Trisomy 9 is a rare and almost always fatal genetic disease. Partial or complete trisomy forms exist and lead to symptoms involving cardiovascular, urinary, nervous, skeletal, gastrointestinal and other systems. The diagnosis can be made prenatally through chorionic villus sampling, amniocentesis, karyotyping and ultrasonography. Neither treatment nor prevention strategies exist at this moment.
The clinical presentation is diverse and various organ systems may be affected       :
- Craniofacial abnormalities - Brachycephaly, enophthalmos, microphthalmia, micrognathia, hypertelorism, cleft lip and palate (CLP), large fontanels, downward slanting eyes, bulbous nose, downturned corners of the mouth, large and poorly lobulated low set ears and short neck have all been identified in trisomy 9 patients   . The Dandy-Walker malformation, involving the cerebellum and fourth ventricle, is commonly observed and is considered one of the hallmarks of this condition .
- Neurocognitive changes - Impaired psychomotor development and retardation, failure to thrive, growth retardation, as well as delayed communication and speech are typical findings.
- Soft-tissue - clinodactyly, camptodactyly, syndactyly, dystrophic nails.
- Genitourinary system - Genital and/or renal hypoplasia, horseshoe kidney, bicornuate uterus, cryptorchidism, penile abnormalities (micropenis)   .
- Gastrointestinal signs - Pyloric stenosis, gastro-oesophageal reflux are common findings, while rare cases include hypoplasia/agenesia of the gall bladder and biliary tract, but also adrenal glands .
- Cardiovascular - Congenital anomalies such as atrial and ventricular septal defects (ASD and VSD, respectively), but also patent ductus arteriosus are frequently encountered in these patients .
- Musculoskeletal - Scoliosis, kyphosis, loose joints, abnormally long and tapered fingers and toes, knee and hip dislocations, as well as bone absences (usually of the ribs, hands, and feet ), are frequent   .
Entire Body System
Multiple Congenital Anomalies
We report on a newborn infant with multiple congenital anomalies and apparent nonmosaic trisomy 9 in the blood (by conventional cytogenetic studies) who died shortly after birth. [ncbi.nlm.nih.gov]
Trisomy 9 mosaicism with multiple congenital anomalies. Journal of Medical Genetics, 10 (2), 180-184. [uthscsa.influuent.utsystem.edu]
Trisomy 9 mosaicism with multiple congenital anomalies. J Med Genet 1973;10:180–184. 2. Bowen P, Ying KL, Chung GSH. Trisomy 9 mosaicism in a newborn infant with multiple malformations. J Pediatr 1974;85:95–97. 3. [e-kjp.org]
A repeat scan at 23 weeks also revealed a dysmorphic face, bilateral microphthalmia, and a cerebellar vermian defect. Follow-up examinations showed progressive growth restriction leading to fetal death at 33 weeks of gestation. [ncbi.nlm.nih.gov]
Failure to Thrive
Neurocognitive changes - Impaired psychomotor development and retardation, failure to thrive, growth retardation, as well as delayed communication and speech are typical findings. [symptoma.com]
Jasmin says that her daughter has always been small for her age, and was diagnosed as failure to thrive at one point. Doctors in her native Florida recognized that this was part of her medical condition, and not something that her family caused. [medicalkidnap.com]
Hypotonia can affect infants, most often related to difficulty feeding, resulting in the failure to gain weight and grow at the expected rate (failure to thrive). In general, growth deficiency primarily begins after birth (postnatally). [rarediseases.org]
Some infants may also experience oropharyngeal dysphagia, in which there is difficulty emptying food or drink from the back of the throat at the back of the mouth (oropharynx) into the esophagus. [rarediseases.org]
Jaw & Teeth
hands, micropenis ( P10), small testes and hallux valgus. [ncbi.nlm.nih.gov]
limitation, cardiovascular defects and urogenital abnormalities. [ncbi.nlm.nih.gov]
She had: (1) severe psychomotor retardation; (2) short stature; (3) progressive microcephaly; (4) flat feet; (5) genu valgum; and (6) severe kyphoscoliosis. [ncbi.nlm.nih.gov]
Low-Set Posteriorly Rotated Ears
Dysmorphic features included low-set, posteriorly rotated ears with squared, simple helices, midface hypoplasia, a broad nasal root with wide nasal alae, small mouth, micrognathia, short neck, overlapping fingers, rocker-bottom feet, prominent heels, [ncbi.nlm.nih.gov]
Face, Head & Neck
Prominent Nasal Root
