Unidad de Perinatologia, Maternidad Las Acacias ,Valencia, Venezuela; ^# Nashville TN

Synonyms: None.

Definition: Trisomy 9 is a genetic disorder characterized by an extra chromosome 9. It is a very rare chromosomal abnormality, which in most cases results in first trimester spontaneous abortion, therefore is rarely seen at near term. Most of those individuals that survive to be born at term are mosaics [2] ^{, [3] , [4] , [5]} .

Trisomy 9 is a chromosomal anomaly associated with specific patterns of multisystem dysmorphism and a wide spectrum of congenital anomalies which affect every possible fetal system with craniofacial, cardiac, skeletal, genitourinary and central nervous system malformations. The phenotypic appearance of the affected individuals varies greatly according to the affected organs, and almost always proves fatal shortly after birth.

Case presentation:

The ultrasound characteristics observed in a fetus with a specific chromosomal anomaly is what we have termed Echo-phenotype. The same chromosomal anomaly can have different form of presentation and that different presentations may be observed in different times along the pregnancy.

Case

A 26 years-old primigravida was referred at 22 weeks pregnancy to our Unit because of a suspected malformed fetus. The sonographic study revealed the following findings:

• 22 weeks biometry,
• hypertelorism,
• Dandy-Walker anomaly,
• absent nasal bones,
• cardiopathy (right heart hypoplasia, critic stenosis of the pulmonary artery, ventricular septal defect, overriding aorta),
• clinodactyly,
• brachydactyly,
• bilateral club foot,
• narrow thorax with pectus excavatum.
• The pulsed Doppler study showed a normal ductus venosus wave. The color Doppler study demonstrated a single umbilical artery. These are the images of the case:

Head-thorax disproportion

Dandy-Walker anomaly

Hypertelorism

Left ventricular cavity

Dilated aorta

Pulmonary stenosis

Normal ductus venosus Doppler wave

Pectus excavatum

Brachydactyly / clinodactyly

Rockerbottom  foot 

Single umbilical artery

And the chromosomes with the extra chromosomes 9.

History: Feingold and Atkins first described Trisomy 9 in 19732 with an example of a child with full trisomy 9 utilizing blood lymphocytes. In that same year Haslam et al. also reported a case of trisomy 9 mosaicism15 . Pfeiffer in 1984 and Francke in 1975 first described the prenatal diagnosis in this genetic disorder. Up to 1998 more than 70 cases had been reported2 ^{, [7]} .

Incidence: Unknown.

Prevalence: Trisomy 9 is a chromosomal disorder of rare occurrence and it comprises only 2.7% of all trisomic cases1 ^,4 . Almost 85% of cases occur in mothers younger than 35 years [8] .

Etiology: This chromosomal abnormality may be present in one of three ways1 :

• Complete trisomy 9
• Mosaic trisomy 9
• Partial trisomy 9p and 9q syndromes

Complete trisomy 9 (non mosaic) and mosaic trisomy 9 are due to meiotic or mitotic non-disjunction, unassociated with parental age [9] .  The incidence and severity of malformations and mental deficiency correlate with the percentage of trisomic cells in the different tissues15 .

In 50% of the cases, trisomy 9p occurs de novo, and the remainders are the result of a familial balanced rearrangement9 .

Trisomy 9q may be a result of an inherited unbalanced translocation from a parent with a balanced translocation. However, de novo cases of trisomy 9q have been described9 .

Pathogenesis: Autosomal trisomic syndrome, Considering the wide variety of anomalies seen in this trisomy, the presence of an extra chromosome 9 can be presumed to present a serious disruption to embryogenesis9 . Genes that could potentially be involved in the formation of the Dandy-Walker phenotype are transcription factors or genes responsible for the regulation of normal and in particular cerebral development but also adhesion molecules. One cause for the Dandy-Walker malformation could be a gene dosage effect of genes located in 9pter-9q22. ¹⁰

Diagnosis: Ultrasonographic findings may orient the diagnosis of a chromosomal abnormality. However, no pathognomonic sonographic criteria exist to ascertain the diagnosis of trisomy 9. However, echographic indicators are useful tools for a correct prenatal diagnostic interpretation ^11,12,13

