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.

Suggestive Findings

PPP1R12A-related UBMS should be suspected in individuals with the following clinical and imaging findings.

Clinical findings

• Atypical external genitalia in individuals with a 46,XY chromosome complement, including:
  • Normal female external genitalia
  • Urogenital sinus abnormalities
  • Undervirilized male external genitalia with a high insertion of the scrotum, bifid scrotum with or without cryptorchidism, micropenis, hypospadias with or without chordee, and anterior positioning of the anus.
• Microcephaly or macrocephaly with variable degrees of developmental delay, intellectual disability, and/or autistic features
• Brain malformations (See Imaging findings.)
• Eye abnormalities such as strabismus, microphthalmia/anophthalmia
• Skeletal anomalies (e.g., unilateral or bilateral fifth-finger clinodactyly, syndactyly of the toes, kyphoscoliosis)

Imaging findings

• Brain MRI imaging demonstrating:
  • Alobar, semilobar, or middle interhemispheric variant holoprosencephaly
  • Abnormalities of the corpus callosum
  • Anencephaly
  • Cortical dysplasia (polymicrogyria, heterotopia)
• Abdominal/pelvic ultrasound/MRI demonstrating:
  • Abnormal internal genitalia in 46,XY individuals, including müllerian duct remnants (uterine structure, cervix and/or upper part of the vagina)
  • Structural renal abnormalities including duplicated renal collecting system

Establishing the Diagnosis

The diagnosis of PPP1R12A-related UBMS is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in PPP1R12A identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include any likely pathogenic variants. (2) Identification of a heterozygous PPP1R12A variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing and genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with undervirilization in 46,XY individuals and/or brain malformations are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Individuals with PPP1R12A-related UBMS present with multiple congenital anomalies including brain abnormalities (holoprosencephaly spectrum and others) and urogenital malformations. To date, 12 individuals have been identified with a pathogenic variant in PPP1R12A [Hughes et al 2020]. The following description of the phenotypic features associated with this condition is based on these reports.

46,XY differences of sex development (DSD) / genitourinary anomalies are the primary manifestations in PPP1R12A-related UBMS.

• Atypical external genitalia in individuals with a 46,XY karyotype range from mild to severe undervirilization and can include:
  • Micropenis
  • Chordee
  • Variable degrees of hypospadias
  • Bifid and high insertion of the scrotum
  • Urogenital sinus abnormalities
  • Normal appearing female external genitalia
• Gonadal abnormalities can range from cryptorchidism to complete gonadal dysgenesis.
  • Gonads may be dysgenetic.
  • In the most severe cases, streak gonads have been found.
• Müllerian structures, including fallopian tubes, uterus, and upper part of the vagina, may be present.

Neurologic. Variable degrees of developmental delay and intellectual disability were reported in seven of 12 affected individuals. Neurodevelopmental abnormalities included attention-deficit/hyperactivity disorder (ADHD) and autistic features. Other neurologic features reported in single individuals include dystonia, appendicular hypotonia with foot pronation, unsteady gait, and seizure disorder. Normal intelligence has also been reported in some cases.

Brain imaging findings. Two individuals with holoprosencephaly (semilobar and syntelencephaly/middle interhemispheric variant) and two with corpus callosum abnormalities have been reported. Other anomalies reported in single individuals include: encephalocele, colpocephaly, acrania/exencephaly, absent septum pellucidum, Chiari malformation, cortical dysplasia/polymicrogyria, leukomalacia, and gray matter heterotopia.

Feeding. In individuals with a severe brain malformation, feeding may be difficult. Neonates with feeding difficulties can develop hyperbilirubinemia. Feeding often improves during the first few months of life, but typically worsens if seizures develop.

• Poor feeding in newborns is usually managed by nasogastric tube feedings, as the feeding problems often improve during the first weeks of life (see Management, Treatment of Manifestations).
• Feeding may worsen with intercurrent illnesses and with advancing age and size. In this scenario, gastrostomy tube placement may be considered.
• Individuals with low central tone frequently develop constipation.