Manifestations such as microcephaly, prominent nasal root, bulbous nose, and down-turned corners of the mouth are common to patients with trisomic segments extending from 9p21 to 9q13, while intra-uterine growth retardation, cleft lip/palate, skeletal [ncbi.nlm.nih.gov]
Abnormalities are variable from individual to individual and may include mental retardation, retarded growth, flat hypoplastic face with short nose, prominent epicanthic skin folds, small low-set ears with prominent antihelix, fissured and thickened tongue [icd9data.com]
To make the diagnosis, a detailed prenatal assessment should be performed. Chorionic villous sampling (CVS) or amniocentesis are considered as gold standard in an evaluation of fetal chromosomal abnormalities  , while a determination of serum free βhCG and maternal serum alpha-fetoprotein (MSAFP) can be useful markers as well . Amniocentesis and CVS are invasive diagnostic methods that are not always taken lightly by women in their pregnancy, however, and the recent introduction of non-invasive prenatal testing (NIPT), comprised of DNA sequencing of placental trophoblasts located in the maternal circulation is becoming more commonly used in practice . In fact, certain reports have shown that NIPT was able to make the diagnosis with negative results of invasive methods . Conventional cytogenetic studies, mainly fluorescence in situ hybridization (FISH), can also be used in the diagnosis  . Fetal ultrasonography is an effective imaging study that can confirm any of the mentioned abnormalities and its role in prenatal care is pivotal . Because numerous structural disorders of the brain have been identified in patients, screening of all individuals with an MRI of the endocranium is highly advocated . Additionally, growth hormone deficiency should be investigated using appropriate diagnostic methods, as many individuals that have confirmed trisomies of any chromosome often have growth abnormalities .
There is no cure or targeted treatment for patients with trisomy 9 and the focus of care is aimed at alleviating present symptoms, but very few patients survive the first few years of life.
In general, the prognosis varies depending on the genotype. Complete trisomies result in spontaneous abortion in the vast majority of cases and newborns have a very short lifespan   . In fact, the mean age of death in the complete form is less than 21 days, with a range of 1-107 days . On the other hand, partial trisomies have shown to be compatible with life and few cases have been described in adults , but a correlation between the extent of mosaicism and the severity of symptoms has not been determined  Nevertheless, multiple cardiovascular, renal, skeletal, craniofacial, and gastrointestinal anomalies are present in virtually all patients, causing a profound effect on the quality of life .
The exact cause of this chromosomal disease remains unknown . Gametal nondisjunction errors during the first and second meiotic phase and subsequent lag of the anaphase in the pre-implantation embryo that undergoes the process of division, or mitotic nondisjunction in an early cell division have been hypothesized as possible mechanisms in partial and mosaic trisomy 9 , but so far, little progress has been made. Mutations may arise de novo or due to reciprocal translocation .
Trisomy 9 comprises approximately 2.7% of all trisomies , and is considered to be the fourth most common trisomy, after trisomies 21 (Down syndrome), 18 (Edward's syndrome) and 13 (Patau syndrome), with over 150 cases described in literature until the end of the first decade of the 21st century . Despite its rare discovery in clinical practice, it was shown that it is responsible for 2.4% of all spontaneous abortions . For still unknown reasons, this condition is more frequently encountered in mothers under 35 years of age . Although patient samples are very small when discussing gender predilections, a preponderance for female fetuses was seen when the diagnosis was made during prenatal assessment .
The pathogenesis model of trisomy 9 is unclear, but various genes involved in normal organogenesis and maturation have been identified on chromosome 9 :
- Thyroid transcription factor 2 gene (TTF2 or FOXE1) is expressed in the nasomaxillary area during embryogenesis and is shown to be important in a regulation of thyroid gland growth and development. In fact, conditions such as congenital hypothyroidism, thyroid agenesis, and cleft palate have been associated with FOXE1 mutations .
