What Is Birt-Hogg-Dubé Syndrome?

A syndrome is a collection of signs and symptoms known to occur together simultaneously indicating a particular disease. In Birt-Hogg-Dubé syndrome, non-cancerous skin lesions,² lung cysts and some renal tumours are known to occur consistently in the same individual.¹

That means if a person develops one of these conditions, the doctors are on alert for the subsequent development of other associated conditions. This syndrome is genetically inherited and can be passed down to further generations.

Introduction

Birt-Hogg-Dubé Syndrome is a rare genetic condition that causes a defect in one of the proteins coded by a tumour suppressor gene.¹ This defect goes on to cause cysts in the lungs, skin lesions and different types of kidney tumours. It can first present at any age, but most conditions occur around an individual's 40s to 50s.

Identifying the syndrome will alert the doctors to monitor for associated conditions. Management includes treating each condition it arises and preventing complications and recurrences. Monitoring for other associated conditions is also part of the management strategy.

What are the skin lesions you get in Birt-Hogg-Dubé syndrome?

Most skin lesions are those originating from hair follicles in the skin.² Some of the common conditions include:

• Fibrofolliculoma – Small, white flesh-coloured dome-shaped papules usually occurring in the head and neck region
• Acrochordon – Small skin tag-like lesions
• Trichodiscomas – Flesh-coloured, dome-shaped papules occurring in face, trunk and thighs⁶

Some reports claim these three are different phases of the same lesion.³

What are the lung conditions that you get in Birt-Hogg-Dubé syndrome?

Lung cysts

These are often air-filled spaces or cavities that replace solid lung tissue. The problem with these cavities is that they can rupture into the vacuum-like space between the two layers of lung coverings called pleura and cause air trapping there. This can obstruct lung expansion and breathing. Most often, the cysts are detected incidentally in chest X-rays done for another cause. They characteristically occur in multiples in the lower lung zones, on both sides and just under the pleura and around blood vessels.³

Spontaneous pneumothorax

Pneumothorax means air trapping between the two outer coverings of the lungs called the pleura, as described above. This usually obstructs lung expansion and sometimes causes lung collapse. While this condition is common in any kind of trauma to the chest, sometimes it seems to occur without an apparent cause. In such a situation it is called a spontaneous pneumothorax. Rupture of previously undetected lung cysts are one of the causes in such cases.

What other conditions in the lung can cause cystic lesions and present similar to Birt-Hogg-Dubé syndrome?

A condition called lymphangioleiomyomatosis can cause similar lung cysts due to abnormalities of the lymphatics and smooth muscle. These cysts are usually said to be scattered and do not have a similar distribution to the cysts in Birt-Hogg-Dubé syndrome. ³

Another condition called langerhan cell histiocytosis can also cause lung cysts, but these are mostly in the upper parts of the lungs and around the main airways, which is in contrast to those in Birt-Hogg-Dubé syndrome, in which the cysts are lower and bilateral.³

What are the kidney tumours that you get in Birt-Hogg-Dubé syndrome?

The kidney lesions that occur in the syndrome include a few benign and a few cancerous conditions. They can present with any urinary symptoms like blood in the urine, pain in passing urine, pain in the loins, etc or can be detected incidentally in a scan.

These include in descending order of frequency.³

• Hybrid oncocytic chromophobe tumour
• Chromophobe renal cell carcinoma
• Clear cell renal cell carcinoma
• Renal oncocytoma

The hybrid oncocytic chromophobe tumour occurs as a mixture of two lesions: one that behaves like a cancer and one that resembles more benign features. This condition, if diagnosed, should raise the suspension of that person having Birt-Hogg-Dubé syndrome.

Some of the other conditions, like chromophobe renal cell carcinoma, and clear cell renal cell carcinoma behave as cancers, while renal oncocytoma is a non-cancerous lesion. 

At what age do the symptoms appear in a person with Birt-Hogg-Dubé syndrome?

Skin conditions associated with Birth-Hogg-Dubé syndrome are reported to appear quite early around a person's 40s to 50s e. Pneumothorax is said to occur in middle age and they are reported to appear before renal cancers.⁵

Who gets Birt-Hogg-Dube syndrome?

