ALLERGIC RHINITIS


INTRODUCTION

 

Allergic rhinitis is an inflammatory condition of nasal mucosa.

  • It is a major chronic respiratory disease of children as it badly affects the quality of life and school performance of children
  • It is most common chronic condition in children
  • 20 -40% children of affluent societies suffer from this condition
  • Its symptoms may appear in infancy and the diagnosis is generally established by the age of 6 years
  • Risk factors include family history of atopy and serum IgE level more than 100 IU/ml before age 6 years.
  • Up to 78% patients with asthma have AR and 38% of patients with AR have asthma.

 

Etiology

Two factors necessary for the development of AR are sensitivity to an allergen and the presence of allergen in the environment.

 

  • Inhalant allergens are the main cause of AR.
  • In India, spring season, February to April is flowering season of trees, in which so many pollens are in the air ,which is potent inhalant allergen.
  • In temperate climates, trees pollinate in spring, grasses in early summer and weeds in late summer.
  • In temperate climates, mold spores persists outdoor only in the summer and in warm climates, mold spores persist throughout the year.
  • Other common allergens are dust mites,pet danders,and cockroaches.

 

CLINICAL MANIFESTATIONS:

 

Symptoms of pediatric allergic rhinitis include the following:

 

  • Rhinorrhea
  • Nasal congestion
  • Postnasal drainage
  • Repetitive sneezing
  • Itching of the palate, nose, or eyes
  • Snoring
  • Frequent sore throats
  • Constant clearing of the throat
  • cough
  • Headaches
  • Epistaxis due to nose picking habits secondary to itching of nose
  • Abnormal sleep pattern due to frequent awakening during night sleep secondary to nose block

 

CLINICAL SIGNS:

Allergic Salute

Allergic Shiner

Dennie Morgan Fold

 Signs:

  • Allergic salute
  • Allergic shiners (dark, puffy, lower eyelids),
  • Morgan-Dennie lines (lines under the lower eyelid),
  • Transverse crease at lower third of nose secondary to allergic salute
  • Allergic gape  as the child keeps the mouth constantly open to breathe through it.
  • Eyes: Marked erythema of palpebral conjunctivae and papillary hypertrophy of tarsal conjunctivae; chemosis of the conjunctivae, usually with a watery discharge; cataracts from severe rubbing secondary to itching
  • Ears: Chronic infection or middle ear effusion
  • Nose: Enlarged turbinates with pale-bluish mucosa due to edema; clear or white nasal discharge (rarely yellow or green); dried blood secondary to trauma from nose rubbing; rarely, polyps (if polyps detected on rhinoscopy, mandatory workup for cystic fibrosis in children)
  • Throat: Discoloration of frontal incisors, high arched palate, and malocclusion associated with chronic mouth breathing (allergic gape); cobblestoning in the posterior pharynx ( Aggregation of lymphoid tissues which appears like cobblestones)secondary to chronic nasal congestion and postnasal drainage

Classification based on severity of symptoms

 

This classification in accordance to ARIA guidelines(allergic rhinitis impact on asthma)has replaced the older classification  of seasonal AR and perennial AR.

 

INVESTIGATION: Diagnosis is mainly clinical

 

  • Skin prick test is the gold standard
  • Total serum IgE indicate allergy to many allergens
  • RAST(Radio-allegro-sorbent assay) indicate allery to specific allergen
  • Blood eosinophilia may be helpful
  • Eosinophils in nasal smear has good positive predictive value
  • Imaging study may help but not mandatory

 

TREATMENT:

 

1 . Allergen avoidance– which is not possible all the time as the child may be allergic to  so many allergens. Allergen proof bed and pillow coverings may reduce the exposure to mite allergen.Bed linen and blankets should be washed every week with hot water(>130dF).

 

2. Antihistaminics -this is the first line treatment mainly effective for mild intermittent AR, may be beneficial for moderate  intermittent   AR. Second generation antihistamines  are preferred as they cause less sedation.

CETRIZINE:6months -24months: 2.5mg once daily in the evening

2-6years :2.5mg to 5mg once or twice daily

more than 6 years 5-10 mg once or twice daily.

LEVOCETRIZINE: 6-12 years:2.5mg once daily in the evening

more than 12 years: 5mg once daily in the evening

DESLORATADINE: -6months to 12months:1mg once daily

1 year to 5years:.1.25mg once daily

6years to 12years: 2.5mg once daily

more than12 years: 5mg once daily

FEXOFENADINE-2-11Years :30mg bd; 12 years and above 60mg bd or 180mg once daily

LORATADINE-2-5 Years 5mg once daily;>6 years 10mg once daily;more effective when given  empty stomach

 

3. INTRANASAL CORTICOSTEROID-this is second line treatment for AR ,most  effective to control all the symptoms and for             maintenanc  therapy.

 

MOMETASONE:recommended for 2years of age and above ,in the form of nasal spray,one spray (50mcg) into each nostril, once daily

 

FLUTICASONE: recommended for 4 years of age and above,in the form of nasal spray,one spray (50mcg) into each nostril,once daily.

 

BUDESONIDE:recommended for 6 years of age and above,in the form of nasal spray,one spray(100mcg)  into each nostril,once daily.

 

TRIAMCENOLONE: recently FDA has approved its use for children 2 years of age and  above,in the form of nasal spray,.one spray into each nostril ,once daily.

 

  • Study has proved that there is no effect on growth of child after long term use.
  • Troublesome adverse effect is epistaxis.
  • Technique of taking it intranasally  should be accurate for it to be effective.

 

Technique:

 

  • make the child to sit comfortably and slightly lean forward
  • ask him to blow the nose gently if possible
  • block one nostril with index finger of your left hand
  • shake the bottle well with your right hand
  • hold the spray bottle upright with index finger and middle finger on either side off nozzle and thumb on the base
  • insert the tip of nozzle into open nostril
  • ask the child to inhale through open nostril
  • as the child starts inhaling ,release the drug by suddenly pressuring over the base of nozzle
  • ask him to exhale through mouth
  • repeat the process on other side

 

4  Intranasal antihistamine: useful only for acute symtoms

 

  • not well studied in children below 5 years of age

 

AZELASTINE:6-12 years:one spray(140mcg) into each nostril bd,

 

;more than 12 years :1-2 sprays into each nostril bd

 

5 Intranasal  ipratropium:useful only for rhinorrhea

 

  • not well studied in children below 5 years of age.

 

6 Monteleukast orally alone or in combination with antihistamine is effective for long  term use

 

7 Immunotherapy:Indicated in children not well controlled with other medication or  having toxic adverse effects with other medications.

 

  • very effective in well chosen children
  • not well studied in children beloe 5 years of age

8 Nasal irrigation with hypertonic saline is effective and inexpensive ;

 

9 Adrenergic agonist: Oxymetazoline-for symptomatic relief of nasal mucosal congestion

 

0.05% solution,instill 2-3 spray into each nostril twice daily

 

therapy should not exceed for more than 3 days

 

should not be repeated more than once a month

 

10.SLIT(sublingual immunotherapy) is a new modality: medicine is kept under tongue  once  daily

 

  • Oralair(slit-medicine) has been recently approved by FDA for the age of 10 years and above: effective only if allergic to single aeroallergen
  • Grastek is another SLIT medicine extracted from grass,recently approved by FDA for use in children 5 years of age and above

 

Bibliography

 

Akdis CA: New insights into mechanisms of immunoregulation in 2007. J Allergy Clin Immunol. 122:700-709 2008 19014761

 

Bousquet J, Khaltaev N, Cruz AA, et al.: Allergic rhinitis and its impact on asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen). Allergy. 63 (Suppl 86):8-160 2008 18331513

 

De Groot H, Brand PL, Fokkens WF, et al.: Allergic rhinoconjunctivitis in children. BMJ. 335:985-988 2007 17991980

 

Howath PH, Myginf N, Silkoff PE, et al.: Preface to outcome measures in allergic rhinitis. J Allergy Clin Immunol. 115:S387-S482 2005 15746879

 

Nelson HS: Allergen immunotherapy: where is it now?. J Allergy Clin Immunol. 119:769-779 2007 17337297

 

Radulovic S, Calderon MA, Wilson D, et al: Sublingual immunotherapy for allergic rhinitis, Cochrane Database Syst Rev (12)CD002893, 2010.

Simoens S, Laekeman G: Pharmacotherapy of allergic rhinitis: a pharmaco-economic approach. Allergy. 64:85-95 2009 19076532

 

Wahn W, Taber A, Kuna P, et al.: Efficacy and safety of 5-grass-pollen sublingual immunotherapy tablets in pediatric allergic rhinoconjunctivitis. J Allergy Clin Immunol. 123:160-166 2009 19046761

 

Wallace DV, Dykewicz MS, Bernstein DI, et al.: The diagnosis and management of rhinitis: an updated practice parameter. J Allergy Clin Immunol. 122:S1-S84 2008 18662584

 

Weinstein S, Qaqundah P, Georges G, et al.: Efficacy and safety of triamcinolone acetonide aqueous nasal spray in children aged 2 to 5 yr with perennial allergic rhinitis: a randomized, double-blind, placebo-controlled study with an open label extension. Ann Allergy Asthma Immunol. 102:339-347 2009 19441606

 

Wright AL, Holberg CJ, Martinez FD, et al.: Epidemiology of physician-diagnosed allergic rhinitis in childhood. Pediatrics. 94:895-901 1994 7971008

 

Blaiss MS: Antihistamines: treatment selection criteria for pediatric seasonal allergic rhinitis. Allergy Asthma Proc. 26 (2):95-102 2005 15971466

 

Fireman P: Therapeutic approaches to allergic rhinitis: treating the child. J Allergy Clin Immunol. 105:S616-S621 2000 10856167

 

Garavello DW, DiBerardino F, Romagnoli M, et al.: Nasal rinsing with hypertonic solution: an adjunctive treatment for pediatric seasonal allergic rhinoconjunctivitis. Int Arch Allergy Immunol. 137 (4):310-314 2005 15970639

 

Gelfand EW: Pediatric allergic rhinitis: factors affecting treatment choice. Ear Nose Throat J. 84 (3):163-168 2005 15871585

 

Passali D: Consensus conference of allergic rhinitis in childhood. Allergy. 54:4-34 1999

 

Ressel GW: AHRQ releases review of treatments for allergic and nonallergic rhinitis. Am Family Phys. 66 (11):2164-2167 2002

 

Stone KD: Atopic diseases of childhood. Curr Opin Pediatr. 14:634-646 2002 12352260

 

Wallace DV, Dykewicz MS, Bernstein DI, et al.: The diagnosis and management of rhinitis: an updated practice parameter. J Allergy Clin Immunol. 122 (2 Suppl):S1-84 2008 18662584

SINUSITIS IN CHILDREN


Introduction:

Sinusitis is an inflammation of mucosal epithelial lining of paranasal sinuses.It is common in children but uncommonly diagnosed by Pediatricians due to low index of suspicion,although it has significant morbidity.Rhinitis is very common associate of this disease,so some paediatricians prefer to use the term Rhinosinusitis.

