Melissa Maisenbacher

Overlapping spectra of SMAD4 mutations in juvenile polyposis (JP) and JP–HHT syndrome†

Juvenile polyposis (JP) and hereditary hemorrhagic telangiectasia (HHT) are clinically distinct diseases caused by mutations in SMAD4 and BMPR1A (for JP) and endoglin and ALK1 (for HHT). Recently, a combined syndrome of JP–HHT was described that is also caused by mutations in SMAD4. Although both JP and JP–HHT are caused by SMAD4 mutations, a possible genotype:phenotype correlation was noted as all of the SMAD4 mutations in the JP–HHT patients were clustered in the COOH‐terminal MH2 domain of the protein. If valid, this correlation would provide a molecular explanation for the phenotypic differences, as well as a pre‐symptomatic diagnostic test to distinguish patients at risk for the overlapping but different clinical features of the disorders. In this study, we collected 19 new JP–HHT patients from which we identified 15 additional SMAD4 mutations. We also reviewed the literature for other reports of JP patients with HHT symptoms with confirmed SMAD4 mutations. Our combined results show that although the SMAD4 mutations in JP–HHT patients do show a tendency to cluster in the MH2 domain, mutations in other parts of the gene also cause the combined syndrome. Thus, any mutation in SMAD4 can cause JP–HHT. Any JP patient with a SMAD4 mutation is, therefore, at risk for the visceral manifestations of HHT and any HHT patient with SMAD4 mutation is at risk for early onset gastrointestinal cancer. In conclusion, a patient who tests positive for any SMAD4 mutation must be considered at risk for the combined syndrome of JP–HHT and monitored accordingly.

Molecular Analysis Expands the Spectrum of Phenotypes Associated with GLI3 Mutations

A range of phenotypes including Greig cephalopolysyndactyly and Pallister‐Hall syndromes (GCPS, PHS) are caused by pathogenic mutation of the GLI3 gene. To characterize the clinical variability of GLI3 mutations, we present a subset of a cohort of 174 probands referred for GLI3 analysis. Eighty‐one probands with typical GCPS or PHS were previously reported, and we report the remaining 93 probands here. This includes 19 probands (12 mutations) who fulfilled clinical criteria for GCPS or PHS, 48 probands (16 mutations) with features of GCPS or PHS but who did not meet the clinical criteria (sub‐GCPS and sub‐PHS), 21 probands (6 mutations) with features of PHS or GCPS and oral‐facial‐digital syndrome, and 5 probands (1 mutation) with nonsyndromic polydactyly. These data support previously identified genotype–phenotype correlations and demonstrate a more variable degree of severity than previously recognized. The finding of GLI3 mutations in patients with features of oral–facial–digital syndrome supports the observation that GLI3 interacts with cilia. We conclude that the phenotypic spectrum of GLI3 mutations is broader than that encompassed by the clinical diagnostic criteria, but the genotype–phenotype correlation persists. Individuals with features of either GCPS or PHS should be screened for mutations in GLI3 even if they do not fulfill clinical criteria. Hum Mutat 31:1142–1154, 2010.

The Barth Syndrome Registry: Distinguishing disease characteristics and growth data from a longitudinal study

Barth syndrome (BTHS); MIM accession # 302060) is a rare X‐linked recessive cardioskeletal mitochondrial myopathy with features of cardiomyopathy, neutropenia, and growth abnormalities. The objectives of this study were to further elucidate the natural history, clinical disease presentation, and course, and describe growth characteristics for males with BTHS. Patients with a confirmed genetic diagnosis of BTHS are referred to the BTHS Registry through the Barth Syndrome Foundation, self‐referral, or physician referral. This study is based on data obtained from 73 subjects alive at the time of enrollment that provided self‐reported and/or medical record abstracted data. The mean age at diagnosis of BTHS was 4.04 ± 5.45 years. While the vast majority of subjects reported a history of cardiac dysfunction, nearly 6% denied any history of cardiomyopathy. Although most subjects had only mildly abnormal cardiac function by echocardiography reports, 70% were recognized as having cardiomyopathy in the first year of life and 12% have required cardiac transplantation. Of the 73 enrolled subjects, there have been five deaths. Growth curves were generated demonstrating a shift down for weight, length, and height versus the normative population with late catch up in height for a significant percentage of cases. This data also confirms a significant number of patients with low birth weight, complications in the newborn period, failure to thrive, neutropenia, developmental delay of motor milestones, and mild learning difficulties. However, it is apparent that the disease manifestations are variable, both over time for an individual patient and across the BTHS population.

