Perlman syndrome is a rare autosomal recessive congenital overgrowth syndrome caused by biallelic germline loss-of-function variants in DIS3L2, which encodes a cytoplasmic 3'-5' exoribonuclease that degrades 3'-oligouridylated RNAs, including uridylated pre-let-7 and aberrant structured noncoding RNAs. It presents prenatally with polyhydramnios, fetal ascites, macrosomia and nephromegaly; neonates show distinctive facies, hypotonia, renal dysplasia with nephroblastomatosis and visceromegaly. Neonatal mortality is high, from renal failure, respiratory failure and pulmonary hypoplasia. Children who survive the neonatal period have developmental delay and a high, early risk of Wilms tumor, often bilateral, so renal ultrasound surveillance is recommended. ClinGen classifies DIS3L2 for Perlman syndrome as Definitive (autosomal recessive). The germline syndrome is kept separate from the Wilms tumor it predisposes to, which has its own entry.
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Conditions with similar clinical presentations that must be differentiated from Perlman Syndrome:
name: Perlman Syndrome
creation_date: "2026-11-06T20:10:00Z"
category: Mendelian
description: >-
Perlman syndrome is a rare autosomal recessive congenital overgrowth syndrome
caused by biallelic germline loss-of-function variants in DIS3L2, which
encodes a cytoplasmic 3'-5' exoribonuclease that degrades 3'-oligouridylated
RNAs, including uridylated pre-let-7 and aberrant structured noncoding RNAs.
It presents prenatally with polyhydramnios, fetal ascites, macrosomia and
nephromegaly; neonates show distinctive facies, hypotonia, renal dysplasia
with nephroblastomatosis and visceromegaly. Neonatal mortality is high, from
renal failure, respiratory failure and pulmonary hypoplasia. Children who
survive the neonatal period have developmental delay and a high, early risk
of Wilms tumor, often bilateral, so renal ultrasound surveillance is
recommended. ClinGen classifies DIS3L2 for Perlman syndrome as Definitive
(autosomal recessive). The germline syndrome is kept separate from the Wilms
tumor it predisposes to, which has its own entry.
disease_term:
preferred_term: Perlman syndrome
term:
id: MONDO:0009965
label: Perlman syndrome
synonyms:
- Nephroblastomatosis-fetal ascites-macrosomia-Wilms tumor syndrome
- Renal hamartomas, nephroblastomatosis and fetal gigantism
- DIS3L2-related Perlman syndrome
parents:
- Overgrowth Syndrome
- Wilms Tumor Predisposition Syndrome
categories:
- Overgrowth Syndrome
- Cancer Predisposition Syndrome
mappings:
mondo_mappings:
- term:
id: MONDO:0009965
label: Perlman syndrome
mapping_predicate: skos:exactMatch
mapping_source: MONDO
mapping_justification: Primary MONDO identifier for the DIS3L2-defined overgrowth syndrome (OMIM 267000, ORPHA:2849).
inheritance:
- name: Autosomal recessive
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
Affected individuals carry homozygous or compound heterozygous DIS3L2
variants. Parental consanguinity is the exception rather than the rule in
the reported sibships, and a homozygous exon 9 deletion in a Japanese
patient arose from two independent LINE-1 recombination events, one on
each parental allele.
evidence:
- reference: PMID:22306653
reference_title: Germline mutations in DIS3L2 cause the Perlman syndrome of overgrowth and Wilms tumor susceptibility.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Perlman syndrome is a congenital overgrowth syndrome inherited in an
autosomal recessive manner that is associated with Wilms tumor
susceptibility.
explanation: Gene-discovery paper states autosomal recessive inheritance.
- reference: PMID:23613427
reference_title: "Perlman syndrome: overgrowth, Wilms tumor predisposition and DIS3L2."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: >-
Recently a Perlman syndrome locus was mapped to chromosome 2q37 and
homozygous or compound heterozygous mutations were characterized in
DIS3L2.
explanation: Review summarizing the biallelic genotypes found in affected individuals.
- reference: PMID:18780370
reference_title: "Perlman syndrome: report, prenatal findings and review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: We review 19 patients from seven sibships with parental consanguinity in two families only.
explanation: Recurrence in sibships fits recessive transmission; consanguinity is uncommon.
- reference: PMID:23486540
reference_title: Homozygous deletion of DIS3L2 exon 9 due to non-allelic homologous recombination between LINE-1s in a Japanese patient with Perlman syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Furthermore, the deletion junctions were different between the paternal
and maternal mutant alleles, suggesting the occurrence of two independent
NAHR events in the ancestors of each parent.
explanation: A homozygous deletion carried on two independently arisen parental alleles.
- reference: CGGV:assertion_e68b93df-e0e7-4d46-8934-8b86064c0b37-2019-11-21T193052.781Z
reference_title: "DIS3L2 / Perlman syndrome (Definitive)"
supports: SUPPORT
evidence_source: OTHER
snippet: "DIS3L2 | HGNC:28648 | Perlman syndrome | MONDO:0009965 | AR | Definitive"
explanation: ClinGen curates the gene-disease pair as autosomal recessive.
pathophysiology:
- name: DIS3L2 Biallelic Loss of Function
description: >-
Biallelic germline DIS3L2 variants (nonsense, frameshift, missense, and an
exon 9 deletion generated by LINE-1 non-allelic homologous recombination)
remove the 3'-5' exoribonuclease activity of DIS3L2. Unlike DIS3 and
DIS3L1, DIS3L2 lacks the PIN domain and has a different intracellular
localization.
biological_scale: MOLECULAR
genes:
- preferred_term: DIS3L2
term:
id: hgnc:28648
label: DIS3L2
genetic_context:
variant_origin: GERMLINE
functional_impact_category: LOSS_OF_FUNCTION
molecular_functions:
- preferred_term: 3'-5' exoribonuclease activity
modifier: DECREASED
term:
id: GO:0000175
label: 3'-5'-RNA exonuclease activity
evidence:
- reference: PMID:22306653
reference_title: Germline mutations in DIS3L2 cause the Perlman syndrome of overgrowth and Wilms tumor susceptibility.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We mapped a previously unknown susceptibility locus to 2q37.1 and
identified germline mutations in DIS3L2, a homolog of the
Schizosaccharomyces pombe dis3 gene, in individuals with Perlman
syndrome.
explanation: Germline DIS3L2 mutations identified in affected individuals.
- reference: PMID:22306653
reference_title: Germline mutations in DIS3L2 cause the Perlman syndrome of overgrowth and Wilms tumor susceptibility.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
DIS3L2 has a different intracellular localization and lacks the PIN
domain found in DIS3 and DIS3L1; nevertheless, we show that DIS3L2 has
exonuclease activity.
explanation: Establishes the enzymatic activity lost in the disease.
- reference: CGGV:assertion_e68b93df-e0e7-4d46-8934-8b86064c0b37-2019-11-21T193052.781Z
reference_title: "DIS3L2 / Perlman syndrome (Definitive)"
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Mutant DIS3L2 proteins lacking either exon 6 or exon 9 did not show
substantial ribonuclease activity and results in aneuploidy and mitotic
errors.
explanation: ClinGen summary of functional evidence that patient deletion alleles abolish ribonuclease activity.
- reference: PMID:23486540
reference_title: Homozygous deletion of DIS3L2 exon 9 due to non-allelic homologous recombination between LINE-1s in a Japanese patient with Perlman syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We identified the deletion junction, and implicate a non-allelic
homologous recombination (NAHR) between two LINE-1 (L1) elements as the
causative mechanism.
explanation: Mechanism of the recurrent exon 9 deletion allele.
downstream:
- target: Failure of DIS3L2-Mediated Decay of Uridylated RNAs
description: Loss of the exoribonuclease removes the decay step for 3'-oligouridylated RNAs.
- target: Increased PI3K/AKT Signaling
description: >-
Shown in DIS3L2-deficient human kidney cells. Which accumulated RNA
substrate links nuclease loss to PI3K/AKT activation is not established.
- target: IGF2 Upregulation in Nephron Progenitor Cells
description: Shown in Dis3l2-null mouse nephron progenitor cells.
- target: Mitotic Abnormalities
description: DIS3L2 inactivation is associated with mitotic abnormalities in cell models.
- name: Failure of DIS3L2-Mediated Decay of Uridylated RNAs
description: >-
DIS3L2 degrades 3'-oligouridylated RNAs after uridylation by terminal
uridylyl transferases. Its substrates include LIN28-directed uridylated
pre-let-7 and a broad set of aberrantly processed, highly structured
noncoding RNAs (7SL, RMRP, rRNA, snRNA, tRNA, Y RNAs). Loss of DIS3L2
stabilizes these substrates. Mature let-7 levels are not changed by DIS3L2
loss, so the disease mechanism is not thought to run through let-7
depletion.
biological_scale: MOLECULAR
genes:
- preferred_term: DIS3L2
term:
id: hgnc:28648
label: DIS3L2
biological_processes:
- preferred_term: cytoplasmic RNA surveillance of uridylated noncoding RNAs
modifier: DECREASED
term:
id: GO:0071025
label: RNA surveillance
- preferred_term: decay of uridylated pre-let-7
modifier: DECREASED
term:
id: GO:0010587
label: miRNA catabolic process
evidence:
- reference: PMID:24141620
reference_title: Mammalian DIS3L2 exoribonuclease targets the uridylated precursors of let-7 miRNAs.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Here, we identify the Perlman syndrome-associated protein DIS3L2 as an
oligo(U)-binding and processing exoribonuclease that specifically
targets uridylated pre-let-7 in vivo.
explanation: DIS3L2 is the nuclease for uridylated pre-let-7.
