Isolated hemihyperplasia is a rare condition characterized by asymmetric overgrowth of the body that is not associated with overgrowth syndromes. We report the case of a 16-year-old adolescent with isolated congenital hemihyperplasia affecting the left hemibody, who had never undergone specific evaluation for this condition, as the clinical manifestations were mild and did not result in significant alterations beyond the observable asymmetry. Notable findings included slightly finer and thinner scalp hair texture on the contralateral side to the hemihyperplasia, as well as bilateral brachymetatarsia of the third toes. Clinical criteria and molecular testing were essential for establishing an accurate diagnosis. Given the association between hemihyperplasia and tumor risk, screening for neoplasms using abdominal ultrasound and serum alpha-fetoprotein testing is recommended. This condition presents a clinical challenge, as coordinated intervention by specialists in orthopedics, nephrology, and genetics is required to ensure effective clinical management.

Beckwith-Wiedemann syndrome (BWS) is a rare genetic and cancer-predisposing disorder characterized by variable clinical and molecular abnormalities. It is considered a spectrum ranging from classical BWS to isolated hemihyperplasia (IHH). This study sought to characterize Omani patients with BWS and IHH clinically and molecularly, evaluate their surveillance results, and assess the tumor's prevalence in the cohort. Nine patients with BWS were retrospectively recruited to the study by searching the medical records of Sultan Qaboos University Hospital between January 2012 and December 2022. Demographics, clinical features, molecular findings, and surveillance test results, including abdominal ultrasound and alpha-fetoprotein, were extracted from the hospital information system and systematically analyzed. Nine patients diagnosed with Beckwith-Wiedemann syndrome were studied, comprising four BWS cases and five IHH cases. Macroglossia was the predominant clinical feature among BWS patients, whereas lateralized overgrowth was consistently observed in IHH patients. All BWS patients tested positive for methylation anomalies: two exhibited loss of methylation at imprinting control 2 (22.2%), one had paternal uniparental disomy of chromosome 11 (11.1%), and another showed a gain of methylation at imprinting control 1 (11.1%). Throughout the surveillance period, none of the patients showed elevated alpha-fetoprotein levels or developed tumors. This is the first study to examine a cohort of patients with BW spectrum in Oman. It reveals comparable clinical and molecular characteristics to the previously reported BWS patients, yet no tumors were detected in this cohort.

Isolated lateralized overgrowth (ILO), formerly referred to as hemihyperplasia/hemihypertrophy, is the overgrowth of one-half of the body to its contralateral in the absence of a recognizable pattern of malformations or genetic syndromes. Our objective was to analyze the growth clinical and radiological characteristics of patients with ILO under follow-up in a tertiary care hospital in Argentina between 1993 and 2020. Retrospective, observational, single cohort study of patients with ILO. A total of 76 cases were included; 41 were males. Median years of follow-up: 5.85 (interquartile range [IQR]: 2.60-10.96), maximum: 15.76 years. Forty-eight of 76 patients had overgrowth compromising more than 1 body segment (complex ILO). The mean birth weight Z-score of term girls with complex ILO was +0.51 (standard deviation [SD]: 0.91) (p 0.022). Most children grew between the 50th and 97th centile of the Argentinian population height reference. The median leg length discrepancy was 1.5 cm (IQR: 1.01-2.2) in patients receiving medical treatment and 3.70 cm (IQR: 2.95-3.98 cm) in those who required epiphysiodesis. Progression of discrepancy ≤ 2 cm was observed in 75% of cases. Renal asymmetry ≥ 1 cm was observed in 8 cases; Wilms tumor was noted in 2 cases: mean age at diagnosis: 0.75 years. Prenatal growth of children with ILO is normal, except in girls with complex ILO, in whom it tends to be increased. The average height of boys and girls tends to be located in high centiles with normal growth over time. Embryonal tumor screening is recommended in this group of children. Introducción. El sobrecrecimiento lateral aislado (SLA), antes denominado hemihiperplasia/hemihipertrofia, se refiere al sobrecrecimiento corporal lateral en ausencia de un patrón reconocible de malformaciones o síndromes genéticos. El objetivo fue analizar el crecimiento y las características clínico-radiológicas de pacientes con SLA en seguimiento en un hospital de tercer nivel en Argentina entre 1993 y 2020. Población y métodos. Estudio retrospectivo, observacional, de una cohorte de pacientes con SLA. Resultados. Se incluyeron 76 casos, 41 varones. Mediana de años de seguimiento: 5,85 (rango intercuartílico [RIC] 2,60-10,96), máximo 15,76 años. Cuarenta y ocho de 76 pacientes presentaron sobrecrecimiento en más de un segmento corporal (SLA complejo). El puntaje Z promedio de peso al nacer de niñas de término con SLA complejo fue +0,51 (desviación estándar [DE] 0,91) (p 0,022). El crecimiento en estatura de la mayoría de los niños se ubicó entre los centilos 50 y 97 de la población de referencia. La mediana de asimetría de longitud de miembros inferiores fue 1,5 cm (RIC 1,01-2,2) en pacientes con tratamiento médico y 3,70 cm (RIC 2,95- 3,98 cm) en aquellos que requirieron epifisiodesis. El 75 % mostró una progresión de la asimetría menor o igual a 2 cm. Ocho casos presentaron asimetría renal mayor o igual a 1 cm; 2 casos presentaron nefroblastoma: edad promedio al diagnóstico 0,75 años. Conclusiones. El crecimiento prenatal de niños con SLA es normal, excepto en niñas con SLA complejo en quienes tiende a estar aumentado. La estatura promedio se ubica en centilos altos con crecimiento normal. Se recomienda realizar cribado de tumores embrionarios en este grupo de niños.

