Abdulla Gori, MD

A 5-year-old boy was brought for evaluation of ongoing thrombocytopenia before undergoing   adenotonsillectomy for obstructive sleep apnea. The child had been given a   diagnosis of "growing pains" after frequent evaluation for leg pain over the past 2 years. He   also exhibited easy bruising and frequent epistaxis without other avenues of blood loss.   There was no family history of a blood disorder, except for his maternal grandfather who   had easy bruising of undetermined cause.

The child was born to Ashkenazi Jewish parents after a pregnancy complicated by 3   maternal transfusions for iron deficiency anemia that resolved postpartum; the delivery and   neonatal stay were unremarkable.

As an infant, he had extensive eczema, abdominal pain, diarrhea, and poor weight gain   attributed to allergic enteropathy; these conditions responded well to an elemental formula.   As a toddler, he had 9 hospitalizations for asthma that became less frequent after age 2 years   through standard controller therapy. His development was appropriate for age, and he had   no history of regression.

Physical examination revealed a well-nourished boy with weight at the 50th percentile   and height at the 16th percentile; vital signs were normal. Significant findings included   coarse facial appearance; prominent forehead; multiple ecchymoses on the trunk and extremities   (none on the mucous membranes); a firm, nontender liver about 5 cm below the   costal margin; and a spleen 8 cm below the costal margin. There was no audible bruit over   the liver, spleen, or abdomen; no pallor, jaundice, hemangioma, lymphadenopathy, rash, or   bony tenderness; and no abnormalities of the genitalia or fundi.

During the 2 years of monitoring for asthma and leg pain, the white blood cell count   ranged from 2.4 to 7.3 x 109/µL and the platelet count from 108 to 160 x 109/µL; the differential   and peripheral smear were normal. Red cell indices showed a mean corpuscular   volume of 81.4 to 87 fL, mean corpuscular hemoglobin concentration of 33.1 to 35.8 g/dL,   and red cell distribution width of 12.7% to 14.8%, with a reticulocyte count of 0.7%. A coagulation   profile, iron studies, electrolyte levels, liver function test results, lipid profile, sweat   chloride test results, C-reactive protein level, erythrocyte sedimentation rate (ESR), and   immunoglobulin levels were all normal. Serological titers of Epstein-Barr virus (EBV), HIV,   Cytomegalovirus (CMV), hepatitis C virus (HCV), and mycoplasma were not elevated. CT   scans of the chest and abdomen were normal, and chest radiographs revealed occasional   infiltrates associated with asthma exacerbations.


TO WHAT DIAGNOSIS     DO THESE FINDINGS POINT-     AND WHAT ARE THE     TREATMENT OPTIONS?

The differential diagnosis for hepatosplenomegaly is extensive and must be refined based on the history and physical examination. This patient’s Ashkenazi Jewish background, "growing pains," marginal leukopenia, and bruising suggested a condition that diminished production of cellular elements in the marrow, consistent with the low reticulocyte count. Aplastic anemia would not explain the splenomegaly. In addition, there was no evidence of hepatocellular or cardiovascular disease, common immunological disturbances, chronic infections (normal titers for CMV, EBV, HCV, and HIV), or inflammatory conditions (normal antinuclear antibody and rheumatoid factor). The duration of symptoms, somewhat short stature, and normal laboratory values ruled out most of the causes of hepatosplenomegaly. Malignancy was unlikely because of the insidious onset of symptoms and the absence of blasts or abnormal cells in the peripheral smear. High in the clinical differential were nonmalignant infiltrative storage diseases that involve carbohydrates, gangliosides, or glycosaminoglycans.

Mucopolysaccharidoses (MPS), such as Hunter disease.

Glycogen storage diseases, such as Anderson disease type IV.

Most of these possibilities were excluded by the lack of a cherry-red spot (NPD), neurodegeneration (MPS, Wolman disease, oligosaccharidoses), and cirrhosis (Anderson disease).

The patient was referred for genetic consultation and underwent a skin biopsy for fibroblast lysosomal enzyme studies. The results revealed a lack of acid β-glucosidase activity, consistent with the diagnosis of Gaucher disease (GD). Levels of angiotensin-converting enzyme, a marker secreted by Gaucher cells, were elevated. DNA analysis did not reveal the 4 common mutations found in GD.



 GD is the most common lysosomal storage disorder, with increased incidence among the Ashkenazi Jewish population (carrier frequency 1:17).

 Its worldwide distribution is around 1 in 75,000 births.

GD is inherited as an autosomal recessive disorder caused by deficiency of lysosomal glucocerebrosidase (also known as acid β-glucosidase). More than 100 different mutations have been discovered, including 4 common mutations that account for 95% of GD in Ashkenazi Jews and 70% of GD in non-Jewish populations.

 This limited sensitivity may explain the negative result of DNA analysis in this patient.

