Janice C. Palumbos

Clinical characteristics and natural history of Freeman-Sheldon syndrome

OBJECTIVE. Freeman-Sheldon syndrome (FSS) is a rare, multiple congenital contracture syndrome that is nonetheless relatively well-known, because affected children have a striking appearance: it was historically called “whistling-face syndrome” because of involvement of the facial muscles. FSS is often confused with other congenital contracture syndromes and, as a result, the clinical characteristics and natural history are poorly understood. The objective of this study was to analyze the presentation, natural history, and outcome of a cohort of individuals ascertained using strict diagnostic criteria for FSS. METHODS. Data from questionnaires, medical charts, examination, and photographs were analyzed to describe the physical features, therapeutic interventions, and functional outcomes in 73 individuals referred with the diagnosis of FSS. RESULTS. Only 32 referred cases (∼40%) met diagnostic criteria for FSS. In addition to contractures, common features in these cases included severe scoliosis (85%), strabismus (42%), and hearing loss (30%). Most infants required supplementary feedings via a nasogastric (45%) or gastrostomy tube (17%). Children walked by an average age of 19 months, but ∼80% required ambulation-assist devices. An average of ∼10 surgeries was performed on each child, and anesthetic and/or surgical complications were reported in 50% of individuals. All individuals were cognitively normal. CONCLUSIONS. The clinical characteristics and natural history of FSS distinguish it from other forms of arthrogryposis, yet FSS is frequently misdiagnosed. Children with FSS require considerable nutritional, surgical, and rehabilitative intervention. Such intensive therapeutic demands differ substantially from most other congenital contracture syndromes. These findings underscore the necessity of making an accurate diagnosis.

Methodology of a multistate study of congenital hearing loss: Preliminary data from Utah newborn screening

A multistate Centers for Disease Control and Prevention (CDC) study was designed to investigate the etiology of congenital hearing loss in infants ascertained through state‐mandated hearing screening or early hearing loss detection and intervention (EHDI) programs. At least 50% of permanent childhood‐onset hearing loss is due to genetic causes, and approximately 20% of all infants with congenital hearing loss have mutations in the GJB2 gene. Another 1% of childhood hearing loss is due to mitochondrial DNA (mtDNA) mutations. The specific aims of this study are to 1) classify the etiology of congenital hearing loss in infants by doing prospective genetic evaluations of all newborns with permanent hearing loss from defined geographic areas, 2) determine the frequency of mutations in GJB2 and two common mitochondrial mutations in these populations, and 3) establish a model infrastructure linking genetic services to statewide EHDI programs. As of April 2003, Utah is the only center evaluating patients. Study subjects identified through the Utah Department of Health EHDI program are contacted by letter and offered a comprehensive medical genetics evaluation with DNA testing for GJB2 and mitochondrial mutations A1555G and A7445G. To date, 25 probands and their immediate family members have been evaluated. We have identified 20 cases with nonsyndromic hearing loss (7 multiplex and 13 simplex), 4 with syndromic hearing loss, and 1 with presumed cytomegalovirus (CMV)‐induced hearing loss. Six of 19 (32%) nonsyndromic cases with sensorineural hearing loss have mutations of one or both alleles of the GJB2 gene, and 21% are homozygous or compound heterozygotes for the 35delG mutation. No A1555G or A7445G mtDNA mutations have been found. Data reported to date include only children born in Utah, but EHDI programs in Hawaii, Rhode Island, and designated areas of Georgia have begun enrolling children in what is now a multistate collaborative study. This is the first comprehensive investigation to determine the etiology of hearing loss from populations ascertained through EHDI programs. The results of this study will facilitate the incorporation of genetic services into EHDI programs.

