Bridget Boyd, MD

A newborn boy born via normal vaginal delivery at 38.6 weeks gestation to a 33-year-old G5P2022 mother presented at birth with an asymptomatic 8-mm red, papulonodule with central crusting on the right cheek (Figure 1). Pregnancy had been complicated by maternal type 2 diabetes mellitus and obesity. Delivery was uncomplicated and the patient was otherwise healthy.

Mother was otherwise healthy and the pregnancy was uneventful. Medications that were used during the pregnancy included prenatal vitamins, insulin, ranitidine, and diphenhydramine. All antenatal ultrasounds, serologies, and labs were unremarkable. Mother reported no relevant personal or family history, specifically no history of herpes simplex virus (HSV) infection, other viral infections, leukemia/lymphoma, or immunodeficiencies.

Initial physical examination revealed a well appearing infant. The Apgar scales were 9, 9, and 9 at 1, 5, and 10 minutes respectively. Patient weighed 3485 grams, an appropriate weight for his gestational age. Vital signs were within normal limits upon delivery.

Skin examination revealed an asymptomatic, round, red, non-blanching, 8-mm firm papulonodule on the right cheek. The lesion had an erythematous base with no drainage or crusting on initial exam. Central crusting later developed on the first day of life. The patient did not appear bothered by the lesion. Physical exam was otherwise unremarkable.

The patient received all routine neonatal labs. Hemoglobin and hematocrit levels were within normal limits. He required 2 oral glucose gels prior to glucose normalization. Metabolic screens were within normal limits. At 24 hours of life, C-reactive protein and a complete blood count were drawn and returned with no abnormalities.

Ultrasound of the lesion of the right cheek demonstrated a heterogeneous, hypoechoic lesion with no evidence of increased vascularity. Pediatric dermatology was consulted for further evaluation of the lesion and performed a biopsy that revealed Langerhans cells with surrounding inflammatory cells and eosinophils (Figures 2 and 3). A cutaneous proliferation of CD1a, CD68, and S100 positive cells was also confirmed via immunohistochemical staining (Figures 4 and 5). Fungal cultures, aerobe-anaerobe cultures, and an acid-fast bacilli culture were negative. These findings were typical of cutaneous Langerhans cell histiocytosis.

The initial differential diagnosis included several infectious and noninfectious etiologies that could account for such a skin lesion (Table). Infantile hemangiomas were high on the differential, as these are the most common skin neoplasms presenting in infancy.

 These are benign vascular tumors with a prevalence of 4%-10% worldwide.1 Ultrasound imaging may demonstrate an increase in internal vascularity. Ultrasound of our patient on day 1 of life indicated no prominent internal vascularity, making the diagnosis of infantile hemangioma less likely. Moreover, the presence of a nodule at birth and uniform blanching erythema with central crusting would not be typical of a classic infantile or congenital hemangioma.

Langerhans cell histiocytosis (LCH) was another diagnosis considered as it has a variable clinical presentation. Manifestations of this hematologic disorder can range from single cutaneous lesions to multiple cutaneous lesions, and to a multi-organ disease. Skin involvement is present in 33% of patients and appearance can vary from dry scaly lesions to crusted vesicles and red papules.

 Biopsy confirms characteristic histologic and immunohistochemistry findings.

Biopsy is also critical to exclude other diagnoses such as congenital juvenile xanthogranuloma. This is a form of non-Langerhans cell histiocytosis which can present as subcutaneous masses with overlying skin changes, papules, or nodules that are erythematous at presentation and become yellow in color over weeks to months.

 These lesions vary from a few mm in diameter to over 3cm, and most commonly involve the head, neck, or trunk.

Leukemia cutis describes skin manifestations that arise as a result of an underlying leukemia. These lesions can also have a variable presentation including red or violet papules, plaques, nodules or hemorrhagic lesions.

 These lesions commonly appear after a diagnosis of leukemia has already been made, but may also appear before there is any involvement of the peripheral blood or any systemic symptoms arise.

