Rationale and design of the familial hypercholesterolemia foundation CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia registry.
Academic Article
Overview
abstract
UNLABELLED: NOTE: THIS PUBLICATION HAS BEEN RETIRED. THIS ARCHIVAL VERSION IS FOR HISTORICAL REFERENCE ONLY, AND THE INFORMATION MAY BE OUT OF DATE. CLINICAL CHARACTERISTICS: 9q22.3 microdeletion, which includes deletion of PTCH1, the gene that is mutated in Gorlin syndrome (nevoid basal cell carcinoma syndrome), is characterized by the clinical findings of this well-described disorder as well as developmental delay and/or intellectual disability, metopic craniosynostosis, obstructive hydrocephalus, pre- and postnatal macrosomia, and seizures. Affected individuals are also at increased risk for Wilms tumor. Common findings in Gorlin syndrome include: calcification of the falx cerebri prior to age 20 years; basal cell carcinomas (BCCs) of the skin; jaw keratocysts; palmar/plantar skin pits; and increased risk for childhood medulloblastomas as well as cardiac and ovarian fibromas. The clinical spectrum of the 9q22.3 microdeletion is variable and the clinical findings depend somewhat on the size of the microdeletion. DIAGNOSIS/TESTING: The diagnosis of the 9q22.3 microdeletion is confirmed by demonstration of a heterozygous microdeletion at chromosome 9q22.3. The minimal critical region that is deleted recurrently in affected individuals (but not in controls) is 352 kb, and includes PTCH1 and FANCC. The 9q22.3 microdeletion cannot be identified by routine analysis of G-banded chromosomes or other conventional cytogenetic banding techniques, except with extremely large deletions. MANAGEMENT: Treatment of manifestations: Routine treatment and management by appropriate specialists for cardiac, neurologic, and dermatologic findings. Comprehensive physical, occupational, and speech therapy services as needed. Surgical intervention as needed for excision or treatment of mandibular keratocysts, basal cell carcinomas, or other tumors that develop, or for management or correction of physical anomalies. Prevention of primary manifestations: Limiting exposure to ionizing radiation, such as by computed tomography and x-rays. Surveillance: Routine monitoring of head circumference and neurologic status throughout childhood with prompt evaluation by a neurologist and/or neurosurgeon for increasing head size, behavioral changes, or change in consciousness for evidence of obstructive hydrocephalus, medulloblastoma, and/or other cerebral tumors. Regular abdominal ultrasound for Wilms tumor, similar to surveillance for Beckwith-Wiedemann syndrome, is recommended. In those over age eight years, orthopantogram every 12-18 months to identify jaw keratocysts and skin examination at least annually. Agents/circumstances to avoid: Excessive sun exposure; use of radiotherapy because of risk of developing multiple BCCs in the treated area. Pregnancy management: Cesarean section delivery may be required for affected fetuses with macrocephaly. GENETIC COUNSELING: The 9q22.3 microdeletion is inherited in an autosomal dominant manner. In the majority of individuals, the microdeletion appears to result from either a de novo event or inheritance of an unbalanced chromosome rearrangement from a parent with a balanced rearrangement; however, inheritance of a deletion from a symptomatic parent mosaic for the deletion has been reported. When neither parent has a balanced chromosome rearrangement or deletion, recurrence risk for future pregnancies is low (probably <5%), but greater than that of the general population because parents may have germline mosaicism or low-level somatic mosaicism that also includes the germline. Prenatal testing is possible for pregnancies at increased risk based on identification of a balanced chromosome rearrangement or a deletion in a parent, and for parents concerned about the possibility of germline mosaicism.
