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Perlman syndrome
This rare condition primarily affects foetuses and newborns, leading to distinctive physical features, kidney abnormalities, and an increased risk of childhood cancers. It is caused by changes in the DIS3L2 gene.
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Overview
Perlman syndrome is a very rare genetic condition identified in foetuses and newborns. Key features include macrosomia (excessive foetal growth), characteristic facial features, and severe kidney problems, often involving Wilms tumour, a type of childhood kidney cancer [PMID:22080327]. The condition can have significant health implications, particularly in the neonatal period.
Since its first description, Perlman syndrome has been recognised as a disorder with a high degree of variability in its presentation, though certain features are consistently observed. It is categorised as a cancer predisposition syndrome due to the increased likelihood of developing certain tumours, notably Wilms tumour [PMID:2962507].
Symptoms & clinical features
Individuals with Perlman syndrome typically present with a distinctive set of features. During pregnancy, accelerated foetal growth (macrosomia) and an excess of amniotic fluid (polyhydramnios) are often noted. At birth, affected infants are usually larger than average and may have a range of physical characteristics, such as a large head, a prominent forehead, widely spaced eyes, a flattened nasal bridge, and a small chin.
Kidney abnormalities are a hallmark of Perlman syndrome, commonly including nephromegaly (enlarged kidneys) and structural changes that can impair kidney function. There is also a significantly increased risk of developing Wilms tumour, a cancer of the kidney, usually in early childhood. Other potential features can include heart defects, genital abnormalities, and, less commonly, developmental delay. The severity of these features can vary between individuals [PMID:28796417].
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Affected organs
The organs most significantly affected in Perlman syndrome are the kidneys, which frequently show enlargement and structural abnormalities, including dysplasia (abnormal development). The kidneys are also the primary site for cancer development, specifically Wilms tumour.
Other body systems can be involved. The skeletal system may show features associated with overgrowth. The facial structures typically exhibit characteristic features as described above. Less commonly, the heart can be affected by structural defects, and the central nervous system may be involved, occasionally leading to developmental differences.
Risks & severity
Perlman syndrome is associated with significant risks, particularly in the neonatal period, due to the severe congenital abnormalities present. The risk of developing Wilms tumour is substantially elevated, estimated to be up to 60% in individuals with the condition [PMID:2962507]. This cancer typically develops in early childhood, often before the age of four.
The overall severity of Perlman syndrome can vary, but it is often a severe condition with a high rate of infant mortality, primarily due to complications arising from kidney problems and prematurity. For those who survive infancy, careful surveillance for Wilms tumour is crucial. Developmental outcomes are also varied, with some individuals experiencing developmental delay.
Genetic causes
Perlman syndrome is caused by pathogenic variants in both copies of the DIS3L2 gene. The DIS3L2 gene provides instructions for making an enzyme called a 3'-5' exoribonuclease. This enzyme plays a crucial role in the cell by breaking down specific RNA molecules, which helps to regulate gene expression and maintain cellular health. It's particularly important in quality control pathways for RNA.
When both copies of the DIS3L2 gene contain pathogenic changes, the enzyme produced is either non-functional or has significantly reduced activity. This disruption prevents the proper breakdown of certain RNA molecules, leading to their accumulation. Research suggests this accumulation interferes with normal cell growth and development, particularly affecting kidney formation and contributing to the overgrowth observed in Perlman syndrome, as well as increasing cancer risk.
- DIS3L2 DIS3 like 3'-5' exoribonuclease 2DIS3L2 encodes a ribonuclease enzyme that degrades specific RNA molecules, and pathogenic variants cause Perlman syndrome, a rare overgrowth disorder with increased cancer risk.
Inheritance pattern
Perlman syndrome follows an autosomal recessive inheritance pattern. This means that an individual must inherit two altered copies of the DIS3L2 gene - one from each parent - to develop the condition.
Parents who each carry one altered copy of the DIS3L2 gene are called carriers. Carriers typically do not show any symptoms of the condition themselves because they have one working copy of the gene. When both parents are carriers, there is a 25% (1 in 4) chance with each pregnancy that their child will inherit two altered copies and thus be affected by Perlman syndrome. There is a 50% chance the child will be a carrier like their parents, and a 25% chance the child will inherit two working copies of the gene and not be a carrier or be affected.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
Diagnosis & testing
Diagnosis of Perlman syndrome is often suspected during pregnancy due to findings such as foetal overgrowth and polyhydramnios on ultrasound. After birth, a diagnosis can be suggested by the characteristic physical features and kidney abnormalities. However, a definitive diagnosis is confirmed through genetic testing.
