Clinical characteristics.

PIK3CA-related overgrowth spectrum (PROS) encompasses a range of clinical findings in which the core features are congenital or early-childhood onset of segmental/focal overgrowth with or without cellular dysplasia. Prior to the identification of PIK3CA as the causative gene, PROS was separated into distinct clinical syndromes based on the tissues and/or organs involved (e.g., MCAP [megalencephaly-capillary malformation] syndrome and CLOVES [congenital lipomatous asymmetric overgrowth of the trunk, lymphatic, capillary, venous, and combined-type vascular malformations, epidermal nevi, skeletal and spinal anomalies] syndrome). The predominant areas of overgrowth include the brain, limbs (including fingers and toes), trunk (including abdomen and chest), and face, all usually in an asymmetric distribution. Generalized brain overgrowth may be accompanied by secondary overgrowth of specific brain structures resulting in ventriculomegaly, a markedly thick corpus callosum, and cerebellar tonsillar ectopia with crowding of the posterior fossa. Vascular malformations may include capillary, venous, and less frequently, arterial or mixed (capillary-lymphatic-venous or arteriovenous) malformations. Lymphatic malformations may be in various locations (internal and/or external) and can cause various clinical issues, including swelling, pain, and occasionally localized bleeding secondary to trauma. Lipomatous overgrowth may occur ipsilateral or contralateral to a vascular malformation, if present. The degree of intellectual disability appears to be mostly related to the presence and severity of seizures, cortical dysplasia (e.g., polymicrogyria), and hydrocephalus. Many children have feeding difficulties that are often multifactorial in nature. Endocrine issues affect a small number of individuals and most commonly include hypoglycemia (largely hypoinsulinemic hypoketotic hypoglycemia), hypothyroidism, and growth hormone deficiency.

Diagnosis/testing.

The diagnosis of PROS is established in a proband with suggestive findings and a heterozygous mosaic (or rarely, constitutional) activating pathogenic variant in PIK3CA. Sequence analysis of DNA derived from clinically affected tissue samples ‒ preferably from freshly obtained dermal biopsy overlying an affected area, from surgical excision of the overgrown tissue, or from uncultured tissues (such as skin fibroblasts or other tissues) ‒ should be prioritized for genetic testing. Targeted capture of the entire PIK3CA coding region followed by next-generation sequencing at very deep coverage is recommended for somatic variant detection, as it allows for detection of very low levels of mosaicism throughout the gene.

Management.

Targeted therapy: Alpelisib (VIJOICE^®) 50 mg orally with food once a day (at about the same time every day) for those between age two years and <18 years with PROS. In those age six years or older, the dose may be increased to 125 mg once a day after 24 weeks. A starting dose of 250 mg orally with food once a day (at about the same time every day) has been approved for those age ≥18 years. Alpelisib has been approved specifically for the reduction of overgrowth, vascular lesions, and other functional complications. To date, it is unknown whether this drug has any efficacy in treating the neurologic manifestations of PROS (as, e.g., in MCAP syndrome).

Supportive care: Significant or lipomatous segmental overgrowth may require debulking; scoliosis and leg-length discrepancy may require orthopedic care and surgical intervention. Neurologic complications (e.g., obstructive hydrocephalus, increased intracranial pressure, progressive and/or symptomatic cerebellar tonsillar ectopia or Chiari malformation, and epilepsy in those with brain overgrowth/malformations) may warrant neurosurgical intervention. Depending on the type of vascular malformations, sclerotherapy, laser therapy, or oral medications such as sirolimus may be used. Similarly, lymphatic malformations may be treated through oral medications or careful surgical debulking, preferably by a vascular anomalies team. For those with pain, evaluation for the source of pain and treatment of the underlying cause is recommended. For those with growth hormone deficiency, evaluation of the hypothalamic-pituitary-adrenal axis is warranted; a trial of growth hormone therapy may be considered with careful monitoring of linear growth and overgrowth. Severe persistent hypoglycemia has been reported, and requires evaluation and ongoing treatment, which can include cornstarch administration. Routine treatment of the following, when present, is indicated: cardiac and renal abnormalities; intellectual disabilities and behavior issues; polydactyly and foot deformities; coagulopathy or thrombosis; Wilms tumor; and hypothyroidism.

