Expanding the clinical spectrum associated with the PACS1 p.Arg203Trp mutational hot‐spot: Two additional Italian patients

The Schuurs – Hoeijmakers Syndrome (SHMS), also known as PACS1 neurodevelopmental disorder (PACS1-NDD), is a rare condi-tion characterized by impaired intellectual development, distinct craniofacial features


To the Editor:
The Schuurs-Hoeijmakers Syndrome (SHMS), also known as PACS1 neurodevelopmental disorder (PACS1-NDD), is a rare condition characterized by impaired intellectual development, distinct craniofacial features, and variable additional congenital abnormalities (Tenorio-Castaño et al., 2021). It is caused by heterozygous pathogenic variants in PACS1 gene (OMIM# 615009) located on chromosome 11q13 (Simmen et al., 2005). Ethnic background is known to affect the clinical manifestations of the syndrome; this can be due both to the impact of the genetic context and to the exposure to different environmental factors (Dutta, 2019). SHMS worldwide prevalence is unknown and only 61 patients have been published so far (Tenorio-Castaño et al., 2021). To date, only two missense variants in PACS1 gene, which affect the same amino acid, have been reported as the cause of SHMS: c.607C>T (p.Arg203Trp) and c.608G>A (p.-Arg203Gln) (Figure 1). The first variant is present in all reported cases except for one patient in which it was identified the second variant (Miyake et al., 2018). PACS1 encodes a trans-Golgi-membrane protein, regulating the protein cargo (Scott et al., 2003). This gene is expressed at high levels in the brain during the embryonic period whereas it is down regulated in the postnatal period (Liu et al., 2021). Experiments in zebrafish have documented a role for the PACS1 protein in cranial neural crest migration, explaining the specific facial features in patients (Schuurs-Hoeijmakers et al., 2012). The mutation is located in the furin cargo binding domain, directly adjacent to a CK2-binding motif that is essential for PACS1 autoregulation as well as for interaction with cargo proteins, or for adaptor complexes binding (Scott et al., 2003). Currently, therapies exploiting antisense RNA are under development (Simmen et al., 2005).
The typical phenotype of the SHMS is characterized by neurodevelopmental delay with variable severity, language delay, hypotonia, feeding difficulties, seizures, behavioral problems, congenital heart anomalies, short stature, and microcephaly (Tenorio-Castaño et al., 2021). Language skills are more severely impaired compared to motor skills (Lusk et al., 2020). Hypotonia and feeding difficulty are common (Schuurs-Hoeijmakers et al., 2016). Nevertheless, a series of unique clinical findings have been reported over the years such as retrognathia, absent nasal bone, and colpocephaly (Tenorio-Castaño et al., 2021).
We present the first Italian patients with SHMS. Patient 1 was an 8-year-old boy born from healthy non-consanguineous parents at the end of a pregnancy complicated by maternal hypertension that occurred in the last trimester. Gastroesophageal reflux and femoral fracture are reported during the perinatal period. At 7 months, head and trunk control had not yet been acquired. He started to walk with support at 3 years of age; his first words at 4 and a half years. He presented a hypertonic crisis in absence of fever, for which he began therapy with valproic acid. Parents reported a regression of his motor skills after the first critical episode. At the age of 7, he still did not speak and walk independently. He suffered from stypsis and followed a semi-solid diet. He underwent bilateral orchiopexy for cryptorchidism. Electroencephalography (EEG) revealed a background slowing and evident multifocal paroxysmal activity. Cerebral magnetic reso- He showed bilateral clubfoot. He had hypertonic lower limbs and hypotrophy of muscle mass. He also presented bruxism, cold extremities, and hand-stereotypies. His array-CGH analysis did not reveal pathogenic alterations.
Patient 2 is a 1 year and 5-month-old girl, who was born at 36 weeks of gestational age by cesarean section due to placenta F I G U R E 1 Phosphofurin Acidic Cluster Sorting Protein 1 (PACS1) organization Patients with a different geographic origin manifest atypical trait that can mislead the medical diagnosis. In this perspective, molecular analysis employing exome sequencing can be supportive in the medical ascertainment of the SHMS in children. Individuals from four continents (Africa, Asia, Europe, America) have been collected. Among the published patients, whose ethnic origin is known, the presence of clubbed nails in a Dutch patient, pigmented nevi in a patient from Belgium, cleft lip in an Indian patient, involuntary movements and lipomyelomeningocele in two Japanese patients, hypogammaglobulinemia in a Turkish patient and absent gonadal development in a Chinese patient were reported as atypical clinical traits (Dutta, 2019;Hoshino et al., 2019;Liu et al., 2021;Lusk et al., 2020;Miyake et al., 2018;Schuurs-Hoeijmakers et al., 2012;Schuurs-Hoeijmakers et al., 2016;Scott et al., 2003;Simmen et al., 2005;van Nuland et al., 2021).
Our findings allow us to update the list of the SHMS clinical traits

ACKNOWLEDGMENTS
We are grateful to our patients for their cooperation. The "Cell lines and DNA bank of Rett Syndrome, X-linked mental retardation, and other genetic diseases," member of the Telethon Network of Genetic Biobanks (project nos. GTB12001 and GFB18001), funded by Telethon Italy, and of the EuroBioBank network provided us with specimens. We thank the European Reference Network of Intellectual Disability, Telehealth, Autism, and Congenital Anomalies (ERN ITH-ACA). Open Access Funding provided by Universita degli Studi di Siena within the CRUI-CARE Agreement.

CONFLICT OF INTEREST
The authors declare that they have no conflict of interest.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.

ETHICS STATEMENT
The procedures employed agreed with the Helsinki Declaration's principles.

INFORMED CONSENT STATEMENT
The parents of the patients provided their written informed consent to participate in this study.