The patient history and clinical manifestations are characteristic of Juvenile Myoclonic Epilepsy. Patients with Juvenile Myoclonic Epilepsy initially experience myoclonic jerks upon waking in the morning, with symptoms subsiding later in the day. Typically a few years later, the patient develops generalized tonic-clonic seizures, which can be precipitated by sleep deprivation or other stressors. Onset is usually between ages twelve and sixteen years.

Lafora disease is a type of severe, progressive myoclonic epilepsy that usually appears in children between ages ten and eighteen years. Initial symtoms include myoclonic jerks that increase in intensity and frequency with disease progression. Neurological findings become prominent, particularly mental deterioration within the first year of onset.

Patients with Frontal lobe epilepsy experience seizures originating in the frontal lobe and have manifestations (including motor and behavioral) concurrent to the specific area affected.

Absence seizures often occur in school-age children, and may be mistaken for inattention or daydreaming.

Acute leukemia occurs 14 times more frequently in children with T21 than in the general population, which works out to a risk of leukemia of 1-1.5%.

In the general population, approximately 80% of all leukemias in children are ALL, whereas 11-17% are AML. This ratio of ALL to AML is actually similar in patients with T21 to that of the general population.

However, T21 patients with AML often develop a specific subtype of AML known as acute megakaryoblastic leukemia (aka AML-M7 or AMKL). The incidence of AMKL is approximately 500 times greater in children with T21 than in the general population. AMKL often develops by 4 years of life, and when it presents in the first 2 years of life, it is invariably associated with mutations in GATA-1. GATA-1 is a gene on the X chromosome that encodes a transcription factor that controls megakaryopoiesis, and has been identified in blasts of patients with trisomy 21 and AMKL. This information suggests that AMKL may result from a gene mutation, which may be acquired in utero and serve as a biomarker for an increased risk of transient leukemia and subsequent AMKL.

Interestingly, in earlier onset AML, patients with T21 have much better outcomes (>80% long-term survival rates) and often require less intensive therapy than children without T21 (<70%). In contrast, myeloid leukemias in people with T21 > 4 years are usually negative for GATA-1 mutations, and their prognosis does not differ from AML in patients without T21.

In patients with T21, ~10-20% of newborns develop a transient leukemia or myeloproliferative syndrome. It is often characterized by blasts in the peripheral blood, with hemoglobin, platelet, and neutrophil counts typically being normal. It resolves spontaneoously in days to weeks and does not require treatment. However, it is important and must be screened for in all infants with T21, because 20-30% of patients with transient leukemia later develop AMKL. GATA-1 mutations are often identified in such patients.

The risk of developing acute lymphoblastic leukemia (ALL) is approximately 10 to 20 times higher in T21 children than in the general population. The clinical presentation and epidemiology of ALL, as well as the expected outcome of treatment is the same in patients with T21 than in other children.

Molluscum Contagiosum is the most likely diagnosis given the history (playmate having similar condition) and physical presentation, particularly the central umbilication and core of the papules.

Molluscum Contagiosum is a viral disease caused by a DNA poxvirus and transmitted via direct skin to skin contact or sharing objects touching the skin. Patients present with flesh-colored papules that contain viral bodies, usually appearing on the extremities, trunk and face. Highest incidence is in children less than 5 years of age. Usually, Molluscum Contagiosum is diagnosed by simple identification of the characteristic central umbilication and core of the papules. Treatment options include topical vesicants and cryotherapy among others. Or, simply waiting for disappearance is advised, as most cases resolve within weeks to months.

Atopic dermatitis, or eczema, is the most common inflammatory skin condition in childhood. It typically presents in skin creases or flexure surfaces as a red, pruritic dermatitis in variable stages of vesicles, scaling and excoriations.

Warts, caused by Human Papilloma Virus, are present in 10-20% of school-aged children. There are many different types, most appearing on the hands and feet.

Granuloma annulare, a benign inflammatory dermatosis, usually presents with groups of papules in an annular arrangement.

