Golder N. Wilson, MD, PhD

 A 16-year-old girl visits her obstetrician for her first prenatal visit. Her genetic history questionnaire notes that her mother has chronic fatigue syndrome with arthritis, migraines, and irritable bowel syndrome. Her mother also has anxiety disorder and is viewed by the family as a hypochondriac. The obstetrician notes joint hypermobility and unusual skin elasticity on examination (

) and tells the girl that he would like her to see a cardiologist even though she has never had signs or symptoms of heart disease.

 Digital extension (A) and joint hypermobility (B); skin elasticity (C) with “cigarette-paper”

 A 12-year-old girl is evaluated by an orthopedist because of frequent fractures and dislocations, particularly affecting her left knee that prevent her from participating on an elite soccer team. She was a “rubber-band” baby according to her mother, able to hold her bottle with her feet and often sitting in the “W” position. She required glasses for myopia at age 4 and will be starting orthodontic treatment for crowded teeth. She was delayed in her motor milestones and was very clumsy, with many falls when learning to walk. She can “pop” many of her joints and shows off by turning her elbows completely anterior and joining her hands, one over her shoulder, the other around her back. She has had 6 fractures of her wrists, elbows, and ankles, and frequently sprains her ankles.

 (D) or keloid (E) scars; pectus and scoliosis due to skeletal flexibility and deformation (F)


Examination shows soft skin; a white scar with fine wrinkles over a site of fracture repair (

); and joint hypermobility, including the ability to bend her fingers back over 90 degrees and to touch her palms to the floor. She also had scoliosis of 8 degrees (

). X-rays films of her knees show lax ligaments and an area of dead bone on her lower left tibia; her hips show some joint erosion.

 A 2-year-old boy is evaluated by a pediatrician for motor delays because he is only now beginning to walk. He has a broad based and wobbly gait, prompting concern about a myopathy. Speech is normal. His physical examination seems otherwise normal except for many violaceous plaques over pressure points and some scars with purplish edges on his forehead, elbows, forearms, and knees (eg, 

). His mother says he is very clumsy and falls frequently, and has required stitches on several occasions. She seems very intense and begins relating her own health problems, which have included disabling back and joint pain with need for vertebral fusion; dizziness on standing with occasional syncope, hypotension, and fatigue; abdominal pain with constipation or diarrhea (diagnosed as gastroparesis); frequent migraines that she attributes to poor circulation because she has Raynaud phenomenon and pooling with discoloration in her pelvic area; metrorrhagia with endometriosis that led to hysterectomy after her son’s birth. Prior physicians raised concern about maternal mental illness and child abuse, but this pediatrician ascertains that the boy was premature and diagnoses a familial illness.  

To what common diagnosis do these disparate symptoms and findings point?

(Answer and discussion on following page.)

All of these patients exhibit signs and symptoms of connective tissue dysplasia or weakness caused by various degrees of Ehlers-Danlos syndrome (EDS).

It is important to recognize EDS in pregnant women (

) so as to anticipate such complications as premature delivery, postpartum hemorrhage, cardiac valve leakage, and uterine or bladder prolapse. Hypermobility (

) are key features, heralding a broad range of potential medical complications (

) illustrated by the early myopia, orthodontic needs, frequent fractures/dislocations (

), and migraines, irritable bowel syndrome, and orthostatic symptoms (

. Many of these complications can be avoided or ameliorated by anticipatory guidance.

Awareness of these diverse manifestations is required for proper interpretation of the family history (usually autosomal dominant inheritance) and appropriate diagnosis of disabling conditions rather than dismissal as hypochondriasis or mental illness (eg, for the mother of 

). Chronic joint pain and the dizziness/fatigue of paroxysmal orthostatic tachycardia syndrome (POTS) can lead to depressive symptoms, just as frequent mitral valve prolapse can lead to panic attacks and anxiety.

 clearly has EDS, and this is the basis for her son’s prematurity, motor delay, frequent falls/poor coordination from lax joints, and multiple scars. Concerns about myopathy or developmental disability for her son can thus be allayed when his delay in walking is attributed to EDS.

The spectrum can be remembered by the comments of a patient relayed by Dr. Peter Beighton, a pioneer and leader in the field: “When I was a baby they called me a floppy infant, and now the doctors tell me that I am a loose woman.”

The Broad Clinical Spectrum of Connective Tissue Dysplasia

Although Marfan syndrome and severe forms of EDS (eg, EDS type IV) are viewed as rare diseases, patients with the broader spectrum of connective tissue dysplasia/EDS are commonly encountered in pediatric, obstetric, and primary care.

 Connective tissue dysplasia refers to congenital structural deficiency rather than the acquired, inflammatory changes of autoimmune connective tissue/ “collagen vascular” disease (eg, lupus or scleroderma). However, the chronic wear-and-tear joint/vascular injuries of connective tissue dysplasia may overlap with joint inflammation in susceptible individuals. The author has recently seen patients with EDS symptoms who presented with HLA B27-positive ankylosing spondylitis.

Signs and symptoms of EDS can affect the face, eyes, dentition, heart, bones, joints, skin, or vasculature (migraines, irritable bowel syndrome, POTS) and are summarized in the 

 Severe forms like Marfan syndrome or EDS type IV are prototypes with extreme complications that are paralleled by milder findings in the more common types.

 The severe aortic dilatation/dissection or anterior disc herniation of Marfan syndrome is echoed by milder aortic root prominence, valve prolapse, or frequent disc herniation and the uterine/bowel ruptures of EDS IV are mimicked by endometriosis/metrorrhagia and abdominal pain/irritable bowel syndrome seen in many EDS patients.

