How Common is α-1-Antitrypsin Deficiency?

Patient Presentation
A 4-year-old male came to clinic with a 3 day history of rhinorrhea and cough. The night before he developed a fever to 101.5°F. and was complaining of left ear pain. He had received ibuprofen with relief. He was drinking and urinating well. The past medical history was positive for α-1-Antitrypsin Deficiency diagnosed in the neonatal period because of prolonged jaundice.

The pertinent physical exam showed a mildly-ill appearing male with normal vital signs except for a temperature of 100.6°F. His growth parameters were between 10-50%. HEENT showed moderate clear rhinorrhea, normal pharynx, and a supprative effusion behind the left tympanic membrane with distorted landmarks. His right tympanic membrane was slightly erythematous but not bulging and without fluid. His lungs were clear. His abdomen was soft, and non-tender without organomegaly. His skin was normal. The diagnosis of left supprative otitis media was made in a patient with α-1-antitrypsin deficiency. The pediatrician prescribed amoxicillin for the ear infection. The parent said, “He’s had that before and it wasn’t a problem. We just want to stay away from any medicines that could cause liver problems because of his problem though.” The patient receive his seasonal influenza vaccine that day also.

α-1-Antitrypsin Deficiency (A1AT) is a common single-gene mutation disease that is homozygous recessive. The normal allele is called M and the most common abnormal allele is Z. There are other alleles though. The gene codes for one of the primary protease inhibitors in the serum, thus those who are homozygous for the Z gene are sometimes referred to as “PIZZ” or “PIZ.” α-1-Antitrypsin is found in all body tissues but is especially important in the serum and lung. As noted it is one of the primary neutrophil protease inhibitors in the serum, and acts to neutralize these enzymes when they leak into the extracellular fluid during inflammation. The Z mutation causes the synthesis of an abnormal protein which is retained in the hepatocytes and accumulates instead of being secreted. This can cause chronic liver disease including cirrhosis and hepatic failure. The Z mutation also causes emphysema in young to middle-aged adults. The natural history of the disease process can be quite variable.

Pediatric patients may be asymptomatic or present with cholestatic hepatitis, hepatomegaly, and nutrition/growth problems. Other important problems include chronic liver disease with cirrhosis and fibrosis (lifetime risk ~50% for ZZ patients). Hepatocellular carcinoma risk is increased. The lungs are particularly sensitive to A1AT. Lung infections, asthma, and emphysema occur and smoking or second-hand smoke increases the risk of serious lung disease. Lung disease more commonly presents in the adult population. Panniculitis and secondary vasculitis have also been reported in the literature. Treatment is supportive and can include organ transplant of the liver or lung. Treatment by giving α-1-Antitrypsin has not been very successful.

Learning Point
A1AT is one of the most common single gene mutations occurring in ~ 1:2,000 – 3,500 births in North American and European populations. There are ~100,000 people affected in the United States but the disease can be unrecognized and thus undiagnosed. This is particularly true because of the variation in the disease presentation.

As this is one of the most common genetic mutations, potentially it is a candidate for neonatal screening and further studies have been called for.

Questions for Further Discussion
1. What is in the differential diagnosis of conjugated hyperbilirubinemia? A review can be found here.
2. What is in the differential diagnosis of unconjugated hyperbilirubinemia? A review can be found here.
3. What are indications for solid organ transplantation?

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, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for this topic: alpha-1-Antitrypsin Deficiency.

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.

Fregonese L, Stolk J. Hereditary alpha-1-antitrypsin deficiency and its clinical consequences. Orphanet J Rare Dis. 2008 Jun 19;3:16.

Teckman J, Pardee E, Howell RR, Appropriateness of newborn screening for α1-antitrypsin deficiency. J Pediatr Gastroenterol Nutr. 2014 Feb;58(2):199-203.

Lane CR, Tonelli AR. Lung transplantation in chronic obstructive pulmonary disease: patient selection and special considerations. Int J Chron Obstruct Pulmon Dis. 2015 Oct 9;10:2137-46.

Online Mendelian Inheritance in Man. Alpha-1-Antitrypsin Deficiency; A1ATD. Available from the Internet at (rev. 8/4/16, cited 2/13/17).

Gotzsche PC, Johansen HK. Intravenous alpha-1 antitrypsin augmentation therapy for treating patients with alpha-1 antitrypsin deficiency and lung disease. Cochrane Database Syst Rev. 2016 Sep 20;9:CD007851.

Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa Children’s Hospital

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What Are the Clinical Symptoms Associated with Friedreich Ataxia?

Patient Presentation
A 12-year-old female came to clinic for her health supervision visit. She complained of new onset intoeing that had been occurring for more than 6 months. She had not seen a physician for more than 2 years and the family could provide few details about the history. She said that she was more “clumsy” over time and would trip and occasionally fall even when walking on even ground. She denied any pain, numbness, tingling, difficulty with walking distances or up stairs, or fine motor problems including writing, tieing shoes, brushing teeth or eating. She denied any visual problems. They weren’t sure if it was getting worse but the intoeing was obvious to other people. She denied any trauma or infectious diseases other than a cold. The travel and animal contact history was negative and she denied any anxiety or depressive symptoms. Her grades at school were the same and she had the same several friends. The family was moving to another state soon.

The past medical history showed her to be underimmuized, but she was fully immunized for varicella. The family history was negative for any neurological or orthopaedic problems including no intoeing or outtoeing as a younger child. The review of systems showed no fevers, nausea, emesis, changes in hair or skin, or dysuria.

The pertinent physical exam showed a well-appearing female with normal vital signs and growth parameters around the 50th percentile. HEENT showed pupils to be equal, round and reactive to light and accommodation and no nystagmus. Visual acuity was 20/30 bilaterally. Thyroid was normal size without masses. Lungs, heart, and abdomen were normal. She was Tanner 2 for breast. Her skin had a few open comedomes on her checks and nose. Neurologically her cranial nerves were intact. Her strength was normal in upper and lower extremities. She had +1/+2 deep tendon reflexes in the lower extremities and had positive Babinski reflexes. There was no clonus. Sensation and position sense were equivocal in the lower extremities because the patient didn’t seem to fully understand the questioning. She did not appear to have a direct sensory level though. She had normal deep tendon reflexes in the upper extremities. She appeared to have normal rapid alternating movements, but had some past pointing with finger-to-nose testing. She had had a positive Rhomberg test, but negative Gower maneuver. When walking she had intoeing bilaterally and a wider-based gait.

The diagnosis of a chronic, possibly progressive, neurological condition affecting mainly the lower extremities was made. The differential diagnoses included infection (which seemed unlikely), tumor affecting the spinal cord or cerebellum, or a underlying hereditary disease including ataxias. The patient’s clinical course showed that she was referred to a pediatric neurologist who felt her clinical examination was most consistent with a hereditary ataxia, most likely Friedreich ataxia. The family wanted minimal testing, so genetic testing was sent and was positive for Friedreich ataxia. The family moved to another state soon after the diagnosis.

Friedreich ataxia (FRDA) was first extensively described in a series of papers from 1863-1877 by Nikolaus Friedreich at the University of Heidelberg, Germany. In 1996 the genetic mutation was described. It is an autosomal recessively inherited, homologous expansion of the GAA repeat in intron 1 of the frataxin gene on chromosome 9q13. It causes a transcription error leading to a decrease in frataxin which is a mitochondrial protein involved in iron metabolism and other cell functions. Frataxin is seen mainly in the central and peripheral nervous systems, heart, pancreas and skeleton. Frataxin is produced but in decreased amounts, and lack of frataxin causes in-utero lethality of the embryo.

FRDA is the most common cause of autosomal recessive ataxia. Point estimates are up to prevalence 3/100,000 and it is estimated that ~9000 patients in the United States with FRDA at any given time. Age of onset is in early teens with a mean of ~15 years with most cases developing by 25 years, although genetic testing has allowed more adult patients to be identified. FRDA is unfortunately progressive and patients’ have a decreased lifespan at 40 years (+/- 20 years). There is a correlation with the number of repeats with an increased number having increased disease severity. There is no generational anticipation where subsequent generations have increased severity or onset at earlier ages.

Unfortunately, FRDA is progressive and many treatments help to support the patients and decrease side effects to help with mobility and nursing care. Potential treatments being used include antioxidants, frataxin-inducing agents and gene therapy.

Learning Point
Patients with FRDA can have several presentations including neurological problems, scoliosis or pes planus, or sometimes cardiomyopathy. Neurological symptoms usually associated with FRDA include gait and limb ataxia, decreased tendon reflexes, positive Babinski reflex, loss of position and vibratory sense and dysarthria. Older individuals may have an atypical presentation with preservation of tendon reflexes or very slow progression.

