A number sign (#) is used with this entry because of evidence that short stature, oligodontia, dysmorphic facies, and motor delay (SOFM) is caused by homozygous or compound heterozygous mutation in the POLR3GL gene (617457) on chromosome 1q21.

SOFM is characterized by marked short stature, oligodontia, mild facial dysmorphism, and motor delay. Endosteal hyperostosis has also been observed, and patients may exhibit some features of progeria (Terhal et al., 2020; Beauregard-Lacroix et al., 2020).

Terhal et al. (2020) reported monozygotic twin sisters and an unrelated woman with endosteal hyperostosis and oligodontia, and mutations in the POLR3GL gene. The 19-year-old twins (P1 and P2) had short stature, localized endosteal hyperostosis that was primarily axial, oligodontia, clubfeet, and 2-3 toe syndactyly. Shared dysmorphic facial features included upslanting palpebral fissures, beaked nose with long columella, thin lips with downturned corners of the mouth, and flat philtrum. One sister (P1) experienced delayed puberty. Both had delayed motor development and used wheelchairs: 1 sister (P2) never walked due to congenital spastic diplegia, believed to be related to perinatal asphyxia; whereas the other sister (P1), who was hypotonic with reduced reflexes, developed foot pain as well as lumbar disc-related back pain and urinary incontinence in her mid-teens. The unrelated 36-year-old woman (P3) had short stature, localized endosteal hyperostosis that was primarily axial, oligodontia, delayed motor development, delayed puberty, and mild varus deformity of the feet as well as short toes and 2-3 toe syndactyly. Facial dysmorphisms included high nasal bridge with long columella, broad nasal tip, downturned mouth, and retrognathia. She also had soft skin, hyperextensible joints, and hypotonia. She had a brother with short stature and oligodontia, but he was unavailable for evaluation.

Beauregard-Lacroix et al. (2020) reported a 3-year-old French-Canadian girl with short stature, oligodontia, dysmorphic facies, and motor delay, who also showed some features of progeria although she did not have lipodystrophy. She had large anterior fontanel, hypertelorism, short palpebral fissures, proptosis, midface hypoplasia with hypoplasia of the nasal bridge and alae, low-set posteriorly rotated ears, and small mouth with high-arched palate. Her fingers were long and ulnarly deviated with distal contractures, and toes appeared short. Other features included axial hypotonia, hypoplastic labia minora, and 2 infantile hemangiomas, in the frontonasal region and on the scapula. Echocardiography revealed bicuspid aortic valve and atrial septal defect type II, and rhinopharyngolaryngoscopy identified choanal atresia and stenosis of the aperture of the pyriform sinus. Cerebral MRI showed mild ventriculomegaly, and follow-up MRI at 33 months was suggestive of communicating hydrocephalus, although no lesion was identified to explain hydrocephalus. Examination at 34 months of age showed short stature, microcephaly, and global developmental delay with few words; she was able to sit without support, but did not walk. A protruding forehead with prominent scalp veins were noted, and the anterior fontanel was still patent.

The transmission pattern of SOFM in the families reported by Terhal et al. (2020) was consistent with autosomal recessive inheritance.

By trio-based whole-exome sequencing in monozygotic twin sisters (P1 and P2) with short stature, oligodontia, dysmorphic facies, motor delay, and endosteal hyperostosis, Terhal et al. (2020) identified homozygosity for a splicing mutation in the POLR3GL gene (617457.0001). Their unaffected parents were heterozygous for the mutation; genealogic analysis revealed a distant relationship between the parents, with a shared ancestor 7 generations previous. In an unrelated but similarly affected woman (P3), Terhal et al. (2020) identified compound heterozygosity for the same splicing mutation and another splicing mutation in POLR3GL (617457.0002); her parents were each heterozygous for 1 of the mutations. The genealogic study did not find evidence of a relationship between the 2 families.

By whole-exome sequencing in a 3-year-old French-Canadian girl with short stature, oligodontia, dysmorphic facies, motor delay, and some features of progeria, Beauregard-Lacroix et al. (2020) identified homozygosity for a nonsense mutation in the POLR3GL gene (R120X; 617457.0003). The authors noted the overlap in phenotype between this patient and the patients described by Terhal et al. (2020), but also noted similarities between some features in their patient and those of neonatal progeroid syndromes such as Wiedemann-Rautenstrauch syndrome (see 264090).