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Case Report
Loeys-Dietz Syndrome with Type 1 Diabetes Mellitus
Clin Pediatr Hematol Oncol 2023;30:99-102.
Published online October 31, 2023
© 2023 Korean Society of Pediatric Hematology-Oncology

Daro Jeong, Jung Hyun Lee and Seom Gim Kong

Department of Pediatrics, Kosin University Gospel Hospital, Kosin University College of Medicine, Busan, Korea
Correspondence to: Seom Gim Kong
Department of Pediatrics, Kosin University College of Medicine, 262 Gamcheon-ro, Seo-gu, Busan 49267, Korea
Tel: +82-51-990-6278
Fax: +82-51-990-3065
E-mail: ana313@hanmail.net
ORCID ID: orcid.org/0000-0003-2361-2221
Received August 31, 2023; Revised October 12, 2023; Accepted October 23, 2023.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Loeys-Dietz syndrome is a hereditary connective-tissue disorder first reported in 2005. It is caused by genetic defects in the transforming growth factor-beta (TGF-β) signaling pathway. TGF-β signaling plays an important role in connective-tissue development, differentiation, and homeostasis. Dysregulation of TGF-β signaling causes various defects in the skull, face, skeletal system, skin, and blood vessels. Symptoms of Loeys-Dietz syndrome include scoliosis, spider finger, joint laxity, club foot, hypertelorism, and cleft palate. In addition, aortic aneurysm, aortic dissection, bleeding tendency, delayed wound healing, allergic disease, and autoimmune disease have been reported. Here, we describe an 11-year-old male with type 1 diabetes mellitus who had frequent epistaxis and easy bruising from an early age, along with skin and joint hyperextension, atrophic scars, and long limbs. He was suspected of having a hereditary connective-tissue disorder and was diagnosed with Loeys-Dietz syndrome type 1 by next-generation sequencing. Similar to Marfan syndrome and Ehlers-Danlos syndrome, this disease has a high risk of aortic aneurysm and aortic dissection. In addition, because aortic dissection can occur at a young age, early diagnosis and periodic examination and treatment for cardiovascular diseases are necessary.
Keywords: Loeys-Dietz syndrome, Receptor, Transforming growth factor-beta type I, Connective tissue diseases, Diabetes mellitus, Type 1
Introduction

Evaluations of patients with a bleeding tendency must consider hereditary connective-tissue disorder (HCTD). Connective tissue is widely distributed in the human body and constitutes cartilage, bone, ligament, skin, muscle, and blood vessel walls. Connective tissue is composed of an extracellular matrix (ECM) of collagenous fibers, elastic fibers, glycosaminoglycan, proteoglycan, and glycoprotein. The ECM physically supports cells, tissues, and organs and plays a role in regulating various cell activities, such as proliferation, migration, differentiation, and apoptosis [1]. HCTD includes not only defects in simple ECM components, but also dysregulation of various signaling pathways.

The most well-known HCTD is Marfan syndrome. In 1991, some 100 years after the syndrome was first reported, mutations in the fibrillin gene were identified [2,3]. Fibrillin microfibrils not only maintain the elasticity of elastic fibers, but also play an important role in regulating transforming growth factor-beta (TGF-β) signaling, disruption of which is a major etiology of HCTD [4]. In 2005, Loeys et al. found heterozygous mutations in the TGF-β receptor gene in families with aortic aneurysm syndrome [5]. In addition, mutations of downstream signaling molecules and TGF-β ligand genes have been confirmed [6]. Diseases caused by TGF-β signaling dysregulation are known as Loeys-Dietz syndrome (LDS).

Similar to Marfan syndrome and Ehlers-Danlos syndrome, LDS is a connective-tissue disorder accompanied by cardiovascular, craniofacial, and skeletal defects. As LDS can cause serious cardiovascular complications such as aortic aneurysm and aortic dissection at a relatively young age, early detection is important [7]. Patients with LDS may visit a hospital with bleeding tendencies at a young age, and interest and understanding of this disease will help in early diagnosis.