Clinical symptoms of Friedreich ataxia include:

  • Neurological
    • Gait ataxia
    • Distal extremity
      • Dysmetria
      • Atrophy and/or weakness
      • Loss of vibratory and proprioception
      • Sensory neuropathy – “stocking and glove”
      • Loss of stretch muscle reflexes
      • Babinski sign positive
    • Head and Neck
      • Nystagmus
      • Head titubation
      • Dysarthria
      • Blindness (rare)
      • Diminished speech perception
      • Vestibular dysfunction
  • Heart
    • Cardiomyopathy – usually hypertropic but can be dilated
    • Mural thrombi can occur and cause embolic strokes
  • Skeletal
    • Scoliosis – very common and progressive
    • Pes cavus
  • Endocrine
    • Diabetes mellitus

Questions for Further Discussion
1. What causes ataxia in general? A review can be found here.
2. What causes hereditary ataxia?
3. What causes intoeing or outtoeing in younger age groups? A review can be found 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, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for these topics: Friedreich Ataxia and Degenerative Nerve Diseases.

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.

Koeppen AH. Friedreich’s ataxia: pathology, pathogenesis, and molecular genetics. J Neurol Sci. 2011 Apr 15;303(1-2):1-12.

Jayadev S, Bird TD. Hereditary ataxias: overview. Genet Med. 2013 Sep;15(9):673-83.

Aranca TV, Jones TM, Shaw JD, Emerging therapies in Friedreich’s ataxia. Neurodegener Dis Manag. 2016;6(1):49-65.

OMIM. Friedreich Ataxia 1; FRDA. Available from the Internet at (rev. 9/13/16, cited 2/6/17).

Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa Children’s Hospital

What Causes Uveitis?

Patient Presentation
A 13-year-old male came to clinic with a 2 day history of blurred vision. He noticed the problem in the evening but thought that it was just because he was tired. The next day it continued and he told his parents that he also had some “black spots” that seemed to move around. He denied pain, photophobia or any visual field cuts or narrowing of the visual fields. His mother said that initially she noticed that his left eye was slightly redder but he had been rubbing it trying to relieve the symptoms. She said that it was now normal after he stopped rubbing the eye. He had been well and denied any eye, head or neck trauma. He had been born in the United States and there was no travel outside the United States nor contact with people who had been visiting overseas. He drank city water and had no animal exposures except for a guinea pig at a friend’s house but he had not touched the animal in several months. The past medical history was positive for a left tibial toddler’s fracture at age 3. The review of systems was negative for fevers, chills, nausea, emesis, diarrhea, dysuria, cough, rhinorrhea, edema, weight loss or gain, skin, hair or nail changes or phonophobia. There was also no arthralgia, myalgia, warmth in any joint or difficulty moving.

The pertinent physical exam showed a well-appearing male with normal vital signs and growth parameters around the 75%. He had a normal weight curve since his last visit. His visual acuity was 20/50 in his left eye and 20/30 in his right eye. Pupils were equal, round, and reactive to light. Extra ocular movements were intact. His eye examination showed some photophobia. There was no obvious leukocoria or hypopyon noted. Disc margins appeared sharp but vessels were difficult to evaluate because he kept closing his eyes. His HEENT was negative including thyroid masses. His skin, hair and joint examinations were normal. The rest of his examination was normal.

The diagnosis of acute onset of visual changes including decreased acuity and “floaters” with an otherwise negative history and physical examination was made. The pediatrician referred the teenager to pediatric ophthalmology the following day who diagnosed him with par planitis after various ophthalmological testing which showed snowbanks and snowballs in the vitreous bilaterally.

The laboratory evaluation included a chest radiograph, and blood and urine testing for immune diseases and infectious diseases. Quantiferon gold was performed for possible tuberulosis. All testing was eventually negative and the patient was started on oral steroids. The patient was to followup in 1 month with the ophthalmologist, but the pediatrician contacted the family by phone after 2 weeks and the patient said that he had less floaters and blurred vision subjectively.

Inflammation of the middle layer of the eye, or uvea, is termed uveitis. Uveitis can be divided into anterior, intermediate or posterior uveitis by involving the anterior (iris and ciliary body), intermediate (vitreous) or posterior (choroid and usually retina) compartments. Panuveitis involves all 3 compartments. Duration can also be used to classify uveitis. Acute is 6 weeks and > 3 months is chronic persistent uveitis. Episodic periods of inactivity and reactivity that last more than 3 months are called recurrent uveitis. A third way to characterize uveitis is if it is granulomatous or not. Uveitis increases with age with the highest incidence and prevalence in > 65 year olds. Only ~10% of uveitis occurs in the pediatric age group. Uveitis can be difficult to identify in younger children as they cannot as readily communicate their visual problems. Younger children unfortunately seem to have worse long-term outcomes too.