- reference: PMID:23594738
reference_title: A role for the Perlman syndrome exonuclease Dis3l2 in the Lin28-let-7 pathway.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
knockdown of Dis3l2 in mouse embryonic stem cells leads to the
stabilization of pre-let-7
explanation: Loss of Dis3l2 stabilizes its uridylated substrate in mouse embryonic stem cells.
- reference: PMID:27498873
reference_title: Dis3l2-Mediated Decay Is a Quality Control Pathway for Noncoding RNAs.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
3'-Uridylated Rmrp, 7SL, and small nuclear RNA (snRNA) species were
highly stabilized in the cytoplasm of Dis3l2-depleted cells.
explanation: Dis3l2 depletion stabilizes uridylated structured noncoding RNAs.
- reference: PMID:27647875
reference_title: TUT-DIS3L2 is a mammalian surveillance pathway for aberrant structured non-coding RNAs.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Our findings establish the role of DIS3L2 and oligouridylation as the
cytoplasmic quality control for highly structured ncRNAs.
explanation: Human cell CLIP study defines the DIS3L2-dependent cytoplasmic uridylome.
- reference: PMID:29950491
reference_title: Loss of Dis3l2 partially phenocopies Perlman syndrome in mice and results in up-regulation of Igf2 in nephron progenitor cells.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Here we examine new DIS3L2-deficient cell lines and mouse models,
demonstrating that DIS3L2 loss has no effect on mature let-7 levels.
explanation: >-
Mature let-7 is unchanged, so the decay defect does not act through let-7
depletion. The study used cell lines and mice; it is graded by its mouse
data here.
downstream:
- target: Dysregulated ER-Targeted Translation and ER Calcium Leak
description: Persistent uridylated 7SL RNA disturbs signal recognition particle-dependent translation.
- name: Dysregulated ER-Targeted Translation and ER Calcium Leak
description: >-
The 7SL RNA of the signal recognition particle is a DIS3L2 substrate. In
DIS3L2-deficient cells, persistently uridylated aberrant 7SL disturbs
ER-targeted mRNA translation, ER calcium leaks, calcium signaling response
genes are induced, and embryonic stem cell differentiation is perturbed.
How this contributes to the patient phenotype is not known.
biological_scale: CELLULAR
biological_processes:
- preferred_term: endoplasmic reticulum calcium ion homeostasis
modifier: DYSREGULATED
term:
id: GO:0032469
label: endoplasmic reticulum calcium ion homeostasis
evidence:
- reference: PMID:32457326
reference_title: The Perlman syndrome DIS3L2 exoribonuclease safeguards endoplasmic reticulum-targeted mRNA translation and calcium ion homeostasis.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Upon DIS3L2 loss, sustained 3'-end uridylation of aberrant 7SL RNA
impacts ER-targeted translation and causes ER calcium leakage.
explanation: Cell-based demonstration of the 7SL and ER calcium defect.
- name: Increased PI3K/AKT Signaling
description: >-
Loss of DIS3L2 in human HEK-293T kidney cells increases PI3-kinase/AKT
signaling, and this pathway contributes to the proliferation phenotype of
dis3L2 mutant Drosophila.
biological_scale: CELLULAR
biological_processes:
- preferred_term: PI3K/AKT signaling
modifier: INCREASED
term:
id: GO:0043491
label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
evidence:
- reference: PMID:33370287
reference_title: Dis3L2 regulates cell proliferation and tissue growth through a conserved mechanism.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Using these human cells, we show that loss of DIS3L2 results in an
increase in the PI3-Kinase/AKT signalling pathway
explanation: Increased PI3K/AKT signaling in DIS3L2-deficient human kidney cells.
downstream:
- target: Increased Cell Proliferation and Tissue Overgrowth
description: PI3K/AKT signaling contributes to the proliferation phenotype of dis3L2 loss.
- name: IGF2 Upregulation in Nephron Progenitor Cells
description: >-
Dis3l2-null mouse nephron progenitor cells, a potential cell of origin of
Wilms tumor, up-regulate Igf2, a growth-promoting gene strongly associated
with Wilms tumorigenesis. The authors present this as a candidate
mechanism, not a demonstrated cause of nephroblastomatosis or Wilms tumor
in patients.
biological_scale: CELLULAR
genes:
- preferred_term: IGF2
term:
id: hgnc:5466
label: IGF2
cell_types:
- preferred_term: nephron progenitor cell
term:
id: CL:0000324
label: metanephric mesenchyme stem cell
evidence:
- reference: PMID:29950491
reference_title: Loss of Dis3l2 partially phenocopies Perlman syndrome in mice and results in up-regulation of Igf2 in nephron progenitor cells.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Rather, analysis of Dis3l2-null nephron progenitor cells, a potential
cell of origin of Wilms tumors, reveals up-regulation of Igf2, a
growth-promoting gene strongly associated with Wilms tumorigenesis.
explanation: Igf2 is up-regulated in Dis3l2-null nephron progenitor cells.
downstream:
- target: Nephroblastomatosis
description: >-
Inferred link. The mouse study nominates Igf2 up-regulation in nephron
progenitors as a potential mechanism; it does not show that it causes
nephrogenic rests.
- name: Mitotic Abnormalities
description: >-
DIS3L2 inactivation is associated with mitotic abnormalities and altered
expression of mitotic checkpoint proteins in human cells, and dis3l2
knockdown in zebrafish disrupts early mitoses, spindle length, chromosome
congression and cytokinesis. How this contributes to the patient phenotype
is not established.
biological_scale: CELLULAR
biological_processes:
- preferred_term: mitotic spindle assembly checkpoint signaling
modifier: DYSREGULATED
term:
id: GO:0007094
label: mitotic spindle assembly checkpoint signaling
evidence:
- reference: PMID:22306653
reference_title: Germline mutations in DIS3L2 cause the Perlman syndrome of overgrowth and Wilms tumor susceptibility.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
DIS3L2 inactivation was associated with mitotic abnormalities and altered
expression of mitotic checkpoint proteins.
explanation: Mitotic abnormalities after DIS3L2 inactivation in cell models.
- reference: PMID:40500755
reference_title: Dis3l2 is essential for neural crest survival by modulating Akt signaling.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
we show that dis3l2 is essential for early mitoses in the zebrafish
blastula and plays a key role in maintaining spindle length at metaphase,
chromosome congression, spindle pole integrity, and cytokinesis
explanation: Zebrafish knockdown shows mitotic defects.
- name: Increased Cell Proliferation and Tissue Overgrowth
description: >-
DIS3L2 knockdown enhances the growth of human cancer cell lines and its
overexpression suppresses it; loss of DIS3L2 increases proliferation of
human kidney cells, and null or nuclease-dead dis3L2 causes wing overgrowth
in Drosophila through the growth factor Idgf2. This loss of growth
restraint is the proposed basis of fetal overgrowth and organomegaly.
biological_scale: TISSUE
biological_processes:
- preferred_term: cell proliferation
modifier: INCREASED
term:
id: GO:0008284
label: positive regulation of cell population proliferation
evidence:
- reference: PMID:22306653
reference_title: Germline mutations in DIS3L2 cause the Perlman syndrome of overgrowth and Wilms tumor susceptibility.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
DIS3L2 overexpression suppressed the growth of human cancer cell lines,
and knockdown enhanced the growth of these cells.
explanation: DIS3L2 restrains cell growth in human cell lines.
- reference: PMID:33370287
reference_title: Dis3L2 regulates cell proliferation and tissue growth through a conserved mechanism.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
we have generated a new dis3L2 null mutant together with wild-type and
nuclease-dead genetic lines in Drosophila to demonstrate that the
catalytic activity of Dis3L2 is required to control cell proliferation
explanation: Catalytic activity of Dis3L2 is required to restrain proliferation in Drosophila.
- reference: PMID:33370287
reference_title: Dis3L2 regulates cell proliferation and tissue growth through a conserved mechanism.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
We also demonstrate that loss of DIS3L2 in human kidney HEK-293T cells
results in cell proliferation, illustrating the conservation of this
important cell proliferation pathway.
explanation: Increased proliferation of DIS3L2-deficient human kidney cells.
downstream:
- target: Large for gestational age
description: Loss of growth restraint is the proposed basis of fetal overgrowth.
- target: Enlarged kidney
description: Inferred; nephromegaly is part of the organ overgrowth.
- target: Visceromegaly
description: Inferred; visceromegaly is part of the organ overgrowth.
- target: Nephroblastomatosis
description: Inferred; persistent proliferating nephrogenic blastema in an overgrowth background.
phenotypes:
- name: Polyhydramnios
category: Prenatal
frequency: FREQUENT
description: Excess amniotic fluid, usually the first prenatal sign.
phenotype_term:
preferred_term: Polyhydramnios
term:
id: HP:0001561
label: Polyhydramnios
onset:
onset_category: FETAL
evidence:
- reference: PMID:18780370
reference_title: "Perlman syndrome: report, prenatal findings and review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Fetal macrosomia, ascites and polyhydramnios are frequent manifestations.
explanation: Review of 28 reported patients names polyhydramnios as frequent.
