Summary

The sudden infant death syndrome (SIDS) remains the number 1 cause of post-neonatal death in the US, despite the success of the “Back to Sleep” campaign launched in 1994 by the National Institutes of Child Health and Human Development and the “Back is Best” recommendations from the American Academy of Pediatrics in 1996. Although the specific cause for SIDS remains undiscovered, researchers are exploring the genetic basis for SIDS susceptibility, in attempts to establish more effective means to prevent sudden death in vulnerable infants. In the unfortunate and devastating event that an infant dies from SIDS, clinicians need to act quickly and sensitively to gather information that can ultimately provide answers to the grieving family. A systematic approach to this investigation can reveal a genetic condition that might have been responsible for the infant’s death, giving the family an invaluable opportunity for early detection and potential treatment if they choose to have another child. It is also important to offer families the tissue bank option as one way their tragedy can ultimately help save lives by furthering research into the genetic causes of SIDS.

Educational objectives

At the conclusion of this activity, participants will be able to:

• Describe the potential genetic diseases that can be uncovered in investigating a SIDS case, to offer families genetic counseling and opportunities to prevent sudden death
• Systematically investigate a SIDS case to rule out conditions that might explain the cause of death, to provide answers to families
• Discuss the tissue bank option with parents of a child lost to SIDS and explain how they can help speed scientific discovery to prevent SIDS

CME credit

This is an article from The Child's Doctor, Spring/Summer 2009 issue. You must read all five articles and complete each related quiz before receiving 2 Category 1 credits for the Spring/Summer 2009 issue.

Author disclosures

Dr. Weese-Mayer has no industry relationships to disclose and does not refer to products that are still investigational or not labeled for the use in discussion.

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SIDS risk factors

SIDS is currently defined as "the sudden and unexpected death of an infant less than 1 year of age, whose death remains unexplained despite a thorough autopsy, death scene investigation, and review of clinical history."[1] Key recommendations targeting modifiable environmental risk factors for SIDS (see Table 1) led to a decrease in SIDS incidence from roughly 7,000 deaths each year in the US to just below 2,000 deaths a year.

Approximately 95% of SIDS deaths occur before 6 months of age, with a peak incidence between 2 and 4 months of age.

Infants of all socioeconomic, racial, and ethnic groups are potentially vulnerable, though with varying risk. Infants at greatest SIDS risk include: preterm infants, especially those weighing less than 1,000 gm; infants who had intrauterine growth restriction; infants born to mothers with little or no prenatal care or under the age of 20 years; males; and African Americans and Native Americans. African American infants succumb to SIDS at a rate 2-3-fold higher than Caucasian infants.

Although 18% of SIDS victims are born prematurely, the vast majority of babies who die from SIDS are born at term and have no overt abnormalities that brought them to medical attention prior to the terminal event.

Researchers have proposed the triple-risk model in efforts to explain SIDS.[2] According to this model, the highest risk for SIDS occurs when 3 major risk factors overlap:

• Critical period of development (first 6 months of life)
• Pre- and post-natal environmental stressors (prone or side sleep position, nicotine exposure, soft bedding, overheating)
• Underlying vulnerability (possible brainstem abnormality, genetic susceptibility)

The underlying vulnerability risk factor has become a promising area of research. The ethnic disparity in SIDS, coupled with the occurrence of SIDS deaths despite improved compliance with modifiable risk factors, led investigators to consider a genetic basis for SIDS.

Search for genetic causes of SIDS

Genetic studies in SIDS have been motivated by clinical, epidemiological, and/or neuropathological observations in SIDS victims, with subsequent pursuit of candidate genes in the following categories.

1. Genes for ion channel proteins, based on electrocardiographic evidence of prolonged QT intervals in SIDS victims
2. Gene for serotonin transporter and other genes in the serotonin network, based on decreased serotonergic receptor binding and other neuropathological findings in brainstems of SIDS victims
3. Genes pertinent to the early embryology of the autonomic nervous system (ANS) and with a link to the serotonin system, based on reports of ANS dysregulation in SIDS victims
4. Genes for nicotine metabolizing enzymes, based on evidence of cigarette smoking as a modifiable risk factor for SIDS and the most important risk factor after prone sleep position
5. Genes regulating inflammation, energy production, hypoglycemia, and thermal regulation, based on reports of postnatal infection, low birth weight, and/or overheating in SIDS victims

Research into the genetic causes of SIDS suggests that a number of genetically controlled networks may be involved in at least some cases. A brief synopsis of findings to date is presented here. A comprehensive discussion can be found in recent review articles.[3,4]

Investigation of SIDS in connection with the long QT syndrome (LQTS) susceptibility genes revealed that an estimated 5%-15% of SIDS cases are caused by a primary cardiac channelopathy. Among the remaining cases, genetic studies of the serotonergic system have documented specific polymorphisms in the serotonin transporter gene in SIDS and may provide initial clues to the ethnic disparity in SIDS. Furthermore, studies suggest that SIDS may be the result of protein-changing mutations in genes involved in the early embryology of the ANS, especially the RET gene and PHOX2B .

