Primary intestinal lymphangiectasia presenting as limb convulsions: A case report

lNTRODUCTlON

Intestinal lymphangiectasia (IL) is a rare protein-losing enteropathy[1], characterized by small intestinal lymphatic drainage obstruction, chylous ascites, and villi distortion that further cause lymphatic congestion and elevate the lymphatic pressure, thereby resulting in leakage of lymph liquid into the small intestinal lumen. IL can be categorized into two forms, primary IL (PIL) and secondary IL (SIL).PIL, first reported by Milroy in 1892, is more common in children and adolescents, though rarely, it can also occur in adults and has a tendency to occur sporadically with an unknown etiology. Waldmann[2] in 1961 after demonstrating protein loss quantification byCr-labelled albumin revealed that the lymphatic vessels present in the mucosal and submucosal layers of the small intestine were abnormally dilated to varying degrees. Hence, this diagnosis came into existence.

The incidence of PIL is likely to be related to lymphatic dysplasia in infants which is more frequently diagnosed in children (less than 3 years old), but also in adolescents and even elderly cases[3]. Although in most cases lymphatic dilation is typically seen in the descending duodenum, lymphatic dilation in the small intestine is usually mild and segmental, and secondary causes should be excluded. In this case report, a 19-year-old adult man complained of limb convulsions for the past 1 year, which after further investigations, was later identified as PIL. The following medium-chain triglycerides (MCT) nutritional support improved the patient’s condition.

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CASE PRESENTATlON

Chief complaints

A 19-year-old Chinese male patient complained of recurrent limb convulsions for the past 1 year.

History of present illness

The patient experienced recurrent limb convulsions and numbness with an unknown medical history in the absence of any aggravating factors like joint inflammation, edema, headache, dizziness, nausea and vomiting, abdominal distention, pain, or diarrhea, leading to a gradual weight loss by five kilograms,but due to the ignorance of the patient as well as his family, no further treatment was initiated. But 1 wk ago, his symptoms, comprising of limb convulsions and numbness, got so aggravated that he visited the community hospital in April 2021 for a thorough examination that was preceded by laboratory investigations that showed reduced levels of blood calcium 1.50 mmol/L (1.95 mmol/L after correction, normal range: 2.08-2.6 mmol/L), magnesium 0.49 mmol/L (normal range: 0.75-1.02 mmol/L), potassium 3.38 mmol/L (normal range: 3.5-5.5 mmol/L), and albumin 17.27 g/L (normal range: 40-55 g/L) while displaying increased parathyroid hormone (PTH) 113.0 pg/mL (normal range: 15-65 pg/mL). The patient had blood phosphorus at 1.12 mmol/L, TSH at 2.5 mIU/L, and a positive fecal occult blood test(FOBT). He was supplemented with albumin, calcium gluconate injections, and potassium magnesium aspartate. Henceforth, the persistent symptoms like limb convulsions and numbness were relieved after symptomatic treatment for 1 week. He went to the Endocrinology Department of our hospital for a further definite diagnosis.

多年以后，阿飞终于等到了真正自由的时候——成家立业。阿飞出生于一个时代经商的世家，几代以来虽说不是大富大贵，但从没做过赔本的生意，到了阿飞这一代已然积攒了不少家业，家境也算殷实。在传统的中国家庭里，一旦有了一点家业，就会开始“讲究”一些看起来很正式但又是牛头不对马嘴的“传统风俗”，这些“习俗”一旦讲究起来，简直比要人命还厉害。

History of past illness

The patient consented to his case being published anonymously.

Personal and family history

The patient was born by spontaneous labor at term, was breastfed in infancy, and had normal physical and cognitive development as his peers along with good academic performance. However, he had a history of hemorrhoids but did not have any long-term chronic abdominal pain and diarrhea in adolescence. His parents were healthy while denying any history of familial genetic disease, psychosis,and infection in the older family generations.

Physical examination

The patient’s height was 174 cm, weight was 52 kg, and body mass index was 17.18 kg/m. He did not exhibit widening of either eye distance or base of the nose-bridge and small external ear while his abdomen was flat and soft, with no abdominal tenderness or rebound pain, non-palpable liver and spleen, normal bowel sounds, and limb strength. Especially, no concave edema was found in both lower limbs, whereas the Babinski’s sign, Chvostek's sign, and Trousseau’s sign were negative (Figure 1).

Laboratory examinations

The results of blood biochemistry were: Calcium 2.37 mmol/L (normal range: 2.08-2.6 mmol/L),magnesium 0.73 mmol/L (normal range: 0.75-1.02 mmol/L), potassium 4.19 mmol/L, phosphorus 1.19 mmol/L, parathyroid hormone 16.7 pg/mL (normal range: 15-65 pg/ mL), and albumin 25.2 g/L(normal range: 40-55 g/L). The FOBT was positive (1+).

