What is the Genetic Inheritance of Alport Syndrome?

Patient Presentation
A 15-year-old male came to clinic for his health supervision visit and clearance to play high school sports. He had recently moved to the area. He reported no problems other than a sprained ankle 2 years previously because of a soccer injury that healed without problems. When reviewing the family history the mother said, “I really haven’t thought about this for a long time, but he has had hematuria a couple of times when he was younger. My father was diagnosed with Alport syndrome after he had kidney failure just before my son was born. He was worked up and they said he had Alport syndrome.” The mother related that she didn’t have any problems she was aware of but she had never been tested for Alport. She did say she had some urinary problem when she had been pregnant but didn’t know more and she had never had her hearing tested. As her father had been a machinist, he and his doctor had always thought his hearing problems were because of his occupation but he found out later it was Alport. Her father’s mother also had hearing problems but the mother didn’t know more about it. Her son had seen a nephrologist after he had the hematuria, “but they told our doctor to just monitor him and if he had more problems to come back. They also said that he was so little at the time that with more time better testing would be available.” “My daughter saw the nephrologist too who said she was okay,” stated the mother. She said that she didn’t think her own brother or sister or their children had any problems and denied any kidney or hearing problems in the paternal family. The review of systems was negative.

The pertinent physical exam showed a healthy appearing teenager at 75% for height/weight and with a 90% blood pressure at 128/82. Repeated readings were consistent. 4-point blood pressures did not reveal differences in upper extremities and lower extremities. The rest of his examination was normal. The diagnosis of a healthy male with an elevated blood pressure, personal history of hematuria and family history of Alport syndrome was made. The laboratory evaluation showed a normal complete blood count, lipid panel, thyroid functions and a urinalysis that had a specific gravity of 1.015 with +1 blood and protein. Audiometry showed some minor sensory neuronal hearing loss. He was referred to a nephrologist and genetic testing for Alport was pending.

Discussion
Alport Syndrome is a genetic disease classically associated with progressive renal disease often leading to end stage renal disease, variable sensory neuronal deafness and ocular findings (perimacular retinopathy).

A. Cecil Alport built on the work of others evaluating families with nephritis and/or hematuria. However he very clearly describes the third generation of a family with an X-linked dominant pattern and also emphasizes the syndrome’s associated deafness.
Alport writes:


“It will be seen from this that nearly all the children of three generations of one family suffer from hematuria or nephritis associated with deafness. The deafness, which has not been stressed in the literature on the subject, is one of the most distressing features of this extraordinary disease.”

“This nerve deafness is apparently the type of defective hearing to which members of his family are subject. It occurs not only in the individuals who have nephritis or haematuria, but also in those who are otherwise perfectly healthy.”

His summary comments include:


“1. Hereditary familiar or congenital nephritis is a definite entity, and the kidneys in these patients are more susceptible to damage by the toxin of an unknown organism that is the cause and the normal person….
5. Deafness is a marked feature in nearly all cases.
6. The male members of a family tend to develop nephritis and deafness and do not as a rule survive. The females have deafness and haematuria and lead to an old age.”

Learning Point
Alport syndrome is genetically heterogeneous. The genetic mutations result in changes to Type VI collagen, the kidney’s basement membrane’s major structural protein. The change is described as a having a laminated basket-weave appearance to the basement membrane.

The majority of cases are X-linked (85%) with variable but highly penetrant. The affected gene is COL4A5 gene on Xq22.3 which codes for the type IV collagen α5 chain.

About 15% are autosomal recessive affecting the COL4A4 or COL4A3 genes on 2q36.3 which code for the Type VI collagen α4 or α3 chains respectively.

Autosomal dominant cases are rare and affect the COL4A3 genes on 2q36.3. Interestingly benign family hematuria (sometimes known as thin basement membrane nephropathy) is an autosomal dominant disorder affecting the COL4A3 genes on 2q36.3 also. It has a thin basement membrane and hematuria, but does not have progressive nephropathy.