In affected patients, the deficiency of glucocerebrosidase leads to accumulation of glucocerebroside and other glycolipids within the lysosomes of macrophages. Macrophages filled with the lipid material are known as Gaucher cells and are a cardinal feature of the disease (

). They have a characteristic histological appearance of wrinkled tissue paper. The clinical manifestations of GD result from the accumulation of Gaucher cells in the spleen, liver, bone marrow, and bone.



 GD is a multisystem lipidosis characterized by organomegaly, hematological manifestations, and skeletal involvement. The 3 clinical subtypes of GD are:

Type 2, the infantile       acute       neuronopathic     form.

Type 3, the juvenile       form,       which can involve       subsequent       insidious       neurological       dysfunction.

Skeletal manifestations are probably the most disabling aspects of GD. (For a list of features that are helpful in distinguishing benign from serious musculoskeletal conditions, see Malleson and Beauchamp.

) Patients commonly have bone pains, some have bone crises, and up to 20% have impaired mobility.

 Radiological findings include Erlenmeyer flask deformity, osteopenia, osteosclerosis, osteonecrosis, fractures, and bone marrow infiltration.

 Often, bone pains are inaccurately labeled as "growing pains." The prevalence of musculoskeletal pain in children ranges from 5% to 30%; growing pains account for 8% of cases.

A child with bone pains should have a thorough history and physical examination followed by a complete blood cell count, ESR, and radiographs of the involved part to evaluate possible infective, inflammatory, and malignant conditions.



 Anemia and/or thrombocytopenia are nearly universal findings in symptomatic patients with GD.

 Leukopenia is also seen, but much less frequently. The basic cause of anemia and/or thrombocytopenia in GD is hypersplenism; however, bone marrow infiltration by Gaucher cells could also cause pancytopenia. If a patient with GD (without splenectomy) presents with significant anemia but a normal or near-normal platelet count, then another cause is probable. The spleen is proportionately more enlarged than the liver in mild or severe GD, and disproportionate enlargement of the liver relative to the spleen in GD mandates evaluation for other causes of hepatomegaly. One study reported no correlation between degree of splenomegaly and signs of hypersplenism.

 Defective platelet function as well as thrombocytopenia causes bleeding tendency in GD.



 Traditional markers for GD include increased levels of angiotensin-converting enzyme and serum acid phosphatase; in addition, the enzyme chitotriosidase can be assayed to quantify the degree of macrophage activation.

 The chemokine CCL18 is a valuable marker, but assays are not readily available.

 However, the newly identified human chemokine PARC (pulmonary and activation-regulated chemokine) is a reliable biomarker for quantitative evaluation and monitoring of GD.



 Enzyme replacement therapy (ERT) with imiglucerase has considerably improved the management of GD by reversing the organomegaly and hematological abnormalities. Treated patients have more normal growth and fewer skeletal manifestations (although some patients still need medication for bone pain, and a few patients need splenectomy).

 ERT is now the treatment of choice for the non-neuronopathic form of GD.

More recently, an enzyme inhibitor (miglustat) that     decreases the production of the substrate was introduced.     This substrate reduction therapy has the advantage of     being administered orally.

Future therapies include chemical chaperones that     correct protein misfolding or abnormal protein trafficking     by binding to glucosidase enzyme, and, in the distant     future, gene therapy.
  

Ancestry figures prominently in the evaluation of infiltrative conditions.

Do not underestimate leg pains, especially when associated with organomegaly or hematological changes.

Consider Gaucher disease in the differential diagnosis of any child with thrombocytopenia, hepatosplenomegaly, and bone pain, especially if the child is of Jewish descent.


1. Zimran A, Altarescu G, Rudensky B, et al. Survey of hematological aspects ofGaucher disease. 

 McGovern MM, Desnick RJ. Lipidosis. In: Behrman RE, Kliegman RM,  Jenson HB, Stanton BF, eds. 

. 18th ed. Philadelphia:  WB Saunders Co; 2007:463-464.  

 Malleson PN, Beauchamp RD. Rheumatology: 16. Diagnosing musculoskeletal  pain in children. 

 Wenstrup RJ, Roca-Espiau M, Weinreb NJ, Bembi B. Skeletal aspects of  Gaucher disease: a review. 

 Anthony KK, Schanberg LE. Assessment and management of pain syndromes  and arthritis pain in children and adolescents. 

 Junnila JL, Cartwright VW. Chronic musculoskeletal pain in children, part I:  initial evaluation. 

 Gielchinsky Y, Elstein D, Hadas-Halpern I, et al. Is there a correlation between  degree of splenomegaly, symptoms and hypersplenism? A study of 218 patients  with Gaucher disease. 

 Maire I, Guffon N, Froissart R. Current development and usefulness of  biomarkers for Gaucher disease follow up [in French]. 

 Guggenbuhl P, Grosbois B, ChalÃ¨s G. Gaucher disease. 

 Deegan PB, Moran MT, McFarlane I, et al. Clinical evaluation of chemokine  and enzymatic biomarkers of Gaucher disease. 

 Sidransky E, LaMarca ME, Ginns EI. Therapy for Gaucher disease: don’t  stop thinking about tomorrow. 

