Cardiovascular Phenotypic Spectrum of 1p36 Deletion Syndrome

Abstract

Chromosome 1p36 deletion syndrome is a common genetic anomaly (prevalence: 1 in 5,000–1 in 10,000). Despite reports of cardiovascular involvement, the cardiovascular phenotypic spectrum of patients with 1p36 deletion syndrome is not well characterized. In this article, we reported the clinical course of a full-term African American boy with chromosome 1p36 deletion syndrome and neonatal onset of severe cardiac disease with moderate-to-severe biventricular dysfunction and severe pulmonary hypertension. Early neonatal onset presentation of 1p36 deletion syndrome is rare and might be associated with a more guarded prognosis. This case based study is supplemented by a comprehensive review of cardiovascular involvement in this relatively common genetic syndrome.

Introduction

Monosomy 1p36 or 1p36 deletion syndrome (OMIM no.: 607872), which is caused by a loss of a segment of DNA in the most distal band of the short arm of chromosome 1, is a relatively common genetic syndrome with a reported prevalence of 1 in 5,000 to 10,000 in the general population. ^{1 2} Molecular characterization and physical mapping of 1p36 in a cohort ( n  = 60) of patients with 1p36 deletion syndrome revealed true terminal deletions in 72% of the patients, whereas interstitial deletions and derivative chromosome were found in 7 and 17% of the patients, respectively, suggesting that variable genetic abnormalities underlie this syndrome. ³ For reasons that are unclear, females are more commonly affected than males. ⁴

Background

Since most of the common clinical features of 1p36 deletion syndrome were noted to occur with distal deletions which were smaller than 3 Mb, earlier studies suggested that no correlation between deletion size and phenotype existed, and the distal region was considered critical for the expression of 1p36 phenotype. ^{5 6} However, more recent studies have challenged this notion and shown that terminal and interstitial deletions of varying lengths located throughout the 30 Mb of DNA that comprise chromosome 1p36 contribute to phenotypic variability noted in patients with 1p36 deletion syndrome. A proximal and a distal critical region have been identified. The location and size of the deletions do matter with more critical regions being involved, as terminal deletions get larger and the phenotype of interstitial deletions is highly dependent on their gene content. ⁷ Several candidate genes associated with expression of 1p36 phenotype, such as MMP23B (∼1.6 Mb, delayed cranial suture closure), GABRD (∼1.95 Mb, neurodevelopmental abnormalities and seizures), SKI (∼2.15 Mb, dysmorphic features, hypotonia, motor delay, mental retardation, and facial clefting anomalies), and KCNAB2 (∼6.05 Mb, seizures) are located in the distal terminal approximately 6 Mb. An additional focus which is critical for hyperphagia and obesity has also been mapped to this region. ⁵ Nonoverlapping distal 1p36 deletions have been associated with similar phenotypic features suggesting a similar role for different deletions or positional effects where genetic alterations at one locus can modify the expression of genes at a distant locus. ⁵ More proximal 1p36 deletions, which are associated with musculoskeletal manifestations such as joint contractures, have also been reported. ⁵ The majority of deletions have been reported to occur on maternally derived chromosomes. ¹

Clinical Manifestations

Common clinical features of this syndrome include developmental delay; seizures; visual and hearing problems; hypotonia; and dysmorphic features such as mid facial hypoplasia, large anterior fontanelle, brachycephaly, straight eyebrows, deep set eyes, low set ears, and pointed chin. Other common features include musculoskeletal abnormalities, like clinodactyly and brachydactyly, which are associated with more proximal deletions, ⁵ hypothyroidism, and behavioral features, such as self-injury, aggression, and hyperphagia, similar to that seen in patients with Prader–Willi syndrome. ⁸ Rare manifestations include dental defects, ⁹ Duane syndrome, ¹⁰ cutis laxa and redundant skin, ¹¹ duodenal atresia, ¹² annular pancreas, intestinal malrotation, ¹³ and nasal pyriform aperture stenosis. ¹⁴ To date, over 100 studies have been published highlighting the genotypic and phenotypic features of this syndrome, and cardiovascular involvement, including congenital heart disease and cardiomyopathy, have been reported in children with deletions involving both the proximal or the distal critical regions ( Supplementary Tables S1 and S2 ; available in the online version). However, the cardiovascular phenotypic features of these patients have not been well characterized.