The DSM-IV-TR defines mental retardation as follows:
A. Significantly subaverage intellectual functioning (IQ of approximately 70 or below)
B. Concurrent deficits or impairments in adaptive functioning in at least 2 of the following areas: communication, self-care, home living, social/interpersonal skills, use of community resources, self-direction, functional academic skills, work, leisure, health, and safety
C. Onset before age 18 years

Hyperactivity, impulsivity and inattention are clinical signs of Attention Deficit Hyperactivity Disorder (ADHD). Although many children with mental retardation present with these behaviors, this may reflect their typical developmental level or a concurrent diagnosis of ADHD. As such, these findings are not included in the DSM-IV diagnostic criteria for mental retardation.

A bit about transitioning from fetal to neonatal circulation and its effect on PVR:
1) Pulmonary vascular resistance (PVR) is as high as the systemic
vascular resistance in a fetus near or at term because:
a Large amounts of smooth muscle in pulmonary arteriole walls
b Lungs full of fluid -> alveolar hypoxia -> pulmonary
vasoconstriction
2) RV is larger and more dominant than the LV as it handles a larger percentage of the combined ventricular output than the LV.
3) At birth:
a Lung expansion leads to increased alveolar oxygen tension, and
with it, a rapid fall in PVR (oxygen has a vasodilating effect
on the pulmonary vasculature), increased pulmonary blood flow,
and decreased pulmonary artery pressure
b Meanwhile, removal of the low resistance placental circulation
leads to an increase in systemic vascular resistance (SVR), and
cessation of umbilical vein flow leading to closure of ductus
venosus
c Increased Left atrial pressure occurs because of increased
pulmonary blood flow and subsequent pulmonary venous return to
the LA, while decreased right atrial pressure results from
closure of the ductus venosus. This relative pressure
difference results in functional closure of the foramen ovale
4) Functional closure of the ductus arteriosus occurs within 10 to
15 hours after birth by constriction of its medial smooth
muscle, which contracts secondary to increased postnatal oxygen
concentration in the systemic circulation
5) Although the PVR falls after birth because of pulmonary
vasodilation, it continues to fall in the first 6-8 weeks of
life, likely because of thinning of the medial layer of the
pulmonary arterioles. It is further reduced over the next 2
years, presumed because of increases in numbers of alveoli and
their associated vessels

This last point helps explain why the LEAST likely etiology of this murmur is a large VSD.
1) Although the PVR drops immediately after birth, it is still relatively higher than that in an infant/child for reasons aforementioned. Since shunting is determined by the relative difference in PVR and SVR, the pulmonary vascular resistance often takes weeks to sufficiently decrease to allow significant left to right shunting through cardiac lesions.
2) Because PVR falls more quickly with small VSDs compared to large VSDs, shunting (and therefore an audible murmur) occurs earlier with small VSDs.

(Why? in large VSD, the relatively high LV pressure can be transmitted directly to the pulmonary artery through the defect, thus maintaining a high pulmonary artery pressure and further delaying the fall in PVR - this high pressure is not as well transmitted through a small VSD, and so PVR falls more quickly in small VSDs)

For all of these reasons, the holosystolic murmur associated with a large VSD does NOT usually appear in the 1st 2 weeks, and often longer. In contrast, a smaller VSD may be auscultated earlier (early systolic).

It is also noteworthy that signs of CHF (tachycardia, tachypnea, hepatomegaly, cardiomegaly) do NOT present until PVR falls enough to allow for significant shunting, so newborns with large VSD’s are often asymptomatic over a similar time period.

This case is also designed to illustrate that newborns have some unique cardiovascular findings that are normal for their age. The history and physical examination described above is considered normal for a newborn, despite some features that would be considered concerning in older children and adults:

1) Vitals:
a) HR normally ranges from 70 to 180, while RR can be 30-60.
b) Mild desaturations in an otherwise well neonate are not unusual, and are attributed to intrapulmonary R to L shunts through portions of the lungs that are not fully expanded and/or small R to L shunts through patent foramen ovale
2)The PMI is often found at the LLSB rather than the apex, and the S2 may be single in the first days of life.
Why? Right ventricle is still relatively hyperactive, and still generates the PMI (point of maximal impulse). The S2 may be single because the PVR is still relatively high and so a degree of relative pulmonary hypertension causes earlier closure of pulmonary valve, bringing A2 and P2 closer so that they may be heard as a single sound
3) Acrocyanosis (intermittent, bilateral, symmetric bluish discoloration of the hands and feet) is common in the neonatal period, attributable to vasomotor instability as the newborn adjusts to extrauterine life.
4) Liver edge is normally palpable 1-2 cm below the right costal margin, whereas hepatomegaly may suggest a heart defect
5) THREE INNOCENT MURMURS are commonly heard in the newborn period. All are systolic, and can be accounted for by the etiologies mentioned as the other possible answers.

