Expanding the Phenotypic Spectrum of TRAF7-Related Cardiac, Facial, and Digital Anomalies With Developmental Delay: Report of 11 New Cases and Literature Review.

BACKGROUND: TRAF7-related cardiac, facial, and digital anomalies with developmental delay (CAFDADD), a multisystemic neurodevelopmental disorder caused by germline missense variants in the TRAF7 gene, exhibits heterogeneous clinical presentations. METHODS: We present a detailed description of 11 new TRAF7-related CAFDADD cases, featuring eight distinct variants, including a novel one. RESULTS: Phenotypic analysis and a comprehensive review of the 58 previously reported cases outline consistent clinical presentations, emphasizing dysmorphic features, developmental delay, endocrine manifestations, and cardiac defects. In this enlarged collection, novelties include a wider range of cognitive dysfunction, with some individuals exhibiting normal development despite early psychomotor delay. Communication challenges, particularly in expressive language, are prevalent, necessitating alternative communication methods. Autistic traits, notably rigidity, are observed in the cohort. Also, worth highlighting are hearing loss, sleep disturbances, and endocrine anomalies, including growth deficiency. Cardiac defects, frequently severe, pose early-life complications. Facial features, including arched eyebrows, contribute to the distinct gestalt. A novel missense variant, p.(Arg653Leu), further underscores the complex relationship between germline TRAF7 variants and somatic changes linked to meningiomas. CONCLUSIONS: Our comprehensive analysis expands the phenotypic spectrum, emphasizing the need for oncological evaluations and proposing an evidence-based schedule for clinical management. This study contributes to a better understanding of TRAF7-related CAFDADD, offering insights for improved diagnosis, intervention, and patient care.

Heterozygous MAP3K20 variants cause ectodermal dysplasia, craniosynostosis, sensorineural hearing loss, and limb anomalies.

Biallelic pathogenic variants in MAP3K20, which encodes a mitogen-activated protein kinase, are a rare cause of split-hand foot malformation (SHFM), hearing loss, and nail abnormalities or congenital myopathy. However, heterozygous variants in this gene have not been definitively associated with a phenotype. Here, we describe the phenotypic spectrum associated with heterozygous de novo variants in the linker region between the kinase domain and leucine zipper domain of MAP3K20. We report five individuals with diverse clinical features, including craniosynostosis, limb anomalies, sensorineural hearing loss, and ectodermal dysplasia-like phenotypes who have heterozygous de novo variants in this specific region of the gene. These individuals exhibit both shared and unique clinical manifestations, highlighting the complexity and variability of the disorder. We propose that the involvement of MAP3K20 in endothelial-mesenchymal transition provides a plausible etiology of these features. Together, these findings characterize a disorder that both expands the phenotypic spectrum associated with MAP3K20 and highlights the need for further studies on its role in early human development.

Platelet Dysfunction in Noonan and 22q11.2 Deletion Syndromes in Childhood.

INTRODUCTION: An underlying thrombocytopathy seems to be responsible for hemorrhagic symptoms in patients diagnosed with 22q11.2 deletion syndrome (22q11DS) or Noonan syndrome (NS). In 22q11DS, it is explained by a defect in the membrane glycoprotein (GP) complex Ib-V-IX. The cause of thrombocytopathy in NS remains unclear. AIM: The objective is to study the incidence of thrombocytopathy in pediatric patients diagnosed with 22q11DS or NS assessing the utility of ISTH-BAT questionnaire and laboratory techniques. MATERIALS AND METHODS: Prospective study between March and December 2018 in children (2-18 years old) diagnosed with 22q11DS or NS. Hemorrhagic symptoms using ISTH-BAT score, total cell blood count, platelet indices, PFA-200 closure times, and platelet aggregation were evaluated in all patients and membrane GP expression in 22q11DS patients. RESULTS: Nearly 70% of NS patients (n = 22) had a platelet aggregation defect without thrombocytopenia. A defect of platelet aggregation with adenosine diphosphate (ADP) and epinephrine was the most frequent pattern. A statistically significant inverse correlation between closure times and aggregation with arachidonic acid (p = 0.049, p = 0.043) and epinephrine (p = 0.021, p = 0.035), and ADP (p = 0.117, p = 0.05) was found. Total 5 out of 29 patients diagnosed with 22q11DS had macrothrombocytopenia; more noteworthy in older patients. Twenty-six patients showed an impairment in ristocetin-induced platelet aggregation that correlated with prolonged collagen/epinephrine (p = 0.034) and collagen/ADP (p = 0.01). A significant association between ISTH-BAT score >3 and closure times (p = 0.022, p = 0.002) and aggregation defect with ristocetin (p = 0.043) was also demonstrated. CONCLUSION: Most NS and 22q11DS patients show an impairment of platelet aggregation that correlates with closure times. In 22q11DS patients, these results were also related to hemorrhagic symptoms.