 Approximately two-thirds of patients presenting with neonatal acute myeloid leukemia also present with skin lesions, but lesions may be limited to the skin and resolve without treatment. However, these patients usually have other findings including hepatosplenomegaly or a high systemic tumor burden.

 Confirmation of this diagnosis is also completed via skin biopsy.

Other potential etiologies include congenital sarcomas, such as rhabdomyosarcoma. These soft-tissue neoplasms can present as red or violaceous nodules if they metastasize to involve the skin.

 Additionally, extramedullary hematopoiesis, or a “blueberry muffin rash”, can also present as similar papules and nodules that can be the result of an underlying infection (often TORCH infections), hemolysis, or malignancy.9

An infectious etiology also cannot be ruled out when a newborn presents with an abnormal skin lesion. Neonatal HSV needs to be considered due to the high morbidity and mortality rates associated with this infection.

 Patients with neonatal HSV usually present with clusters of vesicles localized to the skin, eyes or mouth. Failure to treat could lead to disseminated disease or spread to the central nervous system.

 Cutaneous lesions can also be the manifestation of infections caused by the other congenital TORCH infections, 

Infection could suggest that there is an underlying immunodeficiency such as HIV, malignancy, or a white blood cell disorder. Our patient did not present with any risk factors for these conditions and lab values were reassuring. Additionally, the patient was not exposed to any risk factors that would alter the function of the immune system at this age including maternal illness, prematurity, immunosuppressive medications or inadequate prenatal care.

Langerhans cell histiocytosis has an incidence of 2.6-8.9 cases per million amongst children aged younger than 15 years, and a median age of diagnosis of 3-4 years.

 This disorder is characterized by proliferation of CD1a, S100, CD68, and CD207 myeloid dendritic cells and has a highly variable clinical presentation.

 Any organ system can be affected, thus requiring a comprehensive evaluation of affected patients. Commonly affected sites include the bone, skin, central nervous system, pulmonary, hematopoietic, and hepatobiliary systems.

Among patients diagnosed with LCH, 33% present with skin findings.

 Skin lesions usually present as ulcerated, red papules, as was seen in our patient, but may also appear pustular, vesicular, or petechial in nature.

 In infancy skin manifestations may also resemble other skin disorders such as erythema toxicum neonatorum, eczema, or seborrheic dermatitis. As a result, it is important to accurately diagnose this condition to ensure appropriate treatment.

A rare variant of LCH named congenital self-healing reticulocytosis has also been identified. This condition was first described by Hashimoto and Pritzker and presents at birth or within the first few weeks of life.

 Patients may present with brown to violaceous papules located anywhere on the body. As with classic LCH, these lesions can be single or multiple. It is thought that the true incidence of this variant is underreported because most of these lesions resolve without treatment within the first 3-4 months of life.

Although children with lesions isolated to the skin usually have a good prognosis, patients with LCH who have isolated skin involvement also have an excellent prognosis, however, close observation is still required.

 In 40% of patients with similar isolated cutaneous findings progression to multi system disease or reactivation was observed.

Initial evaluation of patients with LCH requires determining whether there is single or multisystem involvement. Recommended testing includes a complete blood count with differential, complete metabolic panel including liver function tests, and coagulation studies. Imaging assessment should include a skeletal survey, ultrasound of the liver and spleen, and chest radiography.

 Treatment can then be tailored to the individual patient and extent of their disease.

Treatment for LCH is dependent on the site affected and the number of lesions. For patients presenting with isolated skin involvement, surgical resection can lead to cure. If lesions are multiple then topical corticosteroids are first line therapy, with second line agents including topical nitrogen mustard, oral thalidomide, and oral methotrexate.

 Additional studies need to be completed to further assess the efficacy of second line treatment options.