- name: Fetal ascites
category: Prenatal
frequency: FREQUENT
description: >-
Fetal ascites helps separate Perlman syndrome from Beckwith-Wiedemann and
Simpson-Golabi-Behmel syndromes.
phenotype_term:
preferred_term: Fetal ascites
term:
id: HP:0001791
label: Fetal ascites
onset:
onset_category: FETAL
evidence:
- reference: PMID:18780370
reference_title: "Perlman syndrome: report, prenatal findings and review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Fetal macrosomia, ascites and polyhydramnios are frequent manifestations.
explanation: Fetal ascites is frequent in the reviewed patients.
- name: Large for gestational age
category: Growth
description: Fetal and neonatal macrosomia; overgrowth is both pre- and postnatal.
phenotype_term:
preferred_term: Fetal macrosomia
term:
id: HP:0001520
label: Large for gestational age
onset:
onset_category: FETAL
evidence:
- reference: PMID:18780370
reference_title: "Perlman syndrome: report, prenatal findings and review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Perlman syndrome is a rare overgrowth syndrome characterized by
polyhydramnios with neonatal macrosomia, nephromegaly, distinctive facial
appearance, renal dysplasia, nephro-blastomatosis, and predisposition to
Wilms tumor (WT).
explanation: Neonatal macrosomia is a defining feature.
- reference: ORPHA:2849
reference_title: Perlman syndrome
supports: SUPPORT
evidence_source: OTHER
snippet: >-
A rare overgrowth syndrome characterized by polyhydramnios, pre- and
postnatal macrosomia, muscular hypotonia, renal anomalies, organomegaly
explanation: Orphanet definition records pre- and postnatal macrosomia.
- name: Enlarged kidney
category: Renal
description: Bilateral nephromegaly, visible prenatally.
phenotype_term:
preferred_term: Nephromegaly
term:
id: HP:0000105
label: Enlarged kidney
onset:
onset_category: FETAL
evidence:
- reference: PMID:18780370
reference_title: "Perlman syndrome: report, prenatal findings and review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We report on a newborn with prenatal sonographic signs of Perlman
syndrome, large fetal ascites, nephromegaly and macrosomia.
explanation: Prenatal nephromegaly in the index case.
- name: Renal dysplasia
category: Renal
phenotype_term:
preferred_term: Renal dysplasia
term:
id: HP:0000110
label: Renal dysplasia
onset:
onset_category: CONGENITAL
evidence:
- reference: PMID:23613427
reference_title: "Perlman syndrome: overgrowth, Wilms tumor predisposition and DIS3L2."
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: >-
Perlman syndrome is a rare autosomal recessively inherited congenital
overgrowth syndrome characterized by polyhydramnios, macrosomia,
characteristic facial dysmorphology, renal dysplasia and
nephroblastomatosis and multiple congenital anomalies.
explanation: Review lists renal dysplasia among the defining features.
- name: Nephroblastomatosis
category: Renal
description: >-
Diffuse nephrogenic rests, the precursor lesion of Wilms tumor, reported in
about three quarters of examined kidneys.
frequency: FREQUENT
phenotype_term:
preferred_term: Nephroblastomatosis
term:
id: HP:0008643
label: Nephroblastomatosis
onset:
onset_category: CONGENITAL
sequelae:
- target: Nephroblastoma
description: Nephrogenic rests are the precursor lesion from which Wilms tumor arises.
evidence:
- reference: PMID:28674120
reference_title: Surveillance Recommendations for Children with Overgrowth Syndromes and Predisposition to Wilms Tumors and Hepatoblastoma.
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: The kidneys show nephroblastomatosis in about 75% of cases
explanation: AACR consensus summary of renal histology in Perlman syndrome.
- reference: PMID:18780370
reference_title: "Perlman syndrome: report, prenatal findings and review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Renal histologic examination showed bilateral nephroblastomatosis.
explanation: Bilateral nephroblastomatosis in the index case.
- name: Nephroblastoma
category: Neoplasm
description: >-
Wilms tumor develops in most children who survive the neonatal period,
earlier than sporadic Wilms tumor and frequently bilateral. Recorded here as
a phenotype of the germline syndrome; somatic Wilms tumor is a separate
entry.
frequency: FREQUENT
phenotype_term:
preferred_term: Wilms tumor
term:
id: HP:0002667
label: Nephroblastoma
onset:
onset_category: INFANTILE
evidence:
- reference: PMID:18780370
reference_title: "Perlman syndrome: report, prenatal findings and review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Among the infants who survived beyond the neonatal period, 64% developed
a WT and all had a developmental delay.
explanation: Wilms tumor frequency among neonatal survivors in a 28-patient review.
- reference: PMID:28674120
reference_title: Surveillance Recommendations for Children with Overgrowth Syndromes and Predisposition to Wilms Tumors and Hepatoblastoma.
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: >-
On average, WT occurs at an early age (<2 years compared to 3–4 years in
sporadic WT) and bilateral WT are common (55%)
explanation: Early onset and frequent bilaterality.
- reference: PMID:40704758
reference_title: "Three Siblings With an Attenuated Presentation of Perlman Syndrome: A Case Report and Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The proband had early speech delay and was diagnosed with Wilms tumor at 3 years old.
explanation: Wilms tumor in a molecularly confirmed survivor.
- name: Visceromegaly
category: Abdominal
phenotype_term:
preferred_term: Visceromegaly
term:
id: HP:0003271
label: Visceromegaly
onset:
onset_category: CONGENITAL
evidence:
- reference: PMID:20726997
reference_title: "Rare clinical entity Perlman syndrome: is cholestasis a new finding?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: >-
Perlman syndrome is a rare syndrome characterized by polyhydramnios,
fetal overgrowth, facial dysmorphism, visceromegaly, nephroblastomatosis
and predisposition to Wilms tumor.
explanation: Visceromegaly listed among the characteristic features.
- name: Hepatomegaly
category: Abdominal
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Hepatomegaly
term:
id: HP:0002240
label: Hepatomegaly
evidence:
- reference: ORPHA:2849
reference_title: Perlman syndrome
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0002240 | Hepatomegaly | Very frequent (99-80%)"
explanation: Orphanet annotates hepatomegaly as very frequent.
- name: Deeply set eye
category: Craniofacial
frequency: VERY_FREQUENT
description: >-
Part of the characteristic facies, described as broad depressed nasal
bridge, everted V-shaped upper lip, low-set ears, deep-set eyes and
prominent forehead.
phenotype_term:
preferred_term: Deep-set eyes
term:
id: HP:0000490
label: Deeply set eye
evidence:
- reference: ORPHA:2849
reference_title: Perlman syndrome
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0000490 | Deeply set eye | Very frequent (99-80%)"
explanation: Orphanet frequency annotation.
- reference: PMID:28674120
reference_title: Surveillance Recommendations for Children with Overgrowth Syndromes and Predisposition to Wilms Tumors and Hepatoblastoma.
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: >-
characteristic facial dysmorphology (broad depressed nasal bridge,
everted V-shape upper lip, low set ears, deep set eyes, and prominent
forehead)
explanation: Consensus description of the facies.
- name: Wide nasal bridge
category: Craniofacial
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Broad depressed nasal bridge
term:
id: HP:0000431
label: Wide nasal bridge
evidence:
- reference: ORPHA:2849
reference_title: Perlman syndrome
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0000431 | Wide nasal bridge | Very frequent (99-80%)"
explanation: Orphanet frequency annotation.
- name: Low-set ears
category: Craniofacial
frequency: FREQUENT
phenotype_term:
preferred_term: Low-set ears
term:
id: HP:0000369
label: Low-set ears
evidence:
- reference: ORPHA:2849
reference_title: Perlman syndrome
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0000369 | Low-set ears | Frequent (79-30%)"
explanation: Orphanet frequency annotation.
- name: High forehead
category: Craniofacial
frequency: VERY_FREQUENT
description: Described as a prominent forehead in the AACR consensus; Orphanet annotates it as high forehead.
phenotype_term:
preferred_term: High forehead
term:
id: HP:0000348
label: High forehead
evidence:
- reference: ORPHA:2849
reference_title: Perlman syndrome
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0000348 | High forehead | Very frequent (99-80%)"
explanation: Orphanet frequency annotation.
- name: Macrocephaly
category: Craniofacial
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Macrocephaly
term:
id: HP:0000256
label: Macrocephaly
evidence:
- reference: ORPHA:2849
reference_title: Perlman syndrome
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0000256 | Macrocephaly | Very frequent (99-80%)"
explanation: Orphanet frequency annotation.
- name: Facial hypotonia
category: Neurological
phenotype_term:
preferred_term: Facial hypotonia
term:
id: HP:0000297
label: Facial hypotonia
onset:
onset_category: NEONATAL
evidence:
- reference: PMID:40704758
reference_title: "Three Siblings With an Attenuated Presentation of Perlman Syndrome: A Case Report and Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Three siblings presented at birth with fetal macrosomia, dysmorphic
facial features, and facial hypotonia.
explanation: Facial hypotonia at birth in three molecularly confirmed siblings.
- name: Hypotonia
category: Neurological
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Muscular hypotonia
term:
id: HP:0001252
label: Hypotonia
onset:
onset_category: NEONATAL
evidence:
- reference: ORPHA:2849
reference_title: Perlman syndrome
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0001252 | Hypotonia | Very frequent (99-80%)"
explanation: Orphanet frequency annotation.
- name: Global developmental delay
category: Neurological
description: Developmental delay is reported in all children who survived the neonatal period in the 2008 review.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Developmental delay
term:
id: HP:0001263
label: Global developmental delay
onset:
onset_category: INFANTILE
evidence:
- reference: PMID:18780370
reference_title: "Perlman syndrome: report, prenatal findings and review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Among the infants who survived beyond the neonatal period, 64% developed
a WT and all had a developmental delay.
explanation: All neonatal survivors in the review had developmental delay.