From the family history in the case above, X-linked recessive Alport syndrome may be the cause of the teenager’s symptoms. Testing of the family members will also be important to understand who else in the family may be affected. Benign familial hematuria is a possibility but the teenager has evidence of progressive renal abnormalities as well as hearing loss which are not features of this entity.

Questions for Further Discussion
1. What other diseases have a classic X-linked recessive genetic pattern?
2. What are common causes of hematuria? Causes of gross hematuria can be reviewed here
3. What are the most common causes of nephritis?
4. What are causes of proteinuria? The differential diagnosis can be reviewed here

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for these topics: Kidney Diseases and Hearing Disorders and Deafness.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Alport AC. Hereditary Familial Congenital Haemorrhagic Nephritis. Br Med J. 1927 Mar 19; 1(3454):504-506.

Alport Syndrome, Autosomal Dominant #104200. Online Mendelian Inheritance in Man. Available from the Internet at http://www.omim.org/entry/104200?search=alport%20syndrome&highlight=syndromic%20alport%20syndrome (rev. 7/10/2015, cited 7/20/2017).

Alport Syndrome, Autosomal Recessive #203780. Online Mendelian Inheritance in Man. Available from the Internet at http://www.omim.org/entry/203780 (rev. 7/13/2015, cited 7/20/2017).

Alport Syndrome, X-Linked; ATS #301050. Online Mendelian Inheritance in Man. Available from the Internet at http://www.omim.org/entry/301050?search=alport%20syndrome&highlight=syndromic%20alport%20syndrome (rev. 7/10/2015, cited 7/20/2017).

Hematuria, Benign Familial #141200. Online Mendelian Inheritance in Man. Available from the Internet at http://www.omim.org/entry/141200 (rev. 7/21/2015, cited 7/20/2017).

Oka M, Nozu K, Kaito H, Fu XJ, Nakanishi K, Hashimura Y, Morisada N, Yan K, Matsuo M, Yoshikawa N, Vorechovsky I, Iijima K. Natural history of genetically proven autosomal recessive Alport syndrome.
Pediatr Nephrol. 2014 Sep;29(9):1535-44.

Fernandez-Rosado F, Campos A, Alvarez-Cubero MJ, Ruiz A, Entrala-Bernal C. Improved genetic counseling in Alport syndrome by new variants of COL4A5 gene.
Nephrology (Carlton). 2015 Jul;20(7):502-5.

Weber S, Strasser K, Rath S, Kittke A, Beicht S, Alberer M, Lange-Sperandio B, Hoyer PF, Benz MR, Ponsel S, Weber LT, Klein HG, Hoefele J. Identification of 47 novel mutations in patients with Alport syndrome and thin basement membrane nephropathy. Pediatr Nephrol. 2016 Jun;31(6):941-55.

Author
Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa

At What Height Do You Consider Preventative Treatment for Acute Mountain Sickness?

Patient Presentation
A 15-year-old male came to clinic for travel advice. He was traveling to the Andes Mountains for most of his trip. He was going to ~3000m altitude and would be acclimatizing there for a couple of days before going to ~3500 m hiking over 4 days. He then would be returning to sea level. He had hiked in the Rocky Mountains going to an altitude of 2500 m without acclimatization without any problems. The past medical history showed a broken forearm. The family history was non-contributory.

The pertinent physical exam showed normal vital signs and growth parameters of 25-50%. His examination was normal. The diagnosis of a healthy male was made. The Centers for Disease Control website was consulted for the recommendations for the countries he would be visiting and he was offered typhoid and yellow fever vaccine in addition to malaria prophylaxis. Because of the altitude, he and his parents also wanted to use acetazolamide for acute mountain sickness prevention. The physician discussed the need to stay hydrated and hike slowly. “Mom and Dad have been talking non-stop about how I have to tell them if I have a headache or feel sick to my stomach. I know it is important,” the teenager said. The parents also said that they had a guide and also a plan if someone in the group was having problems with mountain sickness and would need to descend.