Routine cytogenetic testing limited to lymphocytes used in earlier studies may not be enough. Geneticists highly recommend that complete trisomy 9, generalized mosaicism, pseudomosaicism or mosaicism confined to the placenta, should be differentiated from each other. In amniotic fluid this is often difficult and complicated by the absence of the trisomic cell line in different tissues. Since the prognosis, survival and life span of the affected individuals highly differ, to provide an appropriate clinical management the prenatal analysis should include5 ^-8

• FISH (Fluorescent In Situ Hybridization) studies conducted in a large number of interphase cells in dishes with or without trisomy 9 colonies. FISH allows the rapid detection of numerical chromosome aberrations in a large number of cultured as well as uncultured cells.
• FISH studies on direct cell preparations from other compartment and or tissue.
• Karyotyping from another tissue and/or compartment.

Clinical findings:  Infants with non-mosaic trisomy 9 are more severely affected than those with mosaicism4 . However, clinical features in non-mosaic and mosaic trisomy 9 usually overlap4 . Multisystem abnormalities are generally encountered in the affected individuals1 ^,2 ^,3 ^,4 ^,6 ^,8 ^,9 ^{,, [10] , [11] , [12] , [13] , [14] , [15]} :

• Craniofacial anomalies: micrognathia (retrognathia); low set anomalous ears; deep-set posterior rotated ears; small palpebral fissures; and broad based nose (prominent nasal bridge) with bulbous tip; microcephaly; wide fontanels and sutures; microphthalmia; anophthalmia; short webbed neck; high palate; cleft lip and palate.
• Cardiac defects: Congenital heart defects have invariable been found; ventricular septal defects; atrial septal defects; persistent left superior vena cava; double outlet right ventricle; patent ductus arteriosus; aortic coarctation; bicuspid pulmonary valve; hypoplastic left atrium or ventricle; pulmonic stenosis.
• Skeletal abnormalities: fixed or dislocated large joints, especially hips and knees, hypoplastic or aplastic bones and hand anomalies are the most common. Other skeletal problems include cranial asymmetry and craniosynostosis; shortened long bones; widening of cranial sutures; dislocations of elbows, radius, wrist, fingers; rocker-bottom feet; hyperconvex nails; overriding of fingers (clinodactyly); brachymesophalangy (hypoplastic phalanges); and clubfoot; decreased calcification of the cranium.
• Genitourinary anomalies: hypoplastic external genitalia; cryptorchidism; hypospadia; double collecting system; subcapsular renal cysts; renal hypoplasia or aplasia; duplication of renal artery; diverticula of the bladder; hydronephrosis; cystic dilatation of the renal tubules with echogenic parenchyma; horseshoe kidney.
• Central nervous system anomalies: brain malformations; neurodevelopmental delay; spina bifida; hypoplasia of the cerebellar vermis; hydrocephalus; Dandy-Walker malformation; subarachnoid cysts; dilated lateral ventricles (bilateral ventriculomegaly); enlarged cisterna magna.
• Others: growth restriction is almost an invariable feature; polyhydramnios; oligohydramnios; liver calcifications; single umbilical artery; Crohn’s disease; diaphragmatic hernia; fetal hydrops; cystic hygroma; hypoplastic lungs; gut malrotation.

Sonographic findings: Detailed prenatal ultrasonographic findings of all fetal anomalies and their incidence have not been described in the literature4 . However, we will list some of the findings that could potentially be seen with ultrasonography according to what has been published ^{16,17,18,19,20,21}

• Craniofacial:

?       Micrognatia (retrognathia)

?       Broad based nose (prominent nasal bridge)

?       Microcephaly

?       Microphthalmia

?       Anophthalmia

?       Cleft lip and palate

·           Cardiac defects:

?       Ventricular septal defects

?       Atrial septal defects

?       Double outlet right ventricle

?       Aortic coarctation

?       Hypoplastic left atrium or ventricle

?       Pulmonic stenosis

• Skeletal abnormalities:

?       Hypoplastic or aplastic bones

?       Hand anomalies

?       Cranial asymmetry and craniosynostosis

?       Shortened long bones

?       Rocker-bottom feet

?       Overriding of fingers (clinodactyly)

?       Brachymesophalangy (hypoplastic phalanges)

?       Clubfoot

?       Decreased calcification of the cranium.