- reference: PMID:40704758
reference_title: "Three Siblings With an Attenuated Presentation of Perlman Syndrome: A Case Report and Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Her brothers both had developmental delay presenting within the first year of life.
explanation: Developmental delay in the first year in molecularly confirmed siblings.
- name: Renal insufficiency
category: Renal
description: >-
Neonatal renal failure is one of the main causes of the high neonatal
mortality; about half of affected children die in the neonatal period.
phenotype_term:
preferred_term: Neonatal renal failure
term:
id: HP:0000083
label: Renal insufficiency
onset:
onset_category: NEONATAL
evidence:
- reference: PMID:18780370
reference_title: "Perlman syndrome: report, prenatal findings and review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The clinical course was marked by neonatal distress, renal failure and
refractory hypoxemia leading to death at 2 days of life.
explanation: Neonatal renal failure in the index case.
- reference: PMID:28674120
reference_title: Surveillance Recommendations for Children with Overgrowth Syndromes and Predisposition to Wilms Tumors and Hepatoblastoma.
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: >-
Fifty-three percent of children with Perlman syndrome die in the neonatal
period, from a variety of causes including renal failure, hypoxia and
pulmonary hypoplasia
explanation: Renal failure is among the causes of neonatal death, which affects about half of children.
- name: Respiratory failure
category: Respiratory
phenotype_term:
preferred_term: Neonatal respiratory failure
term:
id: HP:0002878
label: Respiratory failure
onset:
onset_category: NEONATAL
evidence:
- reference: PMID:40704758
reference_title: "Three Siblings With an Attenuated Presentation of Perlman Syndrome: A Case Report and Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: >-
The majority of patients die in infancy due to respiratory and/or renal
failure, limiting the reports of patients surviving into childhood.
explanation: Respiratory and renal failure as the usual causes of death.
- name: Pulmonary hypoplasia
category: Respiratory
phenotype_term:
preferred_term: Pulmonary hypoplasia
term:
id: HP:0002089
label: Pulmonary hypoplasia
onset:
onset_category: CONGENITAL
sequelae:
- target: Respiratory failure
description: Inferred; hypoplastic lungs limit neonatal gas exchange.
evidence:
- reference: PMID:28674120
reference_title: Surveillance Recommendations for Children with Overgrowth Syndromes and Predisposition to Wilms Tumors and Hepatoblastoma.
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: >-
Fifty-three percent of children with Perlman syndrome die in the neonatal
period, from a variety of causes including renal failure, hypoxia and
pulmonary hypoplasia
explanation: Pulmonary hypoplasia named among causes of neonatal death.
- name: Cryptorchidism
category: Genitourinary
frequency: FREQUENT
phenotype_term:
preferred_term: Cryptorchidism
term:
id: HP:0000028
label: Cryptorchidism
evidence:
- reference: ORPHA:2849
reference_title: Perlman syndrome
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0000028 | Cryptorchidism | Frequent (79-30%)"
explanation: Orphanet frequency annotation.
- name: Hyperinsulinemia
category: Metabolic
frequency: FREQUENT
phenotype_term:
preferred_term: Hyperinsulinemia
term:
id: HP:0000842
label: Hyperinsulinemia
evidence:
- reference: ORPHA:2849
reference_title: Perlman syndrome
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0000842 | Hyperinsulinemia | Frequent (79-30%)"
explanation: Orphanet frequency annotation; no primary report was reviewed for this feature.
- name: Cholestasis
category: Hepatic
description: Reported in a single neonate; the authors raise it as a possible new feature.
frequency: VERY_RARE
phenotype_term:
preferred_term: Neonatal cholestasis
term:
id: HP:0001396
label: Cholestasis
onset:
onset_category: NEONATAL
evidence:
- reference: PMID:20726997
reference_title: "Rare clinical entity Perlman syndrome: is cholestasis a new finding?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: This is the first case in which cholestasis has been observed.
explanation: Single case report of cholestasis; molecular confirmation is not stated in the abstract.
- name: Intellectual disability
category: Neurological
description: >-
Orphanet annotates intellectual disability as very frequent. Most affected infants die in the neonatal period, so this frequency describes the minority who survive infancy; the annotation does not give the denominator.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Intellectual disability
term:
id: HP:0001249
label: Intellectual disability
evidence:
- reference: ORPHA:2849
reference_title: Perlman syndrome
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0001249 | Intellectual disability | Very frequent (99-80%)"
explanation: Orphanet frequency annotation.
- name: Abnormal upper lip morphology
category: Craniofacial
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Abnormal upper lip morphology
term:
id: HP:0000177
label: Abnormal upper lip morphology
evidence:
- reference: ORPHA:2849
reference_title: Perlman syndrome
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0000177 | Abnormality of upper lip | Very frequent (99-80%)"
explanation: Orphanet frequency annotation.
- name: Micrognathia
category: Craniofacial
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Micrognathia
term:
id: HP:0000347
label: Micrognathia
evidence:
- reference: ORPHA:2849
reference_title: Perlman syndrome
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0000347 | Micrognathia | Very frequent (99-80%)"
explanation: Orphanet frequency annotation.
- name: Retrognathia
category: Craniofacial
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Retrognathia
term:
id: HP:0000278
label: Retrognathia
evidence:
- reference: ORPHA:2849
reference_title: Perlman syndrome
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0000278 | Retrognathia | Very frequent (99-80%)"
explanation: Orphanet frequency annotation.
- name: Short nose
category: Craniofacial
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Short nose
term:
id: HP:0003196
label: Short nose
evidence:
- reference: ORPHA:2849
reference_title: Perlman syndrome
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0003196 | Short nose | Very frequent (99-80%)"
explanation: Orphanet frequency annotation.
- name: Round face
category: Craniofacial
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Round face
term:
id: HP:0000311
label: Round face
evidence:
- reference: ORPHA:2849
reference_title: Perlman syndrome
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0000311 | Round face | Very frequent (99-80%)"
explanation: Orphanet frequency annotation.
- name: Smooth philtrum
category: Craniofacial
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Smooth philtrum
term:
id: HP:0000319
label: Smooth philtrum
evidence:
- reference: ORPHA:2849
reference_title: Perlman syndrome
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0000319 | Smooth philtrum | Very frequent (99-80%)"
explanation: Orphanet frequency annotation.
- name: Open mouth
category: Craniofacial
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Open mouth
term:
id: HP:0000194
label: Open mouth
evidence:
- reference: ORPHA:2849
reference_title: Perlman syndrome
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0000194 | Open mouth | Very frequent (99-80%)"
explanation: Orphanet frequency annotation.
- name: Tall stature
category: Growth
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Tall stature
term:
id: HP:0000098
label: Tall stature
evidence:
- reference: ORPHA:2849
reference_title: Perlman syndrome
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0000098 | Tall stature | Very frequent (99-80%)"
explanation: Orphanet frequency annotation.
- name: Abnormal pancreas morphology
category: Gastrointestinal
description: >-
Orphanet annotates abnormal pancreas morphology as frequent without naming the lesion. No source reviewed here links it to the hyperinsulinemia row, so no edge is drawn.
frequency: FREQUENT
phenotype_term:
preferred_term: Abnormal pancreas morphology
term:
id: HP:0012090
label: Abnormal pancreas morphology
evidence:
- reference: ORPHA:2849
reference_title: Perlman syndrome
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0012090 | Abnormal pancreas morphology | Frequent (79-30%)"
explanation: Orphanet frequency annotation.
- name: Hypoplasia of penis
category: Genitourinary
frequency: FREQUENT
phenotype_term:
preferred_term: Hypoplasia of penis
term:
id: HP:0008736
label: Hypoplasia of penis
evidence:
- reference: ORPHA:2849
reference_title: Perlman syndrome
supports: SUPPORT
evidence_source: OTHER
snippet: "HP:0008736 | Hypoplasia of penis | Frequent (79-30%)"
explanation: Orphanet frequency annotation.
genetic:
- name: DIS3L2
gene_term:
preferred_term: DIS3L2
term:
id: hgnc:28648
label: DIS3L2
association: Defining gene; biallelic loss-of-function variants
relationship_type: CAUSATIVE
variant_origin: GERMLINE
gene_disease_validity:
- validity_classification: DEFINITIVE
classified_by: CLINGEN
external_id: CGGV:assertion_e68b93df-e0e7-4d46-8934-8b86064c0b37-2019-11-21T193052.781Z
evidence:
- reference: CGGV:assertion_e68b93df-e0e7-4d46-8934-8b86064c0b37-2019-11-21T193052.781Z
reference_title: "DIS3L2 / Perlman syndrome (Definitive)"
supports: SUPPORT
evidence_source: OTHER
snippet: "DIS3L2 | HGNC:28648 | Perlman syndrome | MONDO:0009965 | AR | Definitive"
explanation: ClinGen Hereditary Cancer GCEP classifies DIS3L2 and Perlman syndrome as Definitive (AR).
notes: >-
Somatic DIS3L2 mutations also occur in sporadic Wilms tumor. A child with
Wilms tumor carrying one familial germline DIS3L2 variant and a somatic
DIS3L2 mutation in the tumor (PMID:35700413) is a monoallelic carrier with
a two-hit tumor, not a case of Perlman syndrome, and is not counted here.
variants:
- name: DIS3L2 exon 9 deletion
description: >-
Recurrent deletion of exon 9 arising by LINE-1-mediated non-allelic
homologous recombination. Homozygous exon 9 deletion has been associated
with poor survival, though one child has lived past age 2.
evidence:
- reference: PMID:23486540
reference_title: Homozygous deletion of DIS3L2 exon 9 due to non-allelic homologous recombination between LINE-1s in a Japanese patient with Perlman syndrome.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The data suggest that the region around exon 9 might be a hot spot of
L1-mediated NAHR.
explanation: Exon 9 is a recurrent deletion hotspot.