Informed interpretation of the family history will often reveal affected males and females; this suggests autosomal dominant inheritance with variable expression that produces a remarkable variety of symptoms in the same family. As with other dominantly inherited conditions, patients with EDS may present as a new mutation without any family history of disease-this absence of family history also occurs with rarer, recessive forms.

Affected individuals usually have one normal and one abnormal allele. The abnormal allele produces a mutated connective tissue protein that has altered shape. The resulting connective tissue “walls” are then constructed from square and curved bricks, producing wobbly structures that are weaker, more deformable, and subject to tearing, hemorrhage, or fracture. Genetic testing initially displayed the altered proteins as with the type I collagens in osteogenesis imperfecta; it then progressed to gene (DNA) diagnosis that is now fairly sensitive for fibrillin mutations in Marfan syndrome. However, the multiple types and at least 30 genes involved in the EDS spectrum do not allow sensitive testing although analysis of selected genes is listed on commercial catalogues. The physician must depend on clinical diagnosis from family and medical history, supplemented by the Beighton score for hypermobility (bending the fingers back, touching hands to floor, etc.) and physical findings like those in the Figures or Table.

Although EDS is classically grouped into types, these are not yet well-correlated with specific molecular mutations or discrete symptoms, and it is more important for the generalist to recognize EDS as a spectrum with multiple clinical implications.

 with hypermobility might be classified as types II or III, while most patients have the broad, variable symptoms of type I EDS, like the mother in 

. Joint hypermobility occurs in children with underlying hypotonia or as a general feature of conditions like achondroplasia where it produces motor delays without cognitive problems, as in 

Other rare disorders fall into the connective tissue category, including Marfan syndrome, homocystinuria, or osteogenesis imperfecta.

 Recent molecular studies of Loeys-Dietz syndrome have placed the transforming growth factor-beta receptor within the fibrillin pathway and joined its well-known inhibitor (the antihypertensive medicine Losartan) with beta-blockers as treatments for aortic root enlargement.

This diversity of genetic causes emphasizes that hypermobility is a multifactorial trait, occurring in healthy people but worthy of medical evaluation when extreme or associated with other symptoms. It is common to find individuals with EDS symptoms on both sides of the family; this supports the interaction of several gene mutations in many EDS patients and suggests that comprehensive molecular analyses foretold by exome sequencing will reveal many more EDS types than are listed in current classifications.

Clinical recognition is paramount because it allows life-enhancing and life-saving strategies.

 Restriction from contact or collision sports is needed for individuals with severe forms of EDS or Marfan who have aortic root enlargement. Emphasis on childhood joint protection can lessen adult arthritis and prevent end-states like fibromyalgia or chronic fatigue syndrome; even teenagers or young adults can become inactive and dysfunctional when faced with chronic pain or cardiogenic lethargy. Weight loss and moderate weight-training can lessen joint load and enhance muscular protection of lax joints. Activities such as swimming as opposed to jogging or cross-country running can lessen joint damage, as can braces on extremity joints with vigorous exercise.

Treatment of frequent sprain/dislocations with RICE (Rest, Ice, Compression, Elevation) and education for individuals to “keep in touch” with their joints will preserve necessary function and activity. Alertness for dizziness on standing, sudden fainting, sensitivity to overheating (particularly after showers), and salt-craving can identify POTS symptoms that respond to hydration/saline or even fludrocortisone/beta-blocker therapies. Attention to hydration and bland diets, even gluten exclusion, also diminishes GI symptoms of hypomotility. Recognition of EDS in children often serves as important therapy for parents and other relatives, because it explains the child’s diverse and disabling symptoms and rescues them from diagnoses like hypochondriasis, psychogenic illness, or malingering.

 Steinmann B, Royce PM, Superti-Furga A. The Ehlers-Danlos syndrome. In: Royce PM, Steinmann B, eds. 

Connective Tissue and Its Heritable Disorders.

  Adib N, Davies K, Grahame R, et al. Joint hypermobility syndrome in childhood. A not so benign multisystem disorder? 

 Volkov N, Nisenblat V, Ohel G, et al. Ehlers-Danlos syndrome: insights on obstetric aspects. Obstet Gynecol Survey. 2007;62:51-57.


 Beighton P, De Paepe A, Steinmann B, et al. Ehlers- Danlos syndromes: revised nosology, Villefranche 1997. 

 Wilson GN, Cooley WCC. Connective tissue disorders. In: 

Preventive Health Care for Children with Genetic Conditions. Providing a Primary Care Medical Home.

 2nd ed. Cambridge: Cambridge University Press, 2006; 413-436.


 Numbers following the disorder access the relevant entry in Online Mendelian Inheritance in Man. 

. EDS type I classical (130000); EDS type II classical (130010); EDS type III hypermobility (130020) EDS type IV vascular (225400); EDS type VI ocular-scoliosis (229200); EDS type VIIA, B arthrochalasis (130060); EDS type VIIC dermatosparaxis (225410); EDS type VIII periodontal (130080).


Marfan syndrome (154700); homocystinuria (236300) osteogenesis imperfecta (166210); Beals contractural arachnodactyly (121050); Loeys-Dietz syndrome (609192);  Pseudoxanthoma elasticum (264800) Stickler syndrome (108300); Larsen syndrome (150250).


Pyeritz RE. A small molecule for a large disease. 

 Eisenstadt L. What is exome sequencing? 

www.broadinstitute.org/blog/what-exome-sequencing

Articles

Digital extension; joint hypermobility; skin elasticity with keloid scars; pectus and scoliosis from skeletal flexibility and deformation; these disparate symptoms and findings point to what diagnosis?

