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Potocki-Lupski syndrome (PTLS) is a recently described microduplication syndrome associated with duplication 17p11.2, including the RAI1 gene. Features of PTLS include hypotonia, feeding difficulties, failure to thrive, developmental delay and behavioral abnormalities including autistic spectrum disorder, anxiety, and inattention. Cardiovascular anomalies were not recognized as a feature of duplication 17p11.2 until 2007 when noted in over 50% of a clinically-characterized cohort. We report on a patient with hypoplastic left heart syndrome whose diagnosis of PTLS was delayed until a genetic evaluation at age 4 years because of severe expressive language impairment. We suggest that array comparative genomic hybridization be performed in infants with severe congenital heart defects.
Potocki-Lupski syndrome (PTLS: MIM 610883) is a developmental disorder associated with a chromosomal microduplication of 17p11.2. The majority of PTLS patients harbor a 3.7 Mb duplication, however, duplications as small as 125 kb, containing only the RAI1 gene have been identified [Potocki et al., 2007; Zhang et al., 2010]. Clinical features of PTLS typically include hypotonia, poor feeding, failure to thrive, and developmental delay during infancy; speech and language impairment, inattention, and hyperactivity in early childhood; and intellectual disability, autistic spectrum disorder, and behavioral abnormalities in older children [Potocki et al., 2007; Treadwell-Deering et al., 2010]. The phenotypic spectrum in adults with PTLS has not been determined. Cardiovascular abnormalities were not reported in persons with duplication 17p11.2 until multiple subjects were studied systematically in a multidisciplinary clinical protocol [Potocki et al., 2007]. Herein, we report on the clinical findings of an individual with PTLS and hypoplastic left heart syndrome (HLHS), review the genetic aspects of left ventricular outflow tract (LVOT) malformations as they relate to this genomic disorder, and discuss the utility of array comparative genomic hybridization (aCGH) in the evaluation of individuals with congenital heart defects (CHD).
We report on a 9-year-old male with Potocki Lupski syndrome (PTLS: OMIM 610883) and hypoplastic left heart syndrome (HLHS) who was diagnosed with duplication 17p11.2 at age 4 years by G-banded chromosome analysis performed because of developmental delay and severe speech and language impairment. He was a product of an uncomplicated pregnancy and born at 40 weeks gestation by vaginal delivery with a birth weight of 3540 grams (75th–90th centile). Hypotonia and oxygen desaturations were noted in the immediate post-natal period and at 12 hours of life an echocardiogram revealed HLHS with aortic atresia and a nonfunctioning mitral valve. At 7 weeks he had abnormal arm movements with eye deviation. An EEG revealed diffuse changes without a seizure focus; repeat EEG was normal. He underwent an orthotopic heart transplantation at the age of 10 weeks, and remained in hospital for the first 3 months of life. Poor feeding with lack of suck and oral dysphagia were evident prior to and after the transplant and he required TPN perioperatively, nasogastric tube feeds during the first 2 months of life, and supplemental high calorie formula during infancy and early childhood.
Global developmental delay was noted in infancy and initially attributed to effects of cardiac transplant surgery. He rolled at 6 months, sat at 11 months, started walking at 18 months, and at the time of diagnosis had a vocabulary of only 3 words. He had several neurologic evaluations during infancy for hypotonia and developmental delay, none of which included a chromosome analysis. Behavioral history was significant for repetitive and obsessive-compulsive behaviors and he was diagnosed with sensory integration dysfunction.
Analysis by a custom human 17p array performed on a research basis, soon after the initial diagnosis, revealed a common-sized (3.7 Mb) duplication of 17p11.2. The molecular results were previously reported [Potocki et al., 2007]; however the patient’s clinical history was not included. At age 9 years and 10 months he was enrolled in an Institutional Review Board (IRB) approved multidisciplinary clinical protocol at Baylor College of Medicine and Texas Children’s Hospital. Physical examination at that time showed weight and FOC at the 50th centile, and height at the 25–50th centile. Mildly dysmorphic facial features include bilateral epicanthal folds, upslanting palpebral fissures, and mild micrognathia (Fig 1). He tested in the moderate range of intellectual disability and did not meet criteria for autism by formal testing. Findings were also significant for borderline hypertension, decreased renal size (2 standard deviations below the mean) by ultrasound, and periodic limb movement disorder without evidence of sleep disordered breathing.
