Ethical implications of early genetic diagnosis in an infant with Lesch-Nyhan syndrome

Abstract

Pathogenic variants in HPRT1 lead to deficiency in hypoxanthine-guanine phosphoribosyltransferase and are responsible for a spectrum of disorders. The severe phenotype is termed Lesch-Nyhan syndrome (LNS) and is inherited in an X-linked recessive manner. Most individuals with LNS have profound intellectual and physical disabilities throughout life including self-mutilating behaviors. Here we present the case of a male infant who was diagnosed with LNS at three weeks of age via rapid exome sequencing (ES), which revealed a hemizygous maternally-inherited deletion of at least 1.3Mb of Xq26.3, including exons 2 to 9 of HPRT1. We discuss the critical time points leading to this diagnosis while highlighting his parents’ values that guided the decision making. Genetic testing provided an early diagnosis for this infant that led to important considerations regarding goals of care in addition to raising new ethical concerns. This highlights the important role that early and rapid diagnostic genetic testing can play in helping families make difficult decisions. Additionally, this case highlights the complexity in discussing rare genetic diagnoses with families and facilitating critical discussions to empower the family towards making an informed decision.

Introduction

Pathogenic variants in HPRT1, on the X-chromosome, are responsible for a spectrum of disorders that range from isolated hyperuricemia to those associated with neurological and behavioral abnormalities (Brooks et al, 2001; Jinnah et al., 2000). The latter phenotype is termed Lesch-Nyhan syndrome (LNS) and is inherited in an X-linked recessive manner. Deficiency in hypoxanthine-guanine phosphoribosyltransferase (HGPRT), encoded by HPRT1, leads to accumulation of uric acid in body fluids and subsequent hyperuricemia with severe gout and kidney issues. Neurobehavioral signs include dystonia and self-mutilating behaviors, such as lip and finger biting (Taniguchi et al., 2011). These signs typically begin at 3 years of age (Andersen et al., 1994). Although there is a treatment to reduce uric acid levels, treatment options for the neurobehavioral manifestations of the condition are purely supportive (Nyhan et al., 1973). Most individuals with LNS have profound intellectual and developmental disabilities throughout life and have a life expectancy of a couple of decades (Jinnah, 2000). Here we present the case of an infant who was diagnosed with LNS at one month of age using rapid exome sequencing (ES), confirmed on concurrent chromosomal microarray analysis (CMA). We discuss the relevance of an early genetic diagnosis for this family and the ethical considerations involved in decision making in early infancy.

Case report

The male proband was one of di-di male twins born to a gravida 3 para 1 32-year-old woman via induction of labor at 36 6/7 weeks gestation due to pregnancy-induced cholestasis diagnosed at 35 weeks. The proband was less active than his twin brother in utero and appeared to have frequent hiccups. The twins were born via vaginal delivery without complication except for a placental abruption noted just prior to delivery. The proband’s Apgar scores were 7, 7, and 8 at 1, 5, and 10 minutes, respectively, and he was sent to the newborn nursery post-delivery. He subsequently required transfer to the special care nursery after a failed critical congenital heart disease screening and ultimately was transferred to the neonatal intensive care unit (NICU) for hypothermia and respiratory insufficiency. Upon transfer to the NICU, he was also found to be hypotensive (possibly related to the antenatal hemorrhage) with significant hypotonia. Baseline bloodwork revealed metabolic acidosis.

During admission to the NICU, a sleep study was performed which was interpreted as normal, although the infant continued to exhibit signs of periodic breathing, obstructive apnea, hypercarbia, and desaturations. Due to persistent conjugated hyperbilirubinemia, a HIDA scan was obtained which ruled out biliary atresia. He continued to require nasogastric tube feedings due to poor tone and an inability to bottle feed adequate volumes. During his first month of age, discussions were held with his parents regarding long-term options to optimize his nutrition. The infant continued to have an abnormal neurological exam with low muscle tone, but he was spontaneously waking up, opening his eyes, and showed improving oral feeding skills. An MRI was obtained due to persistent hypotonia and the genetics team was consulted given his overall lack of expected improvement. A CMA was performed clinically while clinical-grade rapid ES was performed as part of a research project (Gubbels et al., 2020) to aid with the diagnosis after enrollment in a Boston Children’s Hospital’s Institutional Review Board-approved protocol (IRB0021883). The turnaround time was 3 weeks for CMA and 2 weeks for ES.