Unusual Skin Elasticity, Joint Hypermobility, Violaceous Plaques in 3 Different Patients: What’s Your Diagnosis?

You have been following a 9-month-old with low muscle tone, delayed motor milestones, and failure to gain weight. Her family and gestational histories are normal except that her mother was 38 at the time of pregnancy; the child has 4 healthy siblings. The delivery was complicated by long labor and resuscitation was required, with NICU treatment for meconium aspiration. The newborn had significant hypotonia that necessitate tube feeding for a few days, but she was able to bottle-feed by the time of NICU discharge at age 7 days.

Current measurements show a length at the 10th centile for age, a weight just below the 3rd centile, and a head circumference also below the 3rd centile. You have watched her slow weight gain without prompting evaluation because it has paralleled the growth curve, and you have followed sluggish motor milestones with rolling back to front at 4 months and sitting at 8 months. She has appeared alert with good interaction and babbling.

The pictures show a slightly unusual facial appearance, with almond-shaped eyes, down-turned corners of the mouth, and bitemporal hollowing. She also has somewhat unusual genitalia with a question of hypoplastic labia that make the clitoris easily visible.

Should you:
A. Initiate referral at this time, and to which subspecialty?
B. Suspect any particular diagnosis?
C. If there is a likely diagnosis, what diagnostic test would confirm it?

(Please click here for answers and discussion.)


A. Referral for developmental concerns is always a judgment call, but the subtle dysmorphology in this case might prompt referral to pediatric genetics rather than neurology or developmental pediatrics.  

B. Although hypotonia has a huge range of central and peripheral neuromuscular causes, the early hypotonia, facial changes, and hypogonadism suggest the diagnosis of Prader-Willi syndrome. The “advanced” maternal age is likely coincidental although it can be associated with trisomy 15 conception with loss of father’s 15 chromosome to cause uniparental disomy.  

C. About 60% of children with Prader-Willi syndrome have a microdeletion of chromosome 15 on the homologue that was inherited from father. The remainder have other deficiencies of paternal imprinting, either inheriting 2 copies of mother’s 15 (uniparental disomy) or a paternal chromosome 15 that did not acquire the male imprint (abnormal DNA methylation). The Prader-Willi DNA methylation test will detect all 3 causes of Prader-WIlli or its complement-the failure of female chromosome 15 imprinting known as Angelman syndrome.


Prader-Willi syndrome, first reported in 1956, is also referred to as Prader-Labhart-Willi syndrome  or asthe hypotonia-hypomentia-hypogenitalism-obesity (HHHO) syndrome.

It has an incidence of 1 in 16,000 to 25,000 births, usually sporadic (isolated cases).

 Approximately 70% of patients have microdeletion of chromosome 15, while the remaining 30% have either uniparental disomy for the maternally derived chromosome 15 or a failure of genomic imprinting. The latter is a mechanism for gene regulation that ensures complementary expression of genes on the maternal and paternal homologues of each chromosome pair.  

Deletion may be demonstrated by targeted fluorescent in situ hybridization (FISH) testing showing a missing signal on one chromosome 15. Alternatively, one may order routine chromosomes with reflex to (proceed if prior test normal) array-comparative genomic hybridization (aCGH-also known as microarray analysis or CMA) to demonstrate any subtle deletion or duplication (eg, those for DiGeorge, Williams, Prader-Willi, etc). The Prader-WIlli/Angelman DNA methylation test will detect altered methyl patterns in all 3 types of Prader-Willi (or Angelman) syndrome, whether the altered pattern is due to deletion on the paternal 15 homologue, two copies of mother’s 15 homologue (uniparental disomy), or failure of father’s 15 homologue to be properly imprinted. Parental recurrence risks are usually very low (less than 1 in 1000) and parental studies are not required unless rare translocation of the 15q11 region is found.

Clinical diagnosis of Prader-Willi syndrome should be suspected in neonates with hypotonia and hypogonadism, although the latter may be subtle in females.

The facial changes reflect the degree of hypotonia, with bitemporal hollowing and down-turned corners of the mouth. The almond-shaped eyes may help with recognition, but the diagnosis is missed in many infants until the remarkable hyperphagia manifests between 1 and 6 years.  

Early differential diagnosis includes myopathies that may be distinguished by abnormal CPK levels and nerve-muscle studies. Later differentials may include other conditions with obesity and developmental delay (Bardet-Biedl with polydactyly, Cohen with prominent incisors and eye changes, Simpson-Golabi-Behmel with its “bulldog” facies). However, the remarkable hyperphagia of Prader-Willi syndrome is unique.  

Consensus diagnostic criteria include neonatal/infantile hypotonia with its associated facial features, infantile feeding problems, excessive weight gain between ages 1 to 6 years, hypogonadism, global developmental delay/mental disability, and hyperphagia/food obsession.

 Other findings include short stature with small hands and feet, pale hair and complexion (in the deletion form), obstructive or central sleep apnea, strabismus; thick and stringy saliva; recurrent picking at the skin to cause sores and infections, speech articulation problems, and stubborn behaviors with affinity for working puzzles.


