Authors: Maher Ajour, Danielle Bryant, Brooke McKnight, Andrew Hayslett
Categories: Case Report, Trisomy 9 (T9), Trisomy 9 mosaicism (T9M), Neonatal pulmonary hypertension, Rare genetic disorders
Source: Journal of Medical Case Reports
Authors: Maher Ajour, Danielle Bryant, Brooke McKnight, Andrew Hayslett
Trisomy 9 is a rare chromosomal disorder that may occur as complete, partial, or mosaic trisomy. Trisomy 9 mosaicism is often incompatible with life and typically involves multiple congenital anomalies, especially affecting the limbs, craniofacial features, nervous system, and cardiovascular system. However, pulmonary complications are rarely reported.
We present an African American female infant, at 37 weeks and 2 days, diagnosed prenatally with trisomy 9 mosaicism (49%), identified via fetal echocardiogram that revealed multiple cardiac anomalies and intrauterine growth restriction. The infant exhibited micrognathia, dysmorphic facial features, absent external ears, and a two-vessel umbilical cord. Owing to critical airway obstruction from micrognathia, she was intubated at birth. After transitioning to non-invasive ventilation, her respiratory status deteriorated, and an echocardiogram showed an unrestrictive patent ductus arteriosus. She later experienced a pulmonary hypertensive crisis requiring re-intubation, high fraction of inspired oxygen, inhaled nitric oxide, and inotropes, followed by another transient pulmonary hypertensive crisis after patent ductus arteriosus closure. The infant was discharged home with oxygen. Her hospital course was complicated by various abnormalities, including mandibular distraction surgery, hearing loss from absent external ear canals, and retinopathy of prematurity, a rare condition in term infants. She also required gastrostomy tube placement for feeding intolerance and was diagnosed with supratentorial ventriculomegaly and corpus callosum thinning. Orthopedic evaluation revealed bilateral hip dysplasia, requiring closed reduction and Pavlik harness. A follow-up echocardiogram confirmed patent ductus arteriosus closure without pulmonary hypertension. Seizures, obstructive sleep apnea, and a persistent dry skin condition led to further genetic evaluation as an outpatient.
This case is unique for several micrognathia requiring distraction, absent external ears, severe pulmonary hypertension requiring patent ductus arteriosus closure, and long-term oxygen therapy. To our knowledge, this is the first reported trisomy 9 mosaicism case with such a severe pulmonary hypertensive crisis necessitating aggressive intervention. Although historically associated with poor outcomes, improved neonatal care contributes to increasing survival in infants with trisomy 9 mosaicism.
Trisomy 9 (T9) is a rare and complex genetic disorder that can present as a complete, partial, or mosaic trisomy, all of which are associated with multiple anatomical anomalies [1]. Complete trisomy is defined as a full extra chromosome in all cell lines. Partial trisomy results from a partial addition of genetic material traced back to unbalanced gamete meiosis, either from a balanced gamete or de novo. Mosaic trisomy occurs when only some of the cell lines have the full trisomy anomaly [2]. The percentage of affected cells varies from patient to patient, and this variation can influence the severity of the condition. Some individuals may only have a small proportion of cells with trisomy 9, leading to a relatively less severe phenotype.
This particular presentation is largely believed to be the most compatible with life. Prenatal diagnosis can be difficult owing to a large number of patients expiring in utero, and sonography is limited in viewing structural differences.
Most patients with trisomy 9 mosaicism (T9M) are not compatible with life, and the clinical picture for these patients includes multiple system malfunctions if they survive postnatally. Limb and craniofacial abnormalities, as well as involvement of the central nervous system (CNS) and cardiovascular system, are common. Involvement of the pulmonary system, however, has not been commonly reported [3]. In this case, we present a patient who developed pulmonary hypertension in the setting of several severe cardiac anomalies.
Our patient is an African American female infant born at 37 weeks and 2 days via cesarean section owing to malpresentation with the prenatal diagnosis of trisomy 9 mosaicism (T9M). Maternal–fetal medicine followed this patient prenatally for cardiac anomalies seen on fetal ultrasound and performed an amniocentesis. Noninvasive prenatal testing (NIPT) was negative, karyotype was normal (46,XX) but microarray showed T9M at 49%.