If skin involvement is diffuse or there are signs of multisystem disease, a systemic steroid with vinblastine for 6-12 months is first-line treatment. For patients with organ involvement (spleen, liver, bone marrow) 6-mercaptopurine may also be added to this treatment regimen.

 Prognosis for patients who fail these first-line treatment options is typically poor, and salvage therapy is indicated in these situations. This includes treatments such as hematopoietic stem cell transplant or a combination of cladribine and cytarabine.

Recent research has been investigating the use of therapies targeting BRAF-V600E mutations. Patients with this mutation are more likely to have higher risk LCH or have increased resistance to treatment.

 Vemurafenib, a BRAF inhibitor, has been shown to be efficacious, however further studies are required to determine appropriate dosing and duration of therapy.

Current recommendations for follow up for patients treated for isolated skin findings include evaluation of the lesion every 2 to 4 weeks. This includes monitoring for any signs of progression to multisystem involvement. Once the skin lesions have resolved, follow-up is recommended every 6 months for at least 5 years.

The cheek lesion was excised by pediatric dermatology and our patient was evaluated by the pediatric hematology-oncology service. Initial skeletal survey to assess for bone involvement showed a calvarial lesion suspicious for LCH. Follow up whole body positron emission tomography scan was completed and showed no findings of bone or other multisystem involvement. As a result, systemic therapy was not indicated as the cheek lesion was previously excised. It was determined that the patient likely had the congenital self-healing reticulocytosis variant of LCH. The patient continues to follow with serial skeletal surveys and labs, and remains in complete remission.

Acknowledgements: The authors thank Dr Kumaran Mudaliar, MD; Dr Wendy Kim, DO; and Dr Natalie Kamberos, DO for their valuable contributions to this case.

1. Rotter A, de Oliveira Z. Infantile hemangioma: pathogenesis and mechanisms of action of propranolol. 

2. Krooks J, Minkov M, Weatherall A. Langerhans cell histiocytosis in children. 

3. Papadopoulou M, Panagopoulou P, Papadopoulou-Alataki E. The multiple faces of Langerhans cell histiocytosis in childhood: A gentle reminder. 

4. El Demellawy D, Young JL, de Nanassy J, et al. Langerhans cell histiocytosis: a comprehensive review. 

5. Oza VS, Stringer T, Campbell C, et al. Congenital-type juvenile xanthogranuloma: A case series and literature review. 

6. Martínez-Leboráns L, Victoria-Martínez AM, Torregrosa-Calatayud JL, et al. Leukemia Cutis: A report of 17 cases and a review of the literature. 

7. Gru AA, Coughlin CC, Schapiro ML, et al. Pediatric Aleukemic Leukemia Cutis: Report of 3 cases and review of the literature. 

8. Roberts I, Fordham NJ, Rao A, et al. Neonatal Leukemia. 

9. Manning JR, Lee DH. Uncommon Neonatal Skin Lesions. 

10. Harris JB, Holmes AP. Neonatal Herpes Simplex Viral Infections and Acyclovir: An Update. 

11. Stanberry LR. Herpes simplex virus. In: Kliegman RM, Stanton BF, St. Geme JW, et al. 

 20th ed. Philadelphia, PA: Elsevier; 2016.

12. Collins A, Weitkamp JH, Wynn JL. Why are preterm newborns at increased risk of infection? 

13. Carlo WA, Ambalayanan N. High-risk pregnancies. In: Kleigman RM, Stanton BMD, St. Geme J, et al. 

14. Leung AKC, Lam JM, Leong KF. Childhood Langerhans cell histiocytosis: A disease with many faces. 

15. Hashimoto K, Pritzker MS. Electron microscopic study of reticulohistiocytoma: an unusual case of congenital, self-healing reticulohistiocytosis. 

16. Trung A, Ahmad RC, Jennings C, et al. Congenital cutaneous Langerhans histiocytosis with mixed cell populations. 

17. Lau L, Krafchik B, Trebo MM, et al. Cutaneous Langerhans cell histiocytosis in children under one year. 

18. Gadner H, Minkov M, Grois N, et al. Therapy prolongation improves outcome in multisystem Langerhans cell histiocytosis. 

