MON-247 - LZTR1 Haploinsufficiency as A Phenotypic Modifier in 22Q11.2 Deletion Syndromepresenting with A Noonan-Like Endocrine Phenotype

Background: Noonan syndrome (NS) is a RASopathy caused by dysregulation of the RAS/MAPK pathway and is characterised by facial dysmorphism, short stature, congenital heart disease, hypogonadism, and bleeding diathesis. Pathogenic variants in LZTR1 account for approximately 3–5% of NS cases, typically through dominant-negative effects or biallelic loss-of-function. LZTR1 is located within the commonly deleted 22q11.2 region, raising the possibility that its hemizygosity may modify phenotypic expression within the 22q11.2 deletion syndrome (22q11.2DS) spectrum rather than act as a primary monogenic cause of NS.

Case Description: A 12-year-old male presented with micropenis, bilateral cryptorchidism, and easy bruisability. Examination revealed height at the 25th percentile (SDS −0.7), downslanting palpebral fissures, high-arched palate, pectus excavatum, and low posterior hairline. Laboratory evaluation demonstrated thrombocytopenia (80×10³/μL) with giant platelets and an elevated mean platelet volume (12.7 fL). Endocrine evaluation showed markedly reduced inhibin B (4.6 pg/mL), prepubertal gonadotropins (LH 0.4 IU/L, FSH 2.1 IU/L), and testosterone (0.7 nmol/L), indicating Sertoli cell dysfunction and intrinsic gonadal impairment rather than isolated pubertal delay. In view of the dysmorphic features and
associated endocrine and haematological abnormalities, whole-exome sequencing was performed. This revealed a large heterozygous deletion at
chr22:g.(?)18913175_20996975(?)del, which was subsequently confirmed by low-pass whole-genome sequencing (KaryoSeq) as a pathogenic 2.2 Mb deletion at chromosome 22q11.21 encompassing LZTR1, GP1BB, and TBX1. Serum calcium, parathyroid hormone levels, echocardiography, and immunological evaluation were normal, indicating the absence of classical manifestations of 22q11.2DS.
Discussion and

Conclusions: Based on the van der Burgt clinical criteria, the patient met criteria for a suggestive Noonan-like phenotype. Hemizygous loss of LZTR1 may act as a phenotypic modifier contributing to RASopathy-like features within the 22q11.2 deletion
spectrum. Concurrent GP1BB haploinsufficiency plausibly explains the macrothrombocytopenia and bleeding tendency. Importantly, the observed endocrine and craniofacial features are not classically attributed to TBX1 haploinsufficiency. This case expands the phenotypic spectrum of 22q11.2 deletion syndrome and highlights LZTR1 hemizygosity as a potential modifier driving a Noonan-like endocrine and craniofacial
phenotype, underscoring the need for gene-level interpretation beyond syndromic labels.

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