For this major mosaicism, prenatal work up was initiated. Fetal echocardiogram was significant for a dysplastic pulmonary valve, dysplastic aortic valve, moderately dysplastic tricuspid valve leaflets, moderately dysplastic mitral valve, small perimembranous ventricular septal defect (VSD), and a two-vessel umbilical cord.
She was born with intrauterine growth restriction (IUGR) attributed to cardiac abnormalities. Birth weight was 2100 g (< first percentile), birth length was 47 cm (16th percentile), and head circumference was 32 cm (third percentile). Following delivery, she demonstrated respiratory distress. She had a critical airway and severe micrognathia, requiring rigid bronchoscopy for intubation.
Notable features at birth included micrognathia, elongated nose with prominent nasal tip, high arched palate, low-set dysmorphic ears with no external ear canal (Figs. 1, 2), patchy hypopigmentation along Blaschko lines, left clubfoot, small umbilical hernia, and two-vessel umbilical cord.Fig. 1Skin of the abdomenFig. 2Skin of the legs
A postnatal echocardiogram showed a large patent ductus arteriosus (PDA), moderate secundum atrial septal defect (ASD), persistent left superior vena cava to coronary sinus, moderately dilated right ventricle with normal systolic motion, tricuspid valve regurgitation, dysplastic pulmonary valve with mild insufficiency, moderately dilated pulmonary artery, and a mildly dilated right atrium. Initial head ultrasound was significant for small bilateral choroid plexus cysts and a left germinolytic cyst. Abdominal and renal ultrasounds were normal.
Initial subspecialties involved in her care included pediatric genetics, pediatric palliative care, otolaryngology (ENT), and pediatric cardiology. Physical therapy, speech therapy, and occupational therapy were also engaged throughout her neonatal course.
Plastic surgery was consulted to evaluate the patient’s dysmorphic facial features, and she was diagnosed with Pierre Robin sequence due to micrognathia, glossoptosis, and upper airway obstruction, without a cleft palate.A three-dimensional (3D) computed tomography (CT) scan of the face revealed micrognathia, along with short and malformed condyles and rami of the mandible. Additional findings included bilateral microtia, bilateral external auditory canal atresia, atresia of the right middle ear cavity and ossicles, and potential fusion of the left incudomalleolar joint. After careful consideration, a decision was made to proceed with a bilateral mandibular distraction procedure on day of life (DOL) 7. She was successfully extubated on DOL 18 and transitioned to noninvasive mechanical ventilation (NIMV). The maximum distraction of the pins was achieved on DOL 28, and the pins were removed after 6 weeks.
Following pin removal, she had recurrent emesis and was unable to tolerate full volume feeds via nasogastric (NG) tube. Goal feeding volumes were decreased, and formula was fortified to ensure proper caloric intake. During her speech–language evaluation, it was noted that she did not have a coordinated mouth posture for latching and was unable to tolerate her secretions during an oral feed. Oral feeds resulted in desaturations with tachypnea, and it was deemed unsafe for her to continue oral trials. Emesis continued with NG tube feeds. An upper gastrointestinal (GI) study was obtained owing to suspicion of reflux but was normal. A multidisciplinary family meeting was held to discuss her lack of oral skills, and the decision was made to proceed with gastrostomy tube placement. She tolerated this procedure well and received an umbilical hernia repair at the same time. Following gastrostomy tube placement, she was able to tolerate continuous feeds with only intermittent emesis. Formula was ultimately fortified to 26 kcal/oz.
On DOL 25, owing to the inability to wean off NIMV, an echocardiogram was performed, revealing an unrestrictive PDA with left-to-right shunting and elevated right ventricular pressure, raising concerns for pulmonary hypertension. Pediatric cardiology recommended PDA closure when feasible, and diuretic therapy was initiated. However, after 3 days, her respiratory status worsened, requiring increased pressure and oxygen support. Despite maximized noninvasive respiratory support and continued diuretic therapy, she remained in respiratory distress and was intubated.
Repeat echocardiogram showed significant pulmonary hypertension and bidirectional PDA shunting, predominantly from right to left. A pulmonary hypertension treatment was initiated, including 100% fraction of inspired oxygen (FiO2) and inhaled nitric oxide. During this time, she required inotropes such as dobutamine for stabilization.