Innocent murmurs in newborn (SEM = systolic ejection murmur; mid-systolic and cresc-decrescendo pattern):
1. Persistent pulmonary flow murmur of newborn
a) Etiology: In fetus, the main Pulmonary artery trunk is large, but branch pulmonary arteries are hypoplastic (because of low pulmonary blood flow in fetal life). After ductus closes, turbulent flow from large pulmonary artery (PA) into (physiologic) smaller branches at right angles creates murmur.
b) Description: ULSB, SEM, I-II/VI (may be louder in small, preterm babies), Wide radiation (along smaller branches of PA)
c) Comments: If persists beyond 6 months, consider PA stenosis and refer

2. Transient systolic murmur of Ductus Arteriosus
a) Etiology: closing ductus arteriosus in 1st day of life
Note: it is often heard as a systolic rather than a continuous murmur in the newborn because during diastole, systemic & pulmonary pressures are similar so there is little to no L to R shunting through the PDA during this phase. The murmur is noted during systole when L>R pressures and shunting occurs.
b) Description: ULSB, mid-systolic crescendo (SEM-like), I-III/VI
c) Comments: Murmur may persist in PDA (premature, respiratory
distress, other CHD)

3. Transient systolic murmur of TR
a) Theory: Minimal tricuspid valve abnormality, in addition to the relatively high pulmonary vascular resistance, results in tricuspid regurgitation. This murmur disappears as PVR falls (as opposed to VSD murmurs, which increase as PVR falls)
b) Description: II+/VI, similar to VSD in that is holosystolic, albeit tends to be lower pitched and may be loudest at RLSB or LLSB.
c) Comments: usually audible in setting of sick newborn with lung disease and PPHN, not as commonly heard in a well-appearing baby.

Penicillin-class compounds are considered the most common causes of cutaneous drug reactions, seen in ~1-2% of penicillin-exposed and ~4-5% of amoxicillin-exposed patients. Two of the most common reactions to penicillin-class compounds are IgE-mediated acute reactions and morbilliform (e.g. measles-like) rashes.

The story here best fits the picture of a delayed maculopapular, or morbilliform rash, commonly caused by amoxicillin. It is NOT considered a true allergic reaction (classifiable on the Gel and Coombs scheme). Some of its typical features are -

Etiology: May be T-cell mediated, not fully characterized.
Associated with altered lymphocyte function (as
theorized based on predisposed groups)
One theory suggests: Viral infection -> interferon
release -> increased MHC receptor expression on antigen
presenting cells in skin
Histologically: aggregates of perivascular mononuclear cells (esp
lymphocytes), no complement or Ig deposition
At Risk: Children, more with the aminopenicillins. F>M. Viral
illness, especially CMV and EBV(>90% of those treated
dvp rash). CLL, HIV.
Protected: For reasons unknown, spares newborns
Onset: usually within weeks (average 5-9 days)
Duration: average 3 days
Description: Red, maculopapular rash. Often starts on trunk,
tends to spread to face, etc.
Associated Sx: Pruritis may be present
Effect of continuing antibx: no significant change (rash may
worsen after drugs stopped)
Rx: Supportive (+/- antihistamines, topical steroids and
antipruritics)
Penicillin-skin testing: NO increased risk of reactivity compared
to general population
Risk of subsequent reaction: 5% (same as that of general
population)

If a patient clearly describes a rash that did not itch or involve urticaria, then it can be assumed to be non-IgE mediated.

