ESPE Abstracts

Background: Noonan syndrome (NS) is an autosomal dominant disorder characterized by a short stature, congenital heart defects, and characteristic facial features. Gain-of-function mutations of multiple genes in the Ras/mitogen activated protein kinase pathway have been identified in 70–80% of patients with NS. Recently, leucine-zipper-like transcription regulator 1 (LZTR1), which has not previously been associated with the pathway, was reported as a new causative gene for the NS phenotype.

Objective: To report the clinical and molecular findings in a Japanese boy with NS phenotype and a novel heterozygous missense variant in the LZTR1 gene.

Patient: A Japanese male patient was born at 40 weeks of gestation after an uncomplicated pregnancy and delivery. At birth, his length was 49.0 cm (+0 standard deviations [S.D.]), weight 3.42 kg (+0.9 S.D.), and occipital frontal circumference (OFC) 34 cm (+2.2 S.D.). He had distinctive facial features consisting of right-sided ptosis, hypertelorism, downslanting palpebral fissures, low-set ears, a webbed neck, and motor developmental delay. At 5 years and 8 months of age, the patient was referred to us because of a short stature. His height was 99.8 cm (–2.5 S.D.), weight 15.6 kg (–1.3 S.D.), and OFC 51 cm (+1.8 S.D.). Endocrine studies indicated growth hormone (GH) deficiency (peak serum GH values: 3.42 ng/mL at insulin stimulation test, and 2.49 ng/mL at L-dopa stimulation test [cut off values: <6 ng/mL]), and his bone age was assessed as 3 years. The results of provocation tests for other anterior pituitary hormones were within normal ranges. Based on these results, recombinant human GH therapy (0.175 mg/kg per week) was started at 6 years of age, leading to acceleration of his height growth. Brain magnetic resonance imaging, echocardiography, and a skeletal survey revealed no abnormalities. He also had severe intellectual disability (IQ56) and autism spectrum disorder.

Genetic analyses: Trio-whole-exome sequencing identified a de novo heterozygous missense variant in LZTR1 (c.1234C>T, p.Arg412Cys). No pathogenic variants in other genes associated with NS were identified in the patient.

Conclusions: The present report has provided further evidence that a heterozygous germ line missense mutation in LZTR1 can cause the typical phenotype of NS. Further studies are needed to clarify the mechanism by which LZTR1 mutations result in the phenotype of NS.