  • Sinusitis can occur at any age
  • ethmoidal and maxillary sinuses are present at birth but maxillary sinuses pneumatize at about 4 years of age,wherease the ethmoidal sinuses are well pneumatized at birth.
  • sphenoidal sinuses develop at about 5 years of age,wherease,frontal sinuses start to develop at about 7 years of age and continue pneumatization till early adolescent age i,e. 12 years of age
  • acute sinusitis is defined as symptoms of upto 4 weeks duration
  • subacute sinusitis is of 4 weeks to less than 12 weeks duration
  • chronic sinusitis, if 12 weeks or more of duration
  • recurrent sinusitis is 4 or more distinct episodes of sinusitis in one year
  • according to one study, 72% asthmatic children may have chronic sinusitis
  • Wherease 12% children with chronic sinusitis have asthma
  • chronic sinusitis is consistently associated with cystic fibrosis(CF)
  • The prevalence of chronic sinusitis in CF carrier is almost double the general population
  • Pansinusitis is a consistent features of primary ciliary dyskinesia(PCD),

 ETIOLOGY

  • Acute sinusitis is most commonly caused by viruses,like rhinivirus,influenza and parainfuenza virus,human metapneumovirus
  • bacterial causes in decreasing order of prevalence for acute sinusitis are
  • Streptococcus pneumoniae,Haemophilus influenzae,and Moraxella catarrhalis
  • chronic sinusitis is caused by Staphylococcus aureus,MRSA,Coagulase negative Staph aureus(CONS),alpha and beta Streptococcus and gram negatives in addition to causatives of acute condition.
  • causative organism in immunocompromised,diabetic and seriously ill subjects are pseudomonas,gram negatives,Mucor ,Rhizopus and Aspergillus in addition to causatives of acute and chronic conditions
  • Some children may have allergic sinusitis

 

PATHOGENESIS

  • Normally the paranasal sinuses are kept sterile by mucociliary system
  • In case of viral upper respiratory tract infections, the opening of sinuses in the meatus get blocked due to edeme and inflammations,so there is hinderance in washing out of sinuses which predispose to bacterial overgrowth.
  • In allergic individuals, aggregation of eosinophils occur in nasopharynx and sinuses which release major basic proteins ,which in turn hampers mucociliray function and causes inflammation
  • CFTR protein is essential for a good function of mucociliarry  system,as it helps in ionic transport across epithelium,but in cystic fibrosis and in the carrier stage of this disease ,due to mutations of this protein ,mucociliarry funtion is hampered
  • In csaes of PCD, movement of cilia are genetically defective
  • Nose blowing by children creats sufficient pressure to propel bacterial organisms from nasopharynx into sinuses
  • Imaging studies,have revealed mucosal thickeninging,,inflammation and edema in a setting of sinusitis

PPREDISPOSING FACTORS FOR RECURRENT OR CHRONIC SINUSITIS ARE

  •  Children with primary immunodeficiencies particularly IgG,IgG subclass,and IgA deficiency,children with phagocytic defects are predisposed
  • children with acquired immunodeficieny like malignancy,chemothrapy with neutropenia and lymphopenia,HIV infection are predisposed
  • Anatomical defects like cleft palate
  • Gastro-esophgeal reflux diseases
  • cocaine abuse
  • Allergic Rhinitis, Persistent Asthma,cystic fibrosis,Primary or secondary ciliary dyskinesia
  • Nasal foreign body like nasogastric tube,nasal polyp,nasotracheal intubation which blocks ostia of sinuses
  • Adenoid hypertrophy which blocks sinus ostia
  • Regular exposure to tobacco smoke

CLINICAL FEATURES

SYMPTOMS: symptoms of sinusitis are nonspecific, so high index of suspician should be kept to diagnose it.

Symptoms are:

  • cough,which persist for long time,more during day time,it can be the only symptom in some children
  • running nose,may be clear or purulent
  • nasal congestion or stuffiness,blocked nose
  • headache, not usual in children,may aggravate on bending forward,may be frontal,over vertex,may be referred to temporal or occipital region(sphenoidal sinusitis) depending on sinuses involved
  • decreased sense of smell(hyposmia)
  • bad breath odor(halitosis)
  • swelling of  periorbital region
  • persistent throat clearing habits due to pharyngeal irritation
  • pain over face,not usual in children or tooth pain of maxillary region, which aggravates on leaning forward
  • fever ,may be low grade or high grade
  • fullness or pressure sensation over ears
  • some older children complaints of giddiness

Signs: Clinical signs are difficult to appreciate in children,these are

  • tenderness over sinuses but usually not found in children,tenderness over maxillary sinuses or base of frontal sinuses just above inner canthi may be found in older children depending upon sinuses involved.
  • purulent nasal and post nasal secretions
  • nasal and facial erythma
  • nasal mucosal edema with blocked ostia of sinuses due to edema and inflammation,seen on anterior rhinoscopy
  • nasal polyp, blocking the sinus ostium
  • periorbital edema due to ethmoidal sinusitis

DIAGNOSIS

Diagnosis is mainly clinical:

According to American Academy of Pediatrics guideline 2013

  • Bacterial sinusitis should be suspected in children with symptoms of acute upper respiratory tract infection which starts as seveve and persists as severe with fever of 102 degreeF(39dC) for more than 3 days, OR
  • which deteriorates after initial improvement within 7-14 days,OR
  • which persists for more than 10-14 days
  • X-ray PNS waters view or caldwell view is helpful
  • CT scan of PNS should be done in case of severe disease or immunocompromised cases or any polyp is suspected within sinuses, as it may show abnormality in upto 50% of asymtomatic children.
  • diagnostic criteria on imaging are:
  • opacity,mucosal thickening of more than 5 mm or air-fluid level
  • complete blood count are not much helpful,peripheral blood eosinophilia may be seen in allergic individuals.
  • Aspiration and culture of sinus fluid is the only definite method of diagnosis, which is not possible routinely in immunocompetent child. It should be kept reserved for immunocompromised child, mainly to look for fungal infection.
  • SINUSITS

MANAGEMENT

Antimicrobials:

  • ACUTE SINUSITIS:
  • amoxicillin(high dose) 80 -90mg /kg body wt per day bid for 10-14 days OR 7 days after resolution of symptoms
  • In uncomplicated acute bacterial sinusitis amoxicillin 45 mg /kg body wt /day may work
  • clavulanic acid should be added if no response witin 48-72 hours OR
  • onset is severe OR
  • any risk factors for resistance like rcecnt use of antibiotics(in last 1-3 months) ,infections contracted in day care centre or age less than 2 years
  • Alternative medicines are cefuroxime,cefpodoxime ,cefdinir,azithromycin ,rifampicin.
  • In case of failure to these-imaging study should be done and surgical drainage should be considered.
  • CHRONIC SINUSITIS:
  • In view of high percentage of beta lactamase producing isolates in chronic sinusitis
  •  first line antibiotic should be amoxicillin+clavulanic acid for 21 days
  • if no improvement in symptoms ,additional 21 days course of another beta lactamase resistant antimicrobial should be given like
  • cefuroxime axetil,cefpodoxime,cefdinir.
  • Alternatives are cefotaxime, ceftriaxone and clindamycin or vancomycin or flluroquinolone.
  • FOR SERIOSULLY ILL OR IMMUNOCOMPROMISED CHILD:
  • cefepime or piperacillin+tazobactum +/- amphotericinB.

medicines for reduction of swelling:useful in chronic sinusitis

  • for severe nasal swelling 0.05% solution should be given intranasally ,3 drops into each nostril bid for 3 days
  • if swelling persist,oral pseudoephedrine or phenylepropalamine should be given for 7-10 days
  • if swelling again persists, intrnasal corticosteroid should be given for 3-6 weeks
  • If these measures are not working adequately,oral prednisolone should be given in the dose of 0.5mg/kg/day tapered over 5-7days
  • FOR ENHANCING EVACUATION OF SECRETIONS IN CHRONIC SINUSITIS:
  • saline irrigation
  • hot stem inhalation
  • COMPLICATIONS:,
  • Due to close proximation of paranasal sinuses to eyes and brain ,infections readily travel to these region causing
  • Orbital cellulitis,cavernous sinus thrombosis,epidural abscess,subdural empyema
  • Frontal sinusitis can cause edema and swelling of forehead due to osteomyelitis of frontal bone called pott puffy tumour
  • Mucocele usually occurs in chronic frontal sinusitis located near inner canthi which pushes eye causing diplopia

BIBLIOGRAPHY:

 

  • Diane E. Pappas and J.Owen Hendley:sinusitis ,Nelson Textbook of Pediatrics,19e: Kliegman,Stanton,St. Geme,Schor and Behrman:Saunders,An imprint of  Elsevier 1600 John F. Kennedy Blvd. Ste 1800,P hiladelphia, PA19103-2899:1436-1438
  •  Chobot R.The incidence of sinusitis in asthmatic children. Am J Dis Child. 39:257 1930
  • Bullen S.S.Incidence of asthma in 400 cases of chronic sinusitis. J Allergy. 4:402 1932
  • Welsh M.J.Ramsey B.W.Accurso F.Cystic fibrosis. Childs B. Kinzler K.W. Vogelstein B. Molecular Basis of Inherited Disease. 2006 McGraw Hill New York 51215188
  • Wang X.Kim J.McWilliams R.Increased prevalence of chronic rhinosinusitis in carriers of a cystic fibrosis mutation. Arch Otolaryngol Head Neck Surg. 131 (3):237240 2005 15781764
  •  Anon JB (April 2010). “Upper respiratory infections”. Am. J. Med. 123 (4 Suppl): S16–25. doi:10.1016/j.amjmed.2010.02.003PMID 20350632.
  •  Jump up to:a b c Christine Radojicic. “Sinusitis”Disease Management ProjectCleveland Clinic. Retrieved November 26, 2012.
  • Jump up^ Pearlman AN, Conley DB (June 2008). “Review of current guidelines related to the diagnosis and treatment of rhinosinusitis”. Current Opinion in Otolaryngology & Head and Neck Surgery 16 (3): 226–30. doi:10.1097/MOO.0b013e3282fdcc9a.PMID 18475076.
  •  Jump up to:a b c d e f g h i Leung RS, Katial R (March 2008). “The diagnosis and management of acute and chronic sinusitis”. Primary care 35 (1): 11–24, v–vi.doi:10.1016/j.pop.2007.09.002PMID 18206715.
  • Diament M.J.Senac M.O.Gilsanz V., et al.Prevalence of incidental paranasal sinuses opacification in pediatric patients. A CT study. J Comput Assist Tomogr. 11:426431 19873571583
  • Ah-See KWEvans ASSinusitis and its management. BMJ. 334:358361 2007 17303885
  • Coffinet LChan KHAbzug MJ, et al.Immunopathology of chronic rhinosinusitis in young children. J Pediatr. 154:757758 2009
  • Harvey R, Hannan SA, Badia L, et al: Nasal saline irrigations for the symptoms of chronic rhinosinusitis (review). Cochrane Database Syst Rev (3):CD006394, 2007.
  • Lindbaek MButler CCAntibiotics for sinusitis-like symptoms in primary care. Lancet.371:874876 2008 18342666
  • Operative Tech Otolaryngol Head Neck Surg. 15:3741 200
  • Jump up^ Gwaltney JM, Hendley JO, Phillips CD, Bass CR, Mygind N, Winther B (February 2000). “Nose blowing propels nasal fluid into the paranasal sinuses”Clin. Infect. Dis.30 (2): 387–91. doi:10.1086/313661PMID 10671347.
  • Piccirillo JFAcute bacterial sinusitis. N Engl J Med. 351:902910 2004 15329428