The results of routine blood tests were: White blood cell count 3.8 x 10/L, lymphocyte count 0.41 x 10/L (normal range: 1.1 x 10/L-3.2 x 10/L), and lymphatic percentage 10.4% (normal range: 20%-50%)

The patient was treated with a low-fat, high-protein, light diet which contains 1800 calorie each day, and with MCT powder supplement, calcium supplement, and vitamin D supplement.

The results of immunological tests were: Immunoglobulin (Ig)A 0.49 g/L (normal range: 0.82-4.53 g/L), IgG 1.44 g/L (normal range: 7.51-15.6 g/L), IgM 0.18 g/L(normal range: 0.46-3.04 g/L),complement (C)30.67 g/L (normal range: 0.79-1.52 g/L), C40.15 g/L (normal range: 0.16-0.38 g/L);transferrin 1.42 g/L (normal range: 2.0-3.6 g/L); copper orchid protein 10.70 mg/dL (normal range: 22-58 mg/dL); B cell count (CD19+) 38 x 10/L (normal range: 50 x 10/L-670 x 10/L), T cell count(CD3+CD45+) 179 x 10/L(normal range: 470 x 10/L-3270 x 106 /L), T helper count (CD3+CD4+) 46 x 10/L (normal range: 200 x 10/L-1820 x 10/L), T inhibitory cell count (CD3+CD8+) 120 x 10/L (normal range: 130 x 10/L-1350 x 10/L); the number of NK cells was normal.

例如，学习“研究分泌蛋白依次经过的细胞结构的方法”一节后进行归纳。第二次笔记的内容为： 可用“同位素示踪”来确定某种物质在细胞内或生物体内的定位。

The patient had normal liver and kidney function, thyroid function, thyroglobulin, thyroglobulin antibody, and thyroid peroxidase antibody. The results of endocrine tests were: ACTH: 8 am 13.2 ng/L,4 pm 12.6 ng/L, 0 am 5.3 ng/L; cortisol: 8 am 174.3 nmol/L, 4 pm 102.7 nmol/L, 0 am ＜ 25 nmol/L;follicle stimulating hormone 5.98 IU/L, luteinizing hormone 7.74 IU/L, estradiol 98.38 pmol/L,testosterone 27.56 nmol/L; insulin-like growth factor-1208 μg/L, and insulin-like growth factor binding protein-34.8 mg/L. Tumor markers, ANA spectrum, ANCA, rheumatoid factor, ESR, and hepatic fibrosis were all in the normal range. Urine immunoglobulin light chain, 24-h urine protein, and 24-h urine calcium within the normal range.

The HIV + RPR panel was Negative, and blood and stool IBD screening showed no obvious abnormalities.

每个雷达图都是由5个指标组成的三角形，且每个三角形中的一个角度为已知量，可以通过各指标的长度及指标间的角度得到每个三角形的面积，进而得到每个雷达图的面积，见公式(1)；同理周长也可以利用三角函数取得，见公式(2)。

Imaging examinations

B-mode ultrasound imaging of the parathyroid gland revealed a hypo-echoic nodule with a clear boundary and regular shape along with few blood vessels (Figure 2). An MRI examination exhibited no obvious abnormality while an abnormal-signal nodule was found in front of the right middle abdominal psoas muscle, which was considered as an enlarged lymph node followed by a scanty exudate at the abdominal and pelvic cavity, along with cortical soft tissue edema. Capsule endoscopy showed the flat composition of duodenal mucosal villi with no obvious abnormality in the jejunal or ileal mucosa.Gastroscopy exhibited chronic non-atrophic gastritis and duodenal lymphatic dilatation (Figure 3).Subsequent gastric biopsy showed moderate chronic inflammatory cell infiltration distributed around a small mucosal patch in the descending duodenum followed by lymphatic dilatation in the mucosal lamina propria (Figure 4).

FlNAL DlAGNOSlS

Finally, the patient was diagnosed with PIL (Figures 3 and 4).

TREATMENT

The results of fat-soluble vitamin tests were: Vitamin A 0.28 μg/mL (normal range: 0.30-0.70 μg/mL),25-hydroxyvitamin D 5.28 ng/mL (＜ 20 ng/mL suggesting deficiency), vitamin E 4.49 μg/mL (normal range: 0.30-0.70 μg/mL), and vitamin K10.12 ng/mL (normal range: 0.20-2.50 ng/mL).

OUTCOME AND FOLLOW-UP

The patient returned to the clinic 3 mo later, and showed no symptoms of convulsion of the limbs.Meanwhile, blood calcium and albumin in the laboratory examination increased compared with the values before.

