Protein-losing enteropathy and multiple vasculature dysplasia in LZTR1-related Noonan syndrome: A case report and review of literature

Abstract

BACKGROUND

Protein-losing enteropathy (PLE) is a rare cause of hypoalbuminemia that can be attributed to intestinal lymphangiectasia. Patients with Noonan syndrome may present with disorder of lymph vessel formation. However, PLE is rarely reported with Noonan syndrome.

CASE SUMMARY

A 15-year-old female was hospitalized multiple times for recurrent edema and diarrhea secondary to hypoalbuminemia. Additional manifestations included a ventricular septal defect at birth, intermuscular hemangioma, slightly wide interocular and intermammary distances, and absence of the distal phalanx of the left little finger since birth. Abdominal computed tomography revealed cavernous transformation of the portal vein, and liver biopsy indicated “porto-sinusoidal vascular disease”. Whole exome and Sanger sequencing revealed a heterozygous mutation (exon9: C.850C>T:P.R284C) in leucine zipper-like transcription regulator 1, suggesting Noonan syndrome type 10. Further examinations revealed thoracic duct dysplasia and intestinal lymphangiectasia causing PLE in this patient. A multidisciplinary team decided to address thoracic duct dysplasia with outlet obstruction. Approximately two years after the microsurgical relief of the thoracic duct outlet obstruction, the patient achieved persistent normal serum albumin level without edema or diarrhea. Furthermore, the relevant literatures on Noonan syndrome and PLE were reviewed.

CONCLUSION

Herein, we reported the first case of PLE associated with Noonan syndrome caused by a rare genetic mutation in leucine zipper-like transcription regulator 1 (c.850C>T:P.R284C) with newly reported manifestations. This case presented the successful treatment of clinical hypoalbuminemia attributed to thoracic duct dysplasia, intestinal lymphangiectasia and PLE.

Key Words: Noonan syndrome; Leucine zipper-like transcription regulator 1; Protein-losing enteropathy; Porto-sinusoidal vascular disease; Hypoproteinemia; Intestinal lymphangiectasia; Case report

Core Tip: Protein-losing enteropathy (PLE) is rarely reported with Noonan syndrome. This case reported a rare mutation in leucine zipper-like transcription regulator 1 related to Noonan syndrome, thoracic duct abnormalities, small intestinal lymphangiectasia, PLE in a juvenile female with multiple vasculature dysplasia and congenital deformity of the little finger, and the successful treatment of hypoalbuminemia by microsurgical relief of the thoracic duct outlet obstruction. As far as we know, this is the first case describing PLE associated with Noonan syndrome caused by a rare genetic mutation in leucine zipper-like transcription regulator 1 (c.850C>T:P.R284C) with newly reported manifestations. Additionally, this report provides new evidence about the management of Noonan syndrome.

INTRODUCTION

Protein-losing enteropathy (PLE) is a rare cause of hypoalbuminemia. PLE reflects an increased enteric protein loss, which may be attributable to lymphatic dysfunction or protein loss from the intestinal mucosa[1]. Primary intestinal lymphangiectasia represents the most extensively studied etiology of lymphatic dysfunction associated with enteric protein loss in pediatric populations. Patients diagnosed with this condition generally manifest clinical symptoms such as edema, hypoproteinemia, hypoalbuminemia, lymphopenia, and hypogammaglobulinemia. The onset of symptoms is usually observed in early childhood; nevertheless, there are cases where presentation may occur later, extending into adolescence or adulthood. It is essential to rule out secondary etiologies of intestinal lymphangiectasia based on the specific clinical context. A conclusive diagnosis can be established through histological evaluation of mucosal biopsies obtained via endoscopy from the duodenum[2,3].