  • Slavin RGSpector RLBernstein ILThe diagnosis and management of sinusitis: a practice parameter update. J Allergy Clin Immunol. 116:S13S47 2005 16416688

  • Steele RWRhinosinusitis in children. Curr Allergy Asthma Rep. 6:508512 2006 17026877

  • Wald ERNash DEickhoff JEffectiveness of amoxicillin/clavulanate potassium in the treatment of acute bacterial sinusitis in children. Pediatrics. 124:915 2009 19564277

  • Williamson IGRumsby KBenge S, et al.Antibiotics and topical nasal steroid for treatment of acute maxillary sinusitis.JAMA298:2487-2496 2007PMID 18056902
  • Recommendations adapted from American Academy of Pediatrics. Pickering LK, Baker CJ, Kimberlin DW, Long SS (eds): Red book: 2009 Report of the Committee on Infectious Diseases, 28th ed. Elk Grove Village, IL, American Academy of Pediatrics, 2009; and McMillan JA, Siberry GK, Dick JD, et al: The Harriet Lane handbook of pediatric antimicrobial therapy. Philadelphia, PA, Mosby Elsevier, 2009.Goytia VKGiannoni CMEdwards MSIntraorbital and intracranial extension of sinusitis: comparative morbidity. J Pediatr. 158:486491 2011  20970813
  • Harvey R.Hannan S.A.Badia L., et al.: Nasal saline irrigations for the symptoms of chronic rhinosinusitisCochrane Database Syst Rev. (3)2007 CD006394axillary sinusitis.JAMA. 298:24872496 2007 18056902
  • Jonnath Corren MD:The influence of upper airway disease on the lower airway:Kendig and Chernick’s disorders of the respiratory tract in children,Eighth edition:Elsevier Saunders 1600 John F Kennedy Blvd Ste 1800 Philadelphia,PA 19103-2899:749-752

ADENOID HYPERTROPHY


INTRODUCTION:

Adenoid is an aggregation of lymphoid tissues located between nasal septum and posterior pharyngeal wall,also called nasopharyngeal tonsil.

It is separated from underlying structure by thick fibrous capsule.

There is only one adenoid in our body,so the term adenoids should not be used.

It forms a part of  waldeyer’s ring which a defensive ring  of our body.

It is situated at the external opening of pharynx and acts as first defence along with tonsils against external insult.

It induces the formation of secretory immunoglobulins.

It is present at birth but most active between the ages of 4-10 years and in some children may be most active between the ages of 6 months to 5 years. After puberty its immunological role is negligible.

It gets hypertrophied and become enlarged,due to internal and external insults and its increased size causes various troubles to the child.

Adenoid hypertrophy or enlarged adenoid is the most common cause of obstructive sleep apnea in children.

ETIOLOGY:

Infective  causes include viruses which are the commonest cause of adenoid enlargement by causing adenoiditis.

Bacterial causes include both aerobics such as Streptococci and Haemophilus influezae and anaerobics such as Peptostreptococci,Prevotella and Fusobacterium.They are responsible for causing chronic adenoiditis and  consequent adenoid enlargement.

The most common bacterium isolated from chronic adenoiditis is Haemophilus influenzae.

Among non infective causes ,most common  cause of adenoid enlargement is allergic adenoiditis which is often recurrent.

In children with allergic rhinitis,the inflammatory or infected secretions sweep over adenoid regularly and causes its hypertrophy.

In children with gastroesophageal reflux disease ,there is regular contact of gastric contents with adenoid which causes chronic inflammation and hypertrophy.

CLINICAL FEATURES:

Day time symptoms are-

persistent mouth breathing due to nasal obstruction.

Foul smelling breath,due to mouth breathing,which bypasses the nasal filtering mechanism of bacteria.

Earache,due to hindrance of clearance by eustachian tube secondary to blockage by enlarged adenoid,which predisposes to recurrent otitis media.

Day time excessive sleepiness,difficulty in concentration,poor school performance.

Decreased appetite.

Hyponasal speech.

Hyposmia.

Early morning fatigue.

Child takes long time to finish meals,because of compulsion to take breath while swallowing.He or She has to withhold swallowing ,takes breath and then swallow.

 

Night time symptoms are-

Drooling of saliva through angles of  mouth.

Snoring while sleeping which is loud.

Frequent arousals due to obnstructive sleep hypopnea and apnea.

Choking while sleeping,gasping while in sleep,restlessness while sleeping,frequent change in sleep position,sleep talking,night terror,abnomal sleep position.

Diaphoresis.

Somnabulism.

Nocturnal cough.

Nocturnal enuresis.

clinical signs:

Unlike tonsils,adenoid can not be seen on clinical examination.

It can be seen by mirror examination which is held back in the throat.

It is well visualized by flexible endoscopy.

Enlarged neck lymph nodes ,particularly jugulodiagastric may be an associated finding.

DIAGNOSIS:The investigation of choice is 

X-Ray soft tissue neck_lateral view

 

adenoid hypertrophy      adenoid hypertrophy 3   adenoid hupertrophy 2

In these images middle part of the arrow is overlying adenoid while the point of arrow is showing indentation of the airway due to enlarged adenoid.

TREATMENT:

There are two nonsurgical modalities of treatment for adenoid hypertrophy apart from controlling infections if it is the cause.

INTRANASAL STEROIDS: Fluticasone,mometasone or budesonide nasal spray is quite effective in alleviating symptoms  and also reduces the size of adenoids significantly. These should be given for a period of  12 to 24 weeks with a  tapering  dose. These are most effective in allergic individuals. Chances of recurrence is there after stopping therapy.

LEUKOTRIENE RECEPTOR ANTAGONIST(MONTELEUKAST): It is effective in alleviating symptoms and reducing the size of adenoids.

It should be given for a prolonged period,at least 3-6 months.

ATIBIOTICS: If there is evidence of bacterial infections ,causing adenoid enlargement , appropriate antibiotics  should be given for 3 weeks.

GASTRO-ESOPHAGEAL REFLUX should be treated adequately if it suspected to be a cause.

ORAL STEROID-In acute conditions, with severe airway obstruction,prednisolone in the dose of 1-2 mg/kg/day should be given for 5 days to relieve the symptoms.

LONG TERM EFFECTS OF UNTREATED ADENOID HYPERTROPHY

Difficult to control asthma, if it is associated ,as commonly seen in allergic children.

Neurocognitive abormalities.

Attention deficit hyperactivity disordes.

Adenoid facies-elongation of the middle part face with retrognathia.

Growth retardation.

Diastolic hypertension.

Right ventricular hypertrophy.

pulmonary hypertension.

ADENOID FACIES

PICTURE SHOWING ADENOID FACIES

 

INDICATION FOR SURGICAL TREATMENT

Chronic nasal infections- chronic adenoiditis

Chronic sinus infections with failure to medical treatment

Recurrent otitis media including those with tympanostomy tube with recurrent otorrhoea

Recurrent otitis media with effusion

Craniofacial and occlusive developmental abnormality due to adenoid enlargement

Growth retardation

 

BIBLIGRAPHY

  • -Mazrou KAAl-khattaf ASAdherent biofilms in adenotonsillar diseases in children. Arch Otolaryngol Head Neck Surg. 134:20232008 18209130

  • American Academy of Otolaryngology-Head and Neck Surgery:Clinical indicators: tonsillectomy, adenoidectomy, adenotonsillectomy, 2000. (website)www.entlink.net/practice/products/indicators/tonsillectomy.htmlAccessed June 17, 2010

  • Baugh RFArcher SMMitchell RB, et al.Clinical practice guideline: tonsillectomy in children. Otolaryngol Head Neck Surg. 144 (1 suppl):S1S30 2011 21493257

  • Bonuck KAFreeman KHenderson JGrowth and growth biomarker changes after adenotonsillectomy: systematic review and meta-analysis. Arch Dis Child. 94:8391 2009 18684748

  • Brook IShah KBacteriology of adenoids and tonsils in children with recurrent adenotonsillitis. Ann Otol Rhinol Laryngol. 110:8448482001 11558761

  • Cochrane Database Syst Rev. 2008 Jul 16;(3):CD006286. doi: 10.1002/14651858.CD006286.pub2.

    Intranasalcorticosteroids for nasal airway obstruction in children with moderate to severe adenoidal hypertrophy.

    Int J Pediatr Otorhinolaryngol. 2010 Jul;74(7):773-6. doi: 10.1016/j.ijporl.2010.03.051. Epub 2010 Apr 28.

    Medical treatment of adenoid hypertrophy with “fluticasone propionate nasal drops”.

  • [Non-surgical treatment for adenoidal hypertrophy][Article in Chinese]

ACUTE PHARYNGITIS-THE SORE THROAT


INTRODUCTION

Pharyngitis is inflammation of mucosa and underlying tissue of pharynx.

It is clinically divided into two category-nasopharyngitis and pharyngotonsillitis.

Nasopharyngitis is associated with nasal sumptomps like running nose or itching in the nose due to inflammation of nasal mucosa and it is usually of viral origin.

Pharyngotonsillitis is associated with inflammation and enlargement of palatine tonsils.

Sore throat is one of the common symptoms requiring frequent OPD visit  by children which constitutes about 30% of all upper respiratory tract infections in children.

The most important is Group A Beta haemolytic Streptococcal(GABHS) Pharyngitis as  there is 3% chance of it being complicated by acute rheumatic fever with its cardiac complications.

Approximately 25% of all sore throat are caused by bacteria.

GABHS pharyngitis commonly affects children between the age group of 2 to 15 years,Most affected children are of school age.

It commonly spreads by close contacts in the family or in schools

Approximately  50% of  the close contacts  of the index case in the family or in the school get infected by the bacteria through respiratory route.

GABHS Pharyngitis usually occurs in rainy,winter or spring seasons.

ETIOLOGY

Most commonoly ,it is caused by viruses

Common viruses causing acute pharyngitis are adenovirus,enterovirus,influenza virus,parainfluenza virus,coxsackie virus ,Ebstein- barr virus,rhinovirus,metapneumovirus,and herpes simplex virus.Primary infection with HIV may present as pharyngitis.

Less commonly it is caused by bacteria

Most important are GABHS and Corynebacteriun diphtheria

Other bacteria causing pharyngitis are Arcanobacterium hemolyticum,Fusobacteriun necrophorum,Neisseria gonorrhoeae and Mycoplasma pneumonia

PATHOGENESIS

Two major virulence factors of GABHS are M protein and erythrogenic exotoxins

M protein resists phagocytosis by polymorphonuclear neutrophils and causes pharyngitis which confers type specific immunity.

Erythrogenic toxins are of 3 types,A,B and C.The most virulent is type A responsible for causing scarlet fever with fine papular rashes.

