Schuurs-Hoeijmakers syndrome (ORPHA:329224)
A rare genetic syndromic intellectual disability characterized by mild to moderate intellectual disability, developmental delay (with speech and language development more severely affected). Association with infantile hypotonia, seizures, cryptorchidism in males and congenital abnormalities, including cardiac, cerebral or ocular defects, may be observed.
Epidemiology
The prevalence of Schuurs-Hoeijmakers syndrome (also called PACS1-related syndrome) is estimated at <1/1,000,000 birth. To date approximately 60 individuals were reported in the literature, however the disease is most likely under-reported.
Clinical description
The disease is characterized by mild-to-severe neurodevelopmental delays. Language skills are more severely affected than motor skills. Feeding difficulty is common, with many of the children requiring gastrostomy tube to maintain appropriate caloric intake. Common facial features include full, arched eyebrows, hypertelorism, down-slanting palpebral fissures, long eyelashes, ptosis, low-set, simple ears, bulbous nasal tip, flat philtrum, wide mouth with downturned corners and thin upper lip and diastema of the teeth. Other common features include short stature and/or low weight, hypotonia, constipation, seizures, autism, behavioral issues, congenital heart anomalies, genitourinary abnormalities, renal issues, and ocular anomalies.
Etiology
Almost all individuals with PACS1-related syndrome have a c.607C>T (NM_018026.3) mutation in the PACS1 gene, within a region thought to be important for the function of the protein. The expression of the PACS1 gene is significant both during embryonic development and after birth. Pathogenic variations in PACS1 lead probably to a dominant-negative mechanism responsible for disrupting protein trafficking in the golgi apparatus.
Diagnostic methods
The diagnosis of PACS1 syndrome is established by molecular genetic testing. All individuals reported to date have the disorder as the result of a de novo pathogenic variant.
Differential diagnosis
The differential diagnosis includes Winter-Baraitser syndrome and Kabuki syndrome.
Antenatal diagnosis
Once a pathogenic variant has been identified in a family, detection of PACS1 syndrome can be done by amniocentesis and exome sequencing for malformative syndrome screening during pregnancy.
Genetic counseling
Transmission of PACS1 syndrome is autosomal dominant with full penetrance (50% risk of transmission at each pregnancy); however, in most situations, the pathogenic variants arise de novo and thus the risk of sibling recurrence is low. Detection of PACS1-related syndrome should be discussed with the parents of an affected individual during subsequent pregnancies.
Management and treatment
Management requires a lifelong multidisciplinary approach. Regular follow‐up by a clinical geneticist, paediatrician, ophthalmologist, psychologist/psychiatrist, speech therapist, physiotherapist and ophthalmologist will have a major impact on the quality of life and learning at school. Developmental assessments are needed to tailor medical services to each individual's needs. Other specialists can be needed, like a cardiologist, gastroenterologist, nephrologist, otolaryngologists or stomatologist.
Prognosis
Autonomy may be limited and affected individuals will sometimes require life-long support from caregivers. There is little data on adults, so it is not currently possible to provide information on the long-term future of PACS1-related syndrome patients.

                            Last update: 
                            November 2023


                            - Expert reviewer(s): 
                            Pr David GENEVIEVE | ITHACA*


                                * European Reference Network