 JakÃ³bkiewicz-Banecka J, Wegrzyn A, Wegrzyn G. Substrate deprivation  therapy: a new hope for patients suffering from neuronopathic forms of inherited  lysosomal storage diseases. 

 Taha H, Kostandy G. Gaucher’s disease. 

Articles

A 5-year-old boy was brought for evaluation of ongoing thrombocytopenia before undergoing adenotonsillectomy for obstructive sleep apnea. The child had been given a diagnosis of "growing pains" after frequent evaluation for leg pain over the past 2 years.

Bone Pain, Bruising, and Epistaxisin a Young Boy

A 30-month-old girl presented to the emergency department with a 2-day history of shortness of breath, cough, and "wheezing."

The patient had been born at term following an uncomplicated pregnancy and labor. Her growth and development were appropriate. Her immunizations were up-to-date. At about 1 year of age, she began to have "wheezing" episodes. Moderate persis- tent asthma was diagnosed, and treatment with fluticasone and inhaled albuterol was initiated. 

Her current illness started 2 weeks earlier, with gradually worsening hoarseness, mild rhinorrhea, and cough. Her breathing was noisy. There was no report of fever or choking episodes. A review of systems was otherwise normal.

A presumptive diagnosis of croup was made. The patient received racemic nebulized epinephrine and intramuscular injections of dexamethasone. When her symptoms did not improve, nebulized albuterol was administered without benefit. The patient was hospitalized.

Physical examination showed a nontoxic-appearing afebrile child who was well perfused and hydrated. However, she required 1 liter of oxygen by nasal cannula to maintain an oxygen saturation level above 93%. Her voice was hoarse. She had biphasic stridor and labored breathing. There was no rhinorrhea or drooling. Her oropharynx appeared normal; there were no hemangiomas or goiter. Brachial pulses were equal in both arms. The quality of the stridor was not affected by neck flexion or assumption of a prone position. Lung fields were clear except for transmitted sounds. There were no other abnormal physical findings.

Croup typically manifests with stridor--usually on inspiration--of acute onset following an upper respiratory tract infection (URI). A gradual worsening of symptoms, lack of any signs of URI, the presence of hoarseness and hypoxia, and failure to respond to the conventional management of croup suggested an alternate diagnosis. Further studies were done to determine the cause.

A thorough head-to-foot examination may sometimes point to the cause of stridor in a child. For example, a dolicocephalic skull in an infant born prematurely with a history of ventilation problems may indicate subglottic narrowing. Any sign of hydrocephalus should raise suspicion of an Arnold-Chiari malformation leading to stridor. Hemangiomas, particularly those in the "beard area," may indicate a hemangioma in the larynx. A goiter or any other neck mass may point to a retrosternal extension that compresses the airways.

Flexion of the neck may exacerbate stridor caused by vascular rings or slings. If an aberrant right subclavian artery compresses the airways, the brachial pulses may be unequal. Stridor from laryngomalacia diminishes when the patient assumes a prone position. A weak or abnormal cry from birth indicates either vocal cord paralysis or a web.

In extrathoracic obstruction, the vibratory sound of stridor is inspiratory; in intrathoracic obstruction, it is expiratory. When obstruction is evident during both phases of breathing, the obstruction may be variable and may simultaneously affect both the intrathoracic and extrathoracic airways. If this has not occurred, the obstruction may have become critical.

lists causes of recurrent or persistent stridor in children.

WHAT INVESTIGATIONS ARE REQUIRED AT THIS STAGE?

Radiographs were taken of the patient's neck (

). The films showed a soft tissue shadow in the region of the vocal cords. Chest films showed normal findings.

The soft tissue irregularity on the vocal cords was of concern. Possibilities included a growth on the vocal cord or a non-radiopaque foreign body. Consultation with an otorhinolaryngologist was obtained, and surgery was recommended. Microlaryngoscopy showed papilloma-like lesions on the vocal cord that almost obstructed the airway (

). The lesions were surgically excised. The histological picture was consistent with papillomatosis.

Juvenile laryngeal papillomatosis--also known as juvenile respiratory papillomatosis or recurrent respiratory papillomatosis--is relatively uncommon. It is usually characterized by wart-like exophytic lesions that have a predilection for the larynx. The estimated incidence is 4.3 cases per million; the estimated cost of care in the United States ranges from $40 million to $123 million annually.

Juvenile laryngeal papillomatosis is caused by viral infection; the most common culprit is human papillomavirus (HPV) subtypes 6 and 11--the subtypes implicated in genital condylomata. There is strong evidence that the condition is acquired during childbirth. Retrospective studies suggest that about 30% of children who have juvenile laryngeal papillomatosis at a young age are born to mothers with genital condylomata at the time of delivery.

 Additional subtypes, such as 16 and 18, have been identified in juvenile laryngeal papillomas and are thought to pose a great risk for malignant transformation in approximately 2% of cases.

Juvenile laryngeal papillomatosis usually presents in young children, typically during infancy. Hoarseness is a common initial presentation. Stridor usually occurs in later stages of the disease when the airway is obstructed.