With a prevalence of one in every 1000-2500 individuals, Noonan syndrome is a hereditary disorder caused by abnormalities in genes involved in the Ras/mitogen-activated protein kinase (MAPK) signaling pathway. These include distinctive facial characteristics, congenital heart defects, short stature, and intellectual disabilities. There is no definitive treatment and its management focuses on symptomatic therapy. Prognosis depends largely on the severity of the associated heart disease[4]. As the initial clinical presentation can vary and typical facial features recede with age, the diagnosis may be overlooked. Genetic testing is important for identifying the molecular cause, aiding in scenarios such as prenatal diagnosis, and providing guidance for monitoring related clinical symptoms. As least nine genes in the RAS-MAPK signaling pathway cause Noonan syndrome or other closely related conditions [protein tyrosine phosphatase non-receptor type 11, son of sevenless homolog 1, KRAS, NRAS, RAF1, BRAF, SHOC2, Casitas B-lineage lymphoma, and leucine zipper-like transcription regulator 1 (LZTR1)]. Approximately 50% of Noonan syndrome cases are caused by missense gain-of-function mutations in protein tyrosine phosphatase non-receptor type 11, which are more likely to be familial[4-6]. Mutations in LZTR1, known to cause familial schwannomatosis type 2, have recently been implicated in a small number of cases of Noonan syndrome[7-9]. Herein, we present a rare mutation in LZTR1 associated with Noonan syndrome type 10 (Online Mendelian Inheritance in Man #616564), with an initial clinical presentation of recurrent edema and hypoalbuminemia. Two years after the lymphatic obstruction of the thoracic duct was relieved, hypoalbuminemia gradually improved in the patient.

CASE PRESENTATION

Chief complaints

A 15-year-old girl presented to the hepatology clinic with a complaint of recurrent edema for 3 months.

History of present illness

The patient had experienced multiple hospitalizations for recurrent edema since February 2022 due to hypoalbuminemia (16.8-20.0 g/L), which was unresponsive to diet adjustment. Albumin infusion combined with diuretic treatment improved the edema during hospitalization; however, discontinuation of albumin resulted in the recurrence of hypoalbuminemia. The patient did not experience diarrhea, abdominal pain, or weight loss.

History of past illness

History of past illness included a ventricular septal defect at birth, which was surgically repaired at the age of one year; and hemangioma (4.5 cm × 3 cm × 1 cm) in the left gluteus maximus muscles reported at the age of 15 years.

Personal and family history

The patient’s grandmother had a history of congenital valvular heart disease that did not affect her life. She died at the age of 70 years (Figure 1A).

Figure 1 Pedigree and characteristic appearance of the patient. A: In the pedigree of the patient’s family, patients are represented in black, the arrow represents the proband, which is the patient discussed in this case; B: Characteristic craniofacial appearance of widely spaced eyes in adolescence and infant. In addition, the distal phalanx of the left little finger was absent since birth. The patient was informed and agreed to publish the photos (Supplementary material).

Physical examination

Physical examination revealed normal vital signs. Her weight and height were 42 kg and 160 cm, respectively. Interocular and intermammary distances were slightly wider. The distal phalanx of the left little finger was absent since birth (Figure 1B). No perianal lesions were observed.

Laboratory examinations

Laboratory investigations included normal thyroid function, quantification of urine protein and microalbumin, urine immunoglobulin light chain test, and serum immunoglobulin light chain κ/λ. Rheumatic immune indicators, including antistreptolysin O, rheumatoid factors, C-reactive protein, anti-cyclic citrullinated peptide antibody, and erythrocyte sedimentation rate, were within the normal range. Hepatitis virus A-E, cytomegalovirus, Epstein-Barr virus, and coagulation test results were negative. In addition to the low level of serum albumin, the levels of all other proteins including serum globulin (13 g/L), immunoglobulins, and ceruloplasmin (0.118-0.137 g/L) were low, with low lymphocyte (0.57-0.84 × 10⁹/L) and low cholinesterase (4516 U/L) levels. The corneal Kayser-Fleischer ring was not observed, and the urinary copper concentration was within the normal range. Anti-tissue transglutaminase antibody test results were negative. All other liver function test results were within the normal ranges.

Imaging examinations

Cavernous transformation of the portal vein was noted on the abdominal computed tomography (CT) scan (Figure 2A and B); therefore, a liver biopsy was performed, which was diagnosed by an experienced hepatopathologist as porto-sinusoidal vascular disease (Figure 2C-F)[10]. Upper and lower endoscopies were performed, which showed chronic non-atrophic gastritis with no abnormalities in the mucosa of the duodenal bulb and descending parts, and slight edema of the colon wall (Figure 2G-J). Echocardiography, electrocardiography, and gynecological ultrasonography findings were all normal.

Figure 2 Imaging presentation about the liver and gastrointestinal tract. A and B: Abdominal enhanced computed tomography by three-dimensional reconstruction indicating cavernous transformation of portal vein; C-F: Liver histology suggesting porto-sinusoidal vascular disease. The discernable lobular architecture (C: Hematoxylin and eosin staining, 200 ×), stenosis or disappearance of portal veins in portal areas (D: Reticular staining, 400 ×), herniated portal veins into the liver parenchyma, and smooth muscle proliferation in portal areas (E: Masson-trichrome staining, 200 ×), inflammatory cell infiltration not obvious in the portal areas (F: Hematoxylin and eosin staining, 400 ×); G and H: Upper and lower endoscopies showed no obvious abnormalities in the gastric and duodenal mucosa; I and J: No obvious abnormalities in the ileal and colonic mucosa except for the slight edema of the colon wall.

