Examples, inheritance patterns, and clinical descriptions of several types of life-threatening inherited conditions. The listed categories overlap considerably but are a useful framework for thinking about inherited conditions.

Condition type and examples	Inheritance	Description and clinical course
*Metabolic Disease*
MELAS	Mitochondrial	Characterized by mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes that typically present in mid- to late childhood. Early development is often normal. Seizures and hearing loss are common.
Maple syrup urine disease (MSUD)	Autosomal recessive	Caused by branched-chain alpha-ketoacid dehydrogenase complex deficiency that, without treatment, results in poor feeding, irritability, coma, and central respiratory failure. Manifestations vary with level of enzyme activity.
*Multiple Malformations*
Smith-Lemli-Opitz syndrome	Autosomal recessive	Individuals may have multiple anomalies of cleft palate, heart defect, hypospadias, abnormal genitalia, growth retardation. The condition results from mutations in the gene encoding 7-dehydrocholesterol reductase, an enzyme involved in cholesterol metabolism.
Noonan syndrome	Autosomal dominant	Individuals may have congenital heart disease, coagulation abnormalities, cryptorchidism, chest deformities, and developmental delay. There are several genes known to cause the condition; however, a genetic change is not detected in all individuals with a clinical diagnosis.
*Chromosomal*
Trisomy 13	Chromosomal	Often presents prenatally or at birth with multiple anomalies, including congenital heart disease and craniofacial malformations. Infants usually die in the first year of life from central apnea, but the clinical course is variable.
Williams syndrome	Chromosomal	Individuals often have cardiovascular disease, endocrine abnormalities, connective tissue differences, and mild mental retardation. A contiguous chromosomal deletion involving 7q11.2 is present in 99% of cases.
*Neuromuscular Disease*
Duchenne muscular dystrophy (DMD)	X-linked	Affected males often present with delayed milestones, and progressive muscle weakness and atrophy cause wheelchair dependency by age 13 with early death from respiratory and cardiac failure. DMD represents the severe end of the spectrum of dystrophinopathies.
*Neurodegenerative Disease*
Adrenoleukodystrophy	X-linked	The childhood cerebral form typically first presents with attention deficit disorder and progresses to cognitive, motor, vision, and hearing impairment, to complete disability within a few years. Widely variable expression even among individuals in the same family.
*Storage Disease*
Hunter syndrome	X-linked	A lysosomal storage disease that results in progressive excess storage of glycosaminoglycans. Symptoms include hepatosplenomegaly, CNS involvement, coarse facial features, and joint contractures. Respiratory and/or cardiac diseases are the major causes of morbidity and mortality. Onset and symptoms vary widely.
Pompe disease	Autosomal recessive	A glycogen storage disease that often presents with feeding difficulty, muscle weakness, hypotonia, and cardiomyopathy in the severe infantile-onset form. Without enzyme replacement therapy (ERT), infants often die in the first year of life.
*Skeletal Dysplasia*
Campomelic dysplasia	Autosomal dominant	Most individuals die during the neonatal period from respiratory insufficiency. Symptoms include severe laryngotracheomalacia, Pierre Robin sequence, ambiguous genitalia, club feet, bowed limbs, dislocated hips, and short stature. Cervical spine abnormalities, scoliosis, and kyphosis are common. Many females are found to be 46, XY.

Specific Care Challenges

The stigma, recurrence risk, and isolation that inherited life-threatening illnesses impart all affect attitudes and goals about the treatment plan.¹ Understanding the specific challenges faced by families and children affected by inherited life-threatening illnesses allows providers to respond to an individual family’s needs when broaching the subject of palliative care.

Stigma, guilt, and shame

The stigma associated with inherited disease stems from multiple sources. The effect of stigma is heavily influenced by personal, social, and cultural forces and therefore varies significantly from case to case. Understanding the impact of this stigma on individual patients and families is essential for introduction and maintenance of a palliative care plan.

