Family Stories

Excerpts from Your Genes, Your Health: A Critical Family Guide That Could Save Your Life by Aubrey Milunsky, M.D., D.Sc. and published by Oxford University Press

Excerpt: Connective Tissue Disorders (Ehlers-Danlos Syndrome and other disorders)

A brisk, unremitting wind blew across the island, the palm trees lining the shore bowing in unison as if in deference to the power of the wind and the sea. Despite the balmy early evening temperature of Hawaii, the Yamaha family, cozy in their family room, watched a movie. Besides the parents, two of their sons and their daughter were present. One of the sons, age 15 years, had severe mental retardation and epilepsy. He had no intelligible speech and his communications were mostly by gesture. Suddenly, and without warning, he stood up and began banging on his chest and screaming uncontrollably. The family had never seen such behavior from him and being unable to control or quiet him down, they hustled him struggling into their car and rushed to the hospital. Still screaming and tearing at his chest, he was impossible to examine until four emergency department staff grabbed hold of his limbs, placed him on a gurney, and tied him down with a strait jacket, upon which he instantly died.

A mandated autopsy revealed that his aorta had ruptured, with blood filling his chest cavity. Examination of his brain showed a congenital blood vessel malformation in one location and the probable cause of his seizures. A precise cause for his mental retardation remained unclear. The family was devastated and at a loss to understand how this could have happened to a 15-year-old child. Their family doctor opined that some type of rare syndrome accounted for his mental retardation, vascular malformation in his brain, and his ruptured aorta.

About 2 years later, the second son, Ted (age 14 years at the time), was sitting in the same living room watching television when he began to complain of pain in his chest and back. Without a moment’s hesitation, this time, the parents quickly rushed him to the hospital, told their story of their previous child, and waited anxiously while the immediately ordered CT scan for Ted was performed. A leaking aortic aneurysm was detected, and Ted was rushed to the operating room, where he died before surgical repair could be accomplished.

Ted’s grieving family was overwhelmed, and it took many weeks for them to begin to address questions raised by the emergency room physicians. Aortic rupture in two siblings must be genetic, they said, and they advised a genetics consultation, with special reference to the surviving daughter. In due course, they consulted with a clinical geneticist and reviewed the tragedies that had taken their boys’ lives.

Discussions ranged over genetic disorders such as Marfan syndrome and other disorders (see discussion) in which dilatation of the aorta may result in rupture. At that time, no molecular diagnosis was available, and no definitive absolute diagnosis could be made. Their key question about why they had not been referred to a clinical geneticist after the loss of their first child was not satisfactorily answered and resulted in a medical malpractice lawsuit.

A safe rule is that unusual, remarkable, or unexpected adverse health eventsespecially in the young, but in all under age 50 years—should be considered genetic in origin until proved otherwise. This rule would have led to the recommendation of a CT scan of the aortas of Ted and his sister and would have enabled recognition of early dilatation of Ted’s aorta. That, in turn, would have led to careful surveillance and measurement of the dilatation, leading to elective surgery to replace the defective part of his aorta without waiting for spontaneous rupture. That would have saved his life and resulted almost certainly in a close to normal life expectancy.

There had been no family history taken, with the paternal grandparents still alive but the maternal grandparents having died young. Both of Ted’s parents were otherwise healthy, but neither had a scan of the aorta. Neither of the sons had hyperextensible joints with lax ligaments, long arms, long fingers, short-sightedness, scoliosis, or heart murmurs. These are some of the typical features of the dominantly inherited connective tissue disorder called Marfan syndrome, discussed below.

Marfan syndrome FBN1
Loeys-Dietz syndrome TGFBR1
TGFBR2
SMAD3
TGFB2
Ehlers-Danlos syndrome Type I, Type II, Type VII COL5A1
COL5A2
COL1A1
COL1A2
Ehlers-Danlos syndrome Type IV COL3A1
Periventricular heterotopia, Ehlers-Danlos variant FLNA
Osteogenesis imperfecta Type I, Type II, Type III, Type IV COL1A1
COL1A2
Beals contractural arachnodactyly FBN2
Stickler syndrome Type I COL2A1
Stickler syndrome Type II COL11A1
Stickler syndrome Type III COL11A2
Familial thoracic aortic aneurysms ACTA2
MYH11
MYLK
PRKG1
Aortic aneurysm SMAD3
NTM
Intracranial aneurysm TGFBR3
NTM
Aneurysm osteoarthritis syndrome SMAD3
Aortic valve disease NOTCH1

Excerpt: Breast and Ovarian Cancer

It was hot and humid. The fan of an air conditioner clanged noisily from its poorly fitting perch on the wall adjacent to our table in this small restaurant in Playa Del Carmen. I noticed a bead of sweat chasing another down the worried brow of our dinner companion, Richard. We had met Richard and Susan at a Mayan resort at Mayakoba, Mexico, and were having dinner when the conversation turned to books and publishing. When they discovered that I had only recently published Your Genetic Destiny, I noticed a momentary awkwardness. They knew I was a physician but did not know that I was a clinical geneticist. The reasons for the awkwardness became immediately apparent as the story spilled out.