Surveillance: At each visit: measurement of growth parameters including head circumference, length of arms, hands, legs, and feet; assess for new neurologic manifestations (seizures, changes in tone, and other signs/symptoms of Chiari malformation); monitor developmental progress and behavior; assess motor skills; clinical assessment for scoliosis and abdominal examination for organomegaly and/or abdominal masses. Serial head MRI imagining is recommended, with frequency based on the severity of findings on initial assessment and the degree of brain maturation. For those with CNS overgrowth or dysplasia, brain MRI every six months until age two years and then annually until age eight years to monitor specifically for progressive hydrocephalus and Chiari malformation. As clinically indicated: clinical assessment and monitoring of any vascular and/or lymphatic malformations; radiographs of the limbs in those with overgrowth of a limb or portion of a limb; ultrasound or MRI follow up in those with truncal overgrowth; spinal MRI in those with scoliosis or deformities that affect the spine; blood glucose monitoring and evaluation of the hypothalamic-pituitary-adrenal axis for those with persistent hypoglycemia, particularly if they require ongoing treatment for hypoglycemia. Hematology consultation with recommendations for assessment for thrombosis and coagulopathy risk after any surgical intervention, particularly in those with the CLOVES phenotype and/or those with vascular malformations. Consideration of renal ultrasound every three months until age eight years (tumor screening for Wilms tumor is controversial).

Genetic counseling.

PROS disorders are not known to be inherited, as most identified pathogenic variants are somatic (mosaic). No confirmed vertical transmission or sib recurrence has been reported to date. The risk to sibs of a proband with somatic mosaicism for a pathogenic variant in PIK3CA would be expected to be the same as in the general population. All but a few affected individuals with PROS have had somatic mosaicism for a PIK3CA pathogenic variant, suggesting that mutation occurred post fertilization in one cell of the multicellular embryo. Therefore, the risk for transmission to offspring is expected to be less than 50%.

Suggestive Findings

PROS should be considered in individuals with the following clinical, brain MRI, and family history findings [Keppler-Noreuil et al 2015, Mirzaa et al 2016, Kuentz et al 2017].

Clinical features

• Overgrowth of any of a wide variety of tissues including (but not limited to) brain, adipose, vascular, muscle, skeletal, nerve
• Vascular malformations including (but not limited to) capillary, venous, arteriovenous, or mixed malformations
• Lymphatic malformations
• Cutaneous findings including epidermal nevi and hyperpigmented macules
• Single or multiple digital anomalies of the hands or feet (e.g., macrodactyly, syndactyly, polydactyly, sandal-toe gap)
• Kidney malformations
• Benign tumors, with the exceptions of Wilms tumor and nephroblastomatosis (i.e., diffuse or multifocal clusters of persistent embryonal cells)

Brain MRI findings. Focal brain overgrowth (with or without cortical dysplasia) including:

• Hemimegalencephaly (HMEG)
• Focal cortical dysplasia (FCD)
• Dysplastic megalencephaly (DMEG)

Family history. Because PIK3CA is typically caused by a de novo mosaic pathogenic variant, most probands represent a simplex case (i.e., a single occurrence in a family). Rarely, the family history may be consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations).

Establishing the Diagnosis

The diagnosis of PROS is established in a proband with suggestive findings and a heterozygous mosaic (or rarely, constitutional) activating pathogenic variant in PIK3CA [Keppler-Noreuil et al 2015] (see Table 1 and Molecular Genetics).

Molecular diagnosis. Molecular genetic testing approaches typically include use of targeted testing (single-gene testing or multigene panel), although comprehensive genomic testing (exome sequencing, genome sequencing) is available. Because the majority of reported PIK3CA pathogenic variants are postzygotic (and thus mosaic), more than one tissue (excluding blood in most cases) may need to be tested:

• Experience suggests that sequence analysis of DNA derived from clinically affected tissue samples ‒ preferably from freshly obtained dermal biopsy overlying an affected area, from surgical excision of the overgrown tissue, or from uncultured tissues (e.g., skin fibroblasts or other tissues) ‒ should be prioritized for genetic testing.
• The level of mosaicism for an activating variant in affected tissues or cultured cells is extremely variable [Keppler-Noreuil et al 2014, Kuentz et al 2017].
• Testing of blood or DNA isolated from blood is not recommended based on current technologies, as PIK3CA pathogenic variants have not been identified in blood except in two of 24 individuals with megalencephaly-capillary malformation (MCAP) syndrome, who had an apparently de novo germline pathogenic variant in PIK3CA [Rivière et al 2012].

