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Medicina (Buenos Aires)

versión impresa ISSN 0025-7680versión On-line ISSN 1669-9106

Medicina (B. Aires) vol.83 no.2 Ciudad Autónoma de Buenos Aires jun. 2023



Hemoptysis after COVID-19 and the importance of differential diagnosis: Birt-Hogg-Dubé syndrome

Hemoptisis luego de COVID-19 y la importancia de los diagnósticos diferenciales: Síndrome de Birt-Hogg-Dubé

Victoria Ruiz1  * 

Lucas Bujan1 

Pablo G. Kalfayan2 

Alberto Seehaus3 

Indalecio Carboni Bisso1 

Marcos Las Heras1  4 

1 Unidad de Cuidados Intensivos - Hospital Italiano de Buenos Aires

2 Genética Médica - Hospital Italiano de Buenos Aires

3 Servicio de Diagnóstico por Imágenes - Hospital Italiano de Buenos Aires

4 Neumonología - Hospital Italiano de Buenos Aires


Birt-Hogg-Dubé syndrome is a genodermatosis of auto somal dominant inheritance characterized by mutations in the folliculin (FLCN) gene. There is an inappropriate inhibition/activation of a protein, the foliculin, which may cause tumor lesions in skin, renal and lung lesions; they could have more risk of developing pneumothorax compared to the normal population. A 38-year-old male patient with bronchial asthma who consulted for hemop tysis three weeks after recovery from COVID-19 infection. A chest tomography was requested, showing an air cyst in the left lower lobe. Physical examination shows evi dence of thoracic skin lesions which a skin biopsy was performed on. The results were compatible with fibrofol liculoma. Differential diagnoses were proposed. A genetic disorder associated with skin lesions was suspected. A multi-genetic panel that includes BRCA1, BRCA2, TP53 and FLCN genes was requested, which reported the mu tation of the FLCN gene in heterozygosis classified as pathognomonic of Birt-Hogg-Dubé syndrome. Patient is currently under clinical follow-up while genetic counsel ing was requested for relatives.

Key words: Birt-Hogg-Dubé syndrome; Fibrofollicu loma; Spontaneous pneumothorax


El síndrome de Birt-Hogg-Dubé es una genoderma tosis de herencia autosómica dominante caracterizada por mutaciones en el gen foliculina (FLCN), donde existe inhibición/activación inapropiada de una proteína, la foliculina, que puede causar lesiones tumorales sisté micas, principalmente a nivel de la piel, renal y lesiones pulmonares, presentando mayor riesgo de desarrollar neumotórax en comparación con la población normal. Comunicamos el caso de un varón de 38 años con asma bronquial que consultó por hemoptisis 3 semanas des pués de la recuperación de la infección por COVID-19. Se solicitó una tomografía de tórax, que mostró un quiste aéreo en el lóbulo inferior izquierdo. Además, presentaba en el examen físico una lesión cutánea que fue biopsiada, presentando diagnóstico de foliculoma. Se plantearon diagnósticos diferenciales y ante la sospecha de probable desorden genético, un panel genético fue solicitado. Se confirmó síndrome de Birt-Hogg-Dubé ante el hallazgo de la deleción heterocigota que comprende el exón 1 del gen FLCN clasificada como patogénica. Actual mente el paciente se encuentra en seguimiento clínico mientras se solicitó estudio genético para familiares.

Palabras clave: Síndrome de Birt-Hogg-Dubé; Fibrofo liculoma; Neumotórax espontáneo

Birt-Hogg-Dubé (BHD) syndrome is a geno dermatosis of autosomal dominant inheritance characterized by genetic mutations in the FLCN gene located in chromosome 17p11.21,2. It encodes foliculin, a protein that through an inap propriate either inhibition or activation of the mTOR pathway may cause skin lesions, renal cancer, and characteristic lung lesions3.

Clinically, it can be observed in the skin as fibrofolliculomas. Histologically, this is a lesion typically vertical or perpendicular to the epi dermis, centered in the hair follicle, and that presents thin epithelial projections4. It should be noted that despite the fact that skin lesions are a warning sign for a dermatologist, not all patients with Birt-Hogg-Dubé syndrome present them.

Within the extracutaneous manifestations, there is a predisposition to present renal tumors which are characteristically bilateral and multi focal, mostly of the histological type of hybrid forms of oncocytoma and chromophobe carci noma4,5.

Regarding pulmonary compromise, up to 80% of patients with this syndrome have lung cysts which may be asymptomatic but that could have up to 50 times more risk of developing pneumo thorax compared to the normal population. The location of the cysts is mainly in the lung bases and at the subpleural level.

Clinical case

We present the case of a 38-year-old male with bron chial asthma treated with budesonide (160 mcg) and for moterol (4.5 mcg) and no history of smoking, who con sulted for isolated hemoptysis event, three weeks after recovery from COVID-19 infection, with a presumptive di agnosis of post-COVID-19 pulmonary complication.

