Molecular characterization of an embryonal rhabdomyosarcoma occurring in a patient with Kabuki syndrome: report and literature review in the light of tumor predisposition syndromes.

Kabuki syndrome is a well-recognized syndrome characterized by facial dysmorphism and developmental delay/intellectual disability and in the majority of patients a germline variant in KMT2D is found. As somatic KMT2D variants can be found in 5-10% of tumors a tumor predisposition in Kabuki syndrome is discussed. So far less than 20 patients with Kabuki syndrome and a concomitant malignancy have been published. Here we report on a female patient with Kabuki syndrome and a c.2558_2559delCT germline variant in KMT2D who developed an embryonal rhabdomyosarcoma (ERMS) at 10 years. On tumor tissue we performed DNA-methylation profiling and exome sequencing (ES). Copy number analyses revealed aneuploidies typical for ERMS including (partial) gains of chromosomes 2, 3, 7, 8, 12, 15, and 20 and 3 focal deletions of chromosome 11p. DNA methylation profiling mapped the case to ERMS by a DNA methylation-based sarcoma classifier. Sequencing suggested gain of the wild-type KMT2D allele in the trisomy 12. Including our patient literature review identified 18 patients with Kabuki syndrome and a malignancy. Overall, the landscape of malignancies in patients with Kabuki syndrome was reminiscent of that of the pediatric population in general. Histopathological and molecular data were only infrequently reported and no report included next generation sequencing and/or DNA-methylation profiling. Although we found no strong arguments pointing towards KS as a tumor predisposition syndrome, based on the small numbers any relation cannot be fully excluded. Further planned studies including profiling of additional tumors and long term follow-up of KS-patients into adulthood could provide further insights.

Hypermobility in individuals with Kabuki syndrome: The effect of growth hormone treatment.

Kabuki syndrome (KS) is a multiple congenital malformation syndrome which has been described across all ethnic groups. Most KS patients possess two genetic subtypes: KMT2D-associated, autosomal-dominant KS type 1 (KS1; OMIM 147920); and KDM6A-associated, X-linked-dominant KS type 2. Generalized joint hypermobility is one feature of KS, but its exact incidence and pattern is not well described in the literature. As part of our prospective study on the metabolic and growth effect of GH treatment, we assessed children from our Dutch Kabuki cohort who were eligible for growth hormone therapy. We assessed severity and pattern of joint hypermobility, both before and after 24 months of growth hormone replacement therapy. The prevalence of hypermobility was 31% in boys and 14% in girls using the Beighton score and 69% in boys and 57% in girls using the Bulbena score. This varies from the general population where girls are more affected. After 2 years of growth hormone treatment, there was a statistically significant decrease in the presence of joint hypermobility to 6% using the Bulbena score and none with respect to the Beighton score. We hypothesized that this result suggests a direct effect of growth hormone on connective tissue in patients with KS.

Growth Hormone Therapy in Children with Kabuki Syndrome: 1-year Treatment Results.

BACKGROUND/AIMS: Kabuki syndrome (KS) is a rare genetic malformation syndrome, resulting in characteristic features such as short stature. We investigate whether growth hormone (GH) treatment increases linear height and influences body proportions in KS children. METHODS: In this prospective study, 18 genetically confirmed prepubertal KS children (9 females and 9 males) aged from 3.8 to 10.1 years (mean 6.8 ± 2.1 years) were treated with recombinant human GH (rhGH) for 1 year. Calculations for height, height velocity, BMI, sitting height, and subischial leg length were made. Bone age, insulin-like growth factor (IGF-I), and IGF binding protein 3 (IGFBP-3) were also measured. RESULTS: This study showed an increase in height standard deviation score (SDS) for the whole group from -2.40 to -1.69 (p < 0.05) after 1 year of rhGH treatment. The change in height SDS within 1 year was >0.7 SDS for 10 subjects and >0.5 SDS for 3 subjects. The mean IGF-I SDS at the start of the study was -0.70 (±1.07), which increased after 12 months to 1.41 (±0.91) (p < 0.05). KS children who received rhGH at a younger age displayed significantly greater increases in height than those who started when they were older. The same was true for both gene mutation KMT2D versus KDM6A and for GH deficiency versus non-GH deficiency KS children (p < 0.05). Throughout the course of rhGH treatment, the subjects' body proportions remained normal. CONCLUSIONS: All participants experienced catch-up growth during the year of rhGH treatment, but without an influence on body proportions.

Growth pattern in Kabuki syndrome with a KMT2D mutation.

Kabuki syndrome is a multiple congenital malformation syndrome with a spectrum of clinical features including short stature. Since there is no growth data on Kabuki syndrome patients with a proven KMT2D gene mutation, further research on growth and growth patterns is indicated. Data for this growth study on subjects with Kabuki syndrome were collected from referring clinicians. Subjects were eligible for inclusion in the study if the following criteria were met: a genetically confirmed diagnosis of Kabuki syndrome and no current treatment with growth hormones or other drugs that could influence growth. We present a report on growth data (n = 39) in Kabuki syndrome patients. The data showed that postnatal growth retardation is a clinical feature in all cases. All Kabuki syndrome subjects showed a growth deflection during childhood and a diminution of the pubertal growth spurt. A genotype-phenotype correlation was not observed. Further research is required in order to determine whether a defect in the growth hormone/IGF-I axis and estrogen receptor plays a role in the growth retardation. © 2016 Wiley Periodicals, Inc.