Rapid ES, which returned first, revealed a 1.37 Mb deletion in Xq26.3 in the proband (GRCh37:133607450-134978535) which was classified as pathogenic and the deleted interval involved 20 genes including exons 2-9 of HPRT1, the gene associated with LNS. Concurrent CMA confirmed this finding, though returned one week later. He was later found to have hyperuricemia consistent with LNS with uric acid levels of 6.7 and 7.3 mg/dL at day of life 27 and 32, respectively (normal range 2.0 to 6.0 mg/dL for infants). (Lesch and Nyhan, 1964). Bloodspots were analyzed for hypoxanthine-guanine phosphoribosyl transferase (HPRT) enzyme activity levels and the infant had very low HPRT activity (1.81 nmol/hr/spot).

Awaiting the results of a genetic test is difficult not only for the family but also for the care team. A genetic diagnosis can have a significant impact on the predicted life course of a baby and their family. In this case, during a family meeting, the genetics and NICU teams, along with the support of a social worker, compassionately disclosed the findings of LNS. The parents were devastated but extremely thankful for the quick diagnosis, appreciating that many children with this genetic syndrome are not diagnosed until later in life. They felt they could move forward knowing the explanation for the symptoms their child was experiencing and especially when noticing the significant differences observed when comparing with his twin. Concern for the infant’s future quality of life and what the LNS diagnosis meant for their own lives and the quality of life of their other children weighed heavily in their decision-making. Resources such as support groups and informational readings were identified for the parents and they were connected with the Pediatric Advanced Care Team (PACT), which specializes in helping families with complex medical situations.

Ultimately, the family made the difficult and compassionate decision to transition to comfort-focused management for their son and take him home on hospice care, with bottle feeding for comfort but not providing the enteral tube feedings he was receiving in the hospital. While making this decision, the medical team consisting of physicians, neonatal nurse practitioners, nurses, representatives from social work and chaplaincy, and the PACT team served as key medical support systems for the family. The parents were fully aware and in agreement with each other that their goals and values as a family were to provide palliative care to their son, a decision that was fully supported by the medical team. While at home, the parents were supportive of the provision of medications to relieve any perceived suffering. They made a “bucket list” of experiences for him to enjoy with them before he passed away. In the short three weeks they were together as a family, they simulated a year worth of holidays and celebrations which included Halloween costumes, a Christmas tree, Thanksgiving dinner, Easter baskets, his first birthday with his twin and a family trip to the beach.

Discussion

Prior to the availability of massively-parallel sequencing technologies enabling rapid genomic sequencing for genetic diagnosis, the diagnostic odyssey for many infants with a rare disease often spanned for years or even decades (Wojcik et al., 2018). Identifying a molecular genetic diagnosis may substantially impact the care of infants with rare genetic conditions. As seen in our case, a timely diagnosis may help families make informed decisions for their child’s future by providing them with important information at critical junctions in their care. A precise genetic diagnosis may provide some understanding of prognosis and may give parents time to grieve and cope as well as time to heal. In the care of infants with complicated medical situations, providers should consider ethical principles and provide care that respects these principles. Relevant ethical principles to consider in this context include autonomy, beneficence, and nonmaleficence. (Wiegand et al., 2015). Based on the principle of autonomy, care should be centered on the family’s values. Clear education and information pertaining to a diagnosis can empower a family to make informed decisions that are in line with their values. The role of the medical team includes providing the information needed by the decision-makers, participating in the discussions, and supporting the family’s decisions, while consulting experts to determine a prognosis. The genetics team, which typically consists of both physicians and genetic counselors, is critical in explaining the genetic findings, their prognosis, and long-term outcomes. In this case, genetic metabolic specialists as well as external experts in the infant’s specific genetic disorder were consulted. Based on the specific genetic variant, it was predicted that the infant would likely experience moderate to severe intellectual disability and self-injurious behavior by the age of two and would have limited or no ability to ambulate.