Potocki-Lupski syndrome, initially known as 17p11.2 duplication syndrome, is the first predicted reciprocal microduplication syndrome described, as the chromosomal duplication represents the predicted non-allelic homologous recombination (NAHR) reciprocal of the Smith-Magenis syndrome (SMS: MIM 182290) microdeletion [Chen et al., 1997; Potocki et al.2000; Lupski, 2009]. The majority of PTLS patients identified to date harbor a causative common 3.7 Mb duplication copy number variant (CNV) generated by NAHR between the distal and proximal SMS-REPs; however, uncommon recurrent duplications, nonrecurrent PTLS rearrangements, and duplications associated with marker chromosomes, have also been described [Potocki et al., 2007; Yatsenko et al., 2005; Zhang et al., 2009 and 2010]. Clinical features of PTLS include hypotonia, cognitive impairment, autistic features and behavioral abnormalities, failure to thrive, sleep disordered breathing, and structural cardiovascular abnormalities [Potocki et al., 2007; Treadwell-Deering et al., 2010]. Individuals with small (<1 Mb) duplications have not manifested cardiac anomalies [Zhang et al., 2010].
Congenital heart defects (CHD) vary in the degree of severity and need for intervention; likewise, the incidence of CHD is different depending on the type of CHD in question [Hoffman and Kaplan, 2002]. The incidence of severe CHD—including lesions such as HLHS and tetrology of Fallot (TOF)—is estimated to be approximately 3/1000 live births [Hoffman and Kaplan, 2002]. Left ventricular outflow malformations (LVOT) comprise a spectrum of defects which include aortic valve stenosis, bicuspid aortic valve, coarctation of the aorta, and HLHS. LVOT malformations have an estimated birth prevalence of 1/1000 and cause 15–20% of medically significant CHD [McBride et al., 2005]. Although the etiology of LVOT malformations are complex, there are substantial genetic components as evidenced by the high (10–15%) incidence of chromosome abnormalities in persons with LVOT malformations [Ferencz et al., 1989], the presence of these defects in multiple generations of the same family [Gerboni et al., 1993; Wessels et al., 2005], the finding of NOTCH1 mutations in families with LVOT malformations [McBride et al., 2008; Garg et al., 2005], the rare association NKX2.5 [Eliott et al., 2003; Stallmeyer et al., 2010], and GJA1 mutations [Dasgupta et al., 2001] in persons with HLHS, and the identification of multiple loci associated with LVOTs by linkage analysis [Hinton et al., 2009; McBride et al., 2009]. To our knowledge 17p11.2 is not among the regions previously associated with HLHS or other LVOT malformations.
Major organ anomalies were not a recognized feature of the duplication 17p11.2 syndrome until reported in 2007 in subjects who participated in a protocol driven multidisciplinary clinical study regarding duplication 17p11.2 [Potocki et al., 2007]. Of the 35 subjects reported by Potocki et al., , only 10 had participated in the clinical protocol, and 5 of those had structural cardiovascular anomalies which included septal defects, bicuspid aortic valve, and dilated aortic root; some heart malformations revealed for the first time by echocardiographic imaging in protocol subjects. The authors know of one other PTLS patient with HLHS [Yusupov et al., 2008] whose mother also harbored the duplication. While the exact pathogenesis of LVOT abnormalities in PTLS has not been determined, it seems that genes within the critical region other than RAI1 may be involved. Interestingly, while cardiovascular anomalies, including valvular defects are seen in approximately 40% of individuals with SMS [Potocki et al., 2003], those SMS patients exhibiting the more severe end of the cardiac spectrum have CHD involving the right ventricular outflow tract such as TOF [Potocki et al., 2003; Sweeney et al., 1999; Thomas et al., 2000].
The diagnostic yield of array comparative genomic hybridization (aCGH) for patients with CHDs associated with congenital anomalies is as high as 28% [Breckpot et al., 2010; Lu et al., 2008; Richards et al., 2008]; however, the diagnostic yield of aCGH in patients with isolated CHD has not been sufficiently evaluated. The neonatal presentation of our patient was of a severe, yet apparently “isolated” CHD, and delays during infancy were attributed to effects of transplant surgery, thus delaying the etiologic diagnosis. Considering that 1) individuals with genomic disorders may not exhibit dysmorphic features; 2) the neurological findings, such as mild hypotonia may be difficult to discern in a newborn with a major CHD, or be attributed to complications of the CHD itself; and 3) an abnormal aCGH result would have substantial implications in the management of the patient and counseling for the family, we propose that an aCGH analysis be strongly considered in the evaluation of all patients with severe CHD. Further epidemiological studies, clinical investigation, and research in animal models are necessary to determine if LVOT anomalies in general, and HLHS in particular, comprise a high proportion of CHD in PTLS.
The authors thank the patient and his family for participating in the clinical research protocol and James R. Lupski for his critical review of the manuscript. This work was supported in part by the National Institutes of Health General Clinical Research Centers grant M01RR00188.