- Zinc-finger protein 189 (ZNF189) is another transcription factor located on chromosome 9, as is transforming growth factor-b receptor type 1 (TGFBR1), which regulates gene expression . PTCH gene, responsible for causing Gorlin syndrome and cleft lip palate as its main constitutive feature, may also be affected in trisomy 9 . Tyrosine kinase-like orphan receptor 2 (ROR2) is expressed in chondrocyte cell lineages and is involved in growth plate development .
Growth hormone deficiency, which might be one of the deciding factors that determine the extent of body changes in these patients, is rarely associated with trisomy 9, but one of the genes, LHX3, is in close connection to this phenomenon .
Because of the fact that there is no treatment for trisomy 9, prenatal screening and early identification of this genetic disease through fetal ultrasonography and both invasive and non-invasive diagnostic testing is vital in making an early diagnosis, which will aid in further decision making by the parents.
Initially described in 1973 , trisomy 9 is a rare genetic disease characterized by the presence of an additional chromosome 9 (complete trisomy 9) or some parts of it (partial trisomy 9) . Until 2010, a little over 150 patients have been described in the literature and the cause for this chromosomal aberration remains unknown  . Some individuals develop this condition de novo, while translocation between this chromosome and another autosome is mentioned as an underlying mechanism  . Various forms have been documented, including duplication of segments of either long or short chromosomal arms, whereas complete trisomy is the most severe form of the disease  . Namely, it is considered to be incompatible with life and often ends in spontaneous abortions (approximately 2.5% of all miscarriages are due to trisomy 9) . Fetuses suffering from partial forms, on the other hand, may survive pregnancy and the neonatal period, but they rarely reach adulthood . The primary reason is the appearance of numerous abnormalities of cardiovascular, genitourinary, gastrointestinal, musculoskeletal and central nervous systems, with various craniofacial changes, mental retardation, and congenital heart disease being some of the most prominent findings   . The diagnosis of trisomy 9 can be made during prenatal care when identification of pathological changes during fetal ultrasonography are supported by both invasive (chorionic villus sampling and amniocentesis) and noninvasive (DNA evaluation from a maternal blood through cytogenetic studies) diagnostic procedures . Treatment of patients who reach infancy is aimed at symptomatic measures, but profound mental and physical impairment is seen in virtually all cases, which is why early recognition of this genetic disease during prenatal assessment is vital.
Trisomy 9 is a very rare genetic disease in which there is an additional copy of chromosome 9 in cells. Normally, during the process of reproduction, the fetus inherits one copy of each chromosome from each parent and the DNA of each cell is packed into 23 pairs of chromosomes, but in some cases, an additional chromosome may be present, with most common examples being Down syndrome (trisomy 21), Edward's syndrome (trisomy 18) and Patau syndrome (trisomy 13). It is still not known why do these genetic events occur and many patients develop trisomies "de novo" or new mutations without any prior evidence of parental DNA abnormalities. Trisomy 9 is for some reason more frequently diagnosed in women below 35 years of age and it is estimated that about 2.4% of all spontaneous abortions are due to this genetic disease. There are two main forms: complete when the additional chromosome is fully formed and partial when only a certain fragment is present. The importance of this division lies in the prognosis, as complete forms are incompatible with life and very few cases that reached birth have been confirmed, while partial trisomy 9 may enable individuals to survive through infancy and childhood, but the overall outcome is poor, as only a few patients reached adulthood. The reason why this condition has a rather poor prognosis is that it leads to numerous abnormalities of the cardiovascular, musculoskeletal, craniofacial, and genitourinary systems. The patients who do survive have severely impaired physical and mental growth. The diagnosis can be made during prenatal care when fetal ultrasonography can detect these changes and mandate further testing of the fetal karyotype (state of chromosomes in terms of size, shape, and number). Current recommendations suggest that invasive procedures such as chorionic villus sampling (CVS) and amniocentesis should be performed in order to obtain a viable sample for testing. However, isolation of fetal DNA from a maternal blood through specific techniques has been recently introduced as a non-invasive method. There is no cure for this disease and the importance of an early diagnosis lies in providing women to consider their future steps regarding pregnancy.
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