• Genitourinary anomalies:

?       Hypoplastic external genitalia

?       Double collecting system

?       Renal hypoplasia or aplasia

?       Diverticula of the bladder

?       Hydronephrosis

?       Horseshoe kidney

• Central nervous system anomalies:

?       Brain malformations

?       Spina bifida

?       Hypoplasia of the cerebellar vermis

?       Hydrocephalus

?       Dandy-Walker malformation

?       Dilated lateral ventricles

?       Enlarged cisterna magna

• Others:

?       Growth restriction

?       Polyhydramnios

?       Oligohydramnios

?       Liver calcifications

?       Single umbilical artery

?       Diaphragmatic hernia

?       Fetal hydrops

?       Cystic hygroma

In the first trimester suspicious findings reported are: increase nuchal translucency, two-vessels cord, reverse flow in the Doppler of umbilical vein and ductus venosus ¹⁹. There are also reports of smaller than expected fetal crown-rump length, bilateral pyelectasis, hyperechoic bowel, echogenic intracardiac focus and ventricular septal cardiac defects.

In the second and third trimester: microcephaly, cloverleaf skull, dolicho/scaphocephaly, brain anomalies (cerebellar anomalies, ventriculomegaly, choroids plexus cysts), cleft lip and palate, micrognathia, microphthalmia, low-set malformed ears, hypertelorism, corneal opacities, short and webbed neck, heart defects (ventricular septal defects, atrial septal defects, valve defects, double outlet right ventricle, persistent left superior vena cava and endocardiac fibroelastosis), 13 ribs and 13 thoracic vertebrae, diaphragmatic hernia, renal anomalies (multicystic kidneys, dysplastic kidneys, hydronephrosis and hydroureter), genital anomalies.

In the case presented here the findings were: head-thorax disproportion with narrow thorax and pectus excavatum, Dandy-Walker anomaly with cerebellar hypoplasia, hypertelorism, absent nasal bones, right heart hypoplasia with pulmonary stenosis, ventricular septal defect with overriding dilated aorta, clinodactyly, brachydactyly, club foot, single umbilical artery and normal ductus venosus Doppler wave.

Differential diagnosis: Multiple malformation syndromes which include severe growth retardation and congenital heart disease such as trisomy 8, 13, 18 (see table below), triploidy and deletion 4p- (Wolf-Hirschhorn syndrome).

TABLE 1: ECHO-PHENOTYPE OF TRISOMIES

Prognosis: Almost all the affected fetuses, especially those with complete trisomy 9 and mosaic trisomy 9, are miscarried spontaneously in the first trimester. Most of the survivors (usually mosaic forms of the disease) usually die in the immediate neonatal period or within the next few days after birth. Survival beyond four months is unusual9 . Almost invariably, growth restriction and a congenital heart defect, which are present in association to other major and/or multiple malformations, contribute to the worst prognosis⁴ .

For those trisomy 9 mosaics that survive, failure to thrive and severe motor and mental deficiency are the rule. Some remain bedridden throughout their lives, whereas others achieve speech and ability to walk¹⁵ .

In cases of trisomy 9p, mayor structural malformations are infrequent and life expectancy is not diminished. Life span is more likely to be diminished if trisomy 9p is associated with other chromosomal abnormalities⁹ .

Management: when ultrasound findings are consistent with trisomy 10, prenatal karyotyping should be undertaken. Pregnancy termination should be considered. In the case of trisomy 9 mosaicism detected in amniotic fluid analysis or in chorionic villus sampling it is necessary to perform it in fetal blood or tissues to confirm a definitive diagnosis, it is advisable to study the parent in order to establish the parental origin of the anomaly.