Richard’s mother’s non-identical twin sister had died from breast cancer diagnosed at age 39 years. A first cousin once removed and her daughter who both lived out of state were thought to also have and have had breast cancer, respectively. There were no other forms of cancer in the family (see the family pedigree in Chapter 1).

Susan related that in her 40s she had been diagnosed with colon cancer after a single “lump” was found in her colon following an evaluation for anemia. She was sure no polyps were found. Subsequently, cancer of one fallopian tube (the connecting channel from ovary to the uterus traversed by released eggs on their hopeful way to fertilization) was detected by a CAT scan as a follow-up for her colon cancer. Major surgery to remove both tumors had thus far been successful and she had remained cancer-free for the past 8 years. Susan’s father and a paternal uncle had both had colon cancer, diagnosed too late, resulting in an early untimely death of both. Susan’s paternal grandmother apparently also died from colon cancer. No other family member had ovarian or any other cancer.

The inevitable questions tumbled out without hesitation. “Am I at any risk of developing cancer?” asked Richard. “Are there DNA tests to determine whether I have a gene mutation that could affect me and even be transmitted to my son or daughter?” Susan wanted to know if it was possible that she had inherited a colon cancer gene from her father and maternal grandmother and whether a DNA test was available to determine if she had inherited a colon cancer gene that could also be transmitted to either her son or daughter.

I recommended that they see a clinical geneticist when they returned home and suggested testing for specific genes. A few months later, I received an e-mail from Richard. They had followed my recommendations, had family members tested, and were astounded by the results.

Richard found that he harbored a mutation in one of the common breast cancer genes (BRCA1), as did his unaffected mother, who was 83 years old and in good health. Her deceased twin sister’s son also proved positive for the same mutation that his mother must have had. Moreover, Richard’s daughter, Cheryl, inherited his BRCA1 gene mutation. His son declined testing.

Susan was found to have a gene mutation in one of four common hereditary nonpolyposis colon cancer genes. Her sister, who was still in good health, was found to have the same gene mutation. Her brother proved negative. Susan’s paternal first cousin, the son of the affected uncle, was also found to have the same mutation and was also in good health.

Richard expressed his appreciation for this chance meeting in Mexico that resulted in the discovery of two mutant genes in the two families. Lifelong surveillance had now been instituted and would also, by making them aware of risks and taking pre-emptive action, certainly save the lives of those with the mutation if a cancer reared its ugly head.


Excerpt: Autism, Autism Spectrum disorder, Asperger syndrome, developmental delay, macrocephaly

Jerry and Matilda (“Please call me Mattie”) met in college and were inseparable. They married soon after graduation and carefully planned for their future. Jerry focused on information technology and over the years became a networking specialist. Mattie was more interested in medicine and trained as a nurse practitioner. Both were “compulsively neat” and, as Mattie related during one consultation, their house was so neat that a guest recently asked if anyone actually lived in it. They acknowledged that they were “obsessively neat” but loved this characteristic that they shared.

About 5 years after graduation, they planned to start a family. Mattie immediately began taking the folic acid vitamin supplement (to avoid spina bifida) and, 3 months later, happily reported that her pregnancy test was positive. The pregnancy was uneventful and free of any complication. She took no medications and was especially careful with her diet and avoided alcohol. Labor, however, turned out to be rather prolonged and unexpectedly very painful. Later, her obstetrician explained that their son Peter had a rather unexpectedly large head size, which made passage through the birth canal slow and difficult. Nevertheless, at birth, Peter was pink, vigorous, and signaled his entry into the world with a loud cry.

As a nurse practitioner, Mattie understood the importance of breast feeding, and as soon as her “milk came in” she settled down to enjoy this closeness with Peter. Only 2 years later and after direct questioning did Mattie realize that Peter never really looked her in the eye during breast feeding.

Within weeks of birth, it became obvious that Peter was frequently “cranky” and difficult to console when crying, which he did frequently. He also slept poorly and awoke frequently through the night for months on end. The inevitable fatigue steadily wore on the nerves of Jerry and Mattie, who found themselves in arguments that they had never had before.

Peter’s motor development was on track, with him sitting up unsupported at age 7 months and walking at 13 months. In retrospect, Mattie acknowledged that Peter did not seem to like being held or cuddled and did not reach out to be picked up. Between ages 15 and 18 months, he had acquired a significant number of words and appeared to be doing well. However, within weeks of receiving a routine vaccination for measles, mumps, and rubella, he seemed to lose much of his acquired language. He also stopped responding to his name.