PROGRESSION OF THE DISEASE AND MULTIDISCIPLINARY EXPERT CONSULTATION

By the end of July 2022, the patient experienced intermittent diarrhea and frequent numbness of the hands and feet. The serum free calcium was low, 0.80 mmol/L (normal range 1.10-1.34 mmol/L), serum potassium and sodium were normal, and the stool culture found no abnormality. The symptoms were partially relieved after intravenous calcium supplementation and antidiarrheal therapy. In August 2022, she developed limb weakness, muscle spasms, and tetany. Serum electrolyte measurements showed serum calcium to be 1.49 mmol/L (normal range 2.1-2.8 mmol/L), serum magnesium 0.34 mmol/L (normal range 0.75-1.02 mmol/L), and serum potassium 3.26 mmol/L (normal range 3.70-5.20 mmol/L). Abdominal enhanced CT and three-dimensional reconstruction revealed portal hypertension (cavernous transformation of the portal vein and slightly enlarged spleen), abdominal and retroperitoneal cystic low-density shadows (possibly lymphangioma). Emergency correction of the electrolyte disorder was performed, and the patient’s symptoms improved. Whole-exome and Sanger sequencing revealed a heterozygous mutation (c.850C>T:P.R284C) in LZTR1 (Figure 3A), suggesting Noonan syndrome type 10. Genetic testing of her parents and siblings showed no abnormalities. After other causes of hypoalbuminemia were ruled out, combined with the symptoms of intermittent diarrhea, PLE was suspected in the patient[1]. Lymphatic reflux imaging revealed small-intestinal lymphangiectasia (Supplementary Figure 1). In September 2022, radionuclide imaging of intestinal protein loss was conducted, which showed intestinal protein loss; the leakage site may have been located in the ileum or upper part of the small intestine. Whole-body lymphatic radionuclide imaging suggested intestinal lymphangiectasia and thoracic duct dysplasia, with outlet obstruction and bilateral venous angle drainage. Lymphography revealed intestinal lymphangiectasia (Video 1).

Figure 3 Pathogenic genetic variance information of the patient. A: Whole-exome and Sanger sequencing revealed a heterozygous mutation (c.850C>T:p.Arg284Cys) in leucine zipper-like transcription regulator 1; B: Visualization of the protein structures of wild-type using Pymol software; C: Visualization of the protein structures of mutant (c.850C>T:P.R284C) leucine zipper-like transcription regulator 1. After the mutation, the amino acid residue at position 284 changes from arginine to cysteine, resulting in a decrease in the number of hydrogen bonds, which may lead to a loosening of the local structure (the yellow dashed lines representing hydrogen bonds).

FINAL DIAGNOSIS

In the present case, hypoalbuminemia resulted from PLE, which was associated with intestinal lymphangiectasia caused by thoracic duct dysplasia. Combining all the clinical presentations and genetic test results, the final diagnosis was Noonan syndrome, which was attributed to a heterozygous mutation (c.850C>T:P.R284C) in LZTR1.

TREATMENT

A multidisciplinary team decided to treat the thoracic duct dysplasia with outlet obstruction. The patient was transferred to Beijing Shijitan Hospital and thoracic duct exploration was performed in October 2022. During the operation, it was observed that the distal segment of the thoracic duct was compressed by the sheath of the internal jugular vein, leading to adhesion with surrounding dense fibrous tissue, resulting in marked compression of the distal thoracic duct and restricted chylous reflux into the blood. Therefore, the distal segment of the thoracic duct was dissected from the surrounding dense fibrous tissue and the compressing sheath of the internal jugular vein to relieve the pressure on the thoracic duct. Postoperative nutritional interventions, such as restriction of dietary long-chain triglycerides, were recommended for the patient accordingly.

