Clinical and Genetic Comparison of Birt–Hogg–Dubé Syndrome (Hornstein–Knickenberg Syndrome) in Chinese: A Systemic Review of Reported Cases

Abstract

Background Birt–Hogg–Dubé syndrome (BHD), also named Hornstein–Knickenberg syndrome, is a rare autosomal dominant disease characterized by lung cysts, recurrent pneumothoraxes, renal cell carcinoma and skin fibrofolliculomas. Purpose This study summarizes the clinical and genetic information of Chinese BHD patients from all available reported cases and explores the relationship between the clinical and genetic spectrum in the hope of improving the prognosis of Chinese BHD patients. Methods Relative studies were collected by searching PubMed, Cochrane Library, Embase, OVID medicine, SinoMed, Web of Science, China National Knowledge Infrastructure, Wanfang Data and China Hospital Knowledge Database from January 1, 1977 to December 31, 2021. The search strategy included the following term keys: (Birt–Hogg–Dubé syndrome OR Hornstein-Kinckenberg syndrome OR familial pulmonary cysts OR familial spontaneous pneumothorax OR fibrofolliculomas OR trichodiscomas OR inherited renal cancer syndromes OR FLCN ) AND (Chinese OR China). Results In total, 287 Chinese patients from 143 families described in 31 references were included in this article. Chinese BHD patients tended to present more pulmonary symptoms but fewer skin lesions and renal malignancies, which appeared to be atypical when compared with Caucasian patients. The FLCN mutation spectrum among Chinese BHD patients was established with the mutational hot spot c.1285depC/delC as the most frequent mutation. In addition, this mutation spectrum also showed some differences from other races, with a relatively frequent large deletion c.872–429_1740+1763del (exon 9–14 deletion) reported only in Chinese individuals but no observation of the two mutational hot spots found in Japanese individuals. We also attempted to establish potential pheno-genotype correlations in Chinese BHD patients, but the results were negative. Conclusion To improve the prognosis of BHD patients, physicians need to increase their awareness of BHD by focusing on the family history of pneumothorax as well as skin lesions in patients with lung cysts and promptly advising patients on genetic sequencing.

Familial pulmonary cysts: A clue to diagnose Birt–Hogg–Dubé syndrome: A case report and literature review

“…A retrospective study comprising 221 cases from 120 families with BHD in the Chinese population reported c.1285dup/del in exon 11 as a mutation hotspot, accounting for 17.4% of 144 cases reported in detail, consistent with that reported in Caucasian populations 6,20 . The FLCN mutation detected in the patient reported here was c.57‐58del in exon 4, which is a rare mutation and was previously reported only in two Asian families and a few Caucasian families 3,14,21,22 . As for the autosomal dominant inherited manner of BHD, when a pathogenic mutation is detected in an index patient, FLCN ‐mutation surveillance is recommended in at‐risk family members including parents, sibs, and offspring of a proband, other family members depend on whether proband's parents are affected.…”

“…As of 2017, the BHD Syndrome Foundation has reported more than 600 pedigree cases of BHD worldwide. In China, 287 patients from 143 families were identified 3 . Despite continuous reporting of BHD cases, missed diagnoses and misdiagnoses of BHD are common owing to the diversity of its clinical manifestations.…”

A novel mutation in the FLCN gene in a chinese family with Birt-Hogg-Dubé(BHD) syndrome

“…[18] Exon 9 mutations have been closely associated with tumorigenesis, [19] indicating that FLCN gene variations may be more extensive in Asian, and even Chinese populations. [20] BHDS-associated renal tumors are typically bilateral and multifocal, with low malignant potential but a risk of recurrence. It is important to differentiate it from other hereditary renal tumor syndromes, particularly tuberous sclerosis complex (TSC).…”

A novel FLCN gene mutation causing Birt–Hogg–Dubé syndrome in a Korean family

“…Another analysis of 26 Korean patients showed that 65.4% had at least one pneumothorax, whereas only 16% had fibrofolliculoma [ 10 ]. Similarly, 73.5% of 287 Chinese BHD syndrome patients presented with pneumothorax while skin lesions occurred only in 22.3% [ 11 ]. A report by Kunogi et al showed that lung cysts without skin or renal involvement is the most frequent combination of phenotypes in Japanese BHD syndrome patients (70%) [ 12 ].…”