Germline TGF-beta receptor mutations and skeletal fragility: a report on two patients with Loeys-Dietz syndrome.

Loeys-Dietz syndrome (LDS, OMIM # 609192) caused by heterozygous mutations in TGFBR1 and TGFBR2 has recently been described as an important cause of familial aortic aneurysms. These patients have craniofacial and skeletal features that overlap with the Marfan syndrome (MFS), and more importantly, have significant vascular fragility as is seen in MFS and Ehlers-Danlos syndrome Type IV (EDS-IV). The skeletal phenotype with respect to low bone mineral density and skeletal fragility is not clear. We present two patients with LDS with significant skeletal fragility. The first is a 17-year-old male who had talipes equinovarus, diaphragmatic and inguinal and herniae, aortic root dilatation necessitating surgical repair, craniofacial and skeletal dysmorphism consistent with LDS, and a history of numerous fragility fractures leading to significant skeletal deformity. He was found to be heterozygous for a c.923T > C transition in exon 4 of TGFBR2. The second is a 26-year-old male with submucous cleft palate, talipes equinovarus, pectus excavatum requiring surgery, inguinal hernia, and aneurysms in the ascending aorta, abdominal aorta, carotid, subclavian, vertebral and brachial arteries requiring surgical repairs. He also had craniofacial and skeletal dysmorphism consistent with LDS, multiple fractures in childhood, low bone mineral density, and was found to be heterozygous for a c.1561 T > C transition in exon 7 of TGFBR2. These case studies highlight the importance of paying close attention to fractures and bone density in patients with LDS. Osteopenia or osteoporosis may become increasingly important issues as earlier detection and treatment of the vascular complications of LDS improves life expectancy in these patients.

Ornithine transcarbamylase deficiency presenting as encephalopathy during adulthood following bariatric surgery.

BACKGROUND: Neurological complications following bariatric surgery are rare. Whereas nutritional deficiencies are the most common cause of neurological symptoms, the unmasking of previously subclinical metabolic disorders can also lead to significant morbidity. OBJECTIVE: To characterize the clinical presentation, serum biochemical fluctuations, and functional enzymatic analysis of a case of functional ornithine transcarbamylase deficiency unmasked by a dietary change following bariatric surgery. DESIGN: Case report. SETTING: Tertiary referral center, hospital (inpatient) setting. PATIENT: A 29-year-old woman who presented with intermittent encephalopathy associated with recurrent hyperammonemia. INTERVENTIONS: Clinical, biochemical, and mutational studies. RESULTS: The pattern of intermittent hyperammonemia and encephalopathy following oral and parenteral nutrition suggested a urea cycle abnormality. Functional enzymatic assay results showed markedly reduced ornithine transcarbamylase activity in the absence of known coding mutations. CONCLUSION: Previously asymptomatic ornithine transcarbamylase deficiency should be suspected in adult patients who develop recurrent hyperammonemia and encephalopathy following bariatric surgery.

A case of mosaic supernumerary ring chromosome 15 with two copies of the segment 15p11.1-q14.

Although supernumerary marker chromosomes derived from chromosome 15 (SMC(15)) are the most common marker chromosome in humans, ring SMC(15)s are rare. Here we report on a 16-month-old patient who has a ring SMC(15) with two copies of the segment 15p11.1-q14 region. She exhibits hypotonia, developmental delay, speech delay, microstomia, micrognathia, and other mild dysmorphic features. The ring was present in 22% of her peripheral blood lymphocyte cells. FISH study revealed that the ring was derived from chromosome 15, and had neither telomere sequence nor satellite III paracentromeric DNA. It had alpha satellite DNA, and two copies of the segment 15q11.2 to CTD 2125J1 (at 15q14, 2.2 Mbp telomeric of the common breakpoint 5). The ring-containing cells had four copies of 15p11.1-q14. The ring can be described as r(15)(::p11.1 --> q14::q14 --> p11.1::). Southern-blot analysis of the methylation pattern in the PW/AS critical region showed biparental inheritance, and the ring was maternally derived. This patient's phenotype was comparable to ring SMC(15) patients with three copies of the Prader-Willi/Angelman syndrome (PWS/AS) critical region.

Lack of evidence for an association between neurofibromatosis and pulmonary fibrosis.

STUDY OBJECTIVES: To reassess the association between neurofibromatosis and pulmonary fibrosis. DESIGN: Retrospective single-center study with analysis of patients' chest radiographs, CT scans, and medical records. SETTING: Tertiary care, referral medical center. PATIENTS: One hundred fifty-six adult patients with neurofibromatosis seen over a 6-year period between 1997 and 2002. RESULTS: A review of chest radiographs revealed abnormal findings in 70 patients (44.9%). The most common radiographic abnormalities were extrapulmonary nodules or masses seen in 22 patients (14.1%), followed by skeletal abnormalities in 16 patients (10.3%). Bilateral interstitial infiltrates were noted in only three patients (1.9%), all of whom had potential causes other than neurofibromatosis for their lung infiltrates, including smoking-related interstitial lung disease, rheumatoid lung disease, recurrent pneumonias, and a history of ARDS. CT scans were available in two of these patients and revealed nonspecific patterns of abnormalities with no honeycombing. Six patients had bullae or cystic airspaces demonstrated on chest radiography or CT scan; all of these findings occurred in the context of smoking-related emphysema. Combined together, bilateral interstitial lung infiltrates or cystic airspaces were demonstrated in five patients (3.2%) by chest radiography, and in eight patients (5.1%) by chest radiography or CT scanning; one patient had both findings on the CT scan. CONCLUSIONS: We found little evidence to support an association between neurofibromatosis and pulmonary fibrosis or any other form of parenchymal lung disease. Interstitial lung disease and bullae described in association with neurofibromatosis in previous reports may have, in part, represented smoking-induced manifestations.

Nonmosaic smallest duplication of 12q24.31-qter: the first reported case.

Duplication of the terminal region of the long arm of chromosome 12 is not common. In 13 previous cases, duplication of this region was generally associated with deletions of the derivative chromosomes, larger sized duplications or mosaicism. We have studied a young man with a nonmosaic duplication of 12q24.31-qter translocated to chromosome 5pter. This is the first reported case of pure subtle duplication involving less than two terminal subbands of 12q24.31 to qter. The origin of this genetic material was confirmed by whole chromosome paints and subtelomere specific FISH probes. As both the subtelomere signals for 5p and 12q were present in the der(5) chromosome, it is unlikely that there was any loss of unique DNA sequences from the terminal region of chromosome 5p. This case is compared with 13 other reported cases with a duplication of the 12q terminal segment.