At this stage, no defined genetic connection has been established between SIDS and nicotine metabolizing genes. It also is too early to assess the significance of some inconsistently observed associations between SIDS and the genes regulating inflammation, energy production and hypoglyciemia. Overall, given the diversity of results to date, genetic studies support the clinical impression that SIDS is heterogeneous, as opposed to a single entity and with a single genetic etiology.

Potential disorders that might appear as SIDS

When an infant dies suddenly and unexpectedly, it is essential that blood or tissue is collected to help the families and their physicians conclusively rule out known genetic disorders that might explain up to 20% of the deaths. In so doing, the family will have closure for the recent death and information for planning future pregnancies. The family can also be offered participation in research of additional SIDS candidate genes through tissue donation.

Congenital central hypoventilation syndrome (CCHS). CCHS is a related disorder of dysfunction in the ANS (the system that functions automatically to control breathing, heart rate, temperature regulation, and more).[4-7] Children with CCHS typically present in the newborn period with immediate cyanosis upon falling asleep and a broad spectrum of physiologic abnormalities reflecting ANS dysregulation. However, recent data indicate that a subset of cases of CCHS can present after the newborn period even into infancy, later childhood, and adulthood. CCHS is inherited in an autosomal dominant manner, so knowledge of an affected infant is key to family planning and consideration of prenatal testing and/or pre-implantation genetics. Since a subset of children with CCHS are born to mosaic parents, both parents of an affected child should be screened for the child's PHOX2B mutation. With early diagnosis, proper management and ventilatory support, children with CCHS can grow into adulthood.

PHOX2B has been identified as the diseasedefining gene for CCHS.[6,7] DNA testing for mutations in the PHOX2B gene in "SIDS" cases should be performed with the PHOX2B Sequencing Test. One of the few laboratories in the world offering this test is housed at Children's Memorial Hospital.

Cardiac channelopathies. Cardiac channelopathy mutations can result in sudden death in infancy, childhood and adulthood. As mentioned earlier, they account for up to 15% of cases thought to be SIDS. These mutations can be ascertained by analysis of DNA using the FAMILION tests with specific identification of long QT syndrome (LQTS), Brugada syndrome (BrS) and catecholaminergic polymorphic ventricular tachycardia (CPVT). Because the clinical manifestations of cardiac channelopathy mutations respond to pharmacologic intervention, early diagnosis is essential to determine subject's risk and implement treatment strategies. This information is critical for families hoping to have more children and for identifying other affected family members.

Inborn errors of metabolism. MCAD (medium chain acyl CoA dehydrogenase) deficiency is another genetic disorder that can result in sudden death. It accounts for up to 5% of cases thought to be SIDS. MCAD is a disorder in which the body is unable to breakdown fats to make energy because the MCAD enzyme is missing or malfunctioning. Clinical presentation is typically in the first 6 years of life, primarily in the first 2 years, and rarely in adulthood. The symptoms may manifest after an intercurrent illness with decreased oral intake, leading to sudden death. Now that newborn state screening includes testing for inborn errors of metabolism, including MCAD, undiagnosed cases should be rare.

MCAD is an autosomal recessive disease for which prenatal testing is available. Treatment of MCAD deficiency includes avoidance of fasting for more than 10-12 hours, and consumption of carbohydrate-laden meals. Treatment with L-carnitine prevents low blood sugar during an intercurrent illness accompanied by a decreased appetite.

Systematic investigation of SIDS

There is no preparation for the unanticipated tragedy of an infant death. However, the steps that follow will require order and care so parents have as much available information as possible to ascertain the actual cause of the death and/ or to contribute to future understanding of the cause of SIDS.

Death scene investigation. A death scene investigation should be completed to rule out accidental causes and to ascertain the temperature of the room and the sleep position when the infant was placed in the crib and when (s)he was found.

Clinical history. Review of the medical records and clinical history is essential to be certain there are no other underlying abnormalities that might account for the death.

Autopsy. Parents should be asked to consent to a thorough autopsy by a pediatric pathologist, with the aim to ascertain a specific cause of death not immediately apparent from the physical examination. A negative autopsy is requisite to term the death as SIDS. Tissue from each organ system should be divided into specimens such that ˝ is frozen and ˝ is fixed. The frozen tissue will allow for biochemical and genetic studies (present and/or future); the fixed tissue will allow for traditional diagnostic studies.

