Autosomal Recessive FBLN5-Related Cutis Laxa
To date, six families with autosomal recessive FBLN5-related cutis laxa have been described [Van Maldergem et al 1988, Karakurt et al 2001, Loeys et al 2002, Pour-Jafari & Sahiri 2004, Claus et al 2008, Callewaert et al 2013, Kantaputra et al 2014]. Intrafamilial variability in age of onset is observed.
Cutis laxa. The most common finding in FBLN5-related cutis laxa is described as furrowing of the skin of the whole body that is particularly obvious in the neck, axillae, and groin. The face has a "droopy" appearance with eyelid ptosis and drooping cheeks. When one tries to extend the skin, it does not display hyperelasticity as in the Ehlers-Danlos syndromes, but rather keeps its consistency.
Pulmonary emphysema. Most affected individuals have early childhood-onset pulmonary emphysema, and some individuals have presented with emphysema during the neonatal period. Two affected sibs reported by Van Maldergem et al [1988] had recurrent pneumonias.
Arterial involvement. Peripheral pulmonary artery stenosis appears to be specific for this disorder. Peripheral pulmonary artery stenosis leads to ventricular dilatation and contributes to progressive heart failure. Supravalvar aortic stenosis was reported in two related children from Iran who died at ages two years and 14 years [Elahi et al 2006]. Aortic valve dysplasia (stenosis and regurgitation) was reported in one affected child of Lebanese ancestry [Callewaert et al 2013].
Other evidence of a generalized connective disorder including inguinal hernias and hollow viscus diverticula (e.g., intestine, bladder). In one individual, the bladder was described on voiding cystoureterogram as having an unusual "cauliflower" shape secondary to the presence of multiple diverticula. In a Lebanese family, all three affected sibs homozygous for missense variant c.649T>C underwent surgery in the first months of life for pyloric stenosis [Callewaert et al 2013].
Infections secondary to vesicoureteral reflux (e.g., pyelonephritis) are observed. Urinary tract candidiasis with "fungus balls" have been observed on renal ultrasound [Author, personal communication].
Prognosis. Pulmonary artery stenosis, congenital heart disease, and/or hollow viscus diverticula are likely to cause early death, with cardiorespiratory failure from complications of pulmonary emphysema (respiratory or cardiac insufficiency) being the most common cause of death. For those who survive early childhood, pulmonary emphysema, cor pulmonale, and multiple surgeries are the rule. Prolonged survival is exceptional; the oldest known person with this disorder was a high-functioning young woman who died at age 21 years from cor pulmonale.
Hip dislocation is not observed in FBLN5-related cutis laxa.
Intelligence is normal [Van Maldergem et al 1988].
Note: To date, no heterozygous carriers for autosomal recessive FBLN5-related cutis laxa have developed age-related macular degeneration.
Skin histology. Skin biopsy with orcein staining on paraffin-embedded samples on light microscopy shows normal or mild fragmentation and paucity/absence of elastic fibers.
Electron microscopy (EM) shows paucity of elastic fibers with accumulation of elastin (ELN) globules, reflecting lack of assembly of the primary components of elastic fibers [Ledoux-Corbusier 1983]. These findings are in contrast to those of Debré-type cutis laxa (see ATP6V0A2-Related Cutis Laxa) and De Barsy syndrome (see Differential Diagnosis), in which a sparse elastic network, but not defective assembly of ELN fibers, is observed. Because deficiency of other proteins or cofactors involved in the process of elastic fiber assembly could potentially give the same ultrastructural picture, it is not known whether this feature is specific for FBLN5-related cutis laxa. EM studies require a high level of expertise and are only available in specialized centers.