Eye findings. Three of 12 affected individuals were reported with various eye abnormalities including strabismus, astigmatism, hyperopia, unilateral or alternating esotropia, rod and cone dysfunction, decreased vision, and latent nystagmus.

Limb/skeletal anomalies have included fifth-finger clinodactyly, syndactyly of all toes, kyphoscoliosis, joint contractures (not otherwise specified), and ulnar deviation of the hand

Manifestations reported in single individuals

• Growth abnormalities: microcephaly, macrocephaly, intrauterine growth restriction (IUGR), postnatal growth restriction/failure to thrive (FTT) and decreased subcutaneous fat
• Dysmorphic features including long face, facial asymmetry, arched eyebrows, widely-spaced eyes, hypotelorism/closely-spaced eyes, ptosis, long or short palpebral fissures, long eyelashes, epicanthal folds, short and upturned nose, micrognathia, large low-set and protruding ears, preauricular pit, earlobe creases, long philtrum
• Gastrointestinal: omphalocele; jejunal and ileal atresia with aberrant mesenteric blood supply
• Pyelectasis
• Patent ductus arteriosus

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

Prevalence

PPP1R12A-related UBMS is rare: 12 individuals have been reported to date [Hughes et al 2020]. The prevalence has not been determined.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with PPP1R12A-related UBMS, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

PPP1R12A-related urogenital and/or brain malformation syndrome (PPP1R12A-related UBMS) is an autosomal dominant disorder typically caused by a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

• All probands reported to date with PPP1R12A-related UBMS whose parents have undergone molecular genetic testing have the disorder as the result of a de novo pathogenic variant.
• Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable counseling regarding recurrence risk and prenatal diagnosis options.
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant. Note: A pathogenic variant is reported as "de novo" if: (1) the pathogenic variant found in the proband is not detected in parental DNA; and (2) parental identity testing has confirmed biological maternity and paternity. If parental identity testing is not performed, the variant is reported as "assumed de novo" [Richards et al 2015].
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. (To date, parental mosaicism has not been reported in PPP1R12A-related UBMS.) Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is known to have the pathogenic variant identified in the proband, the risk to the sibs for inheriting the pathogenic variant is 50%.
• 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 [Rahbari et al 2016].

Offspring of a proband. Each child of an individual with PPP1R12A-related UBMS has a 50% chance of inheriting the PPP1R12A pathogenic variant.

Other family members. Given that all probands with PPP1R12A-related UBMS reported to date have the disorder as a result of a de novo pathogenic variant, the risk to other family members is presumed to be low.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Risk to future pregnancies is presumed to be low as the proband most likely has a de novo PPP1R12A pathogenic variant. There is, however, a recurrence risk (~1%) to sibs based on the theoretic possibility of parental germline mosaicism [Rahbari et al 2016]. Given this risk, prenatal and preimplantation genetic testing may be considered.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

PPP1R12A encodes a component of myosin phosphatase (MP), a key enzyme instrumental in the regulation of cell morphology and motility [Grassie et al 2011, Kiss et al 2019]. MP activates when PP1c is unphosphorylated and bound. Phosphorylation of specific consensus sites on PPP1R12A by protein kinases leads to inhibition of its activity [Ito et al 2004]. Pathogenic variants in PPP1R12A prevent PPP1R12A from binding to PP1c and result in a nonfunctional MP [Huang et al 2008].

Mechanism of disease causation. Loss of function

Cancer and Benign Tumors

The number of copies of PPP1R12A was correlated with the prediction of recurrence and survival in individuals with Stage III colorectal cancer treated with oxaliplatin-based chemotherapy [Zhang et al 2015]. Moreover, both a pure alveolar and sarcomatoid rhabdomyosarcoma of the urinary bladder demonstrated a novel fusion involving PPP1R12A fusions at the 12q21.1 to 12q21.31 locus; the exact role of this fusion has not been defined [Gupta et al 2019].

Revision History

• 7 March 2024 (ea) Revision: removed information regarding individuals with a 46,XX chromosome complement
• 9 September 2021 (ma) Review posted live
• 8 January 2021 (ea) Original submission

Literature Cited

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