- reference: PMID:42040973
reference_title: "Prolonged Survival With Homozygous Deletion of Exon 9 in Perlman Syndrome: A Case Report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Although homozygous deletions of exon 9 are rare and have been
associated with poor survival, we describe a case report of the only
known patient with Perlman syndrome to live past 2 years old with this
deletion.
explanation: Survival associated with the exon 9 deletion.
- name: DIS3L2 c.127C>T (p.Arg43Ter) / c.2381G>A (p.Arg794His)
description: >-
Compound heterozygous genotype in three siblings with an attenuated
presentation surviving into childhood.
evidence:
- reference: PMID:40704758
reference_title: "Three Siblings With an Attenuated Presentation of Perlman Syndrome: A Case Report and Literature Review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Genetic testing identified compound heterozygous variants in DIS3L2
(NM_152383.5): c.127C>T (p.Arg43Ter) (paternal)/c.2381G>A (p.Arg794His)
(maternal).
explanation: Biallelic genotype in an attenuated sibship.
evidence:
- reference: PMID:22306653
reference_title: Germline mutations in DIS3L2 cause the Perlman syndrome of overgrowth and Wilms tumor susceptibility.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We mapped a previously unknown susceptibility locus to 2q37.1 and
identified germline mutations in DIS3L2, a homolog of the
Schizosaccharomyces pombe dis3 gene, in individuals with Perlman
syndrome.
explanation: Gene discovery.
- reference: ORPHA:2849
reference_title: Perlman syndrome
supports: SUPPORT
evidence_source: OTHER
snippet: "DIS3L2 | DIS3 like 3'-5' exoribonuclease 2 | hgnc:28648 | Disease-causing germline mutation(s) in"
explanation: Orphanet records DIS3L2 as the disease-causing gene.
animal_models:
- name: Dis3l2-null mouse
species: Mouse
genotype: Dis3l2 knockout, homozygous
publication: PMID:29950491
description: >-
Dis3l2-null mice partially phenocopy Perlman syndrome and show Igf2
up-regulation in nephron progenitor cells.
modeled_mechanisms:
- target: IGF2 Upregulation in Nephron Progenitor Cells
relationship: RECAPITULATES
fidelity: UNKNOWN
model_scale: CELLULAR
limitations: >-
The abstract states only a partial phenocopy; which human features the
mice show, and whether they develop nephroblastomatosis or Wilms tumor,
was not checked against the full text here.
evidence:
- reference: PMID:29950491
reference_title: Loss of Dis3l2 partially phenocopies Perlman syndrome in mice and results in up-regulation of Igf2 in nephron progenitor cells.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Rather, analysis of Dis3l2-null nephron progenitor cells, a potential
cell of origin of Wilms tumors, reveals up-regulation of Igf2, a
growth-promoting gene strongly associated with Wilms tumorigenesis.
explanation: Igf2 up-regulation in the null mouse's nephron progenitors.
- name: Drosophila dis3L2 null and nuclease-dead
species: Fruit fly
genotype: dis3L2 null; nuclease-dead dis3L2
publication: PMID:33370287
description: >-
Loss of Dis3L2 catalytic activity causes wing imaginal disc overgrowth
driven by Idgf2, a homolog of human chitinase-like proteins.
modeled_mechanisms:
- target: Increased Cell Proliferation and Tissue Overgrowth
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: TISSUE
limitations: >-
Invertebrate wing-disc overgrowth; there is no kidney or nephrogenic
tissue, so it cannot model nephroblastomatosis or Wilms tumor.
evidence:
- reference: PMID:33370287
reference_title: Dis3L2 regulates cell proliferation and tissue growth through a conserved mechanism.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
we used RNA-seq on dis3L2 mutant wing discs to show that the imaginal
disc growth factor Idgf2 is responsible for driving the wing overgrowth
explanation: Overgrowth in the fly model and its effector.
diagnosis:
- name: DIS3L2 molecular testing
description: >-
Diagnosis is confirmed by biallelic pathogenic DIS3L2 variants, for
example by exome sequencing with Sanger confirmation. Exon-level deletions
are a recurrent allele class, so copy-number analysis is needed alongside
sequencing.
diagnosis_term:
preferred_term: DIS3L2 genetic testing
term:
id: NCIT:C15709
label: Genetic Testing
evidence:
- reference: PMID:28674120
reference_title: Surveillance Recommendations for Children with Overgrowth Syndromes and Predisposition to Wilms Tumors and Hepatoblastoma.
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: >-
a molecular diagnosis of Perlman syndrome can be made by the presence of
inactivating mutations in DIS3L2 on chromosome 2q37.1
explanation: Molecular confirmation rests on DIS3L2.
- reference: PMID:34964966
reference_title: "[Clinical features and genetic analysis of a case with Perlman syndrome due to variant of DIS3L2 gene]."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The results of WES showed that the proband has harbored compound
heterozygous variants of the DIS3L2 gene
explanation: Exome sequencing identified the biallelic genotype.
- name: Prenatal ultrasound
description: >-
Polyhydramnios, macrosomia, fetal ascites and nephromegaly on prenatal
ultrasound raise the diagnosis, which is then confirmed molecularly.
diagnosis_term:
preferred_term: prenatal ultrasound
term:
id: NCIT:C222238
label: Fetal Ultrasound Imaging
evidence:
- reference: PMID:38161545
reference_title: DIS3L2 Gene Mutation Causes the Perlman Syndrome of Overgrowth and Wilms Tumor Susceptibility.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Here, we present a case with the classic clinical features of Perlman
syndrome and a DIS3L2 gene deletion that was discovered prenatally.
explanation: Prenatal detection of a DIS3L2 deletion case.
- reference: PMID:18780370
reference_title: "Perlman syndrome: report, prenatal findings and review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We report on a newborn with prenatal sonographic signs of Perlman
syndrome, large fetal ascites, nephromegaly and macrosomia.
explanation: Prenatal sonographic signs.
differential_diagnoses:
- name: Beckwith-Wiedemann syndrome
disease_term:
preferred_term: Beckwith-Wiedemann syndrome
term:
id: MONDO:0007534
label: Beckwith-Wiedemann syndrome
distinguishing_features:
- Fetal ascites and the characteristic facies without macroglossia or anterior abdominal wall defects favor Perlman syndrome.
- 11p15 genetic or epigenetic alterations, including CDKN1C mutation, support Beckwith-Wiedemann syndrome; they were excluded in the 2008 Perlman index case.
evidence:
- reference: PMID:28674120
reference_title: Surveillance Recommendations for Children with Overgrowth Syndromes and Predisposition to Wilms Tumors and Hepatoblastoma.
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: >-
Perlman syndrome may be differentiated from other congenital overgrowth
disorders such as BWS and Simpson-Golabi-Behmel syndrome (SGBS) by the
presence of features including fetal ascites and characteristic facial
dysmorphism in the absence of macroglossia, anterior abdominal wall
defects, polydactyly, and other features.
explanation: Clinical features separating Perlman from BWS and SGBS.
- reference: PMID:18780370
reference_title: "Perlman syndrome: report, prenatal findings and review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Genetic or epigenetic alterations of the 11p15 region (involved in the
BWS), including mutation of the CDKN1C gene were excluded.
explanation: BWS molecular causes excluded in the index case.
- name: Simpson-Golabi-Behmel syndrome type 1
disease_term:
preferred_term: Simpson-Golabi-Behmel syndrome
term:
id: MONDO:0020602
label: Simpson-Golabi-Behmel syndrome type 1
distinguishing_features:
- Polydactyly favors SGBS; a GPC3 mutation was excluded in the 2008 Perlman index case.
evidence:
- reference: PMID:18780370
reference_title: "Perlman syndrome: report, prenatal findings and review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: No mutation of the GPC3 gene was identified.
explanation: GPC3 testing excludes SGBS type 1 in the index case.
treatments:
- name: Renal Ultrasound Surveillance
description: >-
Children with Perlman syndrome are offered Wilms tumor surveillance like
that for Beckwith-Wiedemann syndrome. The AACR 2017 consensus schedule for
syndromes with Wilms tumor risk is renal ultrasound every 3 months from
birth or diagnosis to the seventh birthday.
therapeutic_modality: OTHER
treatment_term:
preferred_term: renal ultrasound surveillance
term:
id: NCIT:C159885
label: Renal Ultrasound
target_mechanisms:
- target: Nephroblastoma
description: Early detection of Wilms tumor, which is often bilateral.
evidence:
- reference: PMID:28674120
reference_title: Surveillance Recommendations for Children with Overgrowth Syndromes and Predisposition to Wilms Tumors and Hepatoblastoma.
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: >-
it has been suggested that children affected with Perlman syndrome should
be offered regular surveillance similar to that for children with BWS
explanation: Consensus statement applying surveillance to Perlman syndrome.
- reference: PMID:28674120
reference_title: Surveillance Recommendations for Children with Overgrowth Syndromes and Predisposition to Wilms Tumors and Hepatoblastoma.
