In this study, we find an extremely rare family with BHD Syndrome with CCA for the first time. The family of BHD syndrome combined with CCA has not been reported at home and abroad till now. Some data show that compared with white people, Asian patients with BHD syndrome have a lower incidence of skin and kidney manifestations, but a higher rate of recurrence of pneumothorax [8]. The risk of lung collapse (pneumothorax) in BHD patients is 50 times higher than that of the general population [9]. Pulmonary cysts (multiple and bilateral) occur in 80%-100% of patients with BHD syndrome, and 76% of them have a pneumothorax. BHD syndrome is one of the most common causes of familial spontaneous pneumothorax [10]. Family history of pneumothorax is an important clue, suggesting the diagnosis of BHD [11]. The pulmonary manifestations of BHD disease need to be distinguished from other diseases related to diffuse cystic lung diseases (DCLD), such as Lymphangioleiomyomatosis, Langerhans cell histiocytosis, and Lymphocytic interstitial pneumonia [12]. Unlike other cystic lung diseases, BHD disease does not cause progressive loss of lung function and chronic respiratory insufficiency [10]. According to reports in the literature, the prevalence of renal involvement in BHD patients ranges from 6.5–34% [13]. Furuya et al. [14] found that 25.8% of BHD patients have renal damage, especially renal cell carcinoma, the most common histology in chromophobe renal cell carcinoma (43.6%), and all patients with renal involvement also have Lung cyst. Kidney cancer is the most serious manifestation of BHD.
The skin manifestations of BHD include fibrofollicular tumors, hair discomfort, and peri-follicular fibroids. These three types are clinically indistinguishable between 2–4 mm flesh-colored and light gray-white, smooth dome-shaped papules. These papules are commonly found on the face, neck, and trunk [7]. The most common skin manifestation of BHD is fibrofollicular tumors, the number of which can range from 2 to more than 100. Fibrofollicular tumors are rare and unique to BHD syndrome and can be diagnosed by needle biopsy [15]. This patient's family currently has no skin and kidney manifestations, but it needs regular review and follow-up.
The diagnosis of BHD disease needs to be combined with family history, clinical and/or skin histopathological criteria. Management mainly includes early pleurodesis in the case of pneumothorax, regular kidney imaging for tumor detection, and diagnostic tests to find BHD among the patient’s relatives [11]. For patients diagnosed with BHD syndrome, follow-up should be strengthened, with special attention to the condition of the kidneys. Currently, pneumothorax is usually treated symptomatically, and methods such as electrocoagulation, laser, and curettage are generally used for skin lesions. Both the proband and the son in this family have a recurrent spontaneous pneumothorax. First of all, we must be alert to the possibility of familial pneumothorax. After a clear diagnosis, kidney tumors and skin lesions should be ruled out. If corresponding symptoms occur, seek medical attention in time. It is recommended to screen the genetic locus for members of the subject's blood-related family, establish a follow-up plan for carriers as soon as possible, and conduct genetic counseling when there is a need for fertility. At present, there is no special treatment for this disease and regular follow-up observation.
The main clinical features of CCA are spider finger (toe), flexion finger, major joint contracture, scoliosis, pectus excavatum, and helix shrinkage [16]. Marfan syndrome (MFS) is a rare autosomal dominant multi-system disease, manifested by bone, eye, skin, and cardiovascular symptoms [17]. CCA and MFS have many common clinical features, including the so-called Marfan-like appearance, which is composed of tall, slender, and weak appearance and skeletal features, including spider fingers, bipedal deformities, pectus excavatum, and kyphosis [18]. However, most patients with CCA have helix shrinkage, flexion contracture, and muscle hypoplasia [19]. Two similar syndromes, MFS and CCA, are caused by mutations in genes FBN1 and FBN2, respectively [20]. It is difficult to distinguish between MFS and CCA based on clinical symptoms alone [21], and the best way to distinguish between the two diseases is genetic testing.
The clinical manifestations of CCA patients are different, involving the heart, bones, lens, and other parts, requiring individualized treatment for the patients. Flexion contractures of the large joints of the extremities often do not require targeted treatment, while hand joint contractures can loosen joints and skin grafts to improve appearance and function. Kyphosis and scoliosis deformity can be corrected by surgery if it affects life. Severe heart deformities often require early surgical treatment, and regular follow-up monitoring is required for non-severe ones [22]. The proband, mother, and son in this family all have congenital hand deformities with mild symptoms and do not affect normal functions. Since the mother of the proband also has hand deformities, and because the mother is deceased, it is recommended to send samples from the maternal relatives of the proband for screening at this site and establish a follow-up plan for carriers as soon as possible. Genetic counseling when there is a need for fertility.