A number sign (#) is used with this entry because of evidence that seizures, scoliosis, and macrocephaly/microcephaly syndrome (SSMS) is caused by homozygous or compound heterozygous mutation in the EXT2 gene (608210) on chromosome 11p11.

Seizures, scoliosis, and macrocephaly/microcephaly syndrome (SSMS) is an autosomal recessive neurodevelopmental disorder characterized by global developmental delay apparent from early infancy, impaired intellectual development, behavioral problems, poor or absent speech, seizures, dysmorphic facial features with macro- or microcephaly, and skeletal abnormalities, including scoliosis and delayed bone age. Other features may include hypotonia, gastrointestinal problems, and exostoses (summary by Gentile et al., 2019).

Farhan et al. (2015) reported 4 young-adult sibs, born of consanguineous parents from the Old Order Mennonite community, with a developmental disorder characterized by delayed psychomotor development apparent since infancy, poor speech, seizures, macrocephaly, and scoliosis. All patients developed variable seizures between ages 2 and 5 years, with 1 child having a severe episode of status epilepticus resulting in brain injury and hemiparesis. Additional common features included hypotonia, coarse facies with hypertelorism, skin sensitivity, low bone density, gastrointestinal abnormalities, such as gastroesophageal reflux, bowel malrotation, and diarrhea/constipation, and cryptorchidism in males. None had obvious skeletal anomalies aside from scoliosis. Two patients had brain hemorrhage and 2 had hematuria with proteinuria, associated in 1 patient with hemolytic-uremic syndrome necessitating dialysis. One or 2 patients had other variable anomalies, including wide-based gait, ventricular septal defect, hypertension, hepatic dysfunction, overlapping toes, and tremor.

El-Bazzal et al. (2019) reported 2 brothers, born of consanguineous Syrian parents, with severe global developmental delay, hypotonia, microcephaly, gastrointestinal abnormalities with poor feeding and constipation, osteopenia, and neurologic regression. Neither achieved walking or speech by 8 and 5 years of age; 1 was tube-fed. Both developed refractory seizures in the first years of life, and EEG showed abnormalities, including generalized and multifocal discharges and hypsarrhythmia in 1. Other features included flat forehead, large ears, decayed teeth, and gingival hypertrophy. Family history revealed a possibly affected sister who died at age 7 from respiratory distress.

Gupta et al. (2019) reported a 14-year-old girl with developmental delay, autism, and dysmorphic features, including macrocephaly, tall forehead, hypertelorism, long hypoplastic philtrum, preauricular pits, strabismus, and upturned round broad nasal tip. She walked at age 14 months, had poor language skills but could speak, and developed seizures at age 10. She also had aggressive behavior, sleep difficulties, and gastrointestinal problems. Brain imaging was normal. Laboratory studies showed low levels of heparan sulfate in blood and urine. Her less severely affected fraternal twin sister had Asperger syndrome with mild motor, cognitive, and speech delay, but did not have seizures.

Gentile et al. (2019) reported 2 Italian sibs, 21 and 15 years of age, with SSMS. Both had patent ductus arteriosus (PDA) at birth and developed seizures in the first years of life. Both had global developmental delay, but the older sib was more severely affected. He walked independently at 3 years, had severe intellectual disability, repetitive and/or obsessive behavior, and limited speech with poor autonomy for daily life activities. Brain imaging showed thin corpus callosum. His younger sister had developmental delay with poor language skills and unsteady gait, but was able to attend regular school with special education and did not have behavioral abnormalities. Dysmorphic features included hypotonic appearance, large head with high forehead, hypertelorism, broad bulbous nasal tip, flat/long philtrum, prominent lower lip, large ears, preauricular tags, sparse hair, and distal anomalies of the hands and feet, such as flattening of the distal phalanges, dysplastic nails, clinodactyly of the fifth finger, overlapping toes, and flat feet. Both patients also had osteopenia, scoliosis, and multiple exostoses affecting the knees and elbows.

The transmission pattern of SSMS in the family reported by Farhan et al. (2015) was consistent with autosomal recessive inheritance.

In 4 sibs, born of consanguineous parents, with SSMS, Farhan et al. (2015) identified 2 homozygous mutations in cis in the EXT2 gene (M87R and R95C; 608210.0008). The mutations, which were found by a combination of homozygosity mapping and whole-exome sequencing, segregated with the disorder in the family: each unaffected parent was heterozygous for both mutations in cis. The M87R and R95C mutations were present in the Exome Sequencing Project at frequencies of 0.054% and 0.015%, respectively. Neither mutation was found in 311 Caucasian controls; the heterozygous M87R variant was found at a frequency of 3.85% among the Old Order Mennonite community, whereas R95C was not found in this population. Patient-derived fibroblasts showed significantly decreased EXT2 protein and mRNA levels compared to controls. Levels of the EXT2-interacting protein NDST1 (600853) were abolished in patient cells, although transcript levels were normal. In vitro cellular expression studies indicated that both mutations individually resulted in decreased protein levels, with a synergistic effect of both mutations expressed at the same time.

In 2 brothers, born of consanguineous Syrian parents, with SSMS, El-Bazzal et al. (2019) identified a homozygous missense mutation in the EXT2 gene (S4L; 608210.0009). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed.

In a 14-year-old girl with SSMS, Gupta et al. (2019) identified compound heterozygous missense mutations in the EXT2 gene (V373D, 608210.0010 and T672M, 608210.0011). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. The patient also carried a rare heterozygous missense variant (R454C) in the NDST1 gene (600853) gene inherited from the unaffected mother, but the contribution of this variant to the phenotype was unknown. The proband's fraternal twin sister, who was less severely affected, carried all 3 variants. Functional studies of the variants and studies of patient cells were not performed.

In 2 sibs with SSMS, Gentile et al. (2019) identified compound heterozygous missense mutations in the EXT2 gene (Y608C, 608210.0012 and D227N, 608210.0004). The mutations, which were found by targeted exome sequencing, segregated with the disorder in the family. The D227N variant, which had been found in patients with multiple exostoses type II (EXT2; 133701), was inherited from the mother, who also had EXT2 as well as a family history of exostosis, and both sibs had EXT2. The father, who carried the Y608C variant, did not have exostosis. These findings indicated that D227N is a specific variant that contributes to exostosis. Functional studies of the variants and studies of patient cells were not performed.