The other common rash that can occur with penicillins is an IgE-mediated reaction -

Etiology: Type I, IgE-mediated hypersensitivity reaction
At Risk: Prior allergic reaction. M=F
Onset: Minutes to ~ 72 hrs at most
Duration: Hours to weeks
Description: Urticaria - circumscribed, raised, erythematous,
extremely pruritic plaques.
Typically appear in one area, resolve over hours,
then reappear elsewhere. Lesions can enlarge and
develop a central pallor prior to fading.
Associated Sx: Pruritis, flushing, urticaria, angioedema,
wheezing, nausea, vomiting, hypotension
Effect of continuing antibx: Rash will persist, may worsen
Rx: Stop drug, antihistamines, glucocorticoids, epinephrine PRN
Penicillin-skin testing: Frequently reactive
Risk of subsequent reaction: 28% if skin test negative, higher if
positive

SO THE QUESTION NOW IS – what to do with this patient, the girl who likely had a morbilliform rash with amoxicillin use while having a EBV infection that predisposed her to the reaction?

Most would agree that if a clinician is fairly certain that the history is consistent with a delayed, maculopapular rash, then the patient does not require penicillin skin testing, and can receive penicillins in the future without the risk of a more serious type I, IgE reaction. This rash should not be a contraindication to trying penicillins again. If there was any question that the rash was urticarial, then you may avoid penicillins until further skin testing.

Going through wrong answers:
“She will likely test positive on penicllin allergen skin testing” – this is false, as she likely will test negative because this was likely a morbilliform rash.

“The rash represents an IgE-mediated allergy” – unlikely based on Hx provided.

“Her risk of subsequent reactions to amoxicillin is at least 25%” – this would be true if she had an IgE-mediated allergic reaction. This is likely a morbilliform rash and so her risk of a subsequent reaction mimics that of the general popn, about 5%.

“Her next reaction to amoxicillin will be accompanied by bronchospasm and hypotension” – these are features of a severe IgE-mediated allergic, or anaphylactic reaction. Penicillin-induced anaphylaxis is actually quite rare, 1-4/10,000.

“Future use of amoxicillin is contraindicated” – this could be true, if she underwent skin testing and tested positive. It is more likely however, that she would end up testing negative and could resume use of amoxicillins.

This is the description, more or less, of a classic measles infection.

Following a generally asymptomatic incubation period of 10-14 days where the virus replicates locally and spreads via the bloodstream, a 2-7 day prodromal phase occurs.

Prodrome phase is characterized by fever, malaise, anorexia, EXUDATIVE CONJUNCTIVITIS, coryza, and cough. Temperatures can be above 40oC. Also during the prodrome, patients may develop KOPLIK’S SPOTS. They are 1-3 mm white/gray/blue papules on an erythematous base, seen on the buccal mucosa typically opposite the molar teeth, but they can also cover the buccal and labial mucosa. They are considered pathognomonic for measles infection but don’t ppear in all cases of measles. Uncommonly, they can have lymphadenopathy, but in contrast to Kawasaki Disease, it is often generalized rather than localized to unilateral cervical LN chains.

Following the prodrome period, a characteristic rash develops, although it is not pathognomonic for the virus. It is maculopapular, blanches, begins on the face/behind the ears and spreads in a cranial-caudal pattern. The palms and soles are rarely involved. 3-4 days after the rash appears, it will start to fade followed by fine desquamation.

The recovery period may involve a persistent cough for 1-2 weeks. However, fevers rarely last longer than the 3rd day of rash, and if so, complications of the infection should be ruled out.

Kawasaki Disease and Measles often have a similar presentation and must be distinguished. I will contrast them now:

Conjunctivitis in KD is classically bilateral, nonpurulent, while in Measles, the conjunctivitis may be exudative or associated with lacrimation or photophobia.

Localized Koplik’s spots are pathognomonic for Measles, whereas in KD, the oropharyngeal mucosa may be diffusely red with strawberry tongue and dry cracked lips; ulceration is not present.

Leukopenia often occur during Measles infection, and thrombocytopenia also may be seen. In contrast, KD is associated with normal to elevated WBC count. PLT counts are initially normal in the acute phase of KD, but rapidly increase by the 2nd-3rd week.