Pars planitis is a non-granulomatous, chronic, intermediate uveitis of unknown cause (subvariation of idiopathic), but felt to be immune-mediated with a linkage to HLA-DR2 and HLA-DR15. It occurs in children and teens and is possibly more common in males but studies disagree. Patients can be asymptomatic or often have an insidious onset of blurred or decreased vision or floaters. Other less common symptoms are pain, redeye or photophobia. Young children can have strabismus or leukocoria. The eyes are often asymmetrically involved but usually there is some uveitis present in both eyes. Pars planitis is characterized by snowball formation or inferior snowbanking in the vitreous. Potential complications of pars planitis include: cataracts, posterior synechiae, cystoid macular edema (most common cause of visual morbidity), optic disc edema, glaucoma, vitreous hemorrhage, retinoschisis or rarely retinal detachment. Despite these potential complications prognosis is usually good.

Treatment of uveitis tries to balance arresting the inflammation with the potential side effects of the medication. Steroids are often used topically, orally or periocularly injected. Immunosuppressive agents such as methotrexate or biological agents such as adalimamab or infliximab have been used. Complications may need surgical intervention. The outcome of uveitis depends on the diagnosis, treatment and complications encountered by an individual patient.

Learning Point
The workup for uveitis includes evaluation for infectious, immune and malignancies etiologies before any treatment is begun and includes many of these entities below.

Causes of uveitis include:

  • Immune
    • *Idiopathic
    • *Juvenile idiopathic arthritis (JIA)
    • Behçet’s disease
    • Blau syndrome
    • Cogan syndrome
    • Inflammatory bowel disease
    • Multiple sclerosis
    • *Pars Planitis
    • Sarcoidosis
    • Sympathetic opthalmia
    • Tubulointerstitial nephritis-uveitis (TINU) syndrome
    • Vogt-Koyanagi-Harada syndrome
  • Infectious
    • *Viral
      • Cytomegalovirus
      • Epstein Barr virus
      • Herpes simplex virus
      • Rubella
      • Varicella
    • Parasitic
      • *Toxoplasma
      • Ascaris
      • Toxocara
    • Bacteria
      • Tuberculosis
      • Bartonella
      • Borrelia burgdorferi
      • Treponema pallidum
  • Mimicks Uveitis
    • Leukemia
    • Retinoblastoma

* In a study of 527 patients in the US, the most common cause for anterior uveitis was JIA, intermediate uveitis was par planitis and posterior uveitis was toxoplasmosis.

Questions for Further Discussion
1. What is the role of a pediatrician with an uveitis patient?
2. Besides opthalmology, what other specialties may have a role in the care of an uveitis patient?

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, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for this topic: Eye Diseases.

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.

Smith JA, Mackensen F, Sen HN, Epidemiology and course of disease in childhood uveitis. Ophthalmology. 2009 Aug;116(8):1544-51.

Reiff A, Kadayifcilar S, Ozen S. Rheumatic inflammatory eye diseases of childhood. Rheum Dis Clin North Am. 2013 Nov;39(4):801-32.

Ozdal PC, Berker N, Tugal-Tutkun I. Pars Planitis: Epidemiology, Clinical Characteristics, Management and Visual Prognosis. J Ophthalmic Vis Res. 2015 Oct-Dec;10(4):469-80.

Gupta A, Ramanan AV. Uveitis in Children: Diagnosis and Management. Indian J Pediatr. 2016 Jan;83(1):71-7. 2016 Jan;83(1):63-70.

Castiblanco C, Meese H, Foster CS. Treatment of pediatric uveitis with adalimumab: the MERSI experience. J AAPOS. 2016 Apr;20(2):145-7.

Dajee KP, Rossen JL, Bratton ML, Whitson JT, He YG. A 10-year review of pediatric uveitis at a Hispanic-dominated tertiary pediatric ophthalmic clinic. Clin Ophthalmol. 2016 Aug 22;10:1607-12.

Shoughy SS, Kozak I, Tabbara KF. Associations of Systemic Diseases with Intermediate Uveitis. Ophthalmic Epidemiol. 2016;23(1):27-31.

Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa Children’s Hospital