Hemihyperplasia and hemihypoplasia result in leg length discrepancy (LLD) by causing skeletal asymmetry. Beckwith-Wiedemann syndrome (BWS) and Silver-Russell syndrome (SRS) are opposite growth-affecting disorders caused by opposite epigenetic alterations at the same chromosomal locus, 11p15, to induce hemihyperplasia and hemihypoplasia, respectively. Because of their somatic mosaicism, BWS and SRS show a wide spectrum of clinical phenotypes. We evaluated the underlying epigenetic alterations and potential epigenotype-phenotype correlations, focusing on LLD, in a group of individuals with isolated hemihyperplasia/hemihypoplasia. We prospectively collected paired blood-tissue samples from 30 patients with isolated hemihyperplasia/hemihypoplasia who underwent surgery for LLD. Methylation-specific multiplex-ligation-dependent probe amplification assay (MS-MLPA) and bisulfite pyrosequencing for differentially methylated regions 1 and 2 (DMR1 and DMR2) on chromosome 11p15 were performed using the patient samples. Samples from patients showing no abnormalities in MS-MLPA or bisulfite pyrosequencing were analyzed by single nucleotide polymorphism (SNP) microarray and CDKN1C Sanger sequencing. We introduced a metric named as the methylation difference, defined as the difference in DNA methylation levels between DMR1 and DMR2. The correlation between the methylation difference and the predicted LLD at skeletal maturity, calculated using a multiplier method, was evaluated. Predicted LLD was standardized for stature. Ten patients (33%) showed epigenetic alterations in MS-MLPA and bisulfite pyrosequencing. Of these, six and four patients had epigenetic alterations related to BWS and SRS, respectively. The clinical diagnosis of hemihyperplasia/hemihypoplasia was not compatible with the epigenetic alterations in four of these ten patients. No patients showed abnormalities in SNP array or their CDKN1C sequences. The standardized predicted LLD was moderately correlated with the methylation difference using fat tissue (r = 0.53; p = 0.002) and skin tissue (r = 0.50; p = 0.005) in all patients. Isolated hemihyperplasia and hemihypoplasia can occur as a spectrum of BWS and SRS. Although the accurate differentiation between isolated hemihyperplasia and isolated hemihypoplasia is important in tumor surveillance planning, it is often difficult to clinically differentiate these two diseases without epigenetic tests. Epigenetic tests may play a role in the prediction of LLD, which would aid in treatment planning.

The reported incidence of isolated hemihyperplasia (IH) has a very wide range (from 1:13,000 to 1:86,000 live births) and further clarification is needed. We hypothesized that a survey of the birth prevalence of IH among newborn infants may underestimate the incidence of IH by overlooking late-onset cases. The prospective international multicenter study utilized the two-steps selection tool for an anonymous survey of volunteers of 15-18 years old. The initial step was "three measurements-three questions" screening, or "face-palms-calves survey". The subsequent step was an in-depth assessment of selected cases to exclude localized, lesional and syndrome-related cases as well as body asymmetry within normative range and to select suspected cases of IH. This step included measurements of various anatomical regions and a subsequent questionnaire. The participants that were selected in a risk group were advised to refer to medical institutions for clinical, genetic and instrumental investigation. Out of 6000 of selected participants (male, M 3452, female, F 2548), 229 (3.82%) were selected for detailed investigation and 57 (0.95%) were assigned to the risk group. Only 36 of them were actually referred to medical institutions and in two cases the diagnosis of IH was confirmed. Our survey indicated the prevalence of IH at the age of adolescence as approximately 1:3000. While IH is a hereditary genetic disorder, it may not be detected in newborns and infants and the true prevalence of the disease can be estimated if older age children are screened.