the AJMG SEQUENCE
In this issue
Motor skill impairment in children with down syndrome and congenital heart defects
Preliminary data shows older infants with Down syndrome (DS) involving a particular congenital heart defect have more motor skill impairment than do similarly aged children with DS and a normal heart structure, write Visootsak et al (p. 2688).
Approximately half of all children with DS are born with a significant congenital heart defect (CHD), the most common of which is an atrioventricular septal defect (AVSD). As children with comorbid DS and CHDs increasingly survive cardiac surgery, determining their early development trajectories is important to devising early interventions to maximize their individual potential, say researchers.
The team compared scores on a test for cognitive, language, and motor skills in infants and toddlers between children with DS and ASVD and those with DS and normal heart structure. Mean ages for the 2 groups were 14.5 and 14.1 months, respectively.
Although the motor domain was the only one that showed a statistically significant difference between groups, both cognitive and language scores were lower in the ASVD group.
Noting their study is the first to examine the early developmental outcomes of children with DS and AVSD, the authors suggest their findings may help clinicians anticipate their patients' developmental issues. They also call for further studies of neurodevelopment in patients with DS with this heart defect.
NEWLY IDENTIFIED DISEASE AND GENE CAUSE PREMATURE AGING
Cabanillas et al (p. 2617) both describe a new progeria syndrome marked by premature aging and identify the culprit gene.
Figure 2, E-F. The patient's skull has widely open cranial sutures.
Caused by mutations in the BANF1 gene, Nestor—Guillermo progeria syndrome (NGPS) is distinct from other progerias, such as Hutchinson-Gilford progeria syndrome or mandibuloacral dysplasia, that involve aged appearance, growth retardation, decreased subcutaneous fat, thin limbs, and stiff joints.
Their description of the first 2 patients identified with NGPS comprises a unique phenotype. At age 24 and 32, both advanced ages for progeria patients, they have no signs of cardiovascular impairment, diabetes mellitus, or hypertriglyceridemia. In contrast, the patients suffer profound skeletal abnormalities that affect their quality of life. These include marked wear on bones, severe osteoporosis, and loss of fat tissue, the researchers write.
The researchers define NGPS as a chronic progeria because of its slow clinical course and patients' relatively long survival, despite the disease's early onset. Understanding the differences between progeria syndromes might contribute to the development of treatment strategies for common skeletal conditions, as well as aging itself, they write.
ECTOPIA LENTIS MAY INDICATE MARFAN SYNDROME
Zadeh et al (p. 2661) suggest FBN1 mutation analysis for Marfan syndrome (MFS) in patients who present with bilateral ectopia lentis, displacement or malposition of both eyes' crystalline lenses from their normal location.
MFS is a multisystem connective tissue disorder with primary involvement of the ocular, cardiovascular, and skeletal systems, which is usually marked by systemic manifestations.
The researchers report on 8 patients with MFS patients who initially presented with bilateral ectopia lentis (EL) during early childhood but lacked the systemic manifestations and did not fulfill the revised Ghent diagnostic criteria. But the patients all had demonstratable, disease-causing mutations in the FBN1 gene.
Because of these molecular test results, patients underwent cardiovascular imaging that led to the identification of mild aortic root changes in 7 of the 8 patients. The remaining patient had mitral valve prolapse with a normal appearing thoracic aorta.
These patients are at increased risk of cardiovascular complications, the researchers note, adding that the majority of these mutations occurred in the 5′ portion of the FBN1 gene and affected highly conserved cysteine residues, indicating a possible genotype-phenotype correlation.
Figure 1. Pedigree of Patient 7. Note the maternal relatives with ectopia lentis. I-1 died at 63 years of “kidney disease.” II-2 and II-3 had mild “kidney problems” and II-4 died at 44 years of age with “cystic kidneys.” died suddenly at the age of 13 years of unknown etiology. IV-4 is described in the paper in detail.
Patients with isolated features of EL need FBN1 mutation analysis so clinicians can provide prompt MS diagnosis, identification of risk for potentially life-threatening complications, and appropriate medical management, the researchers conclude.