Initially, the condition may be misdiagnosed as asthma, croup, or bronchitis.

 In most children, the condition presents acutely after a viral URI, which can further mislead the clinician. When hoarseness persists in children for more than 6 weeks, or when an acute airway obstruction does not respond to racemic epinephrine or bronchodilator therapy, careful thought should be given to the differential diagnosis, and further otolaryngology workup must be arranged.

The diagnosis of juvenile laryngeal papillomas must be confirmed by direct laryngoscopy. In radiographs of the neck, however, the lesions may appear as subtle changes in the soft tissue--as in this case.

There is no definitive treatment modality available for juvenile laryngeal papillomas. The goal of therapy is to diminish the airway obstruction and improve voice quality. The most common method of treatment is excision of the lesions by microlaryngeal surgery. Excision may be performed with different modalities, such as a microlaryngeal instrument, a carbon dioxide laser, microdebrider, or pulsed dye laser.

Many surgeons still prefer microlaryngeal surgery--the oldest method--because healthy tissue is not damaged, thus preventing scarring and persistent hoarseness. Disadvantages include aspiration of blood or fragments of papillomatous tissue into lower airways after the surgery.

In a 1995 survey of otolaryngologists, a task force on recurrent respiratory papillomas reported that 92% of respondents preferred the carbon dioxide laser for initial treatment; the remaining 8% favored cold excision.

 However, recent studies have shown the pulsed dye laser to be useful in minimizing papilloma burden without scarring; the procedure is shorter and there is less associated morbidity. Moreover, it can be performed in the office.

Papillomas tend to recur, and repeated excisions are not uncommon. It is very difficult to eradicate the papillomavirus from mucosal surface.

Approximately 10% of patients with recurrent respiratory papillomatosis require adjuvant therapy. Such therapy is indicated when recurrences necessitate surgery more than 4 times in a year, when rapid regrowth of papillomas compromise the airway, or when there is distal spread.

 Numerous agents, including isotretinoin, alpha interferon, indole-3-carbinol, methotrexate, acyclovir, and ribavirin, have been tried. None has gained widespread acceptance because of systemic toxicity and dosing.

Cidofovir has antiviral activity against a number of DNA viruses, including herpes simplex virus and cytomegalovirus.

 Intralesional injections of this agent are currently recommended for patients with frequent recurrences. However, reports of carcinogenesis in animal studies have limited the widespread use of cidofovir.

Tracheotomy is indicated if lesions completely obstruct the airway, or if the airway cannot be secured by intubations. Otherwise, tracheotomy should be avoided as much as possible to prevent dissemination of the papillomas to the rest of the respiratory tract.

The currently available prophylactic quadrivalent HPV (6, 11, 16, 18) vaccine is high- ly effective in preventing cervical lesions. The combined efficacy against persistent infection with HPV types 6, 11, 16, and 18 was 90% thirty months after vaccination.

 Whether administration of this new HPV vaccine to female children and adolescents will prevent or reduce the incidence of juvenile laryngeal papillomatosis will become clear after a substantial period of use.

Pediatricians and emergency medicine physicians should entertain a wide differential in children with stridor that does not respond to conventional therapy for croup. Hypoxia is a sign of airway obstruction. Juvenile laryngeal papillomatosis is a rare condition that requires a high index of suspicion--and timely consultation with an otolaryngologist.	*

Brown MA, Morgan WJ, eds. Evaluation of the child with airway obstruction. In: 

Textbook of Pediatric Respiratory Medicine. 

 Boat TF, Green TP. Chronic or recurrent respiratory symptoms. In: Kliegman R, Nelson WF, Behrman RE, et al, eds. 

 18th ed. Philadelphia: WB Saunders; 2007:1758-1762.

Bishai D, Kashima H, Shah K. The cost of juvenile-onset recurrent respiratory papillomatosis. 

Derkay CS. Task force on recurrent respiratory papillomas: a preliminary report. 

Aaltonen L, Rihkanen H, Vaheri A. Human papilloma in larynx. 

Derkay CS, Darrow DH. Recurrent respiratory papillomas. 

Valdez TA, McMillan K, Shapshay SM. A new laser treatment for vocal cord papilloma--585-nm pulsed dye. 

Koufman JA, Rees CJ, Frazier WD, et al. Office-based laryngeal laser surgery: a review of 443 cases using three wavelengths. 

Green GE, Bauman NM, Smith RJ. Pathogenesis and treatment of juvenile onset recurrent respiratory papillomatosis. 

De Clercq E. Therapeutic potential of Cidofovir (HPMPC, Vistide) for the treatment of DNA virus (i.e. herpes-, papova-, pox- and adenovirus) infections. 

Derkay C; Multi-disciplinary Task Force on Recurrent Respiratory Papillomas. Cidofovir for recurrent respiratory papillomatosis (RRP): a re-assessment of risks. 

Villa LL, Costa RL, Petta CA, et al. Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: a randomised double-blind placebo-controlled multicentre phase II efficacy trial. 