Attention to infantile “failure to thrive” is important since the weak suck and thick saliva pose challenges for feeding. The most critical issue is family counseling once the hyperphagia appears because unrestrained eating will lead to early death from morbid obesity. The voracious appetite reflects altered hypothalamic response to satiety, and these patients never feel full. Abnormal eating behaviors include stealing food, nocturnal foraging for food, eating inappropriate foods, and binge eating. The challenge can be summarized as “cherchez la grandmere,” since well-intentioned relatives often cannot resist a hungry child and undermine parental restraints. Nutritional counseling of the entire family is needed with dramatization of calories as death-a team approach involving nutritionists and behavioral modification strategies is often needed, ranging from rewards for weight maintenance to strategies like locking refrigerators or restricting movements at night. Even with the best of counseling, some parents decide to take chances with morbid obesity rather than constantly disappointing a moderately impaired and always hungry child.

Other complications include strabismus that may relate to the oculocutaneous albinism that occurs in deletion patients (a pink gene causing hypopigmentation resides in the Prader-Willi deletion region). Increased dental caries and enamel hypoplasia may reflect frequent high-carbohydrate diets, thick saliva , and rumination (10% of 17% of patients) in Prader-Willi syndrome.

 Anesthesia includes risks of aspiration pneumonitis, cor pulmonale, temperature instability, and cardiac arrhythmias.

Hypogonadotrophic hypogonadism with irregular menses and infertility joins hyperphagia, disruption of the sleep cycle, and temperature instability as evidence of hypothalamic dysfunction. Diabetes mellitus (5% to 15%) accompanies cardiopulmonary and sleep disturbances secondary to obesity.

Behavior problems include violent outbursts, temper tantrums, obsessive-compulsive behavior, rigidity, manipulation, and stubbornness in young children. Autistic behaviors occur in 19% of children with deletion and 38% of those with uniparental disomy. Older children and adults exhibit depression and a “refusal-lethargy syndrome” of hyperkinesis, manipulative refusal of food and drink, and deliberate soiling. These may be exacerbated by daytime fatigue due to obstructive or central sleep apnea. Developmental disabilities are usually moderate: the ability to sit occurs at an average age of 12 to 13 months, walking at 24 to 30 months, and riding a tricycle at 4.2 years.

Cognitive functions include single words appearing at 21 to 23 months and sentences at a mean of 3.6 years. Articulation defects with nasal speech occur. Reading is a relative strength; mathematics and social interactions are weaknesses. A global IQ above 70 occurs in 40% of patients.

After diagnosis, a referral to ophthalmology and endocrinology/nutrition can optimize vision. Counsel for weight control and consider growth hormone therapy (as early as age 2) to enhance stature and muscle strength.

Developmental-behavioral pediatricians can help coordinate early childhood intervention and preschool therapies, assisting with autism assessment, eating behavior modification, and medication management.  

The parent association and its website provide an important resource for Prader-Willi families and their physicians.

References
1. Holm VA, Cassidy SB, Butler MG et al.  Prader-Willi syndrome: Consensus diagnostic criteria. 

Preventive Health Care for Children with Genetic Condition: Providing a Medical Home.

 2nd ed. Cambridge: Cambridge University Press, 2006:241-246.

3. Prader-Willi Syndrome Association USA. 

4. Veltman MW, Craig EE, Bolton PF. Autism spectrum disorders in Prader-Willi and Angelman syndromes: a systematic review. 

Low muscle tone, delayed motor milestones, and failure to gain weight. The mother was 38 at the time of delivery, but nothing else is noteworthy about this 9-month-old.

Infant with Hypotonia, Hypogonadism, and Developmental Delay

A 6-month-old boy with 1-week history of dry cough that worsened at night. He had been wheezing off and on for the past month and had visited the emergency department on one occasion. He had also vomited 4 times in the past 24 hours but had been drinking and eating well. He had no fever. His 2-year-old sister was also sick with cough and diarrhea. Infant lived with an aunt who smoked.

Birth history included mild neonatal jaundice that resolved and a small ventricular septal defect and patent foramen ovale that have been monitored by cardiology.

Temperature was 36.5ºC (97.7ºF); heart rate, 120 beats per minute; respiration rate, 40 breaths per minute with moderate distress; capillary oxygen saturation, 97% on room air. Length at the 10th percentile, weight between the 10th and 25th percentile. Eyes, tympanic membranes, and pharynx normal. Mucous membranes moist and tears present. Chest examination demonstrated subcostal and intercostal retractions. Auscultation revealed good air exchange bilaterally with no rales, but with diffuse wheezing and a grade 2 early systolic ejection murmur over the precordium. Rapid respiratory syncytial virus (RSV) test results negative.

A 2-year-old girl with severe nighttime cough, congestion, and fever (temperature up to 39.5ºC [103ºF]) for the past 2 days. She had recently recovered from a respiratory tract illness of 1 month’s duration. She had been treated with nebulized albuterol, oral prednisolone, and azithromycin. Mother was frustrated because of the child’s persistent illness. Child also had occasional cough with exertion and lived with her parents who claimed to smoke outside the house.

Temperature was 38.9ºC (102.1ºF); heart rate, 95 beats per minute; respiration rate, 38 breaths per minute with considerable distress; capillary oxygen saturation, 87% to 89% on room air. Growth parameters normal. Chest examination demonstrated suprasternal, intercostal, and subcostal retractions with diffuse wheezing and rhonchi. Rapid RSV and influenza test results negative.

Posteroanterior chest radiographs of both patients are shown.

WHAT'S YOUR DIAGNOSIS? 
ANSWER: REACTIVE AIRWAY DISEASE 

. The chest radiograph, which is slightly rotated as evidenced by the clavicles, shows a normal heart contour with an upper border merging with thymic tissue, a right middle lobe infiltrate, and peribronchial cuffing in both lung fields. A lateral film (not shown) revealed flattening of the diaphragm, suggestive of hyperinflation and/or air trapping.

