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Fryns syndrome is an autosomal recessive multiple congenital anomaly syndrome characterized by diaphragmatic hernia, unusual facies, and distal limb hypoplasia. It was first reported as a lethal condition. We report on a three-year-old survivor with Fryns syndrome, and provide a review on the outcome of other survivors. Patients who survive the neonatal period represent 14% of reported cases. Characteristics of survivors include less frequent diaphragmatic hernia and milder lung hypoplasia, absence of complex cardiac malformation, and neurologic impairment. Multiple central nervous system abnormalities have been reported in Fryns syndrome, including agenesis of the corpus callosum, Dandy-Walker abnormality, cerebellar heterotopias, cerebellar hypoplasia, enlarged ventricles, and hypoplasia of the olfactory bulbs. Our patient exhibited profound mental retardation. He had malformations of gyration and sulcation, particularly around the central sulcus, and hypoplastic optic tracts beyond the optic chiasm. Understanding of long-term outcome of survivors is important for counseling of families with Fryns syndrome. Careful brain examination is advised; however, a normal radiological brain examination does not preclude developmental delay. The spectrum of individual outcome and of associated anomalies indicates that individual evaluation, imaging for structural brain malformation, is strongly advised. © 1995 Wiley-Liss, Inc.

Sudden infant death syndrome (SIDS) is defined as the sudden and unexpected death of an apparently healthy infant under 1 year of age. Routine autopsies often provide few clues as to the cause of death and rarely include a biochemical evaluation. Genetic counseling for SIDS can be difficult as recurrence risks vary depending on the age at death and the number of deaths which have occurred in the family. Biochemical disorders may account for up to 5% of SIDS. Of the metabolic disorders known to be involved in SIDS, the most commonly found is medium-chain acyl CoA dehydrogenase deficiency (MCAD). MCAD is an autosomal recessive disorder of fatty acid oxidation which accounts for up to 1% of SIDS. For some families, the addition of a postmortem biochemical investigation can identify an unsuspected metabolic disorder as the cause of death. Once the diagnosis is established, accurate genetic counseling can then be provided. Metabolic testing of the surviving siblings of victims of sudden death, and the subsequent identification of those due to MCAD can prevent the tragedy of recurrent SIDS in some families. In addition, screening the survivors of an acute life threatening event (ALTE) may also prevent a recurrence.

VACTERL association with hydrocephalus is rarely reported, and is thought to be an autosomal recessive uniformly lethal disorder distinct from the VATER association. We have observed 3 patients in a 12-month period with hydrocephalus due to aqueductal stenosis, in addition to vertebral anomalies (3/3), anal anomalies (3/3), cardiac anomalies (3/3), tracheoesophageal fistula (1/3), renal anomalies (3/3), limb anomalies (3/3), single umbilical artery (2/3), hypospadias (1/3), and cryptorchidism (1/2). Chromosomes were normal in all cases. Although one patient died in the neonatal period due to respiratory failure, 2 have survived (30 months and 19 months) with good neurological outcome following early neurosurgical treatment. Although delayed in motor development, both are interactive, social, and continue to make developmental progress. Appropriate surgical treatment, including early ventriculoperitoneal shunting, allowed for the survival of 2 patients with an unexpectedly good outcome. Our experience suggests that the extremely poor prognosis previously ascribed is not universal. We caution against labeling this syndrome as a uniformly lethal, developmentally devastating disorder.