Juvenile Laryngeal Papillomatosis: An Unexpected Cause of Stridor

The patient had been born at term following an uncomplicated pregnancy and labor. Her growth and development were appropriate. Her immunizations were up-to-date. At about 1 year of age, she began to have "wheezing" episodes. Moderate persistent asthma was diagnosed, and treatment with fluticasone and inhaled albuterol was initiated.

 Her current illness started 2 weeks earlier, with gradually worsening hoarseness, mild rhinorrhea, and cough. Her breathing was noisy. There was no report of fever or choking episodes. A review of systems was otherwise normal

Croup typically manifests with stridor-usually on inspiration-of acute onset following an upper respiratory tract infection (URI). A gradual worsening of symptoms, lack of any signs of URI, the presence of hoarseness and hypoxia, and failure to respond to the conventional management of croup suggested an alternate diagnosis. Further studies were done to determine the cause. 

A thorough head-to-foot examination may sometimes point to the cause of stridor in a child. For example, a dolicocephalic skull in an infant born prematurely with a history ofventilation problems may indicate subglottic narrowing. Any sign of hydrocephalus should raise suspicion of an Arnold-Chiari malformation leading to stridor. Hemangiomas, particularly those in the "beard area," may indicate a hemangioma in the larynx. A goiter or any other neck mass may point to a retrosternal extension that compresses the airways. 

 Flexion of the neck may exacerbate stridor caused by vascular rings or slings. If an aberrant right subclavian artery compresses the airways, the brachial pulses may be unequal. Stridor from laryngomalacia diminishes when the patient assumes a prone position. A weak or abnormal cry from birth indicates either vocal cord paralysis or a web. 

The Table lists causes of recurrent or persistent stridor in children.

WHAT INVESTIGATIONS ARE REQUIRED AT THIS STAGE? 

). The films showed a soft tissue shadow in the region of the vocal cords. Chest films showed normal findings. 

Figure 1 - A radiograph of the neck shows a soft tissue shadow at the vocal cord level.

Figure 2 - These microlaryngoscopic pictures of the larynx show multiple papillomas. 

The soft tissue irregularity on the vocal cords was of concern. Possibilities included a growth on the vocal cord or a non-radiopaque foreign body. Consultation with an otorhinolaryngologist was obtained, and surgery was recommended. Microlaryngoscopy showed papillomalike lesions on the vocal cord that almost obstructed the airway (Figure2). The lesions were surgically excised. The histological picture was consistent with papillomatosis. 

 Juvenile laryngeal papillomatosis-also known as juvenile respiratory papillomatosis or recurrent respiratory papillomatosis- is relatively uncommon. It is usually characterized by wart-like exophytic lesions that have a predilection for the larynx. The estimated incidence is 4.3 cases per million; the estimated cost of care in the United States ranges from $40 million to $123 million annually.

Juvenile laryngeal papillomatosis is caused by viral infection; the most common culprit is human papillomavirus (HPV) subtypes 6 and 11-the subtypes implicated in genital condylomata. There is strong evidence that the condition is acquired during childbirth. Retrospective studies suggest that about 30% of children who have juvenile laryngeal papillomatosis at a young age are born to mothers with genital condylomata at the time of delivery.

Additional subtypes, such as 16 and 18, have been identified in juvenile laryngeal papillomas and are thought to pose a great risk for malignant transformation in approximately 2% of cases.

. Juvenile laryngeal papillomatosis usually presents in young children, typically during infancy. Hoarseness is a common initial presentation. Stridor usu-ally occurs in later stages of the disease when the airway is obstructed. 

In most children, the condition presents acutely after a viral URI, which can further mislead the clinician. When hoarseness persists in children for more than 6 weeks, or when an acute airway obstruction does not respond to racemic epinephrine or bronchodilator therapy, careful thought should be given to the differential diagnosis, and further otolaryngology workup must be arranged.

The diagnosis of juvenile laryngeal papillomas must be confirmed by direct laryngoscopy. In radiographs of the neck, however, the lesions may appear as subtle changes in the soft tissue-as in this case. 

 There is no definitive treatment modality available for juvenile laryngeal papillomas. The goal of therapy is to diminish the airway obstruction and improve voice quality. The most common method of treatment is excision of the lesions by microlaryngeal surgery. Excision may be performed with different modalities, such as a microlaryngeal instrument, a carbon dioxide laser, microdebrider, or pulsed dye laser. 

 Many surgeons still prefer microlaryngeal surgery-the oldest method-because healthy tissue is not damaged, thus preventing scarring and persistent hoarseness. Disadvantages include aspiration of blood or fragments of papillomatous tissue into lower airways after the surgery.

However, recent studies have shown the pulsed dye laser to be useful in minimizing papilloma burden without scarring; the procedure is shorter and there is less associated morbidity. Moreover, it can be performed in the office.

 Papillomas tend to recur, and repeated excisions are not uncommon. It is very difficult to eradicate the papillomavirus from mucosal surface.