19. Donadieu J, Bernard F, van Noesel M, et al. Cladribine and Cytarabine in Refractory Multisystem Langerhans Cell Histiocytosis: Results of an International Phase 2 Study. 

20. Heritier S, Emile JF, Barkaoui MA, et al. BRAF mutation correlates with high-risk Langerhans cell histiocytosis and increased resistance to first-line therapy. 

21. Kobayashi M, Tojo A. Langerhans cell histiocytosis in adults: Advances in pathophysiology and treatment. 

22. Morren MA, Vanden Broecke K, Vangeebergen L, et al. Diverse cutaneous presentations of Langerhans cell histiocytosis in children: a retrospective cohort study. 

Articles

A newborn boy born via normal vaginal delivery at 38.6 weeks gestation to a 33-year-old G5P2022 mother presented at birth with an asymptomatic 8-mm red, papulonodule with central crusting on the right cheek. What's the diagnosis?

 Red papulonodule with central crusting on a neonate’s cheek

A previously healthy 4-year-old male, born late preterm by urgent cesarean delivery with an uncomplicated postnatal course, presents to the outpatient clinic for a chief complaint of worsening cough over the past 5 months. He denies current fever, rhinorrhea, shortness of breath, diarrhea, or vomiting. His cough has been worsening in severity and frequency, and mostly occurs during the daytime. The cough does not worsen at night and does not interfere with the patient’s daily activities. The cough is nonproductive and is not exacerbated with activity or laying in the supine position. He does not have any sick contacts at home nor any history of recurrent viral upper respiratory infections.

The patient’s cough symptoms began 5 months ago when the patient was first seen in the emergency department (ED) for a viral upper respiratory infection (URI) and was prescribed Tylenol and ibuprofen. He was subsequently seen in the outpatient setting 2 more times for a persisting and worsening intermittent cough, where supportive care was recommended with a trial of Zyrtec, without symptomatic relief for the patient. Last week, he presented to immediate care for a 4-day history of cough, congestion, diarrhea and vomiting, and a 1-day history of fever. He was prescribed ibuprofen and supportive therapy for a presumed recurrent viral URI, and the majority of his symptoms resolved except for his cough, which continued to worsen and prompted evaluation at this visit.

On examination, the patient is a well-hydrated afebrile child in no acute distress. His growth parameters are normal for his age. His vital signs are all within normal limits, and he is saturating 98% oxygen on room air. He has moist mucous membranes without pharyngeal erythema or tonsillar exudates. He does not have cervical lymphadenopathy, pallor or cyanosis, and he is not tachypneic, wheezing, or in evident respiratory distress.

On auscultation, his lungs are clear bilaterally with good air movement, but bowel sounds are appreciated over his lower-right sternum. His abdomen is nontender, nondistended, with normoactive bowel sounds in all 4 quadrants.

During the patient’s visit to immediate care the previous week, urinalysis, rapid strep test, rapid influenza diagnostic testing, and a frontal chest X-ray to rule out pneumonia were obtained. Urinalysis was within normal limits, and both the influenza testing and rapid strep test results returned negative.

The frontal chest X-ray demonstrated evidence of clustered gas collections at the gastroesophageal junction. Lateral and frontal chest X-rays were repeated at this visit, along with a respiratory polymerase chain reaction (PCR) panel. Respiratory PCR results were positive for parainfluenza. Both lateral and frontal chest X-rays demonstrated large air-filled loops of bowel extending anteriorly from the right diaphragm to medial right lower hemithorax (Figures 1 and 2). Pediatric surgery was consulted for evaluation of the abnormal imaging findings.

Chronic cough in children is typically defined as a cough lasting longer than 4 weeks’ duration in a patient aged younger than 14 years.