The very concept of having passed on a life-threatening condition is a staggering source of guilt for many parents and grandparents. In conditions inherited through a single parent, this guilt can be unevenly distributed.² Feelings of guilt in a parent may influence decisions regarding both care meant to prolong life and care meant to improve quality of life. An overwhelming sense of responsibility may prevent some parents from asking for assistance. Although parental guilt is a normal response to having a child with an inherited illness, medical providers should be alert for signs of caregiver fatigue or family stress related to these feelings. Genetic counselors are specially trained to work with families around the time of initial diagnosis. The responses of family members often stem from a desire to find underlying meaning for the birth of a child with a genetic condition. Some parents may believe that a past action or inaction caused their child to have a birth defect or an inherited condition.³ Some parents are ashamed for having a child who does not fit the ideals they had prior to, or during, pregnancy.⁴ Some children or families who have particular difficulty adjusting to a genetic diagnosis may benefit from psychiatry or psychology consultations to discuss these feelings in greater detail.

Even aside from the issue of parental responsibility, genetic conditions are further stigmatizing society’s tendency to view a genetic difference as an inherent personal flaw. Medical staff should do all possible not to propagate this viewpoint. In fact, assessing the families’ experiences and listening to responses during initial consultations may give clues regarding feelings of guilt or shame. Patients or families experiencing shame will, at times, withdraw from the situation. Those experiencing an internal sense of responsibility or guilt may blame themselves, rationalize, or intellectualize the situation. Lack of control can be particularly painful for parents experiencing this unrealistic sense of responsibility.⁴ Actively engaging in medical decision making may allow families to feel that they have regained some control.

Language choice

In this increasingly protocol-driven medical environment, providers are often tempted to rely on shorthand terms such as Downs baby to refer to an infant with Down syndrome or CF-er to refer to a child with cystic fibrosis. By doing so, however, they unintentionally marginalize the affected child and suggest that he or she is defined entirely by the disease. Providers should be sensitive to the use of person-first language and current terminology. Providers may invite the family to provide their preferred terminology. For example, a family may express concern regarding the use of mental retardation and prefer cognitive impairment or static encephalopathy. Use of potentially offensive terminology may impede the relationship with the family and prevent open discussion of sensitive issues such as prognosis and end-of-life care. Conversely, choosing language that personalizes the child can set the tone for a holistic approach to medical care giving. Language implying that the medical team sees the child as a whole person allows patients and families to share their goals with the care team.⁵

Recurrence

Families affected by life-threatening inherited illnesses often have the unfortunate distinction of going through the process with multiple family members. Experience with the previously diagnosed individual will likely impact care for the next affected individual, but the specific result is not always predictable. Some families who selected a life-prolonging treatment course for their first affected child may provide only comfort measures for their next affected child. The inverse is also true, and still other families may follow the same course with subsequent affected siblings. These care decisions are highly personal and depend on far more than critique of the care supplied to the previous child. In instances where they can be assessed, the affected child’s treatment goals often influence these decisions.

A mother of two boys who had died of muscular dystrophy at ages 17 and 5 shared that her first affected son wanted his life prolonged as much as possible; he achieved this goal with maximum support and intervention. Her second stated at age 3 that he wanted “no tubes.” He also expressed his desire to learn to walk and was able to meet both of these goals, with his parents and treatment team acting as advocates.

While primary care providers generally consider parents to have an expert understanding of their children, this attitude is especially appropriate when conditions recur in the same family. Affected children and their parents may possess expert understanding of the condition at many levels. In very rare conditions, their scientific knowledge of the condition may exceed that of the care team. More importantly, however, their intimate experience with the condition in a previously affected family member gives them an additional kind of expertise. Medical care providers should explore these experiences with families in order to grasp their understanding of the illness and facilitate discussion of a treatment plan. In many cases, providers will be able to adjust or enhance the family’s perspective, as when the family of the second affected child is unaware of the condition’s variability.