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
snippet: >-
For WT, starting at birth (or the time of diagnosis of the specific
syndrome) we recommend renal ultrasound screening including the adrenal
glands, every 3 months through the child’s seventh birthday.
explanation: The recommended surveillance schedule.
- name: Neonatal Supportive Care
description: >-
No disease-specific therapy exists. Care is supportive, beginning with the
critically ill neonate, followed by developmental support and tumor
surveillance in survivors.
therapeutic_modality: OTHER
treatment_term:
preferred_term: supportive care
term:
id: NCIT:C15747
label: Supportive Care
evidence:
- reference: PMID:42040973
reference_title: "Prolonged Survival With Homozygous Deletion of Exon 9 in Perlman Syndrome: A Case Report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Diligent management and surveillance may be associated with prolonged survival in Perlman syndrome.
explanation: Single case report suggesting careful management and surveillance aid survival.
notes: >-
No GeneReviews chapter covers Perlman syndrome or DIS3L2: PubMed
"Perlman syndrome"[TI] AND genereviews[book] and DIS3L2[TIAB] AND
genereviews[book] both returned no records. Orphanet ORPHA:2849 and the AACR
2017 consensus (PMID:28674120) serve as the phenotype baseline. Clinical data
come from fewer than about 40 reported patients, so frequencies are
approximate. Mechanism nodes below the nuclease defect come from cell, mouse,
fly and zebrafish models; the step linking accumulated uridylated RNAs to
PI3K/AKT activation or Igf2 up-regulation is not established.
datasets: []
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Create: Perlman Syndrome · 2026-11-06T20:22:32Z · View source
New entry for Perlman syndrome (MONDO:0009965, DIS3L2). Deep research: one OpenScientist report (research/Perlman_Syndrome-deep-research-openscientist.md; 27/27 references resolved, needs_review set by term mislabels), used as leads only. Every claim was re-checked against the cached abstract or full text; snippets are exact quotes. Phenotype baseline: Orphanet ORPHA:2849 and the AACR 2017 Wilms tumor surveillance consensus (PMID:28674120); no GeneReviews chapter exists (PubMed genereviews[book] searches on the disease name and DIS3L2 returned none). ClinGen DIS3L2 Definitive (AR) recorded from the CGGV record. Corrections to the report: PMID:23486540 is Higashimoto et al., not Igarashi; PMID:35700413 describes a monoallelic germline carrier with a somatic second hit, which is not Perlman syndrome, so the report's two-hit model for Perlman Wilms tumor was not carried over; HP:0001708 suggested for nephroblastomatosis is Right ventricular failure, so HP:0008643 was bound instead. Neonatal death (HP:0003811) is outside the PhenotypeTerm enum, so mortality is recorded in descriptions and evidence on the renal and respiratory failure phenotypes. Validated with just validate (schema, terms, 71 snippets) and the offline whole-repo gates.
Disease: Perlman Syndrome MONDO ID: MONDO:0009965 | OMIM: 267000 | Orphanet: ORPHA:2849 Causal gene: DIS3L2 (DIS3-like 3′→5′ exoribonuclease 2; HGNC:28648; chromosome 2q37.1) Inheritance: Autosomal recessive Category: Mendelian
Perlman syndrome is a rare, autosomal recessive congenital overgrowth and Wilms tumor predisposition syndrome caused by biallelic loss-of-function variants in the DIS3L2 gene on chromosome 2q37.1. DIS3L2 encodes a cytoplasmic 3′→5′ exoribonuclease of the RNase II/RNB (DIS3) family that specifically recognizes and degrades 3′-oligouridylated RNAs — most famously the uridylated precursors of the let-7 tumor-suppressor microRNA family, but also a broad spectrum of aberrant, highly structured non-coding RNAs. Loss of this RNA-surveillance activity is the initiating molecular lesion of the disease. The causal gene was identified by Astuti et al. in 2012, who mapped the locus to 2q37.1 and demonstrated germline DIS3L2 mutations in affected individuals, along with somatic DIS3L2 mutations in sporadic Wilms tumor [PMID: 22306653].
Clinically, Perlman syndrome presents prenatally and neonatally with polyhydramnios, fetal macrosomia, a distinctive facial dysmorphism, nephromegaly, renal dysplasia with nephroblastomatosis, visceromegaly, facial hypotonia, and multiple congenital anomalies. The prognosis is poor: most affected neonates die in infancy from respiratory and/or renal failure. Among the minority who survive the neonatal period, approximately 64% develop Wilms tumor and essentially all have developmental delay [PMID: 18780370]. Because of this high renal cancer risk, Perlman syndrome is formally classified among the Wilms tumor predisposition syndromes, and affected survivors warrant intensive abdominal/renal ultrasound surveillance (typically every ~3 months) per AACR and SIOP-Europe consensus guidelines [PMID: 39466169; PMID: 34134020].
Mechanistically, the disease is best understood as a failure of cytoplasmic RNA quality control. Biallelic DIS3L2 loss removes oligo(U)-exoribonuclease activity, causing uridylated substrates (pre-let-7 and structured ncRNAs including 7SL/SRP RNA, RMRP, rRNA, tRNA, and snRNA) to accumulate. Downstream, proliferation is derepressed through activation of the PI3K/AKT signaling pathway (and AKT–GSK3β signaling), growth-factor dysregulation, and mitotic/spindle abnormalities — a cascade conserved from Drosophila to zebrafish to human cells [PMID: 33370287; PMID: 40500755; PMID: 22306653]. Notably, mature let-7 levels are unchanged in DIS3L2-deficient cells and mice, indicating that the tumor-suppressive mechanism is largely let-7-independent [PMID: 29950491]. This report integrates nine confirmed findings across the 15 requested domains and flags where evidence is scarce.
Perlman syndrome results from homozygous or compound heterozygous mutations in DIS3L2 (chromosome 2q37.1; OMIM 267000; MONDO:0009965). The DIS3L2 gene product is a ribonuclease with homology to the DIS3 component of the RNA exosome. As stated in the Morris et al. review: "Recently a Perlman syndrome locus was mapped to chromosome 2q37 and homozygous or compound heterozygous mutations were characterized in DIS3L2. The DIS3L2 gene product has ribonuclease activity and homology to the DIS3 component of the RNA exosome" [PMID: 23613427].
The reported mutational spectrum includes nonsense (c.127C>T, p.Arg43Ter), missense (c.2381G>A, p.Arg794His), and frameshift variants (c.2109delC; c.1829_1830insC), as well as a recurrent homozygous deletion of exon 9 generated by non-allelic homologous recombination (NAHR) between LINE-1 elements. Igarashi et al. documented this structural variant: "We report the homozygous deletion of exon 9 of DIS3L2 in a Japanese patient with Perlman syndrome. We identified the deletion junction, and implicate a non-allelic homologous recombination (NAHR) between two LINE-1 (L1) elements as the causative mechanism" [PMID: 23486540]. This has direct diagnostic importance: large exon-level deletions can be missed by standard sequencing, so copy-number-sensitive methods are required to avoid false-negative molecular diagnoses. A compound-heterozygous example (c.2109delC maternal; c.1829_1830insC paternal), classified pathogenic under ACMG criteria (PVS1+PS2+PM2), further enriches the known variant spectrum [PMID: 34964966].
DIS3L2 belongs to the RNase II/RNB family and is a DIS3 homolog, but — unlike DIS3 and DIS3L1 — it lacks the PIN domain and does not associate with the core RNA exosome, instead functioning as a free cytoplasmic enzyme. It specifically binds and degrades 3′-oligouridylated RNAs. In the Lin28–let-7 axis, LIN28A/B recruit the terminal uridylyl transferases TUT4/7 to oligouridylate pre-let-7, which DIS3L2 then degrades. Chang et al. established DIS3L2 as the pathway's missing component: "Here, we identify the Perlman syndrome-associated protein DIS3L2 as an oligo(U)-binding and processing exoribonuclease that specifically targets uridylated pre-let-7 in vivo. This study establishes DIS3L2 as the missing component of the LIN28-TUT4/7-DIS3L2 pathway required for the repression of let-7 in pluripotent cells" [PMID: 24141620]. Independent biochemical/structural and cell-based work corroborates this role [PMID: 25119025; PMID: 26080928; PMID: 23594738].
The crystal structure of mouse Dis3l2 bound to oligoU RNA reveals three RNA-binding domains forming an open funnel with uracil-specificity interactions spanning the first ~12 nucleotides and three distinct "U-specificity zones" that explain substrate recognition [PMID: 25119025]. Beyond let-7, DIS3L2 performs quality-control decay (Dis3l2-mediated decay, DMD) of a wide range of aberrant structured ncRNAs: rRNAs, snRNAs, snoRNAs, tRNAs, 7SL, Y RNAs, the RMRP lncRNA, Pol III transcripts, and mRNAs. As Łabno et al. and Pirouz et al. establish: "This establishes Dis3l2-mediated decay (DMD) as a quality-control pathway that eliminates aberrant ncRNAs" [PMID: 27498873], and the cytoplasmic DIS3L2-dependent "uridylome" encompasses a broad spectrum of highly structured, aberrantly processed RNAs [PMID: 27647875]. Critically, in DIS3L2-deficient cell lines and mouse models, mature let-7 levels are unchanged, demonstrating that "DIS3L2 loss has no effect on mature let-7 levels" [PMID: 29950491] — so tumor suppression is not simply mediated by let-7.
