Gorlin syndrome and rhabdoid tumor predisposition syndrome (RTPS) are autosomal dominant syndromes associated with an increased risk of childhood-onset brain tumors. Individuals with Gorlin syndrome ...can manifest a wide range of phenotypic abnormalities, with about 5% of family members developing medulloblastoma, usually occurring in the first 3 years of life. Gorlin syndrome is associated with germline mutations in components of the Sonic Hedgehog pathway, including Patched1 (
and Suppressor of fused (
mutation carriers appear to have an especially high risk of early-onset medulloblastoma. Surveillance MRI in the first years of life in
mutation carriers is, therefore, recommended. Given the risk of basal cell carcinomas, regular dermatologic examinations and sun protection are also recommended. Rhabdoid tumors (RT) are tumors initially defined by the descriptive "rhabdoid" term, implying a phenotypic similarity with rhabdomyoblasts at the microscopic level. RTs usually present before the age of 3 and can arise within the cranium as atypical teratoid/rhabdoid tumors or extracranially, especially in the kidney, as malignant rhabdoid tumors. However, RTs of both types share germline and somatic mutations in
or, more rarely,
, each of which encodes a chromatin remodeling family member.
mutations are particularly associated with small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). The outcome following a diagnosis of any of these tumors is often poor, and the value of surveillance is unknown. International efforts to determine surveillance protocols are underway, and preliminary recommendations are made for carriers of
and
mutations.
Retinoblastoma (RB) is the most common intraocular malignancy in childhood. Approximately 40% of retinoblastomas are hereditary and due to germline mutations in the
gene. Children with hereditary RB ...are also at risk for developing a midline intracranial tumor, most commonly pineoblastoma. We recommend intensive ocular screening for patients with germline
mutations for retinoblastoma as well as neuroimaging for pineoblastoma surveillance. There is an approximately 20% risk of developing second primary cancers among individuals with hereditary RB, higher among those who received radiotherapy for their primary RB tumors. However, there is not yet a clear consensus on what, if any, screening protocol would be most appropriate and effective. Neuroblastoma (NB), an embryonal tumor of the sympathetic nervous system, accounts for 15% of pediatric cancer deaths. Prior studies suggest that about 2% of patients with NB have an underlying genetic predisposition that may have contributed to the development of NB. Germline mutations in
and
account for most familial NB cases. However, other cancer predisposition syndromes, such as Li-Fraumeni syndrome, RASopathies, and others, may be associated with an increased risk for NB. No established protocols for NB surveillance currently exist. Here, we describe consensus recommendations on hereditary RB and NB from the AACR Childhood Cancer Predisposition Workshop.
.
Von Hippel-Lindau disease (vHL) is a hereditary tumor predisposition syndrome that places affected individuals at risk for multiple tumors, which are predominantly benign and generally occur in the ...central nervous system or abdomen. Although the majority of tumors occur in adults, children and adolescents with the condition develop a significant proportion of vHL manifestations and are vulnerable to delayed tumor detection and their sequelae. Although multiple tumor screening paradigms are currently being utilized for patients with vHL, surveillance should be reassessed as the available relevant clinical information continues to expand. We propose a new vHL screening paradigm similar to existing approaches, with important modifications for some tumor types, placing an emphasis on risks in childhood. This includes advancement in the timing of surveillance initiation and increased frequency of screening evaluations. Another neuroendocrine-related familial condition is the rapidly expanding hereditary paraganglioma and pheochromocytoma syndrome (HPP). The tumor spectrum for patients with HPP syndrome includes paragangliomas, pheochromocytomas, renal cancer, and gastrointestinal stromal tumors. The majority of patients with HPP syndrome harbor an underlying variant in one of the
genes (
, and
), although other genes also have been described (
and
). Annual screening for elevated plasma or urine markers along with complete blood count and biennial whole-body MRI accompanied by focal neck MRI is recommended for older children and adults with HPP syndrome to detect tumors early and to decrease morbidity and mortality from HPP-related tumors.
hamartoma tumor syndrome (PHTS),
syndrome, and hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome are pleiotropic tumor predisposition syndromes that include benign and malignant ...neoplasms affecting adults and children. PHTS includes several disorders with shared and distinct clinical features. These are associated with elevated lifetime risk of breast, thyroid, endometrial, colorectal, and renal cancers as well as melanoma. Thyroid cancer represents the predominant cancer risk under age 20 years.
syndrome includes risk for pleuropulmonary blastoma, cystic nephroma, ovarian sex cord-stromal tumors, and multinodular goiter and thyroid carcinoma as well as brain tumors including pineoblastoma and pituitary blastoma. Individuals with HLRCC may develop multiple cutaneous and uterine leiomyomas, and they have an elevated risk of renal cell carcinoma. For each of these syndromes, a summary of the key syndromic features is provided, the underlying genetic events are discussed, and specific screening is recommended.