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 in whom the diagnosis of PROS has not been considered may be diagnosed using genomic testing (see Option 2), if an appropriate sample is used.

Clinical Description

PIK3CA-related overgrowth spectrum (PROS) includes overgrowth of a broad range of tissues that may or may not be accompanied by cellular dysplasia. Prior to the understanding of the molecular nature of PROS, a number of distinct but overlapping phenotypes were clinically described and given names (see GeneReview Scope).

In general, PROS can be divided into an isolated form (when a person has a focal lesion that affects only one tissue or body part; see Table 2) and a syndromic form (i.e., overgrowth plus at least two other features in two systems; see Table 3). A targeted therapy aimed at inhibiting PI3K-related pathway overgrowth has been approved by the FDA (see Table 6).

Figure 1.

Features of CLOVES syndrome in a child with (A) a large lipomatous truncal mass that extends into the surrounding tissues and an overlying capillary malformation and (B) macrodactyly of the left foot

Figure 2.

Features of MCAP syndrome. Photographs of an individual with MCAP syndrome demonstrating the apparent macrocephaly with prominent forehead (D); extensive capillary malformations (A-F1); bilateral 2-3-4 toe syndactyly (G, H); 3-4 finger syndactyly (F1, F2); and postaxial polydactyly of the right hand (F1)

From Mirzaa et al [2012]. Used by permission.

Figure 3.

Features of MCAP syndrome. A boy age 40 months with MCAP syndrome (left) and his unaffected twin sister (right). Note left-sided hemihypertrophy, typical facial features, bilateral 2-3 toe syndactyly, and connective tissue dysplasia with loose redundant skin.

From Conway et al [2007b]. Used by permission.

Neuroimaging

Individuals with PROS who have macrocephaly typically undergo brain imaging shortly after birth or within the first year of life, leading to early identification of the following key neuroimaging features (see Figure 4) [Vogels et al 1998, Nyberg et al 2005, Conway et al 2007a, Conway et al 2007b, Martínez-Lage et al 2010, Mirzaa et al 2012].

Figure 4.

Characteristic brain MRI of MCAP syndrome in three individuals (A-D, E-H, and I-L). Note: Megalencephaly with a prominent forehead (A, E, I); cerebellar tonsillar ectopia with a large cerebellum and crowded posterior fossa (A, E, I); ventriculomegaly (more...)

Megalencephaly [Clayton-Smith et al 1997, Vogels et al 1998, Robertson et al 2000, Nyberg et al 2005, Coste et al 2012]. In some instances, MEG (with or without ventriculomegaly) is detected prenatally on ultrasound examination, along with a thickened corpus callosum. More than 90% of affected individuals have congenital MEG that is universally progressive.

Ventriculomegaly and hydrocephalus. Most affected children have evidence of ventricular dilatation or ventriculomegaly on early brain imaging:

• In a large review of the neuroimaging findings in individuals with MCAP syndrome, 37 (56%) of 65 children had ventriculomegaly ranging from mild-to-frank hydrocephalus, with or without cerebellar tonsillar ectopia [Conway et al 2007b].
• While it is unclear whether ventriculomegaly is obstructive in all these individuals, more than half of affected children undergo ventricular shunting or third ventriculostomy, usually within the first year of life.

Cerebellar tonsillar ectopia (CBTE). A large cerebellum combined with a small posterior fossa leading to cerebellar tonsillar ectopia (Chiari malformation) and syringomyelia are common complications, particularly in those with MCAP syndrome:

• Fifteen of 65 reported affected individuals with MCAP have evidence of CBTE with or without herniation [Conway et al 2007b].
• The degree of ectopia is best objectively assessed by measuring the distance of the cerebellar tonsils below the foramen magnum.
• Unlike ventriculomegaly, CBTE is rarely congenital in individuals with MCAP syndrome.
• In two individuals spontaneous "resolution" of CBTE on follow-up imaging was attributed to disproportionately accelerated skull overgrowth [Mirzaa et al 2012].

Cortical brain malformation and polymicrogyria (PMG). PMG may be present in more than 50% of affected children, most commonly those with the MCAP phenotype [Conway et al 2007b; Gripp et al 2009; Mirzaa et al 2012; Authors, unpublished data].

