Primrose Syndrome

Clinical characteristics: Primrose syndrome is characterized by macrocephaly, hypotonia, developmental delay, intellectual disability with expressive speech delay, behavioral issues, a recognizable facial phenotype, radiographic features, and altered glucose metabolism. Additional features seen in adults: sparse body hair, distal muscle wasting, and contractures. Characteristic craniofacial features include brachycephaly, high anterior hairline, deeply set eyes, ptosis, downslanted palpebral fissures, high palate with torus palatinus, broad jaw, and large ears with small or absent lobes. Radiographic features include calcification of the external ear cartilage, multiple wormian bones, platybasia, bathrocephaly, slender bones with exaggerated metaphyseal flaring, mild epiphyseal dysplasia, and spondylar dysplasia. Additional features include hearing impairment, ocular anomalies, cryptorchidism, and nonspecific findings on brain MRI.

Diagnosis/testing: The diagnosis of Primrose syndrome is established in a proband with characteristic features and a heterozygous pathogenic variant in ZBTB20 identified on molecular genetic testing.

Management: Treatment: Individualized educational program, speech therapy, physical therapy, and occupational therapy as indicated; treatment of behavioral concerns; applied behavioral analysis for autism; standard treatment for seizures, musculoskeletal issues, hearing loss, and thyroid dysfunction; oral hypoglycemics or insulin as needed for diabetes.

Surveillance: Monitor growth and development every six months; speech and developmental assessment every six months; assess for behavioral issues, seizures, and musculoskeletal complications at each visit; brain stem evoked response audiometry annually; annual fasting and postprandial blood glucose, hemoglobin A1c, and assessment for signs and symptoms of thyroid dysfunction.

Genetic counseling: Primrose syndrome is an autosomal dominant disorder. All probands reported to date with Primrose syndrome whose parents have undergone molecular genetic testing have the disorder as a result of a de novo ZBTB20 pathogenic variant. If a parent of the proband is known to have the ZBTB20 pathogenic variant identified in the proband, the risk to the sibs of inheriting the variant is 50%. Once the ZBTB20 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.