 Approximately 10% of patients with recurrent respiratory papillomatosis require adjuvant therapy. Such therapy is indicated when recurrences necessitate surgery more than 4 times in a year, when rapid regrowth of papillomas compromise the airway, or when there is distal spread.

Numerous agents, including isotretinoin, alpha interferon, indole-3- carbinol, methotrexate, acyclovir, and ribavirin, have been tried. None has gained widespread acceptance because of systemic toxicity and dosing. 

Tracheotomy is indicated if lesions completely obstruct the airway, or if the airway cannot be secured by intubations. Otherwise, tracheotomy should be avoided as much as possible to prevent dissemination of the papillomas to the rest of the respiratory tract. 

 The currently available prophylactic quadrivalent HPV (6, 11, 16, 18) vaccine is highly effective in preventing cervical lesions. The combined efficacy against persistent infection with HPV types 6, 11, 16, and 18 was 90% thirty months after vaccination.13 Whether administration of this new HPV vaccine to female children and adolescents will prevent or reduce the incidence of juvenile laryngeal papillomatosis will become clear after a substantial period of use.

 Pediatricians and emergency medicine physicians should entertain a wide differential in children with stridor that does not respond to conventional therapy for croup. Hypoxia is a sign of airway obstruction. Juvenile laryngeal papillomatosis is a rare condition that requires a high index of suspicion- and timely consultation with an otolaryngologist. 

Brown MA, Morgan WJ, eds. Evaluation of the    child with airway obstruction. In: Textbook of    Pediatric Respiratory Medicine. New York: Mosby;    1999:145-146. 
    

    Boat TF, Green TP. Chronic or recurrent respiratory    symptoms. In: Kliegman R, Nelson WF,    Behrman RE, et al, eds. Nelson Textbook of Pediatrics.    18th ed. Philadelphia: WB Saunders; 2007:1758-1762.

    Bishai D, Kashima H, Shah K. The cost of juvenile-    onset recurrent respiratory papillomatosis. Arch    Otolaryngol Head Neck Surg. 2000;126:935-939. 
    

Derkay CS. Task force on recurrent respiratory    papillomas: a preliminary report. Arch Otolaryngol    Head Neck Surg. 1995;121:1386-1391. 
    

Aaltonen L, Rihkanen H, Vaheri A. Human papilloma    in larynx. Laryngoscope. 2002;112:700-707.

    Altman KW. Vocal fold masses. Otolaryngol Clin    North Am. 2007;40:1091-1108. 
    

Derkay CS, Darrow DH. Recurrent respiratory    papillomas. Ann Otol Rhinol Laryngol. 2006;115:1-11. 
    

    Valdez TA, McMillan K, Shapshay SM. A new    laser treatment for vocal cord papilloma-585-nm    pulsed dye. Otolaryngol Head Neck Surg. 2001;124:    421-425. 
    

Koufman JA, Rees CJ, Frazier WD, et al. Officebased    laryngeal laser surgery: a review of 443 cases    using three wavelengths. Otolaryngol Head Neck    Surg. 2007;137:146-151. 
    

Green GE, Bauman NM, Smith RJ. Pathogenesis    and treatment of juvenile onset recurrent respiratory    papillomatosis. Otolaryngol Clin North Am.    2000;33:187-207. 
    

De Clercq E. Therapeutic potential of Cidofovir    (HPMPC, Vistide) for the treatment of DNA virus    (i.e. herpes-, papova-, pox- and adenovirus) infections.    Verh K Acad Geneeskd Belg. 1996;58:19-49. 
    

Derkay C; Multi-disciplinary Task Force on    Recurrent Respiratory Papillomas. Cidofovir for    recurrent respiratory papillomatosis (RRP): a    re-assessment of risks. Int J Pediatr Otorhinolaryngol.    2005;69:1465-1467. 
    

Villa LL, Costa RL, Petta CA, et al. Prophylactic    quadrivalent human papillomavirus (types 6, 11,    16, and 18) L1 virus-like particle vaccine in young    women: a randomised double-blind placebo-controlled    multicentre phase II efficacy trial. Lancet    Oncol. 2005;6:271-278.    

 The patient had been born at term following an uncomplicated pregnancy and labor. Her growth and development were appropriate. Her immunizations were up-to-date. At about 1 year of age, she began to have "wheezing" episodes. Moderate persistent asthma was diagnosed, and treatment with fluticasone and inhaled albuterol was initiated.

Juvenile Laryngeal Papillomatosis in a 30-Month-Old Girl

A 4-year-old Hispanic boy was referred to our facility because of elevated levels of alanine trans- aminase (ALT) and aspartate transaminase (AST), which were detected during an evaluation of transient abdominal pain while the boy was in Puerto Rico. He was otherwise in perfect health; a review of systems was negative. His past medical history and birth history were noncontributory. Immunizations, including hepatitis B, were up-to-date. The family history was significant for tuberculosis and rheumatoid arthritis.

The child was developmentally appropriate, ate a regular diet, and had never received any herbal supplements or blood products. His social history was significant for contact with farm animals and birds.