Discussion
Acute mountain sickness (AMS) is a well-known problem for some people who travel to high altitude, especially altitudes > 2500 m (~8200 feet). Symptoms include headache, nausea or emesis, shortness of breath, dizziness, fatigue, difficulty sleeping and poor appetite. The incidence in adults ranges from 25% at 2975 m to up to 75% at 5896 m. The incidence in children is less clear but it appears that children are more susceptible at 45% for 16-19 year olds for similar altitudes. Risk factors are numerous including age, gender, obesity, ascent rate, altitude for sleeping, previous exposure to high altitude, previous AMS, and history of cardiopulmonary disease. Different studies show physical fitness may or may not be a risk factor. One study of teenage children found for children 11-13 years old, male gender and increased body mass index increased the risk for AMS. This was for an ascent from 25 m to 3386 m over 3 days in Taiwan. Physical fitness was not associated with AMS occurrence in this study. AMS definitions for research and other purposes often use the Lake Louise AMS score which was created in 1991. It looks at presence of headache and at least 1 other symptom including gastrointestinal symptoms (i.e. anorexia, nausea or emesis), fatigue or weakness, dizziness or lightheadedness and difficulty sleeping. HACE (high altitude cerebral edema) and HAPE (high altitude pulmonary edema) severity are also defined. Criteria can be found here and here.

Children born and living in high altitudes have asymptomatic pulmonary hypertension that declines over time. Persistent patent ductus arterosus is higher in these children (delayed 3-4 days instead of usual 24 hours for those at lower levels). HAPE (high altitude pulmonary edema) can occur in these children who go to lower levels and return (re-entry). There are probably some genetic factors at play where the children who have long ancestry have lower incidences of pulmonary artery hypertension, but those without this long ancestry or newcomers have higher rates of pulmonary artery hypertension (Tibet vs Leadville Colorado 3100 m).

Learning Point
The mainstay of treatment for AMS is descent to a lower altitude. Mild forms of AMS may only need this treatment. Additional treatment may include oxygen, acetazolamide, dexamethasone, or hyperbaric oxygen. Acclimatization is one of the best ways to also help prevent AMS. For prevention for altitudes >2500 one may consider using acetazolamide by general convention as risks increase but AMS can occur at lower altitudes also. The optimal dosage is debated. A recent systematic review concluded that “The degree of efficacy of acetazolamide for the prevention of AMS is limited when the baseline risk is low, and there is some evidence of dose-responsiveness.” Dosages of 250 mg, 500 mg and 750 mg/daily are commonly used. Acetazolamide has potential side effects of polyuria, taste disturbance and parasthesias. Being well hydrated and moving slowly and paying attention to one’s exercise effort are always good general precautions.

Questions for Further Discussion
1. What other preventative advice would you give this patient?
2. What are your sources of advice for travel for your patients?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for this topic: Traveler’s Health

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Pollard AJ, Niermeyer S, Barry P, et.al. Children at high altitude: an international consensus statement by an ad hoc committee of the International Society for Mountain Medicine, March 12, 2001. High Alt Med Biol. 2001 Fall;2(3):389-403.

Anand IS, Wu T. Syndromes of subacute mountain sickness. High Alt Med Biol. 2004 Summer;5(2):156-70.

Niermeyer S. Going to high altitude with a newborn infant. High Alt Med Biol. 2007 Summer;8(2):117-23.

Penaloza D, Sime F, Ruiz L. Pulmonary hemodynamics in children living at high altitudes. High Alt Med Biol. 2008 Fall;9(3):199-207.

Wilson MH, Newman S, Imray CH. The cerebral effects of ascent to high altitudes. Lancet Neurol. 2009 Feb;8(2):175-91.

Kayser B, Dumont L, Lysakowski C, Combescure C, Haller G, Tramèr MR. Reappraisal of acetazolamide for the prevention of acute mountain sickness: a systematic review and meta-analysis. High Alt Med Biol. 2012;13:82-92.

