Novel Case of Prader–Willi Syndrome and Ebstein's Anomaly: Implications for Complex Care Management

Abstract

We present a patient with a complex phenotype including diagnoses of Ebstein's anomaly and Prader–Willi syndrome (PWS) as well as additional congenital anomalies and genetic variants with potential clinical effects. This is the first reported case of both diagnoses present in the same patient. The diagnosis of Ebstein's anomaly was made on prenatal ultrasound. She presented with neonatal hypotonia, feeding problems, and dysmorphic features, followed by later onset weight gain, leading to a diagnosis of PWS. Further evaluations revealed Blaschkoid hyperpigmentation, laryngeal cleft, and pigmentary retinopathy. Whole exome sequencing determined a likely pathogenic variant in alkaline phosphatase gene and several mitochondrial DNA variants. We discuss the known genetic mechanisms of PWS and compare them to the heterogenous genetic associations of Ebstein's anomaly. The standard of care treatment for PWS is growth hormone therapy, which is associated with right-sided heart failure risks. This case illustrates the need to complete the diagnostic work up in all patients, as well as the necessity of a multidisciplinary approach for optimal outcomes.

Introduction

Prader–Willi syndrome (PWS, OMIM 176270) is the most common syndromic form of childhood obesity and results due to loss of paternally expressed genes on the long arm of chromosome 15. Individuals with PWS are at an increased risk for congenital defects 5.4 to 18.7 times higher than the general population, with cardiac abnormalities being the most commonly reported malformations. ¹

Background

Review of PWS: The genetics of PWS are well studied and results as a loss of expression of paternally inherited copy of several genes on the PWS critical region on chromosome 15q11.2–13. There are three main molecular mechanisms—deletion of paternal region of chromosome (65–75% of cases), maternal uniparental disomy (20–30%), or an imprinting defect (1–3%). ²

Review of Ebstein's: Ebstein's anomaly (OMIM 224700) is a rare malformation of the tricuspid valve occurring in 1 out of 20,000 live births. ³ The tricuspid valve develops from endocardial cushion tissue and myocardium. Delamination of the innermost layers forms three leaflets, but the failure of this process results in displacement of hinge points into the right ventricle. This causes “atrialization” of the right ventricle, tricuspid valve regurgitation, and right heart enlargement. It is most commonly an isolated anomaly and not a cardinal feature of any well-delineated syndrome.

Genetic Associations in Ebstein's Anomaly

Rare heterogeneous chromosomal abnormalities associated with Ebstein's anomaly have been described in several case reports. Duplication of distal 15q affects the early formation of the tricuspid valve, which was reported in two patients having duplications of 15q22 and 15q24 presenting with Ebstein's anomaly. ⁴ Various case reports described the following chromosome abnormalities in patients with Ebstein's anomaly—1p36 deletion, 5q35.1 mutation, 8p23.1 deletion, trisomy 9p, 10p13–14 deletion, 11q21–23 deletion, 18q21.3 deletion, trisomy 21, and 22q11.2 both deletion and duplication. ^{4 5 6} A canine study showed predisposition for Ebstein's type tricuspid malformation with mutations in the canine CFA9 gene on dog chromosome 9, which demonstrates conserved synteny with the canine tricuspid valve malformation critical region on human chromosome 17q. ⁷

No specific gene linkage has been identified with Ebstein's anomaly; however, two loci have garnered further investigation: variants of the MYH7 gene encoding the sarcomere beta-myosin heavy chain, which is also associated with left ventricle noncompaction cardiomyopathy ⁸ and NKX2.5 gene mutations, which have resulted in a wide variety of cardiac defects including Ebstein's. Neither of these genes has confirmed association with Ebstein's anomaly.

Clinical Manifestation

PWS: Clinical manifestations of PWS are nonspecific and develop gradually over time. In the neonatal period, patients often exhibit severe hypotonia. This often results in lethargy, poor feeding, failure to thrive, and hyporeflexia. Cryptorchidism and hypopigmentation are also common features. Typical facial dysmorphisms include almond-shaped eyes, thin vermillion border, downturned mouth, and narrow forehead. During early childhood, hyperphagia with rapid weight gain is the most striking feature. Other manifestations include hypogonadism, short stature, behavioral issues, and decreased cognition. Some individuals exhibit endocrine abnormalities including hypothyroidism or central adrenal insufficiency.