Physical examination revealed a well-nourished boy with growth at the 90th percentile and normal vital signs. There were no signs of liver disease, and the heart and lungs were normal. Abdominal examination revealed no organomegaly. Results of the neurological evaluation were unremarkable.

What is your differential diagnosis and how would you proceed?

The differential diagnosis of elevated levels of transaminase is vast and usually indicates liver dysfunction. Hepatitis can be of infectious, metabolic, toxic, or autoimmune etiology. Consequently, this patient underwent extensive laboratory tests to determine the cause of the hypertransaminasemia. Tests included a complete blood cell count; a coagulation profile; and measurements of blood urea nitrogen, creatinine, electrolytes, erythrocyte sedimentation rate, C-reactive protein, calcium, amylase, lipase, cholesterol, triglycerides, ferritin, g-glutamyl transpeptidase (GGT), a

-antitrypsin deficiency), copper, ceruloplasmin (to rule out Wilson disease), ammonia (urea cycle defects), serum amino acids (tyrosinemia, galactosemia, and other aminoacidopathies), urinary organic acids (organic acidemia), total protein, albumin, and bilirubin. All test results were within normal limits. Serological tests for hepatitis (types A, B, and C) and for Epstein-Barr virus, Cytomegalovirus, 

Initial ALT and AST levels were 601 IU/L and 407 IU/L, respectively (normal, 7 to 40 IU/L and 9 to 80 IU/L, respectively). Test results for antinuclear antibodies (ANA) were positive (greater than 1:160); however, tests for anti-double-stranded DNA, antimitochondrial antibodies, liver kidney microsomal antibodies, antineutrophilic cytoplasmic antibodies (ANCA), and an extractable nuclear antibody (ENA) panel showed negative results. A tuberculin skin test was positive (greater than 14 mm), but chest films were normal.

Ultrasonograms of the liver were normal. The initial liver biopsy showed portal and lobular inflammation, "suggestive of autoimmune hepatitis." Liver tissue culture was negative for aerobic and anaerobic bacteria, acid-fast bacilli, and fungi.

With a presumptive diagnosis of autoimmune hepatitis, this young patient was treated with azathioprine and corticosteroids. Rifampicin was initiated for latent tuberculosis because of the potential for immunosuppression with immunomodulatory treatment. Despite 5 months of treatment, however, AST and ALT levels remained elevated. Levels were monitored weekly and ranged from 300 to 650 IU/L and 200 to 480 IU/L, respectively. 

On review, the initial liver biopsy was thought to be inconclusive and all of the ancillary tests that help confirm autoimmune hepatitis were normal. Results of a second liver biopsy done later were also normal, despite persistent hypertransaminasemia. The diagnosis of autoimmune hepatitis was thus ruled out.

In view of persistent hypertransaminasemia without clinical or biochemical indicators of liver disease and a normal liver biopsy, hypertransaminasemia was thought to be of nonhepatic origin. Extrahepatic causes of hypertransaminasemia were then suspected, and additional blood tests led us to our final diagnosis.

What additional blood tests would you order?

Serum creatine kinase (CK) and aldolase levels were found to be elevated. These tests are not part of a routine metabolic panel in our institution and have to be specifically ordered.

Persistent asymptomatic elevation of AST and ALT levels may occur in patients with primary muscle disease.

 The CK level was 22,764 IU/L (normal, 32 to 250 IU/L) and aldolase was 264 IU/L (normal, 2 to 8 IU/L). These findings strongly pointed to primary muscle disease.

DNA analysis revealed a deletion at exon 45 of the dystrophin gene, which confirmed the diagnosis of Xp21 dystrophinopathy.

Over time, our patient demonstrated signs of muscle disease with proximal muscle weakness and pseudohypertrophy of calf muscles. He is currently being followed closely in the muscle clinic at our institute by a multidisciplinary team headed by a pediatric neurologist.

An ANA titer of 1:160 can be nonspecific and can even be found in healthy persons. A positive ANA with moderately high titers such as 1:160 when unsupported clinically has little or no significance.

 Five percent of the general population may have a positive ANA titer; also, the false-positive rate for ANA is as high as 20%.

We found no case reports of patients with Xp21 dystrophinopathy and positive ANA in literature. One case in an adult with limb-girdle muscular dystrophy and a positive ANA titer has been reported.

Xp21 dystrophinopathy includes Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy. Some affected patients have cardiomyopathy as the only manifestation of the dystrophinopathy.

Further discussion will be limited to DMD--the most common of the Xp21 dystrophinopathies. It was also the diagnosis in our patient.

The disease carries the name of French neurologist Duchenne, who described some of the clinical and muscle biopsy features. The disorder occurs in about 1 of 3000 male births. Because its inheritance is X-linked recessive, females are rarely affected.

 A genetically determined deficiency of dystrophin (a sarcolemmal membrane protein) adversely affects other membrane proteins leading to muscle fiber breakdown.

