Further delineation of the clinical spectrum of KAT6B disorders and allelic series of pathogenic variants.

PURPOSE: Genitopatellar syndrome and Say-Barber-Biesecker-Young-Simpson syndrome are caused by variants in the KAT6B gene and are part of a broad clinical spectrum called KAT6B disorders, whose variable expressivity is increasingly being recognized. METHODS: We herein present the phenotypes of 32 previously unreported individuals with a molecularly confirmed diagnosis of a KAT6B disorder, report 24 new pathogenic KAT6B variants, and review phenotypic information available on all published individuals with this condition. We also suggest a classification of clinical subtypes within the KAT6B disorder spectrum. RESULTS: We demonstrate that cerebral anomalies, optic nerve hypoplasia, neurobehavioral difficulties, and distal limb anomalies other than long thumbs and great toes, such as polydactyly, are more frequently observed than initially reported. Intestinal malrotation and its serious consequences can be present in affected individuals. Additionally, we identified four children with Pierre Robin sequence, four individuals who had increased nuchal translucency/cystic hygroma prenatally, and two fetuses with severe renal anomalies leading to renal failure. We also report an individual in which a pathogenic variant was inherited from a mildly affected parent. CONCLUSION: Our work provides a comprehensive review and expansion of the genotypic and phenotypic spectrum of KAT6B disorders that will assist clinicians in the assessment, counseling, and management of affected individuals.

Dental and craniofacial characteristics caused by the p.Ser40Leu mutation in IFITM5.

Severe forms of osteogenesis imperfecta (OI) are usually caused by mutations in genes that code for collagen Type I and frequently are associated with craniofacial abnormalities. However, the dental and craniofacial characteristics of OI caused by the p.Ser40Leu mutation in the IFITM5 gene have not been reported. We investigated a 15-year-old girl with severe OI caused by this mutation. She had marked deformations of extremity long bones. There were no clinical or radiological signs of dentinogenesis imperfecta, but one tooth was missing and several teeth were impacted. Cone beam computed tomography revealed a generalized osteopenic appearance of the craniofacial skeleton, bilateral enlargement of mandibular bodies, and areas of cortical erosions. The cranial base and skull showed a generalized granular bone pattern with a mixture of osteosclerosis and osteolysis. Sphenoid and frontal sinuses were congenitally missing. Cephalometric analysis indicated a Class III growth pattern. In this case, the IFITM5 p.Ser40Leu mutation did not affect tooth structure but was associated with deformities in craniofacial bones that resemble those in the other parts of the skeleton.

Evidence-Based Management of Patients with 45,X/46,XY Gonadal Dysgenesis and Male Sex Assignment: from Infancy to Adulthood.

45,X/46,XY gonadal dysgenesis is a disorder of sexual differentiation with a wide clinical presentation, ranging from Turner-like females to individuals with genital ambiguity to azoospermic but otherwise normal-appearing males. Hence, patients can be assigned female or male sex. Female patients are managed according to the Turner Syndrome Guidelines, whereas males are managed on a case-by-case basis. Male patients present with multiple medical challenges: undervirilization, hypogonadism, gonadoblastoma risk, and short stature. Many require surgeries and hormonal treatments that are time-sensitive and irreversible. Nonetheless, these therapeutic decisions are made without evidence-based guidelines. This review describes the medical concerns and possible interventions in male patients with 45,X/46,XY dysgenesis for each stage of development. Interventions should be addressed within a patient-centered framework by a multidisciplinary team and after thorough discussion with the family. We use the GRADE system to appraise the existing evidence and provide recommendations based on the available evidence.

A Multidisciplinary Approach to Puberty and Fertility in Girls with Turner Syndrome.

Women with Turner Syndrome (TS) have a variety of medical needs throughout their lives; however, the peripubertal years are particularly challenging. From a medical perspective, the burden of care increases during this time due to growth optimization strategies, frequent health screenings, and puberty induction. Psychologically, girls begin to comprehend the long-term implications of the condition, including their diminished fertility potential. Unfortunately, clear guidelines for how to best approach this stage have not been established. It remains to be determined what is the best age to begin treatment; the best compound, dose, or protocol to induce puberty; how, when or what to discuss regarding fertility and potential fertility preservation options; and how to support them to accept their differences and empower them to take an active role in their care. Given the complexity of this life stage, a multidisciplinary treatment team that includes experts in endocrinology, gynecology, and psychology is optimal.

Referring patients for a medical genetics consultation and genetic counseling.

Clinical geneticists and genetic counselors provide diagnosis and counseling for genetic disorders affecting every organ system and every age group. Genetic counselors are more focused on informing patients and families about the inheritance of a genetic disorder and providing recurrence risk counseling, support and information about a diagnosis and reproductive options. Medical geneticists may also share some of these roles in addition to establishing a diagnosis and providing medical management. Medical Geneticists receive training in ACGME-accredited residency programs and are certified by the American Board of Medical Genetics. Genetic counseling is a masters degree program and certification is granted by the American Board of Genetic Counseling. When a patient/family is referred to a Clinical Geneticist, they may expect a thorough evaluation in an effort to establish a diagnosis that may provide information about etiology, prognosis, therapy and recurrence risk.