Clinical and molecular characterization of an 18‐month‐old infant with autosomal recessive cutis laxa type 1C due to a novel LTBP4 pathogenic variant, and literature review

Abstract

Background Cutis laxa (CL) is a group of rare connective tissue disorders mainly characterized by wrinkled, redundant, inelastic, and sagging skin. Besides skin anomalies, in most CL forms multiple organs are involved, leading to severe multisystem disorders involving skeletal, cardiovascular, pulmonary, and central nervous systems. CL might be challenging to diagnose because of its different inheritance patterns, extensive phenotypic variability, and genetic heterogeneity. Herein, we report the clinical and molecular characterization of an 18‐month‐old infant with signs suggestive of recessive cutis laxa type 1C (ARCL1C), although with a relatively mild presentation. Methods To confirm the clinical suspicion, mutational screening of all the exons and intron‐flanking regions of the latent transforming growth factor‐beta binding protein 4 gene ( LTBP4 ) was performed by Sanger sequencing on an ABI3130XL Genetic Analyzer. Results Apart from the presence of the dermatological hallmark, the reported patient did not show pulmonary emphysema, which is the most common and discriminative finding of ARCL1C together with gastrointestinal and urinary involvement. Indeed, pulmonary involvement only included episodes of respiratory distress and diaphragmatic eventration; intestinal dilation and tortuosity and hydronephrosis were also present. Molecular analysis disclosed the novel homozygous c.1450del (p.Arg484Glyfs*290) pathogenic variant in exon 12 of LTBP4 , thus leading to the diagnosis of ARCL1C. Conclusion Our findings expand both the knowledge of the clinical phenotype and the allelic repertoire of ARCL1C. The comparison of the patient's features with those of the other patients reported up to now offers future perspectives for clinical research in this field.

Expanding the Spectrum of Neurological Manifestations in Cutis Laxa, Autosomal Recessive, Type IIIA

“…1 To date, 13 different forms of inherited cutis laxa syndromes have been described. 2 Cutis laxa type IIB (OMIM#612940), type IIIA (OMIM#219150), and type IIIB (OMIM#614438), are known as De Barsy syndrome, and are associated with pathogenic variants in PYCR1 and ALDH18A1, two genes playing an important role in proline metabolism. 3 PYCR1 encodes for pyrroline-5-carboxylate reductase, an enzyme involved in the last steps of proline synthesis from glutamate.…”

Bi-allelic premature truncating variants in LTBP1 cause cutis laxa syndrome

“…25 Finally, pathogenic variants in LTBP4 cause AR cutis laxa (CL) type 1C, characterized by loose redundant skin folds, emphysema, and diverticula of the gastrointestinal and urinary tract. [26][27][28] Thus far, the human phenotype associated with LTBP1 (MIM: 150390) deficiency has remained enigmatic.…”

LTBP4 in Health and Disease

“…Autosomal recessive cutis laxa subtype C (ARCL1C) or Urban–Rifkin–Davis syndrome, caused by biallelic variants in the LTBP4 gene, is characterized by early childhood-onset pulmonary emphysema, peripheral pulmonary artery stenosis, inguinal hernias, and hollow-organ diverticula. This severe and variable disorder has, for example, been reported in 22 individuals from 18 families [ 37 , 38 , 39 , 40 ]. Moreover, vascular tortuosity, aneurysm, gastrointestinal diverticulosis, renal dysplasia, and bladder diverticulosis have been reported in patients with ARCL1C [ 37 , 38 , 40 ].…”

“…This severe and variable disorder has, for example, been reported in 22 individuals from 18 families [ 37 , 38 , 39 , 40 ]. Moreover, vascular tortuosity, aneurysm, gastrointestinal diverticulosis, renal dysplasia, and bladder diverticulosis have been reported in patients with ARCL1C [ 37 , 38 , 40 ]. Disruptions in microfibril and elastic-fiber homeostasis and assembly may lead to various pathological conditions and clinical phenotypes.…”