A couple whose first child was diagnosed with maple syrup urine disease (MSUD), a life-threatening inborn error of metabolism, responded to the diagnosis with a seemingly disproportionate degree of despair. Additional conversation revealed that an affected maternal cousin had severe intellectual impairment. The conversation allowed an opportunity to educate the family about the importance of early intervention in this condition.

Isolation

Most inherited illnesses are relatively rare and can have an isolating effect on families. The interdisciplinary approach is particularly important in such circumstances because subspecialists, in addition to providing medical expertise, can provide informational and social resource contacts for families of children with rare, life-threatening inherited illnesses. Genetic counselors and other specialists can provide families with contact information for state, national, or international support organizations and can directly connect families of children with the same or similar conditions. They can also often connect families with the center of excellence where a provider or providers may have expertise in caring for patients with the condition. This connection can ameliorate the sense of isolation and also be a source of valuable information about care, resources, and natural history of the condition.

A family whose infant had been diagnosed with Cornelia DeLange syndrome, a rare inherited multiple malformation syndrome, was put in contact with a syndrome-specific support group at the time of diagnosis. By their daughter’s one-year follow up visit, the family had more than 40 parent contacts throughout the country. This family shared they had learned a great deal about what to expect from other families.

As always, providers should carefully assess each family’s goals and psychosocial milieu before they suggest resources. For some families, the thought of talking to another family with a child with the same condition is overwhelming and frightening at the time of initial diagnosis.

After hearing confirmation that his toddler son had achondroplasia, a father recoiled when we offered resources from Little People of America. He later explained that he could not accept that his son would develop the medical problems and extreme short stature described in the pamphlets we had given him.

Although families should be encouraged to use resources, aggressive promotion of resources can alienate a family still adjusting to a particular diagnosis and prevent future access to care. Some families, though initially reluctant, need time to adjust and accept the diagnosis.

A family whose toddler had been newly diagnosed with Williams syndrome declined an offer to meet a family whose child had the same chromosomal change. As their child prepared to enter school, they began to ask more questions about what to expect in the future. We re-extended the offer and found that they were very interested.

Other families prefer to be prepared for the natural progression of an inherited illness well in advance. One woman whose baby was severely affected by a progressive neuromuscular disorder said she was glad to have met another severely affected child who was later in the course of illness. Although she realized the other child’s extreme weakness and ventilator dependence were likely to occur in her child as well, she felt more prepared after meeting that child and his family. Primary care providers, social workers, subspecialists, palliative care specialists, and genetic counselors can all be called upon to evaluate a family’s need for resources and education throughout the course of an inherited life-threatening condition.

Still another challenge comes with providing support resources for families and children with inherited conditions predisposing them to infection, such as cystic fibrosis (CF). For infection control reasons, individuals with CF often cannot easily connect face to face; however, there are a growing number of online resources for support.

As isolating as a confirmed diagnosis of an inherited life-threatening illness may be, an unknown diagnosis may be even more isolating. Affected children and their families, in addition to being faced with the life-changing effects of a chronic illness and the stigma associated with inherited disease, also must live with a greater degree of uncertainty than those with a known diagnosis. There may be few support resources available to families beyond family members, friends, providers, and community when a diagnosis is unknown. While subspecialists and support staff can still assist these families, prognosis is often less sure when the underlying diagnosis is unknown, and addressing patient and family goals, as well as recurrence risk, may be more difficult for providers.

Role of Diagnostic Workup

Diagnostic workup is indicated to direct treatment in life-threatening illnesses of all etiologies. In life-threatening illnesses suspected to be inherited, diagnostic workup can be particularly prolonged and expensive. Furthermore, diagnosing an inherited condition often has implications for other family members. The medical care team must anticipate these complications and address them with the family throughout the diagnostic and treatment process. Genetic counseling is essential during this process to help with addressing psychosocial issues, obtaining informed consent, interpreting results, and providing resource and recurrence risk information.

