Genetics of craniofacial malformations

The field of craniofacial malformations is comprehensive and does not allow to discuss all craniofacial malformations which have been described as single entities. Many of the syndromes with craniofacial malformations are ultrarare. In this review we have chosen craniofacial malformation syndromes which are of relevance for the pediatrician, especially neonatologist: different types of craniosynostoses, oculo-auriculo-vertebral spectrum, Pierre Robin sequence and Treacher Collins syndrome. These syndromes will be described in detail. Diagnostic and therapeutic options will be discussed.     

Ex utero intrapartum treatment for an infant with cerebro‐costo‐mandibular syndrome

Cerebro‐costo‐mandibular syndrome (CCMS) is a rare disorder characterized by multiple rib abnormalities, micrognathia described as Pierre–Robin sequence, and cerebral involvement. Appropriate management of respiratory distress immediately after birth is crucial to rescue these patients. A boy, having a mother with Pierre–Robin sequence and a sister with CCMS, was diagnosed prenatally with CCMS and successfully treated with ex utero intrapartum treatment (EXIT) at 36 weeks 6 days of gestation. EXIT would be an effective option for rescuing patients with prenatally diagnosed CCMS and preventing neonatal hypoxia.     

Pierre Robin sequence: a series of 117 consecutive cases

A series of 117 cases of Pierre Robin Sequence are classified as isolated (48%), syndromic (35%), and with associated anomalies (17%); the latter group had a poor long-term prognosis. In isolated Pierre Robin Sequence, familial cases and a high incidence of twins were noted. Among syndromic Pierre Robin Sequence, 4 syndromes represent more than 50% of the diagnoses.     

Improved outcome in Pierre Robin sequence: effect of multidisciplinary evaluation and management

Infants with complications of Pierre Robin sequence are at increased risk of airway obstruction and resultant hypoxia, cor pulmonale, failure to thrive, and cerebral impairment. In an effort to minimize such complications, patients with Pierre Robin sequence were examined prospectively by a multidisciplinary team using polysomnography and continuous oximetry. Obstructive apnea and desaturation occurred in 18 of the 21 patients studied. Four children required only home apnea monitoring, and six required only monitoring and supplemental oxygen. Seven children had lip-tongue adhesion procedures performed, and four required tracheostomy. No patients died. All patients with isolated Pierre Robin sequence had normal development at follow-up except for one child who had experienced a respiratory arrest before referral. With improvements in neonatal intensive care, testing for respiratory assessment, improved surgical and postoperative intervention and home monitoring, the morbidity and mortality for children with Pierre Robin sequence can be reduced markedly.     

Congenital heart disease in the Pierre Robin syndrome

Summary Congenital heart disease occurs in about 20 percent of patients with Pierre Robin syndrome. Ventricular septal defect, patent ductus arteriosus, and atrial septal defect are the most common congenital cardiac lesions in this syndrome. The associated upper airway obstruction can produce cor pulmonale, cardiomegaly, pulmonary edema, and cyanosis.     

Diagnosis and treatment of the Pierre Robin sequence: results of a retrospective clinical study and review of the literature

We performed a retrospective study of all children with Pierre Robin sequence (PRS), admitted to our hospital from 1981–1998 in order to evaluate diagnosis, treatment and prognosis. Patients were divided into two categories: isolated PRS (group 1) and PRS plus, i.e. PRS as part of a more complex syndrome (group 2). A total of 74 patients with PRS were found, 29 (39%) males and 45 (61%) females of whom 47 (63.5%) could be categorised as isolated PRS and 27 (36.8%) as PRS plus. The most frequent diagnoses in patients with PRS plus were Stickler syndrome and the velocardiofacial syndrome. Ophthalmological and fluorescent in situ hybridisation of chromosome 22 investigations should therefore be performed in all patients, as soon as the diagnosis of PRS is established. Some form of airway treatment was necessary in the majority of patients (52 of 74), most could be treated conservatively with prone/lateral positioning and close observation. Endotracheal intubation was necessary in one child from group 1 versus five from group 2. Tracheostomy was performed in three children from group 1 and two from group 2. Feeding problems occurred in about 25% of all PRS patients and stunted growth was seen especially in boys with isolated PRS before the age of 10 months. Conclusion In our series, 33% of patients with Pierre Robin sequence plus had Stickler and velocardiofacial syndromes. Conservative airway management was a sufficient treatment for respiratory problems in the majority of patients. Feeding and growth need special attention in patients with Pierre Robin sequence. Received: 4 April 2000 / Accepted: 21 August 2000     

