Endocrine Abstracts

Case History: A 5-year-old South Asian female patient was born at term with very low birth weight (-3.8 SDS). She exhibited short stature (height -3.9 SDS), feeding difficulties (BMI -3.0 SDS) and microcephaly (HC -4.9 SDS). Maternal height was reduced (-3.5 SDS), paternal height was normal (-0.2 SDS). The girl had characteristic syndromic features including triangular face, high-pitched voice, and high-arched palate. She displayed developmental delay manifesting as inattention and poor motor, writing, and reading skills. Silver-Russell syndrome (SRS) was suspected but she did not fulfil Netchine-Harbison Clinical Scoring System (NH-CSS) criteria (score 3/6).

Investigations: Investigations established normal female karyotype (46,XX) and short stature screen with elevated serum IGF-1 levels (+4.4 SDS). Testing for common molecular causes of SRS did not detect hypomethylation of chromosome 11p15 (11p15LOM) or maternal uniparental disomy of chromosome 7 (UPD(7)mat). Whole exome sequencing identified a maternally inherited, heterozygous predicated damaging missense HMGA2 gene variant (c.166A>G; p.K56E). We report the first missense mutation in a highly conserved region (2nd AT-hook adjacent), impacting DNA binding.

Management: SRS is a multisystem disorder requiring early, multidisciplinary clinical management. The identification of a genetic cause for this patient’s phenotype allowed an end to diagnostic testing and the initiation of tailored clinical management including active surveillance for co-morbidities, growth monitoring, nutritional support and referral for genetic counselling.

Conclusions and discussion points: SRS is rare (epi)genetic disorder characterised by pre- and post-natal growth restriction and distinct features. SRS has a varied phenotype and clinical features diminish with age, making diagnosis challenging. ~60% of cases are attributed to 11p15LOM or UPD(7)mat and frequently identified by NH-CSS criteria. Recently, rare (<5%) monogenic defects (CDKN1C, IGF2, PLAG1, HMGA2) have been implicated. Clinical SRS diagnosis (≥4/6 NH-CSS criteria) must include relative macrocephaly and prominent forehead at birth. However, the NH-CSS utility in diagnosing rare monogenic causes of SRS is uncertain. (Epi)genetic testing is recommended for patients scoring ≥3/6 NH-CSS criteria. Rarer monogenic cases should not be overlooked. We analysed the 17 HMGA2 cases reported to date: 35% failed to fulfil NH-CSS criteria, 71% lacked relative macrocephaly and 6% had no body asymmetry. Our patient also had atypical features (developmental delay and microcephaly). Our case highlights that NH-CSS <4/6 and atypical features, such as microcephaly, should not preclude clinicians from investigating SRS. Molecular diagnosis is crucial for stratification of cases and clinical management, enhancing outcomes and reducing the diagnostic odyssey for patients and families.