These exotoxins confers type specific immunity,so scarlet fever can occur for 3 times in life

CLINICAL FEATURES

The most important and the most challenging is to differentiate sore throat due to GABHS from other causes,because of its potential to cause acute Rheumatic fever and its cardiac complications.

There is no single clinical symptom or clinical sign ,which can make a definite diagnosis of GABHS Pharyngitis.

The incubation period is 2-5 days

SYMPTOMS

Usual presentation of GABHS Pharyngitis is sudden onset of sore throat,pain in throat at rest or even after swallowing saliva,fever, in the absence of cough.

Common associated symptoms are headache,pain abdomen and vomiting.Limb pain due to myalgia is also common complaint.

SIGNS

The pharynx is red and erythematous-redness may be a part of generalized redness of viral origin but the differentiating point is that in case of GABHS infection the pharynx is more red as compared to other area of oral redness.

The tonsils are enlarged and in classical case, it is covered with yellow blood tinged exudate.

Exudate may also be seen on posterior pharynx with petechiae or doughnut lesions ,which may also be found over soft palate.

There may be redness and swelling of uvula with stippling

There may be enlargement and tenderness of anterior cervical lymph nodes.

Some additional signs favouring scarlet fever may be present in the form of fine ,red, papular raches over body including face and neck which feels like sand paper and looks line sunburn with goose pimples,perioral pallor and strawberry tongue.

MODIFIED CENTOR SCORING FOR DIAGNOSING GABHS PHARYNGITIS

Components are

  1. age 3-14 years
  2. temperature more than 38 degree celcius
  3. absence of cough
  4. enlarged and tender anterior cervical lymph nodes
  5. swelling or exudates over tonsils

Each component is given one point

Score 4 or more is highly suggestive of GABHS Pharyngitis,score o-1 should not be tested for or given treatment for GABHS Pharyngitis

Another important bacterial cause of acute pharyngitis,which should be looked for and treated in children is Diphtheria.

It is caused by Corynebacterium diphtheria,clinically characterized by grey to black adherent membrane over throat with  extension beyond the faucial area ,especially over soft palate and uvula with symptom of dysphagia and relatively ,lack of fever.,

shallow ulceration of upper lips and external nares and neck swelling may be found.

CLINICAL FEATURES OF VIRAL PHARYNGITIS

Its onset is gradual as compared to bacterial which is sudden in onset.

It is usually associated with cough,coryza,running nose,conjuntivitis and hoarseness of voice.

SPECIFIC FEATURES OF SOME VIRAL PHARYNGITIS

Adenovirus-pharyngitis is associated with conjunctivitis and diarrhoea.

Coxsackievirus- herpangina with small greyish vesicles and punched out ulcers which is extremely painful.There may be yellowish white nodules in the posterior pharynx called acute lymphonodular pharyngitis

Ebstein barr virus- causative agent of infectious mononucleosis

generalized fatigue,rashes over body and face,prominent tonsillar enlargement with exudate.

cervical lymphadenopathy is posterior as compared to anterior in GABHS Pharyngitis.

hepatosplenomegaly.

HERPES SIMPLEX VIRUS –

Pharyngitis with high fever and gingivostomatitis

LABORATORY DIAGNOSIS

The gold standard is throat swab smear examination and culture

Technique of swab collection should be perfect for appropriate result-it should be obtained by vigorous swabbing of both tonsillar surfaces or fossae and posterior pharynx.Swabbing of soft palate and uvula should be avoided as it dilutes the innoculums

It has 90-95% sensitivity

Albert staining should be done, if Diphtheria is suspected, and if drumstick appearance is visible, culture should be done to confirm Corynebacterium Diphtheriae ,because diphtheroids are the commensals in throat ,having similar look on smear examination.

RAPID ANTIGEN DETECTION TEST(RADT) FOR GABHS

It is done on throat swab and detects nitrous acid extraction of carbohydrate antigen of GABHS.

Is has specificity of more than 95% but low sensitivity ,so negative test should be confirmed by culture but positive test need not confirmation by culture.

This test is available at selected centres in India

In case of suspected EBV Pharyngitis IgM Antibody against viral capsular antigen can be dectected in addition to many atypical lymphocytes in CBC

TREATMENT

Viral as well as GABHS Phryngitis is self limiting ,but antibiotic therapy is needed to prevent the complication of Acute Rheumatic fever and its cardiac complications

It works when given within 9 days of onset of symptoms

Child becomes non-infectious after 24 hours of instituting antibiotic therapy

INDICATIONS OF STARTING ANTIBIOTIC WITHOUT AWAITING CULTURE RESULT

  • Symptomatic pharyngitis with positive RADT
  • Pharyngitis with past history of acute rheumatic fever in child or recent history of acute rheumatic fever in family
  • Pharyngitis with a household contact with documented Streptococcal pharyngitis
  • pharyngitis with clinical features suggestive of scarlet fever

ANTIBIOTIC

The preferred drug is oral amoxicillin because it tastes good,easily available,dispersible tablet is available for children and can be given once daily

The dose is 50 mg /kg,minimum of 750 and maximum of 1 gm once daily for 10 days

A single dose of benzathine penicillin ensures compliance and provides adequate blood levels for 10 days.

Dose is 6 lakhs unit i.m. for child <27 kg and 12 lakhs unit i.m. for child more than 27 kg

TREATMENT OPTIONS FOR CHILD ALLERGIC TO PENICILLIN

Azithromycin,12mg/kg ,maximum 500mg,once daily for 5 days

Clarithromycin,15 mg/kg/day bid,a maximum of 250mg bid /day for 10 days

clindamycin 20 mg /kg/day tid,a maximum of 1.8 gm/day for 10 days

In cases of multiple episodes over a period of months or years ,Amoxiclav or clindamycin shoud be given as these yield high rates of eradication of GABHS in these cicumstances.

First to third generations cephalosporins can be given but if given ,it should be given for 10 days.

SYMPTOMATIC TREATMENT

It is an important part of management.

oral paracetamol or ibuprofen should be given for fever and pain in throat.

Warm saline gargle gives relief in throat

Lonzenges containing phenol,menthol or benzocaine provides local relief.

TREATMENT OF DIPHTHERIA

Stabilization of the child with care of airway

Diphtheria antitoxin 50000units to 120000 units i.vi depending on the extent of lesions

Aqueous crystalline penicillinG 40000 units /kg /dose ,i.v. 6hourly or erythromycin 15 mg/kg/dose,maximum 2gm/day oral or i.v. for 14 days.

For contact prophylaxis, same dose of erythromycin for 7 days or single intramuscular injection of Benzathine penicillin ,6 lacs units for <30 kg and 12 lacs unit for 30 kg or more is recommended

COMPLICATION

Parapharyngeal,retropharyngeal and peritonsillar abscess

pronlonged pharyngitis of more than 1-2 weeks durations suggest neutropenia or recurrent fever syndrome

LEMIERRE SYNDROME 

It is a serious complication of pharyngitis caused by Fusobacterium necrophorum

It is characterized by septic thrombophlebitis of internal jugular vein with pulmonary embolism causing pulmonary infiltrates and hypoxia

Non suppurative complications are acute rheumatic fever and acute glomerulonephritis

INDICATION OF TONSILLECTOMY– Severe ,recurrent ,culture proven pharyngitis due to GABHS with >7 episodes in previous year or >5 episodes each year in preceding 2 years.

It lowers the incidence of pharyngitis for 1-2 years

Most children have fewer epsodes over the years spontaneously ,so risk benefit should be balanced

 

BIBLIOGRAPHY

  •                   BhaveSY,Kinikar A,Sane S,Agarwal M,AmbedkarYK.Epidemiology of Streptococcal infection in reference to rheumatic fever.Indian pediatr 1991;28: 1503-1508
  • Jain N,Lodha R,Kabrask.Acute upper respiratory tract infection.Indian J Pediatr 2001;68:1135-1138
  • Dowell SF,Mercy M,Philips WR et al.Principle of judicious use of antimicrobial agents for pediatric upper respiratory tract infection.Pediatrics 1998;101:163-165
  • Ebell MH, Smith MA, Barry HC, Ives K, Carey M. The rational clinical examination.Does this patient have strep throat? J A M A. 2000;284:2912-8.
  •  Linder JA, Bates DW, Lee GM, Finkelstein JA. Antibiotic treatment of children with sore throat. J A M A. 2005;294:294:2315-22.
  • Nandi SW, Kumar R ,Ray P, Vohra H, Gangulay NK. Clinical score card for diagnosis of Group A Streptococcal sore throat. I ndian J Pediatr. 2002;69:471-5
  • Wigton RS, Connor JL Centor RM. Transportability of a decision rule for the diagnosis of streptococcal pharyngitis. Arch Intern Med. 1986;146:81-3.
  • American Academy of Pediatrics,committee on infectious disease.Red book,26th edn.Elk Grove Village,III:American Academy of Pediatrics;2003.pp.578-80.
  • McIsaac WJ,white D,Tannenbaum D,Low DE,A clinical score to reduce unnecessary antibiotic use in patients with sore throat.CMAJ.1998;158:75 -83
  • Van der Veen EL,Sanders EAM,Videler WJM,Van Staaij BK,Van Benthem PPG,Schilder AGM.Optimal site for throat culture:tonsillar versus posterior pharyngeal wall.Eu Arch Otorhinolaryngol.2006;263:750-3
  • Bisno ALRobin FACleary PP, et al.Prospects for a group A streptococcal vaccine: rationale, feasibility, and obstacles—report of a NIAID workshop. Clin Infect Dis. 41:11501156 2005 16163634

  • Burton MJ, Glasziou PP: Tonsillectomy or adeno-tonsillectomy versus non-surgical treatment for chronic/recurrent acute tonsillitis (review). Cochrane Database Sys Rev (1)CD001802, 2009.

  • Centor RMExpand the pharyngitis paradigm for adolescents and young adults. Ann Intern Med. 151:812815 2009 19949147

  • Clegg HWRyan AGDallas SD, et al.Treatment of streptococcal pharyngitis with once daily compared with twice daily amoxicillin: a non-inferiority trial. Pediatr Infect Dis J. 25:761767 2006 16940830

  • Gerber MABaltimore RSEaton CB, et al.Prevention of acute rheumatic fever and diagnosis and treatment of acute streptococcal pharyngitis (American Heart Association Scientific Statement). Circulation. 119:15411551 2009 19246689

  • Jaggi PShulman STGroup A streptococcal infections. Pediatr Rev. 27:99105 200616510550

  • Lennon DRFarrell EMartin DR, et al.Once-daily amoxicillin versus twice-daily penicillin V in group A β-haemolytic streptococcal pharyngitis. Arch Dis Child. 93:474478 200818337284

  • Little PSore throat in primary care. BMJ. 339:467 2009

  • Little PRecurrent pharyngo-tonsillitis. BMJ. 334:909 2007 17478789

  • Martin JMGreen MGroup A streptococcus. Semin Pediatr Infect Dis. 3:140148 2006

  • Park SYGerber MATanz RR, et al.Clinicians’ management of children and adolescents with acute pharyngitis. Pediatrics. 117:18711878 2006 16740825

  • Pfoh EWessels MRGoldmann D, et al.Burden and economic cost of group A streptococcal phayngitis. Pediatrics. 121:229234 2008 18245412

  • Pichichero MECasey JRSystematic review of factors contributing to penicillin treatment failure in Streptococcus pyogenes pharyngitis. Otolaryngol Head and Neck Surg. 137(6):851857 2007

  • Tanz RRShulman STChronic pharyngeal carriage of group A streptococci. Pediatr Infect Dis J. 26:175176 2007 17259882

  • Tanz RRGerber MAKabat W, et al.Performance of a rapid antigen-detection test and throat culture in community pediatric offices: implications for management of pharyngitis.Pediatrics. 123:437444 2009 19171607

  • Wessels MRStreptococcal pharyngitis. N Engl J Med. 364 (7):648654 2011 21323542

Doctors Perform Heart Surgery On Baby Still Inside Womb.