FAILURE OF DETERMINATION OF FETAL LUNG MATURATION DUE TO FALSE-NEGATIVE LECITHIN/SPHINGOMYELIN RATIO IN A CASE OF PIERRE ROBIN SYNDROME

Abstract. A case is reported of a baby with Pierre Robin syndrome born at term with adequate lung maturity. The evaluation of fetal lung maturity before birth by means of the lecithin/sphingomyelin ratio and foam test in the amiotic fluid revealed immaturity of the lungs. Examination of the tracheal aspirate following delivery, however, showed adequate lung maturity in the neonate.     

Kniest disease with Pierre Robin syndrome and hydrocephalus

A 3-month-old male infant with clinical and radiological features of Kniest disease is reported. Additional findings were severe Pierre Robin syndrome and external hydrocephalus. The patient was retarded in mental and motor development. He died at 4 months of age from the complications of tracheostomy. The parents were both normal clinically and radiologically, thus the disease in the child was presumably due to a new mutation. The reported familial cases of Kniest disease suggest autosomal dominant inheritance. The differential diagnosis is discussed in detail.     

Beyond Pierre Robin sequence

The label Pierre Robin sequence is given to infants presenting with a triad of specific congenital anomalies: micrognathia, glossoptosis, and cleft palate. However, this label should be considered the first, not the final, step in the diagnostic process. In approximately 80 percent of newborns with Pierre Robin sequence, the triad of anomalies is part of an underlying genetic condition. This article reviews the variable etiologies of and general clinical considerations for Pierre Robin sequence. To illustrate how clinical management might vary based on the identification of an underlying condition, three case examples of neonates with Pierre Robin sequence and different underlying genetic conditions are presented.     

Congenital rib defects with the Pierre Robin syndrome

A case of Pierre Robin syndrome with associated rib defects is presented. The rib defects were less severe than in previously reported cases, which are reviewed, and the infant has survived.     

A spectrum of bronchopulmonary anomalies associated with tracheoesophageal malformations

The combination of tracheoesophageal and pulmonary malformations is unusual and reportedly carries a high mortality. We have observed six patients with esophageal atresia and tracheoesophageal fistula and one with a bronchoesophageal fistula who had associated bronchopulmonary anomalies ranging from lobar hypoplasia and agenesis to unilateral pulmonary hypoplasia or agenesis. All of the pulmonary malformations were right-sided. Vertebral or rib anomalies were present in five patients, congenital heart disease in two, imperforate anus in one and one patient had radial aplasia and Pierre Robin syndrome. The bronchopulmonary anomalies complicated the surgical care of tracheoesophageal malformations and required radiologic differentiation from aspiration pneumonia and atelectasis. Six of the seven patients survived. Mortality and morbidity were related to complications and associated cardiac anomalies as well as severity of the lung anomaly.     

Frequency of a 22q11 deletion in patients with conotruncal cardiac malformations: A prospective study

Recent molecular studies have revealed that a 22q11 deletion is frequently detected in DiGeorge syndrome (DGS), velo-cardio-facial syndrome (VCFS), and conotruncal anomaly face syndrome (CTAFS). As one of the major clinical manifestations in these three syndromes is conotruncal cardiac malformation, we prospectively studied the frequency of a 22q11 deletion in a group of patients with conotruncal cardiac malformation. Fluorescence in situ hybridization (FISH) analyses using N25 (D22S75) DiGeorge Chromosome Region probe were performed on 64 patients with conotruncal cardiac malformation, who visited our clinic from October 1993 to January 1994. Of the 64 patients studied, a 22q11 deletion was detected in 5 patients (7.8%): 3 out of 30 patients with tetralogy of Fallot, one of three with interruption of the aortic arch, and one hemitruncus patient. No deletion was found in 16 patients with complete transposition of the great arteries, 8 with double outlet right ventricle and 2 with aortopulmonary window. In these five patients with 22q11 deletion, patient 1 was clinically diagnosed as having DGS, patients 2 and 3 had CTAFS, and patient 4 had VCFS. Patient 5 could not be dysmorphologically evaluated. It was noteworthy that all patients with a 22q11 deletion, except a non-evaluated patient, had some symptoms of syndromes DGS, CTAFS or VCFS, and that we failed to identify a non-syndromic 22q11 deletion positive patients in the present series of 64 patients.Conclusion This study suggests that it is advisable to bear 22q11 deletion in mind when a patient with conotruncal cardiac anomalies has some other features of DGS, VCFS or CTAFS.     

