D. T. Cass

Hirschsprung disease, microcephaly, mental retardation, and characteristic facial features: delineation of a new syndrome and identification of a locus at chromosome 2q22-q23.

We have identified six children with a distinctive facial phenotype in association with mental retardation (MR), microcephaly, and short stature, four of whom presented with Hirschsprung (HSCR) disease in the neonatal period. HSCR was diagnosed in a further child at the age of 3 years after investigation for severe chronic constipation and another child, identified as sharing the same facial phenotype, had chronic constipation, but did not have HSCR. One of our patients has an interstitial deletion of chromosome 2, del(2)(q21q23). These children strongly resemble the patient reported by Lurie et al with HSCR and dysmorphic features associated with del(2)(q22q23). All patients have been isolated cases, suggesting a contiguous gene syndrome or a dominant single gene disorder involving a locus for HSCR located at 2q22-q23. Review of published reports suggests that there is significant phenotypic and genetic heterogeneity within the group of patients with HSCR, MR, and microcephaly. In particular, our patients appear to have a separate disorder from Goldberg-Shprintzen syndrome, for which autosomal recessive inheritance has been proposed because of sib recurrence and consanguinity in some families.

Laser Doppler imaging prediction of burn wound outcome in children

The ability of laser Doppler imaging (LDI) to evaluate burn depth in children was investigated. Fifty-seven patients were prospectively studied over a 10-month period. Each patient was clinically assessed, photographed and independently scanned between 36 and 72 h of the burn. Patients were reviewed until wound healing had occurred within 12 days or skin grafting had been performed. The median age was 1 year and 10 months (range 5 months to 15 years and 8 months). The median body surface area burnt was 7.0% (range 0.5-30%). In 30 patients, the burn did not heal within 12 days, 17 of which were grafted. Clinical examination correctly determined 66% of deep partial or full thickness burns between 36 and 72 h of injury compared to 90% using LDI. The LDI was also more specific; correctly diagnosing 96% of superficial partial thickness burns as opposed to 71% on clinical examination. Moderate degrees of movement did not appear to limit the accuracy of the scan.

Frequency of Ret mutations in long- and short-segment Hirschsprung disease

Hirschsprung disease, or congenital aganglionic megacolon, is a genetic disorder of neural crest development affecting 1:5,000 newborns. Mutations in the RET proto‐oncogene, repeatedly identified in the heterozygous state in both long‐ and short‐segment Hirschsprung patients, lead to loss of both transforming and differentiating capacities of the activated RET through a dominant negative effect when expressed in appropriate cellular systems. The approach of single‐strand conformational polymorphism analysis established for all the 20 exons of the RET proto‐oncogene, and previously used to screen for point mutations in Hirschsprung patients allowed us to identify seven additional mutations among 39 sporadic and familial cases of Hirschsprung disease (detection rate 18%). This relatively low efficiency in detecting mutations of RET in Hirschsprung patients cannot be accounted by the hypothesis of genetic heterogeneity, which is not supported by the results of linkage analysis in the pedigrees analyzed so far. Almost 74% of the point mutations in our series, as well as in other patient series, were identified among long segment patients, who represented only 25% of our patient population. The finding of a C620R substitution in a patient affected with total colonic aganglionosis confirms the involvement of this mutation in the pathogenesis of different phenotypes (i.e., medullary thyroid carcinoma and Hirschsprung). Finally the R313Q mutation identified for the first time in homozygosity in a child born of consanguineous parents is associated with the most severe Hirschsprung phenotype (total colonic aganglionosis with small bowel involvement). Hum Mutat 9:243–249, 1997.

Congenital central hypoventilation syndrome and Hirschsprung’s disease

Five cases of the Hirschsprung’s disease–congenital central hypoventilation syndrome (CCHS) association are presented and 41 other published cases reviewed. These children have a distinct pattern of associated features, an equal sex incidence, and a characteristic spectrum of disease severity which suggests that the condition is genetically distinct from other cases of Hirschsprung’s disease. While approximately 1.5% of Hirschsprung’s disease patients, and 10% of those with total colonic aganglionosis, will have CCHS, up to 50% of CCHS patients will have Hirschsprung’s disease. Approximately 20% of CCHS/Hirschsprung patients will also have neuroblastoma or ganglioneuroma, usually multiple. Abnormalities of the eye and autonomic nervous system are also common. The ventilatory abnormality is usually evident on the first day of life. The aganglionosis is also severe, with more than half (59%) of the patients having aganglionosis extending into the small bowel.

HOSE : an objective scoring system for evaluating the results of hypospadias surgery

Objective To determine the accuracy and utility of a scoring system designed to allow an objective appraisal of the outcome of hypospadias repair, based on evaluating meatal location, meatal shape, urinary stream, straightness of erection, and the presence and complexity of any complicating urethral fistula.

Further delineation of the phenotype associated with heterozygous mutations in ZFHX1B.