 In 2 studies evaluating the etiologies behind chronic cough in children, the most common causes included upper airway cough syndrome (UACS), also known as postnasal drip; asthma and asthma-like symptoms; gastroesophageal reflux disease (GERD); and protracted bronchitis.

Recommended initial evaluation in a child presenting with chronic cough is chest radiography and spirometry, although empiric therapy is usually not recommended in a child with a nonspecific chronic cough.

For this patient, his first presentation was consistent with a viral URI, which appeared to be the precipitating event for his cough. While his cough persisted, this was thought to be a self-resolving postviral symptom or a recurrent viral URI. Of note, his viral respiratory PCR was positive for parainfluenza, which indicates that he did indeed have a viral URI at the time of presentation. A Morgagni hernia was detected incidentally on his chest X-ray for a workup of pneumonia when he presented to immediate care for a fever with chronic cough.

The patient’s worsening cough may have been exacerbated by his hernia contacting the pleura and pulmonary lining, which would have been already irritated from multiple viral URIs. Additionally, Morgagni hernias have been reported to present initially as repeated chest infections and gastrointestinal (GI) complaints,

 both of which were present in this patient. However, it is also a possibility that the cough worsened the extent of his hernia by increasing intraabdominal pressure and placing strain on the diaphragm.

Although imaging clearly demonstrated air-filled loops of bowel herniating through the patient’s diaphragm, imaging is not always definitive because the visualized bowel may vary in consistency. Oftentimes, further evaluation with a computed tomography (CT) scan is indicated to evaluate the extent of herniation and to rule out other causes such as a pericardial fat pad, lipoma, or mediastinal cyst.

Although in many cases patients are asymptomatic, surgery is recommended on initial diagnosis of a Morgagni hernia to preserve normal lung function and prevent acute complications such as bowel incarceration.

Congenital diaphragmatic hernia (CDH) occurs at a rate of fewer than 5 in 10,0000 births and is relatively rare compared with other potential etiologies of chronic cough. Most reported cases of CDH are Bochdalek hernias, which present via posterolateral defects in the diaphragm, whereas Morgagni hernias, which present anteromedially, are exceedingly rare, accounting for less than 5% of diagnosed CDHs.

 Interestingly, although cases of CDH classically present on the left hemisphere, Morgagni hernias frequently localize to the right hemisphere.

Whereas CDH typically presents postnatally as acute respiratory distress in the neonate, a small subgroup of patients with CDH present later in life and may be asymptomatic. Compared with Bochdalek hernias, Morgagni hernias are more likely to result in a delayed presentation and diagnosis.

 Also unlike Bochdalek hernias, Morgagni hernias are not associated with lung hypoplasia or pulmonary hypertension, and thus do not present with acute respiratory symptoms postnatally.

For patients with a delayed presentation of Morgagni hernia, common complaints included recurrent respiratory infections, nonspecific GI complaints, and failure to thrive. However, many Morgagni hernias are found incidentally on imaging.

 Acute symptoms such as neonatal respiratory distress and GI obstruction also have been reported.

 Morgagni hernias have been shown to be related to other congenital abnormalities, such as heart defects and chromosomal abnormalities.

Morgagni hernias occur when the septum transversum fails to fuse with the costal arches during embryonic development, leading to a defect known as the foramen of Morgagni or the sternocostal triangle, which lies retrosternal, anteriorly and medially adjacent to the sternal and costal diaphragmatic attachments. Loops of large bowel, small intestine, or omentum subsequently can herniate through this open defect. The best initial imaging modality to diagnose a Morgagni hernia is chest radiograph in the postnatal period and beyond, which will demonstrate loops of bowel in the thoracic cavity, and ultrasound in the prenatal period, which will reveal a mass in the fetal thoracic cavity accompanied by a mediastinal shift.

This case demonstrates the importance of a thorough physical exam, as not all diaphragmatic hernias present acutely or with obvious symptoms.