Children’s Hospital of Philadelphia is world-renowned for its fetal surgery in which an operation is performed on a baby still inside the womb.

Recently, in yet another historic procedure, CHOP doctors undertook a risky and delicate operation on a tiny fetal heart.

Health reporter Stephanie Stahl has the exclusive story of what it took to save an unborn baby named Juan.

After some setbacks, an excited family who learned they were finally going home to South America said goodbye to the team that saved their baby.

Baby Juan and his parents, Cecilia Cella and Pablo Paladino, are headed back to Uruguay where the infant has become a celebrity.

“We receive calls, messages from people we don’t know,” said Pablo Paladino.

Since October, the family has been camped out at CHOP where doctors saved little Juan’s life with an intervention that is largely unheard of in many places.

“It was a hard time, crazy time, but we are extremely happy how everything was solved,” said Paladino.

When Cella was five months pregnant, a routine ultrasound showed a mass on the baby’s heart.

Their doctor in Uruguay sent the images to his friend, Dr. Jack Rychik, who is the director of the Fetal Heart Program at CHOP.

“The minute I saw this I recognized there was a giant tumor sitting on the heart,” said Rychik.

It was a rare pericardial teratoma and the only hope was fetal surgery where doctors would operate on the baby Juan’s heart inside the womb.

“We never heard this before,” said Paladino.

“I started laughing, like what, they do that,” said Cella.

The family raced to Philadelphia because CHOP is the only place where the risky fetal heart operation has been done successfully on just one other occasion.

“We’re operating on two patients here with the single intent,” said Rychik. “Our goal is to get to the tumor and resect the tumor but we also have mother and baby.”

Juan is now the second baby to survive the fetal surgery.

The procedure was performed when his mother was 21 weeks pregnant with the baby.

“His heart at the time of surgery was the size of a peanut. The size of the tumor was three-times the size of the heart,” explained Rychik. “Had we waited an additional day, we probably would have been too late.”

After the fetal surgery, the pregnancy continued as the family waited in Philadelphia.

At 31 weeks, Juan was born on Dec. 11, but the tumor had grown back so there was a second heart surgery.

“There were a lot of chances the baby was going to die,” said Paladino.

And now, with a big scar on his chest, Juan is 3 months old and healthy.

 

However, his prognosis is unknown.

“There are no other human beings alive today who have had fetal surgery for this removal of this type of tumor that are 30, 40, 50, 60 years old. We could then say what the prognosis is going to be,” says Dr. Rychik.

But for Cella and Paladino, at least their son has a chance after the fetal surgery that still has their heads spinning.

“Crazy, unbelievable, I look at him, I can’t believe what they did here,” said Cella. “It’s awesome.”

“We are grateful that we came here,” added Paladino. “The doctors are amazing.”

The family is now back home in Uruguay where little Juan continues to thrive.

The tumor that was on his heart was benign.

It’s unknown as to what causes this type of tumor, but it is usually a fatal condition.

Source:http://philadelphia.cbslocal.com

The Internet Is Going Crazy Over These ‘Apple Eye’ X-rays.


A doctor at Stanford Medical Center may have accidentally uncovered a prototype eye implant made by Apple. Yes, think Black Mirror but in real life!

When radiology resident Dr Poakyu Indaii noticed an unusual device in the eye of a Cupertino man he x-rayed on Friday he quickly snapped a few pics with his phone.

“This was clearly not due to the car accident, so I tweeted the photos to my radiology colleagues in case they’d ever seen something similar. I hadn’t noticed the Apple [logo] at all but boy the internet did!” said Dr Indaii.

The trainee radiologist hastily deleted his tweet fearing he may have breached his employer’s image sharing guidelines. But he was too late to stop the x-rays going viral.

The internet was quick to make the link between the Apple device and an episode of the Netflix series Black Mirror in which people with eye implants can re-watch moments from their life on demand.

Apple, notoriously secretive about their projects, refused to comment directly on the tweets but did confirm that a member of their bio-design team had been involved in a “minor car accident”.

News of the device seems all the more feasible given the recent Apple takeover of Astley Labs, a bionics firm in Lancashire. Headed by Professor Fuldja Aggen, the company’s patents on bionic retinas and animal neural interfaces are considered Farnsworthian by most experts.

Even President Trump took time out of his daily golf round Friday afternoon to type a tiny-handed tweet on the issue.

Only one thing is certain – we will never be able to trust what we see again, even when the truth is just one click from being right before our eyes.

Source:radiopaedia.org

Management of Sciatica.


Mr. Winston, a 50-year-old bus driver, presented to your office with a 4-week history of pain in his left leg and lower back. He described a combination of severe sharp and dull pain that originated in his left buttock and radiated to the dorsolateral aspect of his left thigh, as well as vague aching over the lower lumbar spine. On examination, passive raising of his left leg off the table to 45 degrees caused severe pain that simulated his main symptom, and the pain was so severe that you could not lift his leg further. There was no leg or foot weakness. His body-mass index (the weight in kilograms divided by the square of the height in meters) was 35, and he had mild chronic obstructive pulmonary disease as a result of smoking one pack of cigarettes every day for 22 years. Mr. Winston had taken a leave of absence from his work because of his symptoms. You prescribed 150 mg of pregabalin per day, which was gradually increased to 600 mg daily because the symptoms had not abated.

Now, 10 weeks after the initial onset of his symptoms, he returns for an evaluation. The medication has provided minimal alleviation of his sciatic pain. He has to return to work and is concerned about his ability to complete his duties at his job. He undergoes magnetic resonance imaging, which shows a herniated disk on the left side at the L4–L5 root. You discuss options for the next steps in managing his sciatica. He is uncertain about invasive procedures such as lumbar disk surgery but feels limited by his symptoms of pain.

TREATMENT OPTIONS

Which of the following would you recommend for Mr. Winston?

  • 1. Undergo lumbar disk surgery.

  • 2. Receive nonsurgical therapy.

To aid in your decision making, each of these approaches is defended in a short essay by an expert in the field. Given your knowledge of the patient and the points made by the experts, which option would you choose? Make your choice, vote, and offer your comments at NEJM.org.

  • Option 1: Undergo Lumbar Disk Surgery
  • Option 2: Receive Nonsurgical Therapy

Mr. Winston’s case represents a common scenario in the management of symptomatic lumbar disk herniation. In this particular case, the patient’s symptoms and the physical examination are consistent with nerve-root compression and inflammation directly from an L4–L5 herniated disk on his left side. The patient does not have weakness but has ongoing pain and has been unable to work for the past 10 weeks despite receiving pregabalin. Two questions emerge: first, does lumbar disk surgery (microdiskectomy) provide outcomes that are superior to those with continued nonoperative therapy in patients with more than 6 weeks of symptoms; and second, does lumbar microdiskectomy improve the likelihood of return to work in patients with these symptoms?

The highest quality data on the topic come from the Spine Patient Outcomes Research Trial (SPORT).1 The results of the randomized, controlled trial are difficult to interpret because adherence to the assigned treatment strategy was suboptimal. Only half the patients who were randomly assigned to the surgery group actually underwent surgery within 3 months after enrollment, and 30% of the patients assigned to nonoperative treatment chose to cross over to the surgical group.2 In this study, the patients who underwent surgery had greater improvements in validated patient-reported outcomes. The treatment effect of microdiskectomy was superior to that of nonoperative treatment at 3 months, 1 year, and 2 years. Moreover, in an as-treated analysis, the outcomes among patients who underwent surgery were superior to those among patients who received nonoperative therapy. Overall, the results of SPORT support the use of microdiskectomy in this case.

Results of clinical trials are based on a comparison of treatment options in study populations and may or may not apply to individual patients. SPORT did not specify what type of nonoperative therapy was to be used. Physical therapy was used in 73% of the patients, epidural injections in 50%, and medical therapies (e.g., nonsteroidal antiinflammatory drugs) in more than 50%. In the case of Mr. Winston, pregabalin has been tried, but physical therapy and epidural glucocorticoid injections have not been attempted. Despite widespread use of physical therapy for the treatment of lumbar disk herniation, the evidence supporting its effectiveness is inconclusive, according to published guidelines of the North American Spine Society.3 On the other hand, there is evidence that transforaminal epidural glucocorticoid injection provides short-term relief (30 days) in patients with nerve-root symptoms directly related to a herniated disk.4 Overall, there is evidence, from SPORT and from a randomized trial from the Netherlands published in the Journal,5 that early surgery between 6 and 12 weeks after the onset of symptoms provides greater alleviation of leg pain and better overall pain relief than prolonged conservative therapy.

The ability to return to work has not been formally studied in comparisons of operative with nonoperative treatments for lumbar disk herniation. Registry data from the NeuroPoint-SD study showed that more than 80% of the patients who were working before disk herniation returned to work after surgery.6 The ability to return to work may be dependent on the type of vocation, since patients who are manual laborers may need more time to recover to reduce the risk of reherniation.

It is well recognized that many patients who have a symptomatic lumbar disk herniation will have improvement spontaneously over several months. Surgery can alleviate symptoms more quickly by immediately removing the offending disk herniation from the affected nerve root. The risk–benefit equation will vary among individual patients. In the case of Mr. Winston, obesity and mild pulmonary disease might increase the risk of complications from surgery, although in SPORT, 95% of surgical patients did not have any operative or postoperative complication. For Mr. Winston, a patient with pain that has persisted for more than 6 weeks, microdiskectomy is a rational option that is supported by high-quality evidence.

Source:nejm.org

Hutchinson-Gilford Progeria: Practice Essentials, Background, Pathophysiology


Practice Essentials

Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare hereditary disease that affects the skin, musculoskeletal system, and vasculature. HGPS is characterized by signs of premature aging most notable in the skin, cardiovascular system, and musculoskeletal systems. HGPS is caused by mutations in LMNA that result in the production of an abnormal form of lamin A termed progerin.

 Background

The term progeria is derived from the Greek word geras, meaning old age. Significant morbidity and mortality result from accelerated atherosclerosis of the carotid and coronary arteries, leading to premature death during the first or second decade of life. HGPS is considered a segmental aging syndrome, as affected patients do not manifest all of the typical features of aging, such as increased incidence of cancer and neurocognitive decline.

See the image shown below depicting Hutchinson-Gilford progeria syndrome in an infant.