In KD, almost universally during the acute phase, ESR and CRP will both be elevated. While acute phase reactants may also be elevated during Measles, if levels are normal, this is much more suggestive of Measles.

The rash in Measles, as aforementioned, begins in the face/ears, and is maculopapular. The rash in KD may be polymorphous - often maculopapular, but may also present as erythema multiforme or as a scarlet fever-like, sandpaper rash. Thus a maculopapular rash is actually the least distinguishing feature between the two. In fact, accentuation of the rash in the groin is more commonly seen in KD, whereas in Measles it is most confluent/involved in the face, where it begins. Also, erythema of the palms and soles may develop in KD as one of its criteria, whereas in Measles, the exanthem rarely involves the palms or soles.

Before we get to the answer here, a bit of a word about functional constipation (which Timmy has), and the approach to constipation in children.

Constipation in the neonatal/infant period often conjures up worries about organic etiologies (hypothyroidism, meconium ileus associated with CF, Hirschsprung’s disease, spinal cord pathology, and CMPI). Constipation of onset > 3 months, and certainly past one year of age, is rarely organic in nature.

Still, assessment of constipation at any age requires physicians to look for alarming features on history and physical, followed by exploration of the likely functional cause:

On history, red flags suggesting organic etiology include:
- Anorexia/weight loss/poor weight gain
- Blood in stool (not associated with fissure)
- Delayed passage of meconium (after 48 hours), constipation present from infancy
- Fever, vomiting, or diarrhea (suggesting inflammation of GIT)
- Extraintestinal symptoms
- Enuresis (Note that enuresis/voiding dysfunction are commonly associated with functional constipation, but neurogenic disorders must also be excluded)
Examination should include: inspecting perianal area, sensory/motor function, and DRE
- spinal dysraphism: sensory/motor deficits in LE, absent anal wink/cremasteric reflex, and sacral dimpling/pigmentation/hair tuft
- inspection should also reveal anal stenosis/imperforate anus, or an anteriorly displaced anus (too close to fourchtette/scrotum)
- DRE: In Fxnl constipation – a distended rectum full of stool is noted
o In Hirschsprung’s, classically a tight anal canal with empty ampulla, and DRE may stimulate a BM

As you can tell from above, Timmy had no red flags, and actually exemplifies a classic presentation for functional constipation

FXNL CONSTIPATION essentially means without evidence of a primary anatomic or biochemical cause. In 4-18 y/o, it requires >2/6 criteria, present for two months:
- Two or fewer defecations per week
- At least one episode of fecal incontinence per week
- History of retentive posturing or excessive volitional stool retention
- History of painful or hard bowel movements
- Presence of a large fecal mass in the rectum
- History of large-diameter stools that may obstruct the toilet

ETIOLOGY OF FUNCTIONAL CONSTIPATION —
Infants/Children are prone to constipation in 3 major periods:
introduction of solid food into the infant's diet
toilet training
during the start of school (as with Timmy)
Contributing factors include
- Painful defecation – child avoids defecation, stool accumulates in rectum and becomes hard, which is more painful to pass and sets up a vicious cycle…
- Toilet training - To master toileting, a toddler must retain a bowel movement until he/she reaches a toilet ? this frequently leads to less frequent defecation, and sometimes hard/painful stools (especially as child enters school/daycare). This problem is often worse when toilet training is vigorously encouraged before the child is developmentally ready as power struggles may develop
- Dietary considerations — The modern diet has been cited as a major cause -children consume large amounts of highly processed food items at the expense of fruit, vegetables, or fiber
- Familial tendency?

