A mutation in FBN1 disrupts profibrillin processing and results in isolated skeletal features of the Marfan syndrome.

Dermal fibroblasts from a 13-yr-old boy with isolated skeletal features of the Marfan syndrome were used to study fibrillin synthesis and processing. Only one half of the secreted profibrillin was proteolytically processed to fibrillin outside the cell and deposited into the extracellular matrix. Electron microscopic examination of rotary shadowed microfibrils made by the proband's fibroblasts were indistinguishable from control cells. Sequencing of the FBN1 gene revealed a heterozygous C to T transition at nucleotide 8176 resulting in the substitution of a tryptophan for an arginine (R2726W), at a site immediately adjacent to a consensus sequence recognized by a cellular protease. Six other individuals in the proband's family had the FBN1 mutation that segregated with tall stature. None of the affected individuals have cardiac or ocular manifestations of the Marfan syndrome. This mutation identifies a putative site for profibrillin to fibrillin processing, and is associated with isolated skeletal features of the Marfan syndrome, indicating that the FBN1 gene is one of the genes that determines height in the general population. The cellular effect of the mutation may be equivalent to a "null" FBN1 allele and may define the phenotype associated with FBN1 "null" alleles.

The use of different induction and maintenance chemotherapy regimens for the treatment of advanced yolk sac tumors.

Four children with yolk sac tumor were treated with an aggressive combination chemotherapy program. Three children had presacral primary tumors, one having pulmonary metastases, and one had a testicular primary tumor with pulmonary metastases. Three children were treated when they had measurable disease, and one had no measurable disease. The chemotherapy program consisted of a 6-wk induction period with vincristine (VCR), cis-diamminedichloroplatinum (DDP), and bleomycin. Maintenance therapy consisted of VCR, actinomycin D, and cyclophosphamide (cytoxan) every 3-4 wk as tolerated. Treatment was discontinued after 12 mo of complete remission. All three patients with evaluable disease had a partial response (PR) to induction therapy. Two underwent surgical exploration following induction therapy, one a laparotomy and the other a thoracotomy, and were found to have only scar tissue at the sites of presumed residual disease. The third child with measurable disease progressed to a clinical complete response (CR) during maintenance therapy. Two patients have had no evidence of disease (NED) for 42+ and 41+ mo since starting therapy (28+ and 27+ mo since completing treatment). Two patients are NED 11+ and 7+ mo since starting therapy and remain on treatment. We have encountered no significant renal or pulmonary toxicity, and there have been only two hospitalizations during maintenance therapy for fever and neutropenia. These preliminary results employing different induction and maintenance chemotherapy programs and planned second-look surgical intervention appear encouraging.

Prenatal cocaine exposure and fetal vascular disruption.

The question of the potential teratogenicity of cocaine has been raised by the increasing frequency of its abuse in the United States. In previous studies, an increased incidence has been documented of spontaneous abortion, placental abruption, prematurity, intrauterine growth retardation, and neurologic deficits in the infants of women who abused cocaine. More recently, it has been suggested in studies that fetal vascular disruption accompanying maternal cocaine abuse may lead to cavitary central nervous system lesions and genitourinary anomalies. In this article, 10 children born of women who abused cocaine are described, 9 of whom have congenital limb reduction defects and/or intestinal atresia or infarction. The spectrum of anomalies associated with embryonic and fetal vascular disruption accompanying maternal cocaine abuse is thus enlarged. The specific risk for congenital anomalies accompanying maternal cocaine abuse during an individual pregnancy is unknown. However, data from these patients and the available literature suggest that counseling pregnant women concerning cocaine use should incorporate warnings about the possibility of associated embryonic or fetal vascular disruption.

Holzgreve syndrome: recurrence in sibs.

We report on 2 sibs with cardiac and renal abnormalities. The first had hypoplastic left heart sequence and renal hypoplasia; the second had a complex congenital heart defect, renal agenesis, and cleft lip and palate. We suggest that these cases represent the first familial examples of the Holzgreve syndrome. As such, they demonstrate the phenotypic variability seen in sibs, and may serve to further delineate the syndrome.

Lethal bone dysplasia in a fetus with manifestations of atelosteogenesis I and Boomerang dysplasia.

