Varied imaging manifestations in EFEMP2 Related Cutis Laxa Associated Arterial Tortuosity
Correspondence Address :
Jini Joseph,
“Menampadathil House” Maikkavu, P.O. Thamarassery, Calicut-673573, Kerala, India.
E-mail: jini.joseph@asterhospital.com
Case 1
An eight-month-old male baby was brought to the hospital by his parents due to poor weight gain, lower respiratory tract infection, and exertional dyspnoea (noticed by the parents) for one month. During the clinical examination, a grade-III ejection systolic murmur and end diastolic murmur were observed. A hyperdynamic apex and mild tachypnoea were also noted. Echocardiography (ECHO) was performed to investigate the suspicion of cardiac disease. The ECHO revealed aneurysmal aortic dilatation, moderate to severe aortic regurgitation, and was suggestive of Arterial Tortuosity Syndrome (ATS). Subsequently, a Computed Tomography (CT) pulmonary angiogram was conducted (Table/Fig 1),(Table/Fig 2),(Table/Fig 3),(Table/Fig 4),(Table/Fig 5),(Table/Fig 6),(Table/Fig 7),(Table/Fig 8).
At the time of discharge, the baby was stable and able to tolerate feeds. The caregivers were counselled regarding the progressive nature of the disease, its genetic aetiology and the prognosis.
Case 2
A 10-month-old female baby, who was developmentally normal, presented with complaints of breathing difficulty that worsened in the lying down position and improved in the sitting position, as well as decreased urine output for the past two weeks. There was no significant antenatal, natal or postnatal history. The baby had a history of head sweating and a suck-rest-suck cycle. There was no history of cough.
Upon clinical examination, cutis laxa was observed along with a hyperdynamic apex, cardiomegaly, an ejection systolic murmur, an end diastolic murmur, tachypnoea and subcostal retractions. ECHO showed dilated aorta from the sinuses to the proximal arch, aneurysmal dilation of the ascending aorta, tortuous descending aorta, severe mitral regurgitation, aortic regurgitation and pulmonary artery hypertension. Multidetector Computed Tomography (MDCT) pulmonary angiogram was advised to further assess the anatomy of the vessels (Table/Fig 9),(Table/Fig 10),(Table/Fig 11),(Table/Fig 12).
Initially, the baby was stable and able to tolerate feeds. However, four months after the diagnosis, the patient developed severe respiratory distress. Venous blood gas analysis showed severe respiratory acidosis. The baby was intubated and started on inotropes and diuretics. While being extubated, the patient was unable to tolerate Bilevel Positive Airway Pressure (BiPAP) and experienced bradycardia, desaturation, and ultimately succumbed to death despite resuscitative measures.
Case 3
A male baby, born at term and appropriate for gestational age, was referred from an outside hospital at 78 hours of life (HOL) due to respiratory distress. Clinical examination at 48 HOL revealed a systolic murmur. Chest X-ray showed well-expanded lung fields and normal cardiac shadows. Sepsis screen and blood culture were negative. ECHO was performed, which revealed a dilated main pulmonary artery and ascending aorta, myxomatous Arteriovenous (AV) valve leaflets, severe bilateral peripheral Pulmonary Stenosis (PS), turbulent flows across the arch vessels and descending aorta, Right Pulmonary Artery (RPA) stenosis, and moderate Pulmonary Arterial Hypertension (PAH). Due to suspicion of ATS, a CT pulmonary angiogram was conducted. The CT pulmonary angiogram showed levocardia, mild tortuosity and elongation of the aortic arch, tortuosity of the origin and course of bilateral common carotid and left subclavian arteries, tortuous aberrant right subclavian artery, dilated main pulmonary artery (12.8 mm) with narrowing of the origin of the left pulmonary artery (3.4 mm), and mild tortuosity of the descending thoracic aorta and inferior mesenteric artery was (Table/Fig 13),(Table/Fig 14),(Table/Fig 15). The baby remained haemodynamically stable and had good oral feeding tolerance, leading to his discharge.