The neurologist to whom Peter had been referred raised the possibility of autism. He was, however, concerned about the sudden change in development and the associated “big head” that Peter had. This latter observation resulted in a brain MRI, which revealed no abnormality. Peter’s parents seriously questioned the role of the vaccination in precipitating Peter’s loss of abilities.

The ensuing 18 months provided little comfort. Repetitive hand-flapping and walking in circles became an unrelenting behavior with an accompanying high-pitched hum. Peter seemed unable to play or interact with other children of his own age. In fact, as Mattie reported, he could literally trample on a child’s hand or foot without noticing or recognizing the resultant cry of pain. It seemed, Mattie reported, that other children seemed to be like “inanimate objects.” Peter also had a frantic reaction to loud noises, such as those made by the vacuum cleaner, and would rapidly exit the room holding his ears and even running into a wall. He also seemed to have a high pain threshold. He continued to dislike being touched or held, and finding foods he would eat became a major challenge. Just prior to his fifth birthday, Peter had a major seizure in the absence of any obvious precipitating fever or infection. By then it was clear to Jerry and Mattie that Peter’s IQ was in the retarded range and that the diagnosis of autism was certain.

I saw them both in consultation after they had decided to consider another pregnancy. Careful review of their family history revealed that Jerry, his sister, and his father all had large heads (called macrocephaly). One nephew, then age 6 years, had experienced some speech and language delay but, following speech therapy, was doing well. Mattie herself was well and in passing mentioned that she had perfect pitch. [1] She, too, had a nephew, the son of her sister, who had been diagnosed with dyslexia after his teachers had pointed out his persistent letter reversals and difficulties in reading.

I discussed the fact that no definitive associated recognizable disorder explained Peter’s autism, given that the neurologist had obtained numerous genetic tests that yielded only normal results. The risk of recurrence approximated 6% with a potential additional 4% risk for somewhat milder disorders that involve language and social development, as well as psychiatric disorders. No prenatal diagnosis would be possible, given the absence of a definitive DNA or biochemical diagnostic test. Mattie was insistent that the preservative Thimerosal (which contained mercury) in the vaccine that Peter received was the cause of his autism. She remained unconvinced about published studies that did not support any role of Thimerosal in causing autism.

There was no basis to relate Jerry’s nephew’s speech and language delay or Mattie’s nephew’s dyslexia to Peter’s autism.

Jerry and Mattie decided on a second pregnancy and just over a year later delivered their son Matthew. This time, Mattie noticed the lack of eye contact that Matthew exhibited when breast feeding and many of the same features that Peter manifested over the ensuing months and years, confirming yet again a diagnosis of autism.

[1] Perfect pitch or absolute pitch is the rare ability to identify tones with their corresponding musical note names without the help of a reference tone. Just as most of us can recognize the individual colors of a rainbow without thinking, individuals who possess the trait of perfect pitch can identify the precise pitch of a tone. Studies of identical and non-identical twins as well as families whose members have perfect pitch indicate the important role of genes in transmitting this fascinating trait. Undoubtedly, environmental factors such as early musical training have some influence on the development of this rare ability.


Excerpt: Marfan syndrome, Loeys-Dietz syndrome, Ehlers-Danlos syndrome, aortic aneurysm, brain aneurysm, ruptured artery or vein

Cecil C. (or CC, for calm and cool, as the girls called him) was certainly not a doctor. He was the first to profess his limited knowledge of medical matters, although he had been an emergency medical service technician before becoming the high school girls basketball coach.

All of his charges were tall, lanky girls. To his trained eye, one girl stood out. Shanika was 16 years old and in her stockings  measured 6 feet, 2 inches in height. He also noted that she had flat feet and felt certain that she had a spinal curvature (scoliosis). Her long arms seemed like windmills to him, and when she sprained a ligament in her hand, he thought she had the longest fingers he had ever seen. Haunted by an image he would never forget while working as an EMT, he insisted she have a check-up with her doctor and bring him a note affirming that she was in good health. As an EMT, he was part of the ambulance crew that rushed to the home of a young mother who had collapsed on the kitchen floor. He recalled the chaotic scene around her and the attempts to resuscitate her, which culminated in her death in the ambulance. The autopsy later revealed a ruptured aortic aneurysm.

Shanika duly returned with a note stating that she was in good health and fit to play basketball. He expressed his delight to Shanika, who offhandedly mentioned that the doctor had stated she had a slight murmur but that it was “innocent” and of no importance.

That evening Coach CC called Shanika’s mother, with whom she lived, and urged her to have Shanika consult a cardiologist. When she expressed doubt about the need to have a specialist consultation given her doctor’s report, Coach CC related the catastrophic loss of the young mother he had witnessed who had Marfan syndrome.