OUTCOME AND FOLLOW-UP

During the approximately two years after surgery, the patient still experienced intermittent hypoproteinemia, resulting in edema and diarrhea, which was relieved by a nearly monthly intravenous albumin infusion. During regular follow-ups in April 2023, the patient’s height increased to 163 cm, with a normal weight of 50 kg. The left cervical thoracic duct was unobstructed, and abdominal enhanced CT showed cavernous transformation of the portal vein and a slightly enlarged spleen. Meanwhile, the lowest serum albumin levels gradually raised from 18.6 to 22.6 g/L after surgery. From August 2024, she stopped receiving the intravenous albumin infusion due to financial burden and got a full-time job, surprisingly, the patient did not experience edema or diarrhea anymore, and the serum albumin level gradually increased to 53.0 g/L in March 2025.

DISCUSSION

The most distinctive characteristics of Noonan syndrome are primarily linked to the obstruction or dysfunction of the lymphatic system during developmental stages. These include neck webbing, notable prominence of the trapezius muscle, cryptorchidism, widely spaced nipples, ears that are low-set and rotated posteriorly, hypertelorism, and ptosis. Furthermore, essential diagnostic criteria for Noonan syndrome encompass congenital heart anomalies, an upper pectus carinatum accompanying a lower pectus excavatum, developmental delays, reduced stature, and lymphatic dysplasia[4,11]. Considering the clinical manifestations of widely spaced eyes, a ventricular septal defect, chest deformity with widely spaced nipples, and intestinal lymphangiectasia due to dysplasia of the thoracic duct, the patient was clinically diagnosed with Noonan syndrome. While it has been documented that lymphedema resulting from abnormalities in lymphatic vessel development occurs in as many as 20% of individuals with Noonan syndrome, the occurrence of PLE in conjunction with Noonan syndrome is infrequently observed (Table 1)[12]. This case highlights the difficulties in diagnosis and the possibility of misdiagnosis or missed diagnosis of Noonan syndrome due to the lack of awareness, and it being a rare cause of PLE and hypoalbuminemia to hepatologists and gastroenterologists[4]. As demonstrated in this case, addressing the medical and developmental complications of Noonan syndrome requires regular detailed follow-up with a multidisciplinary approach to assess the involvement of multiple organs.

Table 1 Summary of all patients with Noonan syndrome-associated protein-losing enteropathy identified in the literature (1972-2025).

Ref.	Sex	Onset of NS, years	Onset of PLE, years	Symptoms	Cardiac disorder	Lymphangiography	Genetic information	Treatment	Follow-up
Vallet et al[23], 1972	M	0.3	6	Diarrhea, anasarca, chylorrhea from the inguinal skin	Pulmonary valve stenosis	NA	NA	MCT and a low-fat die	Died
Herzog et al[24], 1976	F	0.9	15	Ankle swelling	Atrial septal defect, pulmonary valve stenosis	Hypoplasia of the lymphatics of the lower extremity and multiple ectatic lymph vessels in the mediastinal area and right supraclavicular area	NA	MCT diet	Relieved
Keberle et al[25], 2000	M	19	21	Tibial edema clubbing	Fallot’s tetralogy	Intestinal protein loss predominantly in the ileum	NA	Low-fat, protein rich, MCT diet	Relieved
Strehl et al[26], 2003	NA	43	43	Chronic diarrhea	NA	NA	NA	A protein-rich diet, with reduced fat content enriched by middle-chain fatty acids, as well as twice-daily injections of 200 micrograms octreotide	Relieved
Hasegawa et al[12], 2009	M	< 13	13	Edema of legs	Pulmonary stenosis and atrial septum defect	NA	NA	Albumin infusion followed by resting and raising legs	Relieved
Mizuochi et al[27], 2015	F	15	8	Edema, abdominal pain, diarrhea	Atrial septal defect, pulmonary valve stenosis	NA	NA	Diuretics treatment	Relieved
Matsumoto et al[28], 2015	F	17	17	No obvious clinical symptoms	Hypertrophic cardiomyopathy	Absent thoracic duct; abdominal collateral lymphatics and bilateral iliac lymphangiectasia	NA	Steroid therapy (1 mg/kg/day); low-fat, protein-rich diet supplemented with MCT	Relieved
Joyce et al[29], 2016	M	55	NA	Bilateral lower limb and suprapubic swelling, diarrhea	Atrioventricular septal defect	NA	PTPN11 (c.188A>G:p.Tyr63Cys)	Diuretics treatment and albumin infusions	Died
Joyce et al[29], 2016	M	26	27	Bilateral lower limb and genital swelling	Hypertrophic cardiomyopathy	Lymph reflux/rerouting, bilateral popliteal lymph nodes, contrast in scrotum, multiple widened channels	BRAF (c.770A>G:p.Gln257Arg)	Low fat, high-protein diet	Relieved
Wang et al[30], 2020	F	7	30	Severe recurrent edema	Fallot’s tetralogy	Lymphangiectasis and bilateral widening of the venous angle in the mediastinum and small intestine	PTPN11 (c.A922G: p.N308D)	Low-fat, MCT diet	Relieved
Dori et al[31], 2020	F	5	14	Difficulty in gaining weight, delayed puberty, chronic fatigue and bleeding	Ventricular septal defect	Diffusely abnormal central lymphatic system with retrograde mesenteric flow; the leak of contrast into the duodenal lumen, and extensive perfusion of the left chest and lung	SOS1 (c.2536G>A:p.E846K)	Mitogen-activated protein kinase inhibitor trametinib	Relieved
Kleimeier et al[32], 2022	M	27	Adulthood	NA	NA	Normal ante-grade flow in the thoracic duct; retrograde flow into the mesentery	SOS1 (c.1277A>C:p. Gln426Pro)	NA	NA
Ou et al[33], 2023	F	19	19	Edema of both lower limbs	Atrial septal defect	NA	PTPN11 (c.184T>G:p.Tyr62Asp)	Low-fat, MCT diet	Relieved
Koike et al[20], 2024	M	NA	25	Painful erythema of his trunk and lower extremities	Fallot’s tetralogy	Normal uptake in the transverse colon	NA	Antibiotic therapy for cellulitis with sepsis	Recurrent cellulitis
Our case	F	15	15	Edema of both lower limbs	Ventricular septal defect	Intestinal lymphangiectasia and thoracic duct dysplasia, with outlet obstruction and bilateral venous angle drainage.	LZTR1 (c.850C>T:p.Arg284Cys)	Microsurgical relief of the thoracic duct outlet obstruction; low-fat, protein rich, MCT diet	Relieved