Bifid epiglottis: Syndromic constituent rather than isolated anomaly

Background: Bifid epiglottis is a congenital malformation defined as a midline‐cleft of the epiglottis, which can be presented as an isolated anomaly as well as a part of malformation complexes. Its common occurrence in Pallister–Hall syndrome (PHS) has recently been attracting special attention. In the embryo, epiglottis, hypothalamus, and digital buds develop synchronously. Some disturbances during this stage may account for the concurrence of bifid epiglottis, hypothalamic hamartoma, and polysyndactyly in PHS. The incidence of bifid epiglottis remains unknown. Methods: We report here four children with bifid epiglottis out of 472 children who underwent laryngoscopy during the period from January 1995 to December 2004 in our hospital. Results: All four children presented stridor of variable degrees. One had a partial cleft of the epiglottis associated with only tracheomalacia. The other three had a complete cleft of the epiglottis associated with complex malformations: one had accessory auricles with preauricular sinus, polycystic kidney disease with intrahepatic biliary dilatation, endocardial cushion defect, and postaxial polydactyly; another had hypothalamic hamartoma, Hirschsprung disease, and polydactyly, which warranted a diagnosis of PHS; the other had no other dysmorphic features. Conclusion: Bifid epiglottis can be presented as a syndromic constituent of congenital malformation syndromes rather than as an isolated anomaly. A high index of suspicion of bifid epiglottis should be raised in children with brachy‐poly‐syndactyly and clinical symptoms of upper airway obstruction.     

A case of severe Pierre Robin sequence with failure to thrive and tachycardia resolved after redo-fundoplication and hiatoplasty

We report an infant suffering from Pierre Robin sequence complicated by gastro-oesophageal reflux and failure to thrive, which were resistant to conservative therapy and a hemifundoplication. Gastro-oesophageal reflux was accompanied by supraventricular tachycardia, treated with propafenone. Tachycardia may be present in Pierre Robin sequence as a consequence of cardiac parasympathetic imbalance. The patient recovered completely from the gastro-oesophageal reflux and tachycardia after redo-fundoplication (Nissen) and a hiatoplasty were performed. Conclusion:This case shows that a thorough search for gastro-oesophageal reflux is indicated in each case of Pierre Robin sequence with failure to thrive.     

Natal teeth

I conducted a retrospective study based on record reviews of 50,892 infants born at the Foothills Provincial Hospital, Calgary, Alberta, Canada, from 1967 to 1984 to determine the incidence and possible causes of natal teeth. Fifteen infants were affected, for an incidence rate of one in 3,392 births. The affected teeth were the lower central incisors. The condition was more common in female infants. Two of the affected patients were twins. One patient each had Ellis-van Creveld syndrome, Pierre Robin syndrome, adrenogenital syndrome, cleft palate, and rickets. One mother each had pernicious anemia, vaginal infection, and diabetes mellitus.     

Growth in children with Pierre Robin sequence and isolated cleft palate

Postnatal height and weight growth were assessed in 50 children (20 boys) with Pierre Robin sequence and in 58 children (27 boys) with isolated cleft palate, born in 1967–86. The height and weight measurements from birth to 12 years were collected retrospectively from child health centers and schools. The current Finnish relative weight and SD scores for height were used for growth assessment. The birth size of children with Pierre Robin sequence did not differ from those with isolated cleft palate or from healthy children, on the basis of Finnish norms. During the first year after birth, children with Pierre Robin sequence were shorter and lighter than those with isolated cleft palate but later caught up with them and the Finnish norms. Children with Pierre Robin sequence born prematurely or with associated anomalies showed more deficient growth.