DR. KRISHNAN is a pediatric cardiology fellow at Children's National Medical Center, Washington, D.C.
DR. ALY is director, newborn services, The George Washington University Hospital, Washington, D.C.
DR. SIBERRY is an assistant professor of pediatrics in the divisions of general pediatric and adolescent medicine and pediatric
infectious diseases at Johns Hopkins Hospital, Baltimore.
The authors and section editor have nothing to disclose in regard to affiliations with, or financial interests in, any organization
that may have an interest in any part of this article.
It's the second week of your internship. Nursery call is just beginning when the neonatal intensive care unit (NICU) transport
team arrives with a 12-hour-old baby from a rural hospital two hours away. Immediately, you observe multiple, dark, reddish-brown
patches over the baby's trunk, back, and forehead. He appears otherwise healthy, however, and is vigorous.
The baby, you learn, is the 3.3 kg product of a 38-week gestation accomplished by in vitro fertilization. The pregnancy was
complicated by gestational diabetes and hyperthyroidism. The mother's prenatal lab tests and screening for group B streptococcus
were negative. Delivery was complicated by maternal fever, for which antibiotics were administered. In the delivery room,
the on-call pediatrician noted that the baby was in respiratory distress and had multiple skin lesions resembling petechiae
and purpura. He was also hypoglycemic, with a blood glucose of 22 mg/dL, which was corrected quickly with intravenous dextrose.
A complete blood count and blood cultures were drawn and antibiotics were started. Because of the rash, the baby was transferred
to your NICU to rule out sepsis.
Your initial physical examination yields the following: temperature, 36.9 C; heart rate, 145/min; respirations, 62/min;
blood pressure, 75/36 mm Hg; and oxygen saturation, 98% on room air. The baby is alert and pink. Lungs are clear and heart
rate is regular.
The remainder of the exam is unremarkable—except for the skin. He has obvious blue discoloration over the nose that does not
blanch. There are multiple 2- to 5-mm red-brown patches over the trunk, shoulders, and extremities (Figure 1) and one 3-mm
patch on the right forehead. You push on one of the patches; it blanches, and you breathe a sigh of relief. There is a round
depression at what you suspect was the site of a scalp electrode.
You study the newborn's chart. Lab tests at birth showed a serum glucose concentration of 22 mg/dL; a CBC with a leukocyte
count of 5.8 X 103/μL (including a differential count of 44% lymphocytes, 27% bands, 22% segmented neutrophils, 6% monocytes, and 1% basophils),
and hemoglobin of 16.3 g/dL, hematocrit of 47.9%, and a platelet count of 145 X 103/μL. You send specimens of blood and cerebrospinal fluid for culture and axillary, nasopharyngeal, rectal, and ear swabs to
be tested for herpes simplex virus. The CSF is also sent to the lab for microscopic and chemical analysis.
Several ships at sea
Differential diagnosis of erythematous neonatal rash
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The combination of maternal fever and infant respiratory distress prompt you to continue the ampicillin and gentamicin started
at the other hospital and to treat the baby for presumed sepsis. But the rash just doesn't fit the picture. Some congenital
infections, such as herpes simplex, toxoplasmosis, syphilis, rubella, and cytomegalovirus, can present with a combination
of petechiae and purpura; none produce this odd, blanching, ruddy-brown rash (see the table).
You consider the numbers: Results of CSF analysis are consistent with a traumatic tap, with 13,120/mm3 red blood cells and no white cells. Protein concentration in the cerebrospinal fluid is 276 mg/dL, and glucose concentration
is 87 mg/dL. Results of the CSF culture are not back yet.
You return to see your young patient again. On closer examination, you realize that more than one rash may be present. The
bluish discoloration around the nose and mouth is likely bruising related to his face presentation at delivery. The petechiae
may be related to birth trauma, as they are localized and the platelet count and coagulation studies are normal. The scalp
lesion appears to be a scalp electrode injury. But the patches on the forehead, arms, trunk, back, and legs are unlike any
rash that you have seen. Your initial suspicion is congenital hemangiomas. You request a dermatology consult; the consultant
agrees with you.
New cargo to consider
It's now Day 5 of hospitalization for the baby. All cultures have returned negative, and he is breastfeeding well and afebrile.
He also looks much improved—except for a severe diaper dermatitis that has developed. The petechiae have faded, and the scalp
electrode wound is healing. The remaining patches have turned a deeper brown, however, and the lesion on his right shoulder
has grown nodular. The distribution and color of the lesions, you conclude, simply do not fit the diagnosis of congenital
hemangioma. Vascular malformations can present as dark-red macules, but are usually confined to the face or an extremity,
not scattered diffusely. One form of hemangioma—diffuse neonatal hemangiomatosis—can manifest as scattered lesions and can
involve internal organs, but those lesions are usually raised at birth.1
Figure 2: Mast cell infiltrate throughout the dermis
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You call your dermatology colleagues back for another look. They agree: The rash does not truly fit the description of congenital
hemangioma. The differential diagnosis broadens, therefore, to include some zebras: juvenile xanthogranulomatosis, congenital
self-healing reticulohistiocytosis, and mastocytosis. The dermatologist applies gentle pressure to one of the lesions and
notes that a wheal and flare—the classic Darier sign—develop around it. A skin biopsy is obtained, but your suspicion now
leans strongly in one direction, and you alert the pathologist that special staining, with toluidine blue or Giemsa, is needed.
