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

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.

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.

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.