Birt–hogg–dube‘syndrome

Review Article

BIRT–HOGG–DUBE‘ Syndrome

Antonious Maria Selvam.S¹, Praveen.R², Yuvarajan.S³, and Kamal Barathi.S⁴

^{1, 2}Assistant professor, ³Associate professor, ⁴Post graduate,
Sri Manakula Vinayagar Medical College & Hospital, Puducherry

Corresponding Author: Dr. Antonious Maria Selvam.S, Assistant professor, Sri Manakula Vinayagar Medical College & Hospital, Puducherry

Birt–Hogg–Dubé syndrome (BHD) is an inherited disorder characterised by multiplefibrofolliculomas, pulmonary cysts, pneumothorax, renal cysts and renal tumours. In 1977, Birt, Hogg and Dubé evaluated some members of Canadian family who presented them with thyroid cancers and found that they had similar type of fibrofollicular skin tumours with autosomal dominant inheritance.^[1]The German dermatologists Hornstein and Knickenberg examined a middle-aged woman and her brother with multiple perifollicular fibromas and intestinal polyps and found that the disorder was probably inherited from their father who had bilateral renal cysts and unilateral lung cysts with skin tumours.^[2] In 2001, two groups of investigators found the chromosomal location of the gene responsible for BHD following which Nickerson et al delineated the susceptibility locus of the gene on chromosome 17p11.2 and named as folliculin gene later.^[3]

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The common pulmonary presentation is spontaneous pneumothorax. Cystic lung lesions develop in early to mid-adulthood (30–40 years), but also described in patients ranging from 20 to 85 years. There is no gender predilection and there is no adequate studies about the role of cigarette smoking in development of cysts. Most of the patients (75 %) had recurrent pneumothorax. Toro et al. done a study on association of lung cysts, spontaneous pneumothorax and genetic relation in 89 families with Birt–Hogg–Dubé syndrome and indicated that presence of lung cysts was significantly associated with pneumothorax.^[4] Hartman et al found incidental development of pulmonary adenoma and adenocarcinoma in FLCN heterozygous mice by regulation of Target of rapamycin complex 1 (TORC1). Further studies are warranted whether haploinsufficiency in FLCN predisposes to lung cancer.^[5]

Skin lesions appears usually after 20 years of age which manifests as multiple, dome-shaped, whitish papules in the face. These lesions are seen mainly on the nose and cheeks, can be common on the neck, and sometimes on the trunk or the ears. Histologically, the skin tumours are benign hair follicle tumours designated as fibro-folliculoma. Birt and colleagues described fibrofolliculomas, trichodiscomas, and acrochordons as a triad of skin lesions that characterises BHD. Oral lesions may also occur in BHD. The diagnosis of BHD-associated skin lesions is based on both clinical presentation and histological examination.^[6]

The most threatening complication of BHD is renal cancer. In serial studies by Pavlovich and colleagues, 34 of 124 individuals (27%) with BHD had renal tumours at a mean age of 50. However, the risk of renal cancer in BHD is uncertain forseveral reasons.^[7] Firstly, identification of families with BHD has varied and was mostly based on dermatological signs. Secondly, the risk of renal cancer might not be the same for all BHD families. In particular, families in whom the pathogenic FLCN mutations have been described, lung cysts and pneumothorax were the only or predominant clinical manifestations. Based on current data, the risk of renal cancer should probably be considered the same for all carriers of FLCN mutations. Renal cancer is multifocal or bilateral in more than half of patients with BHD, which has implications for clinical management.

FLCN is currently the only gene known to be associated with BHD. Detection of a pathogenic FLCN mutation not only confirms the diagnosis in the index patient but also allows presymptomatic testing of unaffected at-risk relatives. When a pathogenic mutation has been detected, cascade genetic testing aimed at identifying and counselling at-risk family members is indicated. Surveillance in FLCN-mutation carriers usually begins at the age of 20 years.

On CT thorax more than 80% of adult patients with BHD had multiple lung cysts with basal predominance. The characteristic chest CT findings of patients with BHD can be summarized as multiple, irregularly-shaped, thin-walled pulmonary cysts of various sizes, predominantly distributed to the lower medial and subpleural regions of the lung. The histology of pleuro pulmonary lesions in BHD has been studied in several patients and is consistent with emphysematous changes.

The lung parenchyma generally appears normal in patients with BHD. Despite the presence of multiplelung cysts, lung function is usually unaffected. Zbar and colleagues found a 50-fold increase in the risk of pneumothorax for BHD-affected individuals and this increase is probably related to the presence of lung cysts. Patients may have a single episode of spontaneous pneumothorax, but recurrent disease is more common.^[8]

DNA-based diagnosis of hereditary tumour syndromes has led to new classifications of these conditions based on the underlying gene defects.

• At Least 5 fibrofolliculomas or trichodiscomas, at least 1 confirmed histologically, of adult onset
• Pathogenic germline mutation in FLCN

• At Least 5 fibrofolliculomas or trichodiscomas, at least 1 confirmed histologically, of adult onset
• Pathogenic germline mutation in FLCN

• Multiple lung cysts: basally located with no other apparent cause, with or without spontaneous pneumothorax
• Renal cancer: early onset (
• First-degree relative with Birt-Hogg-Dube syndrome.
• Patients should fulfil 1 major or 2 minor criteria for diagnosis.

The management of BHD from a pulmonary perspective is largely focused on the approach to treatment of pneumothorax. The management of pneumothorax in patients with BHD differs from that recommended for primary spontaneous pneumothorax and is similar to that of LAM. In patients with primary spontaneous pneumothorax, the initial pneumothorax is usually managed with conservative measures (observation, aspiration, tube thoracostomy). Measures such as video assisted thoracoscopy (VATS) and mechanical or chemical pleurodesis are typically reserved for recurrent or non-healing cases. However, patients with BHD are at very high risk for recurrent pneumothorax.

Smoking is a known risk factor for development of primary spontaneous pneumothorax. Although no clear association has been found between smoking and the risk of pneumothorax in patients with BHD.^[9] These patients should get regularly immunized. Pneumococcal vaccination and annual influenza vaccination should be strongly encouraged in patients with BHD. Currently, there is no evidence that patients with BHD should be advised against air travel.

Treatment for skin fibrofolliculomas are limited. Case reports indicate that laser ablation using ND YAGor fractional CO2 laser is not curative, but gives temporary improvement. Pendulous fibrofolliculomas or skin tags can often be easily excised.

Because of the increased risk of renal cancer, surveillance for renal tumours is indicated for carriers of FLCN germline mutations and for at-risk relatives in families with clinical BHD but without confirmed FLCN mutation. Currently, there are no established guidelines regarding surveillance for renal cancer in BHD. Lifetime screening is needed for individuals with BHD. Annual renal MRI seems to be the best available surveillance method, with high sensitivity and no radiation side-effects. If renal cancer is diagnosed, staging is done with standard procedures Treatment consists of nephron sparing surgery.

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