The Philadelphia story: the 22q11.2 deletion: report on 250 patients.

A submicroscopic deletion of chromosome 22q11.2 has been identified in the majority of patients with the DiGeorge, velocardiofacial, and conotruncal anomaly face syndromes, and in some patients with the Opitz G/BBB and Cayler cardiofacial syndromes. We have been involved in the analysis of DiGeorge syndrome and related diagnoses since 1982 and have evaluated a large number of patients with the deletion. We describe our cohort of 250 patients whose clinical findings help to define the extremely variable phenotype associated with the 22q11.2 deletion and may assist clinicians in providing genetic counseling and guidelines for clinical management based on these findings.

The 22q11.2 deletion: screening, diagnostic workup, and outcome of results; report on 181 patients.

A submicroscopic deletion of chromosome 22q11.2 has been identified in the majority of patients with the DiGeorge syndrome, velocardiofacial syndrome, conotruncal anomaly face syndrome, and in some patients with isolated conotruncal cardiac anomalies, Opitz G/BBB syndrome, and Cayler cardiofacial syndrome. We have evaluated 181 patients with this deletion. We describe our cohort of patients, how they presented, and what has been learned by having the same subspecialists evaluate all of the children. The results help define the extremely variable phenotype associated with this submicroscopic deletion and will assist clinicians in formulating a management plan based on these findings.

Comparison of self-referred and physician-referred patients to a pediatric diagnostic center.

Self-referral of children by parents without the knowledge of the child's regular physician can lead to redundant or unnecessary testing and difficulty in arranging follow-up care. This study was designed to investigate reasons for self-referral in a hospital-based pediatric diagnostic center. During the study period, 59 patients were referred by their regular physicians and 51 were self-referred. In multiple-choice questionnaires completed by 85% of the parents, nearly half (18/39; 46%) of those who were self-referred but only 2/51 (4%) of physician-referred parents said the child's regular physician was unconcerned about the medical problem. Further study on the causes for this perception is needed before recommendations can be made to physicians about demonstrating their concern to families.

Reliability of sleep sonography in detecting upper airway obstruction in children.

In children, lymphoid hyperplasia is by far the most common cause of airway obstruction during sleep, but the determination as to presence or degree of obstruction is seldom made objectively, because of the expense and stress of polysomnography. If audio recordings are made by parents at home with standardized equipment, however, obstruction can be recognized readily. Such recordings obtained from 50 patients were computer processed and the resulting displays were independently rated by two judges. Interobserver correlation was 0.87 and split-half reliability was 0.83, demonstrating very good reliability of the processing and scoring procedures. Recordings made on successive nights were highly consistent as well (test-retest reliabilities of 0.78 and 0.86 for the two raters). This recording method, which is well accepted by parents and children, has both clinical and research value in the assessment of airway obstruction.

General body growth in children with cleft palate and related disorders: age differences.

Clefts of the lip and palate, separately or in combination, are among the most frequent congenital defects seen today. Their etiology is heterogeneous and may include hormonal factors, which suggest the possibility of growth effects. Whether affected children are smaller than others has not been determined. We recently showed that growth status is associated with type of cleft. We hypothesized genetic alterations in metabolic pathways that alter prenatal growth, producing clefts; some of these alterations also alter postnatal growth. Since the levels of growth-regulating hormones change during ontogeny, we expected age differences in the degree of growth deficit seen. To test this hypothesis, we examine here the cross-sectional means and distributions of standard deviation (z) scores for height and body mass indices (BMIs) for 144 children with the diagnoses unilateral cleft lip and palate (uCLP) and isolated cleft palate (iCP). We find that alteration in growth status is associated with age group as well as sex and diagnosis.

General body growth in children with clefts of the lip, palate, and craniofacial structure.

This paper discusses general body growth in children with craniofacial clefts. Body growth is important in such patients because morphology reflects the cumulation of metabolism over time. The same hormones that direct general body growth also govern the ontogeny of the head and face. Body growth varies in children with different types of clefts. We found no average differences from US norms for those with isolated clefts of the lip alone or those with bilateral clefts of the lip and palate. Children with unilateral clefts of the lip and palate and with isolated cleft palate were significantly shorter than their unaffected peers. Males with these defects were also thinner than normal based on average standard deviation scores for body mass indices. Both unilateral and bilateral clefts of the lip and palate predominated in males, while isolated cleft lip was more frequent in females. Our results indicate that congenital metabolic variation contributes to the development of orofacial clefting and influences postnatal development in certain types of cleft. Accordingly, cleft type is important to growth prognosis, and growth status is relevant to optimization of therapy in orofacial cleft patients.

Hydrocephalus, cervical cord lesions, and spinal deformity.