Early Hutchinson-Gilford progeria syndrome. Note t

Early Hutchinson-Gilford progeria syndrome. Note the alopecia, prominent scalp veins, and frontal bossing apparent in this 12-month-old infant with Hutchinson-Gilford progeria syndrome. Midface hypoplasia and micrognathia are less apparent.

 Pathophysiology

Patients with Hutchinson-Gilford progeria syndrome (HGPS) develop clinical features of accelerated aging, including accelerated atherosclerosis of the cerebral and coronary arteries. Unlike arteriosclerosis in the general population, however, in progeria, the only lipid abnormality is decreased high-density lipoprotein cholesterol levels. Interestingly, patients with HGPS do not develop other disease processes associated with aging, such as increased tumor formation, cataract development, or senility. In this sense, HGPS is considered a segmental progeroid syndrome in that it does not recapitulate all of the characteristic phenomena of aging.

Patients with HGPS also develop loss of subcutaneous fat and muscle, skin atrophy, osteoporosis, arthritis, poor growth, and alopecia. There is evidence that patients with HGPS also manifest features of skeletal dysplasia with abnormalities in bone structural geometry and skeletal strength. [6] Extensive lipofuscin deposition, a marker for aging, is extensively distributed in patients with HGPS. Affected organs include the kidneys, brain, adrenal glands, liver, testes, and heart.

 These clinical manifestations occur as the result of defects in processing and function of lamin A, an intermediate filament protein component of the nuclear membrane that regulates a diverse number of cellular functions, including nuclear morphology and integrity, DNA repair, regulation of gene expression, and telomere stability; the end result of these defects is genomic instability, decreased cell proliferation, and premature cell senescence and death. [7] The abnormal protein, progerin, represents a truncated form of the lamin A precursor prelamin A and results from mutations in LMNA. It is interesting to note that mutations in LMNA are associated not only with premature aging syndromes (HPGS, restrictive dermopathy, and atypical Werner syndrome), but also with several muscular dystrophies, lipodystrophic syndromes, and mandibuloacral dysplasia.

Marked loss of vascular smooth muscle cells within the great vessels, arteries, and arterioles associated with sclerosis and fibrosis is a consistent finding in patients with HGPS. [8] Preferential accumulation of progerin in vascular endothelial and smooth muscle cells has been observed. [9]

 Clinically, children with progeria develop atherosclerosis, arteriosclerosis of small vessels, and prominent adventitial fibrosis with increasing deposition of progerin within coronary arteries. [10] The accelerated vascular stiffening and peripheral vascular occlusive disease that develop resemble the cardiovascular features of normal aging and atheroscleroisis. [11] Together with the clinical observations of accelerated and often fatal arteriosclerosis, these findings suggest that the effects of progerin on the cardiovascular system are a major contributor to the pathophysiology of HGPS.
 Interestingly, spontaneous accumulation of progerin has been observed in cultured fibroblasts from normally aged individuals in combination with similar nuclear defects, further reinforcing the theory that HGPS results, at least in part, from accelerated production and accumulation of progerin. [12] It is important to note that the pathophysiology of HGPS results from the presence of progerin and a dominant-negative effect on lamin A function and not simply from the absence of normal lamin A.
 Epidemiology

International frequency

HGPS is a rare disease with a reported prevalence of 1 in 8 million births. The true prevalence, however, has been suggested to be closer to 1 in 4 million births because many cases likely go undiagnosed or are misdiagnosed. The incidence in the Netherlands over the last century was 1:4,000,000. Approximately 100 cases of HGPS have been reported in the literature.

Race

White persons represent 97% of reported patients. The reason for this racial disparity is unknown.

Sex

HGPS has a slight male predilection; the male-to-female ratio is 1.5:1.

Age

Clinical manifestations of HGPS may not be recognized or apparent at birth, although many affected children present with sclerodermatous skin changes. Delayed recognition of the characteristic facial features along with the cutaneous and musculoskeletal manifestations may not occur until age 6-12 months or older, when the development of failure to thrive engenders a more thorough evaluation.

 Prognosis

The average life expectancy for a patient with HGPS is 13 years, with an age range of 7-27 years.

 Data from the largest cohort of HGPS patients indicated a mean survival of 14.6 years, with an increased mean survival of 1.6 years in patients treated with a protein farnesylation inhibitor after a median follow-up of 5.3 years from treatment initiation.[13]

Morbidity and mortality in persons with HGPS occur primarily as a result of atherosclerosis of the coronary and cerebrovascular arteries, with at least 90% of patient deaths directly related to complications of progressive atherosclerosis. Cardiovascular complications include myocardial infarction and congestive heart failure. Interstitial fibrosis, diffuse myocardial fibrosis, and calcification of the mitral and aortic valves may occur. Cerebrovascular complications occurring as a result of cerebrovascular infarction include hemiplegia, subdural hematoma, and seizures. Other causes of morbidity and mortality include marasmus, loss of mobility, and inanition.

History

Evidence of Hutchinson-Gilford progeria syndrome (HGPS) begins within the first 2 years of life. At birth, infants usually appear healthy, although sclerodermatous skin changes have been noted in some patients. Typically, the onset of the disease occurs at age 6-12 months, when skin changes and alopecia are first noted and when the infant fails to gain weight. The following are other suggestive findings [14] :

  • High-pitched voice
  • Short stature and low weight for height, with prenatal onset of growth failure
  • Incomplete sexual maturation
  • Generalized osteoporosis and pathologic fractures
  • Feeding difficulties
  • Delayed dentition, anodontia, hypodontia, or crowding of teeth
  • Low-frequency conductive hearing loss
  • Hypertension
  • Prolonged prothrombin time, elevated platelet counts, and elevated serum phosphorus levels

Emotionally, patients with HGPS share the same feelings as age-matched healthy persons with regard to expressing proper mood and affect. Patients with HGPS are keenly aware of their different appearance and remain reserved in the company of strangers; in the presence of friends, they display affection and good social interaction.

Intelligence is normal.

Physical Examination

The characteristic clinical findings of Hutchinson-Gilford progeria syndrome (HGPS) include abnormalities of the skin and hair in conjunction with characteristic facial features and skeletal abnormalities. [15] The composite appearance of the characteristic facies and parieto-occipital alopecia creates a “plucked-bird” appearance. Evidence of significant growth failure manifests within the first 1-2 years of life and prenatal growth failure is often apparent. [16] The skeletal anomalies are best characterized as a skeletal dysplasia and are thought to be related to microvascular insufficiency and extracellular matrix abnormalities. [16]

Skin and hair findings are as follows:

  • Sclerodermatous skin changes involving the trunk and extremities (see the images below) but sparing the face: These are usually present within the first 6-12 months of life, although they may be present at birth. The skin changes manifest as indurated, shiny, inelastic skin as depicted in the images below. [17]
  • Prominent scalp veins
  • Generalized lipodystrophy with loose, aged-appearing skin: Areas of skin may appear loose, wrinkled, and aged because of the loss of subcutaneous fat, particularly over the hands and feet.
  • Progressive frecklelike hyperpigmentation in sun-exposed areas
  • Hair loss: Scalp hair and eyelashes are progressively lost, resulting in baldness with only a few vellus hairs remaining.

    Sclerodermatous skin changes in Hutchinson-Gilford

    Sclerodermatous skin changes in Hutchinson-Gilford progeria syndrome. This 12-month-old infant with Hutchinson-Gilford progeria syndrome has indurated, shiny skin and mild joint contractures involving the extremities and trunk.

    Sclerodermatous skin changes in Hutchinson-Gilford

    Sclerodermatous skin changes in Hutchinson-Gilford progeria syndrome. This 12-month-old infant has indurated, shiny skin with dyspigmentation.

 Characteristic facies are as follows (see the image shown below):
  • Protruding ears with absent lobes
  • Beaked nose
  • Thin lips with centrofacial cyanosis
  • Prominent eyes
  • Frontal and parietal bossing with pseudohydrocephaly
  • Large anterior fontanel

    Early Hutchinson-Gilford progeria syndrome. Note t

    Early Hutchinson-Gilford progeria syndrome. Note the alopecia, prominent scalp veins, and frontal bossing apparent in this 12-month-old infant with Hutchinson-Gilford progeria syndrome. Midface hypoplasia and micrognathia are less apparent.

Oral and craniofacial anomalies are as follows:

  • Midface hypoplasia with micrognathia
  • Dental anomalies, including hypodontia and delayed dentition [18]
  • Palatal anomalies [18]
  • Stiff auricular cartilage, small or absent lobules, shortened ear canals [19]

Musculoskeletal abnormalities are as follows:

  • Thin limbs with prominent joints
  • Joint contractures and coxa valga with mild flexion of the knees resulting in a wide gait and “horse-riding” stance as depicted in the image below
  • Pyriform (pear-shaped) thorax with short, dystrophic clavicles
  • Bilateral hip dislocations
  • Avascular necrosis of the femoral head

    Enlarged joints, mild flexion contractures, and sc

    Enlarged joints, mild flexion contractures, and sclerodermatous skin changes are seen in this 12-month-old infant with Hutchinson-Gilford progeria syndrome.

Other reported anomalies are as follows:

  • Dystrophic nails
  • Hypertrophic scars
  • Hypoplastic nipples

Causes

Hutchinson-Gilford progeria syndrome (HGPS) is related to aberrant processing of the nuclear envelope protein lamin A and accumulation of a farnesylated, truncated prelamin A (progerin). [20]

 Autosomal dominant mutations in the LMNA gene, located on band 1q21.1-1q21.3, are responsible for most cases of HGPS. De novo mutations associated with advanced paternal age are responsible for most cases, although maternal transmission of a mutant LMNA gene from an asymptomatic mother who manifested somatic and gonadal mosaicism has also been reported. In addition, autosomal recessive transmission has also been suggested to account for the reported development of HGPS in several sets of siblings born to unaffected parents.
The LMNA genes encodes the nuclear A-type lamins, which are type V intermediate filament proteins that localize to the cell nucleus and form the nuclear lamina, a structure that supports the nuclear envelope. They are important in maintaining nuclear stability and organizing nuclear chromatin. The nuclear lamins also play a role in regulating gene expression, DNA synthesis, and DNA repair. [21]
The most common LMNA mutation and the one associated with classical HGPS involves a C–>T transition at nucleotide 1824 (G608G). Note the following:
  • This substitution results in the activation of a cryptic splice donor site in exon 11, which results in a 150-base pair deletion and a truncated lamin A protein, called progerin.
  • The abnormal progerin protein acts in a dominant-negative manner to prevent the normal assembly of nuclear lamins into the nuclear lamina.
  • After translation, the mutant preprogerin protein undergoes normal farnesylation of a CAAX tetrapeptide motif located at the carboxyterminus.
  • The farnesylated preprogerin protein is then incorporated into the nuclear membrane. However, the mutant, truncated protein lacks an important posttranslational processing signal required for cleavage of the preprogerin protein at the carboxyterminus. This cleavage is required for the release of prelamin A from the nuclear membrane, thus allowing its incorporation into the nuclear lamina. The abnormal progerin protein forms insoluble cytoplasmic aggregates.
  • As a result of the absence of lamin A in the nuclear lamina, the cell nuclei from HGPS patients display abnormal nuclear blebbing and aberrant nuclear shapes. Abnormal chromosome segregation and delayed onset and progression of mitosis have also been demonstrated. [22, 23]
 The presence of the homozygous missense mutation G1626C (K542N) in LMNAwas demonstrated in 5 siblings born to asymptomatic, consanguineous carrier parents. This study confirms that autosomal recessive inheritance of HGPS can also occur.
Somatic mosaicism for two different LMNA mutations, c.1968+2T>A and c.1968+2T>C, has been described in a child with an intermediate phenotype. [24]

A transgenic mouse model for HGPS has been created by introducing a splicing defect into intron 9 of the mouse LMNA gene. [25] Transgenic mice display many of the features of HGPS, including loss of subcutaneous fat, decreased bone density, growth failure, craniofacial deformities, skeletal abnormalities, and early death.

