FBLN5-Related Cutis Laxa Syndrome: A Case with a Novel Variant and Review of the Literature

• FBLN5-related cutis laxa is a rare autosomal recessive syndrome characterized by loose, wrinkled, and redundant skin, sagging cheeks, emphysema, aortic or pulmonary artery abnormalities, inguinal hernia, and diverticula of the gastrointestinal and urinary tract.

• To date only 8 families have been reported with FBLN5-related cutis laxa syndrome, and the family presented here is the ninth in the literature.

• A novel FBLN5 variant, p.(Asp288Tyr), located within the epidermal growth factor calcium-binding domains was detected. This residue is conserved in different FBLN5 homologs.

• Only kyphoscoliosis has been reported as a skeletal finding in FBLN5-related cutis laxa till now. The case presented here adds fourth finger contracture as an additional skeletal finding to the spectrum of this syndrome.

Cutis laxa (CL) syndromes comprise a rare group of connective tissue disorders characterized by redundant skin with loss of elasticity and variable systemic manifestations [Gharesouran et al., 2021]. There are both acquired and inherited forms of CL. Acquired forms have later onset and are mainly caused by infections or medications [Lewis et al., 2004]. Heritable forms are grouped as autosomal dominant CL (ADCL), autosomal recessive CL (ARCL), and X-linked CL. The X-linked form is now named occipital horn syndrome and classified as a copper transport disease (OMIM #304150). Skin findings of ADCL vary from hyperextensibility to generalized loose redundant skin folds. Although previously considered as a relatively benign condition with only skin manifestations, recent reviews report emphysema in 55% and aortic root dilatation/dissection in 35% of ADCL patients [Beyens et al., 2021]. The ARCL is a more common and severe form of CL that often has life-threatening systemic manifestations of the cardiopulmonary system, gastrointestinal and urinary tracts in addition to skin manifestations [Morava et al., 2009]. ARCL is classified clinically into 3 types. ARCL1 manifests with predominantly severe cardiopulmonary complications as a systemic involvement. On the other hand, central nervous system and skeletal abnormalities are common in ARCL2 and ARCL3, but the presence of ocular findings differentiates ARCL3 from ARCL2 [Bicknell et al., 2008; Reversade et al., 2009]. ARCL type 1 is also divided into 3 subgroups as ARCL1A, ARCL1B, and ARCL1C. There is a high overlap in phenotypic presentations between ARCL1A and ARCL1C, such as emphysema and motility disorder of gastrointestinal and urinary tracts [Callewaert et al., 2013]. However, ARCL1B typically shows tortuosity and aneurysm of large and middle-sized arteries [Hucthagowder et al., 2006].

Biallelic pathogenic variants in FBLN5 lead to ARCL1A. ARCL1A is characterized by loose and wrinkled skin, childhood-onset emphysema, aortic and pulmonary artery stenosis, inguinal hernia, and diverticula of the intestine or bladder. Intelligence is usually normal [Loeys et al., 2002]. Cardiorespiratory failure secondary to pulmonary emphysema is the most common cause of death [Callewaert et al., 2013].

FBLN5 is located on chromosome 14q32.12 and encodes the extracellular matrix protein fibulin-5 which is essential for elastic fiber formation. Fibulin-5 protein is mostly found in elastic-fiber-rich tissues such as skin, aorta, and lungs.

Here, we present a girl with a novel missense variant in the FBLN5 gene and compare her findings with those of previously reported individuals with ARCL1A.