Case Report

An 11-year-old boy was referred to the department of pediatric hematology at our hospital with a history of frequent epistaxis, particularly in winter, and sometimes the bleeding would continue for 1 to 2 h. He experienced easy bruising from minor trauma, continued bleeding after tooth extraction, and suffered an ankle fracture and hemarthrosis 2 years prior to presentation. In addition, the wound did not heal well and scarred bad. Physical examination revealed atrophic scars on the legs, thin arms and legs, and hyperextension of the skin. On the Beighton scale, both elbow joints were hyperextended by more than 10°, there was lumbar flexion with palms touching the floor, and the patient was positive for the Walker-Murdoch sign.

At the age of 10 years, the patient was diagnosed with type 1 diabetes mellitus and was prescribed insulin treat-ment. At that time, his serum glucose was greater than 800 mg/dL, HbA1c was 11.3%, and an anti-glutamic acid decarboxylase antibody test was positive at 21.83 U/mL. A review of his family history revealed that his father’s younger brother and younger cousin had similar symptoms, including thin skin, thin body, long arms and legs, shoulder joint abnormality, and cleft palate.

Blood tests showed a leukocyte level of 6,600/mL, hemoglobin level of 12.3 g/dL, platelet level of 378,000/mL, prothrombin time of 12.8 s, and activated partial thromboplastin time of 29.4 s. His Factor XIII and von Wille-brand factor were normal. In an HCTD panel test using next-generation sequencing, heterozygous duplication of nucleotides 73-78 in the TGFBR1 gene was confirmed, and the patient was diagnosed with Loeys-Dietz syndrome type 1 (Fig. 1). After diagnosis, magnetic resonance angiography of the head, carotid artery, and abdomen and echocardiography showed no abnormalities such as aneurysms and arterial tortuosity. Follow-up examinations for vascular disease are scheduled.

Figure 1. DNA sequencing of TGFBR1 revealed duplication of the nucleo-tide sequence from the 73rd to 78th nucleotides (c.73_78dup), and it is expected that the 26th alanine from the 25th alanine will dupli-cate (p.Ala25_Ala26dup).
Discussion

More than 3,800 cases of LDS have been reported, and the prevalence is not yet known [8]. Autosomal dominant inheritance has been established, and six genes have been identified [5,6]. These include genes for TGF-β receptor 1 (TGFBR1), TGF-β receptor 2 (TGFBR2), TGF-β2 (TGFB2), TGF-β3 (TGFB3), and receptor-regulated Smads (SMAD2 and SMAD3), which are downstream signaling substances [5,6]. TGF-β signaling begins when TGF-β ligands (TGF-β 1-3) bind to receptors. When a ligand binds to TGF-β receptor 2, the receptor is phosphorylated and forms a heterodimer complex with TGF-β receptor 1 [1]. Smad2 and Smad3 are then phosphorylated and bond with Smad4 to form a trimeric complex. After the Smad complex enters the nucleus, it regulates the transcription of related genes. TGF-β is a cytokine that regulates cell growth and differentiation along with activins, inhibins, and bone morphogenic proteins [1]. It plays an important role in connective-tissue development, differentiation, and homeostasis not only during embryonic development, but also after birth. Specifically, it regulates vessel wall homeostasis, limb and digit development, palate development, endochondral ossification, and longitudinal bone growth [1].