Anyone at any age can present the features of this syndrome but most conditions appear around the third to fourth decade. There is no gender difference in the chance of occurrence of this syndrome.³ 

How will a doctor suspect whether you have this syndrome?

Having unexplained multiple cysts in the lungs, especially in a young person, that are incidentally detected in scans or X-rays could suggest this disease. In addition, sudden breathlessness that turns out to be pneumothorax or air trapping in the pleura without an apparent cause is also suggestive of this. 

Kidney lesions of a certain type can also be suggestive of this syndrome. One or more combinations of these conditions or a family history, especially in a young person will make a doctor suspect this syndrome.

What are the less commonly known conditions that are reported to occur in Birt-Hogg-Dubé syndrome?⁵

• Large connective tissue nevus a non-cancerous lesion in the skin
• Parathyroid adenoma – Growth of a hormone-secreting gland in the neck called parathyroids
• Bullous emphysema – A chronic lung condition with dilated air spaces
• Lipoma – A non-cancerous fatty lump
• Angiolipomas – A non-cancerous fatty lump with increased blood vessels
• Parotid oncocytomas – A non-cancerous salivary gland lesion

How is Birt-Hogg-Dubé syndrome diagnosed?

A formula for diagnostic criteria has been set by Menko et al.^1,4

This states that at least one major criteria or two minor criteria needs to be included to make a diagnosis of Birt-Hogg-Dubé syndrome.

What investigations are needed for diagnosis?

The above criteria need some imaging, including CT or MRI scans. Sometimes kidney biopsies may be needed from a kidney mass that can demonstrate the type of kidney cancer. Genetic testing can be used for confirmation of the syndrome. Once this syndrome is diagnosed and confirmed, serial monitoring always needs to be done, as kidney cancers can develop much later as well.

Can Birt-Hogg-Dubé syndrome be passed down to family?

Birt-Hogg-Dubé syndrome is a condition that can be genetically inherited. The type of inheritance pattern is called autosomal dominant. This means that 50% of children of a person with the syndrome have the chance of inheriting it. Basically half the children are likely to carry the genetic pattern to inherit the disease.

How do you treat this condition and what is the outcome?

Management of this syndrome needs to be tailored to each person depending on the manifestation of the medical conditions. The outcome depends on each lesion the patient develops.

• Lung conditions: pneumothorax or air trapping in the lung covering can be a serious condition. Due to this, after the first episode of pneumothorax, it is recommended to do a procedure called pleurodesis or fusion of the pleura to prevent gas trapping in it.⁵

Patients at risk are sometimes told to avoid certain high-risk behaviours that can increase the chance of pneumothorax, such as diving, smoking and even air travel, the latter especially after a recent pneumothorax.⁵ However none of the lung conditions in this syndrome lead to chronic lung impairment.

• Skin conditions: these lesions do not progress to cancer hence the only requirement for treatment is for aesthetic effect. Various methods like excision, laser treatment, dermabrasion etc, are done with variable success and some chance of recurrence¹
• Kidney cancers: it is recommended that every person with Birt-Hogg-Dubé syndrome undergo regular scans to detect developing kidney tumours.¹ Even when one mass is detected, sometimes surgery is delayed since there can be subsequent tumours during a person’s lifetime, and prior surgery can complicate further surgeries⁵

What advice must be given to family members of those with Birt-Hogg-Dubé syndrome?

Screening in the family for the genetic defect needs to be done, and they should be counselled on the possibility of acquiring the disease.¹

Summary

Birt-Hogg-Dubé syndrome includes a collection of medical conditions/symptoms ranging from skin lesions on the head and neck to lung cysts and sudden lung collapses, as well as kidney cancers.

This is a genetically inherited condition with a pattern of inheritance called autosomal dominant which means half of your children can inherit the disease if you have it. About 80% of people present with skin lesions, usually in middle age, and later develop lung cysts and then kidney cancers. Treatment includes managing each condition individually and monitoring for other conditions that can occur later.