Beyond the genome: a rare case report of cutis laxa

Introduction

Cutis laxa is a rare disease that is characterized by wrinkled, redundant, inelastic, and sagging skin. It is attributed to structural abnormalities of the extracellular matrix or defective elastin synthesis (1). Cutis laxa can be either inherited or acquired (2). Acquired cutis laxa has an unknown genetic etiology, which can be triggered by environmental factors. Whereas the inherited form has an extremely rare incidence. Inherited cutis laxa has different patterns, including autosomal dominant, autosomal recessive, and X-linked recessive inheritance (3). Additionally, inherited cutis laxa has several subtypes that are linked to 11 different genes (4). The age of onset, the severity of skin appearance, and the associated symptoms of inherited cutis laxa differ according to the causative genes (2). Cutis laxa is diagnosed either by genetic testing or by skin biopsy, incorporating an elastin stain that can identify the diminished elastic fibers (2).

Autosomal recessive cutis laxa type 1B (ARCL1B) is associated with the gene EGF-containing fibulin-like extracellular matrix protein 2 (EFEMP2) (chromosome 11q13.1) (2). The mutation of gene EFEMP2 causes an abnormal coding of the fibulin-4 protein. This abnormal coding negatively affects the vascular patterning, skeletal function, and formation of elastic fibers (4). ARCL1B is characterized by bone fragility, inguinal hernia, vascular tortuosity, vascular aneurysm, pectus excavatum, joint laxity, diaphragmatic hernia, emphysema, and milder loose skin compared to other subtypes (4). Other features include hypertelorism, a high forehead, and marfanoid skeletal features. The onset of this subtype is observed during early childhood; moreover, it can occur very early, as in the prenatal stage (2). This case report and literature review presents a sporadic case of cutis laxa type 1B with severe systemic malformations, suspected prenatally, and rapidly deteriorated after birth. We present this article in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-2025-254/rc).

Case presentation

An Emirati 30-year-old lady, gravida 2 para 1, a patient with a previous uncomplicated spontaneous vaginal delivery of a healthy female infant 3 years ago. She was rubella immune, and her Group B Streptococcus status was unknown, with negative serology. She suffered from gestational diabetes mellitus and was on glucophage. A non-invasive prenatal test was done in the first trimester, which was of low risk, and no microdeletions or microduplications were detected.

The patient did not perform her scheduled nuchal translucency scan; therefore, an anatomy scan was performed at 20 weeks of gestation. The anatomy scan showed a narrow thorax, unilateral clubfoot with bilateral clubhands, suspected interrupted aortic arch, clenched hands, and hyperechogenic kidneys. However, the patient refused to undergo an amniocentesis, and weekly scans at the fetal medicine unit were conducted till delivery. The last anomaly scan before delivery was performed at 32 weeks and showed an abnormal Doppler, cardiomegaly, a tortuous aorta with suspected coarctation and suspected pulmonary stenosis, pleural effusion, suspected exomphalos, fractured ribs, and femurs. However, no history of prelabor rupture of membranes or preterm prelabor rupture of membranes or chorioamnionitis was clinically found.

The patient delivered a male neonate weighing 2 kg at 33 weeks’ gestational age through an emergency grade 1 cesarean section due to fetal distress observed on antenatal cardiotocography (CTG), prompting delivery on the 9^th of January 2025. During the resuscitation of the newborn, he was hypotonic with poor respiratory effort & cyanosed. His apgar scores were 5, 7 and 8 at 1, 5 and 10 minutes, respectively. The newborn was positioned appropriately with dry stimulation and suction. His heart rate was <100 bpm, respiratory rate was 60/min, and peripheral oxygen saturation was 80–85%. Positive pressure ventilation started for 15 seconds with no improvement.

Clinical examination of the neonate showed dysmorphic features, small eyes, loose folds, sagging and inelastic skin, and a droopy or wrinkled appearance. Chest intubation ensued with accepted air entry and mild recessions, and he was transferred to the neonatal intensive care unit (NICU). He was hemodynamically unstable with hypotension, and no murmur was evident. The abdomen was soft with a massive inguinal hernia, and the genitalia were not visible (Figure 1). Multiple limb deformities were also apparent (Figure 2). Whole-exome sequencing was performed, whereby a pathogenic variant was detected in a homozygous state in chromosome 11 [EFEMP2: Chr11 (GRCh37): g65638079; NM_016938.4: C.418T>A; p.Cys140Ser; exon5/11], which causes ARCL1B. Both parents were found to be carriers of the EFEMP2 gene mutation. Additionally, the radiographs of the neonate showed multiple in utero fractures of the ribs and the long bones. The umbilical venous catheter was seen overlapping the stomach air on the left side, the small bowel was herniated, the left femur fracture healed with callus formation, a healing fracture of the left 7th posterior rib, and right angular rib fractures (Figure 3).

