Congenital hypothyroidism with preserved fifth digits in SMARCA4-related Coffin-Siris syndrome: a case report

Introduction

Coffin-Siris syndrome (CSS) is a rare neurodevelopmental disorder that occurs because of the pathogenic variants of genes that encode the SWI/SNF (BAF) chromatin-remodeling complex (1-4). It is known to have developmental delay, mental disability, abnormalities in behavior, craniofacial dysmorphism and variable fifth digits involvement (5). Although hypoplasia or aplasia of the fifth digit used to be regarded as a typical case, the latest genotype phenotype correlation studies have shown that there can be a great deal of variability among the genetic subtypes (6,7). ARID1B variants are most closely linked with classical fifth-digit anomalies, and SMARCA4-related CSS is more frequently dominated by strong neurobehavioral characteristics with variable or normal fifth digits (8,9). Consequently, clinically mild or non-classical physical manifestations may occur in cases related to SMARCA4, thereby raising the risk of missing the diagnosis if reliance is placed solely on classic phenotypic criteria. This report aims to report a patient with genetically confirmed SMARCA4-related CSS whose fifth digits are preserved and who has congenital hypothyroidism, which underscores the significance of the interpretation of phenotypes by specific genes. We present this case in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-2025-309/rc).

Case presentation

Patient information

The patient is a 10-year-old girl who immigrated to the United States from Mexico in 2024. She was referred for genetic evaluation due to a complex history that included developmental delay, repaired cleft palate, congenital hypothyroidism diagnosed at 3 months of age, severe anxiety with nonverbal features, and behavioral concerns suggestive of autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). Congenital hypothyroidism was diagnosed at the age of about 3 months after the newborn had undergone follow-up examination. Clear biochemical values at the diagnosis, serum thyroid-stimulating hormone (TSH) and free thyroxine (free T4) were not reviewed because the historical medical records were only available in early childhood. Consequently, it became impossible to determine the exact etiology of hypothyroidism (primary or central) conclusively. Since infancy, the patient has been on stable levothyroxine replacement therapy, and her endocrinology is being followed.

Her family history was non-contributory for similar congenital anomalies. A brother had a speech delay, while the maternal grandmother had hypertension and kidney disease, and the maternal grandfather had schizophrenia. There was no history of cleft palate, intellectual disability, or thyroid disease in the family, and consanguinity was denied. Paternal history was unavailable.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient’s guardian for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Clinical findings

At age 10 years, physical examination revealed proportionate growth restriction, as height, weight, and head circumference are below the 2nd percentile (height Z-score is about −2.6, weight Z-score is about −2.3 and head circumference Z-score is about −2.5), which is in line with short stature and microcephaly. Although she displayed subtle craniofacial dysmorphism and hypertrichosis, she notably lacked the classical fifth digit hypoplasia/aplasia and coarse facial features typical of CSS (Figures 1,2). Behavioral examination highlighted severe anxiety with predominantly nonverbal manifestations. The findings highlight a clinically subtle CSS phenotype with endocrine involvement and absence of the classic fifth digit anomalies, expanding the known clinical spectrum (Tables 1,2).

Figure 1 Facial features of the patient at age 10 years, demonstrating low-set posteriorly rotated ears, subtle hypotelorism, and repaired cleft palate scar. This image is published with the consent of the patient’s parents.

Figure 2 Patient’s hands and feet showing normal fifth digits and nails, absence of hypoplasia, and flat feet (pes planus). This image is published with the consent of the patient’s parents.

Diagnostic assessment and therapeutic course

The patient underwent a systematic diagnostic process beginning with routine genetic tests, including karyotype, fragile X testing, and chromosomal microarray, all of which were normal. Persistent developmental delay, congenital anomalies, and behavioral symptoms prompted trio exome sequencing, which identified a de novo pathogenic SMARCA4 variant confirming CSS. A variant of uncertain significance (VUS) in AP1S2 was also detected, requiring future monitoring. Electroencephalogram (EEG) for staring spells was normal, and magnetic resonance imaging (MRI) is pending. Diagnosis was challenging due to the absence of classic fifth-digit anomalies and coarse facial features, compounded by delayed access to genetic services before immigration. Severe anxiety and nonverbal behavior further masked the underlying syndrome. Differential diagnoses included other SWI/SNF-related disorders and SATB2-associated syndrome, which were excluded through molecular findings.

A variant of uncertain significance of AP1S2, an X-linked gene related to neurodevelopmental disorders was also discovered by trio exome sequencing. It is not enough to prove causality, but its existence is significant considering maternal grandfather schizophrenia family history. The patient’s severe anxiety and non-verbal behavior may arise from oligogenic genetic influences, including a de novo SMARCA4 variant that may interact with an inherited predisposition to neurodevelopmental vulnerability. It was not possible to interpret it definitively because the segregation analysis and X-inactivation studies were absent.

Therapeutic intervention and follow-up

The patient underwent two cleft palate repairs in infancy and a revision surgery at age 10, which improved feeding and reflux, although speech therapy is still needed. Levothyroxine for congenital hypothyroidism has remained stable since infancy with good adherence. Fluoxetine was introduced for severe anxiety, and cyproheptadine supports appetite and sleep. Ibuprofen is used as needed for pain, and allergy management includes nasal sprays and an epinephrine auto-injector. She receives behavioral therapy through Hope Services, speech therapy, and special education support. Multiple specialists are involved, with only mild ophthalmologic abnormalities detected.

Post-surgery, gastroesophageal symptoms improved, and anxiety became more manageable. Despite persistent developmental and communication challenges, adherence to treatment is excellent. Long-term prognosis remains guarded but stable, and the confirmed SMARCA4 variant provides clarity for surveillance and genetic counselling.

Discussion

Key findings

This case highlights a clinically subtle presentation of SMARCA4-related CSS in a child who lacked the hallmark fifth-digit hypoplasia and coarse facial features. Instead, she presented with congenital hypothyroidism, repaired cleft palate, developmental delay, severe anxiety, and nonverbal behavior. The diagnosis was only confirmed through trio exome sequencing, underscoring the limitations of relying on classic clinical markers alone. Her positive response to multidisciplinary management, including surgical revision, endocrine treatment, behavioral therapy, and educational support, demonstrates the value of coordinated care. This case broadens the phenotypic spectrum of CSS and suggests that endocrine manifestations may be clinically relevant.

The SMARCA4 mutation c.3315G>T detected in this patient was defined as pathogenic based on American College of Medical Genetics and Genomics (ACMG) criteria as PS2 (de novo occurrence confirmed by trio testing), PM2 (not present or very rare in population databases), and PP3 (multiple in silico tools supporting a deleterious effect). Although certain community databases show conflicting interpretations in this variant, molecular evidence and phenotypic concordance show its pathogenic classification in this case.

Strengths and limitations

This case is strengthened by thorough clinical assessment and genetic testing, with trio exome sequencing providing diagnostic certainty despite the clinically subtle presentation. Multidisciplinary follow-up addressed developmental, behavioral, and medical needs, while surgical outcomes and caregiver perspectives offered a holistic understanding of the patient’s journey. However, the report has limitations. The paternal family history is incomplete, limiting evaluation of hereditary risk. MRI results were unavailable, leaving the cause of staring spells uncertain. Although the coexistence of congenital hypothyroidism and CSS is noteworthy, one case cannot confirm causality. Larger studies are needed to determine whether this represents a true phenotypic expansion.

Comparison with similar research

Classically, SMARCA4-related CSS is described with hypoplasia or aplasia of the fifth digit and coarse facial features as key diagnostic clues. Behavioral challenges are also well-documented, often surpassing cognitive delays in severity (9,10). However, this patient did not exhibit digital anomalies or coarse facial features, underscoring the phenotypic variability of the disorder. Reports of craniofacial anomalies in CSS usually highlight broad nasal tips, thick eyebrows, and hypertrichosis, while structural defects such as cleft palate are rare (11,12). To date, congenital hypothyroidism has not been described in association with CSS, making this case notable for potentially expanding the endocrine dimension of the phenotype (13). The findings therefore challenge clinicians to maintain diagnostic vigilance when evaluating children with developmental delays, even when hallmark anomalies are absent.

Explanations of findings

The absence of fifth-digit anomalies and coarse facial features in this patient illustrates the expanding phenotypic variability of SMARCA4-related CSS. Genetic confirmation was essential because clinical features alone were misleading. The presence of congenital hypothyroidism, which has not been previously linked to CSS, raises the possibility of an endocrine component or overlapping developmental pathways involved in the syndrome. Delayed diagnosis was influenced by limited access to genetics prior to immigration and behavioral symptoms that obscured the underlying disorder.

Implications and actions needed

This case urges clinicians to consider CSS even when classical features are absent and to prioritize genetic testing in children with unexplained developmental and congenital findings. Diagnostic frameworks should move beyond reliance on fifth-digit anomalies to include behavioral and endocrine features. Early identification enables timely multidisciplinary care, which improves functional outcomes and family support. Endocrine evaluation may need integration into CSS management protocols. Health systems must also address inequities in access to genetic services, particularly for immigrant or underserved populations. Future research should explore genotype–phenotype correlations and investigate whether congenital hypothyroidism represents a true expansion of the CSS spectrum.

Conclusions

This case emphasizes the extensive phenotypic heterogeneity of SMARCA4-related CSS, as it proves the existence of the condition that does not have classical fifth digit defects or coarse facial characteristics. The simultaneous presence of the case of congenital hypothyroidism, which has not been previously reported in the literature, further increases the likelihood of a new endocrine relation. In reporting such unusual presentation, we highlight the importance of genetic testing in clarifying complicated developmental syndromes and emphasize the need to have fair access to these types of diagnostics among children in the various health care environments.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-2025-309/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-2025-309/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-2025-309/coif). S.J.S. reports volunteer membership at large in the Sigma Xi Scientific Society, membership in American Physicians in Clinical Research, and service as a Volunteer Area Director with the American Academy of Pediatrics (AAP). The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient’s guardian for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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