Atelosteogenesis I (AT-I) and Boomerang dysplasia have been described as separate lethal bone dysplasias. The possibility of a common cause of both conditions was suggested by Hunter and Carpenter (Clin Genet 39(6): 471-480, 1991) in their report of a patient with apparent manifestations of both AT-I and Boomerang dysplasia. We report on a male fetus of 31 weeks gestation whose clinical, radiologic and histologic findings are compared to reported cases of AT-I, Boomerang dysplasia and the patient of Hunter and Carpenter (Clin Genet 39(6): 471-480, 1991). From the documentation of clinical and radiologic findings we demonstrate overlap of AT-I and Boomerang dysplasia in our patient, and, from histologic examination, suggest a defect of cartilage and bone formation as the basic abnormality in this lethal bone dysplasia.

Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) associated with interstitial deletion of band 3q22: review and gene assignment to the interface of band 3q22.3 and 3q23.

We report on a child with blepharophimosis, ptosis, and epicanthus inversus (BPES), developmental delay and an interstitial deletion of band q22 of chromosome 3. A review of chromosome 3q anomalies associated with eye abnormalities, specifically blepharophimosis and ptosis, strongly suggests that a locus for eyelid development is present at the interface of bands 3q22.3 and 3q23.

Najjar syndrome revisited.

We describe 2 brothers with cardiomyopathy and hypergonadotropic hypogonadism and conclude that this is the first description of the Najjar syndrome in the United States. The inheritance may be autosomal recessive.

Prenatally diagnosed de novo apparently balanced complex chromosome rearrangements: two new cases and review of the literature.

Complex chromosome rearrangements (CCR) are rare structural rearrangements. Currently six cases of prenatally diagnosed balanced de novo CCR have been described. We present two new cases of prenatally ascertained balanced de novo CCR. In the first case, an amniocentesis revealed a balanced de novo three-way CCR involving chromosomes 5, 6, and 11 with a pericentric inversion of chromosome 5 [four breaks]. In the second case, a balanced de novo rearrangement was identified by amniocentesis which involved a reciprocal translocation between chromosomes 3 and 8 and a CCR involving chromosomes 6, 7, and 18 [six breaks]. The use of whole chromosome painting helped elucidate the nature of these rearrangements. A review of the postnatally ascertained cases suggests that most patients have congenital anomalies, minor anomalies, and/or developmental delay/mental retardation. In addition, there appears to be a relationship between the number of chromosome breaks and the extent of phenotypic effects. The paucity of information regarding prenatally diagnosed CCR and the bias of ascertainment of postnatal CCR cases poses a problem in counseling families.

Gaucher's disease: a case history with extensive lipid storage in the brain.

Patients with acute infantile or type II neuropathic Gaucher's disease demonstrate neurologic deficits that are seemingly greater than the extent of the central nervous system involvement found at autopsy. Examination of the brain of an affected child shows widespread deposition of lipid in a pattern not recognized heretofore. Based on these observations, the authors hypothesize that widespread deposition of the Gaucher glucocerebroside elicits a mild tissue response, which functionally becomes highly significant.

Intramural hematoma of the duodenum.

Intramural duodenal hematoma in children is one of the least common injuries encountered. Because of the rarity of this problem, there has been little conformity of opinion as to the relative merits of operative vs nonoperative management. We reviewed 182 cases of this condition, of which 168 were taken from the English literature and 14 from our hospital. Pancreatitis was the most common associated intra-abdominal lesion (21%), while central nervous system, skeletal, and thoracic injuries (5%) accounted for the major extra-abdominal injuries. Hemophilia, von Willebrand's disease, and idiopathic thrombocytopenic purpura occurred in 7 cases and played a major role in the prognosis. Of these cases, 121 patients were treated surgically and 61 conservatively. The average hospitalization was 14 days for the surgical group and 11 days for the conservative group. There were 18 complications in the surgical group. It appears that most patients with intramural duodenal hematoma would respond well to conservative management. Surgery should be reserved for those cases that remain obstructed over seven to ten days or have evidence of perforation.

Presentation of congenital diaphragmatic hernia past the neonatal period.

