ルビンシュタイン・テイビ症候群

OBJECTIVE: This study describes the social-communication and behavioral profile associated with Kabuki syndrome (KS), including exploratory comparisons between individuals with a pathogenic variant in KMT2D (KS1) versus KDM6A (KS2). METHOD: Thirty-five caregivers of children/adults with KS (25F, Mage = 13.45, SD = 7.60) completed the Social Responsiveness Scale 2nd Edition (SRS-2), Colorado Learning Difficulties Questionnaire, and/or Strengths and Difficulties Questionnaire. Descriptive analyses and non-parametric tests were conducted to examine behavioral trends in the entire cohort and to explore differences in social behaviors and autism characteristics between those with KS1 versus KS2. RESULTS: About a third of the sample have a prior diagnosis of autism spectrum disorder, with rates more elevated in KS2 versus KS1 (67% vs. 23%). In the full cohort, 72% fell in borderline/clinical ranges for Peer Problems, while only 3% yielded atypical scores for Prosocial Behaviors. Those with KS1 were rated to show most challenges in restricted/repetitive behaviors (RRBs), which fell in the moderately severe range, compared to other social domains (social communication, social awareness, social motivation). In contrast, social motivation was the sole area rated within normal limits. CONCLUSION: Those with KS2 showed greater difficulties across all social behavior/cognitive domains than KS1 counterparts, albeit both presented with similar severity in RRB and prosocial behaviors. Prominent features of the KS social behavioral phenotype include pronounced difficulties with inflexible behaviors and restricted interests juxtaposed with strong prosocial tendencies. KS2 may confer increased risk for autism-related characteristics, underscoring the need for more systematic investigations.

INTRODUCTION AND IMPORTANCE: Brachymetatarsia is a rare deformity characterized by abnormal shortening of one or more metatarsals due to premature physeal closure. If conservative treatment fails, surgical options such as one-stage lengthening or progressive distraction with an external fixator are the usual alternatives. This report presents the case of a patient with type 1 Rubinstein-Taybi syndrome and first-metatarsal brachymetatarsia, who was treated by progressive distraction with a hexapod external fixator. This is the first such case reported in the literature. PRESENTATION OF CASE: An 11-year-old girl presented with plantar pain and central metatarsal keratosis in the left foot. After 1 year of unsuccessful conservative treatment, progressive distraction with a hexapod external fixator was indicated to achieve multiplanar correction. Distraction began 7 days later at a rate of 1 mm per day. Premature healing required a second osteotomy, while a metatarsophalangeal subluxation was corrected by fixator adjustment. Two superficial infections were resolved with antibiotic therapy. The fixator was removed at 6 months after achieving 40 mm of lengthening and 12 mm of plantar translation, with a homogeneous regenerate. At 24 months, the patient had complete symptom resolution and substantially normalized function. CLINICAL DISCUSSION: Progressive distraction using a hexapod external fixator can serve as an effective alternative in cases requiring extensive lengthening and multiplanar corrections. CONCLUSION: This is the first documented case in which brachymetatarsia was treated using a hexapod system, achieving a healing index of 45 days per centimeter and a final AOFAS score of 85.

Menke-Hennekam syndrome types 1 and 2 (MKHK1 and MKHK2) are autosomal dominant neurodevelopmental disorders characterized by psychomotor developmental delay, intellectual disability, and dysmorphic features. MKHK1 is caused by heterozygous variants in exons 30-31 of the CREBBP gene, whereas MKHK2 results from heterozygous variants in EP300. Although these genes are classically associated with Rubinstein-Taybi syndrome (RTS), Menke-Hennekam syndrome presents a distinct phenotype despite involvement of the same alleles. We report 2 patients who exhibited developmental delay, intellectual disability, and dysmorphic features without typical RTS findings. Genetic analysis revealed a novel frameshift variant in EP300 in one patient and a de novo missense variant in CREBBP in the other. Long-term follow-up and increasing use of whole-exome sequencing have facilitated recognition of Menke-Hennekam syndrome as a distinct clinical entity. Reporting 2 patients with exon 31 variants in CREBBP and EP300, we aim to improve awareness and diagnostic accuracy of this rare disorder.

BACKGROUND: Rubinstein-Taybi syndrome (RTS) is a rare autosomal dominant disorder defined by intellectual disability, short stature, broad thumbs and halluces, and distinct craniofacial features. The genetic etiology of RTS is primarily attributed to point mutations or deletions in the CREB-binding protein gene (CREBBP) or the E1A-binding protein gene (EP300). Endocrine abnormalities in RTS remain underreported. CASE PRESENTATION: A 7-year-9-month-old girl with characteristic facial features of RTS presented with growth retardation [height -2.09 standard deviation score (SDS)] and premature thelarche. Genetic and endocrinological assessments confirmed EP300-mutated RTS complicated by growth hormone deficiency (GHD) and central precocious puberty (CPP). Sequential therapy was initiated: recombinant human growth hormone (rhGH) monotherapy, followed by combination therapy with rhGH and gonadotropin-releasing hormone analog (GnRHa), and ultimately transitioned to GnRHa monotherapy. Her height SDS reached a peak of -0.19 during rhGH therapy. Following rhGH withdrawal, her height SDS dropped to -0.48 at 10 years and 7 months of age. Her body mass index (BMI) increased from 13.88 to 20.68 kg/m2 throughout the clinical course. CONCLUSIONS: In children with EP300-mutated RTS and short stature, evaluation for GHD via growth hormone stimulation testing should be considered, as rhGH and GnRHa therapy is effective. However, in children with RTS who have not yet reached final adult height and retain residual growth potential, premature rhGH withdrawal may compromise acquired height benefits and exacerbate weight gain. Regular monitoring of growth velocity, pubertal progression, and metabolic parameters is essential to optimize long-term outcomes.

Rubinstein-Taybi syndrome type 2 (RSTS2) results from pathogenic variants in the EP300 gene, manifesting with intellectual disability, facial dysmorphism, and multisystem anomalies. Variants of uncertain significance (VUS) require family segregation studies for reclassification. A 17-year-old male adolescent with intellectual developmental disorder and autism spectrum disorder (ASD) presented at the age of 12 with pneumonia complicated by severe infection, bilateral pleural effusion, and rupture of the left renal excretory system. A multigene panel identified a VUS in the EP300 gene (c.4331_4332delinsGA; p.Asp1444Gly). Family segregation analysis demonstrated a de novo origin, allowing reclassification as likely pathogenic and establishing the diagnosis of RSTS2. This case highlights the value of family segregation analysis for VUS reclassification in autosomal dominant disorders. The associated urinary abnormalities and severe infectious manifestations reinforce the importance of multidisciplinary assessment and long-term follow-up in patients with RSTS2.