Shanika’s mother eventually agreed and Shanika subsequently saw a cardiologist. His evaluation included an echocardiogram, which to the family’s amazement and dismay revealed dilatation of the ascending aorta. He made the diagnosis of Marfan syndrome[1] on the basis of her armspan being longer than her height, her very long fingers (called arachnodactyly), scoliosis, and of course the dilated ascending aorta. She also had joints with lax ligaments, a high arched palate, and dental malocclusion (upper front teeth extending over her lower front teeth). No dislocation of the lenses in her eyes was present.

The cardiologist immediately recommended that both of Shanika’s parents come in for an evaluation including an echocardiogram. It took some time to find Shanika’s father, who eventually materialized for his evaluation. He indicated that he worked as a security guard at night and slept most days. He had long parted from Shanika’s mother, whom he had never married. The echocardiogram revealed a well-advanced aneurysmal dilatation of his ascending aorta at a size that demanded immediate surgical attention to avert what could have been an imminent rupture. Elective surgery was accomplished in a teaching hospital and his recovery was uneventful. Coach CC had vicariously saved his life.

Subsequently, both of Shanika’s siblings were evaluated, and the youngest, then 12 years of age, was suspected to have Marfan syndrome and placed on a schedule of echocardiograms to monitor her aorta on an annual basis. Subsequently, analysis of the Marfan syndrome gene (FBN1) revealed a mutation that Shanika, her sister, and her father all harbored. Shanika’s paternal grandfather had died suddenly in the South, and his death had been ascribed to a heart attack, without an autopsy having been done. Shanika’s father said that he thought he had siblings but did not know any of them or where they were.

But for an observant, caring coach, Shanika could well have eventually dropped dead on the basketball court—the type of incident that has happened elsewhere in other sports venues.

[1] This syndrome was named after a French pediatrician, Bernard-Jean Antonin Marfan, who described the typical physical features in 1896.


Excerpt: When Good Cells Go Wrong

It was hot and humid. The fan of an air conditioner clanged noisily from its poorly fitting perch on the wall adjacent to our table in this small restaurant in Playa Del Carmen. I noticed a bead of sweat chasing another down the worried brow of our dinner companion, Richard. We had met Richard and Susan at a Mayan resort at Mayakoba, Mexico, and were having dinner when the conversation turned to books and publishing. When they discovered that I had only recently published Your Genetic Destiny, I noticed a momentary awkwardness. They knew I was a physician but did not know that I was a clinical geneticist. The reasons for the awkwardness became immediately apparent as the story spilled out.

Richard’s mother’s non-identical twin sister had died from breast cancer diagnosed at age 39 years. A first cousin once removed and her daughter who both lived out of state were thought to also have and have had breast cancer, respectively. There were no other forms of cancer in the family (see the family pedigree in Chapter 1).

Susan related that in her 40s she had been diagnosed with colon cancer after a single “lump” was found in her colon following an evaluation for anemia. She was sure no polyps were found. Subsequently, cancer of one fallopian tube (the connecting channel from ovary to the uterus traversed by released eggs on their hopeful way to fertilization) was detected by a CAT scan as a follow-up for her colon cancer. Major surgery to remove both tumors had thus far been successful and she had remained cancer-free for the past 8 years. Susan’s father and a paternal uncle had both had colon cancer, diagnosed too late, resulting in an early untimely death of both. Susan’s paternal grandmother apparently also died from colon cancer. No other family member had ovarian or any other cancer.

The inevitable questions tumbled out without hesitation. “Am I at any risk of developing cancer?” asked Richard. “Are there DNA tests to determine whether I have a gene mutation that could affect me and even be transmitted to my son or daughter?” Susan wanted to know if it was possible that she had inherited a colon cancer gene from her father and maternal grandmother and whether a DNA test was available to determine if she had inherited a colon cancer gene that could also be transmitted to either her son or daughter.

I recommended that they see a clinical geneticist when they returned home and suggested testing for specific genes. A few months later, I received an e-mail from Richard. They had followed my recommendations, had family members tested, and were astounded by the results.

Richard found that he harbored a mutation in one of the common breast cancer genes (BRCA1), as did his unaffected mother, who was 83 years old and in good health. Her deceased twin sister’s son also proved positive for the same mutation that his mother must have had. Moreover, Richard’s daughter, Cheryl, inherited his BRCA1 gene mutation. His son declined testing.

Susan was found to have a gene mutation in one of four common hereditary nonpolyposis colon cancer genes. Her sister, who was still in good health, was found to have the same gene mutation. Her brother proved negative. Susan’s paternal first cousin, the son of the affected uncle, was also found to have the same mutation and was also in good health.

Richard expressed his appreciation for this chance meeting in Mexico that resulted in the discovery of two mutant genes in the two families. Lifelong surveillance had now been instituted and would also, by making them aware of risks and taking pre-emptive action, certainly save the lives of those with the mutation if a cancer reared its ugly head.