Congenital diaphragmatic hernias (CDHs) presenting beyond the neonatal period are a rare and unusual problem; they occurred in 11 of 83 children at our institution. Two discrete clinical groups were apparent: (1) younger children, with mainly respiratory symptoms; and (2) older children with gastrointestinal (GI) complaints. Chest roentgenograms suggested CDHs, but GI contrast studies were necessary for confirmation in eight patients. The diagnosis was made preoperatively in ten of 11 children. At operation, no peritoneal sacs were found, the hernial contents were viable in all patients, and malrotation was present in six of 11 patients. None had evidence of pulmonary hypoplasia. Congenital diaphragmatic hernias do present beyond the neonatal age group in a significant number of cases (13% in our series), and a diagnosis of CDH should be considered in any child with persistent GI or respiratory problems and abnormal chest x-ray film findings. The mortality rate in these patients is small, but morbidity may be significant.

Velocardiofacial syndrome: incidence of immune cytopenias.

BACKGROUND: Velocardiofacial syndrome (VCFS) is associated with a broad clinical spectrum that frequently overlaps the DiGeorge syndrome. Both have been linked to chromosomal microdeletions of chromosome 22 (22q11.2). DiGeorge syndrome is associated with T-cell dysfunction. What is the incidence of immune cytopenias in children with VCFS? OBJECTIVES: To (1) identify, (2) characterize, (3) quantify, and (4) follow up the immunologic deficits in children initially seen in our institution with VCFS. DESIGN: Prospective clinical evaluation of patients with the features of VCFS. PATIENTS: Twenty consecutive children with the clinical diagnoses of VCFS. SETTING: Tertiary care children's hospital. MAIN OUTCOME MEASURES: All 20 children had genetics evaluation with chromosomal analysis. Immunologic evaluations included serum immunoglobulin concentrations, lymphocyte studies, and mitogen and antigen stimulation studies. RESULTS: Five (25%) of 20 children were noted to have T-cell dysfunction with a clinical presentation marked by recurrent upper respiratory tract infections. Three of these 5 children had resolution of the T-cell dysfunction over a 2-year period. The 2 children with persistent cytopenias combined with immunoglobulin dysfunction required intravenous IgG infusions to control their infections. CONCLUSIONS: Velocardiofacial syndrome is associated with an increased incidence of immune cytopenias and, thus, warrants evaluation in any child with the clinical diagnosis of VCFS. This immune deficit may be transient and depends on the age of the evaluation of the child.

Surgical management of hiatal hernia in children.

Hiatal hernia should be included in the differential diagnosis of all children with emesis and failure to thrive, since early diagnosis is imperative to prevent the irreversible esophageal damage from long-standing peptic esophagitis. The Nissen fundoplication as described in this paper appears to be far superior to gastropexy in preventing recurrence of gastroesophageal reflux. Colon interposition should be reserved for those cases in which hiatal herniorrhaphy is technically impossible. Successful repair of the hiatal hernia results in rapid improvement in the nutritional status of these children.

Omphalocele with pyloroduodenal obstruction by extrinsic hepatic compression: a case report.

The diagnosis of gastroduodenal obstruction by hepatic compression following omphalocele closure must be suspected in the presence of persistent nonbilious vomiting. We feel that computed tomography (CT) is the appropriate imaging method to define the liver abnormality. Nonsurgical management is the best approach with nutritional support maintained by total parenteral nutrition until physiological resolution of the obstruction occurs.

Acute scrotal swelling as the first evidence of intraabdominal trauma in a battered child.

Acute scrotal pathology often reflects intraabdominal disease. A bluish discoloration of the scrotum may represent blood migrating from a ruptured intraabdominal organ. A case of a battered child presenting with a swollen bluish scrotum is reviewed to draw attention to an early sign of intraperitoneal hemorrhage.

A long-term follow-up on a duplication of the entire small intestine treated by gastroduplication.

Duplication of the entire small intestine resulting in gastrointestinal hemorrhage was managed by excision of the ulcerogenic lesion, ileo-ileostomy, and diversion of the gastric-lined intestinal duplication into the stomach. A 25 yr followup study reveals no evidence of recurrent bleeding or malabsorption secondary to bind-loop syndrome. This operative procedure is worthy of consideration in patients with this congenital anomaly.

The umbilical polyp.

Anomalies of the omphalomesenteric duct (OMD) present a variety of surgical problems. The most readily apparent of these lesions is the umbilical polyp. One-third of patients explored at our hospital and 56% of patients reviewed had an additional OMD anomaly when explored for an umbilical polyp. The preferred treatment for this lesion should be a mini-laparotomy after the presence of intestinal mucosa at the umbilicus is confirmed.