显效:患者的血压和血脂恢复正常,心绞痛发作率减少80%;有效:患者的血压血脂改善,心绞痛减少50%至80%;无效:患者血压血脂无改善,心绞痛发作减少不足50%。总有效率=显效率+有效率。

DlSCUSSlON

Since the PIL etiology is ambiguous and standardized treatment is inadequate, a study by Alfano[14] revealed that the primary goal of PIL treatment is to reduce protein loss, maintain circulating blood volume, and inhibit excessive tissue fluid production, thereby indicating that pharmacological treatment is the first-line treatment prescribed in the clinic. In the gastrointestinal tract, MCT is decomposed into glycerol and medium-chain fatty acids that are directly absorbed in the portal vein blood flow by small intestinal epithelial cells without going through lymphatic vessels, thus reducing the pressure in lymphatic vessels, lymph leakage, and protein loss. Incorporating an MCT-rich diet in daily life could significantly improve the symptoms and long-term mortality of PIL patients, although it might not improve the inherent lymphatic abnormalities; thus, the patients might need to take the required medications for a longer period of time.

Laboratory tests at presentation suggested hypocalcemia, hypomagneemia, hypoproteinemia, and lymphocytopenia. Further investigation revealed elevated PTH, decreased vitamin D, low immunoglobulinemia, and positive FOBT. First, the patient had hypocalcemia and hypomagnesemia, and the convulsions of the limbs were relieved by treatment with calcium gluconate and potassium magnesium aspartate. Elevated PTH and hypoproteinemia gave us the impression of renal insufficiency, but subsequent negative results of renal function and urinary protein precluded this diagnosis. Laboratory tests revealed normal liver function and negative rheumatoid and tumor markers, so we focused on the parathyroid gland. According to B-ultrasonography, hyperplasia of nodules, elevated PTH, and hypocalcemia were suggested, which first promoted us to consider a disease of endocrinology.

在“导生制”教学中，学生的主动性、主体性得到了很好体现，但也会出现一些问题。此时，教师的主导作用就显得尤为重要，课前教师必须统筹规划，使教学有条不紊地进行。

Considering the possibility of protein-loss enteropathy, subsequent gastroscopy revealed duodenal lymphatic dilation, confirming our assessment. IL could be divided into primary and secondary types.Primary IL is a congenital lesion with an ambiguous incidence rate and disease mechanism though occurring more sporadically despite the involvement of genetic factors in the pathogenesis[5], whereas secondary IL can be caused by several factors as autoimmune diseases (, Crohn’s disease[6],ulcerative colitis[7], and Henoch-Schonlein purpura), tumors (such as non-Hodgkin’s lymphoma[8]),infections (such as rotavirus), portal hypertension, constrictive pericarditis[9], trauma, or surgical injury[10]. In our case report, Crohn’s disease was first excluded as FOBT results showed 1+ repeatedly while blood and stool IBD screening was negative. As the patient had a previous history of hemorrhoids, the anorectal department considered it as hemorrhoid bleeding after the consultation.

2014年11月，辽南地区首个医疗联盟——大连医科大学附属二院医疗联盟(简称“联盟”)正式成立，成为三级医院牵头，包括庄河市中心医院、普兰店市中心医院、大石桥市中心医院等14个成员单位，贯穿二级医院和基层医疗机构，横向覆盖疑难重症治疗、急诊急救、居民健康管理的多维度、三级联动区域医联体，意在以信息化为支撑，强化联盟单位间远程会诊和双向转诊、医师多点执业和新农合实时报销等功能。

PHP is a genetic disease in which peripheral cells are resistant to PTH[4]. The central link of the disease is PTH resistance, which leads to high blood phosphorus and activation disorders of 25-(OH)D3,eventually leading to hypocalcaemia. Although this disease is common in women but more severe in men, the reported patients showed symptoms at 2 years of age, which became more obvious after the age of 10 but can rarely be seen in people aged 20 years or above. Tetany and intracranial calcification are usually the most common clinical manifestations and imaging features of PHP. PHP patients with vitamin D deficiency have more severe clinical symptoms, and vitamin D deficiency increases the risk of autoimmune disease. Vitamin D is mainly synthesized in the skin of the body, and then converted into 25-(OH)D by the hydroxylation of 25-hydroxylase (CYP27A1) in the liver, which is the main form of vitamin D in the circulation. 25-(OH)D binds to vitamin D binding protein into the blood circulation and generates active metabolite 1,25-(OH)2D under the catalysis of renal 1αhydroxylase (CYP27B1). 1,25-(OH)2D acts on the intestine, kidney, and bone to regulate the metabolism of calcium and phosphorus.In the small intestine, 1,25-(OH)2D promotes the absorption of calcium and phosphorus, and serum 25-(OH)D is inversely proportional to PTH. When the serum 25-(OH)D level decreases, blood calcium decreases and PTH increases. The increased PTH stimulates the activity of 1αhydroxylase and increases the efficiency of 25-(OH)D conversion to 1,25-(OH)2D. In addition, PTH also normalizes blood calcium levels by stimulating osteoclast proliferation, and increasing bone absorption and calcium release. In this case, the patient had low calcium, with a compensatory increase of PTH, and the blood phosphorus level was within the normal range during the onset. The reexamination of PTH returned to normal during the further correction of low calcium, proving that it was a secondary factor, so PHP could be excluded. Parathyroid nodules were also considered nonfunctional.