• The most common type of PMG in those with MCAP syndrome is bilateral perisylvian PMG, although other types including bilateral frontal and focal PMG occur.
• PMG broadly, and bilateral perisylvian PMG in particular, increase the risk for: epilepsy; oral motor weakness leading to feeding, swallowing, and expressive language difficulties; developmental delay; and tone abnormalities.

Genotype-Phenotype Correlations

There are several mutational hot spots in PIK3CA (see Molecular Genetics and Table 9) that are more commonly associated with highly focal phenotypes (CLOVES syndrome, fibroadipose hyperplasia, lymphatic/vascular malformations, hemimegalencephaly and focal cortical dysplasia), namely: p.Glu542Lys, p.Glu545Lys, p.His1047Arg, p.His1047Lys [Mirzaa et al 2016]. These mutational hot spots, when present in the brain, are associated with more severe epilepsy phenotypes as well [Pirozzi et al, in press]. The same PIK3CA missense variants may be found in individuals with PROS and in unaffected individuals with PIK3CA-related cancer (Tables 8 and 9).

Further, analysis of individuals with PROS suggests that MCAP syndrome in particular is primarily associated with a wide range of PIK3CA variants that are widely distributed across the gene, and less likely associated with PIK3CA mutational hot spots [Mirzaa et al 2016] (see Molecular Pathogenesis).

Nomenclature

Due to the phenotypic variability of the disorders caused by somatic PIK3CA pathogenic variants, researchers at an NIH Workshop in 2013 proposed the umbrella term PIK3CA-related overgrowth spectrum [Keppler-Noreuil et al 2015]. The PIK3CA-related overgrowth spectrum encompasses all the unique, clinically defined entities but highlights the continuum and overlap between the phenotype diagnoses.

Prevalence

The prevalence of PIK3CA-related overgrowth spectrum (PROS) is difficult to estimate due to variation in ascertainment and the broad phenotypic spectrum. More than 200 individuals with MCAP syndrome have been reported.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual with PIK3CA-related overgrowth spectrum (PROS), the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Note: Assessment is complicated by variable findings in individuals with this condition. Accurate and thorough assessment of medical history is necessary to evaluate for vascular malformations as well as other clinical features.

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

Some studies have demonstrated the efficacy of the mammalian target of rapamycin (mTOR) inhibitor sirolimus for lymphatic diseases [Padilla et al 2019, Zenner et al 2019]. Ongoing understanding of the PI3K/AKT/mTOR signaling pathway and the natural history of PROS will provide the basis for developing new targeted therapeutic strategies. Systemic agents under investigation for PROS target different components of the PI3K signaling pathway. These include inhibitors of mTOR, AKT, and PI3K genes:

• Sirolimus has been investigated in several clinical trials in individuals with complex lymphatic anomalies, vascular malformations, and overgrowth disorders [Adams et al 2016, Hammer et al 2018, Adams & Ricci 2019, Parker et al 2019, Van Damme et al 2020] (see ClinicalTrials.gov), some of whom had PROS. Sirolimus is currently used in an off-label capacity to treat these disorders [Seront et al 2019, Dekeuleneer et al 2020]. Sirolimus has shown efficacy in multiple Phase II studies for individuals with complicated vascular anomalies and individuals with PROS and progressive overgrowth [Adams et al 2016, Erickson et al 2017, Hammer et al 2018, Parker et al 2019, Ricci et al 2019].
• Miransertib, an AKT1 inhibitor, has been studied in clinical trials for expanded access, and in Phase I/II clinical trials [Wassef et al 2015, Zampino et al 2019].

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.

Mode of Inheritance

PIK3CA-related overgrowth disorders (PROS) are not known to be inherited, as most identified pathogenic variants are somatic (mosaic). No confirmed vertical transmission or sib recurrence has been reported to date.

Risk to Family Members

Parents of a proband

• Parents of children with somatic mosaicism for a pathogenic variant in PIK3CA have not been reported to have any significant distinctive manifestations of the disorder, nor would such findings be expected given the somatic nature of these genetic alterations.
• Theoretically, a parent of a child with PROS caused by a de novo germline PIK3CA pathogenic variant may have germline mosaicism for the PIK3CA pathogenic variant. The theoretic risk for parental germline mosaicism is estimated to be less than 1%.