Objectives. To further define the clinical spectrum of the disease for pediatric and metabolic specialists, and to suggest that the general pediatrician and pediatric neurologist consider succinic semialdehyde dehydrogenase (SSADH) deficiency in the differential diagnosis of patients with (idiopathic) mental retardation and emphasize the need for accurate, quantitative organic acid analysis in such patients. Patients. The clinical features of 23 patients (20 families) with SSADH deficiency (4-hydroxybutyric aciduria) are presented. The age at diagnosis ranged from 3 months to 25 years in the 11 male and 12 female patients; consanguinity was noted in 39% of families. Outcome Measurements. The following abnormalities were observed (frequency in 23 patients): motor delay, including fine-motor skills, 78%; language delay, 78%; hypotonia, 74%; mental delay, 74%; seizures, 48%; decreased or absent reflexes, 39%; ataxia, 30%; behavioral problems, 30%; hyperkinesis, 30%; neonatal problems, 26%; and electroencephalographic abnormalities, 26%. Associated findings included psychoses, cranial magnetic resonance or computed tomographic abnormalities, and ocular problems in 22% or less of patients. Therapy with vigabatrin proved beneficial to varying degrees in 35% of the patients. Normal early development was noted in 30% of patients. Conclusions. Our data imply that two groups of patients with SSADH deficiency exist, differentiated by the course of early development. Our recommendation would be that accurate, quantitative organic acid analysis in an appropriate specialist laboratory be requested for any patients presenting with two or more features of mental, motor, or language delay and hypotonia of unknown cause. Such analyses are the only definitive way to diagnose SSADH deficiency; the diagnosis can be confirmed by determination of enzyme activity in white cells from whole blood. We think that increased use of organic acid determination will lead to increased diagnosis of SSADH deficiency and a more accurate representation of disease frequency. As additional patients are identified, we should have a better understanding of both the metabolic and clinical profiles of SSADH deficiency.

Infants with inborn errors of fatty acid metabolism may present with apnea, periodic breathing, and sudden infant death syndrome (SIDS). Recognition of these disorders and initiation of appropriate therapy may prevent SIDS. Metabolic pathways develop during gestation and post-natally. We report three siblings with apnea and periodic breathing, as well as biochemical defects consistent with a non-specific abnormality of beta oxidation. One infant died a witnessed sudden infant death. The two survivors were treated with L-carnitine supplementation resulting in rapid resolution of both respiratory and metabolic abnormalities. Enzyme activity for short, medium, and long chain acyl coenzyme A dehydrogenases was normal in these two infants. Although a unique enzymatic deficiency was not identified, our experience with this family supports the need for routine biochemical evaluation of infants with “near miss” SIDS, also called acute life-threatening events (ALTE), as well as those who have died of SIDS. Pediatr Pulmonol. 1995; 20:167–171. © 1995 Wiley-Liss, Inc.

Medium-chain acyl-coenzyme A dehydrogenase deficiency is an autosomal recessive disorder of beta-oxidation of fatty acids manifested by episodic hypoglycemia, encephalopathy, apnea, and sudden death. Medical data were obtained on 120 patients with medium-chain acyl-coenzyme A dehydrogenase deficiency referred to Duke University Medical Center for biochemical testing. There were 55 male and 65 female subjects ranging from birth to 19 years of age; 118 subjects were white. Twenty-three children (19%) died before the diagnosis was made. Follow-up data were available in the 97 surviving patients for an average of 2.6 years after diagnosis. Psychodevelopmental data were collected on 73 patients older than 2 years of age. Unexpected morbidity included developmental and behavioral disability, chronic muscle weakness, failure to thrive, and cerebral palsy. We conclude that unidentified patients with this disorder have a significant risk of sudden death in early childhood and that survivors have a significant risk of developmental disability and chronic somatic illness.

We report one new case of congenital hypothalamic hamartoblastoma syndrome (Pallister-Hall syndrome) and one case of a diencephalic nodule associated with craniofacial malformations. Based on a review of 11 cases of Pallister-Hall syndrome documented by pathological examination, two cases presumed by phenotype, three cases of hypothalamic hamartoma with craniofacial anomalies only, and several cases of related interest, we delineate the clinical, neuroradiologic, and neuropathologic manifestations which aid in differential diagnosis. Clinical manifestations in infants with Pallister-Hall syndrome included postaxial polydactyly with nail dysplasia, short nose with flat nasal bridge, apparently low-set, posteriorly angulated ears, kidney and lung anomalies, congenital heart defects, imperforate anus, and micropenis with undescended or hypoplastic testes in males. These manifestations were associated with varying degrees of panhypopituitarism and pituitary aplasia. In three cases of hypothalamic hamartoma associated with craniofacial anomalies only, the face resembled that of holoprosencephaly. Other cases of hypothalamic hamartoma have had associated palate or heart defects or presented with precocious puberty. Of the infants with a hypothalamic hamartoblastoma at autopsy, neuropathologic findings were consistent with a primitive neuroectodermal tumor. Surgical tissue from our sole survivor suggested such tumors might mature, and the tumor has not recurred. Neuroradiologic diagnosis may be difficult but should be attempted in infants with these clinical manifestations; due to the need for prompt initiation of appropriate therapy.