Ebstein's: The clinical presentation of Ebstein's anomaly is widely variable and dependent primarily on the degree of tricuspid displacement. Neonates may present with cyanosis at birth due to right to left shunting at the atrial level. Milder cases may go undetected and present as a murmur (due to pulmonary stenosis or tricuspid regurgitation) or arrhythmia. ⁹

Diagnosis

PWS: Diagnosis begins with karyotype and DNA methylation analysis. Abnormal methylation study confirms the diagnosis of PWS but will not differentiate the genetic mechanism. A fluorescence in situ hybridization study (probe SNRPN) or chromosomal microarray will identify gene deletion. If no deletion is detected, testing proceeds with microsatellite probes or single-nucleotide polymorphisms which can identify uniparental disomy. If the above studies are normal, an imprinting center mutation is likely and can be tested via whole-exome sequencing, high-resolution chromosomal microarray analysis (CMA), or droplet digital polymerase chain reaction (these may help determine the risk of recurrence in future pregnancies).

Ebstein's: Transthoracic echocardiography is the gold standard for diagnosis. If echocardiography is nondiagnostic, cardiac magnetic resonance imaging (MRI) may be obtained.

Management

PWS: Treatment is symptomatic and typically requires a multidisciplinary team. The primary goal is restricting caloric intake to limit obesity. Many therapies treat comorbidities associated with morbid obesity including insulin for type 2 diabetes mellitus and positive pressure ventilation for sleep apnea.

The standard of care, FDA-approved treatment for PWS is recombinant growth hormone (GH) therapy. It has been shown to improve linear growth, body composition, muscle tone, bone density, and cognitive ability. ¹⁰ Consensus guidelines advocate for initiation of therapy if there is genetic confirmation of PWS, regardless of laboratory evidence of GH deficiency. No consensus on age to initiate therapy exists; however, it is frequently started between 4 and 6 months of age. ¹¹ Contraindications to starting therapy include severe obesity, uncontrolled diabetes, untreated severe obstructive sleep apnea, active cancer, and active psychosis.

Ebstein's: In newborns with extreme cyanosis, prostaglandin is typically started with inotropic support until surgical repair can be attempted. Surgical options range from single ventricle repair, biventricular repair, tricuspid valvuloplasty (including the cone procedure) to replacement. Additionally, surgery may include plication of atrialized right ventricle, closure of intracardiac shunts, or ablations for arrhythmias.

Prognosis

PWS: About 70% of individuals with PWS live into adulthood; however, the mean age at death is 29.5 years ± 16 years. Shortened life expectancy is primarily due to complications of hyperphagia and obesity-related causes. Respiratory failure is the most common cause of death followed by accidents/injuries, and then cardiopulmonary factors. ¹²

Ebstein's: Prognosis varies with disease severity. Perinatal mortality rates are as high as 45%. A review of patients showed 67% liveborn survival rate at 1 year and 59% at 10 years. The main cause of death was heart failure or perioperative complications. ^{9 13}

Case Presentation

A baby girl was delivered via planned C-section at 39 weeks gestation to a 40-year-old G6P5 mother. Pregnancy was complicated by prenatal diagnosis of Ebstein's anomaly with severely dysplastic tricuspid valve leaflets, marked tricuspid regurgitation, mildly obstructed antegrade pulmonary valve flow, and diminished right ventricular (RV) function. Prenatal genetic testing was not performed. Birth weight was 3,920 g with APGAR scores of 8 at 1 minute and 8 at 5 minutes. Oxygen saturations were in the mid-90's shortly after birth. She was initially placed on prostaglandins given concern for inadequate pulmonary blood flow. Echocardiogram confirmed prenatal findings of Ebstein's anomaly with adequate antegrade pulmonary flow along with a large atrial septal defect (ASD). Prostaglandin was discontinued at this point and tolerated well. She was noted to have dysmorphic features, including low-set ears, wide square nasal root, micrognathia, and hypotonia. Her initial blood work was unremarkable, and X-ray of chest–abdomen–pelvis showed cardiomegaly but no other abnormalities. Genetics was consulted for the evaluation of multiple congenital anomalies and dysmorphic features. Chromosomal microarray testing was normal. The combination of cardiac and ear anomalies was suggestive of CHARGE syndrome. Head MRI was normal with confirmed normal inner ear anatomy, and CHD-7 sequencing with CNV detection was normal. Our patient demonstrated appropriate weight gain with nasogastric tube feeds and was discharged home after a 68-day NICU stay.

Over time, she continued to show significant hypotonia with global developmental delay. She crawled at 15 months, sat independently at 18 months, held head up at 20 months, and said her first words at 23 months. At her 9-month-old primary care appointment, they noted hyperpigmented linear and whorled markings along her legs and abdomen ( Fig. 1 ). Dermatology performed a punch biopsy and diagnosed these as Blaschkoid hyperpigmentation, also known as pigmentary mosaicism. Ophthalmology found a similar pigment pattern of her retina, diagnosed as pigmentary retinopathy.