Sibs of a proband

• The risk to sibs of a proband with somatic mosaicism for a pathogenic variant in PIK3CA would be expected to be the same as in the general population.
• The risk to sibs of a proband with a de novo germline PIK3CA pathogenic variant is slightly greater than that of the general population because of the theoretic risk (estimated to be <1%) of parental germline mosaicism.

Offspring of a proband

• Reproductive outcome data on adults with PROS are limited; there are no instances of vertical transmission of these disorders. While adults with PROS have been reported, the developmental outcome of affected individuals is unknown. Individuals with significant neurologic involvement (e.g., DMEG, HMEG) have a poor prognosis.
• All but a few affected individuals with PROS have had somatic mosaicism for a PIK3CA pathogenic variant, suggesting that mutation occurred post fertilization in one cell of the multicellular embryo. Therefore, the risk for transmission to offspring is expected to be less than 50%.
• Several individuals with PROS have had a de novo germline pathogenic variant in PIK3CA [Rivière et al 2012, Mirzaa et al 2016]. The offspring of individuals with a constitutional germline PIK3CA pathogenic variant have a 50% risk of inheriting the pathogenic variant.

Other family members. The risk to other family members is the same as that of the general population.

Related Genetic Counseling Issues

Family planning

• Counseling for recurrence risk in PROS should emphasize that, while no pregnancy is at zero risk, all empiric evidence suggests that the risk for recurrence in sibs of a proband is not increased over that of the general population, due to the mosaic nature of most of these disorders. The rare families with PROS caused by a de novo germline PIK3CA pathogenic variant should be counseled regarding the theoretic risk for parental germline mosaicism (~<1%).
• The optimal time for determination of genetic risk is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Because vertical transmission of PROS has not been reported to date, family members are not known to be at increased risk of being affected and prenatal diagnosis and preimplantation genetic testing are usually not indicated for family members. However, low-level germline mosaicism may theoretically be present in a parent of a child with a germline PIK3CA pathogenic variant. Prenatal testing or preimplantation genetic testing may be an option for such rare families.

In addition, molecular genetic prenatal testing may be an option for pregnancies identified by ultrasound examination to be at risk for PROS.

• Findings on ultrasound examination that suggest MCAP syndrome include marked fetal overgrowth and progressive macrocephaly with no indication of maternal hyperglycemia or fetal hyperinsulinism. Other reported fetal ultrasound findings include ventriculomegaly, pleural effusions, polyhydramnios, hydrops, limb asymmetry, and frontal bossing [Nyberg et al 2005]. A fetal MRI in an affected fetus with megalencephaly and ventriculomegaly revealed diffuse bilateral polymicrogyria and polysyndactyly of one foot [Gripp et al 2009].
• Findings on prenatal ultrasound examination in CLOVES syndrome include prenatal overgrowth, lipomatous truncal masses, and vascular or lymphatic malformations [Sapp et al 2007, Alomari 2009, Alomari 2011].

Molecular Pathogenesis

PIK3CA-related overgrowth spectrum disorders are typically caused by postzygotic somatic variants in the gene that encodes phosphatidylinositol-3-kinase (PI3K) catalytic subunit alpha (p110alpha) [Engelman et al 2006]. These variants are associated with hyperactivation of the PI3K signaling pathway, which includes multiple downstream effectors such as AKT and mTOR, resulting in abnormal growth of various tissues and vascular malformations.

The PIK3CA protein is critical for the action of insulin to lower blood glucose, and for the action of insulin-like growth factor 1 (IGF1), which promotes tissue growth through a receptor closely similar to the insulin receptor, and which mediates many actions of growth hormone. Pathologically activated PIK3CA may mimic the action of insulin and/or IGF1 in cells. For such a mechanism to translate into a clinically important endocrinopathy, target tissues need to have a high variant burden. This mechanism may explain why some affected infants have clinical features similar to hyperinsulinism.

Mechanism of disease causation. Gain of function

PIK3CA-specific laboratory technical considerations. Because most affected individuals having a mosaic PIK3CA pathogenic variant, use of custom restriction fragment length polymorphism (RFLP) assays or digital droplet PCR on an appropriate sample may be necessary. Standard-depth exome sequencing can miss mosaic PIK3CA variants, especially if performed on blood-derived DNA.

