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

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.

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.