The avoidable excesses in the management of perforated appendicitis in children.

During a five-year period from 1979 to 1985, 100 consecutive children with perforated appendicitis were managed at our institution. These patients were divided into two groups, which were determined by length of illness and physical findings. Group A consisted of 88 children with signs and symptoms of peritonitis from appendiceal perforation. They were treated with fluid resuscitation, antipyretics, and triple antibiotics (ampicillin, gentamicin, clindamycin), and appendectomy within a few hours of hospitalization. Saline lavage was used. Group B was composed of 12 patients with a periappendiceal mass without generalized peritonitis who had symptoms of 6 to 12 days duration. They were treated nonoperatively with triple antibiotics and underwent interval appendectomy 4 to 6 weeks later. The complication rate for Group A was 6.8%. This included three wound infections (3.4%), one intra-abdominal abscess (1.1%), one patient with pneumonia and ileus (1.1%), and a small bowel obstruction (1.1%). These results are equivalent to the lowest complication rate reported in the literature, in which the treatment included transperitoneal drainage, antibiotic lavage, and parenteral antibiotics. Group B patients had a 16.7% complication rate, which included one small bowel obstruction and one recurrent intra-abdominal abscess. Our method of management resulted in the lowest complication rate reported to date in children with perforated appendicitis. Transperitoneal drainage, delayed wound closure, and antibiotic lavage were not used. Subcuticular incisional closure resulted in minimal wound care and excellent cosmetic results. The experience demonstrates that with proper timing of surgery and appropriate use of contemporary antibiotics, the morbidity of perforated appendicitis can be limited and excesses of treatment can be avoided.

Advances in the management of infected urachal cysts.

Persistent urachal remnants are uncommon congenital anomalies. Unless an umbilical fistula exists, infection may be the first indication of this abnormality. Five children received initial treatment for this problem at the Children's Hospital of Buffalo during a 20-year period, 1964 to 1984, and a sixth was seen secondarily. There were four boys and two girls; their ages ranged from 8 months to 9 years. Lower abdominal mass with fever and local tenderness were the most common presenting signs. Ultrasound was the most accurate study, correctly diagnosing the cyst in both patients so examined. Incision and drainage alone was performed in one patient. The other five were managed with antibiotic therapy and complete excision as the primary procedure. Cultures were obtained in five patients and were positive in four, growing Staphylococcus aureus in three and Escherichia coli in one. Significant genitourinary abnormalities were discovered in four of the five patients evaluated. It is concluded that the previously recommended therapy of incision and drainage followed by delayed resection was developed in the preantibiotic era to minimize the mortality from sepsis and the morbidity from recurrence. Our experience indicates that the use of appropriate antibiotics followed promptly by complete cyst excision as a primary procedure is both possible and safe in most cases. Furthermore, the large number of associated genitourinary abnormalities suggests that a complete work-up for these conditions should be performed.

Percutaneous central venous catheterization in children: first line choice for venous access.

Percutaneous central venous (CV) catheters using the jugular and subclavian veins have been widely used for hemodynamic monitoring and for venous access in difficult clinical situations. However, peripheral venous cutdowns (PVC) still remain the primary mode of short-term venous access in children. To evaluate percutaneous CV line insertion as a routine procedure, a prospective study of 115 patients (75 CV and 40 PVC) was performed. Ages ranged from 1 day to 17 years; age and weight were similar in both groups. Eighty-three CV lines were attempted, with a success rate of 93%, while 82% of 49 PVC insertions were successful. Complications occurred in 11 (14%) patients with CV access and 31 (78%) with PVC lines. In the latter group, poor flow was a problem in 65%, infiltration in 37.5%, and phlebitis in 27.5%. In the CV group, arterial puncture occurred during insertion in 2 (3%) patients with no adverse sequelae, catheter slippage occurred in 4 (5%), and poor flow in 2 (3%). A large majority (79.2%) of CV lines functioned successfully until no longer needed, as compared with 15% of PVC catheters. The latter were removed before completion of treatment because of poor flow (40%), phlebitis (20%), or catheter problems (10%). Catheter sepsis was documented in only one CV line. Two cutdowns had major local infections. The average catheter longevity was 10.2 days for CV lines, 4.1 days for PVC.(ABSTRACT TRUNCATED AT 250 WORDS)