Twenty-six children (4-16 years) had hydrocephalus and spinal deformity; 22 children had scoliosis over 50 degrees, and five children had kyphosis over 100 degrees. Twenty-one children had metrizamide enhanced cord CT scans, and 12 had additional head scans. Two children died, and one was autopsied. Three children had intracranial pressures monitored during spinal surgery. All children had Type I and II Arnold-Chiari malformations, 58% had cord cavitation (syringo/hydromyelia), 67% had cord tethering. The anatomic study showed extensive fibrosis and scarring of the upper cord and brain stem, but intraoperative studies showed that there is free transmission of fluid pressure wave from the cord across the foramen magnum with a consequent rise in intracranial pressure. This study documents frequent coexistence of spinal deformity and central nervous system lesions (hydrocephalus, Arnold-Chiari malformation, cord tethering with atresia, and cord cavitation). It supports the theory that the Arnold-Chiari malformation is a primary developmental deformity and that cord cavitation noted in these patients is primarily syringomyelia formed on the basis of ischemic necrosis within the cord. The free transmission of a fluid pressure wave from the cord to the lateral ventricle supports the Williams theory of propagation of syringomyelic cavities once they have developed. It is conjectural but likely that the CNS lesions cause spinal deformity by disrupting coordinating control of spinal musculature by the normal postural reflex mechanisms. Hydrocephalic patients who develop spinal deformity require thorough investigation for CNS lesions with head scans, CT scans, and metrizamide enhanced CT scans. NMR technology, however, may supplant techniques currently employed.

Relief of upper airway obstruction by adenotonsillectomy.

Adenotonsillectomy is often performed to relieve upper airway obstruction, even in children who do not present with severe apnea. Although adenotonsillectomy provides dramatic relief from obstructive sleep apnea, little evidence is available as to the efficacy of surgery in the far more prevalent cases of partial airway obstruction. We report the results of a prospective study of 100 children with adenotonsillar obstruction (without severe apnea) and 50 age-matched control children. The majority of patients exhibited appreciable sleep disturbances preoperatively, as compared to controls, and had substantial postoperative improvement, as demonstrated by parental questionnaire and sleep sonography--the computer-aided analysis of respiratory sounds. Mouth breathing and behavior problems were also prevalent preoperatively and were affected positively by adenotonsillectomy. It appears that surgery in such cases can have far-ranging benefits, even for the child whose obstruction does not demonstrate severe apnea.

The lateral neck radiograph in adenotonsillar hyperplasia.

In this study we have considered whether the lateral neck radiograph is useful in predicting the degree of airway obstruction, and whether supine and erect views are more useful than a single film. We evaluated the supine and erect lateral neck radiographs of 50 patients with upper airway obstruction due to enlarged tonsils and adenoids. Our results show that the supine radiograph, which is technically easier to perform, is entirely satisfactory for appraising the size of the tonsils and adenoids, but that neither view tells us much about the degree of airway obstruction during sleep.

The pathogenesis of progressive cavitation of the spinal cord.

It has been suggested that the pathogenesis of cord cavitation is multifactorial, but that there may be a common mechanism, if not for their actual cause then at least for the increase in size. A case is discussed in which the location of the cavitation suggested the cause was chronic ischemia of vascular origin.

Fever therapy: an educational intervention for parents.

Fever in children is a common problem, but one which often alarms parents. Parental misconceptions often lead them to unnecessarily aggressive and inappropriate management of fever in their children. A prospective controlled trial of an educational intervention to improve parental understanding and management of fever, involving the parents of 108 children, aged 6 months to 4 years, was performed in a private group practice. Although the majority of these patients were well educated, most were found to be misinformed about many aspects of the seriousness of fever and its management. Parents in the intervention group received a standardized interview in which the management of fever was discussed, demonstrated, and practiced. In addition, they received a printed information sheet for reinforcement 2 months after the initial interview. Parents in both the control group and intervention group revealed an increase in knowledge about fever over time, but only in the intervention group were inappropriate physician contacts and medication errors reduced. The effectiveness of an active learning approach to anticipatory guidance for the management of transient febrile illness was documented and it is suggested that extension of this approach to other common problems in the private practice setting be examined.

A thyroxine-binding protein in human breast milk similar to serum thyroxine-binding globulin.