Karyotype/phenotype correlations in duplication 4q: Evidence for a critical region within 4q27‐28 for preaxial defects

Varying degrees of partial duplication of 4q (dup 4q) have been reported in over 70 patients since 1972 [reviewed by Lundin et al., 2002; Rinaldi et al., 2003]. The majority of the cases include partial trisomy with breakpoints at q25 to ter, mostly due to unbalanced inherited translocations. The different breakpoints, the associated monosomies, and the varying ages of reported patients make it difficult to delineate a recognizable syndrome. However, there are six patients reportedwithpreaxial defects, ranging from thumbhypoplasia to duplication, mostly having renal malformations as well. In the past, Zollino et al. [1995] suggested the presence of genes involved in the development of the acrorenal field at 4q22-23. Since then additional informative patients with partial 4q trisomy have been reported [Mikelsaar et al., 1995; Guillen Navarro et al., 1996; Goodman et al., 1997; Celle et al., 2000]. The karyotype-phenotype correlations derived from these recently described patients have moved the proposed critical region for preaxial defects (or acrorenal field defect) more telomeric to 4q25-28.Wedescribe twopatientswith dup 4q28.1 to ter and dup 4q31.3 to ter, respectively, the first one of which is especially helpful in elucidating the critical region for thumb defects in dup 4q.

Three novel GJB2 (connexin 26) variants associated with autosomal dominant syndromic and nonsyndromic hearing loss

Connexin 26 (Cx26), encoded by the GJB2 gene, is a key protein involved in the formation of gap junctions in epithelial organs including the inner ear and palmoplantar epidermis. Pathogenic variants in GJB2 are responsible for approximately 50% of inherited sensorineural deafness. The majority of these variants are associated with autosomal recessive inheritance; however, rare reports of dominantly co‐segregating variants have been published. Since we began offering GJB2 testing in 2003, only about 2% of detected GJB2 variants from our laboratory have been classified as dominant. Here we report three novel dominant GJB2 variants (p.Thr55Ala, p.Gln57_Pro58delinsHisSer, and p.Trp44Gly); two associated with syndromic sensorineural hearing loss and one with nonsyndromic hearing loss. In the kindred with the p.Thr55Ala variant, the proband and his father present with only leukonychia as a cutaneous finding of their syndromic hearing loss. This phenotype has been previously documented in conjunction with palmoplantar hyperkeratosis, but isolated leukonychia is a novel finding likely associated with the unique threonine to alanine change at codon 55 (other variants at this codon have been reported in cases of nonsyndromic hearing loss). This report contributes to the short list of GJB2 variants associated with autosomal dominant hearing loss, highlights the variability of skin and nail findings associated with such cases, and illustrates the occurrence of both syndromic and nonsyndromic presentations with changes in the same gene.

Variable expressivity and incomplete penetrance in a large family with non-classical Diamond-Blackfan anemia associated with ribosomal protein L11 splicing variant

Diamond‐Blackfan anemia (DBA) is a group of clinically and genetically heterogeneous bone marrow failure disorders with or without congenital anomalies. Variable expressivity and incomplete penetrance have been observed within affected families. Diamond‐Blackfan anemia‐7 (DBA7), caused by heterozygous mutations in ribosomal protein L11 (RPL11), accounts for approximately 5% of DBA. DBA7 is usually characterized by early‐onset bone marrow failure often accompanied by congenital malformations, especially thumb defects. Here, we present the case of a 2‐year‐old boy with chronic mild normocytic anemia, short stature, bilateral underdevelopment of the thumbs, atrial septal defect, and hypospadias. Hematological testing revealed slightly decreased hematocrit and hemoglobin, normal HbF, and elevated eADA. Family history included maternal relatives with thumb defects, but the mothers thumbs were normal. Clinical exome sequencing detected a maternally‐inherited RPL11 variant, c.396+3A>G, that is predicted to affect splicing. A family correlation study of the identified variant demonstrates segregation with thumb anomalies in the mothers family. RNA studies suggest that the variant produces an alternative transcript that is likely susceptible to nonsense‐mediated decay. This report summarizes the prevalence of non‐anemia findings in DBA7 and describes a non‐classical familial presentation of DBA7 more associated with thumb anomalies than with anemia.