Diagnosis

Chromosome 1p36 deletion syndrome should be suspected in anyone with the above-mentioned constellation of clinical abnormalities. A multistep approach to diagnosis was suggested in the past. The initial step involved careful cytogenetic analysis and fluorescent in situ hybridization (FISH) with a probe containing the CDC2L1 locus. Subsequent steps involved the use of telomere length specific FISH probes to identify derivative chromosomes and using informative FISH probes in parents of those with the derivative chromosome to detect parental translocations. ² Pursuing FISH with at least two subtelomeric region-specific probes or comparative genomic hybridization microarray was also recommended. ¹⁵ More recently, array-based copy number detection assays that provide information on both the location and the extent of the deletion have superseded the prior diagnostic approaches. ⁷

Management

Given the broad range of clinical symptoms and disabilities in patients with 1p36 deletion syndrome, a comprehensive multispecialty team approach, involving specialists from general pediatrics, neurology, genetics, child development, speech therapy, ophthalmology, audiology, otorhinolaryngology, endocrinology and cardiology, is recommended for their care. During infancy and childhood, in addition to symptom-specific evaluation, cardiology and ophthalmology evaluations, audiological screening, thyroid function screening, developmental evaluation and prompt referral for early intervention, if needed, and genetic counselling are recommended. ¹⁵

Prognosis

There is a lack of systematic long-term follow-up studies in patients with chromosome 1p36 deletion syndrome. The evidence is therefore limited to patient reports. However, improvement in gross and fine motor abilities, adaptive behavior, and social interaction over time has been reported in some patients. ¹⁵

Case Report

Video 1 Markedly diminished left ventricular function, moderately diminished right ventricular function, moderate-to-severe right ventricular dilation, and bowing of interventricular septum into the left ventricle, suggesting markedly elevated right ventricular pressure, are noted on this parasternal short axis two-dimensional echocardiographic clip.

Download video file ^{(1.4MB, mp4)}

Video 2 Markedly diminished left ventricular function and mild to moderately diminished right ventricular function are noted on this apical four-chamber echocardiographic clip.

Download video file ^{(1.3MB, mp4)}

We reported the case of a full-term (39 weeks' gestation) small for gestational age (birth weight: 2,435 g; 1.97 percentile as per World Health Organization [WHO] growth chart) African American boy who was born via spontaneous vaginal delivery to a G2P1 mother. The mother had an uneventful antenatal course and there was no history of birth asphyxia. The patient was, however, noted to have respiratory distress at birth and required intubation and ventilation. The physical examination was notable for dysmorphic features including low set ears, widely spaced nipples, atypical facial ridges, flat nasal bridge, ocular hypertelorism, long philtrum, and scaphocephaly. Due to multiple episodes of desaturation on 100% oxygen and dysmorphology, an echocardiogram was obtained and showed a moderate-sized patent ductus arteriosus with bidirectional shunting, moderate-to-severe systolic dysfunction of the left ventricle, mild-to-moderate systolic dysfunction of right ventricle, and evidence of severe pulmonary hypertension with suprasystemic right ventricular pressure ( Videos 1 and 2 [available in the online version]; Fig. 1 ). The findings were corroborated by elevated age referenced plasma N-terminal pro-brain-type natriuretic peptide concentration (32,238 pg/mL, normal <141 pg/mL for infants, 1 month–1 year). ¹⁶ Because of progressively worsening cardiopulmonary status, dopamine (maximum dose: 25 µg/kg/min) and milrinone (maximum dose: 1 µg/kg/min) infusions were initiated on day 2 of life. Epinephrine (maximum dose 0.22 µg/kg/min), dobutamine (9 µg/kg/min), and hydrocortisone (1 mg/kg in every 6 hours) were added the next day due to a lack of improvement. Serial echocardiograms continued to show severe pulmonary hypertension for which therapy was initiated with inhaled nitric oxide (maximum dose: 40 ppm) and intravenous epoprostenol (maximum dose: 80 ng/kg/min). The pulmonary hypertension and ventricular function showed gradual improvement over the ensuing month. However, an echocardiogram obtained at that time continued to demonstrate a hemodynamically significant (left-atrial and left-ventricular dilations) moderate-sized patent ductus arteriosus with left-to-right shunting. A decision was made to treat the patent ductus arteriosus (PDA) and the patient ultimately responded to a second 5-day course of acetaminophen which was combined with four doses of indomethacin. The patient was eventually weaned-off inotropic and ventilator support and was discharged home on an age appropriate dose of captopril which was initiated for mild residual left ventricular dysfunction.