Genetic testing revealed that all of these babies had a similar genetic result, with a mutation in the Epidermal Growth Factor-containing Fibulin-like Extracellular Matrix Protein 2 (EFEMP2) gene causing Autosomal Recessive Cutis Laxa type 1B (ARCL1B) associated with arterial tortuosity. Specifically, a homozygous missense variation in exon 7 of the EFEMP2 gene (chr11:65637447T>G; c.608A>C) resulting in the substitution of alanine for aspartic acid at codon 203 (p.Asp203Ala) was identified, confirming the diagnosis of ARCL1B (Table/Fig 16).
Autosomal recessive cutis laxa type 1B, Epidermal growth factor containing fibulin extracellular matrix protein 2, Multisystem disease, Vascular structures
The gene EFEMP2 related cutis laxa, also known as autosomal recessive cutis laxa type 1B (ARCL1B), is a rare multisystem disease that affects the skin, skeleton and vascular structures (1). ARCL1B is caused by mutations in the EFEMP2 gene located on chromosome 11q13.1, which encodes the EFEMP2. The severity of the disease can range from perinatal death to a spectrum of disease compatible with survival (2).
This condition is characterised by cutis laxa, facial dysmorphism, arterial involvement (arterial tortuosity, aneurysms, or stenosis), respiratory involvement (emphysema, diaphragmatic hernia, or hypoplasia), craniofacial involvement (retrognathia, widely spaced eyes, and high palate), bony deformities (scoliosis and chest wall abnormalities), and other features commonly seen in connective tissue disorders, such as joint laxity and arachnodactyly. The affected arteries are typically large and medium-sized vessels (3).
Loeys-Dietz syndrome, Occipital horn syndrome, connective tissue diseases including Ehler-Danlos syndrome-type III and Ehler-Danlos syndrome-vascular type IV, wrinkly skin syndrome, Gerodermia osteodysplastica, Marfan syndrome, and Menkes disease can present with typical features that mimic ARCL1B (4). Genetic testing is the gold standard for diagnosing these mimics. Fibrillin-1 (FBN1) mutations can help differentiate between these conditions. For example, an FBN1 mutation is specific for Marfan syndrome, Transforming Growth Factor Beta Receptor 1 (TGFBR1) or TGFBR2 mutations are associated with Loeys-Dietz syndrome (LDS), and Collagen alpha-1(III) (COL3A1) and Collagen type I alpha 1 (COL1A1) mutations are seen in vascular Ehlers-Danlos syndrome (EDS). The ATPase Copper Transporting Alpha (ATP7A) gene is responsible for occipital horn disease, and biallelic pathogenic variants in the SLC2A10 gene are associated with ATS.
The Tortuosity Index (TI) of intracranial arteries can also aid in distinguishing between Marfan syndrome and LDS. An intracranial ICA TI greater than 132 shows higher specificity (98%) for connective tissue disorders, like Marfan syndrome, while a Vertebral basilar system TI greater than 60 is 97% specific for LDS (4). Awareness of the early signs of arterial tortuosity in ARCL1B and recognition of the described signs (such as the aortic elongation sign and “V” sign of the pulmonary artery) can lead to early diagnosis of clinically asymptomatic cases.
The authors express heartfelt gratitude to Dr. K.G. Ramakrishnan, Head of Department, Department of Radiodiagnosis, for his continual guidance, efforts, encouragement and suggestions for the present article. The authors are thankful to Dr. Tajimal, Senior Consultant, Department of Radiodiagnosis, for the support and constant guidance. Authors express their gratitude to Dr. Divya Pachat, Medical Geneticist, Malabar Institute of Medical Sciences, Calicut, Kerala, India, for her valuable contribution in the present article. Authors are thankful to Dr. Rekha, Dr. Shan, Dr. Nasmin, Dr. Angita and their colleagues for the support and suggestions.
DOI: 10.7860/JCDR/2023/62595.18233
Date of Submission: Jan 01, 2023
Date of Peer Review: Mar 24, 2023
Date of Acceptance: Jun 05, 2023
Date of Publishing: Jun 01, 2023
AUTHOR DECLARATION:
• Financial or Other Competing Interests: None
• Was Ethics Committee Approval obtained for this study? Yes
• Was informed consent obtained from the subjects involved in the study? Yes
• For any images presented appropriate consent has been obtained from the subjects. Yes
PLAGIARISM CHECKING METHODS:
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• iThenticate Software: Jun 02, 2023 (15%)
ETYMOLOGY: Author Origin
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