Impaired cardiac reserve and severely diminished skeletal muscle O2 utilization mediate exercise intolerance in Barth syndrome

Barth syndrome (BTHS) is a mitochondrial myopathy characterized by reports of exercise intolerance. We sought to determine if 1) BTHS leads to abnormalities of skeletal muscle O(2) extraction/utilization and 2) exercise intolerance in BTHS is related to impaired O(2) extraction/utilization, impaired cardiac function, or both. Participants with BTHS (age: 17 ± 5 yr, n = 15) and control participants (age: 13 ± 4 yr, n = 9) underwent graded exercise testing on a cycle ergometer with continuous ECG and metabolic measurements. Echocardiography was performed at rest and at peak exercise. Near-infrared spectroscopy of the vastus lateralis muscle was continuously recorded for measurements of skeletal muscle O(2) extraction. Adjusting for age, peak O(2) consumption (16.5 ± 4.0 vs. 39.5 ± 12.3 ml·kg(-1)·min(-1), P < 0.001) and peak work rate (58 ± 19 vs. 166 ± 60 W, P < 0.001) were significantly lower in BTHS than control participants. The percent increase from rest to peak exercise in ejection fraction (BTHS: 3 ± 10 vs. control: 19 ± 4%, P < 0.01) was blunted in BTHS compared with control participants. The muscle tissue O(2) saturation change from rest to peak exercise was paradoxically opposite (BTHS: 8 ± 16 vs. control: -5 ± 9, P < 0.01), and the deoxyhemoglobin change was blunted (BTHS: 0 ± 12 vs. control: 10 ± 8, P < 0.09) in BTHS compared with control participants, indicating impaired skeletal muscle extraction in BTHS. In conclusion, severe exercise intolerance in BTHS is due to both cardiac and skeletal muscle impairments that are consistent with cardiac and skeletal mitochondrial myopathy. These findings provide further insight to the pathophysiology of BTHS.

Craniosynostosis: Another feature of the 22q11.2 deletion syndrome

We report on the presence of craniosynostosis in four patients with the 22q11.2 deletion. In light of previous reports of the association, we propose that the occurrence is higher than the general population incidence. Therefore, we suggest that craniosynostosis should be considered a manifestation of the 22q11.2 deletion and conversely that the 22q11.2 deletion should be considered in the differential diagnosis of craniosynostosis.

Identification of copy number variants associated with BPES-like phenotypes

Blepharophimosis–Ptosis–Epicanthus inversus syndrome (BPES) is a well-characterized rare syndrome that includes an eyelid malformation associated with (type I) or without premature ovarian failure (type II). Patients with typical BPES have four major characteristics: blepharophimosis, ptosis, epicanthus inversus and telecanthus. Mutations in the FOXL2 gene, encoding a forkhead transcription factor, are responsible for the majority of both types of BPES. However, many patients with BPES-like features, i.e., having at least two major characteristics of BPES, have an unidentified cause. Here, we report on a group of 27 patients with BPES-like features, but without an identified genetic defect in the FOXL2 gene or flanking region. These patients were analyzed with whole-genome high-density arrays in order to identify copy number variants (CNVs) that might explain the BPES-like phenotype. In nine out of 27 patients (33%) CNVs not previously described as polymorphisms were detected. Four of these patients displayed psychomotor retardation as an additional clinical characteristic. In conclusion, we demonstrate that BPES-like phenotypes are frequently caused by CNVs, and we emphasize the importance of whole-genome copy number screening to identify the underlying genetic causes of these phenotypes.