Although some genetic conditions are easily diagnosed based on clinical features, others may be more difficult to classify. Often, a life-threatening condition is suspected to be genetic in origin, but the underlying cause is not obvious. In such cases, medical caregivers must communicate these suspicions openly to help the family come to an informed decision about how exhaustive the workup should be. Communication must occur in the context of a holistic, interdisciplinary approach to a treatment plan that encompasses disease-directed and palliative measures. Care providers are responsible for conveying to the family that a diagnostic workup, which can tax both the child and family, is carried out to guide their child’s treatment and to provide answers for the family. Even when parents and children would rather not undergo additional procedures for their own purposes, they may agree to them if they believe it will benefit the larger medical establishment. Medical providers may be unaware of this attitude, blithely performing tests they imagine are desired by the family. The medical risks and benefits, as well as the potential monetary cost to the family, of each diagnostic step should be discussed with the family and, when appropriate, with the child.

When a thorough diagnostic evaluation fails to provide an answer, DNA banking, in which a blood or tissue sample is stored for future studies, is also an option. Banking tissue can provide some comfort for families who fear that their child’s death will forever be unexplained. The necessary tissue can be obtained before or after death. Banked DNA can then be sent for studies as advancements in medical science allow.

As diagnostic technology improves, input from geneticists and genetic counselors becomes increasingly important. Genetic testing results are easily misinterpreted. For example, comparative genomic hybridization, a relatively new diagnostic technique that scans the genome for very small losses or gains of DNA, has a high diagnostic yield in children with multiple life-threatening congenital anomalies. However, a genetic specialist’s input is essential for interpretation of results to this study. A given result may have few or no reported previous occurrences, and thus its implications for disease-directed and palliative care may be difficult to discern without specific training and a review of the medical literature and genome browsers. A geneticist or genetic counselor is best equipped to discuss such results with families and may be able to provide social and educational resources as well.

Such a specialist is also best able to address the implications of a genetic diagnosis for other family members. Although taking the focus from a patient with a life-threatening illness may seem distasteful, it is essential to family-centered care to consider other family members in the workup and treatment for inherited life-threatening conditions.⁶ For some children and families, finding a diagnosis that will facilitate treatment and family planning for relatives is seen as a legacy left by the patient.

A family whose daughter died of a progressive cardiomyopathy, allowing her affected sister to be diagnosed and treated early, found solace in the fact that their child’s short life had made a real difference in the life of her sister.

The needs of other family members, including current and future siblings, should be included in discussion of the family’s and child’s goals for diagnosis and treatment.

At times, the diagnostic workup can include postmortem investigations. If postmortem investigations might be diagnostically useful, the matter should be discussed before death whenever possible. The provider might want to discuss the possibility that postmortem studies may represent the last or only chance to obtain diagnosis in a child who has died of an inherited illness. Diagnosis can answer questions for the family and may also provide information about risk for future siblings. Furthermore, performing a postmortem biopsy can spare a procedure in a dying child who is suspected to have an inherited illness. In certain conditions, such as some metabolic diseases, postmortem investigation can be useful, but specimens should be obtained as soon after death as possible, and the necessary materials and procedures should be set up in advance.

Uncertainty, prognosis, and treatment

Although some inherited illnesses have no specific therapy, treatment options are expanding. Children and parents are presented with the difficult task of sorting through these options at the turbulent time of diagnosis. Confirming a genetic change underlying a child’s life-threatening illness is usually not sufficient to give a certain prognosis; therefore, an array of treatment options is usually available. An interdisciplinary approach is essential at this point. Treatment and life goals of the child and family should be assessed continually and communicated clearly to the medical team.

