Birt-Hogg-Dubé Symptoms in Smith-Magenis Syndrome Include Pediatric-onset Pneumothorax

To the editors:

Birt-Hogg-Dubé syndrome (BHD) is a primarily adult-onset condition first described as a dermatological disorder (Birt et al., 1977) and later recognized as having multi-system manifestations (Toro et al., 2007; Roth et al., 1993). Typically characterized by a triad of skin, lung, and kidney findings, BHD is most often identified as a rare familial etiology of renal cell carcinoma (Table 1) (Jensen et al., 2017; Schmidt et al., 2015). Pathogenic loss-of-function variants in the folliculin gene (FLCN) are considered causative of BHD, with wide variability in clinical presentation and age of onset (Schmidt et al., 2015). The mode of inheritance is postulated to be autosomal dominant with a somatic second hit triggering renal manifestations in adulthood. Coincidentally, FLCN is among dozens of genes included within the 17p11.2 chromosomal region recurrently deleted in 90% of patients with Smith-Magenis syndrome (SMS), a well-described neurodevelopmental disorder (Finucane & Haas-Givler, 2009). Although most individuals with SMS are haploinsufficient for FLCN, there have been very few published reports of BHD phenotypes in SMS (Dardour et al., 2016; Smith et al., 2014; Truong et al., 2010). This limited description is not surprising given the clinical focus on SMS as a pediatric disorder; however, its potential association with BHD phenotypes has important long-term implications for medical surveillance.

Table 1.

Major Clinical Features in Birt-Hogg-Dubé Syndrome

Feature	Age of Onset (years)	Reported Frequency
Benign cutaneous manifestations including fibrofolliculomas, trichodiscomas, and achrochordons	Typically after 25	58-90% (Jensen et al., 2017)
Pulmonary cysts	--	67-90% (Jensen et al., 2017; Gupta et al., 2016; Schmidt et al., 2015)
Spontaneous pneumothorax, often recurring	Median: 38 Earliest: 7	24-48% (Gupta et al., 2016; Schmidt et al., 2015)
Renal Cancer	Mean: 50.7 Earliest: 20	12-34% (Jensen et al., 2017; Gupta et al., 2016; Schmidt et al., 2015)

As an initial investigation into the prevalence of BHD symptoms in SMS, we administered an online survey to families affiliated with the international support organization Parents and Researchers Interested in Smith-Magenis Syndrome (PRISMS). Founded in 1993, the PRISMS organization reaches over 2,000 contacts worldwide and is the primary medical and support resource for families living with a Smith-Magenis diagnosis. Information about the study was disseminated to families by email and publicized through PRISMS’ social media posts and an online newsletter. To provide background information for families, the survey was linked to a previously published PRISMS newsletter article about BHD and its potential connection to SMS (PRISMS, 2020). Participation was open to all families, regardless of the age of the person with SMS, in order to capture early manifestations of BHD. To encourage responses, the survey was anonymous and required fewer than five minutes to complete. Survey questions focused on three hallmark phenotypic features of BHD: spontaneous pneumothorax, renal cancer, and pathognomonic skin findings (fibrofolliculoma and trichodiscoma). Although we were not able to review medical records to corroborate diagnoses, these symptoms are highly specific and unlikely to be inaccurately reported by families.

During the five weeks that the survey was available online, we received 117 responses, key findings of which are summarized in Table 2. The median age of individuals with SMS was 22.42 years (range: 6 months – 49 years). One hundred and two individuals with SMS (87.18%) reported having a 17p11.2 deletion, 10 (8.55%) had an RAI1 mutation, and 5 (4.27%) were unsure of the genetic etiology of the SMS diagnosis. Overall, seven respondents (5.98%) reported at least one of the three major BHD features (Table 2). As expected, given the relatively young age of the cohort, no one was diagnosed with renal cancer. Fifteen (12.82%) respondents affirmed having skin growths surgically removed by a health professional from the upper torso and/or face. Of these, the growths were specifically identified as fibrofolliculomas in two cases, whereas other types of skin growths were removed in eight individuals, with five survey respondents being unsure of the lesion type. Spontaneous pneumothorax was reported in five individuals (4.27%), including recurrent episodes at ages 2 and 7 years in one child. Particularly remarkable is the early age of onset of pneumothorax in these SMS patients, with all but one occurring before the age of ten and three in children under four years. Spontaneous pneumothorax is rare in pediatric populations, affecting 5-10 per 100,000 children younger than 18 years (Sahn & Heffner, 2000). Prior to this survey, the youngest patient with BHD reported to have pneumothorax was seven years, while this relatively common BHD manifestation more typically presents in adulthood (median age: 38 years). One of our survey respondents with pneumothorax had SMS due to an RAI1 mutation rather than a 17p11.2 deletion (Table 2), similar to a separate report by Truong et al. (2010). In that case, the individual had a single nucleotide variant in FLCN that was classified as a variant of uncertain significance. Population frequency data has since led one clinical testing laboratory to classify that FLCN variant as benign, per their ClinVar submission (SCV000198122.4) (Landrum et al., 2018). As there is almost complete clinical overlap between patients with SMS due to the recurrent deletion and those with RAI1 mutations (Edelman et al., 2007), this second reported case of pneumothorax in a patient with an RAI1 mutation provides additional evidence for its potential role in regulation of neighboring genes (Elsea & Williams, 2011), including FLCN.

Table 2.

Reported BHD Symptoms Among 117 Respondents with SMS

Survey respondent	Age at survey (years)	Genetic etiology	Age at spontaneous pneumothorax (years)	Fibrofolliculoma
SMS 1	35	17p11.2 del	2 and 7	−
SMS 2	7	17p11.2 del	3	−
SMS 3	4	17p11.2 del	3	−
SMS 4	9	RAI1 mutation	9	−
SMS 5	26	17p11.2 del	22	−
SMS 6	20	17p11.2 del	−	+
SMS 7	21	17p11.2 del	−	+

Our survey adds to the number of reported individuals with SMS manifesting BHD symptoms and provides further evidence for co-occurrence of these clinical conditions. A main limitation of this study is the reliance on patient-entered data without the ability to review medical records. Further research is needed to corroborate the BHD symptoms reported here and to more broadly investigate the prevalence of these and other BHD manifestations in individuals with SMS. The occurrence of pneumothorax in young children with SMS was an unexpected finding and should be further explored, as this has important implications for medical management. Children with SMS have very significant delays in speech acquisition and can also exhibit severe behavioral disturbance. While a major pneumothorax would not go unnoticed, a partial lung collapse in the context of a young, nonverbal child in distress could be misinterpreted as a behavioral outburst. In addition, as many children with SMS diagnosed decades ago are now entering middle age, caregivers and medical providers need to be made aware of the potential for renal cancer and offered anticipatory medical guidance similar to that provided to BHD families with FLCN variants (Jensen et al., 2017).

Data sharing statement:

A sample of the survey used in this study, as well as the study data that support our findings, are available from the corresponding author upon reasonable request.