Clinical characteristics: Most females with osteopathia striata with cranial sclerosis (OS-CS) present with macrocephaly and characteristic facial features (frontal bossing, hypertelorism, epicanthal folds, depressed nasal bridge, and prominent jaw). Approximately half have associated features including orofacial clefting and hearing loss, and a minority have some degree of developmental delay (usually mild). Radiographic findings of cranial sclerosis, sclerosis of long bones, and metaphyseal striations (in combination with macrocephaly) can be considered pathognomonic.

Males can present with a mild or severe phenotype.

Mildly affected males have clinical features similar to affected females, including macrocephaly, characteristic facial features, orofacial clefting, hearing loss, and mild-to-moderate learning delays. Mildly affected males are more likely than females to have congenital or musculoskeletal anomalies. Radiographic findings include cranial sclerosis and sclerosis of the long bones; Metaphyseal striations are more common in males who are mosaic for an AMER1 pathogenic variant.

The severe phenotype manifests in males as a multiple-malformation syndrome, lethal in mid-to-late gestation, or in the neonatal period. Congenital malformations include skeletal defects (e.g., polysyndactyly, absent or hypoplastic fibulae), congenital heart disease, and brain, genitourinary, and gastrointestinal anomalies. Macrocephaly is not always present and longitudinal metaphyseal striations have not been observed in severely affected males, except for those who are mosaic for the AMER1 pathogenic variant.

Diagnosis/testing: The diagnosis of OS-CS is established in a female proband with characteristic features and a heterozygous pathogenic variant in AMER1 identified by molecular genetic testing. The diagnosis of OS-CS is established in a male proband with characteristic features and a hemizygous pathogenic variant in AMER1 identified by molecular genetic testing.

Management: Treatment: Scoliosis management per orthopedic surgeon; physiotherapy may be helpful for joint contractures; management of oral facial clefts per otolaryngologist; hearing loss is managed by audiology, speech and language therapy, and otolaryngology; vision loss management per ophthalmologist and neurosurgery for nerve compression as indicated; early intervention services and special education as indicated; standard treatments for cardiac, genitourinary, and gastrointestinal anomalies and Wilms tumor or other malignancy.

Surveillance: Annual clinical assessment for skeletal manifestations such as scoliosis, joint contractures, stress fractures, and persistent bone pain. Annual audiology and ophthalmology evaluations for evidence of cranial nerve compression due to sclerotic bone disorder. Consider abdominal ultrasound every three months until age seven years to screen for Wilms tumor.

Genetic counseling: OS-CS is inherited in an X-linked manner. The risk to sibs of a male proband depends on the genetic status of the mother. The risk to sibs of a female proband depends on the genetic status of the mother and the father. If the mother of the proband has an AMER1 pathogenic variant, the chance of transmitting it in each pregnancy is 50%. If the father of the proband has an AMER1 pathogenic variant, it should be presumed he will transmit the AMER1 pathogenic variant to all his daughters and none of his sons (to date, paternal transmission has only been reported in mosaic fathers). Females who inherit an AMER1 pathogenic variant will be heterozygotes and will have variable manifestations of OS-CS. Males who inherit a pathogenic variant will be hemizygotes and will have variable manifestations ranging from mid-late gestation and neonatal lethality to the mild phenotype. Once the AMER1 pathogenic variant is identified in an affected family member, prenatal and preimplantation genetic testing are possible.