A thyroid hormone-binding substance (TBGw) similar to serum T4-binding globulin (TBG) has been identified in the whey fraction of human breast milk. TBGw coeluted with serum TBG, as determined by Bio-Gel P-100 chromatography, and has an isoelectric point of 4.2-4.8, similar to that of serum TBG. The affinity constant of TBGw for T4 was similar to that of serum TBG(Ka, 1.54 +/- 0.38 X 10(9) M-1). Marked inhibition of TBGw binding of [125I]T4 was achieved by the addition of 1.5 X 10(-3) M 8-anilino-1-naphthalene-sulfonic acid. An albumin-like low affinity site (Ka, greater than 10(7) M-1) was also found. RIA of whey concentrates serially diluted in TBG-depleted serum indicated nearly identical binding curves for TBGw and TBG, with slopes of 2.33 (n = 15; r = 0.947) and 2.54 (n = 7; r = 0.996), respectively. Using a specific TBG RIA, a TBGw concentration of 0.29 +/- 0.08 microgram/ml (mean +/- SD) in breast milk (n = 26) was determined. Paired serum and whey specimens from individuals between 6 and 20 weeks of lactation were analyzed by TBG RIA; in these individuals, mean serum TBG concentrations were 25.0 +/- 3.4 micrograms/ml (n = 7); corresponding TBGw levels were 0.26 +/- 0.08 micrograms/ml (n = 7), i.e. approximately 1% of serum levels. Nonetheless, linear regression analysis of the data revealed no significant correlation between serum and whey TBG concentrations in these individuals.

Hip dislocation in cerebral palsy: selection for treatment.

Forty-five patients with cerebral palsy hip-dislocation were reviewed and it was found that some did well without treatment. For patients with hip pain, the best results were obtained with extensive resection arthroplasty: soft-tissue surgery alone was unsuccessful. Open reduction with femoral osteotomy achieved concentric reduction in all 15 patients who had this type of surgery: however, most retained their abnormal postural reflex activity to such a degree that subsequent scoliosis, pelvic obliquity, hip extension contractures and knee flexion deformities compromised the success of the hip surgery.

Central nervous system lesions and developmental scoliosis in myelomeningocele.

Hydrocephalus, spinal cord tethering, cord atresia, hydromyelia, syringomyelia and various manifestations of the Arnold-Chiari malformation occur in association with scoliosis in patients with myelomeningocele. While the causes of the cord lesions remain debatable, these lesions appear to be progressive and causally related to the scoliotic deformity. We have reviewed seventeen myelomeningocele patients with developmental scoliosis and have found that aggressive orthopaedic treatment combined with neurosurgical treatment can satisfactorily control spinal deformity in most cases. Before undertaking orthopaedic treatment of severe spinal deformities in patients with myelomeningocele a careful investigation of the central nervous system with myelography and cord and head CT scans should be carried out.

Persistent cytomegalovirus infection: association with profound immunodeficiency and treatment with interferon.

Cytomegalovirus (CMV) was repeatedly isolated from urine and saliva of a 20-month-old male child with recurrent episodes of pneumonia, high fever, rash, lymphadenopathy, oral ulceration, and neutropenia. Immunologic evaluation revealed decreased serum IgG and IgA, increased IgM, depressed T- and B-lymphocyte functions, and decreased natural killer (NK) activity for herpes simplex-type I virus-infected targets. NK activity was augmented following exposure of the patient's lymphocytes to interferon (IF) in vitro. The child was treated with interferon (four courses, dosage varying from 2 million U/day to 1 million U three times/week for periods of 10, 28, 80, and 67 days, respectively, interspersed over 9 months) and hyperimmune plasma infusions every 3 weeks. Toward the end of interferon therapy oral Levamisole was started and a feeding gastrostomy was inserted to provide nutritional support. Clinical recovery was associated with reversal of immunologic abnormalities except for the hypogammaglobulinemia. Aggressive antiviral therapy (e.g., with IF) followed by immunostimulation (e.g., with Levamisole) may prove effective in controlling certain viral infections in immunodeficiency disorders.

Facial malformations and spinal anomalies. A predictable relationship.

Facial malformations have generally been associated with spinal anomalies, but this report reviews patients with specific facial abnormalities and attempts to document accompanying spinal anomalies. The results indicate that the most common types of facial malformations vary predictably in their influence on spinal or other musculoskeletal abnormalities. Apert and Goldenhaar syndromes are associated with significant spinal anomalies.

Multiple dislocations of the cervical spine in a patient with juvenile rheumatoid arthritis and Down's syndrome.

Both Down's syndrome and juvenile rheumatoid arthritis can cause instability of the cervical spine. Patients with Down's syndrome usually have instability of the atlantoaxial joint. With juvenile rheumatoid arthritis, cervical instability is a manifestation of a more generalized process involving ligamentous laxity, posterior facet ankylosis, and growth disturbances of the vertebral bodies. When the two syndromes occur in the same patient, the potential exists for serious cervical instability. In the 14-year-old girl reported here, the two conditions coexisted, and more severe cervical spine involvement occurred than was originally anticipated. Prior awareness of the combined effects of Down's syndrome and juvenile rheumatoid arthritis on the stability of the cervical spine should be useful in the management of future cases.

The thoracic outlet syndrome produced by costochondritis.

Thoracic outlet syndrome (TOS) is a rare condition in children. Compression of the neurovascular bundle as it passes from the neck through the thorax into the arm may be produced by numerous anatomic and structural abnormalities. This case represents compression produced by spasm of the pectoralis minor muscle originating from costochondritis.