Fig. 1.

Continuous wave Doppler interrogation of the tricuspid valve shows severely elevated right ventricular pressure (peak tricuspid regurgitant jet velocity = 4.19 m/sec; right ventricular pressure estimate = 70 mm Hg plus clinical estimate of the right atrial v wave pressure).

Given the dysmorphic features, clinically significant biventricular systolic dysfunction and severe pulmonary hypertension of unknown etiology, genetic and metabolic evaluations were performed. Both the newborn and comprehensive metabolic screens did not show any abnormality. The whole genome microarray analysis however revealed an approximately 7.8 Mb heterozygous deletion in the terminal region of chromosome 1p36.33p36.23 {arr[GRCh37] 1p36.33p36.23(849466_7790627) X 1}, thus confirming the diagnosis of 1p36 deletion syndrome.

Additional testing included a brain magnetic resonance imaging (MRI) which showed delayed myelination for age and bilateral diffuse increase in T2 signal in the cerebral white matter. Additional findings included underdeveloped frontal lobes, inferior cerebellar vermis hypoplasia, and a small cystic cavity in the left caudothalamic groove. A renal ultrasound was also obtained and showed grade-2 hydronephrosis of the left kidney.

Following discharge from the hospital, the patient initially did well, but developed generalized seizures at 5 months of age. He was started on levetiracetam but was noted to have infantile spasms a few months later which necessitated a switch to adrenocorticotropic hormone. The patient continues to be on captopril (1.2 mg in every 8 hours, 0.34 mg/kg/day) which was initiated to prevent adverse cardiac remodeling. He was also started on digoxin (6 µg/kg divided twice a day) at 4 months of age which was discontinued at 12 months as pulmonary hypertension and biventricular systolic function had improved significantly. Over 18 months of follow-up, he has continued to do well from a cardiovascular standpoint, and his most recent echocardiogram showed normal biventricular systolic function and a small patent foramen ovale with left-to-right shunting. Ongoing problems include severe global developmental delay, hypotonia, and recurrent episodes of aspiration pneumonia which are thought to be related to reflux. He is currently being fed via a nasogastric tube but is being considered for surgical G-tube placement. His growth has been satisfactory (weight: ∼50th and height ∼85th percentile for age).

Discussion

We describe the clinical course of a newborn with 1p36 deletion syndrome who had severe pulmonary hypertension and significant biventricular dysfunction early in the neonatal period. He responded well to medical therapy with stabilization of cardiac function and continues to do well from a cardiovascular standpoint.

Since the cardiovascular involvement in patients with chromosome 1p36 deletion syndrome is not well characterized, we performed a comprehensive review of the data from 68 studies which included patients with 1p36 deletion syndrome ( Supplementary Table S1 ; available in the online version). A total of 818 patients were described in these studies out of which only 507 patients had 1p36 deletion syndrome. Cardiovascular involvement was noted in 211 (41.6%) of these patients ( Table 1 ; Supplementary Table S2 [available in the online version). These findings are consistent with the results of a previous study which reported cardiovascular abnormalities in 50% of the patients with 1p36 deletion syndrome. ¹⁷ Several patients had multiple cardiac abnormalities, hence 261 structural and functional cardiac defects were described in these 211 patients. Cardiac septal defects were highly prevalent (94/261; 36%) and predominantly consisted of ventricular septal defects (VSDs; 63/94; 67%). Atrial septal defects (ASDs) constituted the rest (33% [31/94]). PDA was the second most common clinically significant cardiac abnormality (52/94; 20%; Table 1 ). After physiological decrease in pulmonary artery pressures, persistent moderate- to large-sized patent ductus arteriosus is likely to lead to left heart enlargement and eventually cardiac failure. Since these patients are also predisposed to cardiomyopathy, often with onset in infancy, ¹⁷ the volume load imposed by the patent ductus arteriosus may be poorly tolerated. Our patient had moderate-to-severe biventricular dysfunction, severe pulmonary hypertension, and a moderate-sized hemodynamically significant patent ductus arteriosus at birth and was symptomatic in the immediate postnatal period. Such severe life-threatening early neonatal onset symptomatic cardiac involvement has only been reported in one patient. Saito et al reported a full-term female newborn with 1p36 deletion who was noted to have progressive pulmonary hypertension and congestive cardiac failure leading to death at 48 days of life. She also had intractable epilepsy and structural abnormalities of the brain including bilateral polymicrogyria and polyventricular nodular heterotopia. ¹⁸ Keppler-Noreuil et al also reported a term newborn with 1p36 deletion syndrome who had a patent ductus arteriosus and left ventricular dysfunction resulting in congestive heart failure at 3 weeks of age. The neonate, however, did well with complete resolution of cardiomyopathy at 2 years of age. ¹⁹ An additional patient who was born premature at 31 weeks' gestation and died within 48 hours of birth has been reported. ⁵ This patient had the tetralogy of Fallot and carried the largest contiguous 1p36 deletion (16 Mb, involving both the proximal and the distal 1p36 regions) reported to date. ⁶