Mutations or deletions involving ZFHX1B (previously SIP1) have recently been found to cause one form of syndromic Hirschsprung disease (HSCR), associated with microcephaly, mental retardation, and distinctive facial features. Patients with the characteristic facial phenotype and severe mental retardation, but without HSCR, have now also been shown to have mutations in this gene. Mutations of ZFHX1B are frequently associated with other congenital anomalies, including congenital heart disease, hypospadias, renal tract anomalies, and agenesis of the corpus callosum (ACC). We present the clinical data and mutation analysis results from a series of 23 patients with this clinical syndrome, of whom 21 have proven ZFHX1B mutations or deletions (15 previously unpublished). Two patients with the typical features (one with and one without HSCR) did not have detectable abnormalities of ZFHX1B. We emphasize that this syndrome can be recognized by the facial phenotype in the absence of either HSCR or other congenital anomalies, and needs to be considered in the differential diagnosis of dysmorphism with severe mental retardation +/− epilepsy.

Abnormalities of peptide-containing nerve fibers in infantile hypertrophic pyloric stenosis.

The distributions of nerve cells and fibers with immunoreactivity for the peptides enkephalin, gastrin-releasing peptide, neuropeptide Y, somatostatin, substance P, and vasoactive intestinal peptide were examined in specimens of myenteric plexus and external muscle from the pylorus of 20 infants with hypertrophic pyloric stenosis. These were compared with peptide distributions in pyloric samples from unaffected infants and adults. In the normal pylorus the circular muscle was richly supplied with fibers reactive for enkephalin, neuropeptide Y, substance P, and vasoactive intestinal peptide. In pyloric stenosis, these immunoreactive fiber bundles were either missing or less than 5% of normal. In contrast, there were reactive cell bodies and nerve fibers in the myenteric plexuses of both normal and affected specimens. In the samples from cases of stenosis, swollen nerve fibers that appeared to be in the process of degeneration were frequently encountered. It is concluded that infantile hypertrophic pyloric stenosis is associated with a loss of peptide immunoreactivity in nerve fibers in the circular muscle, although the same peptides are still revealed in fibers and in nerve cell bodies in the myenteric plexus.

Gastroschisis: determinants of neonatal outcome

Abstract. This retrospective study elicits information regarding the dependence of neonatal outcome in gastroschisis upon: (1) the mode of delivery, (2) place of birth, (3) time for birth to surgery, (4) method of closure, (5) time from operation to commencement of first enteral feeds. The neonatal intensive care database from five major tertiary centres was used to identify 181 neonates with gastroschisis from 1990 to 2000. There were 8 deaths. There were no significant differences in outcome for infants delivered vaginally (102) versus Caesarean section (79), those born near the tertiary centre (133) as compared to infants born away (48), ones operated within 7 hours (125) compared with those operated after 7 hours (56), with delayed closure (30) versus primary closure (151). Neonates fed within 10 days of operation (85) had significantly lower incidence of sepsis, duration of TPN and hospital stay when compared to those fed after 10 days (96). Early commencement of feeds decreases the incidence of sepsis, duration of total parenteral nutrition (TPN) and hospital stay. Place of delivery, mode of delivery, time to surgery and type of closure do not influence neonatal outcome.

Facial fractures in children.

Objective To determine the pattern of injury of facial fractures in children, the relative contribution of plain radiography and CT scanning in the diagnosis of these injuries, and factors leading to delayed diagnosis. Design Retrospective case note review. Participants All children with facial fractures identified using the trauma and medical record databases at our institution. Results Forty-six children with 59 facial fractures presented over a 4-year, 2-month period from November 1995 to December 1999. The median age was 10 years, with a range from 1 to 14. There was a 2-to-1 male-to-female sex ratio. A motor vehicle accident (MVA) involving a child as passenger, pedestrian, or cyclist accounted for 63% of cases. In seven of these, the child was either a front seat passenger or inappropriately restrained for their age and size. In all but one case, the presence of a fracture was associated with an overlying laceration, abrasion, or significant soft tissue edema. Initial examination and plain radiologic assessment by a pediatric clinician led to diagnostic delay in nine children. Facial CT was performed in 38 children, and all results were positive. Twenty-six patients required operative intervention for their facial fracture. Associated injuries, particularly of the head and limbs, were present in all but six patients. Conclusions Facial fractures were uncommon overall but occurred more frequently in children with major trauma. Plain facial radiographs provided limited additional diagnostic information to careful clinical examination and often fail to detect or clearly define a facial fracture in children. In the correct clinical setting, a facial CT scan allows accurate diagnosis of the injury and can reveal previously unsuspected additional fractures.

Advances in the treatment of oesophageal atresia over three decades: the 1970s and the 1990s

Oesophageal atresia management has evolved alongside the development of paediatric surgery. An analysis of a 30-year prospective collection of oesophageal atresia cases treated at the Royal Alexandra Hospital for Children, NSW, Australia is presented. There has been a dramatic change in the surgical approach. Fewer infants are undergoing operations of cervical oesophagostomy, gastrostomy and oesophageal replacement. More, including fragile infants, are surviving with a repaired native oesophagus. Fewer infants are suffering morbidity secondary to anastomotic leak. The progression in treatment has been enabled by improved neonatal support due to advances in neonatology, neonatal anaesthesia, nutritional support and antimicrobial therapy. Oesophageal atresia treatment and outcome has changed markedly over three decades. Cooperative multi-centre database development is now required to provide data in order to further refine treatment for clinical challenges that remain.