• In order to detect new or very rare variants, sequencing of entire exons is typically necessary.
• Sanger sequencing can be used only if the pathogenic variant allele fraction is relatively high (~20%).
• Targeted capture of the entire PIK3CA coding region followed by next-generation sequencing at very deep coverage may be better suited for somatic variant detection, as it allows for detection of very low levels of mosaicism throughout the gene.
• In MCAP syndrome, sequence analysis of DNA derived from saliva or skin fibroblasts (whether visibly affected or not) has a higher detection rate than peripheral blood-derived DNA [Mirzaa et al 2016].
• In focal brain overgrowth disorders (HMEG, FCD, DMEG), analysis of DNA derived from affected brain tissues (for example, removed at the time of epilepsy surgery) has a higher detection rate than peripheral tissues (blood or saliva) [Jansen et al 2015].

Cancer and Benign Tumors

PIK3CA is somatically mutated in many cancers including colorectal, ovarian, breast, hepatocellular carcinomas, and glioblastomas. These PIK3CA pathogenic variants are located mostly at hot spots within the kinase domain (encoded by exon 20), and result in gain of function implicated in oncogenicity [Samuels et al 2004, Ikenoue et al 2005, Kang et al 2005].

Most (>80%) activating PIK3CA pathogenic variants in cancer (Table 10) and PROS (Table 9) cluster at three hot spots: two glutamic acid (Glu) residues at codons 542 and 545, and a histidine (His) residue at codon 1047. The distribution of PIK3CA pathogenic variants in cancer was obtained from the Catalogue of Somatic Mutations in Cancer (COSMIC, v85, May 2018). PIK3CA pathogenic variants in PROS comprise published cases from larger cohort studies. The risk for tumorigenesis and development of malignancies is a theoretic concern because PIK3CA is somatically mutated or overexpressed in many cancers. The pathogenic variants in PIK3CA in cancers and in a large proportion of individuals with PROS (especially those with the phenotypes of CLOVES, fibroadipose hyperplasia, and isolated macrodactyly) are most commonly located at hot spots within the helical and kinase domains.

Among the approximately 160 PIK3CA pathogenic variants listed in the Catalogue of Somatic Mutations in Cancer (COSMIC), common variants in three amino acids (p.Glu542Lys, p.Glu545Lys in exon 9, and p.His1047Arg and p.His1047Leu in exon 20) account for 80% of tumor-associated PIK3CA variants and show the highest oncogenic activity [Samuels et al 2004, Samuels & Ericson 2006, Janku et al 2012]. See Table 10.

Author Notes

Dr Ghayda Mirzaa is an Associate Professor of Medical Genetics and Pediatrics at the University of Washington School of Medicine. Her research is focused on developmental brain disorders including megalencephaly with multiple publications related to PIK3CA-related overgrowth spectrum (PROS) including the natural history, molecular diagnosis, and potential therapies.

Dr John M Graham Jr is a Professor Emeritus of Pediatrics at David Geffen School of Medicine at UCLA and Consulting Clinical Geneticist at Cedars-Sinai Medical Center and Harbor UCLA Medical Center. He has had a long-term clinical interest in PROS with many publications on this topic.

Dr Kim Keppler-Noreuil is a clinical geneticist and Division Chief of Genetics & Metabolism at the University of Wisconsin School of Medicine and Public Health; she has multiple publications related to PROS, including invited review articles and original research focused particularly on the clinical and molecular diagnosis, and potential therapies for PROS.

Acknowledgments

We would like to thank the patients, their families, and our collaborators for their valuable contribution to our knowledge about these disorders.

Author History

Robert Conway, MD; Wayne State University (2013-2021)
Willliam B Dobyns, MD; Seattle Childfren's Hospital (2013-2021)
John H Graham Jr, MD, ScD (2013-present)
Kim Keppler-Noreuil, MD, FAAP, FACMG (2021-present)
Ghayda Mirzaa, MD, FAAP, FACMG (2013-present)

Revision History

• 6 April 2023 (ma/aa) Revision: expanded information on management of hypoglycemia; Targeted Therapy linked as a Key Section
• 25 August 2022 (aa) Revision: FDA approval of alpelisib for treatment of PROS (Table 6)
• 23 December 2021 (ma) Comprehensive update posted live
• 15 August 2013 (me) Review posted live
• 11 March 2013 (gm) Original submission

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