc. pp. 555–568.

Collinsworth A, Lacassie Y. 2008. An unusual presentation of Trisomy 13.Am J Med Genet Part A 146A:1490–1492.

Crider KS, Olney RS, Cragan JD. 2008. Trisomies 13 and 18: Populationprevalences, characteristics, and prenatal diagnosis, MetropolitanAtlanta, 1994–2003. Am J Med Genet Part A 146A:820–826.

Edwards JH, Harnden DG, Cameron AH, Crosse VM, Wolff OH. 1960. Anew trisomic syndrome. Lancet 1:787–789.

Jones KL. 2006. Smith’s recognizable patterns of human malformation.6th edition. Philadelphia: Elsevier, Inc. pp. 13–17.

Kennedy D, Chitayat D, Winsor EJT, Silver M, Toi A., 1998.Prenatally diagnosed neural tube defects: Ultrasound, chromosome,and autopsy or postnatal findings in 212 cases. Am J Med Genet 77:317–321.

Ravnan JB, Tepperberg JH, Papenhausen P, Lamb AN, Hedrick J, Eash D,Ledbetter DH, Martin CL. 2006. Subtelomere FISH analysis of 11688cases: An evaluation of the frequency and pattern of subtelomererearrangements in individuals with developmental disabilities. J MedGenet 43:478–489.

Repping S, van Daalen SKM, Brown LG, Korver CM, Lange J, Marszalek JD,Pyntikova T, van der Veen F, Skaletsky H, Page DC, Rozen S. 2006. Highmutation rates have driven extensive structural polymorphism amonghuman Y chromosomes. Nat Genet 38:463–467.

Sepulveda W, Corral E, Ayala C, Be C, Gutierrez J, Vasquez P. 2004.Chromosomal abnormalities in fetuses with open neural tube defects:Prenatal identification with ultrasound. Ultrasound Obstet Gynecol23:352–356.

Smith DW, Patau K, Therman E, Inhorn SL. 1960. A new autosomaltrisomy syndrome: Multiple congenital anomalies caused by an extrachromosome. J Pediatr 57:338–345.

Tanigawa T, Nakayama D, Miura K, Miura S, Shimada T, MasuzakiH. 2007. Prenatal ultrasonographic findings may be useful inpredicting the prognosis of trisomy 18. Prenatal Diagnosis 27:1039–1044.

PATEL ET AL. 221