C. Pion Kao, MD

The mother of this 11-month-old girl was concerned that her infant’s vagina was almost obscured by a membrane. This was noted incidentally a few days earlier. The mother was sure that the membrane was not there in the immediate neonatal period. Urination was unimpaired, and the infant was asymptomatic. She had no history of trauma to the genital area. Her past health was unremarkable. In particular, she had no history of unexplained fever, foul-smelling urine, or an overt urinary tract infection.

On examination, the vulva was flat. The edges of the labia minora were sealed in the midline by a thin, translucent membrane that extended from the posterior fourchette to just below the clitoris.

Labial fusion refers to partial or complete adherence of the labia minora. The condition is rare at birth and occurs most commonly in girls between 3 months and 4 years of age. The peak incidence is between 13 and 23 months, during which about 3.3% of girls are affected.

Labial fusion probably develops after denudation of the superficial squamous epithelial layer of the labial mucosa. Denudation occurs with inflammatory conditions of the labia minora, such as vulvitis or vulvovaginitis, most often secondary to poor perineal hygiene. Estrogen deficiency is associated with a reduction in the thickness of the labial epithelial cells and is a possible pathogenic factor.

Most girls with labial fusion are asymptomatic. The condition is usually discovered incidentally by a physician during a routine examination or by the mother while she is bathing the child. Labial fusion may predispose the child to asymptomatic bacteriuria or to urinary tract infection. Occasionally, the labial fusion causes urinary outflow obstruction with resultant bladder distention and hydronephrosis.

Treatment consists of precise application of a topical estrogen cream to the fused area twice a day until lysis of the adhesion is complete. Most cases resolve within 2 to 3 months. As the labia minora separate, petroleum jelly should be applied to the edges to prevent readhesion.


 • Leung AK, Robson WL. Labial fusion. 

. 2004;3:31-35.
 • Leung AK, Robson WL, Kao CP, et al. Treatment of labial fusion with topical estrogen therapy. 

 (Phila). 2005;44:245-247.
 • Leung AK, Robson WL, Tay-Uyboco J. The incidence of labial fusion in children. 

Articles

The mother of this 11-month-old girl was concerned that her infant’s vagina was almost obscured by a membrane. This was noted incidentally a few days earlier.

Labial Fusion

A 4-year-old boy was brought for evaluation of a tiny cystic mass on the penis. The lesion was first noted a year earlier when the foreskin became retractable. At that time, the child was asymptomatic and the family did not seek medical attention. There was no history of urethral discharge or meatal ulceration. Urination was normal. Past health was unremarkable.

The cystic lesion was located at the 3 o'clock position on the glans penis near the urethral meatus and measured 2 mm in diameter. It was nontender. The cyst was excised. Histological examination showed that the cyst was lined by columnar epithelium. The postoperative course was uneventful. The patient was followed up for 2 years with no recurrence of the lesion.

The cause of parameatal urethral cysts is unclear. Congenital lesions are believed to be caused by faulty separation of the foreskin from the glans or occlusion of the parameatal duct. Acquired cysts may result from an infection.

The cysts are usually asymptomatic, although they can be itchy or painful. Large cysts and those in close proximity to the urethral meatus may cause deflection and spraying of the urinary stream.

Treatment consists of complete excision of the cyst. The lesion often recurs after spontaneous rupture or aspiration.


 • Koga S, Arakaki Y, Matsuoka M, Ohyama C. Parameatal urethral cysts of the glans penis. 

. 1990;65:101-103.
 • Onaran M, Tan MO, Camtosun A, et al. Parameatal cyst of urethra: a rare congenital anomaly. 

. 2006;38:273-274.
 • Yoshida K, Nakame Y, Negishi T. Parameatal urethral cysts. 

A 4-year-old boy was brought for evaluation of a tiny cystic mass on the penis. The lesion was first noted a year earlier when the foreskin became retractable.