Children and adolescents who present with neuroendocrine tumors are at extremely high likelihood of having an underlying germline predisposition for the multiple endocrine neoplasia (MEN) syndromes, ...including MEN1, MEN2A and MEN2B, MEN4, and hyperparathyroid-jaw tumor (HPT-JT) syndromes. Each of these autosomal dominant syndromes results from a specific germline mutation in unique genes: MEN1 is due to pathogenic
variants (11q13), MEN2A and MEN2B are due to pathogenic
variants (10q11.21), MEN4 is due to pathogenic
variants (12p13.1), and the HPT-JT syndrome is due to pathogenic
variants (1q25). Although each of these genetic syndromes share the presence of neuroendocrine tumors, each syndrome has a slightly different tumor spectrum with specific surveillance recommendations based upon tumor penetrance, including the age and location for which specific tumor types most commonly present. Although the recommended surveillance strategies for each syndrome contain similar approaches, important differences do exist among them. Therefore, it is important for caregivers of children and adolescents with these syndromes to become familiar with the unique diagnostic criteria for each syndrome, and also to be aware of the specific tumor screening and prophylactic surgery recommendations for each syndrome.
.
The integration of genomic testing into clinical care enables the use of individualized approaches to the management of rare diseases. We describe the use of belzutifan, a potent and selective ...small-molecule inhibitor of the protein hypoxia-inducible factor 2α (HIF2α), in a patient with polycythemia and multiple paragangliomas (the Pacak–Zhuang syndrome). The syndrome was caused in this patient by somatic mosaicism for an activating mutation in
EPAS1
. Treatment with belzutifan led to a rapid and sustained tumor response along with resolution of hypertension, headaches, and long-standing polycythemia. This case shows the application of a targeted therapy for the treatment of a patient with a rare tumor-predisposition syndrome. (Funded by the Morin Family Fund for Pediatric Cancer and Alex’s Lemonade Stand Foundation.)
Pacak–Zhuang syndrome is an inherited tumor-predisposition disorder characterized by polycythemia and paragangliomas. A patient with this disorder had polycythemia, headache, hypertension, and norepinephrine-secreting paragangliomas. She had activating mutations in
HIF2A
. Use of belzutifan, a HIF2α inhibitor, led to paraganglioma regression, normalized hemoglobin levels, and symptom resolution.
Abstract
Context
Thyroid ultrasound screening is recommended in children with PTEN hamartoma tumor syndrome (PHTS) due to increased risk of thyroid neoplasia, but the natural history of thyroid ...disease in children with PHTS is unclear.
Objective
Determine the prevalence and natural history of thyroid disease in children with PHTS.
Methods
Retrospective cohort study (1998-2019) in an academic pediatric hospital of individuals with genetically confirmed PHTS diagnosed before age 19 years. Clinical, thyroid ultrasound, and laboratory characteristics are described. Primary outcomes were the prevalence of thyroid nodules ≥10 mm diameter and time course and risk factors for nodule development assessed by Cox regression analysis. Secondary outcomes included thyroid nodule requiring biopsy, other ultrasound findings, and prevalence of autoimmune thyroid disease.
Results
Among 64 subjects with PHTS, 50 underwent thyroid ultrasound. A thyroid nodule ≥10 mm was diagnosed in 22/50 (44%) subjects at median (range) age 13.3 (7.0-22.9) years. Nodules were diagnosed earlier in females than in males (10.8 7.0-17.9 vs 14.2 9.9-22.9 years, P = .009). In multivariate analysis, risk of thyroid nodules was significantly associated with female sex (hazard ratio 2.90, 95% CI 1.16-7.27, P = .02) and inversely associated with the presence of neurologic findings of PHTS (HR 0.27, 95% CI 0.10-0.69, P = .007). Abnormal-appearing lymph nodes with echogenic foci were observed by ultrasound in 20% of subjects, but these were not associated with malignancy. Autoimmune thyroid disease was present in 10/33 (30.3%) of subjects in whom it was assessed.