Fig. 1.

Typical facies of Prader–Willi syndrome along with whorled pattern of Blaschkoid hyperpigmentation on patient's back, trunk, and lower extremities.

At 1 year of age, her pulmonary valve stenosis worsened, and she underwent catheter balloon pulmonary valvuloplasty. Her postinterventional echocardiogram showed moderate pulmonary valve stenosis and regurgitation with normal RV systolic function. At that time, she was still unable to take feeds by mouth, felt to be due to her hypotonia rather than her cardiac condition. A gastrostomy tube was then placed for feeding. Otolaryngology evaluated her and diagnosed her with laryngotracheomalacia, dysphagia, and a laryngeal cleft. By 18 months, our patient was seen by a multidisciplinary team in the genodermatosis clinic. On examination, she was noted to have bitemporal narrowing, almond-shaped eyes, prominent nasal bridge, short-rounded nasal tip, downturned corners of mouth, and a short neck ( Fig. 1 ). She remained globally delayed and her weight for length at that time had increased to the 96th percentile for age. DNA methylation analysis test demonstrated abnormal methylation of 15q11.2–15q13.1 with loss of paternal expression of SNRPN gene, consistent with PWS.

Whole exome sequencing was subsequently ordered as PWS did not explain many of her clinical features. Whole exome sequencing results showed:

• Heterozygous paternally inherited likely pathogenic variant in alkaline phosphatase (ALPL) gene (c.542 C > G p.S181W). This encodes alkaline phosphatase and causes hypophosphatasia, a disease characterized by defective bone mineralization resulting in fractures, early tooth loss, or seizures. Neither our patient nor her father displayed these symptoms. Alkaline phosphatase levels were normal at birth (101 U/L, reference range 73–226) but fell below range for age by 7 months old (114 U/L, reference 154–442) and remained persistently low.

• Maternally inherited homoplasmic variant of uncertain significance (VUS) in MT-ND3 (m.10336 T > C p.L93S). This encodes mitochondrial subunit ND3 of complex-1 in the respiratory chain. Neither our patient nor her mother showed evidence of mitochondrial disease at this time.

• VUS in MT-ATP6 (m.9070 T > C p.S182P) with approximately 2% heteroplasmy. This low level of heteroplasmy is unlikely to cause a phenotypic effect.

• VUS in MT-TI (m4271 G > A) with approximately 2% heteroplasmy.

Due to the identification of several mitochondrial DNA variants, plasma amino acid profile, lactic acid, and pyruvate levels were obtained, all of which were within normal limits. Further evaluation for complications of PWS were performed including a sleep study. Initial results showed a total sleep time of 485 minutes, sleep efficiency of 90%, mean oxygen saturation 83.3%, minimum O2 66%, entirety of the study had O2 below 90%, hypopnea index of 9.6 events/h, central apnea of 0.6 events/h, 0 obstructive apneas, and total apnea–hypopnea index of 10.3 events/h—this was consistent with a diagnosis of moderate-to-severe obstructive sleep apnea. She underwent adenotonsillectomy and postoperative sleep study had a total sleep time of 414 minutes, efficiency of 80%, mean O2 84.6%, minimum O2 77%, entirety of study with O2 below 90%, hypopnea index of 9.7 events/h, central apnea index of 3.6, 0 obstructive apneas, and total apnea–hypopnea index of 13.3 events/h. This again demonstrated moderate-to-severe obstructive sleep apnea with increased central apneas; thus, she was started on BIPAP at night. Endocrinologic evaluation showed normal levels of cortisol, ACTH, IGF-1, IGF-BP3, free thyroxine, with slightly elevated TSH (repeat levels normalized). After discussion with her numerous specialists, she was started on GH therapy.

Discussion

Our patient demonstrated many of the classic clinical characteristics of PWS including dysmorphic facies, developmental delay, and hypotonia. She did, however, have several features that were not explained by this diagnosis ( Table 1 ). As our patient had a normal CMA, her PWS was due to either uniparental disomy or an imprinting defect. Whole exome sequencing identified four other gene variants; however, none of them explain this constellation of malformations. Her skin and ophthalmologic findings and rare cardiac anomaly make mosaicism for a fourth condition a possibility.

Table 1. Summary of patient findings.