Parameatal Urethral Cyst

The mass protruding from the introitus of this 1-month-old girl was first noted at birth. She was born to a 26-year-old primigravida at term after an uncomplicated pregnancy and normal spontaneous delivery. The mother was not taking any medications during the pregnancy. There was no history of birth trauma.

The infant was not in distress. The flesh-colored smooth-surfaced lesion protruding from the vagina was characteristic of a hymenal tag. The rest of the examination findings were unremarkable.

Hymenal tags are present in 3% to 13% of normal female newborns. The tags are commonly located in the superior and inferior positions and tend to resolve spontaneously. New hymenal tags may appear postnatally as a result of extension of an intravaginal or external hymenal ridge.

The parents were reassured of the benign nature of the lesion and that it will resolve with time.


 • Berenson AB, Grady JJ. A longitudinal study of hymenal development from 3 to 9 years of age. 

. 2002;140:600-607.
 • Heger AH, Ticson L, Guerra L, et al. Appearance of the genitalia in girls selected for nonabuse: review of hymenal morphology and nonspecific findings.

The mass protruding from the introitus of this 1-month-old girl was first noted at birth. She was born to a 26-year-old primigravida at term after an uncomplicated pregnancy and normal spontaneous delivery.

Hymenal Tag

A 6-year-old boy presented with a swollen penis and lip within an hour after ingesting some peanuts. The swelling was nonpruritic. The child described a sense of tightness in the lips. He had no associated rash, abdominal pain, dysphagia, stridor, dyspnea, dysuria, or abnormality in the urinary stream. He was not taking any medications. He had no history of a recent viral infection, insect bite or sting, oral or genital trauma, or blood transfusion. There was no family history of asthma, atopic dermatitis, allergic rhinitis, or angioedema.

Examination revealed no signs of an allergic reaction other than the angioedema of the lips and penis. The foreskin could be retracted, and the urethral meatus was normal. The child was treated with hydroxyzine, 10 mg orally 4 times a day. The angioedema subsided within 72 hours.

Angioedema is most commonly caused by a type I-anaphylactic or IgE-mediated-immediate hypersensitivity reaction to food (notably, peanuts, cow’s milk, eggs, chocolate, or seafood), drugs (notably, antibiotics, opiates, or sedatives), stinging insect venom, preservative, latex product, or aeroallergen. Angio edema may also be a consequence of a type II cytotoxic reaction (transfusion reaction) or a type III antigen-antibody complex reaction (serum sickness). Vibratory angioedema and exercise-induced angioedema result from hypersensitivity to a mechanical or physical factor. Hereditary angioedema is an autosomal dominant disorder associated with the absence or dysfunction of C1 inhibitor.


 • Estrada JL, Gozalo F, Cecchini C, Casquete E. Contact urticaria from hops (

) in a patient with previous urticaria-angioedema from peanut, chestnut and banana. 

. 2002;46:127. • Leung AK, Robson WL. Penile and oral angioedema associated with peanut ingestion. 

. 2006;98:2011-2012.
 • Smith GA, Sharma V, Knapp JF, Shields BJ. The summer penile syndrome: seasonal acute hypersensitivity reaction caused by chigger bites on the penis. 

A 6-year-old boy presented with a swollen penis and lip within an hour after ingesting some peanuts.

Penile Angioedema After Peanut Ingestion

17-Year-old girl with a 7-month history of small, red papules on her arms and thighs. Rash is not painful or itchy. Otherwise in good health.

Numerous, red, cone-shaped follicular papules with keratotic plugs noted on her arms and thighs. Physical examination results otherwise unremarkable.

Keratosis pilaris is a disorder of keratinization of the infundibulum of pilosebaceous follicles that results in horny plugs that fill the follicular orifice.

Keratosis pilaris is a very common disorder: 40% of the population is affected.

 It develops during childhood and reaches its peak during adolescence. The prevalence in adolescents of both sexes is estimated to be at least 50%, while up to 80% of adolescent girls may be affected.

 The disorder involutes spontaneously and is less common during adult life.

