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PubMed2005

Isolated sulfite oxidase deficiency: a case report with a novel mutation and review of the literature.

Isolated sulfite oxidase deficiency is a rare but devastating neurologic disease that usually presents in early infancy with seizures and alterations in muscle tone. Only 21 cases have been reported in the literature. We report a case of a newborn infant boy with isolated sulfite oxidase deficiency who presented with generalized seizures on his fourth day of life. Plasma total homocysteine was not detectable. Urinary sulfite, thiosulfate, and S-sulfocysteine levels were elevated. The patient began a low-methionine and low-cysteine diet and was treated with thiamine and dextromethorphan. However, he became increasingly microcephalic and was severely developmentally delayed. Mutation analysis of the sulfite oxidase gene revealed that the patient was homozygous for a novel 4-base pair deletion, and both of his parents were found to be heterozygous carriers of the same deletion. We reviewed the clinical, biochemical, neuroradiologic, and neuropathologic features in all published cases of isolated sulfite oxidase deficiency. Seizures or abnormal movements were prominent features in all cases. Developmental delays were reported in 17 cases. Ectopia lentis was detected in 9 cases. Clinical improvement with dietary therapy was seen in only 2 patients, both of whom presented after the age of 6 months and had relatively mild developmental delays. Plasma or urinary S-sulfocysteine levels were elevated in all cases. Urinary sulfite was detected in all except 1 case. Cerebral atrophy and cystic encephalomalacia were observed with neuroradiologic imaging and were noted in all 3 postmortem reports of isolated sulfite oxidase deficiency. The main alternative in the differential diagnosis of isolated sulfite oxidase deficiency is molybdenum cofactor deficiency.

Amino Acid Metabolism, Inborn Errors↗

PubMed2007

Clinical correlation of chromosome 22q11.2 fluorescent in situ hybridization analysis and velocardiofacial syndrome.

OBJECTIVE: To identify characteristics associated with microdeletions of chromosome 22q11.2 ascertained by fluorescent in situ hybridization (FISH) analysis in patients with velopharyngeal insufficiency (VPI), cleft palate, or other clinical features of velocardiofacial syndrome (VCFS). DESIGN/SETTING: Retrospective review of all patients entered at one tertiary-level multidisciplinary cleft lip and palate and craniofacial anomalies panel from January 2000 to December 2003. PATIENTS: The study consisted of 115 patients. The presence or absence of the following clinical features was documented: cleft palate (submucous and overt), VPI, cardiac anomalies, renal anomalies, small stature, characteristic facies, developmental delay, psychiatric dysfunction, and family history. MAIN OUTCOME MEASURE: Correlation between presence or absence of clinical features of VCFS and presence or absence of 22q11.2 microdeletion by FISH analysis. RESULTS: Of the 16 patients (13.9%) who demonstrated 22q11.2 microdeletion by FISH analysis, 16 had VPI (100%), 16 had small stature (100%), 14 had cleft palate (88%), and 13 had characteristic facies (81%). Developmental delay was also present in 13 of these patients (81%), and seven had cardiac anomalies (44%). Multiple regression analysis revealed that the presence of characteristic facies and small stature statistically correlated with microdeletions of chromosome 22q11.2 by FISH studies (p < .05). CONCLUSIONS: Patients with microdeletions of chromosome 22q11.2 as demonstrated by FISH analysis were more likely to have VPI, small stature, cleft palate, characteristic facies, and developmental delay, in descending order. Statistical analysis showed that only characteristic facies and small stature correlated with 22q11.2 microdeletions.

Adolescent↗

PubMed2000

Health of children adopted from China.

