Utility of Genetic Testing in Fetal Alcohol Spectrum Disorder.

OBJECTIVE: To study the utility of genetic evaluation and testing in patients with suspected fetal alcohol spectrum disorder (FASD). STUDY DESIGN: We performed a retrospective chart review of all patients (n = 36) referred for evaluation for suspected FASD to the genetics clinic at Boston Children's Hospital between January 2006 and January 2013. Records of all patients were reviewed to obtain the medical history, family history, examination findings, and investigations, including genetic testing. RESULTS: Of the 36 patients, definite prenatal exposure was documented in 69%. Eight patients did not fulfill clinical criteria for FASD. Chromosomal microarray analysis (CMA) detected 19 copy number variants (CNVs) in 14 patients. Among patients who fulfilled criteria for FASD and underwent CMA, pathogenic CNVs were detected in 3 patients (2q37del, 22q11.22dup, and 4q31.21del syndromes), giving a yield of 14.3%. All 3 patients had overlapping features between FASD and the genetic syndrome. CONCLUSION: Genetic testing, especially CMA, should be considered in patients referred for evaluation of FASD, as a significant proportion have a clinically significant CNV even when they fulfill diagnostic criteria for FASD spectrum.

Musculoskeletal Conditions in a Pediatric Population with Ehlers-Danlos Syndrome.

OBJECTIVE: To describe musculoskeletal conditions in children with Ehlers-Danlos syndrome (EDS). STUDY DESIGN: A retrospective medical record review was performed, which evaluated 205 patients with EDS (ages 6-19 years) seen in sports medicine or orthopedic clinic at a large pediatric hospital over a 5-year period. RESULTS: Female (n = 147) and male (n = 57) patients were identified (mean age 12.7 years). The most common EDS subtype (55.6%) was hypermobility type. Patients had between 1 and 69 visits (median 4), and 764 diagnoses were recorded, most commonly laxity/instability, pain, subluxation, and scoliosis/spinal asymmetry. Nearly one-half of patients (46.8%) received a general diagnosis of pain because no more specific cause was identified, in addition to 8.3% who were diagnosed with chronic pain syndrome. The most common sites of presenting issue were knee (43.4%), back (32.2%), and shoulder (31.2%). Over three-fourths (77.1%) of patients had imaging. Most (88.1%) were prescribed physical therapy and/or other conservative measures, such as rest (40.5%), orthotics (35.6%), and medication (32.2%). Surgery was recommended to 28.8% of the study population. CONCLUSIONS: Many pediatric and adolescent patients with EDS experience joint pain, instability, and scoliosis, along with other musculoskeletal issues. Despite extensive workup, the etiology of pain may not be identified. Large numbers of office visits, imaging studies, treatment prescriptions, and specialist referrals indicate considerable use of medical resources and highlight a great need for injury prevention and additional study.

Whole exome sequencing reveals a novel mutation in CUL7 in a patient with an undiagnosed growth disorder.

We present the case of a 19-year-old man with a growth disorder, which was undefined, despite extensive evaluation. Whole exome sequencing demonstrated a novel homozygous frameshift mutation in CUL7, one of the causative genes of 3-M syndrome. We discuss the utility of exome sequencing in diagnosing rare disorders.

Alcohol dehydrogenase 2 genotypes, maternal alcohol use, and infant outcome.

OBJECTIVE: To determine whether different alleles of the ADH2 gene (ADH2-1, ADH2-2 and ADH2-3) with differing levels of enzymatic activity can alter the risk of fetal alcohol effects. STUDY DESIGN: ADH2 genotypes were performed on 404 pregnant high-risk women and 139 infants as part of a larger study of alcohol use in pregnancy. Mothers were interviewed about alcohol use during pregnancy, and their infants were examined for alcohol-related features without knowledge of the exposure status. RESULTS: The ADH2-1/3 genotype was more prevalent among black women (46%) than expected (33%); the rate among white women was low as expected (2%). More black women who reported high alcohol use during the pregnancy had the ADH2-1/3 genotype compared with those who reported no alcohol use (70% vs 44%). Sixty percent of the affected black infants had the ADH2-1/3 genotype compared with 29% of the unaffected infants (P <.045). The maternal genotype correlated with her chance of having an infant with alcohol-related physical features (odds ratio = 2.49). This association remained significant after accounting for confounders, such as smoking and maternal weight gain. Alcohol exposure was not significantly associated with infant outcome in black infants after accounting for genotype, smoking, and maternal weight gain, but this association could only be tested in 10 infants of mothers with high exposure. CONCLUSION: Women with the ADH2-1/3 genotype may be at greater risk for having an affected infant, which may be the result of greater ingestion of alcohol.