Figure 1 The abdomen of the neonate was soft with a massive inguinal hernia, and the genitalia were not visible. This image is published with the parents of the patient’s consent.

Figure 2 Multiple limb deformities were apparent in the neonate. This image is published with the parents of the patient’s consent.

Figure 3 X-ray of the neonate showing multiple in utero fractures of the ribs and the long bones. The small bowel was herniated, healing with callus formation of the left femur shaft fracture, a healing fracture of the left 7th posterior rib, and right angular rib fractures.

The neonate was commenced on a mechanical ventilator on conventional ventilation, with escalated high-frequency oscillation and inhaled nitric oxide with a fraction of inspired oxygen of 100% oxygen. Echocardiography of the neonate showed a small atrial septal defect with left-to-right shunting, severe right atrial enlargement and moderate left atrial enlargement, and severe tricuspid regurgitation with a peak gradient of 51 mmHg. Findings included moderate mitral regurgitation, a moderate patent ductus arteriosus, a tortuous descending aorta without evidence of coarctation and mild pleural effusion. When echocardiography was repeated, it showed weak contractility, secondary pulmonary hypertension, and a left ventricular fraction of 37.7%. Therefore, the neonate was started on epinephrine, dobutamine, and hydrocortisone.

The neonate received fluids intravenously via a Broviac line. He was started on ampicillin and gentamicin for infection, and his central nervous system was sedated by morphine, in addition to receiving sodium bicarbonate (NaHCO₃) for metabolic acidosis.

Abdomen ultrasound (US) of the neonate showed ballooning of the suprahepatic inferior vena cava, mild to moderate free perihepatic and perisplenic fluid, and mild bilateral pleural effusions (Figure 4). A brain US was also performed; however, it was unremarkable. Pelvis US showed both testes are within the large infra-pelvic hernial sac that contains the bowel loops for surgical review and bilateral hydroceles, which were larger on the right side (Figure 5). The refractory severe hypotension and difficulty in maintaining the oxygen saturation despite facilitating maximal medical intervention couldn’t improve the condition of the neonate, and he eventually succumbed at nine days of age. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the parents of the patient for the publication of this case report and any accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Figure 4 Ultrasound of the neonate showed ballooning of the suprahepatic inferior vena cava, mild to moderate free perihepatic and perisplenic fluid, and mild bilateral pleural effusions.

Figure 5 Pelvis ultrasound showing both tests are within the large infra-pelvic hernial sac that contains the bowel loops, and bilateral hydroceles, which were larger on the right side. The lines (a) and (b) represent the longitudinal and transverse dimensions of the testes respectively, used to assess testicular size and asymmetry.

Discussion

Cutis laxa is a rare group of disorders of connective tissue origin, manifested by loose and inelastic skin folds, which gives the appearance of premature aging. The hallmark of cutis laxa is fragmented dermal elastic fiber, which is the main cause of excessive skin folds. It mainly affects the neck, hands, groin, and face. Cutis laxa is present in congenital and acquired forms. Congenital cutis laxa is the result of genetic defects, while acquired cutis laxa can be caused by some medications, infections, and paraneoplasm, especially in individuals who are susceptible to elastic fiber degradation (3). This is an extremely rare condition with only a few cases documented in the literature (Table 1).

A recent case of cutis laxa type 1B was reported by Singh et al. (5), who showed homozygous variation in the EFEMP2 gene, similar to our case. However, the variation was detected in exon 4 (c.169G>A; p.Glu57Lys), unlike our case, whose variation was in exon 5/11 (C.418T>A; p.Cys) (5). Unlike our case, which presented with cutis laxa features at birth, the case reported by Singh et al. (5) presented at the age of 8 months with a delay in all spheres of developmental milestones. While our case presented with various dysmorphologies, such as a narrow thorax, unilateral clubfoot, bilateral clubhands, clenched hands, suspected exomphalos (abdominal wall defect), and fractured femurs, and systemic abnormalities, such as a suspected interrupted aortic arch, cardiomegaly, tortuous aorta with suspected coarctation and suspected pulmonary stenosis, pleural effusion, and hyperechogenic kidneys. Singh et al.’s case showed only developmental and morphological abnormalities, such as lax skin, deep-set eyes, quadrangular skull, frontal bossing, and hypotonia, with normal systemic examination (5).