Once stabilized from the pulmonary hypertension crisis, the decision was made to proceed with PDA closure via a transcatheter procedure on DOL 43. After the procedure, she developed transient pulmonary hypertension, requiring inhaled nitric oxide for 2 days, and sildenafil therapy was started. She also received a course of periextubation dexamethasone and was extubated to NIMV on DOL 47. Her respiratory status continued to improve, and she was gradually weaned to 250 mL/minute low-flow nasal cannula (LFNC), on which she was ultimately discharged.
From a neurologic perspective, a subsequent head ultrasound showed mild supratentorial ventriculomegaly, chronic white matter volume loss with corpus callosum thinning and mildly dysmorphic lateral ventricular contours, and small volume intraventricular blood products in the left lateral ventricles. Owing to these findings, neurosurgery and pediatric endocrinology were consulted.
Neurosurgery opted for conservative management, monitoring daily head circumferences and conducting weekly head ultrasounds, which remained stable. A magnetic resonance image (MRI) obtained before discharge showed resolved germinal matrix hemorrhage and moderate ventriculomegaly affecting the occipital horns and third ventricle, suggestive of possible periventricular leukomalacia and white matter loss. In addition, there was nonspecific prominence of the subarachnoid spaces in the posterior fossa, likely indicating mild cerebellar volume loss. No further intervention was necessary, and she was scheduled for outpatient follow-up.
Endocrinology evaluated for risk of hypopituitarism owing to the head ultrasound findings. There was no concern for optic nerve hypoplasia, which was favorable for this patient. Screening laboratory tests were performed for central adrenal insufficiency, central hypothyroidism, hypogonadotropic hypogonadism, growth hormone deficiency, and diabetes insipidus. Of note, cortisol was suboptimal, but she tolerated multiple surgical procedures without a crisis, which made adrenal insufficiency unlikely. She was clinically euthyroid on evaluation, but luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol were elevated. Her electrolytes and glucose levels remained stable. No acute intervention was required while she was an inpatient and she was followed as an outpatient by endocrinology.
Ophthalmology performed an examination, which showed small palpebral fissures and a possible smaller left orbit compared with her right orbit. On the same examination, it was surprising to find retinopathy of prematurity on a term infant with stage 0 zone 2 bilaterally. Subsequent examinations resulted in stage 0 zone 3 bilaterally.
Audiology conducted an inpatient evaluation owing to ear malformations and noted some degree of hearing loss. However, further outpatient evaluation was recommended, as the bone conduction testing on the right side was inconclusive.
Orthopedic surgery was consulted owing to bilateral developmental dysplasia of the hips, with a dislocated left hip. It was determined that the patient would require outpatient formal closed reduction of the left hip, followed by the use of a Pavlik harness after discharge.
At almost 4 months old, she was ready to be discharged home on oxygen and continuous gastrostomy tube (G-tube) feedings with multiple subspecialist follow-ups. After about a week at home, she developed abnormal movements concerning for seizure, so her parents decided to have her evaluated in the emergency room. She was admitted to the hospital, and the electroencephalogram (EEG) confirmed the seizure. She was discharged on anti-epileptic medication.
After being discharged home, she had poor weight gain and was admitted to the hospital for work and to increase the calories in the formula. She developed hyponatremia with the high-calorie formula. In addition, she developed an asymptomatic epigastric hernia; she is following up closely with pediatric surgery for the time of repair.
She was evaluated by dermatology owing to her chronic dry skin; she was diagnosed with erythroderma covering 90% of her body surface area, intrinsic atopic dermatitis, and seborrheic dermatitis. She developed a staphylococcal and streptococcus skin infection at around 6 months old, which was treated with an outpatient antibiotic. Dermatology referred her to genetics for further workup of ichthyosiform disorders.
At 7 months old, she followed up with the cardiology clinic. An echocardiogram revealed no residual PDA, though a small atrial septal defect was noted, which is expected to close on its own. There was no indication of pulmonary hypertension. She was referred to pediatric pulmonology for evaluation of obstructive sleep apnea, which was confirmed by a sleep study.