The defining features of Perlman syndrome are polyhydramnios, fetal macrosomia, characteristic facial dysmorphism, nephromegaly, renal dysplasia and nephroblastomatosis, facial hypotonia, and multiple congenital anomalies. Most patients die in infancy from respiratory and/or renal failure; survivors have developmental delay and a high Wilms tumor risk. The Three Siblings case report notes: "The majority of patients die in infancy due to respiratory and/or renal failure, limiting the reports of patients surviving into childhood" [PMID: 40704758].
A genotype–phenotype correlation is emerging: the homozygous exon-9 deletion is associated with poor survival, while some missense or partial-function alleles (e.g., p.Arg794His) permit prolonged survival into childhood. A recent case report states: "Survival is predicted by differences among various germline mutations in the DIS3L2 gene on chromosome 2q37.1, with prolonged survival documented in heterozygous mutations allowing partial exoribonuclease function" [PMID: 42040973]. For Wilms tumor development, a two-hit model operates, combining a germline DIS3L2 lesion with a somatic second hit: "revealed 1 somatic mutation and 1 familial germline mutation in the DIS3L2 gene, suggesting a 2-hit causation of Wilms tumor" [PMID: 35700413].
The proliferative mechanism is conserved and PI3K/AKT-dependent. In Drosophila, dis3L2-null and nuclease-dead lines show catalytic-activity-dependent overproliferation driven by the growth factor Idgf2 (homolog of human chitinase-like CHI3L1/YKL-40); in human HEK-293T kidney cells, DIS3L2 loss increases proliferation and activates PI3-Kinase/AKT signaling. Towler et al. report: "we show that loss of DIS3L2 results in an increase in the PI3-Kinase/AKT signalling pathway, which we subsequently show to contribute towards the proliferation phenotype" [PMID: 33370287].
In zebrafish, dis3l2 morphants show neural crest apoptosis, mitotic/spindle defects, and Akt–GSK3β dysregulation: "dis3l2 regulates neural tissue apoptosis and progenitor functions through the Akt-GSK3β signaling pathway" [PMID: 40500755]. At the subcellular level, DIS3L2-mediated decay safeguards 7SL/SRP-dependent ER-targeted translation and ER calcium homeostasis; its loss causes sustained 7SL uridylation, calcium leak, and impaired stem-cell differentiation: "Upon DIS3L2 loss, sustained 3'-end uridylation of aberrant 7SL RNA impacts ER-targeted translation and causes ER calcium leakage" [PMID: 32457326].
The landmark gene-discovery paper (Astuti et al., 2012, Nature Genetics) mapped the Perlman locus and identified the causal gene: "We mapped a previously unknown susceptibility locus to 2q37.1 and identified germline mutations in DIS3L2, a homolog of the Schizosaccharomyces pombe dis3 gene, in individuals with Perlman syndrome" [PMID: 22306653]. The same study established DIS3L2's tumor-suppressor function and its relevance to sporadic (non-syndromic) Wilms tumor: "DIS3L2 inactivation was associated with mitotic abnormalities and altered expression of mitotic checkpoint proteins. DIS3L2 overexpression suppressed the growth of human cancer cell lines, and knockdown enhanced the growth of these cells. We also detected evidence of DIS3L2 mutations in sporadic Wilms tumor" [PMID: 22306653]. Thus DIS3L2 bridges a rare Mendelian overgrowth syndrome and common pediatric kidney cancer biology.
Perlman syndrome is classified among the Wilms tumor (WT) predisposition syndromes by consensus guidelines. The AACR Pediatric Cancer Working Group update notes: "members of the AACR Pediatric Cancer Working Group met to update surveillance guidelines for patients with a predisposition to Wilms tumors with a review of recently published evidence and risk estimates" [PMID: 39466169; PMID: 39320341]. The SIOP-Europe Host Genome Working Group provides an independent consensus: "the International Society of Pediatric Oncology (SIOP)-Europe Host Genome Working Group and SIOP Renal Tumour Study Group hereby present updated WT surveillance guidelines" [PMID: 34134020]. These groups recommend abdominal/renal ultrasound surveillance (typically every ~3 months) in children at increased WT risk.
Nephroblastomatosis/nephrogenic rests are the precursor lesions for Wilms tumor. Importantly, a large SIOP-WT-2001 analysis found that in unilateral Wilms tumor cohorts, the presence of nephrogenic rests did not independently worsen relapse-free or overall survival, indicating they are precursor markers rather than independent adverse prognostic factors once a tumor has formed [PMID: 42535789].
Alessandri et al. (2008) reviewed 28 reported Perlman syndrome patients and quantified the natural history. The prognosis is poor with high neonatal mortality: "The prognosis of Perlman syndrome is poor with a high neonatal mortality rate" [PMID: 18780370]. Among those surviving the neonatal period: "Among the infants who survived beyond the neonatal period, 64% developed a WT and all had a developmental delay" [PMID: 18780370]. Frequent manifestations include fetal macrosomia, ascites, polyhydramnios, nephromegaly, renal dysplasia, nephroblastomatosis, and distinctive facies.
Regarding inheritance in practice, reported sibships showed parental consanguinity in only 2 of 7 families: "We review 19 patients from seven sibships with parental consanguinity in two families only" [PMID: 18780370] — consistent with sporadic autosomal recessive occurrence rather than a requirement for consanguinity. Cholestasis has also been reported as a possibly novel feature [PMID: 20726997].
Perlman syndrome shares features (macrosomia, visceromegaly, Wilms tumor risk) with Beckwith-Wiedemann syndrome (BWS; 11p15 imprinting/CDKN1C) and Simpson-Golabi-Behmel syndrome (SGBS; GPC3), prompting frequent diagnostic confusion [PMID: 18780370; PMID: 24215131; PMID: 38161545]. "Clinical overlaps with other overgrowth syndromes particularly Beckwith-Wiedemann syndrome and Simpson-Golabi-Behmel syndrome have been emphasized" [PMID: 18780370].
However, in molecularly confirmed Perlman cases, the 11p15 region/CDKN1C and GPC3 were specifically excluded: "Genetic or epigenetic alterations of the 11p15 region (involved in the BWS), including mutation of the CDKN1C gene were excluded. No mutation of the GPC3 gene was identified" [PMID: 18780370]. This establishes Perlman as a distinct autosomal recessive DIS3L2 disorder, not an imprinting (BWS) or X-linked (SGBS) condition. Diagnosis therefore requires demonstration of biallelic DIS3L2 variants, with care to detect large exon-9 deletions missed by sequencing [PMID: 23486540; PMID: 22306653].
Synthesis of the mechanistic evidence defines the Perlman pathophysiology as a stepwise cascade (detailed in the Mechanistic Model below). The key integration points: (1) biallelic DIS3L2 loss removes cytoplasmic 3′→5′ oligo(U)-exoribonuclease activity [PMID: 22306653; PMID: 25119025]; (2) uridylated substrates accumulate via failed DIS3L2-mediated decay [PMID: 24141620; PMID: 23594738; PMID: 27498873; PMID: 27647875; PMID: 32457326]; (3) proliferation is derepressed through elevated PI3K/AKT (and AKT-GSK3β) signaling and growth-factor dysregulation, with mitotic/spindle defects [PMID: 33370287; PMID: 40500755; PMID: 22306653]; (4) mature let-7 is unchanged, so tumor suppression is largely let-7-independent [PMID: 29950491]; (5) the pathway is conserved from Drosophila to humans [PMID: 33370287]. The clinical outcome is fetal overgrowth, nephroblastomatosis, and Wilms tumor (via two-hit somatic inactivation) [PMID: 35700413].
Perlman syndrome (MONDO:0009965; OMIM 267000; Orphanet ORPHA:2849) is a rare autosomal recessive congenital overgrowth syndrome with Wilms tumor predisposition, caused by biallelic variants in DIS3L2. It was first described clinically by Perlman and colleagues as a familial syndrome of renal hamartomas, nephroblastomatosis, and fetal gigantism.
| Phenotype | Type | Onset | Frequency | Suggested HPO |
|---|---|---|---|---|
| Polyhydramnios | Prenatal sign | Fetal | Very frequent | HP:0001561 |
| Fetal macrosomia / overgrowth | Physical | Fetal/neonatal | Very frequent | HP:0001520, HP:0000098 |
| Fetal ascites | Clinical sign | Fetal | Frequent | HP:0001791 |
| Nephromegaly | Physical | Neonatal | Very frequent | HP:0000105 |
| Renal dysplasia | Structural | Congenital | Frequent | HP:0000110 |
| Nephroblastomatosis / nephrogenic rests | Pathologic | Congenital | Characteristic precursor | HP:0001708 |
| Wilms tumor (nephroblastoma) | Neoplasm | Infancy/childhood | ~64% of neonatal survivors | HP:0002667 |
| Distinctive facial dysmorphism | Physical | Congenital | Characteristic | HP:0001999 |
| Facial/generalized hypotonia | Neurologic | Neonatal | Frequent | HP:0000297 / HP:0001252 |
| Developmental delay / intellectual disability | Neurologic | Infancy | ~100% of survivors | HP:0001263 / HP:0001249 |
| Visceromegaly / organomegaly | Physical | Congenital | Frequent | HP:0003271 |
| Cholestasis | Lab/clinical | Neonatal | Rare (reported) | HP:0001396 |
Not applicable. No environmental factors, lifestyle factors, toxins, or infectious agents are implicated. Perlman syndrome is a fully genetic Mendelian disorder [PMID: 22306653; PMID: 23613427].
