Case Report SATB2-associated syndrome: a case report

-- Introduction : SATB2-associated syndrome is an extremely rare genetic disorder. It is characterized by delayed neurocognitive development, craniofacial anomalies and dental defects. Observation : This case report highlights the craniofacial and dental phenotype linked to a mutation resulting in SATB2-associated syndrome affecting a 13-year-old boy. Conclusion : The diagnosis of this syndrome is very dif ﬁ cult. The management using a multidisciplinary strategy includes among others, oral hygiene maintenance, orthodontic treatment and intensive speech therapy.


Introduction
SATB2-associated syndrome, also known as Glass syndrome or SAS, is a genetic disorder first reported in 1989 [1].It is caused by alteration of the SATB2 (Special AT-rich sequencebinding protein 2) protein on chromosome 2.This syndrome is extremely rare, with an estimated prevalence of 56 cases in France and 634 cases worldwide [2].It is characterized by delayed neurocognitive development, craniofacial anomalies and dental defects.More recently, skeletal disorders and growth delay have been added to the description of the disease [3].
We present here the phenotypic description linked to a mutation resulting in SATB2-associated syndrome, our management and recent prospects for this syndrome.

Case report
A 13-year-old boy with SAS was referred by his geneticist to the odontology department of our hospital for comprehensive care in a center of expertise.He presented with facial dysmorphia associated with dental anomalies.
He was the only child of a non-consanguineous French couple.He was born at full term.The origin of the dysmorphia was investigated at birth, and the default diagnosis was an atypical Pierre Robin sequence.At the age of 9, exome sequencing revealed a heterozygous substitution mutation in the CUT1 domain of the SATB2 gene.The variation found on chromosome 2 was c.1196G>A, resulting in the Arg399His modification on the SATB2 protein (Tab.1).This pathological mutation is responsible for the SATB2-associated syndrome (OMIM#612313) [4].
Clinically, the patient was hypotonic and underweight (38 kg for 1.59 m).Neurocognitively, he had a severe intellectual deficit, virtually no language, praxis disorders and difficulty falling asleep.From a craniofacial prospective, the palpebral slits were slanting downwards and outwards, and the ears were low set.His facial features included: a long, narrow face, a short upper lip, a pendulous lower lip, drooling due to lip incompetence and micrognathia.He presented with Ballard skeletal class II with mandibular retrognathia, left lateral deviation of the mandible and maxillary hypoplasia (Fig. 1).He had an ogival palate with sequelae from a cleft affecting only the hard palate, which was operated on at 1 yr.
On oral examination, the patient's dental hygiene was moderate, the periodontium was healthy and no decay were visible.Dental brushing was done by his parents.The teeth had a mottled appearance.We observed mandibular incisal dental crowding and macrodontia on teeth 11, 13, 55, 21, 75, 84, 85.Inter-arch examination showed Angle's class 2 division 1, increased overjet and deep overbite.(Fig. 2).Ventilation was buccal.Mastication was alternating unilateral but slow, and swallowing was normal.No parafunction was observed.
It was decided that the patient would receive semi-annual pediatric odontology consultations to maintain good oral health.Education in oral and dental hygiene was mentioned at every visit.No dental extraction had been performed but dental scaling was performed every six months.During care, he was treated with nitrous oxide.Orthodontic treatment was initiated and is still ongoing.It consisted of placing a palatal expansion device and then performing orthodontic traction of the impacted right maxillary canine on the dental arch.Speech therapy led to improved sensitivity of the oral sphere, more efficient mastication and reduced drooling by increasing labial tone and learning a mouth-closure-swallowing sequence.

Discussion
SAS is extremely rare.Diagnosis of this syndrome is difficult and delayed: the clinical signs are not very specific to this syndrome and are found in several genetic conditions (facial dysmorphia, clefts, dental anomalies).A definitive diagnosis requires exome sequencing by experienced and well-equipped geneticists.In a previous study, Zarate and al. found that there was an average time to diagnosis of 6.6 yr in a cohort of 72 patients [5].
In 2022, Li et al. described the dental phenotype of a 6-year-old child with the same mutation as our patient: a missense variation c1196G>A (p.Arg399His).Several similarities were visible: Both patients presented dental crowding, no mandibular second bicuspids and underwent cleft palate surgery.Both orthopantomogram showed delayed formation of permanent teeth roots and taurodontism.More specifically our patient presented a hypotaurodontism according to Seow and Lai [9].However, our patient also presented macrodontia, had no parafunction, no caries or chronic periapical periodontitis.This was probably explained by the patient's age and his autonomy, allowing for better dental hygiene.The c.1196G>A p.(Arg399His) mutation in the SATB2 gene has been described twice in the literature.So far, no study has correlated a mutation with a particular phenotype [6,10].
SAS management is therefore symptomatic, no specific treatment has proven effective.Monitoring guidelines have been proposed.Most studies recommend close dental follow-up with oral hygiene education and regular preventative care without describing a precise treatment plan [11,12].Dental cares for these patients are difficult.Most received care by a pediatric dentist or in a special needs dentistry unit.Surgeries are often under general anesthesia [8].Orthodontic treatment plan should be undertaken by an experienced practitioner in collaboration with an oral surgeon.
On other prospectives, syndrome sufferers have an increased risk of developing vascular disease and pulmonary hypertension [13].They also have a particular metabolic profile.In fact, there is a reduction in the capacity to use glucose as an energy substrate [14].This could contribute to neurological anomalies and developmental disorders.Finally, individuals with this syndrome show an increased response to certain hormones, such as estradiol.
The SATB2 gene is present on the long arm (q) of chromosome 2, it has been highly conserved throughout evolution.It is an essential gene for craniofacial patterning and cognitive development in humans [10].It is an important epigenetic regulator during neurodevelopment [15].More recently, this gene has also been described as playing a role in the oncogenesis of colorectal adenocarcinomas and intestinal neuroendocrine tumors [16].In conclusion, SATB2-associated syndrome is extremely rare.The diagnosis of this syndrome is very difficult, and requires exome sequencing as the clinical signs are not very specific.The cares are interdisciplinary and symptomatic.Dental follow-up must be carried every 6 months to 1 yr for life by a pediatric dentist or in a special needs dentistry unit.

Table I .
Conclusion of exome sequencing.