In terms of other follow-ups, audiology confirmed bilateral mixed hearing loss, with poor bone conduction on both sides. Owing to her abnormal ear anatomy, a traditional hearing aid would not be suitable, but she may be a candidate for a cochlear implant in the future. Ophthalmology follow-up revealed pathological myopia bilaterally and microphthalmia in her left eye. Correction of her hip dysplasia is planned for around 8 months.
Despite exhibiting several physical characteristics commonly seen in other cases of T9M and experiencing various complications throughout her clinical course, her case is unique owing to the severe impact of a pulmonary hypertension crisis during her time in the NICU.
Mosaic trisomy 9 is a rare chromosomal abnormality that means some of the body’s cells have three copies of chromosome 9 (trisomy). In comparison, other cells have the usual two copies of this chromosome [4]. Its high lethality and very low prevalence make prenatal and postnatal diagnosis difficult. Most cases are not inherited; they occur sporadically as a random event during the formation of the gametes’ or as the fertilized egg divides. The prevalence of mosaic T9 is less than one in a million [5].
Children born with T9 usually die following birth or within 1 year of birth, whereas those born with T9M can survive into adulthood. It depends on how severe the symptoms are and how severe the mosaicism is. Multiple challenges are common and can involve different organ systems such as the heart, kidneys, brain and CNS, genital and urinary tract, muscles (hypotonia/hypertonia), and digestive tract. Phenotypic manifestations of T9M are variable between individuals. In this case, we have a rare presentation with micrognathia that required distractions, absence of external ears, and pulmonary hypertension crisis. Also, although our case was a term infant, she had a retinopathy of prematurity stage at birth, and she had a PDA that required closure by the device.
In the T9M case described in this report, the primary affected facial features displayed by the infant were severe micrognathia, glossoptosis, elongated nose with prominent nasal tip, high arched palate, and low-set dysmorphic ears with no external ear canal. Other features include patchy hypopigmentation skin lesions, left clubfoot, small umbilical hernia, and a two-vessel cord. However, in contrast to other infants with a similar T9 mosaicism, cardiac abnormalities are frequent (around 70% of cases), and the most common types are similar to this case, that is, ventricular and atrial septal defects and patent ductus arteriosus [6]. As far as we know, however, this is the first case report of mosaic T9 with a severe pulmonary hypertension crisis that required inhaled nitric oxide and sildenafil, as well as home oxygen and continued maintenance dose of sildenafil.
Many babies with T9M initially have hypotonia in the mouth and face muscles and facial anomalies that can cause difficulty feeding [7]. In this case, the severity of the micrognathia that required surgical intervention made the initiation of feeding difficult. After the procedure, the infant had severe regurgitation that did not improve with positioning, medication, or changes in formula. The only thing that helped the regurgitation and weight gain was extending the feeds to be continuous feeds, making the gastrostomy tube the ideal alternative to get this infant home.
Neuropsychomotor delays and intellectual disabilities are common among surviving patients with T9M. While no central nervous system abnormalities were initially observed in our patient, she presented to the emergency room after discharge with seizure-like activity, which was confirmed by an electroencephalogram (EEG). As a result, she was started on anti-epileptic medications.
Our patient is doing well and is now approaching 8 months of age. The mean survival of infants with T9M is still not known. Nevertheless, survival beyond the first year is considered uncommon [6]. For the patients with T9M, we believe that the advancements in health care over the past decades may have contributed to their improved outcomes and survival. This will make the difference in counseling parents prenatally about the outcome and the survival.
There are reports of patients with T9M living to as old as 24 years of age [8]. With advances in health care, it is reasonable to expect more patients with T9M to live longer, and this could make a difference in counseling parents prenatally.
T9M is a multifaceted genetic condition with varying degrees of severity. Although the prognosis for T9M has traditionally been poor, the increasing survival rates, especially beyond infancy, are likely a result of advances in medical care and early intervention [9]. Even when faced with complex and rare conditions such as micrognathia, absence of external ears, and pulmonary hypertension crises, ongoing supportive care, early medical interventions, and multidisciplinary management are key factors contributing to this improved survival and can be a vital part of the counseling and care plan for parents.