Ordered causal chain (initiating lesion → clinical manifestation):
Note: mature let-7 is unchanged in DIS3L2-deficient cells/mice, so tumor suppression is largely let-7-independent — the operative driver is the broader RNA-surveillance failure converging on PI3K/AKT [PMID: 29950491].
Molecular pathways: PI3K/AKT (GO:0043491), AKT-GSK3β; LIN28–TUT4/7–DIS3L2 uridylation/decay axis.
There is no disease-specific or curative therapy; management is supportive and oncologic.
| Model | Type | Key findings | Recapitulation | PMID |
|---|---|---|---|---|
| Drosophila dis3L2-null / nuclease-dead | Invertebrate, genetic | Catalytic-activity-dependent overproliferation via Idgf2; PI3K/AKT link | Overgrowth/proliferation mechanism | [PMID: 33370287] |
| Zebrafish dis3l2 morphant | Vertebrate | Neural crest apoptosis, mitotic/spindle defects, Akt-GSK3β dysregulation | Developmental + signaling aspects | [PMID: 40500755] |
| Mouse embryonic stem cells / Dis3l2 knockdown | Mammalian cellular | pre-let-7 stabilization; mature let-7 unchanged; DMD of ncRNAs | Molecular/RNA-surveillance | [PMID: 23594738; PMID: 29950491; PMID: 27498873] |
| Human HEK-293T (kidney) DIS3L2 loss | In vitro human | Increased proliferation + PI3K/AKT activation | Proliferation mechanism in kidney cells | [PMID: 33370287] |
| Human cell lines (CLIP uridylome; 7SL/ER) | In vitro human | Broad uridylome; 7SL/SRP, ER translation, Ca²⁺ leak | Subcellular mechanism | [PMID: 27647875; PMID: 32457326] |
Biallelic DIS3L2 loss-of-function (2q37.1)
(nonsense / frameshift / missense / exon-9 LINE-1 NAHR deletion)
│ [PMID 22306653, 23486540]
▼
Loss of cytoplasmic 3'->5' oligo(U) exoribonuclease activity
│ [PMID 24141620, 25119025]
▼
Failure of Dis3l2-mediated decay (DMD) of 3'-uridylated RNAs
│ [PMID 27498873, 27647875]
┌──────────────┼───────────────────────────┐
▼ ▼ ▼
pre-let-7 aberrant 7SL / SRP RNA rRNA/tRNA/snRNA/
accumulates accumulates RMRP accumulate
│ │ [PMID 32457326] │
│ ▼ │
│ impaired ER translation + │
│ ER Ca2+ leak; stem-cell defects │
│ │
▼ (NOTE: mature let-7 UNCHANGED) │
let-7-INDEPENDENT ────────────────────────────────┘
│ [PMID 29950491]
▼
PI3K/AKT activation (+ AKT-GSK3beta), growth-factor (Idgf2)
dysregulation, mitotic/spindle & checkpoint abnormalities
│ [PMID 33370287, 40500755, 22306653]
▼
Cell overproliferation / impaired apoptosis
│
▼
Fetal overgrowth: macrosomia, visceromegaly, nephromegaly,
nephroblastomatosis, dysmorphism, developmental delay
│ [PMID 18780370, 40704758]
▼
+ somatic second hit at DIS3L2 in nephrogenic rest (2-hit)
│ [PMID 35700413]
▼
WILMS TUMOR (~64% of neonatal survivors)
The central interpretive insight is that Perlman syndrome is a cytoplasmic RNA quality-control disease. The historical emphasis on let-7 (because DIS3L2 is the pathway's terminal nuclease) is mechanistically incomplete: steady-state mature let-7 is unchanged on DIS3L2 loss [PMID: 29950491], so the tumor-suppressive and overgrowth phenotypes derive from the broader surveillance failure — accumulation of aberrant structured ncRNAs and consequent PI3K/AKT-driven overproliferation. This reframes DIS3L2 as a general guardian of the cytoplasmic transcriptome whose loss produces growth dysregulation and cancer predisposition.
| PMID | Role in this report | Evidence type |
|---|---|---|
| PMID: 22306653 | Gene discovery; DIS3L2 tumor suppressor; sporadic WT mutations | Human genetics + in vitro |
| PMID: 23613427 | Locus, inheritance, enzyme identity | Review |
| PMID: 23486540 | Exon-9 deletion via LINE-1 NAHR; diagnostic pitfall | Case/molecular |
| PMID: 24141620 | DIS3L2 = terminal nuclease of LIN28-TUT4/7 pathway | In vitro/mechanistic |
| PMID: 25119025 | Crystal structure; oligoU recognition | Structural |
| PMID: 23594738 | Dis3l2 degrades uridylated pre-let-7 (mESC) | Model organism |
| PMID: 27498873 | DMD as ncRNA quality-control pathway | Mechanistic |
| PMID: 27647875 | DIS3L2-dependent uridylome of structured ncRNAs | Human in vitro |
| PMID: 32457326 | 7SL/SRP, ER translation, Ca²⁺ homeostasis | In vitro/mechanistic |
| PMID: 29950491 | Mature let-7 unchanged → let-7-independent | In vitro/model |
| PMID: 33370287 | PI3K/AKT-driven proliferation; conserved fly↔human | Model organism + human cells |
| PMID: 40500755 | Akt-GSK3β, neural crest apoptosis | Model organism (zebrafish) |
| PMID: 18780370 | Prognosis: 64% WT, developmental delay; BWS/SGBS exclusion | Human review/case series |
| PMID: 40704758 | High neonatal mortality; attenuated sibling cases | Human case report |
| PMID: 42040973 | Genotype-survival correlation; prolonged survival | Human case report |
| PMID: 35700413 | Two-hit Wilms tumor causation | Human case report |
| PMID: 34964966 | Compound het variants; ACMG classification | Human case/molecular |
| PMID: 39466169 | AACR WT surveillance guidelines | Guideline |
| PMID: 39320341 | AACR WT/hepatoblastoma surveillance update | Guideline |
| PMID: 34134020 | SIOP-Europe WT surveillance guidelines | Guideline |
| PMID: 42535789 | Nephrogenic rests and relapse risk | Human cohort |
| PMID: 24215131 | BWS/Perlman clinical overlap | Human case |
| PMID: 38161545 | DIS3L2 deletion; prenatal diagnosis; differentials | Human case |
| PMID: 20726997 | Cholestasis as novel feature | Human case |
| PMID: 34503817 | Pediatric cancer predisposition syndrome management | Review |
Report compiled from 9 confirmed findings and 33 reviewed papers across 5 investigation iterations. Evidence types span human clinical/genetic, model organism (Drosophila, zebrafish, mouse), in vitro, and structural studies.
Checked with linkml-reference-validator 0.5.1.
| Outcome | Count |
|---|---|
| References checked | 27 |
| Resolved | 27 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| References weighed for topical relevance | 27 |
| On topic | 23 |
| Off topic | 0 |
All extracted references resolved successfully.
Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 30 |
| Resolved | 28 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 0 |
| Unverifiable | 2 |
| Terms whose name was checked | 18 |
| Terms named correctly | 3 |
| Terms named as a different term | 11 |
| Terms whose name is worth a second look | 4 |
These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:
HP:0001561 (1 mention) - the report calls it "Very frequent"; HP calls it PolyhydramniosHP:0001791 (1 mention) - the report calls it "Frequent"; HP calls it Fetal ascitesHP:0000105 (1 mention) - the report calls it "Very frequent"; HP calls it Enlarged kidneyHP:0000110 (1 mention) - the report calls it "Frequent"; HP calls it Renal dysplasiaHP:0001708 (1 mention) - the report calls it "Characteristic precursor"; HP calls it Right ventricular failureHP:0002667 (1 mention) - the report calls it "~64% of neonatal survivors"; HP calls it NephroblastomaHP:0001999 (1 mention) - the report calls it "Characteristic"; HP calls it Abnormal facial shapeHP:0003271 (1 mention) - the report calls it "Frequent"; HP calls it VisceromegalyHP:0001396 (1 mention) - the report calls it "Rare (reported)"; HP calls it CholestasisGO:0006401 (1 mention) - the report calls it "Cellular processes: RNA catabolism/surveillance"; GO calls it RNA catabolic process**GO:0005737 (1 mention) - the report calls it "Subcellular compartments: Cytoplasm"; GO calls it cytoplasm**The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:
GO:0043491 (2 mentions) - the report calls it "Molecular pathways: PI3K/AKT", "PI3K/AKT"; GO calls it phosphatidylinositol 3-kinase/protein kinase B signal transduction**, and lists "PI3K-PKB/Akt pathway" among its other namesGO:0000175 (1 mention) - the report calls it "3′-5′ exoribonuclease activity"; GO calls it 3'-5'-RNA exonuclease activity, and lists "3'-5' exoribonuclease activity" among its other namesGO:0071028 (1 mention) - the report calls it "nuclear mRNA surveillance — analogous cytoplasmic QC"; GO calls it nuclear mRNA surveillanceUBERON:0002113 (2 mentions) - the report calls it "Kidney", "Primary organ: Kidney", "kidney"; UBERON calls it kidney, and lists "reniculate kidney" among its other namesThe report gives these identifiers more than one name of its own:
GO:0043491 - called "Molecular pathways:** PI3K/AKT", "PI3K/AKT"UBERON:0002113 - called "Kidney", "Primary organ: Kidney", "kidney"Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.