PPP1R12A-Related Urogenital and/or Brain Malformation Syndrome

Clinical characteristics: Individuals with PPP1R12A-related urogenital and/or brain malformation syndrome (UBMS) usually present with multiple congenital anomalies, most commonly involving the brain and/or urogenital systems. The brain abnormalities are variable, with the most severe belonging to the holoprosencephaly spectrum and associated with moderate-to-profound intellectual disability, seizures, and feeding difficulties. In individuals without brain involvement, variable degrees of developmental delay and/or intellectual disability may be present, although normal intelligence has been seen in a minority of affected individuals. Eye (strabismus, microphthalmia/anophthalmia) and skeletal abnormalities (kyphoscoliosis, joint contractures) can also be present in affected individuals of either sex. Regardless of the presence of a brain malformation, affected individuals with a 46,XY chromosome complement may have a difference of sex development (DSD) with gonadal dysgenesis associated with ambiguous genitalia or phenotypic female genitalia.

Diagnosis/testing: The diagnosis of PPP1R12A-related UBMS is established in a proband with suggestive findings and a heterozygous pathogenic variant in PPP1R12A identified by molecular genetic testing.

Management: Treatment of manifestations: Gonadectomy should be considered in individuals with dysgenetic gonads; referral of 46,XY undervirilized individuals to a urologist or gynecologist for consideration of surgery to address hypospadias, bifid scrotum, urogenital sinus abnormalities, and cryptorchidism; referral to an endocrinologist for treatment for induction of puberty and postpubertal hormonal issues for those with gonadal abnormalities; referral to a psychologist or multidisciplinary DSD clinic, if available. Treatment of feeding difficulties including consideration of gastrostomy tube placement for those with persistent feeding issues or failure to thrive; standard treatment for renal anomalies, epilepsy, developmental delay/intellectual disability, constipation, bowel atresia, hearing impairment, vision abnormalities/strabismus, kyphoscoliosis, and joint contractures, as needed.

Surveillance: Regular follow up by an interdisciplinary DSD team (if available) including endocrinology, genetics, gynecology, psychology, and urology for those who had DSD as part of their features. Measurement of growth parameters, evaluation of nutritional status and safety of oral intake, assessment for constipation, monitoring of developmental progress and educational needs, monitoring for changes in seizures, and assessment for new neurologic manifestations at each visit; monitoring for timing and progression of puberty at each visit starting in late childhood through adolescence; assessment for scoliosis or kyphosis at each visit until growth is complete; ophthalmology and audiology evaluations annually or as clinically indicated.

Genetic counseling: PPP1R12A-related UBMS is an autosomal dominant disorder typically caused by a de novo pathogenic variant. If the PPP1R12A pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism. Once the PPP1R12A pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.