Table 1. Cardiac abnormalities in patients with 1p36 deletion syndrome.

Cardiac abnormality	Number of defects ( n  = 261)	Percentage
Septal defects	94	36
ASD	31/94 ( n  = 94)	33
VSD	63/94 ( n  = 94)	67
PDA	52	20
Cardiomyopathy	40	15.3
LVNC	25/40 ( n  = 40)	62.5
DCM	12/40 ( n  = 40)	30
Unspecified	3/40 ( n  = 40)	7.5
Ebstein's anomaly	16	6.1
TOF	6	2.3
Valvular defects	25	9.6
Aortic and Pulmonary vessel defects	13	5
Others a	15	5.7

Abbreviations: ASD, atrial septal defect; DCM, dilated cardiomyopathy; DORV, double outlet right ventricle; HLHS, hypoplastic left heart syndrome; LV, left ventricle; LVNC, left ventricular noncompaction; PAPVR, partial anomalous pulmonary venous return; PDA, patent ductus arteriosus; PFO, patent foramen ovale; TOF, tetralogy of Fallot; VSD, ventricular septal defect.

Note: Total studies reviewed: 68; total number of patients in these 68 studies: 818; patients with 1p36 deletion: 507; patients with cardiac features related to 1p36: 211; 26 patients (12%) had complex chromosomal rearrangements and translocations; and total number of cardiac defects noted: 261.

^aOthers include: PFO, interatrial and trabeculated interventricular communications, dextrocardia with situs solitus, DORV, HLHS, PAPVR, positional anomaly of the sinus of Valsalva, left ventricular dilation without cardiomyopathy, and infundibular stenosis of right ventricle.

In addition to congenital cardiac defects, cardiomyopathies are common in patients with 1p36 deletion syndrome. Of 261 cardiac abnormalities reported in these patients, cardiomyopathies comprised 15.3% (40/261); left ventricular noncompaction (LVNC) cardiomyopathy was more prevalent (25/40; 62.5%) than dilated cardiomyopathy (DCM; 12/40; 30%). These findings are consistent with the findings of a prior study which reported on a smaller cohort of patients ( n  = 60). ¹⁵ Given the variability in both the time of onset of cardiomyopathy ^{20 21} and the severity of ventricular dysfunction, serial clinical cardiovascular evaluation is warranted with not only electrocardiographic and echocardiographic monitoring but also with cardiac MRI which has a higher sensitivity than echocardiography. ²²

Complex congenital heart defects, such as Ebstein's anomaly ( n  = 16 [6.1%]) and the tetralogy of Fallot ( n  = 6 [2.3%]), are less common in these patients. In contrast, valvular anomalies ( n  = 25 [9.6%]) are fairly common ( Table 1 ). The aortic valve is most commonly affected and the reported findings include bicuspid aortic valve, dysplastic aortic valve, aortic regurgitation, aortic stenosis, positional anomaly of the sinus of Valsalva, and aortic valve prolapse. Tricuspid regurgitation and pulmonic valve stenosis have rarely been reported. Of note, mitral valve anomalies have not been reported in patients with 1p36 syndrome to date.

