Expanding the Coffin-Siris syndrome spectrum: genetic, dysmorphic, and endocrine findings in eight cases.

This study aims to expand the spectrum of Coffin-Siris syndrome (CSS), a rare and heterogeneous disorder, by thoroughly discussing its genetic, dysmorphic, and endocrine features through new cases and contributing to the literature. Eight patients who were referred to the genetics clinic with various complaints and subsequently diagnosed with CSS through microarray or clinical exome sequencing analyses were included in the study. The dysmorphic, genetic, and endocrine characteristics of eight genetically confirmed patients were evaluated. The patients, aged between 5 months and 6 years at the time of referral, comprised four females and four males. The most common reasons for referral were developmental delay and dysmorphic features. All patients exhibited varying degrees of dysmorphic facial features. Hypertrichosis, a typical feature of the syndrome, was present in five patients. Another characteristic finding was mild hypoplasia of the terminal fifth phalanges, observed in patients 1, 2, and 6. Consistent with this, mild/subtle hypoplasia and/or slight positional changes of the fifth fingernails were noted in these patients, rather than overt nail anomalies. In our study, eight variants were identified, two of which were novel. In our cohort, pathological short stature was observed in three patients, while hypothyroidism, transient hypercalcemia, cryptorchidism, and recurrent fractures were each identified in one patient. All three patients with short stature had delayed bone age with head circumference and BMI <  - 2 SDS. Seven patients were diagnosed with ARID1B-related CSS type 1, while one patient was diagnosed with SMARCA4-related CSS type 4. Among the eight findings across patients, two were deletion-type copy-number variations (CNVs) identified by microarray analysis, and six were sequence variants: two frameshift, two splice-site, one nonsense, and one synonymous. Seven variants were classified as pathogenic and one as likely pathogenic. Family studies confirmed that the variants were de novo and validated their clinical relevance.

conclusionCSS is a clinically and genetically heterogeneous syndrome. Patients may present with highly variable features, and typical signs of the syndrome may not be observed in all cases. This study expands the clinical spectrum of this rare syndrome and contributes to its genetic spectrum with the identification of new variants. WHAT IS KNOWN: • Coffin-Siris syndrome (CSS) is a clinically and genetically heterogeneous neurodevelopmental disorder most commonly caused by variants in SWI/SNF (BAF) complex genes (e.g., ARID1B, SMARCA4) and characterized by dysmorphic features, developmental delay, hypertrichosis, and fifth-digit/nail anomalies. • Endocrine and growth-related manifestations can occur in CSS, but their frequency and phenotypic range vary across cohorts and require individualized clinical follow-up. WHAT IS NEW: • This case series of eight genetically confirmed CSS patients (7 ARID1B, 1 SMARCA4) expands the phenotypic spectrum by detailing dysmorphic findings together with endocrine features including pathological short stature with delayed bone age, hypothyroidism, transient hypercalcemia, cryptorchidism, and recurrent fractures. • We identified eight pathogenic/likely pathogenic variants, including two novel variants, and highlight that fifth digit/nail involvement may be subtle (mild terminal fifth phalanx hypoplasia and minor fifth nail changes) rather than overt.