Some PIL patients are found with abnormal immune system responses in which the decrease of B cells is manifested by the decreasing IgG, IgA, and IgM levels[11]. Some previous studies also reported that PIL patients’ peripheral blood samples contain a very low number of CD4T cells[12] that were significantly lesser than B cells, while the remaining CD4T cells became highly differentiated and sensitized, thereby showing poor proliferation[13]. It was also observed that the patient’s T lymphocytes kept on decreasing in varying degrees in this case. Further evidence will be necessary to determine whether T lymphocytes mediate the immune functions in the intestine, and further lead to the occurrence and development of the disease.

The clinical manifestations of PIL are diverse as they may cause dilatation of the intestinal lymphatic vessels, leading to loss of lymph fluid into the gastrointestinal tract. While it is mainly characterized by edema of varying degrees, it can also manifest as pleural effusion, pericarditis, chylous ascites, diarrhea,fat vitamin deficiency, weight loss, and other symptoms occurring in severe cases. In our case, due to unknown past medical history, diagnosing and providing prompt treatment were initially challenging as there was no clear history of diarrhea and abdominal pain, limb convulsions, or disease symptoms in childhood. The now obvious limb convulsions first appeared when the patient was 18 years of age and manifested themselves as hypocalcemia, hypomagneemia, and hypoproteinemia, along with elevated PTH levels. Due to similar propensity and characteristics, this disease can easily mimic pseudohypoparathyroidism (PHP) and some other similar diseases in internal medicine, which might lead to misdiagnosis and a plethora of unpleasant side effects. Therefore, the foremost thing that is recommended is to reach a definite diagnosis for a positive outcome.

CONCLUSlON

Based on this case, PIL as a potential diagnosis should be considered even in the absence of any adolescent-illness history for adults with recurrent limb convulsions, low calcium and magnesium,hypoproteinemia, and high PTH levels. MCT diet, as a dietary supplement, can effectively improve the clinical symptoms of PIL patients while providing pharmacotherapy after the final diagnosis was made by a thorough detailed analysis.

FOOTNOTES

Cao Y and Feng XH contributed to literature review and manuscript drafting; Cao Y and Ni HX contributed to patient management and data analysis; and all authors approved the final article and assured all the questions regarding the accuracy of the article.

The patient was healthy until the age of 18, with no trauma or any history of tumor.

The authors declare that they have no conflicts of interest to disclose.

The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).

This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BYNC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is noncommercial. See: https://creativecommons.org/Licenses/by-nc/4.0/

Q陈教授，我家宝宝今年3岁，只喜欢古诗古文，对绝大部分绘本、动画片不感兴趣，平时想通过绘本教他常规习惯他都不听，所以也不会和小朋友一起玩，只在旁边看着笑，不参与，参与了就说古诗，不会说句子或用词组表达。现在上幼儿园了，明显与班上孩子差距大，我该怎么引导孩子呢？

China

Yun Cao 0000-0002-8788-6312; Xiao-Hong Feng 0000-0002-8991-9384; Hai-Xiang Ni 0000-0002-7005-4851.

信阳师范学院充分挖掘大别山区红色文化，教育引导大学生传承革命传统，传承红色基因，大力弘扬中华优秀传统文化和革命传统文化、社会主义先进文化，深化党史、国史、改革开放史和社会主义发展史的学习教育。积极探索实践育人模式，打通了“讲台”到“舞台”到“平台”的通道，不断夯实教育效果。信阳师范学院红色文化育人的实践表明，高校思想政治教育过程中要摒弃简单生硬的“大水漫灌”，不断开辟新的路径，以鲜活的事例感染学生，以实践活动使学生在参与中提升思想水平。高校思想政治教育要不断提升亲和力、覆盖面和实效性，积极总结优秀的个别经验，不断改进成为可复制、高覆盖的普遍经验。

Ma YJ

Wang TQ

Ma YJ