Vascular anomalies affecting the aorta and the pulmonary vasculature were noted in 5% (13/261) of the patients. These include coarctation of aorta, dilated aortic root, hypoplastic and narrow aortic arch, right aortic arch, dextroposition of aorta, pulmonary atresia, and left pulmonary artery stenosis.

A small proportion of patients (5.7%) with cardiac involvement had dextrocardia with situs solitus, double outlet right ventricle, hypoplastic left heart syndrome, and partial anomalous pulmonary venous return ( Table 1 ).

As discussed earlier, underlying genetic loci responsible for many of the structural and functional abnormalities have been defined and mapped to both the critical proximal and distal regions ⁶ ; however, the precise genetic determinants that lead to cardiovascular abnormalities in patients with 1p36 deletion syndrome are not well defined. Recent studies have identified several genetic loci which are highly associated with cardiovascular abnormalities in patients with 1p36 deletion syndrome. PRDM16 acts as a transcription factor with zinc finger DNA-binding domains and positive regulatory, repressor, and acidic domains. PRDM16 -deficient mice have gross cardiac ventricular hypoplasia, lending credence to the notion that PRDM16 plays a key role in cardiac development. PRDM16 has a dominant-positive effect on cardiomyocyte proliferation in zebrafish where either activated or repressed levels of activity of PRDM16 impair cardiomyocyte proliferation. Arndt et al studied patients with 1p36 deletion syndrome who had LVNC or DCM and were able to identify a minimal interval containing only part of a single gene ( PRDM16 ) in these patients, suggesting that mutations in this gene are critical to expression of these phenotypes. ²³ Arginine-glutamic acid dipeptide repeats ( RERE ) is located in the proximal 1p36 critical region. RERE is a widely expressed nuclear receptor coregulator that positively regulates retinoic acid signaling. Animal models suggest that RERE deficiency might contribute to many of the structural and developmental birth defects, including congenital heart defects in individuals with 1p36 deletion syndrome. Fregeau et al reported 10 patients with 1p36 deletion syndrome and RERE sequence changes, 40% of whom had congenital heart defects such as VSD and PDA. ²⁴ Jordan et al reported nine patients with neurodevelopmental disorder and abnormalities in RERE , four of whom also had congenital heart defects (ASD [ n  = 3], VSD [ n  = 1], and truncus arteriosus [ n  = 1]). ²⁵ The authors also showed that point mutations affecting the atrophin-1 domain of RERE are associated with an increased risk of structural eye defects, congenital heart defects, renal anomalies, and sensorineural hearing loss than loss-of-function variants that are likely to lead to haploinsufficiency. ²⁵ Drosophila split ends homolog gene ( SPEN ) encodes a transcriptional repressor commonly deleted in proximal del1p36 syndrome and is located centromeric to the proximal 1p36 critical region. ²⁶ Radio et al recently reported 34 individuals with truncating variants in SPEN and a neurodevelopmental disorder which overlapped with 1p36 deletion syndrome. ²⁶ Congenital heart defects were reported in 64% of these patients. ²⁶

Though systematic long-term studies are lacking and the data are limited to patient reports, the prognosis of patients with 1p36 deletion syndrome and cardiovascular involvement appears to be good. Our patient and most of the other reported patients were able to recover well either with appropriate medical therapy or after correction of congenital cardiac abnormalities. ^{11 19 27} However, two of the three previously reported patients with 1p36 deletion syndrome and neonatal presentation died early due to cardiorespiratory failure. These findings suggest that the prognosis in patients with neonatal onset symptomatic cardiac disease could be more guarded. ^{5 18 19}

Conclusion

Cardiac involvement is common in patients with 1p36 deletion syndrome. Left-to-right shunts, such as atrial and VSDs, and patent ductus arteriosus constitute a vast majority of these abnormalities. These patients are also at a risk for developing cardiomyopathy which can worsen the hemodynamic perturbations associated with left-to-right shunts. Given the risks, serial clinical cardiovascular evaluation with appropriate imaging studies is of importance in patients with 1p36 deletion syndrome. Patient reports suggest that patients with 1p36 syndrome and symptomatic cardiovascular involvement who present in the neonatal period might have a more guarded prognosis.

Funding Statement

Funding None.