Although congestive heart failure might be considered on the basis of the patient’s symptoms, the intermittent wheezing, stable cardiac lesions, and acute pulmonary infiltrate favor a diagnosis of recurrent respiratory illness, manifested as acute bronchiolitis and right middle lobe pneumonia.

. The chest radiograph, which is minimally rotated, shows right middle lobe atelectasis, supported by a slight rightward shift of the mediastinum and mild hyperinflation in the upper and lower lung fields bilaterally. Persistent wheezing with right middle lobe atelectasis is suggestive of asthma.

RECOGNITION OF RECURRENT RESPIRATORY DISEASE


Reactive airway disease, whether transient or persistent, is one of the most common pediatric complaints.

 The essential symptom of wheezing may appear insidiously at night with accompanying cough, after exercise (which in infants can include crying or excitement), or with respiratory distress and fever that reflect bronchiolitis or pneumonia or both. Pediatricians must recognize the initial symptoms of wheezing, tachypnea, and/or cough; document their recurrence and frequency; and eliminate other causes before making a diagnosis of asthma.


About 12.7% of children receive an asthma diagnosis some time before age 18 years; this amounts to 6 million children in the United States.

 Despite the advent of remarkably effective therapies and protocols,

 asthma still causes 7 million ambulatory visits; 200,000 hospitalizations; and 13 million missed school days each year.


Reactive airway disease has many causes of which asthma, defined by atopy and entwined with allergic rhinitis and eczema, is the most common.

 A history of prematurity favors lung injury (bronchopulmonary dysplasia), and association with eating or ingestion favors aspiration or a foreign body. Infection with a virus (eg, RSV) or bacteria (eg, 

, pneumococcus) can produce transient wheezing; in this setting, patient age determines whether pneumonitis presents as bronchiolitis or cough.

Congenital anomalies of the trachea or pulmonary tree must be suspected in children with birth defect patterns, and wheezing caused by dysphagia and aspiration should be suspected in those with global delays. Singlegene disorders, such as cystic fibrosis, often have associated symptoms and familial cases that reveal the diagnosis. Similarly, a family history of atopy supports the diagnosis of asthma and draws attention to the “allergic march” of eczema/allergic rhinitis/asthma that can be slowed by effective therapy.

Closely intertwined with asthma is bronchiolitis- the most common lower respiratory tract disease in young children. In children younger than 2 years, bronchiolitis is defined by rhinorrhea, cough, wheezing, tachypnea, and increased respiratory effort (grunting, nasal flaring, intercostal/subcostal retractions).

 RSV infection is a major contributor to these reactive airway diseases, infecting 90% of children younger than 2 years, with 40% of infections involving the lower respiratory tract. RSV infection causes 90,000 hospitalizations per year in the United States and reinfections can occur throughout life.

Symptoms of bronchiolitis with a negative result on a rapid test for RSV-as in Case 1-identifies a child at risk for recurrent respiratory disease. A diagnosis of bronchiolitis rather than asthma is important because bronchodilator therapies are not recommended for bronchiolitis unless a positive response to this therapy has been previously documented for the patient by objective measures (eg, oxygen saturation, flow parameters).

Evidence of recurrence and findings associated with asthma (atopy by skin testing, positive family history) are needed to determine whether an episode of bronchiolitis foretells a diagnosis of asthma.


Accurate diagnosis is important to differentiate asthma from disorders that may not respond well to asthma therapy. The latter include allergic rhinitis, gastroesophageal reflux disease, cardiac failure, laryngotracheomalacia, and vocal cord dysfunction.

A retrospective review of 50 children younger than 3 years evaluated for recurrent respiratory symptoms showed that 20% had wheezing, 12% had wheezing and cough, 11% had cough alone, and 7% had other symptoms (such as, “hard-breathing,” rhinorrhea, or retractions).

 Asthma was diagnosed in 35 of the 50 children, sinusitis in 5, aspiration in 2, and recurrent croup in 1; 7 had no definitive diagnosis at the time of chart review. Those with a diagnosis of asthma were more likely to have recurrent otitis (23 patients), worsening symptoms after exercise (21), a family history of asthma (14), and/or a mother who smoked (10); the patients with asthma were also more likely to snore (11) or have coexisting eczema (7).

The 50 children underwent 1 or more of the following: chest radiography, sweat chloride test, allergy skin test, sinus radiography, and pulmonary function testing/ bronchoscopy.

 Initial chest radiographs often revealed infiltrates during acute attacks; however, findings from subsequent films were normal (with some peribronchial cuffing or perihilar densities), except in children with chronic aspiration. None of the 50 children had pulmonary anomalies, although vascular rings and cystic adenoid malformations have been reported in patients with recurrent respiratory symptoms. In another study, chest radiographs documented asthma findings (hyperinflation with increased lucency, flattened diaphragms, horizontal ribs, increased anteroposterior diameter of the chest) in 94% of 371 patients who had first asthma attacks; 20 of these patients (6%) also had segmental atelectasis and/or pneumonia.