Conferring a clear diagnosis of an inherited life-threatening condition would seem to also confer a clear prognosis. However, the phenotypic variability in inherited conditions can be great enough that the affected child’s eventual clinical and developmental outcome may not be predictable. The concept of genotype-phenotype correlation must be explored on a case-by-case basis. Genotype-phenotype correlation is highlighted by the example of autosomal aneuploidies such as trisomy 18 and trisomy 21. Specialists will counsel families that infants with trisomy 18 have significant risk for early mortality despite reasonable intervention, whereas infants with trisomy 21 will generally do well. However, counseling always includes the caveat that children affected by either condition may have better or poorer health and development than expected. This uncertainty affects treatment decisions in diverse ways. At times, families may want to proceed with intensive interventions when prognosis seems bleak; in other cases, a family may desire to withdraw life-sustaining interventions despite a seemingly good prognosis. These decisions are highly personal and can confound well-meaning medical providers. Social work, genetic counseling, and interdisciplinary care conferences are helpful in such cases to educate the child and family regarding complex medical issues and to alleviate any fundamental misunderstanding on the part of the family or care team. If cultural differences have contributed to a misunderstanding, a cultural liaison may also be helpful. Ethics consultation and spiritual staff can also be useful in helping guide the family and medical team through this difficult process.

As happens in treating life-threatening illness of any etiology, the line between comfort care and life-prolonging measures is not always clear. Children and families who elect not to pursue curative medical therapies for an inherited illness might still benefit from certain treatments that will probably increase both life span and quality of life.

A family with a symptomatic child newly diagnosed with Hunter syndrome chose not to pursue intravenous replacement of the genetically missing enzyme, as replacement does not improve neurological outcome. However, progressing joint stiffness and other medical problems associated with the condition led the family to pursue the treatment one year later.

Delineation of the molecular basis of inherited disease has ushered in novel therapies, some available only on a research basis. Consulted specialists may know of specific trials for which an affected patient would be eligible. Clinical trials can also be sought through the government-sanctioned website www.clinicaltrials.gov. There may already be some evidence of medical benefit, or lack thereof, of the experimental treatment in question. In other trials, the benefit is less clear. Most families are interested in learning of open trials; some are interested in enrolling and may actually raise the subject. The care team should recognize that participation in these trials may be of greater significance to a patient or family than as last-ditch attempt at treatment; engaging in research-based activities may fulfill the deeper obligation of doing everything to fight an illness. Furthermore, families may be interested in involvement of clinical research studies solely to benefit other families in the future and have comfort in knowing they may be contributing to advancing knowledge about the condition.

Commercially available but non–FDA-approved treatments such as stem cell therapy may also be sought by families. Oftentimes, these treatments are available only outside of the United States, and the medical team may not be able to obtain records or speak with the professionals providing the therapies. Such situations can espouse the worry that these procedures may somehow harm the child. Ethics consultation is indicated where there is reasonable concern for harm or fraud. However, when conventional medicine offers no curative measure for a life-threatening condition, casting aspersions at what a family might consider the only curative treatment can be alienating and ultimately sabotage the family’s relationship with the medical team.

Interventions such as stem cell therapy, an offshoot of Western medical practice, are distinct from complementary and alternative medicine forms, which are also important resources for many families. Clinicians should keep track of complementary and alternative treatments and medications as they would any treatment or medication. This step is especially important in treatment of inborn errors of metabolism; certain ingredients in supplements or alternative medications might be contraindicated in children with specific enzyme deficiencies.

Inherited life-threatening illnesses are often associated with medical, developmental, and anatomic differences that are not in and of themselves life-threatening. To medical providers, these differences may seem of relatively low priority. To patients and families, however, these external stigmata of disease may be close to the top of the list of concerns. Facial and hand anomalies, even those that are of primarily cosmetic importance, are particularly upsetting for many families. However, this reaction is not consistent from family to family.

A Hmong family referred to hand surgery for their child’s postaxial polydactyly was shocked to hear that the surgeon actually wanted to remove what to them was a sign of good fortune. Had they known the purpose of this appointment, they would have declined consultation.

The Somali parents of a neonate with Prader Willi syndrome expressed greater anguish over their child’s transient inability to eat by mouth than over the high likelihood that she would have cognitive impairment throughout life. This family appreciated a visit from endocrinology ahead of schedule to discuss hormonal treatment for hypotonia.

Promptly addressing specific parental and patient concerns expresses a commitment to personalize care and fosters trust and respect between the family and the care team.