The exact cause is not known. An autosomal dominant mode of inheritance with incomplete penetrance has been postulated.

 The high prevalence and intensity seen at puberty suggest a hormonal influence. Hyperandrogenism in the presence of obesity is associated with an increased incidence and severity of keratosis pilaris.

Keratosis pilaris is more common in patients with ichthyosis vulgaris and atopic dermatitis.

 Keratosis pilaris has also been reported to occur as a reaction to contact with cutting oil.

Other conditions associated with keratosis pilaris include Cushing disease, hypothyroidism, vitamin A intoxication, vitamin C deficiency, monilethrix, Hodgkin disease, monosomy 18p, and cardio-facio-cutaneous syndrome.

 Given the high prevalence of keratosis pilaris, caution is suggested in the interpretation of these associations.

	Treatment
	Measures should be taken to prevent excessive skin dryness. These include decreasing the frequency of skin cleansing; taking brief, tepid showers rather than long, hot baths; using mild soaps; and humidifying the home.

 In mild cases, an emollient-such as hydrophilic petrolatum-or a 10% to 20% urea cream usually alleviates the rough surface. More pronounced or widespread lesions may require treatment with a keratolytic agent, such as lactic acid, salicylic acid, or urea in combination with a topical corticosteroid or retinoic acid.

The follicular orifice is distended by a keratotic plug that may contain twisted hairs.

Keratosis pilaris presents as minute, discrete, keratotic, follicular papules with variable perifollicular erythema.

 The lesions are not grouped and show no tendency to coalesce to form plaques. The affected skin looks like gooseflesh and feels like sandpaper. The lesions are not pruritic. Keratin plugs cannot be expressed with pressure and are usually painless.

 The lesions may be isolated or widespread; they have a predilection for the lateral aspects of the upper arms, thighs, and buttocks. The hands and feet are usually spared, but palmoplantar markings are more accentuated.

The differential diagnosis includes folliculitis, acne, phrynoderma, pityriasis rubra pilaris, and lichen spinulosus.

 The clinical features of keratosis pilaris are so distinct that usually there is little difficulty in diagnosis.

 Barth JH, Wojnarowska F, Dawber RP. Is keratosis pilaris another androgendependent dermatosis? 

 Poskitt L, Wilkinson JD. Natural history of keratosis pilaris. 

 Lateef A, Schwartz RA, Janniger CK. Keratosis pilaris. 

 Novick N. Practical management of widespread, atypical keratosis pilaris. 

 Georgouras K. Oil contact keratosis pilaris. 

 Thomsen K, Nyfors A. Keratosis pilaris: skin marker of Hodgkin disease? 

 Zouboulis CC, Stratakis CA, Rinck G, et al. Ulerythema ophryogenes and keratosis pilaris in a child with monosomy 18p. 

 Darmstadt GL. Diseases of the epidermis. In: Behrman RE, Kliegman RM, Jenson HB, eds. 

. Philadelphia: WB Saunders Company; 2000:2001-2006.

 Frieden IJ. Other disorders of hair follicles. In: Rudolph AB, Hoffman JI, Rudolph CD, eds. 

. Stamford, CT: Appleton & Lange; 1996:926.

Teenager With Small Red Papules on Her Arms and Thighs

Figure – This 4-year-old girl has a relatively small head, deep-set ears, a protruding tongue, and a wide mouth-all characteristic features of Angelman syndrome. In addition- although not visible in this photograph-she has intermittent exotropia, a flat occiput, widespaced teeth, and drooling.

This 4-year-old girl was born to a 27-year-old gravida, 1 para 0 mother at 37 weeks' gestation via vaginal delivery. The pregnancy was uncomplicated. Apgar scores were 8 at 1 minute and 9 at 5 minutes. The child's birth weight, head circumference, and length were 3045 g, 33 cm, and 50 cm, respectively. Her mother noted global developmental delays (particularly in the areas of speech and fine motor skills), abnormal sleep habits, obstructive sleep apnea, and seizure disorder. Family history was unremarkable.