An 8-year-old Turkish girl was referred to the Medical Genetics department because of short stature and loose, sagging cheeks. She was the only child of consanguineous parents and was born at term by spontaneous vaginal delivery following an uneventful pregnancy. Birth weight was 3,010 g, but her birth length and head circumference were unknown. At birth, she had loose skin all over the body, which became milder with time. She was found to have a cardiac murmur at 4 months and echocardiography revealed peripheral pulmonary artery stenosis. At her 4-year follow-up, her pulmonary stenosis was at a level that did not require invasive procedures. The patient also had frequent pulmonary infections. Abdominal ultrasound, eye examination, hearing test, and her karyotype were normal. She had fourth-finger flexion contractures on both hands. She had surgical correction for the contractures and left inguinal hernia. Her developmental milestones were normal, and she attended normal school. On physical examination, she had short stature, diffuse but mildly loose skin on face, trunk, and extremities, sagging cheeks, a prematurely aged appearance, a high forehead, broad eyebrows, a bulbous nose, large ears, and operation scars from the fourth finger contractures (Fig. 1). Weight was 24.8 kg (−0.53 SD), height 113 cm (−2.92 SD), and head circumference was 50.5 cm (−1.05 SD). Thorax CT of the patient showed only some local atelectasis areas secondary to previous pneumoniae in the lungs. Investigation of other systemic involvements did not reveal any gastrointestinal or genitourinary abnormalities. We made a clinical diagnosis of CL. The first-degree cousin parents were phenotypically normal except short stature (mother was 153 cm [lower than –2 SD] and father was 168 cm [lower than –2 SD]). The mother had undergone 3 abortions at 10, 16, and 18 weeks.

Informed consent was obtained from the parents for genetic analyses and for publication of the patient’s photographs. Genomic DNA was extracted from peripheral blood samples of the proband and her parents using a QIAamp DNA Mini Kit (Qiagen, Hilden, Germany) according to the manufacturer’s protocol. The exome libraries from the patient’s sample were prepared using the TruSeq Rapid Exome Library Prep kit (Illumina) according to the manufacturer’s instructions; the process was completed on NextSeq platform.

Variant filtering steps were performed using Seq Genomize Variant Analysis Platform. Due to the consanguinity, rare homozygous variants with minor allele frequencies less than 1% were prioritized. After the filtration, we further analyzed the variants in clinically compatible genes. We considered only protein-altering variants, including frameshift, start loss, stop gain or loss, missense variants, canonical splice-site variants, and inframe indels affecting protein-coding regions. The potential impact of rare exonic variants on protein function were predicted by Mutation Taster [Schwarz et al., 2014], SIFT [Vaser et al., 2016], and PolyPhen2 [Adzhubei et al., 2010].

A novel homozygous c.862G>T, p.(Asp288Tyr) missense variant in exon 8 of FBLN5 (NM_006329.3) was detected (Fig. 2a). Both parents were found to be heterozygous for this variant (Fig. 2b, c). The variant was classified as pathogenic according to the ACMG guidelines based on the following criteria: the variant was at the last base before the splice site (PVS1) and was not found in the gnomAD population database (PM2); in silico predictions were pathogenic for this missense variant (SIFT score: 0, PolyPhen-2 score: 1.000, and Mutation Taster prediction: disease causing) (PP3).

Table 1 summarizes the patients with ARCL1A reported to date. When we reviewed all patients, low birth weight was an extremely rare finding. Only the case of Tekedereli et al. [2019] had prenatal-onset growth retardation.

Loose skin is generally more prominent at birth and improves with age. Only the patient described by Kantaputra et al. [2014] was noted to have progressive CL.

Regardless of whether it is specified, when looking at the published patient pictures, they all have a high forehead, frontal bossing, broad but sparse eyebrows, a bulbous nasal tip, large ears, and a square chin [Kantaputra et al., 2014; Tekedereli et al., 2019; Gharesouran et al., 2021].

Interestingly, our patient had fourth-finger contractures on both hands, for which she underwent surgical correction. To the best of our knowledge, this is the first ARCL1A patient with contractures. Whole-exome sequencing did not reveal any variation associated with contractures. Another rare skeletal finding may be kyphoscoliosis, which was specified in the report of Claus et al. [2008]. Our patient also had short stature, which seems to be familial short stature because both parents were below –2 SD.

Cardiovascular manifestations are frequent and vary widely among the patients. Peripheral pulmonary stenosis and supravalvular aortic stenosis are the most frequent and severe cardiovascular problems. Our patient was diagnosed with peripheral pulmonary artery stenosis at infancy which improved to a level that did not require invasive procedures by the age of 4 years.