 Using microarray analyses, 3 recent studies. [26, 27, 28] compared the gene expression profiles of cultured fibroblasts from patients with progeria with those of healthy people of various ages. In general, changes in gene activity detected in older patients correlated with changes in gene activity in progeria patients.

Of the genes expressed differentially in progeria patients, several that help control mitosis were down-regulated. Many genes that control cell division and DNA or RNA synthesis and processing were also shown to be down-regulated in progeria patients; many of these changes are also seen with normal aging. Some of these changes were postulated to lead to genetic instability and a variety of disturbances in gene function.

 Changes were also seen in the expression of many genes involved in collagen remodeling and the formation of the extracellular matrix. In general, the changes favored excess extracellular matrix deposition, which may lead to the characteristic changes seen in the skin and the vasculature in progeria patients. Expression of transforming growth factor-beta, a factor that regulates tissue homeostasis and whose sustained expression is responsible for tissue fibrosis, is highly up-regulated in patients with progeria.
 The expression of several transcription factors, including many involved in musculoskeletal development, were also decreased in progeria patients. Expression of MEOX/GAX, a negative regulator of cell proliferation in mesodermal tissue, is elevated almost 30-fold in patients with HGPS, suggesting a contributory role in the development of the musculoskeletal abnormalities seen in HGPS.
 A characteristic finding in persons with progeria is an increase in hyaluronic acid excretion. In addition to persons with progeria, it is only detected in those with Werner syndrome, a disease characterized by a later onset of premature aging that occurs during the second decade of life.
 Usually, hyaluronic acid and other glycosaminoglycan production increases during the fifth to seventh decades of life. Possibly, the increase in hyaluronic acid is a normal feature of advancing age. Fibroblasts from patients with progeria show a 3-fold increase in total glycosaminoglycan production and, in particular, hyaluronic acid production, compared with age-matched control groups. This increase results from an abnormality in degradation and is not caused by increased synthesis.

Data from embryonic development suggest that changes in the level of hyaluronic acid are extremely important for morphological development. Experiments performed in chick embryos have demonstrated a correlation between cell differentiation and hyaluronic acid degradation. Hyaluronic acid is also necessary for the morphologic development of blood vessels in chick embryos. A reduction or absence of blood vessels is noted in regions of high hyaluronic acid levels. The decreased density of vasculature, sclerodermatous changes in the skin, and the high prevalence of cardiovascular disease present in persons with progeria may be induced by increased hyaluronic acid levels. Increased hyaluronic acid levels may also promote calcification of blood vessels, thus contributing to arteriosclerosis.

In the past, studies of the link between progeria and aging (among other topics) have investigated the role of fibroblast life span.

 Cells from older donors exhibit a reduced number of cell divisions in comparison to younger donor cells. The reduction of life span in cultured fibroblasts derived from patients with progeria has revealed inconsistent results. A significant reduction in fibroblast life span has been claimed in some studies but has been questioned in later investigations. A recent thorough study indicates the life span of fibroblasts in culture is independent of donor age.

Further abnormalities observed in cultured fibroblasts from patients with progeria include reduced mitotic activity, DNA synthesis, and cloning efficiency and a reduced capacity for DNA repair in cultured progeria fibroblasts after gamma irradiation. Mutant fibroblasts have been shown to demonstrate impaired DNA damage checkpoint signaling, which results in increased DNA double-strand breaks. [29]

Complications

Death due to cardiovascular abnormalities occurs in approximately 75% of HGPS patients. Other causes of death mentioned in the literature include stroke, marasmus, inanition, seizures, and accidental head trauma.

Diagnostic Considerations

Werner syndrome (pangeria) findings are as follows:

  • Onset age of 15-30 years
  • Prematurely aged appearance
  • High-pitched voice
  • Beak-shaped nose
  • Sclerodermatous skin
  • Immature sexual development
  • Cataracts
  • Hypogonadism
  • Arteriosclerosis: Complications of arteriosclerosis reduce life expectancy to the fifth decade.
  • RECQL2 (a DNA helicase gene) mutations

Acrogeria (Gottron type) findings are as follows:

  • Onset occurring up to age 6 years
  • Premature aging of extremities
  • Cutaneous atrophy and subcutaneous wasting of the face and extremities
  • Hair unaffected
  • No atherosclerosis or systemic disease

Rothmund-Thomson syndrome findings are as follows:

  • Onset age of 3-6 months
  • Cataracts
  • Poikilodermatous skin changes
  • Premature graying of the hair and/or alopecia
  • Increased photosensitivity
  • Short stature
  • Microcephaly
  • Hypogonadism
  • RECQL4 (a DNA helicase) mutations

Cockayne syndrome findings are as follows:

  • Onset during second year of life
  • Marked loss of subcutaneous fat
  • Growth failure
  • Increased photosensitivity
  • Ocular abnormalities (eg, optic atrophy, pigmentary retinopathy)
  • Microcephaly
  • Ataxia and progressive mental deterioration
  • Disproportionally large hands and feet
  • Protruding ears
  • Sensorineural hearing loss

Seckel syndrome findings are as follows:

  • “Bird-head” facies
  • Dwarfism
  • Trident hands
  • Skeletal defects
  • Hypodontia
  • Hypersplenism
  • Premature graying
  • Stiff skin syndrome
  • Diffuse progressive hardening of the skin, usually starting in the gluteal region, beginning at birth or early infancy
  • Joint contractures
  • Hypertrichosis
  • Hyperpigmentation
  • Increased cutaneous (but not systemic) mucopolysaccharide levels
  • In the autosomal recessive Paraná type, severe growth retardation and respiratory insufficiency leading to early death
  • Congenital fascial dystrophy
  • Diffuse, progressive hardening of the skin, usually starting in the gluteal region, beginning at birth or early infancy
  • Joint contractures
  • No systemic disease
  • Histologically, abnormally thickened fascia along with giant amianthoidlike fibrils and myofibroblasts
  • Restrictive dermopathy
  • Profound intrauterine growth retardation
  • Severe arthrogryposis (joint contractures)
  • Diffuse skin hardening
  • Pulmonary hypoplasia
  • Characteristic facies
  • Lethal in neonatal period
  • LMNA or ZMPSTE24 mutations

Wiedemann-Rautenstrauch syndrome findings are as follows [30] :

  • Onset at birth
  • Pseudohydrocephalus with wide sutures
  • Triangular facies
  • Aged appearance
  • Growth retardation
  • Generalized lack of subcutaneous fat
  • Prominent scalp veins
  • Sparse hair

DeBarsy syndrome findings are as follows:

  • Onset at birth
  • Aged appearance
  • Joint laxity
  • Loose, wrinkled skin
  • Hypotonia
  • Developmental delay
  • Ocular abnormalities (eg, strabismus, cataracts, myopia)

Berardinelli-Seip syndrome findings are as follows:

  • Onset at birth
  • Decreased subcutaneous fat/lipodystrophy
  • Pseudohypertrophy of muscles
  • Acanthosis nigricans
  • Hyperinsulinemia
  • Acromegaloid appearance
  • Hypertriglyceridemia

Donahue syndrome (leprechaunism) findings are as follows:

  • Onset at birth
  • Elfin facies
  • Hyperinsulinemia
  • Failure to thrive
  • Hypertrichosis
  • Acanthosis nigricans
  • Decreased subcutaneous fat
  • Loose skin
  • Prominent nipples
  • Insulin receptor gene mutation

GAPO (growth retardation, alopecia, pseudoanodontia, optic atrophy) syndrome findings are as follows:

  • Onset age of 1-2 years
  • Growth retardation
  • Alopecia
  • Pseudoanodontia
  • Optic atrophy
  • Craniofacial dysmorphism
  • Coarse facies
  • Aged appearance
  • Joint laxity
  • Loose skin

Hallermann-Streiff syndrome findings are as follows:

  • Onset at birth
  • Brachycephaly
  • Mandibular hypoplasia
  • Beaked nose
  • Alopecia
  • Cutaneous atrophy of the face and scalp
  • Ocular abnormalities (eg, cataracts, nystagmus, microphthalmos)
  • Dental anomalies

Familial mandibuloacral dysplasia findings are as follows:

  • Onset age of 3-5 years
  • Alopecia
  • Beaked nose
  • Premature loss of teeth
  • Acroosteolysis
  • Dysplastic clavicles
  • Atrophy of extremity skin
  • Mandibular hypoplasia
  • Delayed cranial suture closure
  • LMNA mutations

Differential Diagnoses

Laboratory Studies

Abnormalities in serum lipid levels are limited to low high-density lipoprotein levels, which are associated with atherosclerotic disease. Serum low-density lipoprotein and total cholesterol levels are normal in patients with Hutchinson-Gilford progeria syndrome (HGPS).

Elevated levels of hyaluronic acid excretion are seen in the urine of patients with HGPS but are not diagnostic. The significance is unknown.

Imaging Studies

Radiography findings usually begin to manifest within the first or second year of life and most commonly involve the skull, thorax, long bones, and phalanges. [16, 31]Typical findings are as follows:

  • Generalized osteopenia
  • Acroosteolysis (distal bone resorption) of the phalanges and distal clavicles
  • Pseudoarthrosis of the distal clavicle
  • “Fish-mouth” vertebral bodies
  • Coxa valga and hip dysplasia
  • Attenuated cortical bone
  • Widened metaphyses, epiphyseal overgrowth, and narrow diaphyses
  • Avascular necrosis of the femoral head
  • Focal concave cortical defects at or near to the insertion of a major muscle group
  • Dystrophic calcification, typically distal to the tufts of the fingers
  • Normal bone age
 Use of CT and MRI has identified a spectrum of craniofacial structural bone and soft tissue abnormalities. [32] Common craniofacial abnormalities seen in progeria include the following:
  • J-shaped sella
  • Increased calvarial vascular markings
  • Abnormal mandibular condyles
  • Hypoplastic articular eminences
  • Small zygomatic arches
  • Prominent parotid glands
  • Optic nerve kinking

Brain magnetic resonance angiography may identify cerebrovascular occlusive disease. Features of a distinct vasculopathy may be seen, including intracranial steno-occlusive arterial lesions, basal cistern collateral vessels, and slow compensatory collateral flow over the cerebral convexities; vertebral artery stenosis with stenosis and calcification of both the cervical internal and common carotid arteries; and high percentage of both early symptomatic and clinically silent infarcts.