It is also important for the medical team to discuss the overall goals of care along with principles and values with the family to guide them through the decision-making process. A specialized multidisciplinary team dedicated to helping families with complex medical situations (PACT, in our institution) can play an important role in aiding families through difficult decisions. For the family described here, their preference was for the infant to live as long as possible with what they would consider an acceptable quality of life. They particularly valued cognitive and physical abilities and were primarily concerned with self-injurious behaviors in the years to come. They were quite concerned about the associated physical and emotional suffering that the infant would experience as a result of this genetic disorder. The parents requested descriptions of the worst-case scenario, best-case scenario, and most likely case scenario with the understanding that symptoms cannot be predicted with certainty. The mother was a special education teacher that made her aware of the challenges associated with caring for a child with severe LNS. The family made an informed, thoughtful decision that they did not wish for their child to experience what they considered a poor quality of life. However, severe intellectual and developmental disability may not be considered poor quality of life for all families and this highlights the need for open and thoughtful discussions to understand each family’s values (Reinders et al., 2019). In this case, after many discussions with the clinical team, the family opted for home hospice care for the infant given the severity of his prognosis with a realistic understanding of what such care entails. Without a genetic diagnosis, the parents might have proceeded with life-sustaining interventions such as a tracheostomy and gastrostomy tube to support their son’s feeding and respiratory issues.

The ethical principle of beneficence centers on providing care that benefits the patient and non-maleficence is on avoiding and minimizing harm. However, in complex medical situations, it may be difficult to determine a course of action; for example, is it ethically permissible to withhold life-sustaining interventions such as enteral tube feeds or supplemental oxygen when the condition is not immediately terminal? The present case demonstrates that home hospice care may be an appropriate and ethically-supported alternative given the predicted future progression of the disease. The American Academy of Pediatrics supports palliative care, encompassing home hospice, when it may benefit the infant early in the course of the illness (American Academy of Pediatrics, 2000). In contrast to curative treatments which aim to reverse the disease process, palliative care focuses on relieving symptoms and should be introduced promptly instead of waiting to exhaust all curative options (American Academy of Pediatrics, 2000). Additionally, the assumption that palliative care should not be considered until all curative options have been used may delay an early discussion of issues such as the limitations of unduly burdensome interventions at the end of life.

The early genetic diagnosis of a potentially devastating syndrome in this infant, prior to the development of symptoms, raised ethical questions about withholding life-sustaining care such as enteral tube feeding for an infant whose condition was not immediately lethal or terminal, and whether the neurologic prognosis including the high likelihood of pain and suffering was sufficient to justify withholding of nutrition. These questions would not have been raised without the genetic diagnosis, which ultimately allowed the family to make a compassionate decision that was ethically supported and in line with their values and principles. This highlights the important role that genetic testing and diagnosis can play in helping the families of infants in the NICU with suspected rare genetic syndromes to make difficult decisions. Additionally, in managing NICU infants with such complex medical situations, diverse and multidisciplinary healthcare providers, from physicians to nurses to genetic counselors are tasked to facilitate numerous discussions to not only provide medical information but also support and guide families in making informed decisions for the infant and their family.

What is known about this topic:

Lesch-Nyhan syndrome is an X-linked recessive disorder characterized by hyperuricemia, dystonia, and self-mutilating behaviors and caused by pathogenic variants in the HPRT1 gene.

What this paper adds to the topic:

This paper discusses the ethical considerations related to the care of neonates found to have Lesch-Nyhan syndrome who do not yet have the neurodevelopmental manifestations.

Data Availability Statement:

No new data were generated for this manuscript.