Reference

[1] Roshanfekr D, Dahl-Lyons C, Pressman E, Ural S, Blakemore K.Complete trisomy 9 in a term fetus: a case report.J Matern Fetal Med. 1998 Sep-Oct;7(5):247-9

[2] Seller MJ, Bergbaum A, Dacker MG. Trisomy 9 in an embryo with spina bifida. Clinical Dysmorphology. 1988, 7;217-219

[3] Pinette MG, Pan Y, Chard R, Pinette SG, Blackstone J. Prenatal diagnosis of nonmosaic trisomy 9 and related ultrasound findings at 11.7 weeks. The Journal of Maternal Fetal Medicine. 1988, 7;48-50

[4] Sandoval R, Sepulveda W, Gutierrez J, Be C, Altieri E. Prenatal diagnosis of nonmosaic trisomy 9 in a fetus with severe renal disease. Ginecologic and Obstetric investigation,1999;48:69-72

[5] Cantu E, Eicher DJ, Pai S, Danahue CJ, Harley RA. Mosaic vs nonmosaic trisomy 9: report in a liveborn infant evaluated by fluorescence in situ hybridization and review of the literature. American Journal of Medical Genetics. 1966, 62:330-335

[6] Bureau YA, Fraser W, Fouquet B. Prenatal diagnosis of trisomy 9 mosaic presenting as a case of Dandy Walker malformation. Prenatal Diagnosis. 1993 Feb;13(2):79-85.

⁷Van den Berg C, Ramlakhan SK, Van Opstal D, Brandenburg H, Halley DJ, Los FJ.  Prenatal diagnosis of trisomy 9: cytogenetic, fish, and DNA studies. Prenat Diagn. 1997 Oct; 17(10):933-40

⁸McDuffie RS Jr. Complete trisomy 9: case report with ultrasound findings. Am J Perinatol. 1994 Mar;11(2):80-4

9 Buyse ML: Birth Defect Encyclpedia. Cambridge , England , Blackwell Scientific, 1990

¹⁰ Saura R, Traore W, Taine L, Wen ZQ, Roux D, Maugey-Laulom B, Ruffie M,

Vergnaud A, Horovitz J. Prenatal diagnosis of trisomy 9. Six cases and a review of the literature. Prenat Diagn. 1995 Jul; 15(7):609-14.

¹¹ Chitayat D, Hodgkinson K, Luke A, Winsor E, Rose T, Kalousek D. Prenatal diagnosis and fetopathological findings in five fetuses with trisomy 9.Am J Med Genet. 1995 Apr 10; 56(3):247-51.

¹² Benacerraf BR, Pauker S, Quade BJ, Bieber FR. Prenatal sonography in trisomy 9 Prenat Diagn. 1992 Mar; 12(3):175-81.

¹³Benacerraf B.Ultrasound of Fetal Syndromes. Churchill Livingstone.USA.1998:312-14

1⁴Chen CP, Shih JC. Prenatal diagnosis of bilateral ventriculomegaly and an enlarged cisterna magna in a fetus with partial trisomy 9 and partial trisomy 21. Prenat Diagn. 1999 Dec;19(12):1175-6

¹⁵Chitayat D, Hodgkinson K, Luke A, Winsor E, Rose T, Kalousek D. Prenatal diagnosis and fetopathological findings in five fetuses with trisomy 9. Am J Med Genet. 1995 Apr 10;56(3):247-51

¹⁶Smoleniec JS, Davies T, Lunt P, Berry PJ, James D. Complex mosaicism associated with trisomy 9. Prenat Diagn. 1993 Mar;13(3):211-3

¹⁷Benacerraf BR, Pauker S, Quade BJ, Bieber FR. Prenatal sonography in trisomy 9. Prenat Diagn. 1992 Mar;12(3):175-81

¹⁸Jones K.  Smith’s Recognizable Patterns of Human Malformation. Saunders. 5^th Edition. 1997. Pg 28

¹⁹Murta C, Moron A, Avila M, Franca L, Vargas P. Reverse flow in the umbilical vein in a case of trisomy 9. Ultrasound Obstet Gynecol. 2000 Nov; 16(6):575-7.PMID: 11169355

²⁰ McDuffie RS Jr. Complete trisomy 9: case report with ultrasound findings. Am J Perinatol. 1994 Mar; 11(2):80-4.

²¹ Merino A, De Perdigo A, Nombalais F, Yvinec M, Le Roux MG, Bellec V. Prenatal diagnosis of trisomy 9 mosaicism: two new cases. Prenat Diagn. 1993 Oct; 13(10):1001-7.