OBJECTIVE: To demonstrate a high-yield molecular diagnostic workflow for lateralized overgrowth (LO), a congenital condition with abnormal enlargement of body parts, and to classify it by molecular genetics. and STUDY DESIGN: We categorized 186 retrospective cases of LO diagnosed between 2003 and 2023 into suspected Beckwith-Wiedemann spectrum (BWSp), PIK3CA-Related Overgrowth Spectrum (PROS), vascular overgrowth (VO) , or isolated (ILO), based on initial clinical assessments, to determine the appropriate first-tier molecular tests and tissue for analysis. Patients underwent testing for 11p15 epigenetic abnormalities or somatic variants in genes related to PI3K/AKT/mTOR, vascular proliferation, and RAS-MAPK cascades using blood or skin DNA. For cases with negative initial tests, a sequential cascade molecular approach was employed to improve diagnostic yield.
RESULTS: This approach led to a molecular diagnosis in 54% of cases, 89% of cases consistent with initial clinical suspicions and 11% reclassified. BWSp was the most common cause, with 43% of cases exhibiting 11p15 abnormalities. PROS had the highest confirmation rate, with 74% of clinically diagnosed patients showing a PIK3CA variant. VO demonstrated significant clinical overlap with other syndromes. Molecular diagnosis of ILO proved challenging, with only 21% of cases classifiable into a specific condition.
CONCLUSIONS: Despite, LO is underdiagnosed from a molecular viewpoint and to date has had no diagnostic guidelines, which would be crucial for addressing potential cancer predisposition, enabling precision medicine treatments, or guiding management. This study sheds light on the molecular etiology of LO, highlighting the importance of tailored diagnostic approach and of selecting appropriate testing to achieve the highest diagnostic yield.

Beckwith-Wiedemann syndrome (BWS) is a genetic disorder that affects fetal growth in which those afflicted present with features pertaining to that, such as macrosomia, macroglossia, hemihypertrophy, and abdominal wall defects. This case reports the presentation of an infant diagnosed with BWS who was born with an extremely low birth weight of 980 grams, in contrast to the typical presentation of overgrowth and macrosomia. As a result, reaching a diagnosis of BWS was delayed until the patient reached eight months of age, when other clinical features of BWS, such as hemihypertrophy, became apparent on follow-up visits. Although genetic testing can be used to diagnose this condition, a clinical scoring system consisting of a patient\'s clinical features is sufficient, allowing for a timely and precise diagnosis, which is of great significance to allow for early screening and detection of the associated embryonal tumors with such a syndrome.

Germline pathogenic variants found in the phosphatase and tensin homolog gene are associated with a range of rare syndromes that collectively fall under the umbrella of phosphatase and tensin homolog hamartoma tumor syndromes. Due to the wide array of possible clinical presentations and the varying degrees of symptom severity, many individuals with phosphatase and tensin homolog hamartoma tumor syndromes might remain undiagnosed for an extended period. We describe a case of a male child who received the diagnosis at the age of 12. His clinical features included macrocephaly, hypertrophy in the left arm, thyroid nodules, penile freckles, developmental delay, and an autism spectrum disorder. Whole exome sequencing revealed a de novo heterozygous variant in the phosphatase and tensin homolog. The case highlights the diverse and complex nature of phosphatase and tensin homolog hamartoma tumor syndromes, emphasizing the necessity for early diagnosis, multidisciplinary care, and surveillance protocols, offering the potential for improved prognostic outcomes and enhanced quality of life for affected individuals.

Fetal Wilms tumor (WT) is extremely rare, but with advances in fetal imaging, more cases are being reported. The management of these cases remains challenging. Herein, we present the case of a full-term female infant diagnosed antenatally at 32 weeks of gestation with a right solid renal mass detected on routine prenatal ultrasound without polyhydramnios. At birth, the infant was healthy, with no evidence of dysmorphic features or abnormal laboratory tests to suggest a predisposition syndrome. Her family history was also unremarkable. A successful radical right nephrectomy was performed on day 2 of life revealing a classic WT. She received vincristine as adjuvant chemotherapy without any complications. At the age of 1 month, the infant developed isolated lateralized overgrowth of the right lower limb suspicious of Beckwith-Wiedemann syndrome. At the latest follow-up of 4 years, the child is healthy and disease-free with conserved asymmetry of lower limbs. The case provides insights into the challenging diagnosis and treatment of fetal WT. A review of the literature suggests that the presence of polyhydramnios is a worse prognostic factor while the combination of best supportive care and surgery remains the best management. Fetal WT can be associated with predisposition syndromes; however, their first manifestations can develop after the diagnosis of cancer has been made, as in our patient. We propose starting active surveillance programs and genetic testing for any case of fetal WT.