Her weight, height, and head circumference were 18 kg (90th percentile), 100 cm (50th percentile), and 48.5 cm (25th percentile), respectively. The child appeared quite happy. She had deep-set eyes, a posteriorly flattened head, intermittent left exotropia, occasional hand flapping, and tremors of her upper extremities. Deep tendon reflexes were 2+ and symmetrical bilaterally, with a downgoing plantar reflex. Results of the remainder of the physical examination were unremarkable.

An electroencephalogram (EEG) showed diffuse slow (2 to 3 Hz), high-voltage delta waves and moderate posterior discharges.

Colloquially referred to as "happy puppet" syndrome or 

, Angelman syndrome was first described by Harry Angelman in 1965.

 Characteristic features of this syndrome include unusual facial characteristics, an especially happy demeanor, severe global developmental delays (particularly in language), seizures, and a jerky, marionettelike spasticity.

 Along with its sister condition, Prader-Willi syndrome, Angelman syndrome is commonly cited as a prime example of the effects of abnormal parental genomic imprinting.

The incidence of Angelman syndrome ranges from 1 per 10,000 to 1 per 40,000 live births.

Males and females are equally affected with no geographical clustering noted. There is controversy over whether a slightly increased incidence is associated with use of assisted reproductive technology-a result of the epigenetic dysregulation potentially caused by the process.

Angelman syndrome results from a defective maternally derived copy of the ubiquitin protein ligase E3A (

) gene located at chromosome 15q11.2-q13.

 UBE3A is subject to genomic imprinting and is mainly expressed from the maternal allele within the brain.

 defects occur through 4 known mechanisms, each of which is associated with a slightly different phenotype:

Class I: interstitial deletions of maternal DNA from 15q11.2-q13 (70% of cases).

Class II: uniparental disomy of paternal chromosome 15 (2% to 7% of cases).

Class III: genomic imprinting malfunctions (2% to 5% of cases).

Class IV: direct mutations of the maternal UBE3A gene (8% to 11% of cases).

In addition, 10% to 20% of patients with an Angelman phenotype display no genetic abnormalities and hence have an unknown mechanism; these patients are said to have class V Angelman syndrome.

Class I defects tend to produce the most severe phenotypes, while class II and class III defects usually produce phenotypes with more atypical features.

 Recurrence risks also vary with the underlying genetic defect.

 In this patient, fluorescent in situ hybridization (FISH) identified a 15q11.2-q13 deletion (a class I defect), with no evidence of genetic abnormalities in the mother. This result suggests that a de novo mutation occurred-the most common manner in which class I Angelman syndrome arises.

Interestingly, while Angelman syndrome results from defects in maternally derived DNA at chromosome 15q11.2-q13, Prader-Willi syndrome, by contrast, results from defects in paternally derived DNA in the same region.

According to consensus diagnostic criteria published in 2005, the clinical manifestations of Angelman syndrome are divided into 3 prevalence-based categories. 

 The first category consists of features that are seen in all patients. These include severe developmental delay; behavioral changes (hypermotor behavior, easily elicited excitement, laughter, smiling, uplifting, and hand flapping); speech impairments, with minimal use of verbal language; and lastly, movement disorders ("puppet-like" tremulous movement of limbs with hypertonicity) and/or balance disorders (usually ataxia).

 In the second category are frequently seen features, which occur in more than 80% of patients. These include microcephaly, seizures, and abnormal EEG patterns.

In the third category are associated features that are seen in 20% to 80% of patients with Angelman syndrome. Features in this category include characteristic facial appearance (flat occiput, occipital groove, protruding tongue, tongue thrusting, wide mouth with widespaced teeth and frequent drooling), feeding problems, strabismus, increased heat sensitivity, abnormal sleep-wake cycles (reduced total and REM sleep time, frequent nocturnal awakenings, leg movements without excessive daytime sleepiness), feeding difficulties, and abnormal fixations with water and "crinkly" items.

