In this study, we identified BHD
germline mutations in five of eight patients with multiple lung cysts and recurrent pneumothorax. None of the affected patients had the skin lesions or renal tumours that are considered to be the clinical hallmarks of BHD syndrome.10
Other studies have reported that pneumothorax can be the only clinical sign of BHD syndrome as an underlying disease.18,19
The development of the clinical features of BHD syndrome seems to be age‐dependent. Fibrofolliculomas are reported to occur in patients with BHD after the age of 25–35 years10,17,22
and may be easily missed if they appear as subtle papules with normal skin colour or are hidden by makeup. In contrast, renal neoplasms predominantly develop after the age of 40 years.10,17
We carefully investigated for the presence of both skin and renal lesions in our study population, but could not identify either. However, we cannot exclude the possibility that they may develop in the future, as the mean age of the patients diagnosed with BHD syndrome at the time of genetic testing was 36.6 years old (range 30–40). In other words, pulmonary feature may precede the development of the other two phenotypes,10
as one (patient B2) experienced her first pneumothorax at the age of 16 years and one case report exists describing a boy who had a spontaneous pneumothorax at the age of 7 years.23
There is increasing evidence that BHD syndrome shows not only genetic but also considerable clinical heterogeneity. The skewed clinical expression in our study population could be a variable genotype–phenotype correlation or the result of involvement of a combination of three major organs rather than the chronological development of each phenotype. All mutations we detected in this study were insertions or deletions, including one splice donor site mutation, and four of the five are novel. All mutations are predicted to cause a frameshift leading to protein truncation, which is in agreement with the results of studies reported by other groups.13,17
To date, one example of the genotype–phenotype relationship in BHD syndrome has been reported. The frequency of renal tumours was significantly lower in patients with BHD with a C deletion mutation in the C8 tract of exon 11 than those with a C insertion mutation in the same mutational hotspot.17
have already reported that germline BHD
mutation is a genetic defect associated with hereditary spontaneous pneumothorax, and none of our family members had skin or renal features of BHD syndrome. Painter et al18,19
identified a 4 bp deletion in exon 4 in a large Finnish family with spontaneous pneumothorax, and Graham et al18,19
found nonsense mutations of exon 9 and 12, respectively, in 2 of 12 families with familial spontaneous pneumothorax.
Our study examined patients with multiple lung cysts of undetermined cause, who had episodes of pneumothorax. Germline BHD
mutations were found in five index cases whose family members had pneumothorax, but not in the remaining three index cases whose family members had no pneumothorax. Accordingly, eight BHD
mutations, which predisposed only to the pulmonary features of BHD syndrome, were collected but there does not at present appear to be any specific genotype–phenotype correlation with these pulmonary features. Further study is needed, however, to resolve the question of whether BHD
mutations that preferentially predispose to pulmonary features of BHD syndrome exist. Although a high detection rate of BHD
mutations was noted in our study population compared with that of Graham et al
this may be due to differences in study populations.
It is recognised that the clinical presentation in tumour‐suppressor gene syndromes can be variable. Phenotypic features may vary due to the combination of the involvement of skin, lung and kidney, three target organs affected by BHD
mutations. Schmidt et al17
reported that of their 53 families with BHD syndrome whose members had either a germline BHD
mutation or the affected BHD
haplotype, 41.5% (22/53) of the families had skin, lung and renal features, 41.5% (22/53) had members with skin and lung phenotypic features, 2% (1/53) had renal and lung phenotypic features, 13% (7/53) had only skin papules and 2% (1/53) had renal tumours and skin papules. The lungs appear to be frequently involved in BHD syndrome, as in their study, 85% (45/53) of the families had members who developed lung cysts or spontaneous pneumothorax, and 85% (110/129) of patients with BHD who were examined by chest CT scan were found to have one or more lung cysts. In our study, only the relatives of patient B1 were willing to participate in genetic testing and the proband's mother (56 years old) was found to have BHD, although she had neither skin lesion nor a history of pneumothorax. She did, however, have lung cysts but not renal tumours on CT scan. Although the number of study subjects and family members we examined was very small, the study indicates that pulmonary features can be an isolated phenotypic expression of BHD syndrome.
Given that multiple lung cysts with or without the occurrence of pneumothorax can be an isolated phenotypic expression of BHD syndrome, and has a high incidence, BHD syndrome should be considered in the differential diagnosis for spontaneous pneumothorax, especially in patients with a family history18,19
and those with cystic lung diseases, such as lymphangioleiomyomatosis (LAM) and LCH, which frequently complicate pneumothorax. It has been reported that chest HRCT of BHD patients shows thin‐walled cysts of varying sizes with normal intervening lung parenchyma,24
and the predominant distribution of cysts is in the basilar and mediastinal regions of the lungs.25
We confirmed these findings in our five patients with BHD (figure 3). Furthermore, we found that the number of cysts in the lung fields is usually <100 (table 1). LAM and LCH, particularly in the early stages, need to be carefully distinguished from BHD syndrome. LAM, especially in association with tuberous sclerosis complex, may have several clinical feature in common with BHD syndrome: facial skin lesions (angiofibromas, but not fibrofolliculomas), renal tumours (usually angiomyolipomas, but may be renal cell carcinomas) and recurrent episodes of pneumothorax, even in the early stage of the disease when the number of lung cysts is still limited.26
In one case report,27
a biopsy of a facial rash in a pre‐menopausal woman (42 years old) with recurrent pneumothorax and radiological findings of multiple cysts was initially interpreted as a sebaceous adenoma. The patient was eventually diagnosed with BHD syndrome from the results of a lung biopsy, a detailed family history and re‐evaluation of the skin pathology. BHD syndrome appears to have no gender predilection10,17
whereas LAM occurs exclusively in female.28
All patients identified with a BHD
germline mutation in this study were women, but this may have been subject to bias, as our hospital is the main institution in Japan to which patients with suspected or diagnosed LAM are most often referred.
In conclusion, our study confirms that pulmonologists should be aware of and be able to recognise this rare inherited disorder. Descriptions of BHD syndrome are mainly published in the dermatological literature and are rather scanty in the respiratory literature. However, pulmonologists have the opportunity of early diagnosis and management for possible future cancer development in patients with this syndrome. Molecular analysis of the BHD gene should be systematically conducted in patients with multiple lung cysts even in the absence of characteristic fibrofolliculomas on the face and renal tumours.
- It is increasingly recognised that BHD syndrome shows not only genetic but also considerable clinical heterogeneity. Phenotypic features can be variable due to involvement of the combination of the skin, lung and kidney, three target organs affected by BHD mutations.
- We found that five of eight patients with multiple lung cysts and recurrent pneumothorax, but no skin lesions or renal tumours, had BHD germline mutations. All mutations we detected were insertions or deletions, including one splice donor site mutation, and four of them are novel.
- Pulmonologists should be aware that BHD syndrome can occur as an isolated phenotype with pulmonary involvement.