A chest tomography was requested, showing multiple bilateral, basal and adjacent to mediastinum air cyst. The biggest one (28 × 27 mm) in the left lower lobe (Fig. 1A). The lesions were followed up for 3 months, a period in which did not show changes in its size, nor association with interstitial lesions. Neither was evidence of compro mise in computed tomography of the abdomen and pelvis with intravenous contrast, excluding kidney affectation. In this context, different diagnoses were proposed, such as Langerhans cell histiocytosis, lymphangioleiomyoma tosis, lymphocytic interstitial pneumonia and BHD syn drome (Table 1).

Figure 1 A: Chest tomography. Left lower lobe air cyst (28 x 27 mm) B: Skin biopsy (Hematoxylin/eosin stain x40): circumscribed tumoral lesion with central cystic cavity surrounded by concentrically arranged collagen fibers 

Table 1 Differential diagnosis of Birt Hogg Dube syndrome 

During the follow-up of the patient, physical exami nation revealed firm, whitish, papular skin lesions 2 to 4 mm in diameter, asymptomatic throughout the thorax. An interconsultation with Dermatology was requested, who biopsed this lesion, resulting in a circumscribed tumor lesion with a central cystic cavity surrounded by concentrically arranged collagen fibers, compatible with the diagnosis of fibrofolliculoma (Fig. 1B).

Within the family history of the patient, there was a maternal aunt who presented spontaneous pneumotho rax on three occasions; a maternal grandmother with recurrent adrenal carcinoma; and maternal grandfather with leukemia.

Given the suspicion of a genetic disorder associated with skin lesions and cystic lung lesions, a multi-genetic panel was requested (BRCA1/BRCA2/TP53/FLCN) resulting in a pathological variant of the FLCN gene (exon 1 deletion, heterozygous) associated with autosomal dominant BHD syndrome. This variant is a large deletion that occurs in a non-coding region of the FLCN gene. It does not change the encoded amino acid sequence of the FLCN protein. Studies have shown that a similar copy number variant alters FLCN gene expression6. For these reasons, this vari ant has been classified as pathogenic. In this context, the molecular finding explained the clinical condition. Genetic counseling was requested from relatives: both the grandmother and the aunt were diagnosed with the disease. His mother, during the follow-up process, under went a chest tomography that showed cystic lesions in the lungs, but the genetic study is still in process. These patients are currently under clinical follow-up, and fam ily screening is going on.

The patient did not repeat new episodes of hemop tysis.


The follow-up of patients after suffering from SARS-CoV-2 virus disease has led us to carry out imaging studies that can generate the diagnosis of incidentalomas, which require a differential diagnosis approach and follow-up to carry out an early treatment if necessary7.

The management of BHD syndrome must be carried out by a multidisciplinary group of physicians. The two essential components of the clinical follow up of the BHD syndrome are the management of recurrent spontane ous pneumothorax and screening of kidney tumors. The high probability of pneumotho rax is well known, nearly 30% will have it as personal medical history before 40 years old. The optimal method and timing of treating BHD associated pneumothorax is unclear and controversies exist as randomized prospective trials are lacking. Some reviews suggested that BHD-associated pneumothorax should be managed in the same way as in the general population; others argue that with the lower likelihood of spontaneous resolution and re currence, pneumothoraxes should be man aged more aggressively8,9.

Renal tumors are usually multiple and bilat eral, frequently appearing at a median age of 30 to 40 years. In comparison with most inherited renal cancers syndromes, that are commonly related to a single histologic tumor type, BHD syn drome is related to a wide range of tumor histologies, most typically chromophobe tumors and hybrid chromophobe/oncocytic tumors. Clear cellular carcinoma, papillary carcinoma, and blended-kind carcinoma can also occasionally be seen. Some experts recommend abdominal imaging starting at age 21 (or following diagnosis) and at least every 36 months until a mass is identified, at which time interval imaging is determined in the individual patient based upon the size and growth rate of the tumor. Ultrasonography may miss small isoechoic renal masses, and, therefore, computed tomography imaging or magnetic resonance imaging to minimize radiation exposure should be used when possible5. Favorably, the reported patient did not present pneumothorax or renal involvement.

In conclusion, a new medical paradigm has emerged as a result of the SARS-CoV-2 virus pandemic in a number of ways. The increased neumological follow-up made possible early diagnosis of pathologies less common in everyday practice. This case serves as an illustration of dealing with a challenging pathology in terms of the differential diagnosis of cystic lung diseases. The patient and his family should be treated in a multidisciplinary manner focusing on the treatment of potential complications, avoiding late diagnosis of possible oncological pathology, and providing genetic counseling for the patient and his family10.

It is interesting to note that neither Argen tina’s epidemiological statistics nor internation al management guides specify the screening method, frequency, or ideal age for this condi tion; which provides an excellent opening for future research.


The investigation team especially thanks María de los Ángeles Magaz for spelling and grammar check, Dr. Silvia Mion for fibrofolliculoma diagnosis.


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Received: July 12, 2022; Accepted: November 29, 2022

*Dirección postal: Victoria Ruiz, Servicio de Terapia Intensiva, Hospital Italiano de Buenos Aires, Tte. Gral. J. D. Perón 4190, 1199 Buenos Aires, Argentina E-mail:

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