NS: Noonan syndrome; PLE: Protein-losing enteropathy; NA: Not available; MCT: Medium chain triglyceride; F: Female; M: Male; PTPN11: Protein tyrosine phosphatase non-receptor type 11; SOS1: Son of sevenless homolog 1; LZTR1: Leucine zipper-like transcription regulator 1.

The detection rate of LZTR1 variants is low in patients with Noonan syndrome (approximately 4% in an Argentinean cohort). Patients with LZTR1-related Noonan syndrome typically exhibit facial dysmorphisms, cardiac abnormalities, short stature, ectodermal involvement, coagulation abnormalities, and cognitive disabilities[9]. These patients are particularly at risk for developing severe early onset hypertrophic cardiomyopathy[13-16]. The physiopathology may be attributed to disease-causing mutations that alter genes encoding proteins involved in the RAS-MAPK pathway, leading to sustained or excessive activation of ERK, which defines RASopathies[5,17,18], thereby causing Noonan syndrome-associated phenotypes[19]. Furthermore, the MAPK signaling pathway is initiated by vascular endothelial growth factor receptor 3, which plays a critical role in the process of lymphangiogenesis. While the relationship between genotype and phenotype in Noonan syndrome remains inadequately elucidated, the extent of abnormalities in lymphatic vessel development may vary based on specific genetic mutations. This variability could result in a range of clinical manifestations of Noonan syndrome, which may include being asymptomatic, presenting solely with lymphedema, or exhibiting both lymphedema and PLE, as well as differing onset times, either early or late[12,20].

In this case, whole-exome and Sanger sequencing revealed a genetic diagnosis of Noonan syndrome type 10, caused by a rarely reported heterozygous mutation (c.850C>T:P.R284C) in LZTR1 (Table 2, Figure 3B and C). This variant was previously reported in a 26-year-old patient with Noonan syndrome and oligoastrocytoma[21]. Despite of the same variant causing Noonan syndrome, the two cases presented significant differences in clinical manifestations: The previous one with tumors of the nervous system, and the present one with hypoalbuminemia and PLE due to thoracic duct dysplasia without any tumor demonstrated by positron emission tomography-CT. To the best of our knowledge, this is the first case of PLE associated with Noonan syndrome caused by a rare genetic mutation in LZTR1 (c.850C>T:P.R284C).

Table 2 Details of genetic variance c.850C>T:p.R284C in leucine zipper-like transcription regulator 1.