TO UNDERSTAND the treatment of Fxnl Constipation, one must know what goes on:
- When the child avoids defecation, stool accumulates in the rectum and increased water absorption makes it harder
- When chronic rectal distention occurs, secondary anatomic changes occur
o Anal canal shortens
o Internal anal sphincter dilates
- Rectum may dilate to a point that insufficient pressure can be generated to push stool into the anal canal – further worsening constipation
- Some manometry results suggest that although the child consciously contracts the external anal sphincter (EAS) to withhold a BM, this may become automatic over time, known as “anismus”
- When hard stool presses on the external anal sphincter for significant periods, it can cause relaxation of the voluntary muscle – allowing semisolid stool to leak onto the perianal skin and clothing ? retentive encopresis
As you can see, chronic functional constipation can lead to an ongoing spiral that should be prevented by early identification and management

Treatment takes a four-pronged approach
1) Education – very important, should be tailored to child’s developmental level, and they should be motivated to change their behavior or else things will never work!
2) Behavioral – strategies include: Daily, scheduled toileting attempts, with proper positioning (feet flat on surface), and positive reinforcement (e.g. every time sits on toilet for 5 mins, a star, every time has a BM, three stars)
3) Dietary – Increased fiber (whole grains, fruits, vegetables) and fluids, decrease complex carbs/processed foods
4) Bowel retraining with goals of (a) relieving impaction (b) laxatives administered to achieve once daily formed bowel movement (c) discontinuing laxatives gradually once the child's bowel becomes re-conditioned
a. Initial disimpaction – may be oral/rectal, options in children include
i. Mineral oil, lactulose, PEG-3350, stimulant (sennokot, bisacodyl)
ii. Glycerin/bisacodyl suppositories intermittently
iii. Severe cases – enemas, po/NG Peglyte or picosalax
b. Maintenance therapy
i. Mineral oil, PEG-3350, lactulose

Which leads us back to Timmy:
I hope it was evident by the clinical vignette that Timmy has severe functional
constipation!!! He needs a disimpaction thus the correct answer involves the use of multiple laxatives with different mechanisms of action in order to clean him out (some may even opt for Picosalax in this case)
A urinalysis may be useful given his PHx of UTI and Sx of frequency.

Going through wrong answers:
“Daily benefibre and increased fluids. FUP in 1 month” – while improved diet is recommended, it is not effective for severe constipation

“Refer to GI for anorectal manometry +/- colonic transit times - performed mainly in children with intractable constipation, or when there is suspicion of intestinal pseudo-obstruction or Hirschsprung disease

“Order CBC, TSH, lytes, Ca, U/A” – While we haven’t technically ruled out hypothyroidism, hyperCa, etc. Functional constipation is still more common and further tests should only be done if he fails management for constipation or new red flags arise.

“Barium enema and consider general surgery referral for suction rectal biopsy” – nothing on Hx or physical exam suggest Hirschsprung’s

“Substitute cow’s milk for soy milk products” – While we know that CMPI can present with constipation, it rarely presents like this alone, and usually presents in infancy and resolves over time.

'BROW' (barley, rye, oats (though still controversial), and wheat) is a useful acronym that can be used to remember grains that contain gluten. Along with rice, other examples of allowed foods include corn, flax, millet, and soy.

Quinoa is also a fantastic alternative to gluten.

Children with abusive head trauma (shaken baby syndrome) can present quite variably. Some children may present with poor feeding, irritability or increasing head circumference. Other children can be seizing or in cardiopulmonary arrest. The presentation can be quite subtle and can mimic other conditions. There may be no findings on physical examination.

Retinal hemorrhages should raise suspicion of inflicted head trauma in the absence of a consistent medical condition (e.g. leukemia, clotting disorder, congenital infection).

On CT, the hallmarks of abusive head trauma are subdural hematomas (described as a thin rim of bleeding around the brain) and cerebral edema.

Specific fractures are also associated with abusive head trauma. These are posterior rib fractures and classic metaphyseal fractures. The latter group consists of fractures across the growth plates of long bones. Classic metaphyseal fractures are also known as bucket handle fractures, corner fractures.

The most likely cause in the above case is abusive head trauma. Although accidental head injuries can mimic some elements of abusive head trauma, the key thing to remember is that LARGE amounts of force are required to produce this pattern of injury. A high-speed motor vehicle accident or fall from greater than two stories could mimic this type of injury. However, this was not reported in the history. In cases of abusive head trauma, caregivers may attribute the injury to a fall from a much shorter height.

Aside: The term ‘abusive head trauma’ is currently used in the child abuse literature. It is synonymous with ‘shaken baby syndrome’.