Recurrent respiratory tract infections and early emphysema are other frequent features. Only the twins reported by Gharesouran et al. [2021] were noted not to have any pulmonary complications. Long-term follow-up may be helpful to clarify the frequency of features. Inguinal hernia is another frequent feature of ARCL1A.

If the patients do well with pulmonary infections, developmental milestones and intelligence are generally normal. Only patient A of Callewaert et al. [2013] had hypotonia. Among the families reported to date, almost half of the patients with ARCL type 1A died at early ages because of cardiopulmonary complications.

Inherited CL is a genetically and phenotypically heterogenous group of disorders that result from impaired elastic fiber synthesis (ELN), regulation of elastic fiber formation (LTBP4/FBLN5/EFEMP2), vesicular trafficking (ATP6V0A2/ATP6V1E1/ATP6V1A), and proline metabolism (ALDH18A/PYRCR1) [Beyens et al., 2021]. To our knowledge, there are 8 families with FBLN5-related CL in the literature, and the family presented here is the ninth with this syndrome.

In this paper, we describe a Turkish girl with a novel, homozygous c.862G>T, p.(Asp288Tyr) missense variant in the FBLN5 gene, detected by whole-exome sequencing, confirming the diagnosis of ARCL type 1A. Fibulin-5 protein consists of an intracellular N-terminal signal peptide, 6 calcium-binding EGF-like (cbEGF) motifs, and a C-terminal fibulin module. Hu et al. [2006] showed that pathogenic FBLN5 variants impair the interaction between fibulin-5 and other proteins that participate in elastic fiber formation. Asp288Tyr is located in the first aspartic acid residue of the consensus calcium-binding sequence (D-X-D/N-E) within the last cbEGF motif [Downing et al., 1996]. This residue is highly conserved across fibulin-5 homologs (Fig. 3). So far, 6 different mutations have been reported in the literature, one of which is nonsense and the others missense (Table 1). Moreover, all reported missense mutations were located in cbEGF motifs.

When the patients reported so far are evaluated according to their clinical features, all patients have high forehead, frontal bossing, broad but sparse eyebrows, bulbous nasal tip, large ears, and square chin. Frequent features are cardiovascular problems (peripheral pulmonary stenosis and supravalvular aortic stenosis are the most frequent), recurrent respiratory tract infections, emphysema, inguinal and umbilical hernia. Developmental milestones are usually normal. Rare features may include low birth weight, short stature, hypotonia, progressive CL, and kyphoscoliosis.

This patient is the first case of ARCL1A with finger contractures. Finger contractures have been shown in ARCL1B (OMIM #614437), ARCL2C (OMIM #617402), ARCL2D (OMIM #617403), and ARCL3A (OMIM #219150). Contractures reported in ARCL1B involve 3rd–5th fingers and accompany arachnodactyly [Hoyer et al., 2009]. ARCL2C shows clenched hands, ulnar deviation of the fingers, congenital hip dysplasia, flexion contractures of the knees, and club feet. ARCL2D and ARCL3A involve multiple joint contractures including camptodactyly [Skidmore et al., 2011; Van Damme et al., 2017]. Among the finger contractures reported in patients with CL, the contracture of our patient seems to be more limited. This report expands the clinical findings of ARCL1A. Further clinical reports and genotype-phenotype studies are needed to confirm our findings.

The authors would like to thank the patient and her family for their collaboration.

Written informed consent was obtained from the patient’s parents for publication of the details of their medical case and any accompanying images. The study was conducted in accordance with the Declaration of Helsinki. Ethical approval was not required for this study in accordance with national guidelines.

The authors have no conflicts of interest to declare.

There was no funding for this study.

Aysel Tekmenuray-Unal is the major contributor in designing of the work, collecting the data, and writing the manuscript. Ceren Damla Durmaz took part in collecting and evaluating the data, also writing the manuscript. Both authors read and approved the final manuscript.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.