LDS is characterized by widespread defects in the skull, face, skeletal system, skin, and blood vessels. Cha-racteristic symptoms include hypertelorism, cleft palate, bifid uvula, and blue sclera, and these are accompanied by skeletal abnormalities such as scoliosis, cervical vertebrae malformation, spider finger, joint laxity, and club foot [8]. The syndrome can be accompanied by allergic complications such as asthma, rhinitis, eczema, and food allergies; gastrointestinal complications such as consti-pation, growth retardation, eosinophilic gastrointestinal disease, and inflammatory bowel disease; and respiratory complications such as pneumothorax and restrictive lung disease [8]. Women are at high risk of aortic dissection, uterine rupture, and postpartum hemorrhage during pre-gnancy and delivery [7,8]. There have been no reports of type 1 diabetes mellitus in LDS, but because TGF-β signaling plays an important role in immune system, it is also associated with autoimmune diseases [9]. The bruising and bleeding tendency in HCTD is due to the vulnerability of subcutaneous tissue and blood vessel walls [10]. In addition, abnormalities in TGF-β signaling cause delayed wound healing due to impaired recruitment of mono-cytes and fibroblasts, as well as dysfunctional regulation of the expression of major ECM proteins [9]. There are no established guidelines for the prevention and treatment of bleeding in patients with LDS. For vascular Ehlers-Danlos syndrome, it is recommended to avoid vascular damage, anticoagulants, contact sports, and heavy exercise and to assure appropriate ascorbic acid supplementation [10].

The most serious complication is cardiovascular disease. Arterial tortuosity has been reported in various locations, and aortic aneurysm and aortic dissection can progress rapidly. In one study, 27 of 90 patients with LDS died at a mean age of 26 years (0.5-47 yr) [7]. The main cause of death was thoracic aortic dissection in 67% of cases, and abdominal aortic dissection and cerebral bleeding were the other causes. Aortic dissection has also occurred at less than 1 year of age [7]. In a previous study, the median survival of LDS was 37 years, lower than those of vascular Ehlers–Danlos syndrome (48 yr) and Marfan syndrome (70 yr) [7]. This was presumed to be due to the higher risk of aortic dissection compared with other connective-tissue diseases and the relatively early age of occurrence [7,8].

Initially, cardiovascular disease progression was thought to be due to structural defects in connective tissue. But in 2003, increased TGF-β signaling was confirmed in mice with fibrillin-1 deficiency [4]. As fibrillin microfibrils sequester latent TGF-β complexes and release them rapidly when needed, fibrillin defects can cause uncontrolled activation of TGF-β [3]. Similarly, increased TGF-β signaling has been confirmed in the aortic wall of LDS patients [5]. It has become clear that cardiovascular disease in HCTD is associated with paradoxical upregulation of TGF-β signaling.

Proper blood pressure control and follow-up are important to reduce death from aortic and cardiovascular diseases [11]. Periodic angiography by MRI or CT may be required, and the aortic root dimension should be measured by echocardiography every year [11]. Until 10 years ago, drugs that lowered blood pressure or reduced cardiac contractility were the most common therapy. How-ever, as the association with TGF-β signaling was confirmed, the administration of losartan, an angiotensin II type 1 receptor antagonist, has become more popular [3]. Losartan is known to inhibit TGF-β signaling, reduce aortic growth rates, and prevent progressive elastic fiber fragmentation in a mouse model of Marfan syndrome [12]. A study on LDS mutant mice confirmed that losartan normalizes the growth of the aortic root and prevents deterioration of the aortic wall [13]. In a randomized controlled study comparing atenolol and losartan in Marfan syndrome, both treatment groups showed a significant decrease in the Z-scores of aortic dimensions, and they were more effective when initiated at a younger age [14]. Although clear criteria for surgical treatment of aortic disease in LDS have yet to be established, surgery is actively being considered because dissection can occur at a younger age compared with Marfan syndrome. Sur-gery should be considered if the diameter of the aortic root is greater than 4 cm in adults and if aortic dilatation is progressing rapidly in children [11]. In a study of prophylactic surgery for LDS, the 10-year survival rate was relatively high at 89% [15].

Although patients with HCTD experience a wide range of symptoms throughout their lives, diagnosis is often delayed. Early diagnosis is important because cardiovas-cular disease can progress at an early age in many HCTDs. For early diagnosis, it is important to suspect HCTD by detailed examination and examination of various symptoms. Even if blood tests are normal in patients with bleeding tendencies, evaluation of skin hyperextension, joint hyperextension, delayed wound healing, blue sclera, and long limbs is necessary. In such cases, genetic testing for HCTD should be considered [6].

Conflict of Interest Statement

The authors have no conflict of interest to declare.

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  • Seom Gim Kong