Other Tests

Serial ECG and echocardiography should be performed to monitor for coronary artery disease and congestive heart failure.

Histologic Findings

Skin biopsy specimens from firm, sclerotic areas reveal the characteristics of scleroderma.

 In the early stages, the epidermis appears moderately acanthotic with some effacement of the rete ridges. Thickened collagen bundles may be seen in the dermis. Progressive deposition of thickened, homogenized collagen that extends into the subcutaneous tissue is observed. In the upper dermis, a mild perivascular infiltrate may be observed. The amount of acid mucopolysaccharides is increased.
 At later stages, the subcutaneous fat is greatly reduced, except for some sparse fat lobules surrounded by connective tissue. Hyalinized dermal collagen is prominent. Blood vessels exhibit a moderate thickening of the muscle wall with a narrowing of the vascular lumen. Hair follicles may appear atrophic.

Approach Considerations

Pharmacologic approaches to the treatment of Hutchinson-Gilford progeria syndrome (HGPS) may involve attempts to reduce the expression or accumulation of progerin and promote autophagy.

Medical Care

To date, there is no approved therapy for HGPS.

 In vitro, exposure of cultured HGPS fibroblasts to rapamycin, a macrolide antibiotic that has been shown to regulate aging-related cellular pathways, and its analog temsirolimus, has been demonstrated to prevent or reverse nuclear blebbing, retard cellular senescence, enhance autophagic degradation of progerin, and delay the development of cellular senescence, suggesting that it may be a useful therapy for children with progeria. [34, 35, 36, 37, 38] The addition of all-trans retinoic acid to low-dose rapamycin reduces the expression of progerin and prelamin A in cultured fibroblasts and suggests an additional pharmacologic treatment for progeria. [39]
Careful monitoring for cardiovascular and cerebrovascular disease is essential. The use of low-dose aspirin is recommended as prophylaxis against cardiovascular and cerebrovascular atherosclerotic disease.

Physical and occupational therapy can help to maintain physical activity and an active lifestyle. The use of hydrotherapy may be particularly effective in improving joint mobility and minimizing symptoms of arthritis.

 Infants with HGPS may exhibit poor feeding. Provision of adequate nutritional intake may require placement of a gastrostomy tube for supplemental enteral feeding. In older children, the daily consumption of high-energy supplements is recommended, along with careful monitoring of growth and nutrition.

The use of growth hormone has been used to decrease catabolic demands and augment weight gain and linear growth in a small number of patients with progeria.[40]

 Sulforaphane, an antioxidant derived from cruciferous vegetables, has been demonstrated to stimulate proteasome activity and autophagy in cultured HGPS fibroblasts, to enhance progerin clearance by autophagy, and to restore a normal cellular phenotype. [41]
In vitro studies also suggest a possible role for the use of farnesyltransferase inhibitors (FTIs) in HGPS. [42] FTIs appear to promote the release of the mutant prelamin A (preprogerin) from the nuclear membrane, allowing it to be correctly incorporated into the nuclear lamina, thus correcting the structural and functional nuclear defects, although it remains to be determined whether use of FTIs also has an effect on the abnormalities seen in HGPS that result from loss of normal lamin A function.

In vivo studies using FTIs in transgenic mouse models have demonstrated encouraging results with regards to prevention of the cardiovascular complications seen in progeria [43] as well as reversal of the cutaneous manifestations [44] and overall improvement in many of the phenotypic features of progeria, including increased longevity. [45, 46]

 Treatment of transgenic mice expressing progerin in the epidermis with FTI-276, a farnesyltransferase inhibitor, or a combination of pravastatin, a lipid-lowering agent, and zoledronic acid, an agent used to increase bone mineral density, has been shown to reverse the morphological nuclear abnormalities that are seen in HGPS.[47]

Results from a clinical trial of lonafarnib, an FTI, in progeria have indicated that treatment with lonafarnib may improve weight gain, increase bone mineral density, reduce vascular stiffness, and result in improved sensorineural hearing in patients with progeria. [48] Lonafarnib treatment has also been shown to reduce the frequency of clinical stroke, headaches, and seizures. [49]

 Results from a clinical trial that combined use of lonafarnib with two additional protein farnesylation inhibitors, pravastatin and zoledronic acid, demonstrated increased bone mineral density without any additional cardiovascular benefit as compared with lonafarnib monotherapy. [50]

Preliminary in vitro studies using transfection of modified oligonucleotides that target the cryptic splice site that occurs in patients with the common 1824C–>T mutation have also produced encouraging results. Transfection of an exon 11 antisense oligonucleotide reduced lamin A expression in wild-type mice and progerin expression in an HGPS mouse model. [51] By eliminating the production of the mutant LMNA mRNA and protein, normal nuclear morphology is restored, with resultant normalization of heterochromatin structure and gene expression. These nascent studies provide early support for the rationalization of genetic therapy for HGPS patients.

 In vitro, use of rapamycin, a macrolide antibiotic, and its analog temsirolimus, has been demonstrated to prevent nuclear blebbing, enhance autophagic degradation of progerin, and delay the development of cellular senescence, suggesting that it may be a useful therapy for children with progeria. [34, 35, 36, 37, 38]
 Patients, families, and physicians may obtain further information, including opportunities for possible enrollment in clinical trials, through the Progeria Research Foundation.

Consultations

Appropriate care for children with HGPS requires coordinated care from several specialists.

 Pediatric cardiologists provide regular assessment of cardiovascular status, including monitoring and treatment for early atherogenic cardiac disease.

Physical and occupational therapists can develop individualized physical therapy programs to help to maintain physical activity, coordination, and flexibility.

 Dermatologists and/or geneticists may be the first specialists to evaluate an infant with suspected HGPS and can perform diagnostic testing, including genetic mutation analysis and skin biopsies, as needed.

Pediatric gastroenterologists, feeding therapists, and nutritionists can aid in diagnosing and treating feeding disorders and failure to thrive.

 Pediatric dentists with experience in treating children with dental anomalies can be helpful. Routine fluoride supplementation should be provided to minimize the risks of dental caries. Regular, gentle dental care minimizes the development of periodontal disease.

Diet

Infants and children with HGPS may experience feeding difficulties and failure to thrive. The use of age-appropriate nutritional supplements is recommended.

Activity

Children with HGPS do not require activity restrictions. With adequate supervision, most children are able to experience a wide range of physical activities.

Guidelines Summary

There are currently no peer-reviewed clinical guidelines for the management of Hutchinson-Gilford progeria.

The Progeria Research Foundation published The Progeria Handbook for parents and clinicians in 2010. It is available through the Progeria Research Foundation.

References:

 

A Woman with Hyponatremia.


What are some of the clinical and laboratory findings associated with primary adrenal insufficiency?

Hyponatremia can occur in all forms of adrenal insufficiency, although it tends to occur most prominently in primary adrenal insufficiency (Addison’s disease). Primary adrenal insufficiency is caused by impairment of the adrenal glands, whereas secondary adrenal insufficiency is the result of corticotropin deficiency caused by either pituitary or hypothalamic disease. A Case Record of the Massachusetts General Hospital explains.

Clinical Pearl

  • What is the most common cause of primary adrenal insufficiency in high-income countries?

Primary adrenal insufficiency is a rare entity, and in high-income countries, autoimmune adrenalitis is the most common cause.

Clinical Pearl

  • Do patients with adrenal insufficiency have a normal life expectancy?

Patients with adrenal insufficiency have a mortality rate that is 2 or 3 times the normal rate, and they have an increased incidence of certain cancers. Morbidity is considerable. Patients often have absences from school or work, frequent hospitalizations, and alterations in work life, social life, family life, and physical activity.

Morning Report Questions

Q: What are some of the clinical and laboratory findings associated with primary adrenal insufficiency?
A: The signs and symptoms are nonspecific and include fatigue, dizziness, gastrointestinal illness, salt craving, and hyperpigmentation. Hyperpigmentation is almost always present in chronic primary adrenal insufficiency. There are also some case reports of chronic primary adrenal insufficiency in which hyperpigmentation is absent, most likely because there are adequate resting levels of plasma cortisol, which would prevent increased corticotropin secretion and subsequent melanocyte stimulation. Among patients with adrenal insufficiency, hyperkalemia occurs only in those with the primary form, owing to the aldosterone deficiency. Hyperkalemia occurs in only 50 to 60% of patients with primary adrenal insufficiency, perhaps because of aldosterone-independent regulatory mechanisms in the distal nephron that maintain eukalemia. A fraction of patients with adrenal insufficiency have a peripheral eosinophilia.

Figure 1. Laboratory Abnormalities in Primary Adrenal Insufficiency.

 

Q: How sensitive is the 21-hydroxylase antibody test for autoimmune adrenal insufficiency?
A: A 21-hydroxylase antibody test is approximately 60 to 75% sensitive, so a positive test would indicate an autoimmune cause, but a negative test does not rule it out. Other antibodies have been identified in patients with autoimmune primary adrenal insufficiency, such as antibodies against the steroid 17α-hydroxylase and side-chain cleavage enzymes. These tests are not widely available and are not specific.

Source:nejm.org

Miniature brain and skull found inside 16-year-old girl’s ovary.


Appendix surgery
A very unusual teratoma was discovered during appendix surgery

A tumour containing a miniature brain has been found growing on the ovary of a 16-year-old girl in Japan.

The 10-centimetre-wide tumour was discovered when the girl had surgery to remove her appendix. When doctors cut the tumour out, they found clumps of greasy, matted hair inside, and a 3-centimetre-wide brain-like structure covered by a thin plate of skull bone.

Closer analysis revealed that it was a smaller version of a cerebellum – which usually sits underneath the brain’s two hemispheres. A mass on one side resembled a brain stem – the structure that normally joins to the spinal cord.

 Monsters within

About one-fifth of ovarian tumours contain foreign tissue, including hair, teeth, cartilage, fat and muscle. These tumours, which are normally benign, are named teratomas after the Greek word “teras”, meaning monster.

Although the cause of ovarian teratomas is unknown, one theory is that they arise when immature egg cells turn rogue, producing different body parts.

Brain cells are often found in ovarian teratomas, but it is extremely unusual for them to organise themselves into proper brain-like structures, says Masayuki Shintaku at the Shiga Medical Centre for Adults in Japan, who studied the tumour.

Angelique Riepsamen at the University of New South Wales in Australia, agrees. “Neural elements similar to that of the central nervous system are frequently reported in ovarian teratomas, but structures resembling the adult brain are rare.”

The miniature brain even developed in such a way that electric impulses could transmit between neurons, just like in a normal brain, says Shintaku.

Brain confusion

The girl didn’t experience any symptoms, neurological or otherwise. However, there have been a handful of reports worldwide of women with ovarian teratomas who have developed personality changes, paranoid thoughts, confusion, agitation, seizures or memory loss.

Some of these neurological symptoms can arise when the immune system recognises brain cells in the ovary as foreign and launches an attack, because cells in the woman’s real brain can end up being attacked as well, leading to inflammation.

These symptoms can usually be stopped by removing the tumour.

The 16-year-old girl has had the tumour removed without any complications and she has recovered well.

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