Bradwell AR, Myers SD, Beazley M, et.al.; Birmingham Medical Research Expeditionary Society. Exercise limitation of acetazolamide at altitude (3459 m). Wilderness Environ Med. 2014 Sep;25(3):272-7.

Wu SH, Lin YC, Weng YM, et.al. The impact of physical fitness and body mass index in children on the development of acute mountain sickness: A prospective observational study. BMC Pediatr. 2015 May 8;15:55.

Rimoldi SF, Rexhaj E, Duplain H, et.al. Acute and Chronic Altitude-Induced Cognitive Dysfunction in Children and Adolescents. J Pediatr. 2016 Feb;169:238-43.

Author
Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa

What Should Parents Teach Their Children About Stranger Safety?

Patient Presentation
A 5-year-old female came to clinic with her mother for her health supervision visit. She was starting kindergarten in the fall and had not been in a childcare or an educational setting before. Her mother described her as a sociable child whom other children and adults liked. She was a very trusting child and therefore her mother was concerned that she would be vulnerable to a stranger abduction. The pertinent physical exam showed a well-developed child with normal vital signs and growth parameters in the 90-95%. Her pertinent physical examination was normal. She was quite gregarious with advanced speech content. Her other development was on track for her age.

The diagnosis of a healthy female was made. The pediatrician talked with the girl about a couple of potential scenarios for when a child should be wary of strangers. It was obvious that she needed some more information and practice regarding stranger safety. The pediatrician gave the mother some ideas about how to practice stranger safety with her daughter over the next few months in addition to information about developmental readiness for kindergarten.

Discussion
Fortunately, when a child goes missing it is usually for short periods of time and is often because of miscommunication or expectations. Familiar examples are a child wandering away, or not returning at the proper time. Unfortunately, child abduction does occur.

Data from the U.S. Department of Justice’s Office of Juvenile Justice and Delinquency Prevention provides the statistics below. Problems with definitions and reporting make these statistics more difficult to gather.

  • ~340,500 children (43%) reported in 1999 as missing, were because of benign causes and no harm occurred to the child. Most were because of communications problems such as failing to come home or coming home later than expected.
  • ~43,700 missing children in 1999 were injured but only 10,200 were reported to authorities to help locate the child.
  • There were ~58,200 child victims of non-family abductions in 2002.
  • ~ 105 children in 2002 were victims of stereotypical kidnapping in 2011. Most of these were teenage, white females and most ended with recovering the child alive.
  • Cellphone, Internet and other technologies helped law enforcement solve ~2/3 of these crimes.

A missing child, emergency reference guide is available here.

Tips for getting ready to go to Kindergarten can be reviewed
here.

Learning Point
Parents can help their child be safe from strangers by:

  • What is a stranger?
    • Stranger are people that the child or your family doesn’t know or doesn’t know well.
    • Strangers can look like anyone. Nice looking strangers can be as dangerous and strangers who look “bad” or “mean” can be safe strangers.
    • Remind the child that if they need help, most strangers are not bad. It is just that they are strangers and the child needs to decide whether or not to trust them.
    • Most strangers actually can be trusted to help a child.
  • What is a safe stranger? Where can you find a safe stranger?
    • Safe strangers are people that can be asked for help if needed.
    • Police and firefighters are common, recognizable safe strangers.
    • Other common safe strangers would be teachers, librarians, and spiritual advisors.
    • Public places are good places to teach children to find safe help. During your usual day, point out places you would choose as a safe place to find help such as a local store, restaurant, recreation center, school or house of worship.
    • Point out that the workers in stores or restaurants usually have a uniform – all wearing a similar shirt and have a name tag.
    • Point out homes of family friends in the neighborhood that children could go for help too.
    • Make sure the child knows their name, parents first and last name, and street they live on. This information can help the safe stranger contact the parent or local police.
  • How do you recognize potentially dangerous situations?
    • Children should be taught to be wary of potentially dangerous situations and strangers. That doesn’t mean that they need to be scared of every stranger or situation but need to be taught to be cautious.
    • Children should learn to recognize suspicious behavior. Examples include an adult who:
      • Asks the child to do something the child knows is wrong to do
      • Asks the child for help (adults ask other adults for help)
      • Makes the child feel uncomfortable
  • The child should be taught how to handle these situations – one way is “No, Yell, Go, Tell”
    • No – in a dangerous situation the child should say No. Even better if they describe what they are saying No to. For example, “No. You are not my father” Or “No, I do not want any candy from you.”
    • Yell – Yell very loudly to get others attention – Yell “Help” or “Fire” to attract attention.
    • Go – Run away from the situation and go to a place that they feel is safe
    • Tell – tell a trusted adult as soon as possible
    • For example, a stranger asks for directions on your child’s way home from school. The child can say No – “No I’m not going with you, ” continue to yell while running back toward the school. Then finding a teacher and telling about the incident.
    • A child should be taught they can do this inside (ex. a mall or hospital) or outside (ex. park, street, etc.)
    • If they are grabbed, teach children to resist, kick, bite or hit to try to get away.
  • Practice makes perfect
    • Parents can talk about and model appropriate behavior with their children. When you get lost, how do you get directions from a safe stranger?
    • Talk about different situations that could come up and practice what a child should do.
      • Ask “If you got lost now in the grocery store, what would you do?” and tell, “That’s right, the safe strangers in our grocery store have a uniform with white shirts and a black name badge.”
      • Ask “If that woman over there wanted to give you candy, or go outside to pet her dog, what would you do?” and tell, “Never take candy from a stranger or go with a stranger. You can just say No, yell real loud and run away until you can find a safe stranger.”
      • Point out safe places and safe strangers in your community.
    • Teach children to trust their instincts. If they feel uncomfortable they should “No, Yell, Go, Tell”
      • If they are wrong about the situation, that is okay. Better to “No, Yell, Go, Tell” than to have a problem.
    • Teach children play with other children and to have trusted adults around.
      • Remind children that if they cannot see the trusted adult then the trusted adult cannot see them. They are too far away and need to come back to the trusted adult.
    • Teach children to never accept any item from a stranger or go any place or accept a ride from a stranger.
  • When can a child be left alone?
    • That depends on many factors which can be reviewed here.
    • Parents should know where their child is at all times.
      • The child should know how to contact the parent.
      • The parent should have a way to contact the child and check in with them such as a cellphone.
      • Teach children how and when to dial 911 and how to use a cellphone or regular phone.
      • Teach children about online/Internet safety – some recommendations can be reviewed here.

Questions for Further Discussion
1. What are safety tips for online/Internet safety?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for this topic: Child Safety

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Finkelhor D, Hammer H, Sedlak AJ. Nonfamily Abducted Children: National Estimates and Characteristics. U.S. Department of Justice. Office of Juvenile Justice and Delinquency Prevention. Available from the Internet at https://www.ncjrs.gov/pdffiles1/ojjdp/196467.pdf (rev. 10/2002, cited 6/1/17)

Sedlak AJ Finkelhor D, Hammer H. National Estimates of Children Missing Involuntarily or for Benign Reasons. U.S. Department of Justice. Office of Juvenile Justice and Delinquency Prevention. Available from the Internet at https://www.ncjrs.gov/pdffiles1/ojjdp/206180.pdf (rev. 7/2005, cited 6/1/17)

Wolak J, Finkelhor D, Sedlak AJ. Child Victims of Stereotypical Kidnappings Known to Law Enforcement in 2011. U.S. Department of Justice . Office of Juvenile Justice and Delinquency Prevention. Available from the Internet at https://www.ojjdp.gov/pubs/249249.pdf (rev. 6/2016, cited 6/1/17)

National Crime Prevention Council. What to Teach Kids About Strangers.
Available from the Internet at http://www.ncpc.org/topics/violent-crime-and-personal-safety/strangers (rev. 2017, cited 6/1/17).

Author
Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa