De novo ARID1A Coffin-Siris syndrome with hypothyroidism and dyslipidemia: A case report and literature review

Abstract

BACKGROUND

Coffin-Siris syndrome (CSS) is a rare BRG1/BRM-associated factor (BAF) - SWI/SNF (SWItch/Sucrose non-fermentable) - related neurodevelopmental disorder. Endocrine manifestations primarily involve growth disturbances, whereas thyroid dysfunction and dyslipidemia are not considered recurrent syndromic features.

CASE SUMMARY

A 4-year and 4-month-old boy with typical CSS features (coarse facies with long eyelashes, fifth-digit distal phalanx/nail hypoplasia/aplasia, dorsal hypertrichosis, developmental delay/intellectual disability) and short stature developed subclinical hypothyroidism at the age of 4 years and 2 months old, while also exhibiting hypercholesterolemia. Whole-exome sequencing identified a pathogenic ARID1A variant (c.4102-1G>A) consistent with CSS and a heterozygous likely pathogenic LDLR variant (c.251C>T), consistent with familial hypercholesterolemia. Levothyroxine treatment achieved biochemical euthyroidism, and along with lifestyle interventions, was followed by transient improvement in growth velocity. Dyslipidemia was managed conservatively. Subsequent decline in growth velocity and low insulin-like growth factor 1 concentrations prompted growth hormone (GH) stimulation testing, which proved to be pathological. Consideration of recombinant GH therapy raised concerns due to the reported increased hepatoblastoma risk in ARID1A-related CSS and insufficient clinical evidence and recommendations.

CONCLUSION

Although not typical for CSS, this proband highlights that thyroid and lipid abnormalities may coexist, and supports selective thyroid-stimulating hormone/free T4 (thyroxine) and lipid screening in CSS when clinically indicated, while attributing hypercholesterolemia primarily to LDLR-mediated familial hypercholesterolemia. Individualized endocrine surveillance and follow-up are essential for the optimal management of CSS in children.

Key Words: Coffin-Siris syndrome; Short stature; Hypercholesterolemia; Subclinical hypothyroidism; Dual molecular diagnosis; Diet; Neurodevelopmental disorder; Growth hormone deficiency; Lifestyle intervention; Neurodivergent; Case report

Core Tip: Coffin-Siris syndrome (CSS) is a rare neurodevelopmental disorder involving the BRG1/BRM-associated factor (SWI/SNF) chromatin-remodeling complex, characterized by coarse facial features, distal phalanx hypoplasia/aplasia, developmental delay, and multisystem involvement. We report a child with CSS, subclinical hypothyroidism, and familial hypercholesterolemia caused by a heterozygous LDLR variant. Lifestyle changes and levothyroxine initially improved growth (7.6 cm/year), but growth velocity subsequently declined (4.2 cm/year) in parallel to insulin-like growth factor 1 levels. A glucagon stimulation test confirmed growth hormone (GH) deficiency. Recombinant GH therapy in ARID1A-related CSS should be individualized because impaired tumor suppression and possible hepatocyte damage may increase hepatoblastoma risk.

INTRODUCTION

Coffin-Siris syndrome (CSS), also known as “fifth digit syndrome” is a rare neurodevelopmental disorder of the BRG1/BRM-associated factor (BAF) -SWI/SNF (SWItch/Sucrose Non-Fermentable) chromatin-remodeling complex[1,2]. It is caused by pathogenic variants in genes such as ARID1B (most common) and, less frequently, ARID1A, ARID2, and SMARCA4, among others[2,3], in various sites of the genes and with different implications each (frameshift, splice-site, nonsense, missense, or deletion of the whole gene as a part of a copy-number variation)[4]. Hallmark clinical features include coarse facial appearance (e.g., thick eyebrows and/or eyelashes, wide mouth) together with hypertrichosis, hypoplasia or aplasia of the distal phalanx or nail of the fifth digit, developmental delay/intellectual disability, and variable multisystem involvement[5]. More specifically, many patients present with feeding difficulties, hypotonia, frequent infections, or epilepsy, while other clinical characteristics that can appear involve joint laxity, scoliosis, congenital heart defects, genitourinary malformations or behavioral problems[4,5]. Inheritance is autosomal dominant and is typically de novo[4,6].

The exact prevalence of CSS remains unknown; the syndrome is very rare, with registry counts indicating a few hundred molecularly confirmed cases worldwide[7]. One important reason for this low incidence may be underdiagnosis, as CSS has a variable phenotype[6], ranging from mild to severe, with many patients lacking the classic signs like coarse facial features or fifth digit abnormalities[8].

Endocrine and metabolic issues in CSS primarily involve failure to thrive, attain linear growth and adequate body weight[6,9]. Nutritional interventions aim to promote optimal growth, while treatment with recombinant human growth hormone (rhGH) has been applied in few cases of ARID1B-CSS[9-11]. Although there are some reports of thyroid dysfunction in CSS[1,3,4,10], the literature is scarce on the incidence of dyslipidemia, particularly in ARID1A-CSS, with only one case having been reported to date[4]. However, animal studies suggest that Arid1a^LKO mice exhibit abnormal lipid metabolism in the liver[12], indicating that the gene may be directly involved in lipid metabolism[13]. Loss of ARID1A can promote fat production while hindering fatty acid breakdown[12], leaving the cells vulnerable to metabolic dysfunction while accelerating the development of fatty liver disease, especially when exposed to high-fat conditions[12]. On the other hand, the Global Lipids Genetics Consortium study also revealed that among people of European and mixed ancestry, the ARID1A rs6598860 variant is associated with elevated high-density lipoprotein (HDL)[14] and triglyceride concentrations[15].

Herein, we present the case of a child with ARID1A-related CSS who developed subclinical hypothyroidism and hypercholesterolemia in the setting of a heterozygous LDLR variant. We also discuss the interventions applied, aiming to enhance the child’s psychomotor development and concerns that arose regarding the management of suboptimal linear growth. The CARE guidelines[16] for case reports were followed while preparing this case.

CASE PRESENTATION

Chief complaints

A 4-years and 4-month-old male visited the Pediatric Endocrinology Unit at the Hippokration General Hospital in Thessaloniki, Greece. The boy was accompanied by his parents, seeking endocrinological and growth assessment.

History of present illness

No special notes.

History of past illness

No special notes.

Personal and family history

The boy presented the following medical history: Perinatally, the boy was born via Caesarian section (C-section) at 38 weeks of gestation, and was deemed appropriate-for-gestational-age based on the anthropometric measurements at birth (birth weight 2600 g, birth length 50 cm and head circumference 33 cm). This was the first pregnancy of the mother, and no complications were recorded. The parents were non-consanguineous, healthy, and the mother was under treatment for Hashimoto thyroiditis. The Apgar score at birth was 5 in the 1^st minute, 7 in the 5^th minute and 10 in the 10^th minute. In the first 4 hours of life, the neonate presented two episodes of stridor accompanied by cyanosis and oxygen desaturation during crying, requiring admission to neonatal intensive care unit (NICU). The clinical examination revealed stridor, which was exacerbated when crying, level eyelid hemangioma, wide nasal base, hypertelorism and high-arched palate. Laryngoscopy was performed, revealing laryngomalacia. The newborn remained in the NICU for a total of 9 days.

Physical examination

As an infant, the patient demonstrated a delay in reaching developmental milestones. Namely, neck control was accomplished at 5-6 months, unsupported sitting at 8 months, standing at 10 months, supported walking at 13 months and independent walking at 23 months, whilst also having a delay in speech development. With regards to his nutritional intake, breastfeeding was exclusive until 5 months of age, but was ceased completely at 22 months of age, once “normal” food intake was achieved. Additionally, regarding his growth, body weight and stature remained below the 3^rd percentile based on the World Health Organization (WHO) growth standards[17] since the age of 4 months.

At 3 years of age, an assessment by an experienced pediatric neurologist confirmed the developmental delay, and the child initiated speech and occupational therapy sessions, later incorporating physiotherapy sessions, as well. The molecular cytogenetic analysis (comparative genomic hybridization) revealed a male karyotype with a duplication in the short arm of chromosome 6 (6p21.1), which was not associated with the patient’s phenotype. A psychiatric evaluation at 3 years and 7 months of age revealed a developmental language disorder, with severe delay of expressive speech with high perception, normal cognitive function and an uneven skills profile (high performance in some fields compared with others). Throughout this period, a clinical geneticist also assessed the young patient. Due to the observed psychomotor delay and phenotypic features (low-set ears, long eyelashes, failure to thrive), whole exome sequencing (WES) was recommended but was not performed.

During the initial assessment at the pediatric endocrinology unit at the age of 4 years and 4 months, the patient’s stature and body weight were below the 3^rd percentile according to the WHO growth standards[17] and signs of developmental delay were apparent. Additional phenotypic observations included wide mouth with prominent lower lip, thick eyelids and long eyelashes, possible hypoplasia of the 5^th digit and hypertrichosis of the back.

Laboratory examinations

Comprehensive laboratory tests revealed thyroid stimulating hormone (TSH) concentrations of 6.238 mIU/L accompanied by normal thyroid hormone levels (T₃, T₄), hypercholesterolemia [total cholesterol: 210 mg/dL; low density lipoprotein: 152 mg/dL; HDL: 44 mg/dL] and low insulin growth factor 1 (IGF-1) concentrations (25.4 ng/mL), findings that were consistently observed in subsequent follow-up evaluations. Based on these results, the diagnosis of subclinical hypothyroidism was established.

These findings along with the observed neurodevelopmental delay and clinical appearance of the child led to WES analysis at the age of 4 years and 5 months. The findings revealed a de novo heterozygous pathogenic c.4102-1G>A variant of the ARID1A gene. Taken together, WES analysis, clinical and laboratory findings, the patient was diagnosed with CSS. WES analysis revealed a second de novo likely pathogenic variant of the LDLR gene (c.251C>T), likely explaining the familial hypercholesterolemia.

Imaging examinations

In the context of syndromic investigation, echocardiography and renal ultrasound (US) were unremarkable, whereas brain magnetic resonance imaging demonstrated a shortened posterior corpus callosum and slightly low positioning of the cerebellar tonsils relative to the foramen magnum.

MULTIDISCIPLINARY EXPERT CONSULTATION

A multidisciplinary expert team consisting of pediatric endocrinologists, endocrinologists, pediatricians, registered dietitians and residents consulted for the patient.

FINAL DIAGNOSIS

The findings were indicative of de novo ARID1A-CSS, with clinical hypothyroidism, familial hypercholesterolemia and short stature.

TREATMENT

Daily 20 μg levothyroxine treatment was initiated for subclinical hypothyroidism.

The developmental delay was closely monitored by experts in the pediatric endocrinology unit. In addition to speech, occupational and physical therapy sessions, the parents were also instructed to promote the child’s physical activity and increase interaction with nature, including freestyle playtime in the mountains and seaside, according to nature-based biopsychosocial resilience theory[18], to facilitate behavioral and emotional release. Over subsequent months, these interventions, alongside treatment for subclinical hypothyroidism, resulted in a significant improvement in the child’s expressive abilities, social interaction and skills, and psychomotor development. The improved neurodevelopmental trajectory was also apparent in the child’s academic performance, as he attended a common school, instead of a school for children with special education needs.

The child’s growth patterns are presented in Figure 1, detailing body mass index-for-age and height-for-age, according to WHO growth standards[17].

Figure 1 Growth patterns of the child regarding body mass index-for-age and height-for-age, plotted using the World Health Organization growth standards[17]. A: Growth patterns of the child regarding body mass index-for-age; B: Growth patterns of the child regarding height-for-age. WHO: World Health Organization.

In follow-up visits, subclinical hypothyroidism was adequately controlled with the appropriate titration to the prescribed therapy, and circulating IGF-1 concentrations improved. Hypercholesterolemia was addressed with a tailored lifestyle intervention based on the National Cholesterol Education Program II[19,20] and the portfolio diet[21-23], a plant-based dietary pattern encompassing five cholesterol-lowering food group pillars, including nuts and seeds, viscous fiber, plant protein, plant sterols, and monounsaturated fatty acids[22]. Dietary recommendations were tailored to the child’s condition ensuring adequate energy and nutrient intake supporting normal growth and development, while limiting the consumption of total and saturated fats[24]. Furthermore, nutritional management of CSS was also considered, focusing on addressing common feeding difficulties[25,26] including poor sucking, swallowing, chewing, hypersensitivity to new foods[27], or reflux, affecting up to 90% of children with CSS[6,9]. For this, emphasis was placed on high-energy, nutrient-dense foods and specialized textured foods, as detailed in Table 1.

Table 1 Dietary recommendations for the patient[19-21,23,30-32,34,36].

Diet components	Dietary components	Recommendation
Nutrients	Total fats	≤ 30% of DEI
	SFA	< 7% of DEI
	MUFA	< 15% of DEI
	PUFA	< 10% of DEI
	Cholesterol	< 200 mg/day
	Proteins	> 15% of DEI (including meat)
	Plant proteins	50 g/day of plant proteins (soy and pulses)
	Carbohydrates	13% carbohydrate replacement with MUFA (mainly avocados and olive oil)
	Fiber	20-30 g/day
	Viscous fibers	20 g/day of viscous fibers (oats, psyllium, barley, eggplant, okra, apples, oranges and berries)
	Phytosterols	2 g/day phytosterols
	Iron	Increase intake of Fe-rich foods (lean beef, soy, egg yolks, lentils, beans, spinach)
	Calcium	Increase intake of Ca-rich foods (dairy and Ca-fortified products)
Food groups	Nuts	42 g/day of nuts (tree nuts or peanuts)
	Sugar	Limit intake
Others	Enhance dietary diversity
	Emphasis on high-energy, nutrient-dense foods and specialized textured foods

Ca: Calcium; DEI: Daily energy intake; MUFA: Mono-unsaturated fatty acids; PUFA: Poly-unsaturated fatty acids; SFA: Saturated fatty acids.

In addition to the lifestyle changes for hypercholesterolemia, frequent monitoring with laboratory tests was also performed.

Because nutrients are known modifiers of the growth hormone (GH)/IGF-1 axis, and both hormones participate in the utilization of nutrients in cell and tissues[28], additional dietary recommendations were provided, aiming to improve GH secretion (Table 1). Recommendations aiming at improving dietary intake due to GH deficiency involved increased dietary diversity[29], the intake of iron- and calcium-rich foods and ensuring adequacy in the energy, macro-, and micronutrient intake, to meet requirements[30]. Particular emphasis was placed on adequate protein intake[31-33], including meat[34], while reducing sugar consumption[28,35].

OUTCOME AND FOLLOW-UP

During the first 2.5 years of follow-up, these interventions resulted in an apparent improvement in linear growth, with an annual growth velocity reaching up to 7.6 cm/year. However, in recent months, a decline in growth velocity was observed (4.2 cm/year), accompanied by low IGF-1 concentrations. Based on these findings, a glucagon stimulation test was performed for evaluation of GH secretion, highlighting pathological results (peak GH: 4.02 ng/mL). On the basis of these results, consideration was given to whether further evaluation should be pursued to initiate rhGH therapy (see discussion). The timeline of key clinical findings and patient history are presented in Table 2.

Table 2 Timeline of key clinical findings and patient history.

Age	Event	Details/findings/actions
Birth (at 38 weeks via C-section)	Neonatal course	Birth weight: 2600 g; length: 50 cm; OFC: 33 cm; Apgar score 5/7/10; two cyanotic episodes with stridor (first 4 hours of life) aggravated by crying; wide nasal base, hypertelorism, high-arched palate eyelid capillary hemangioma; laryngoscopy: Laryngomalacia; NICU length of stay: 9 days
4 months	Failure to thrive	Weight and length < 3rd PC
5-6 months	Developmental delay	Delayed head control
8 months	Motor milestone	Unsupported sitting achieved
10 months	Motor milestone	Standing with support
13 months	Motor milestone	Assisted walking
23 months	Motor milestone	Independent walking
2 years, 7 months	Neurological evaluation	Developmental delay
2 years, 8 months	Molecular karyotype	46XY, 6p21.1 duplication
3 years	Therapies initiated	Speech, occupational and physical therapy were initiated
3 years, 7 months	Psychiatric evaluation	Developmental language disorder; severe expressive delay with high receptive skills; normal cognitive function; uneven skills profile
4 years, 2 months	Brain MRI	Short posterior corpus callosum
4 years, 4 months (first clinic visit)	Initial labs & treatment	TSH: 6.238 mIU/L with normal T3/T4 → subclinical hypothyroidism; low IGF-1 levels; hypercholesterolemia; T4 prescribed (20 μg/day)
4 years, 5 months	Genetic testing (WES)	De novo pathogenic ARID1A c.4102-1G>A → established CSS diagnosis; de novo pathogenic LDLR variant → familial hypercholesterolemia
5-7 years	Follow up	Euthyroid, improved IGF-1 levels; hypercholesterolemia addressed with diet; ongoing monitoring; freestyle exercise
Recent months (8 years)	Current status	Decline in growth velocity, pathologic GH stimulation test

C-section: Caesarian section; CSS: Coffin-Siris syndrome; GH: Growth hormone; IGF-1: Insulin growth factor 1; MRI: Magnetic resonance imaging; NICU: Neonatal intensive care unit; OFC: Occipitofrontal circumference; PC: Percentile; TSH: Thyroid stimulating hormone; WES: Whole exome sequencing.

DISCUSSION

Herein, we describe a proband with ARID1A-CSS, concurrent subclinical hypothyroidism and hypercholesterolemia, attributed to a heterozygous likely pathogenic LDLR variant. While endocrine and metabolic issues are known CSS-manifestations, thyroid dysfunction and dyslipidemia have not been systematically reported and data are scarce, particularly as far as ARID1A-CSS is concerned. Table 3 offers a detailed overview of the reported cases of thyroid disease, dyslipidemia and GH deficiency in patients with CSS and specific CSS-responsible variants.

Table 3 Reported cases of thyroid disease, dyslipidemia and growth hormone deficiency in patients with Coffin-Siris syndrome and specific Coffin-Siris syndrome variants.

Pathology	Study design	Patients	CSS variant	Results	Ref.
Hypothyroidism	Cross-sectional	n = 79 patients with ARID1B-CSS	ARID1B	38 patients (15.8%) exhibited hypothyroidism	van der Sluijs et al[10]
	Cross-sectional	n = 54 patients with ARID1B-CSS	ARID1B	15% of the sample exhibited hypothyroidism	van der Sluijs et al[3]
	Case report	6-year-old girl	ARID1B	The patient received low-dose thyroid hormone (levothyroxine 25 μg/day)	Lee and Ki[42]
	Case series	8 cases of ARID1B-CSS (5 month-6 years)	ARID1B	Of the 8 cases, only one girl exhibited hypothyroidism	Kolkiran et al[4]
	Case series	n = 12 children with CSS	BICRA	Out of 12 children, only a 28-month-old girl exhibited hypothyroidism	Barish et al[39]
	Case report	10-year-old girl	SMARCA4	At the age of 3 months, the girl was diagnosed with congenital hypothyroidism and has been on levothyroxine since	Shah et al[40]
	Case report	30-year-old woman	SMARCA4	Diagnosed with Hashimoto hypothyroidism, receiving 75 μg T4 daily	Mitrakos et al[41]
Dyslipidemia	Case series	8 cases of ARID1B-CSS (age: 6 years and 5 months)	ARID1B	Of the 8 cases, only one girl exhibited hyperlipidemia	Kolkiran et al[4]
GH deficiency	Cross-sectional	n = 79 ARID1B-CSS patients	ARID1B	33 patients (18.2%) exhibited GH deficiency, of which 31 received rhGH supplementation	van der Sluijs et al[10]
	Cross-sectional	n = 54 patients with ARID1B-CSS	ARID1B	2% of the sample exhibited GH deficiency	van der Sluijs et al[3]
	Case report	12-year-5-month-old girl	ARID1B	GH deficiency was diagnosed at the age of 9 years and rhGH therapy was initiated	Mouskou et al[10]
	Case report	12yearold Chinese girl	ARID1B	GH deficiency was diagnosed and rhGH was given, resulting in significantly improved height	Tao et al[53]
	Case report	4-year-old girl	NR	The patient initiated rhGH replacement therapy	Bilha et al[52]
	Case report	Girl aged 2 years and 3 months	NR	rhGH therapy improved growth; however, it was ceased at the age of 7 after parental request	Baban et al[54]
	Case series	n = 17 children with CSS	ARID2	2 out of 17 children received rhGH therapy	Schrier Vergano et al[55]
	Case report	22-year-old male of mixed European descent	BICRA	Diagnosed with GH deficiency in early childhood, received rhGH therapy (Omnitrope) for 2 years with partial improvement in growth velocity	Wang[56]
	Case series	n = 8 children with CSS	DPF2	The child with the DPF2 variant (c.894_904+6del; p.Cys298Trpfs*38) had GH deficiency	Mcglacken-Byrne et al[57]
	Case report	5 years and 7 months old girl	DPF2	rhGH therapy was initiated at the age of 5 years and 7 months old at a daily dose of 2 IU	Li et al[11]

CSS: Coffin-Siris syndrome; GH: Growth hormone; IU: International units; NR: Not reported; rhGH: Recombinant human growth hormone.

The ARID1A gene encodes a scaffolding protein-subunit of the BAF-chromatin remodeling complex that repositions nucleosomes to regulate enhancer/promoter accessibility[36]. The c.4102-1G>A variant of the gene affects splicing, leading to a dysfunctional protein[37]. This, in turn, results in decreased and abnormal gene expression, especially in development-related and tumor-suppression genes, thus promoting the specific appearance and developmental impedance characteristic of CSS. ARID1A reduces peroxisome proliferator-activated receptor α driven fatty-acid oxidation in the hepatocytes of mice, while promoting steatosis and insulin resistance, creating a plausible explanation for the metabolic involvement in CSS[38].

There is a lack of reports detailing the relationship between hypothyroidism and hypercholesterolemia in CSS. Table 3 details the reported cases of hypothyroidism in patients with CSS, along with specific CSS gene variants. All reported hypothyroidism cases involve ARID1B-CSS[1,3,4,10], one case reports BICRA-CSS[39], whereas two cases involve SMARCA4-related CSS[40,41]. In an adult ARID1B-related cohort, elevated cholesterol concentrations were reported in approximately 7% of individuals, and hypothyroidism was diagnosed in 8% of the population[3]. In a follow-up of the same cohort, hypothyroidism was documented in 19% of the patients, with one of them demonstrating hypothyroidism for 2 years before spontaneously resolving[10]. The Kaplan-Meier plot of age at which hypothyroidism developed indicated that the exact prevalence may be greater, affecting 25% of patients with ARID1B-CSS[10]. There is only one report in the literature involving a female patient harboring de novo heterozygous missense variant clusters in the ARID1A gene, with no familial history of Hashimoto thyroiditis but with subclinical hypothyroidism, and receiving therapy since the age of 4 years old[42]. This cannot rule out that in the present case report, hypothyroidism could also be the epiphenomenon of the maternal Hashimoto diagnosis, and as such, it is not easy to establish a cause-effect relationship between ARID1A and thyroid dysfunction. Notably, hypothyroidism in this case was subclinical; notably, hypothyroidism is an atypical symptom of CSS[43].

The other important finding in this case was familial dyslipidemia. WES revealed a variant of the LDLR gene (c.251C>T). This is a missense variant that leads to replacement of the amino acid proline by leucine, in the 84th position of the initial peptide produced by the LDLR gene (p.Pro84 Leu), leading to dysfunctional LDLR protein, cholesterol management dysregulation and dyslipidemia. The aforementioned variant has been detected in a patient with familial hypercholesterolemia, and in-silico bioinformatics analysis suggests a pathogenic effect. As such, the c.251C>T LDLR variant is considered likely pathogenic. In the present case report, we attributed hypercholesterolemia was to this likely pathogenic LDLR variant, as per the Mendelian inheritance of familial hypercholesterolemia. To further support this, we conducted a targeted literature review to investigate any clinical relationship between ARID1A-CSS and recorded abnormalities in lipid metabolism. Table 3 details the reported cases of dyslipidemia in the literature involving patients with CSS. The results revealed the lack of clinical evidence supporting hypercholesterolemia, dyslipidemia or metabolic syndrome as established manifestations of ARID1A-CSS, with only one patient case having been reported[4]. In parallel, one animal study showed that hepatocyte-specific knock-out of the Arid1a gene resulted in abnormal lipid metabolism[12]. The evidence is not adequate to support a direct effect between the human ARID1A gene and lipid-related disorders and, as a result, the LDLR mutation was deemed as the most plausible causative agent for hypercholesterolemia in our case, with any contribution of ARID1A-related metabolic dysregulation remaining speculative. Notably, in a case series of patients with 19p13.2 microdeletions[44], one adolescent participant exhibited a partially overlapping deletion of 573 kb involving seven genes, including SMARCA4 and LDLR. For SMARCA4 in particular, it has been suggested that, because it is located near the LDLR gene on chromosome 19, rare large microdeletions spanning 19p13.2 may occur and simultaneously affect both SMARCA4 and LDLR[41,44]. In these cases, patients exhibit the classic features of CSS and several metabolic issues, including hyperlipidemia, due to loss of the LDLR gene[4].

Another concern in the present case involved linear growth. When a combination of short stature and dysmorphic features is present, WES should be considered[45]. Although the child had previously been evaluated by physicians across different specialties, the WES that ultimately established the diagnosis of CSS had not been performed. Initiation of thyroid disease treatment in combination with lifestyle modification initially resulted in a marked increase in the child’s growth velocity. Clinicians must always consider the impact of lifestyle treatment on both the psychological well-being and growth of affected children. Exposure to nature and engagement in naturebased activities has been associated with improved psychological wellbeing and reduced stress among children[45]. Research has revealed that the physical environment is essential to the development of neurodiverse children[46] in particular. In further detail, nature improves the health of neurodivergent children by: (1) Reducing harm with mitigated exposure to environmental stressors; (2) Restoring capacities including cognitive, emotional, and physiological well-being; (3) Building capacities while promoting social, physical and psychological functioning; and (4) Reducing distress or discomfort[47]. Targeted interventions to reduce stress during childhood can confer extensive benefits for long-term health while supporting optimal growth[45]. However, in the present case, these interventions proved insufficient to sustain long-term normal growth; the patient’s height remained below the 3^rd percentile and there was a decrease in growth velocity.

While primary GH deficiency is reported in some cases of children with CSS[9,48,49], the GH/IGF-1 axis is suppressed at multiple levels in overt hypothyroidism, and IGF-1 levels commonly decrease, rising again after levothyroxine replacement[45]. This makes hypothyroidism a more plausible cause for the observed reduced IGF-1 concentrations. In subclinical hypothyroidism however, the effects on IGF-1 levels are smaller and inconsistent, particularly among children; thus, the low IGF-1 concentrations observed herein were interpreted cautiously and re-evaluated post-thyroid normalization[45,50]. Once levothyroxine was initiated, IGF-1 levels improved; however, a subsequent decline was observed, accompanied by a decline in growth velocity, as previously described. This prompted further evaluation for GH deficiency, with pathological results being established in the first stimulation test. Of note, scientific societies suggest performing two or more GH stimulation tests in children with suspected GH deficiency, as a single subnormal test can lead to false positives[51]. As such, rhGH therapy was not initially considered due to the lack of the appropriate number of tests along with the limited available data for the effect of rhGH in CSS. To date, few cases of rhGH therapy in CSS have been reported[9,52] (Table 3). These cases provide up to 10 years of treatment follow-up with satisfactory improvements in growth velocity and no specific reported adverse events[11,49,52]. However, they involved patients with non-ARID1A variants, harboring either ARID1B[49,52-54], ARID2[55], BICRA[56], or DPF2 variants[11,57]. Furthermore, the potential need for rhGH therapy in a child with CSS and a pathogenic variant in the ARID1A gene raises particular concerns because of the combination of perturbances in tumor suppression and plausible hepatocyte damage, all increasing the risk of hepatoblastoma among young children with ARID1A-CSS (3%-5%)[58]. This is why liver US and close monitoring of α-fetoprotein (AFP) blood concentrations[59] should be considered in all children with ARID1A-CSS, at least until they reach the age of 4 years old. Findings from the US registry indicate that patients with ARID1A-CSS have an increased risk for hepatoblastoma, warranting frequent and systematic surveillance[59]. A recent review[59] combined all reported cases of ARID1A-CSS, indicating a pooled estimated 3.6% prevalence of hepatoblastoma (95%CI: 0.79%-10.4%). Due to these wide confidence intervals, the authors concluded[58] that although patients with ARID1A-CSS exhibit an increased hepatoblastoma risk, it cannot be determined if this risk exceeds 1%, the cut-off established by the American Association for Cancer Research international expert panel for surveillance[60]. Nonetheless, in Europe and the United Kingdom, the current relevant cancer risk surveillance threshold is set at 5%[61]. It is recommended that healthcare providers and families of patients with CSS collaborate in making a shared decision on whether hepatoblastoma surveillance is required for children with ARID1A-CSS, including abdominal US and frequent evaluation of AFP concentrations[59]. According to Cárcamo and associates[58], ARID1A-CSS should be included as a cancer predisposition syndrome such that tumor surveillance must also be considered for these patients. In patients without cancer predisposition on rhGH treatment, there is no known association between therapy and neoplasia, whereas in children with cancer predisposition syndromes, the available evidence remains insufficient to draw definitive conclusions[62-66]. Coupled with the lack of specific hepatoblastoma evidence, no relationship between rhGH therapy and hepatoblastoma was deduced. In the existing literature, only patients with non-ARID1A-CSS and GH deficiency treated with rhGH have been described, and tumor surveillance was not considered for these patients[10,11,49,52], making the present case an excellent example of a contemporary treatment dilemma. If GH deficiency is indeed confirmed, the physician should weigh treatment benefits with the risk for developing cancer, seek multidisciplinary support and proceed to a shared decision-making process with the patient’s parents, while incorporating close follow-ups and hepatoblastoma surveillance. A low-dose rhGH strategy cannot currently be endorsed, as there is lack of evidence confirming that low-dose rhGH reduces tumor risk in ARID1A-CSS; if treatment is selected, standard individualized dosing with careful monitoring is advised. Alternatively, as already detailed, non-pharmacological treatment options such as nature exposure and nature-based activities can also be considered. Irrespective of the final therapeutic choice, continued optimization of thyroid replacement, tailored nutrition recommendations, and auxological follow-up remains essential for achieving optimal growth results.

This report describes the symptoms and therapeutic approach of a single patient, limiting generalizability of the findings.

CONCLUSION

Hypothyroidism and dyslipidemia are not typical features of CSS; thus, secondary causes of both abnormalities should be ruled out and other genetic findings (e.g., LDLR pathogenic variants) must be weighted appropriately. The potential need for rhGH replacement therapy in a child with CSS and a pathogenic ARID1A variant poses therapeutic challenges, requiring individualized risk-benefit assessment due to the reported hepatoblastoma predisposition and the lack of genotype-specific safety data considering rhGH treatment. Encouraging unstructured activity in natural settings alongside a combination of lifestyle and conventional therapies may enhance psychomotor development and improve height velocity.