Virtual autopsy. For families who oppose an autopsy for religious reasons, a virtual autopsy may be considered via magnetic resonance imaging (MRI) or computed tomography (CT) of the body to identify focal abnormalities that might account for the death.

Blood collection or skin biopsy. If possible, blood should be collected to conduct genetic tests that might explain the cause for death, including PHOX2B testing to rule out CCHS, FAMILION screen to rule out cardiac channelopathy mutations, and MCAD screen to rule out inborn errors of metabolism. If no blood is obtainable, parents should be advised to consent to a skin biopsy in order to have tissue for future DNA testing and not lose an opportunity to learn about a potential genetic disease.

Facial photographs. Because faces can be typical for certain diseases, such as CCHS,[8] it is suggested that parents consent to having digital photographs taken of the child's face. The photograph size should allow the face to fill the viewfinder. Front view and both side views should be taken, with a horizontal ruler included in each of the 3 color photographs.

Autonomic dysregulation questions. It also might be useful to ask parents about symptoms of ANS dysregulation in the deceased child while their recollection is recent. (See Table 2 for a brief questionnaire.) Going on the premise that unexplained deaths labeled as SIDS are due to other disorders of ANS,[5] the above steps and the questionnaire responses might inform the practitioner of other diseases to consider and other information that may help advise parents for future pregnancies.

Tissue bank donation. Lastly, and especially if parents consent to an autopsy, they should be advised about an option to donate tissue to the National Institute of Child Health and Human Development (NICHD) funded University of Maryland Brain and Tissue Bank. This tissue bank collects tissue from individuals who have succumbed to many diseases and is an important tissue source for SIDS investigators. By donating tissue, the family is helping scientific inquiry that ultimately will prevent SIDS deaths. Parents who have donated tissue from autopsy to the tissue bank have described a sense of gaining comfort by helping others in their own grief. Arrangements between the hospital and the University of Maryland tissue bank (btbumab@umaryland.edu, phone: 800.847.1539 or fax: 410.706.2128) will need to be made to assure the proper collection of tissue.

Conclusion

With too many infants still dying from SIDS each year, it behooves clinicians, researchers, and parents to combine efforts to achieve a common goal of preventing SIDS. Until the genetic basis for SIDS is determined, it remains the responsibility of medical personnel to teach and model optimal SIDS risk reduction strategies, and for parents and caregivers to practice these prevention measures, thereby minimizing the role of environmental cofactors in the demise of vulnerable infants at heightened risk for SIDS. And in the unfortunate and devastating event of the sudden death of a seemingly normal infant, it is imperative that paramedics, medical personnel, and parents maintain a sense of order with the ultimate goal to provide answers for the grieving family.

References

[1.] Willinger M, James LS, Catz C. Defining the sudden infant death syndrome (SIDS): Deliberations of an expert panel convened by the National Institute of Child Health and Human Development. Pediatr Pathol 1991;11:677-684.

[2.] Filiano JJ and Kinney HC. A perspective on neuropathologic findings in victims of the sudden infant death syndrome: The triple-risk model. Biol Neonate 1994;65:194-197.

[3.] Weese-Mayer DE, Ackerman MJ, Marazita ML, Berry-Kravis EM. Sudden infant death syndrome: Review of implicated genetic factors. Am J Med Genet 2007;143A:771-788.

[4.] Weese-Mayer DE, Berry-Kravis EM, Ceccherini I, Rand CM. Congenital central hypoventilation syndrome and sudden infant death syndrome: Kindred disorders of autonomic regulation. Respir Physiol & Neurobiol 2008;164:38-48.

[5.] Axelrod FB, Chelimsky GG, Weese-Mayer DE. Pediatric autonomic disorders: State of the Art. Pediatrics 2006;118:309-321.

[6.] Weese-Mayer DE, Marazita ML, Berry-Kravis EM. Congenital central hypoventilation syndrome. In: GeneReviews at GeneTests: Medical Genetics Information Resource [database online]. Seattle: University of Washington; 1997-2007. Updated July 24, 2008. Available at http://www.genetests.org. Accessed April 2, 2009.

[7.] Weese-Mayer DE, et al. Congenital central hypoventilation syndrome from past to future: Model for translational and transitional autonomic medicine. Pediatr Pulmonol 2009 May 6. Epub ahead of print.

[8.] Todd ES, Weinberg SM, Berry-Kravis EM, Silvestri JM, Kenny AS, Rand CM, Zhou L, Maher BS, Marazita ML, Weese-Mayer DE. Facial phenotype in children and young adults with PHOX2B–determined congenital central hypoventilation syndrome: Quantitative pattern of dysmorphology. Pediatr Res 2006;59:39-45.