A number sign (#) is used with this entry because of evidence that Schuurs-Hoeijmakers syndrome (SHMS) is caused by heterozygous mutation in the PACS1 gene (607492) on chromosome 11q13.

Schuurs-Hoeijmakers syndrome (SHMS) is characterized by impaired intellectual development, distinct craniofacial features, and variable additional congenital abnormalities (summary by Schuurs-Hoeijmakers et al., 2016).

Schuurs-Hoeijmakers et al. (2012) reported 2 unrelated boys from a cohort of 5,000 individuals with impaired intellectual development who had remarkable similarity in facial features. Both had a low anterior hairline, hypertelorism with downslanting palpebral fissures, mild synophrys with highly arched eyebrows, long eyelashes, bulbous nose, flat philtrum, large low-set ears, wide mouth with downturned corners, thin upper lip, and diastema of the teeth. One boy had an IQ of less than 50; the other boy had an IQ of 53. The first boy had a single umbilical artery, unilateral cryptorchidism, malrotation, as well as widely spaced nipples, slender fingers with broad thumbs, clubbed nails, a single transverse palmar cleft on the left hand, and pes planus. MRI showed a cavum septum pellucidum but was otherwise normal. The second boy was large at birth and had strikingly similar dysmorphic facial features. He also had cryptorchidism. On neurologic examination he had some balance problems and mild dysarthric speech. He was hypotonic. MRI showed partial agenesis of the cerebellum vermis and hypoplasia of the cerebellar hemispheres, more pronounced on the right side.

Schuurs-Hoeijmakers et al. (2016) reported the clinical features of 19 patients with genetically confirmed SHMS, including the 2 patients reported by Schuurs-Hoeijmakers et al. (2012) and 1 reported by Gadzicki et al. (2015). All had a distinctive facial appearance with full and arched eyebrows, long eyelashes, hypertelorism, downslanting palpebral fissures, ptosis, low-set simple ears, bulbous nasal tip, wide mouth with downturned corners, thin upper lip, flat philtrum, and diastema of the teeth. All had delayed psychomotor development with mildly to moderately impaired intellectual development and poor or absent speech; most had hypotonia. Fifteen patients had additional variable congenital anomalies, including cardiac septal defects and eye abnormalities, such as coloboma, high myopia, nystagmus, and strabismus. Feeding difficulties were common, and many patients showed oromotor sensitivity with problems eating solid food. Gastric reflux and constipation were also noted in some patients. Motor development was delayed, with walking achieved between 2 and 3 years in most patients, and some had persistent gait difficulties. Twelve patients had seizures that could be controlled with medication. Twelve of 16 individuals who underwent brain imaging had variable abnormalities, including cerebellar hypoplasia, enlarged ventricles, and nonspecific white matter changes. Three patients had kidney abnormalities and 6 males had cryptorchidism. Although most had a pleasant demeanor, some had behavioral difficulties, such as aggression or increased frustration. Six had autistic features.

Martinez-Monseny et al. (2018) described a 12-year-old girl with genetically confirmed SHMS. Clinical features included overgrowth from birth, with height and head circumference greater than the 97th centile and hand and foot length greater than the 99th centile. She also had fifth finger clinodactyly and camptodactyly, high plantar arches without evidence of a neuropathy, and dysmorphic facial features, including hypertelorism, downslanting palpebral fissures, eversion of the lateral third of lower eyelids, a bulbous nasal tip, long philtrum, thin upper vermilion, a wide mouth with downturned corners, and low-set ears. She also had a persistent ductus arteriosus, patent foramen ovale, and bicuspid aortic valve. She had partial seizures since the age of 3 years, treated with carbamazepine, and she had laughing episodes since the age of 10 years, treated with aripiprazole. She had 3 episodes of ataxia lasting a few hours during periods when she had recurrent mycoplasma respiratory tract infections involving the right upper lobe of the lung. The ataxia resolved spontaneously. Laboratory testing showed a maintained decrease in complement factor C3 (less than 110 U/ml; normal, 890-1950). In contrast to previously reported patients, she had no digestive or feeding disturbances and her communication skills were only mildly impaired.

Hoshino et al. (2019) reported 2 Japanese patients with Schuurs-Hoeijmakers syndrome. In addition to the typical findings of impaired intellectual development and dysmorphic facial features, both patients had additional findings, which might expand the phenotypic spectrum. The first patient had paroxysmal movements including massive myoclonus, chewing and twitching around the mouth, and forward tilting of the head. An EEG showed no epileptiform discharges. The movements, interpreted as nonepileptic involuntary movements, were treated successfully with trihexyphenidyl hydrochloride. This led the authors to speculate that she had an inherent dopaminergic insufficiency resulting from her PACS1 mutation. The second patient had severe constipation that had been treated with laxatives. After recognition of a relaxed anal sphincter muscle, a lumbar MRI was performed at age 2 years and 8 months, which showed a lipomyelomeningocele. The authors noted that many patients with SHMS have constipation, and a diagnosis of lipomyelomeningocele could be missed when the lesion is closed and not accompanied by a cutaneous lesion, as was the case in their patient.

The recurrent heterozygous mutation in the PACS1 gene that was found in patients with SHMS by Schuurs-Hoeijmakers et al. (2012), Gadzicki et al. (2015), Schuurs-Hoeijmakers et al. (2016), and Martinez-Monseny et al. (2018) occurred de novo.

In 2 unrelated boys with impaired intellectual development and similar dysmorphic facial features, Schuurs-Hoeijmakers et al. (2012) identified identical de novo heterozygous mutations in the PACS1 gene (R203W; 607492.0001). The mutation was not identified in 150 alleles from the Dutch population, in 2,304 alleles from the local variant database, or in 7,020 alleles of European American origin from the NHLBI Exome Sequencing Project database. Expression of mutant PACS1 mRNA in zebrafish embryos induced craniofacial defects most likely in a dominant-negative fashion. The phenotype was driven by aberrant specification and migration of SOX10 (602229)-positive cranial, but not enteric, neural crest cells.

In a 3-year-old boy with SHMS, Gadzicki et al. (2015) identified the same de novo heterozygous R203W mutation in the PACS1 gene. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant were not performed.

Schuurs-Hoeijmakers et al. (2016) reported 16 additional patients with SHMS resulting from the recurrent de novo heterozygous R203W mutation in the PACS1 gene. All patients were diagnosed by exome sequencing. Functional studies of the variant were not performed.

In a 12-year-old girl with SHMS, Martinez-Monseny et al. (2018) identified the recurrent de novo R203W mutation in the PACS1 gene. The mutation was found by exome sequencing and confirmed by Sanger sequencing.

By whole-exome sequencing in 2 Japanese children with SHMS, Hoshino et al. (2019) identified the recurrent de novo heterozygous R203W mutation in the PACS1 gene.