Children with suspected reactive airway disease need thorough inspection and chest examination for affect (playful vs ill-appearing), posture (relaxed vs upward straining to expand the chest), nasal flaring/obstruction, breath sounds (wheezing with prolonged expiration vs stridor with prolonged inspiration, presence of rales and rhonchi, overall intensity with alertness for silent areas dull to percussion), and respiratory distress (suprasternal, intercostal, and subcostal retractions). Monitor objective data, such as respiration rate and capillary oxygen saturation, as a function of therapy; obtain chest radiographs when warranted by the child’s age, ill appearance, degree of distress/tachypnea, or accessory findings and history (prior rapid progression/recurrence, RSV positivity, poor therapy response). Radiographic findings, including hyperinflation (flattened diaphragms, increased anteroposterior chest diameter, decreased density), peribronchial cuffing, and/or atelectasis, will attest to the bronchiolar involvement of obstructive airway disease and show infiltrates that may suggest coexisting bacterial pneumonia.

However, even with the help that radiographic evidence and other test results can provide, diagnosing the cause of wheezing in children younger than 3 years remains “one of the last true art forms in medicine”

-one that requires broad thinking, the ability to gain the trust and respect of families, and persistence in ruling out possible diagnoses.

Both of these patients have onset of wheezing at an early age, and their histories could indicate intermittent or mild to moderate persistent asthma at presentation. Additional follow-up is needed to determine whether wheezing episodes persist up to age 6 years to justify the diagnosis of asthma. Parental diaries are useful to document recurrent wheezing episodes, along with their severity and response to therapy regimens.

. Acute therapy in this 6-month-old boy involved intramuscular ceftriaxone (75 mg/kg) and home nebulizer treatments with albuterol (1.25 mg every 4 hours). The next day, he presented with minimal respiratory distress. A second injection of ceftriaxone was administered; the parents were instructed to continue oral therapy with cefdinir (250 mg/d) and albuterol treatments for 2 days and to bring the child back if symptoms of fever, wheezing, or respiratory distress developed.

This infant was not given an asthma diagnosis or detailed asthma education/preventive care pending general pediatric follow-up to determine the recurrence of wheezing. The frequency of bronchiolitis in reaction to viral or bacterial infection for children younger than 2 years mitigates the likelihood of recurrent respiratory illness in this child. This conclusion is supported by his prompt response to antibiotics and bronchodilators.

. Acute therapy in this 2-year-old girl involved continued treatment with nebulized albuterol (1.25 mg every 4 hours) in the hospital plus intravenous prednisolone (2 mg/kg/d) and oral cefdinir (250 mg/d). She was discharged after 2 days.

Persistent asthma is more likely in this child, given her 1-month history of severe respiratory illness and atelectasis on the chest radiograph. Thus, the parents were instructed to continue her medications and follow up with the pulmonology clinic. The clinic prescribed therapy with an albuterol inhaler and spacer and provided parental asthma education. Note that her follow-up could also have been handled by the pediatric clinic; it was only because of time considerations that she was referred to pulmonology.


Given the suggestive radiographic findings and 1-month history of respiratory tract illness in the 2 patients described, it is important to follow up for recurrent symptoms and to urge cessation of smoking by family members. If symptoms continue to recur, then therapy will be based on whether the children are classified as having intermittent or persistent (mild/moderate/ severe) asthma. Poorly controlled disease warrants referral to pulmonology and/or allergy subspecialists for consideration of spirometry or skin testing for allergens.

 Follow-up is essential for classifying children with reactive airway disease and guiding long-term therapy.

For a complete discussion of how to assess asthma severity and tailor treatment regimens accordingly, see the 2-part series by Benjamin Tippets, DO, MPH, and Theresa W. Guilbert, MD, in CONSULTANT FOR PEDIATRICIANS on managing asthma in children.

 Tippets B, Guilbert TW. Managing asthma in children, part 1: making thediagnosis, assessing severity. 

 Tippets B, Guilbert TW. Managing asthma in children, part 2: achieving andmaintaining control. 

 Strunk RC. Defining asthma in the preschool-aged child. 

 Plint AC, Johnson DW, Patel H, et al; Pediatric Emergency Research Canada(PERC). Epinephrine and dexamethasone in children with bronchiolitis. 

 American Academy of Pediatrics Subcommittee on Diagnosis and Managementof Bronchiolitis. Diagnosis and management of bronchiolitis. 

 Gershel JC, Goldman HS, Stein RE, et al. The usefulness of chest radiographsin first asthma attacks. 

A 6-month-old boy with 1-week history of dry cough that worsened at night. He had been wheezing off and on for the past month and had visited the emergency department on one occasion.

History of Cough in an Infant and a Toddler

A 2-year-old girl has been followed for developmental delays and slow weight gain by her pediatrician and early childhood intervention therapists. She was the product of the first pregnancy of a single mother, age 17, who had run away from home and who had avoided early prenatal care.

Ultrasonography at a later gestational stage showed a small head size, and the uncomplicated vaginal delivery yielded a normal-appearing infant with good Apgar scores. Urine drug screens from the mother and infant were negative. The infant had difficulty breastfeeding but fed well on formula. Slow weight gain was noted despite involvement of the maternal grandmother with care; the grandmother thought the infant was irritable and less responsive than her daughter and 5 other children had been.

Weight gain improved somewhat with strategies and medication for GE reflux but remained in the 3

 percentile relative to a length in the 25

 percentile. At age 8 months, left esotropia was noted; this was treated with patching and glasses. Motor milestones included sitting at age 8 months and walking at 16 months. At 2 years, the child is somewhat clumsy with a wide gait. She says 2 to 3 words consistently without phrases, and is less responsive to commands than her grandmother thinks appropriate. She and the mother feel that the child’s behavior is hyperactive and impulsive.

The family history is unremarkable except for possible diagnosis of bipolar disorder in the mother and the maternal grandfather; the father’s history is unknown.

Review of systems is normal, except that the child has difficulty going to sleep and has decreased pain sensitivity.

 percentile, and head size below the 3rd percentile.