Clinical manifestations are uncommon at birth. Some boys may exhibit delayed motor milestones, especially in walking, running, jumping, climbing stairs, etc. A wide-based waddling gait with exaggerated lumbar lordosis is characteristic. Gower sign is positive and the affected muscles feel firm and rubbery.

Muscle weakness follows a stereotypical pattern. Weakness first appears in the muscles of the pelvic girdle and proximal muscles of the lower extremity; this is followed by weakness of other skeletal muscle groups. Muscles innervated by cranial nerves remain relatively unaffected. Usually by age 8, patients lose their ability to walk and climb stairs; by age 10, they are dependent on long leg braces; by age 12, they are wheelchair-bound.

Once a patient is wheelchair-bound, scoliosis sets in and progresses over time, which leads to respiratory insufficiency. Unless patients receive respiratory support, death ensues in the third decade of life--most commonly from respiratory insufficiency and pneumonia.

Ninety percent of patients with DMD have ECG abnormalities. Tall R waves in right precordial leads with an increase in R/S amplitude ratio in V

, and deep narrow Q waves in left precordial leads are common. Congestive heart failure and arrhythmias may occur.

Acute gastric dilatation or intestinal pseudo-obstruction consists of sudden episodes of emesis and abdominal pain and distention, which may lead to death.

The average IQ of patients with DMD is 1 standard deviation below the mean. This impairment is not progressive; verbal ability is mainly affected.

CK is the most important enzyme in the diagnosis of DMD and other myopathies. Elevated CK levels at birth precede obvious clinical manifestations.

Besides CK, levels of aldolase, AST, and ALT also tend to be elevated and follow the same course as CK levels.

 Early recruited, short duration, low amplitude, polyphasic motor unit potentials are characteristic on electromyography. Muscle biopsy typically shows variability of fiber type distribution, consisting of type 1 fiber predominance and type 2 fiber deficiency followed by the eventual replacement of muscle by fibrofatty connective tissue.

The definitive diagnosis of DMD can be made by demonstrating abnormalities in dystrophin. DNA analysis identifies deletions and duplications in approximately 56% of patients with DMD, and full sequencing of the gene identifies 97% of affected patients.

Although the inheritance is X-linked recessive, 33% of all DMD cases represent new mutations. A DMD phenotype can be observed in females in the following scenarios:

•If the female has an XO genotype (Turner syndrome).

•If she has a structurally abnormal X chromosome.

A DMD phenotype can also be observed in a female if a patient with Xp21 dystrophinopathy fathers a child with a carrier female.

Carrier detection can be done by pedigree analysis, CK determination, and DNA analysis. DNA analysis is the gold standard for diagnosis if the mutation is known. Carrier detection and prenatal diagnosis are important for genetic counseling. Such counseling should be offered to all families with X-linked dystrophinopathies.

Patients with muscular dystrophy need the care of a multidisciplinary team at a tertiary care center; physical therapy, occupational therapy, and bracing are extremely important. Surgical release of heel cords may be necessary along with tendon transfer surgeries. A proper fitting wheelchair that promotes extensor posture can delay the onset of scoliosis. Surgical stabilization of the spine should be considered in patients with curves of 35 to 45 degrees.

Trials have shown that prednisone can improve muscle strength, pulmonary function, and functional ability in patients with DMD. Maximal improvement occurs within 3 months at a dosage of 0.75 mg/kg every day or on alternate days. Prednisone increases strength by increasing muscle mass and decreasing muscle breakdown. Corticosteroids are associated with several adverse effects and must be carefully considered before their use is initiated.

Gene therapy for muscular dystrophy is still experimental and clinical trials are under way.

There is a need to be aware of the possibility of occult muscle disease when evaluating patients with persistent unexplained mild to moderate elevation in AST and ALT. Extrahepatic sources of ALT and AST include muscle, heart, pancreas, lung, erythrocytes, and kidney. In the absence of a definitive hepatic cause, simple tests that measure CK and aldolase early in the workup may redirect the diagnostic workup and help avoid invasive tests, such as liver biopsy.	*

Schwarz KB, Burris GC, deMello DE, et al. Prolonged elevation of transaminase concentration in children with unsuspected myopathy. 

Rutledge J, Andersen J, Fink CW, et al. Persistent hypertransaminasemia as the presenting finding of childhood muscle disease. 

Malleson PN, Sailer M, Mackinnon MJ. Usefulness of antinuclear antibody testing to screen for rheumatic diseases. 

Kavanaugh A, Tomar R, Reveille J, et al. Guidelines for clinical use of antinuclear antibody tests and tests for specific autoantibodies to nuclear antigens. American College of Pathologists. 

Funauchi M, Nozaki Y, Yoo BS, et al. A case of limb-girdle dystrophy with serum anti-nuclear antibody which led to a mistaken diagnosis of polymyositis. 

Munsat TL, Baloh R, Pearson CM, Fowler W Jr. Serum enzyme alterations in neuromuscular disorders. 

Manzur AY, Kuntzer T, Pike M, Swan A. Glucocorticoid corticosteroids for Duchenne muscular dystrophy. 

Author | Abdulla Gori, MD

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