Surgical repair is the first-line treatment following diagnosis of a Morgagni hernia. A transthoracic approach to the repair is preferred over a transabdominal approach because the transthoracic method offers adequate visualization and better control and avoids potential adhesions that may complicate a transabdominal approach.

 Reduction of hernia contents with primary closure is performed, oftentimes with a synthetic patch for larger defects and tension-free repair.

A minimally invasive laparoscopic approach is also gaining favor, and is associated with a shorter operating time, shorter hospital length of stay, and a more pleasant cosmetic appearance.

 However, cases of hernia recurrence have been reported primarily in laparoscopic repairs without supportive prosthetic patches, and better visualization is obtained with an open approach.

 Open approaches are still more common than laparoscopic approaches.

Lastly, as congenital heart defects and trisomy 21 are common comorbidities associated with Morgagni hernias, echocardiography and karyotype can be considered based on clinical suspicion.

The patient was referred to pediatric surgery, where he underwent a laparoscopic repair of his Morgagni hernia with an uncomplicated operative and postoperative course. His chronic cough subsequently resolved after the hernia repair surgery. 

1. Chang AB, Oppenheimer JJ, Weinberger M, Weir K, Rubin BK, Irwin RS. Use of management pathways or algorithms in children with chronic cough: systematic reviews. 

2. Karabel M, KelekÃ§i S, Karabel D, GÃ¼rkan MF. The evaluation of children with prolonged cough accompanied by American College of Chest Physicians guidelines. 

3. Asilsoy S, Bayram E, Agin H, et al. Evaluation of chronic cough in children. 

4. Al-Salem AH, Zamakhshary M, Al Mohaidly M, Al-Qahtani A, Abdulla MR, Naga M. Congenital Morgagni’s hernia: a national multicenter study. 

5. Minneci PC, Deans KJ, Kim P, Mathisen DJ. Foramen of Morgagni hernia: changes in diagnosis and treatment. 

6. Horton JD, Hofmann LJ, Hetz SP. Presentation and management of Morgagni hernias in adults: a review of 298 cases. 

7. Griffiths EA, Ellis A, Mohamed A, Tam E, Ball CS. Surgical treatment of a Morgagni hernia causing intermittent gastric outlet obstruction. 

8. Wong NA, Dayan CM, Virjee J, Heaton KW. Acute respiratory distress secondary to Morgagni diaphragmatic herniation in an adult. 

9. Taylor GA, Atalabi OM, Estroff JA. Imaging of congenital diaphragmatic hernias. 

10. Ambrogi V, Forcella D, Gatti A, Vanni G, Mineo TC. Transthoracic repair of Morgagni’s hernia: a 20-year experience from open to video-assisted approach. 

11. Tsai J, Sulkowski J, Adzick NS, Hedrick HL, Flake AW. Patch repair for congenital diaphragmatic hernia: is it really a problem? 

12. Laituri CA, Garey CL, Ostlie DJ, Holcomb GW 3rd, St Peter SD. Morgagni hernia repair in children: comparison of laparoscopic and open results.

13. Garriboli M, Bishay M, Kiely EM, et al. Recurrence rate of Morgagni diaphragmatic hernia following laparoscopic repair. 

14. Paul S, Nasar A, Port JL, et al. Comparative analysis of diaphragmatic hernia repair outcomes using the nationwide inpatient sample database. 

15. Martin MJ, Harrison TW. Causes of chronic productive cough: an approach to management. 

A previously healthy 4-year-old male, born late preterm by urgent cesarean delivery with an uncomplicated postnatal course, presents to the outpatient clinic for a chief complaint of worsening cough over the past 5 months. He denies current fever, rhinorrhea, shortness of breath, diarrhea, or vomiting. His cough has been worsening in severity and frequency, and mostly occurs during the daytime.

Bridget Boyd, MD

Articles

Red papulonodule with central crusting on a neonate’s cheek

Chronic cough in a 4-year-old boy