She is a quiet child who appears well-nourished, with normal subcutaneous tissue and good skin turgor. The facial appearance (

) appears normal except for a broad nasal root. Cardiac, pulmonary, and abdominal exams were unremarkable. Her palms showed a single crease bilaterally with inward curving of the fifth fingers (

). Neurologic exam revealed an irritable child with mild generalized hypotonia.


1. What diagnosis besides strabismus and developmental delay should be considered in this child?

2. Do you agree that the facial appearance in Figure 1 is normal, and if not, what changes do you see?

3. What laboratory tests might be considered?

4. Given the likely diagnosis, what preventive health care issues should be addressed?

ANSWERS (please see Discussion for further details)

1. What diagnosis besides strabismus and developmental delay should be considered in this child? 


An important diagnosis to consider would be fetal alcohol syndrome (FAS), which could account for the microcephaly, failure to thrive, behavior differences, strabismus, and minor anomalies (facial and hand changes). An underlying disorder should be suspected in young children with hyperactivity since true ADHD is best assessed by poor school performance.

2. Do you agree that the facial appearance in Figure 1 is normal, and if not, what changes do you see?


The photograph shows subtle facial changes (minor anomalies) that are typical of fetal alcohol syndrome-broad nasal root, absent or flat philtrum, and thin upper lip.

3. What laboratory tests might be considered?


No biochemical or molecular markers correlate with the effects of ethanol on the fetus, so the diagnosis of FAS is clinical. Chromosome studies should be considered in any child with unexplained developmental delays, particularly when the child has an unusual appearance and growth discrepancies (disproportionate weight and head size in this case). Routine chromosomes with reflex to high resolution chromosome (array-CGH or microarray) analysis should be considered since the latter technique often reveals submicroscopic aberrations in individuals with minimal dysmorphology and behavior differences (autism, mental illness, etc.). The routine and high resolution chromosome studies (reflex means proceed to the next test if the previous one is normal) can prevent inappropriate diagnoses of maternal substance abuse, especially important because mental illness or disability often underlies maternal chemical dependency and/or neglect.

4. Given the likely diagnosis, what preventive health care issues should be addressed?


Preventive health care for FAS will include alertness for cognitive and behavioral differences, strabismus, heart defects, and orthopedic anomalies such as club foot.

 This boy with fetal alcohol syndrome shows triangular facies, broad nasal bridge, right eye ptosis, flat philtrum, and a thin upper lip.

As with other malformation syndromes, FAS is first a clinical diagnosis through recognition of a malformation pattern.

 A smaller head size in proportion to length is suggestive as is early failure to thrive and irritability. The face often has minor anomalies including the broad nasal root, absent or flat philtrum, and thin upper lip shown in Figure 1.

 With age, the face is more triangular, with smaller eyes as shown by the child with FAS in 

FAS is thought to be the most common syndrome at 1.5-1.7 per 1000 births in some North American regions. This may represent an underestimate because over half of mothers give no history of drinking during pregnancy.

 Constant rather than early binge drinking is thought more harmful: the threshold is at least 2-3 drinks daily.

Some have proposed the term fetal alcohol effects for children with typical behaviors (impulsivity, irritability) but without facial changes (exposures after the first trimester). However, the lack of objective laboratory markers makes general use of FAS or of fetal alcohol spectrum disorders preferable.

Exercise care in making the diagnosis without maternal admission or testing because foster placement will often follow. Alcoholism and its comorbid mental illnesses have significant hereditability, further contributing to the instability of alcoholic families.

 Attention to social concerns is as important as monitoring for complications (

) in providing preventive health care through the medical home model.

 CDC. Surveillance for fetal alcohol syndrome using multiple sources-Atlanta, Georgia, 1981–1989. 

 1997;46:1118-1120. (Note: The CDC website has excellent lay and medical information- 

 Famy C, Streissguth AP, Unis AS. Mental illness in adults with fetal alcohol syndrome or fetal alcohol effects. 

 Hoyme HE, May PA, Kalberg WO, et al. A practical clinical approach to diagnosis of fetal alcohol spectrum disorders: clarification of the 1996 institute of medicine criteria. 

Preventive Health Care for Children with Genetic Condition: Providing a Medical Home, 2nd ed. 

Cambridge: Cambridge University Press, 2006.

A 2-year-old girl has been followed for developmental delays and slow weight gain by her pediatrician and early childhood intervention therapists. The 17-year-old, first-time mother was also a runaway and had avoided early prenatal care. More details and questions for you, here. 

Toddler With Microcephaly, Growth Delay, and Subtle Facial Changes: What Diagnosis Besides Strabismus and Developmental Delay?



A 14-month-old girl presented with persistent fever, cough, and worsening rash of 5 days’ duration. On the first day of the illness, the infant was brought to an acute care clinic for evaluation. Upper respiratory tract infection was diagnosed; her parents were instructed to use nasal saline and provide acetaminophen, as needed. Two days before presentation, she was brought to an outpatient clinic, where secondary otitis media on the left side was diagnosed and treatment with amoxicillin, 40 mg/kg/d in 2 doses for 10 days, was prescribed. On the day of presentation, the parents reported that the rash, which began on the cheeks and chest, had spread to other areas and the cough and fever had persisted.



Temperature was 37.6ºC (99.7ºF); respiration rate, 33 breaths per minute, without retractions or signs of distress. Maculopapular rash on the forehead, cheeks, neck, chest, back, and arms, with fewer macules on the upper thighs and sparing of the lower limbs. Gingival mucosa showed some hyperemia of the posterior palate, no enanthem; tonsils red and inflamed, with no white plaques. Infant had been taking solids and liquids without problem. Heart, abdominal, and genital findings normal.