Item	Information
Gene name	LZTR1 (leucine zipper-like transcription regulator 1)
Identifiers	NM_006767.4 (LZTR1): c.850C>T(p.Arg284Cys)
Sequence	CCCGCAGCGG[C/T]GCTACGGGCA
Amino acids change	ENSG00000099949: ENST00000215739 exon9: c.850C>T:p.R284C (Arginine→Cysteine) (based on Ensembl gene)
Molecular consequence	Missense
Type and length	Single nucleotide variant, 1 bp
Location	Cytogenetic: 22q11.21 22: 20991686 (GRCh38) [NCBI UCSC]
DbSNP	Rs797045165
Clinical significance	Pathogenic (ClinVar)
Damaging score	0.91 (D:A algorithms, 21:23)
Phneotype	Noonan syndrome 10
Allele frequency in population	Not available in east Asian (gnomAD_genome, ExAC and ExAC_nontcga dataset)
In silico missense prediction
Algorithm	Prediction
SIFT	Damaging
Polyphen-2_HDIV	Probably_damaging
Polyphen-2_HVAR	Probably_damaging
LRT	Deleterious
MutationTaster	Disease_causing
MutationAssessor	High
FATHMM	Damaging
PROVEAN	Damaging
VEST3	Damaging
MetaSVM	Damaging
MetaLR	Damaging
M-CAP	Damaging
CADD	Damaging
DANN	Damaging
FATHMM_MKL	Damaging
Eigen	Damaging
GenoCanyon	Tolerable
FitCons	Damaging
GERP++	Conserved
PhyloP	Conserved
PhastCons	Nonconserved
SiPhy	Conserved
REVEL	Damaging
ReVe	Pathogenic
ClinPred	Pathogenic

LZTR1: Leucine zipper-like transcription regulator 1.

Long-term follow-up data on Noonan syndrome are limited. A research investigation involving 112 British participants diagnosed with Noonan syndrome, either through clinical evaluation or molecular genetics, revealed an average age of 25.3 years at the time of assessment. Furthermore, the average final adult height was determined to be 1.70 meters for males and 1.53 meters for females. Some patients may experience learning difficulties, whereas others may have diplomas. Adults requiring long-term cardiac follow-up had ongoing cardiac disorders. The mortality rate was 9%, with age at death ranging from a few months to 61 years[22]. In the present case, the patient was diagnosed with Noonan syndrome at the age of 15 years with a height of 1.63 m, without any previous treatment with growth hormones. She did not experience learning difficulties but she did not go to college as the hypoalbuminemia seriously affected her life. Echocardiography did not reveal any other defects except for the previous surgical repair of the ventricular septal defect. The latest laboratory test results showed a normal serum albumin level of 53 g/L (normal range: 42-56 g/L) in March 2025.

In addition, whether the vascular deformities, including cavernous transformation in the portal vein, the porto-sinusoidal vascular disease in the liver, and hemangioma in the gluteus maximus muscles, could present as manifestations of Noonan syndrome, remains to be clarified, since they have not been previously reported. Furthermore, the absence of the distal phalanx of the left little finger from birth is noteworthy. Considering the congenital vascular deformities may present as part of the vasculature dysplasia/abnormality, we hypothesize that these presentations are new and possible complications of LZTR1-related Noonan syndrome, which needs to be verified in the future reports. Notably, during the first two years after the relief of the thoracic duct outlet obstruction, the patient still experienced intermittent hypoalbuminemia, resulting in edema and diarrhea, which may have been discouraging and could have led to the discontinuation of further treatment. This may be attributed to the delayed recovery of intestinal lymphangiectasia and PLE, which warrants medical care and close monitoring during follow-up. This case presented the successful treatment of clinical hypoalbuminemia attributed to thoracic duct dysplasia, intestinal lymphangiectasia and PLE.

CONCLUSION

Dysplasia of the thoracic duct causes intestinal lymphangiectasia, a significant clinical manifestation of Noonan syndrome, leading to PLE and hypoalbuminemia, which are rare causes of clinical edema. Nutritional intervention combined with microsurgical disposal of thoracic duct stenosis finally eliminated the hypoalbuminemia. The present case describes the successful management of hypoalbuminemia due to PLE and LZTR1-related Noonan syndrome in a juvenile female patient. However, the long-term quality of life and survival in such patients requires further follow-up.

ACKNOWLEDGEMENTS

We deeply appreciate the generous help of Professors Ji-Dong Jia, Xin-Yan Zhao, Zhi-Jun Zhu, Wei Chen, Dong-Hu Zhou (Beijing Friendship Hospital, China), Wen-Bin Shen (Beijing Shijitan Hospital, China) and Kymberly DS Watt (Mayo Clinic, Rochester, MN, United States) in the diagnosis and treatment of this patient and in the presentation of this case report.