Ingmar Gassner

Mutations in GDF5 Reveal a Key Residue Mediating BMP Inhibition by NOGGIN

Signaling output of bone morphogenetic proteins (BMPs) is determined by two sets of opposing interactions, one with heterotetrameric complexes of cell surface receptors, the other with secreted antagonists that act as ligand traps. We identified two mutations (N445K,T) in patients with multiple synostosis syndrome (SYM1) in the BMP–related ligand GDF5. Functional studies of both mutants in chicken micromass culture demonstrated a gain of function caused by a resistance to the BMP–inhibitor NOGGIN and an altered signaling effect. Residue N445, situated within overlapping receptor and antagonist interfaces, is highly conserved among the BMP family with the exception of BMP9 and BMP10, in which it is substituted with lysine. Like the mutant GDF5, both BMPs are insensitive to NOGGIN and show a high chondrogenic activity. Ectopic expression of BMP9 or the GDF5 mutants resulted in massive induction of cartilage in an in vivo chick model presumably by bypassing the feedback inhibition imposed by endogenous NOGGIN. Swapping residues at the mutation site alone was not sufficient to render Bmp9 NOG-sensitive; however, successive introduction of two additional substitutions imparted high to total sensitivity on customized variants of Bmp9. In conclusion, we show a new mechanism for abnormal joint development that interferes with a naturally occurring regulatory mechanism of BMP signaling.

Gastric lactobezoar - a rare disorder?

Gastric lactobezoar, a pathological conglomeration of milk and mucus in the stomach of milk-fed infants often causing gastric outlet obstruction, is a rarely reported disorder (96 cases since its first description in 1959). While most patients were described 1975-1985 only 26 children have been published since 1986. Clinically, gastric lactobezoars frequently manifest as acute abdomen with abdominal distension (61.0% of 96 patients), vomiting (54.2%), diarrhea (21.9%), and/or a palpable abdominal mass (19.8%). Respiratory (23.0%) and cardiocirculatory (16.7%) symptoms are not uncommon. The pathogenesis of lactobezoar formation is multifactorial: exogenous influences such as high casein content (54.2%), medium chain triglycerides (54.2%) or enhanced caloric density (65.6%) of infant milk as well as endogenous factors including immature gastrointestinal functions (66.0%), dehydration (27.5%) and many other mechanisms have been suggested. Diagnosis is easy if the potential presence of a gastric lactobezoar is thought of, and is based on a history of inappropriate milk feeding, signs of acute abdomen and characteristic features of diagnostic imaging. Previously, plain and/or air-, clear fluid- or opaque contrast medium radiography techniques were used to demonstrate a mass free-floating in the lumen of the stomach. This feature differentiates a gastric lactobezoar from intussusception or an abdominal neoplasm. Currently, abdominal ultrasound, showing highly echogenic intrabezoaric air trapping, is the diagnostic method of choice. However, identifying a gastric lactobezoar requires an investigator experienced in gastrointestinal problems of infancy as can be appreciated from the results of our review which show that in not even a single patient gastric lactobezoar was initially considered as a possible differential diagnosis. Furthermore, in over 30% of plain radiographs reported, diagnosis was initially missed although a lactobezoar was clearly demonstrable on repeat evaluation of the same X-ray films. Enhanced diagnostic sensitivity would be most rewarding since management consisting of cessation of oral feedings combined with administration of intravenous fluids and gastric lavage is easy and resolves over 85% of gastric lactobezoars. In conclusion, gastric lactobezoar is a disorder of unknown prevalence and is nowadays very rarely published, possibly because of inadequate diagnostic sensitivity and/or not yet identified but beneficial modifications of patient management.

Partial nephrectomy in a cystic partially differentiated nephroblastoma

Cystic partially differentiated nephroblastoma (CPDN) is a rare neoplastic disorder consisting of a well-demarcated cystic lesion of the kidney where blastemal or other embryonic cells are present in the septa of the cysts. Magnetic resonance imaging can detect the cystic character of the lesion and will produce imaging features that are highly suggestive of either CPDN or cystic nephroma (CN) (synonym: multilocular cyst of the kidney), a benign entity. Although malignant potential exists in CPDN, all cases reported to date have had a favorable prognosis after surgery alone. Partial nephrectomy is considered safe, and the treatment of choice in the newborn period. We report a case of CPDN in a newborn that was successfully treated with partial nephrectomy. More than five years after nephron sparing surgery, the involved kidney shows normal anatomical structure except for a diminished upper pole, no evidence of tumor recurrence and good renal function.

Disintegration of large gastric lactobezoars by N-acetylcysteine.

108 oar is a freely floating A gastric lactobez mass in the lumen of the stomach composed of undigested milk and mucous secretions. In infants and small toddlers it is the most common type of bezoar as compared with other bezoar types such as tricho-, phyto-, mixed food, or medication bezoars (1). The etiopathogenetic factors implicated are inadequate milk composition, and disturbed gastric emptying, which impedes food fragmentation as well as abnormal secretion of gastric acid, pepsin, and mucus. Bezoar formation has been reported with every type of milk, including human breast milk (2,3), cow’s milk, and cow’s milkor soy-based commercial infant formulas (4,5). Gastric lactobezoars may grow to considerable sizes. With a high index of suspicion, diagnosis can be easily made by plain or contrast radiography and, provided an experienced examiner, also by ultrasonography. Successful treatment measures include discontinuation of oral feeding, intravenous fluids, and gastric lavage (4,6). However, despite these therapies, in a few published cases lactobezoars did not disintegrate as expected and caused serious complications such as persistent gastric outlet obstruction or gastric perforation (7–12). We here describe 3 patients with large gastric lactobezoars that did not readily dissolve with the standard treatment of nil per mouth and intravenous fluids. Having in mind serious complications reported in the literature (8–10), we looked for options other than endoscopy or surgery to quickly disintegrate lactobezoars resistant to the established standard therapy. N-Acetylcysteine (ACC) has been known as an effective bronchial mucolytic agent for a long time and was successfully used for the treatment of a mixed food bezoar in an adult (13). We report for the first time the use of intragastric ACC for the rapid dissolution of large gastric lactobezoars in 3 female toddlers.

Lower Urinary Tract Anomalies of Urogenital Sinus and Female Genital Anomalies

Congenital anomalies of the female genital tract result from mullerian duct anomalies and/or abnormalities of the urogenital sinus or cloaca. Failure of fusion of the mullerian ducts results in a wide variety of fusion abnormalities of the uterus, cervix, and vagina (Gruenwald 1941). Mullerian duct abnormalities may occur alone or in association with urogenital sinus or cloacal malformations. Persistence of the cloaca is believed to be caused by an abnormal development of the dorsal part of the cloaca and the urorectal septum (Stephens 1983b; Nievelstein et al. 1998). Urogenital sinus malformations occur after the cloaca has been organized into the urogenital sinus and the anus (Williams and Bloomberg 1976). Early and complete assessment of the patients, including radiological and biochemical examinations, is mandatory to provide an optimal basis for treatment that will have a great influence on the quality of the patient’s later life. Due to the close embryologic relationship between the urinary and the genital tract, malformations involving both organ systems are very common. Understanding the development of the urogenital system is necessary to comprehend the full spectrum of congenital anomalies of the female genitalia.

Ultrasound of the Neonatal Thorax

As reflected by the other issues in this volume diseases of the newborn chest are commonly evaluated by means of the three dominant imaging modalities: conventional chest radiographs, computed tomography (CT) and magnetic resonance (MR).