Used-Gavín et al. (6) reported a case of a 26-year-old Colombian male with ARCL1B who presented with a large ascending aorta aneurysm and massive pleural effusion. The case had a homozygous variant (p.Ser137Cys) in the EFEMP2 gene, which is potentially functionally related to our case report (p.Cys140Ser) (6). This may explain the major cardiovascular manifestations of both cases. However, no skin or morphological abnormalities were reported in this case. Letard et al. (7) reported a case of a fetus with EFEMP2-related cutis laxa and diagnostic features detected before birth, resulting in termination of pregnancy. The case was examined at autopsy, and molecular analysis showed a homozygous mutation in exon 7 in the EFEMP2 protein (c.639C>A, p.Cys213). An ultrasonography examination was done and revealed some similarities to our case. It showed redundant soft tissue, clubfoot, clenched hand, bowing of long bones, tortuosity of the aorta and umbilical arteries, and suspected left-sided diaphragmatic hernia. The external examination showed a slender fetus with cutis laxa, clinodactyly, clubfoot, arachnodactyly, micrognathia, and camptodactyly (7). Furthermore, Loeys et al. reported 49 cases of pathogenic variants in EFEMP2, with arterial/aortic aneurysms and arterial tortuosity being the most common presentations (4). Other common presentations included arterial stenosis, diaphragmatic abnormalities, and hernia. Early mortality was a common finding among these cases.

EFEMP2 is a gene that codes for fibulin-4, a protein that is highly expressed in conductance arteries, notably in the ascending thoracic aorta (8). It is an essential protein in the development and maintenance of the extracellular matrix and its elastic fibres and plays a role in the differentiation of smooth muscle cells (4). Fibulin-4 is involved in the transforming growth factor-beta (TGF-β) pathway and interacts with other proteins such as fibrillin-1, lysyl-oxidase, and tropoelastin (4). Biallelic pathogenic EFEMP2 variants lead to ARCL1B, a rare disorder marked by decreased fibulin-4, resulting in disrupted elastin architecture and a subsequent upregulation of transforming growth factor beta signaling (4). Types of EFEMP2 variants have been reported: truncating variants and missense variants. Truncating variants result in a severe phenotype, characterized by skeletal involvement, which commonly leads to perinatal death (6,7). This is attributed to the complete lack of fibulin-4 associated with truncating variants. On the other hand, missense variants lead to milder phenotypes, characterized by predominant vascular involvement, as these variants affect specific calcium or cysteine binding residues critical for fibulin-4 stabilization. Missense variants result in variable fibulin-4 deficiency.

To detect any genotype-phenotype correlations, Letard et al. performed a survival analysis comparing patients with truncating EFEMP2 pathogenic variants with patients with biallelic missense EFEMP2 pathogenic variants patients, and found a shorter median survival in the truncating EFEMP2 pathogenic variants group (7). Thus, patients with biallelic missense EFEMP2 pathogenic variants, like our case, should have longer survival times. Additionally, it has been reported that similar cases with this type of mutation experience predominant vascular involvement, similar to our case (4,6).

Cutis laxa is a rare connective tissue disorder that requires more attention from health professionals and policies. Antenatal diagnosis of cutis laxa can be vital in guiding parental counseling. Genetic counseling, including identification of consanguinity and family history, is critical. Cases of cutis laxa, especially ARCL1B, should receive multidisciplinary management, as they always have various morphological and systemic disorders. The cardiopulmonary compromise associated with ARCL1B is a major cause of mortality; thus, it is critical to perform echocardiographic monitoring and prepare the NICU. Furthermore, families should be counseled about the poor prognosis of this disorder. This case report and literature review adds to the existing literature discussing an extremely rare case, aiming to fill the gap present in the literature.

Specific limitations of our case report include the unavailability of some important data, such as consanguinity and the presence of intrauterine stress. Strengths of this case report include the documentation of a rare condition, prenatal detection through US, the use of advanced diagnostic methods, and multidisciplinary insights.

Conclusions

Cutis laxa can be a perturbing and unforeseen finding in the obstetric fetal medicine unit during antenatal visits, especially if it’s a new genetic variant or occurrence within the parents’ history. This case illustrates a rare presentation of ARCL1B with multiple dysmorphic and systemic abnormalities, confirmed by EFEMP2 mutation. Although our case succumbed shortly after delivery, it accentuates the significance of an expeditious diagnosis, especially when the diagnosis can be missed antenatally or when faced with parental refusal of testing. This case report and literature review aid in building future research theories and shaping the format of guidelines in modern world clinical practice, whereby a better understanding of the molecular mechanisms may pave the way for future targeted therapies.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-2025-254/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-2025-254/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-2025-254/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the parents of the patient for the publication of this case report and any accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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