Many complications of Angelman syndrome result from the progression of clinical features that first manifest in childhood.

 As affected children grow, gastroesophageal reflux and obesity develop; tremors and facial characteristics also become more pronounced (more pointed chin, macrostomia, deeper-set eyes, marked mandibular prognathism).

 Reduced mobility, joint contractures, and thoracic scoliosis often become issues in adulthood because of hypertonicity.

Frequent epileptic seizures develop in about 80% to 90% of children.

 Osteopenia has also been noted,possibly as an adverse effect of long-term use of antiepileptic medications.

Behaviorally, patients tend to sleep more regularly and become less excitable with age, although aggression and frustration increase because of continued communication difficulties that significantly impair quality of life. Danger perception and activities of daily living continue to be challenges; thus, patients generally require ongoing supervision and are unable to live independently. The life span is not greatly reduced.

Clinical suspicion of Angelman syndrome tends to arise around age 3 years, when the characteristic behavioral changes predominate over the nonspecific neurological signs seen in infancy (such as microcephaly, flat occiput, protruding tongue, seizures).

 Before this age, mild and moderate cases tend to remain undiagnosed. 

 Conditions with which Angelman syndrome is commonly confused are loosely organized as follows:

Single-gene conditions (Rett syndrome, Gurrieri syndrome, and N

-methylenetetrahydrofolate reductase deficiency).

Symptom complexes (cerebral palsy, Lennox-Gastaut syndrome, autism spectrum disorder, pervasive developmental delays, and encephalopathy).

Microdeletions/duplications of chromosome regions 2, 4, 15, 17, and 22.

Angelman syndrome is characterized by an abnormal childhood EEG with the following possible changes:

Rhythmic 2- to 3-Hz triphasic delta waves accentuated over anterior regions and superimposed by interictal epileptiform discharges (most commonly observed).

Persistent, rhythmic 4- to 6-Hz activity not associated with drowsiness.

High-amplitude 3- to 4-Hz spike and sharp waves in posterior regions, elicited by eye closure.

These EEG changes are highly specific to Angelman syndrome and can be helpful for diagnosis in the context of clinical features consistent with the condition.

 There are no significant differences between the EEGs of affected patients who suffer from seizures/epilepsy and the EEGs of those who do not. EEG changes tend to become less pronounced by age 9 years.

The diagnosis of Angelman syndrome can also be confirmed with genetic testing according to a specific diagnostic algorithm involving DNA methylation testing, FISH and 

 mutation testing; however, normal results do not exclude the condition, because of the potential for class V defects.

CT/MRI scans and results of blood, metabolite, and urine tests are usually unremarkable.

Because no known cure for Angelman syndrome exists, management goals are to improve the quality of life by relieving active symptoms and preventing disease progression. A multidisciplinary team approach is encouraged to manage the various aspects of the syndrome. 

 Early special education programs are vital since communication difficulties are often the most disabling feature of this syndrome.

 Involvement of a pediatric neurologist is often required because seizures can be especially difficult to control in early childhood. Valproate, clonazepam, phenytoin, and lamotrigine have been shown to be effective antiepileptic drugs.

 In adult patients, physiotherapy and occasionally orthopedic surgery may be needed to manage contractures. Finally, because a variety of genetic mechanisms can underlie Angelman syndrome, medical geneticists and genetic counselors play an important role in organizing genetic testing and educating patients and parents about recurrence risks.

 This patient's management team included a general pediatrician, a developmental pediatrician, a pediatric neurologist, a pediatric pulmonologist, a pediatric ophthalmologist, a geneticist, a physiotherapist, and a speech therapist.

 Angelman H. "Puppet children": a report on three cases. 

 Clayton-Smith J, Laan L. Angelman syndrome: a review of the clinical and genetic aspects. 

 Oliver C, Horsler K, Berg K, et al. Genomic imprinting and the expression of affect in Angelman syndrome: what's in the smile? 