Summary of patient findings
Findings consistent with Prader–Willi syndrome	Congenital hypotonia Laryngotracheomalacia Obstructive sleep apnea Short stature Gradual weight gain Developmental delay Typical facies (Bitemporal narrowing, almond-shaped eyes, and broad nasal bridge)
Findings not related to Prader–Willi syndrome	Ebstein's anomaly with pulmonary stenosis Likely pathogenic variant for hypophosphatasia Mitochondrial gene variants Type I laryngeal cleft Blaschkoid hyperpigmentation Pigmentary retinopathy

Cardiac Defects Associated with Prader–Willi Syndrome

Individuals with PWS are at an increased risk for congenital heart defects. Torrado et al reviewed the findings in 180 children with PWS and 22% had congenital defects, of which cardiac anomalies were most common (reported in 4.4%). Isolated ASDs were most common, with remaining defects including patent ductus arteriosus, ventricular septal defect (VSD), and pulmonary stenosis. ¹ There were no correlations found between the subtypes of PWS and any congenital defects studied. To our knowledge, this is the first reported case of a child having both PWS and Ebstein's anomaly.

Treatment Considerations

As explained above, there are no cardiac stipulations to starting GH treatment, which is likely a result of the rare cooccurrence of congenital heart defects in PWS. In comparison, echocardiography is recommended in both Turner and Noonan syndrome prior to GH initiation. This is especially relevant in Noonan syndrome, as they more commonly have right-sided heart defects such as pulmonary stenosis. One study followed 21 patients with Noonan syndrome over 5 years of GH treatment—two developed progression of pulmonary stenosis but did not require discontinuation of GH therapy. Recent reviews advocate for echocardiograms every 1 to 2 years if a congenital heart defect is present. ¹⁴ Routine sleep studies are also recommended, as obstructive sleep apnea develops independently of GH initiation. While some studies have demonstrated an improved oxygen desaturation index after GH initiation, others show no significant impact sleep or respiratory parameters. It is safe to use in both adults and children with PWS. ^{15 16 17} While GH has been shown to provide cardiovascular benefits to adult patients with PWS, this is mostly related to body composition, lipid profile, sleep-breathing disorders, and pulmonary function. ¹⁸ Marzullo et al conducted several studies involving GH's structural effects in adults with PWS. They noted left ventricle mass significantly increased—specifically end diastole diameter and interventricular septum thickness, likely reflecting cardiomyocyte hypertrophy. One potentially adverse effect of GH noted in that study was a decreased right ventricle ejection fraction.

In addition to the aforementioned benefits, GH therapy was especially important for our patient due to the diagnosis of hypophosphatasia. This along with her hypotonia put her at an increased risk for falls and fractures. We were concerned, however, that GH therapy in the setting of a right-sided heart lesion such as Ebstein's anomaly would increase right-sided strain. This could progress to increased tricuspid regurgitation, RV hypertrophy, and eventually right-sided heart failure. Ultimately, the benefits outweighed the risk for our patient and GH therapy was started at 2 years old. Echocardiogram after 2 months demonstrated stable RV function with no change in pulmonary valve gradient. Her RV pressure increased from 42 mm Hg above right atrium (RA) to 59 mm Hg above RA. Surveillance echocardiography monitoring ventricular wall thickness, chamber size, and function will continue during GH therapy.

Conclusions

We present a case of a patient demonstrating multiple separate genetic disorders. She has both Ebstein's anomaly and genetically confirmed PWS, as well as a likely pathogenic variant for hypophosphatasia. She carries multiple asymptomatic mitochondrial DNA variants; however, she will need monitoring for the development of clinical symptoms. Finally, she has several findings suggestive of yet another disorder, possibly in a mosaic form. This case broadens the spectrum of cardiac anomalies associated with PWS. Alternatively, this patient may have a separate multiple malformation syndrome characterized by Ebstein's anomaly, laryngeal cleft, and Blaschkoid hyperpigmentation. Further genetic testing in the form of whole genome sequencing or tissue genetic testing may shed further light on the etiologies of these findings. The presence of congenital heart disease in the setting of PWS raises concern about potential risks and side effects of treatment. GH therapy is the standard of care for individuals with PWS, but current guidelines do not specify cardiac restrictions to withhold therapy. We advocate for a thorough evaluation of cardiac anatomy and specifically right-sided heart function prior to introducing GH. Additionally, we recommend surveillance echocardiography every 1 to 2 years during GH therapy, consistent with guidelines for Turner's and Noonan syndrome. This case also illustrates the need to complete the diagnostic work up in all patients, especially those with atypical findings, as dual diagnoses may be present. Concurrent diagnoses may require adjustments in medications or surgical planning, to prevent significant morbidity and mortality associated with each diagnosis and/or the standard treatment of each separate disorder. A multidisciplinary approach is essential for complex cases such as this, to provide patients with appropriate care and the best possible outcome.