White blood cell count of 15,900/µL, with 4% bands, 12% neutrophils, 67% lymphocytes, 9% atypical lymphocytes, and 6% eosinophils; hemoglobin, 11.3 g/dL; and hematocrit 32.4%, with normal red cell indices. Bicarbonate level, 17 mEq/L (normal, 21 to 33 mEq/L), with anion gap of 20 mEq/L; liver enzyme levels normal; and alkaline phosphatase level, 1736 U/L (normal, 108 to 317 U/L).

Results of a heterophile antibody screen were normal. Serological testing revealed an elevated level of IgM antibody to viral capsid antigen (VCA), consistent with a diagnosis of Epstein-Barr virus (EBV) infectious mononucleosis.

Infectious mononucleosis causes viral pharyngitis through proliferation of EBV in the nasopharynx, frequently producing asymptomatic infection in children (50% seroconversion by age 5 years).

 Infected college-aged adults usually are symptomatic with fever, sore throat, lymphadenopathy, and fatigue-12% of them seroconvert each year.1-3 EBV proliferates in the nasopharynx, is shed in oropharyngeal and other secretions (including those from the uterine cervix), and is highly contagious. Infected B-cell blasts produce acute heterophile antibodies that are diagnostic in 90% of cases; this IgM response includes antibodies to VCA. The humoral response switches over 3 to 6 weeks to IgG antibodies that target viral proteins or nuclear antigens; these antibodies persist as evidence of past infection and are found in the majority of adults.

Figure – This maculopapular rash on the back of a 14-month-old girl was probably an exacerbation of Epstein-Barr virus infection; her caregivers insisted that the rash was present before amoxicillin administration.

Countering the spread of EBV-infected B cells are the CD8+ cytotoxic T lymphocytes with atypical morphology.2 An efficient T-cell response suppresses the primary EBV infection and enforces transition of B-cell blasts to B memory cells that persist in the oropharyngeal saliva and are detectable in 15% to 25% of healthy adults. Failure of the T-cell response allows uncontrolled B-cell proliferation that can lead to B-cell lymphomas and other EBV-associated conditions (see below).

Cytomegalovirus, herpesvirus, adenovirus, HIV, hepatitis B virus, and rubella virus infections can produce fever, pharyngitis, and lymphadenopathy similar to that of infectious mononucleosis; group A streptococcal pharyngitis and even parasitic disease, such as 

 infection, can also produce these findings.

 EBV infection can present with other clinical findings that may include the peripheral rash of Gianotti-Crosti syndrome; the fever, lymphadenopathy, and maculopapular rash of hemophagocytic syndrome; and the fever, cervical lymphadenopathy, and fatigue of Kikuchi necrotizing lymphadenitis.

Infectious mononucleosis is diagnosed primarily on the basis of the clinical presentation of fever, sore throat, tonsillar enlargement/exudates, generalized lymphadenopathy, erythematous maculopapular rash, and-in teens or adults-a palpable spleen.

 Fatigue lasting weeks to months differentiates mononucleosis from streptococcal pharyngitis.

Diagnostic laboratory results may include leukocytosis of 70% or more with lymphocytes of atypical morphology in the peripheral blood smear.

 Elevated liver enzyme levels, mild to moderate thrombocytopenia without purpura, and hemolytic anemia may also be found. Results of the monospot test are unreliable in children younger than 4 years, necessitating a test panel including quantitative heterophile and IgM antibody to VCA, as in this patient.

 EBV nuclear antigens appear later and, along with IgG antibodies, may reflect past seroconversion rather than acute infection.

Serological studies help distinguish infectious mononucleosis from other illnesses in the differential diagnosis. However, bone marrow and other studies to rule out leukemia or lymphoma may be considered in the presence of severe thrombocytopenia, hemolytic anemia, persisting unusual lymphocytes, and/or lymphadenopathy.

Newer diagnostic technologies include quantitative measure of EBV viral load in blood or tissues using the polymerase chain reaction assay.

 This is helpful in patients with immune suppression, such as those with EBV-associated cancers (eg, Hodgkin disease, nasopharyngeal carcinoma) and AIDS patients with brain lymphomas.

 Detection of EBV-encoded RNA or proteins in tissues by in situ hybridization can complement viral load studies and is particularly useful in patients with posttransplant lymphoproliferative disorder.

Airway compromise and breathing difficulties from swollen tonsils and lymphadenopathy may necessitate hospitalization during the acute phase of illness. Administration of a corticosteroid burst (eg, 1 mg/kg of prednisolone every 12 hours for 5 days) may be considered to minimize the hospital stay.

Subcapsular splenic hemorrhage or splenic rupture can occur during the second week of infection. Fortunately, these are rare in children and can be managed conservatively in hemodynamically stable patients using activity limitations, serial CT scans, and monitoring in the pediatric ICU.

Chronic fatigue syndrome-a complication more common and severe in adolescent girls-may develop within 24 months of EBV infection.6 EBV-related malignancies, including B-cell lymphomas and B-cell lymphoproliferative syndromes (in patients with poor T-cell response), Burkitt lymphoma, nasopharyngeal carcinoma, Hodgkin disease, T-cell lymphomas, and gastric carcinoma, usually occur several years after infection.

A 14-month-old girl presented with persistent fever, cough, and worsening rash of 5 days’ duration. On the first day of the illness, the infant was brought to an acute care clinic for evaluation.