Conclusion
Thyroid disease is common in children with PHTS. This study supports current consensus recommendations for ultrasound screening.
Ultrasound screening for thyroid cancer is recommended in familial adenomatous polyposis (FAP). This study investigated the prevalence of thyroid neoplasia in children with FAP.
Cross-sectional study ...of children with FAP at an academic hospital. Clinical and ultrasound data were analyzed for the prevalence of thyroid nodules and cancer.
Of 37 children with FAP, 8 (22%) had thyroid nodules and 2 (5%) had thyroid cancer. Nodules (30%) and cancer (9%) were more common among females and rare among males.
Thyroid ultrasound screening in adolescence may benefit females with FAP but has limited utility in males.
The spectrum of neoplasms associated with DICER1 variants continues to expand, with the recent addition of primary "DICER1-associated central nervous system sarcoma" (DCS). DCS is a high-grade ...malignancy predominantly affecting pediatric patients. Six pediatric DCS were identified through a combination of clinical diagnostic studies, archival inquiry, and interinstitutional collaboration. Clinical, histologic, immunohistologic, and molecular features were examined. Genomic findings in the 6 DCS were compared with those in 14 additional DICER1-associated tumors sequenced with the same assay. The six patients presented at ages 3-15 years with CNS tumors located in the temporal (n = 2), parietal (n = 1), fronto-parietal (n = 1), and frontal (n = 2) lobes. All underwent surgical resection. Histologic examination demonstrated high-grade malignant spindle cell tumors with pleuropulmonary blastoma-like embryonic "organoid" features and focal rhabdomyoblastic differentiation; immature cartilage was seen in one case. Immunohistochemically, there was patchy desmin and myogenin staining, and patchy loss of H3K27me3, and within eosinophilic cytoplasmic globules, alfa-fetoprotein staining. Biallelic DICER1 variants were identified in all cases, with germline variants in two of five patients tested. DCS demonstrated genomic alterations enriched for Ras pathway activation and TP53 inactivation. Tumor mutational burden was significantly higher in the 6 DCS tumors than in 14 other DICER1-associated tumors examined (mean 12.9 vs. 6.8 mutations/Mb, p = 0.035). Postoperative care included radiation (n = 5) and chemotherapy (n = 3); at the last follow-up, three patients were alive without DCS, and three had died of disease. Our analysis expands the clinical, histologic, immunohistological, and molecular spectrum of DCS, identifying distinctive features that can aid in the diagnosis, multidisciplinary evaluation, and treatment of DCS.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background
Pleuropulmonary blastoma (PPB) is the most common lung cancer of infancy and early childhood. Type I PPB is a purely cystic lesion that has a microscopic population of primitive small ...cells with or without rhabdomyoblastic features and may progress to type II or III PPB, whereas type Ir lacks primitive small cells.
Methods
Children with suspected PPB were enrolled in the International PPB/DICER1 Registry. Pathology was centrally reviewed, and follow‐up was ascertained annually.
Results
Between 2006 and 2022, 205 children had centrally reviewed type I or Ir PPB; 39% of children with type I and 5% of children with type Ir PPB received chemotherapy. Outcomes were favorable, although 11 children (nine with type I and two with type Ir PPB) experienced progression to type II/III (n = 8) or regrowth of type I PPB at the surgical site (n = 3), none of whom received chemotherapy before progression. Age and cyst size in combination were more suitable than either factor alone in predicting whether a particular lesion was type I or Ir PPB.
Conclusions
For young children with type I PPB, outcomes are favorable, but complete resection is indicated because of the risk for progression. Chemotherapy may be useful in a subset of children at increased risk for recurrence/progression. Efforts to risk stratify children with type I PPB to optimize outcomes while reducing treatment‐related side effects are underway.
Outcomes for children with type I and Ir pleuropulmonary blastoma (PPB) are favorable, although progression to advanced disease is noted in some children. Chemotherapy may be useful in a subset of children with type I PPB who are at increased risk for recurrence/progression.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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