At issue is the tissue
Figure 3: Toluidine blue stain
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The verdict is in from the histology lab: Skin biopsy shows a mononuclear cell infiltrate with eosinophils, consistent with
cutaneous mastocytosis (Figure 2), and toluidine blue staining confirms the presence of mast cells in the dermis (Figure
3). Degranulation of mast cells by mechanical irritation caused the Darier sign that you saw earlier. Your instincts were
right: Juvenile xanthogranulomatosis (multiple soft, yellow-brown nodules on the skin, eyes, lungs, liver, spleen, or heart)
would not have this wheal-and-flare characteristic. Nor would congenital self-healing reticulohistiocytosis, which is characterized
by discrete dark-red nodules and papules that can develop a central ulcer.1Cellular overflow
Mastocytosis is a rare skin disorder in which an elevated number of mast cells infiltrates the dermis of the skin and, sometimes,
internal organs. Mast cells are normally present in blood, skin, and the gastrointestinal (GI) and respiratory tracts. Among
other compounds, they contain histamine, heparin, prostaglandins, leukotrienes, and other cytokines. Systemic symptoms that
can be seen in mastocytosis result from degranulation and release of those chemicals.
More than half of affected persons have symptoms before the age of 2 years. Of these, one quarter have lesions at birth and
one half develop them by 6 months.2
Affected children have a range of presentations, from cutaneous symptoms only to systemic disease. In children, cutaneous
disease is usually self-resolving and considered benign.
Figure 4: The differing presentations of mastocytosis
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There are four major categories of skin disease: mastocytoma, urticaria pigmentosa, diffuse erythrodermic mastocytosis, and
telangiectasia macularis eruptiva perstans (Figure 4). Mastocytomas are 3- to 4-cm solitary lesions consisting of a cluster of mast cells in one area of the skin.3 They appear first in infancy and childhood and resolve before adulthood. Urticaria pigmentosa is another benign cutaneous disease that usually develops in infants. Babies exhibit tan or reddish-brown macules that develop
first on the trunk and spread, but tend to spare the face, palms, and soles.3The more severe skin disorders, diffuse erythrodermic mastocytosis and telangiectasia macularis eruptiva perstans, are rare indeed. In the former, young children develop a thickened, orange peel texture to the skin (peau-de-orange) and
severe blistering and have an increased frequency of systemic symptoms. The latter consists of small lesions that usually
affect adults.
Systemic involvement is rare in children. In affected patients, mast cells can infiltrate the liver, causing hepatosplenomegaly;
bone marrow, causing bone pain and anemia; and GI tract, causing malabsorption. Hematologic disorders, such as mast cell leukemia
and lymphadenopathic mastocytosis with eosinophilia, are likewise rare in children.2 Serum tryptase is a very sensitive marker for systemic disease.
If systemic symptoms are present, urine histamine and serum tryptase concentrations should be measured. A serum tryptase >20
ng/mL or a 24-hour urine histamine >30 ng/mL with evidence of bone marrow or internal organ involvement indicates systemic
disease.4 Bone marrow biopsy can be performed if the CBC is abnormal; specifically, if anemia, thrombocytopenia, leukocytosis, or
eosinophilia are seen. However, bone marrow biopsy may show an elevated mast cell count in children with skin disease only.5 If systemic signs are absent, observation is a reasonable strategy for a child.
Let parents take the helm
Management of mastocytosis focuses on educating the parents. They should be alerted to the signs of mast cell degranulation
and anaphylaxis and possible triggers of this immunoglobulin E-mediated release. Systemic symptoms are the direct result of
the activity of the mast cell contents. Children can develop itching and flushing of the skin, hypotension, nausea, diarrhea,
GI bleeds, and irritability. Children with urticaria pigmentosa can have flares resulting from triggers (exercise, cold, heat,
mechanical irritation, insect bites, bee stings, foods, radioactive contrast, or drugs such as opioids, aspirin, and dextromethorphan).6 These can be managed with H1 blockers such as loratidine or hydroxyzine for skin symptoms, H2 blockers for peptic ulcer/GI bleeding, and nedocromil specifically for nausea, abdominal pain, and diarrhea.2
Parents should be educated about the signs of anaphylaxis and given a supply of subcutaneous epinephrine and instructions
on its use. They can be reassured that one half of children become symptom free by adolescence2 and, in urticaria pigmentosa, most children become asymptomatic by age 5, with only residual pigmentation at the sites of
lesions.1 Children should be followed every six months with a physical exam and CBC until the disease resolves.2
This ship docks at last—or does it?
Although your patient has no systemic symptoms, you agree to further testing because his parents have obvious concerns about
internal organ involvement. The serum tryptase level (5.5 ng/mL) and urine histamine level (9 ng/mL) are both within normal
ranges. Because these tests are sensitive for systemic involvement, you feel confident reassuring the parents. The patient
is discharged with a prescription for subcutaneous epinephrine.
At 3 months of age, your colleague sees the boy at a return visit. This time, he has a more severe rash as well as extreme
pruritis, vomiting, and diarrhea. This exacerbation is managed with hydroxyzine, ranitidine, and nedocromil. He does well
and is symptom free one year afterward—sailing, you hope, on calmer waters!
REFERENCES
1. Weston W, Lane A, Morelli J: Vascular reactions: Urticaria, erythemas, and purpuras, in Color Textbook of Pediatric Dermatology, ed 3, 2002, Mosby, pp 208-210
2. Hartmann K, Metcalfe D: Pediatric mastocytosis. Hematol Oncol Clin North Am 2000;14:625
3. Alto W, Clarcq L: Cutaneous and systemic manifestations of mastocytosis. Am Fam Physician 1999;59:3047
4. Castells MC: Mastocytosis: Classification, diagnosis, and clinical presentation. Allergy Asthma Proc 2004;25:33
5. Mastocytosis Pediatric Information and Parent Support, in www.mastokids.org
6. Brockow K: Urticaria pigmentosa. Immunol Allergy Clin North Am 2004;24:287