Genetic testing involves analysing the DIS3L2 gene to identify pathogenic variants. This testing is available through the NHS Genomic Medicine Service (GMS) pathways, typically initiated following a referral to a clinical genetics service or a paediatric specialist. The NHS National Genomic Test Directory includes R-codes for testing suspected cases where there is a strong clinical indication or for confirmed family history.
Management & lifestyle
The management of Perlman syndrome focuses on addressing the specific health issues individuals face, particularly kidney problems and the increased risk of Wilms tumour. Care is multidisciplinary, involving paediatricians, nephrologists (kidney specialists), oncologists (cancer specialists), and geneticists.
Regular screening for Wilms tumour is a critical component of management. This typically involves frequent abdominal ultrasound scans during early childhood to detect any tumour development as early as possible, which can improve treatment outcomes. Kidney function is also closely monitored. Other interventions may be necessary depending on specific symptoms, such as managing feeding difficulties or developmental support. Genetic counselling is vital for families, providing information about the condition, inheritance patterns, and future reproductive options within the NHS framework.
UK care pathway
In the UK, individuals and families affected by Perlman syndrome primarily access care through the NHS. A suspected diagnosis often leads to a referral to a Clinical Genetics service. These services coordinate genetic testing, which is delivered via the NHS Genomic Medicine Service (GMS), using specified R-codes for DIS3L2 gene analysis. Genetic counsellors within these services provide essential support and information, helping families understand the genetic basis of Perlman syndrome, its inheritance, and implications for relatives.
Frequently asked questions
What is the life expectancy for someone with Perlman syndrome?
Perlman syndrome is often severe, with a high rate of mortality in infancy due to significant health complications, particularly associated with kidney problems and prematurity. For those who survive early childhood, regular health monitoring, especially for Wilms tumour, is essential.
Can Perlman syndrome be detected before birth?
Yes, Perlman syndrome can often be suspected during pregnancy through routine ultrasound scans. Findings such as unusual foetal overgrowth (macrosomia) and an excess of amniotic fluid (polyhydramnios) are common indicators, which may prompt further investigations.
How often should a child with Perlman syndrome be screened for Wilms tumour?
Children with Perlman syndrome typically undergo frequent abdominal ultrasound scans in early childhood to screen for Wilms tumour. The exact frequency will be determined by specialist paediatricians and oncologists, but often involves scans every three months until around the age of seven.
What support is available for families affected by Perlman syndrome?
Families in the UK can access support through NHS Clinical Genetics services, where genetic counsellors provide information and emotional support. Patient advocacy groups and rare disease organisations may also offer resources and connect families for shared experiences.
Is Perlman syndrome inherited?
Yes, Perlman syndrome is an inherited condition with an autosomal recessive pattern. This means a child needs to inherit a pathogenic variant in the DIS3L2 gene from each parent to develop the condition. Parents who carry one altered gene copy are usually unaffected.
References
- Alessandri JL, Cuillier F, Ramful D. Perlman syndrome: report, prenatal findings and review. American journal of medical genetics. Part A. 2008. PMID: 18780370
- Al Ghadeer HA, Alghazal FA, Alessa MA. DIS3L2 Gene Mutation Causes the Perlman Syndrome of Overgrowth and Wilms Tumor Susceptibility. Cureus. 2023. PMID: 38161545
- Morris MR, Astuti D, Maher ER. Perlman syndrome: overgrowth, Wilms tumor predisposition and DIS3L2. American journal of medical genetics. Part C, Seminars in medical genetics. 2013. PMID: 23613427
- Ferianec V, Bartova M. Beckwith-Wiedemann syndrome with overlapping Perlman syndrome manifestation. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians. 2014. PMID: 24215131
- Meyer AP, Koboldt DC, Ramadesikan S. Three Siblings With an Attenuated Presentation of Perlman Syndrome: A Case Report and Literature Review. Molecular genetics & genomic medicine. 2025. PMID: 40704758
- Henneveld HT, van Lingen RA, Hamel BC. Perlman syndrome: four additional cases and review. American journal of medical genetics. 1999. PMID: 10508986
- Łabno A, Warkocki Z, Kuliński T. Perlman syndrome nuclease DIS3L2 controls cytoplasmic non-coding RNAs and provides surveillance pathway for maturing snRNAs. Nucleic acids research. 2016. PMID: 27431325
- Neri G, Martini-Neri ME, Katz BE. The Perlman syndrome: familial renal dysplasia with Wilms tumor, fetal gigantism and multiple congenital anomalies. 1984. American journal of medical genetics. Part A. 2013. PMID: 24166810