BACKGROUND: Beckwith-Wiedemann syndrome (BWS) is a genomic imprinting disorder caused by diverse genetic and/or epigenetic disorders of chromosome 11p15.5. BWS presents with a variety of clinical features, including overgrowth and an increased risk of embryonal tumors. Notably however, reports of patients with BWS and breast tumors are rare, and the association between these conditions is still unclear. Insulin-like growth factor-2 (IGF2) expression is known to be associated with the development of various cancers, including breast cancer, and patients with BWS with specific subtypes of molecular defects are known to show characteristic clinical features and IGF2 overexpression.
METHODS: A 17-year-old girl who had been diagnosed with BWS based on an umbilical hernia, hyperinsulinemia, and left hemihypertrophy at birth, visited our department with a gradually swelling left breast. Her left breast was markedly larger than her right breast on visual examination. Imaging examinations showed two tumors measuring about 10 cm each in the left breast, and she was diagnosed with juvenile fibroadenoma following core needle biopsy. The two breast tumors were removed surgically and the patient remained alive with no recurrence. The final diagnosis was juvenile fibroadenoma without malignant findings. Immunohistochemical staining using IGF2 antibody revealed overexpression of IGF2 in the cytoplasm of ductal epithelial cells. Because of her clinical features and IGF2 overexpression, molecular defects of 11p15.5 including a possible genetic background of paternal uniparental disomy of chromosome 11 or hypermethylation of imprinting center 1 was suspected.
CONCLUSIONS: In this case, overexpression of IGF2 suggested a possible relationship between BWS and breast tumors. Moreover, the characteristic clinical features and IGF2 staining predicted the subtype of 11p15.5 molecular defects in this patient.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by a mutation in either of the two tumor suppressor genes, TSC1 and TSC2. Due to dysregulated activity of the mammalian target of rapamycin (mTOR) pathway, hamartomas or benign tumors frequently occur in many organs and are often treated with mTOR inhibitors. Hemihypertrophy is a rare complication of TSC. Although not being a tumor, progressive overgrowth of the affected limb may cause cosmetic and functional problems, for which the efficacy of mTOR inhibitors has not been reported previously. We herein report a case of TSC-associated hemihypertrophy. In this case, genetic studies revealed TSC1 loss of heterozygosity as the cause of hemihypertrophy. Clinically, pharmacological treatment with an mTOR inhibitor sirolimus successfully ameliorated cosmetic and functional problems with no intolerable adverse effects.

UNASSIGNED: Lipid hemihypertrophy should be considered in the differential diagnosis of neonatal asymmetry. Early recognition and further evaluation for associated disorders are important for appropriate management and surveillance of potential complications.
UNASSIGNED: We present the case of a 5-day-old female neonate who presented with a visibly enlarged right thigh, right labia majora, and below the right mandible. This case report highlights the importance of early identification, comprehensive evaluation, and multidisciplinary management in neonates with lipid hemihypertrophy to optimize their long-term outcomes and quality of life.

Pigmentary mosaicism (PM) is a clinical condition of dyspigmentation with chromosomal abnormality. PM presents with both cutaneous and extracutaneous manifestation. Hypomelanosis of Ito and linear and whorled nevoid hypermelanosis are syndromic disorders in which PM is one of the manifestations. We present a case of a 1-year-old child with a unique constellation of symptoms of unilateral syndactyly, hemihypertrophy, and skin hyperpigmentation. Karyotype from peripheral blood was normal. We found genetic aberration (mosaic 2q35 deletion) in the present case from fibroblast cultured from the affected area. This unique constellation of symptoms was previously reported once but genetic study was not done from the affected tissue. This case highlights the need of considering fibroblast culture-based genetic study rather than doing simple karyotype from peripheral blood. Genetic study also established the molecular basis of symptoms in the above case.

Beckwith-Wiedemann syndrome (BWS) is a rare imprinting disorder and overgrowth syndrome with a prevalence of 1 in 10,000 live births. It is characterized by predilection for embryonal tumor growth, especially Wilms tumor (WT), and manifestations like lateralized overgrowth/hemihypertrophy, macroglossia, macrosomia, anterior abdominal wall defects, and hyperinsulinism. Our case is a 1 year of female child who presented with abdominal swelling and limb length discrepancies. A clinical diagnosis of BWS was made based on multifocal WT and hepatomegaly and nephromegaly detected on contrast-enhanced abdominal computed tomography and physical examination findings of lateralized overgrowth and umbilical hernia. A molecular genetic test was not available. The patient was started on preoperative chemotherapy with good tolerance. Clinical criteria can be used to diagnose WBS in a setting where confirmatory molecular testing is unavailable. This will considerably change approaches to management of presenting complications such as WT .

The phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS) is a collection of diseases stemming from mutations in the PTEN tumor suppressor gene and is characterized by variable expressivity and abnormal overgrowth in multiple body systems. Its clinical manifestations include, but are not limited to, lipomas, limb overgrowth, dermatologic lesions, and malignancy. The infrequency of occurrence and broadness of clinical presentation has made the diagnosis and differentiation of different subtypes of PHTS challenging. This case report describes a five-year-old patient with a history of autism and macrocephaly who presented to the emergency department with right lower quadrant (RLQ) pain concerning for appendicitis. A physical exam was significant for right leg hemihypertrophy. Imaging ruled out appendicitis but diagnosed two large right-sided abdominal lipomas. The patient was discharged with the recommendation to pursue genetic testing given the physical exam findings and history. Following confirmation of a PTEN tumor suppressor gene mutation, the patient continued to have increased frequency of abdominal pain, developed vision changes, and was diagnosed with a benign follicular thyroid nodule. Hemihypertrophy, recurrent unilateral lipomas, and a confirmed PTEN mutation are consistent with a diagnosis of Proteus-like syndrome, a rare subtype of PHTS.