OBJECTIVE: Since 1989, American parents have adopted 18 846 Chinese children. This study assesses the health and developmental status of these children after their arrival in the United States. PATIENTS AND METHODS: A total of 452 children (443 girls) in 2 groups were evaluated. The clinic group children (n = 192) included all Chinese adoptees seen in an international adoption clinic between 1991 and 1998. The travel group comprised 260 of 325 Chinese children placed by a single Massachusetts adoption agency between 1991 and 1996 whose adoptive parents and American physicians responded to mailed questionnaires. One hundred ninety-one of the travel group children were cared for by 1 of us (N.W.H.) during the adoption process in China. RESULTS: Growth and developmental delays were frequent in the clinic group. Z scores </=-2 were found in 39% of children for height, 18% for weight, and 24% for head circumference. The duration of orphanage confinement was inversely proportional to the linear height lag (r =.9), with a loss of 1 month of height age for every 2. 86 months in the orphanage. Of the children, 75% had significant developmental delay in at least 1 domain: gross motor in 55%, fine motor in 49%, cognitive in 32%, language in 43%, social-emotional in 28%, activities of daily living in 30%, and global delays in 44%. The incidence of medical problems was similar in both groups of children (travel group and clinic group). Overall, among the 452 children, elevated lead levels were found in 14%, anemia in 35%, abnormal thyroid function tests in 10%, hepatitis B surface antigen in 6%, hepatitis B surface antibody in 22%, intestinal parasites (usually Giardia) in 9%, and positive skin test results for tuberculosis in 3.5%. One child each had hepatitis C exposure and congenital syphilis. No child had human immunodeficiency virus infection. Unsuspected significant medical diagnoses, including hearing loss, orthopedic problems, and congenital anomalies, were found in 18% (81/452) of the children. CONCLUSIONS: Chinese adoptees display a similar pattern of growth and developmental delays and medical problems as seen in other groups of internationally adopted children. An exception is the increased incidence of elevated lead levels (overall 14%). Although serious medical and developmental issues were found among the children, overall their condition was better than expected based on recent publicity about conditions in the Chinese orphanages. The long-term outcome of these children remains unknown. China, adoption, orphanage, institutionalized child.

Adoption↗

PubMedDate not supplied

Pediatric AIDS: comparative cranial MRI and CT scans.

Fourteen consecutive children (age range: 4 months to 11 years; median: 4 years) with acquired immunodeficiency syndrome (AIDS) were studied prospectively with cranial magnetic resonance imaging (MRI) and unenhanced computed tomography (CT). In 4 children, human immunodeficiency virus infection was transfusion-related, while in 10, transplacental transmission occurred. Twelve children had abnormal neurologic examinations; of these, 10 had developmental delay and 2 were normal by developmental history and neurologic examination. Standardized neuropsychologic tests were given to all children; 5 were in the normal range and 9 demonstrated significant delays in verbal or motor/perceptual development. All children with abnormal neuropsychologic results were developmentally delayed; however, in 2 infants with normal neuropsychologic assessments, developmental delay and abnormal neurologic examinations were documented. Brain parenchymal volume loss (8 patients) and cervical lymphatic hypertrophy (4 patients) were demonstrated equally well by MRI and CT. CT alone demonstrated striatal-thalamic calcification (1 patient), whereas MRI alone demonstrated delayed myelination (1 patient). The extent of focal white matter lesions in 1 patient was demonstrated better by MRI than by CT. No intracranial mass lesions were demonstrated; however, significant correlations were found between peripheral volume loss imaged by either MRI or CT and both verbal and performance scores. In our small series, MRI offered no apparent advantage over CT in evaluating children with AIDS. We suggest that CT alone is sufficiently sensitive in evaluating pediatric AIDS-related brain abnormalities.

Acquired Immunodeficiency Syndrome↗

PubMed1996

A fragile X mosaic male with a cryptic full mutation detected in epithelium but not in blood.

Individuals with developmental delay who are found to have only fragile X premutations present an interpretive dilemma. The presence of the premutation could be an unrelated coincidence, or it could be a sign of mosaicism involving a full mutation in other tissues. To investigate three cases of this type, buccal epithelium was collected on cytology brushes for Southern blot analysis. In one notable case, the blood specimen of a boy with developmental delay was found to have a premutation of 0.1 extra kb, which was shown by PCR to be an allele of 60 +/- 3 repeats. There was no trace of a full mutation. Mosaicism was investigated as an explanation for his developmental delay, although the condition was confounded by prematurity and other factors. The cheek epithelium DNA was found to contain the premutation, plus a methylated full mutation with expansions of 0.9 and 1.5 extra kb. The three populations were nearly equal in frequency but the 1.5 kb expansion was the most prominent. Regardless of whether this patient has clinical signs of fragile X syndrome, he illustrates that there can be gross tissue-specific differences in molecular sub-populations in mosaic individuals. Because brain and epithelium are more closely related embryonically than are brain and blood, cryptic full mutations in affected individuals may be evident in epithelial cells while being absent or difficult to detect in blood. This phenomenon may explain some atypical cases of the fragile X phenotype associated with premutations or near-normal DNA findings.

Adult↗

PubMed2005

Outcomes in pediatric epilepsy: seeing through the fog.

To identify clinical and predictive features of outcome in cryptogenic epilepsy in pediatric neurology practice, the medical records of all patients with cryptogenic epilepsy (as defined by the International League Against Epilepsy) in a single pediatric neurology practice over a 12-year interval with at least 2 years of follow-up were systematically and retrospectively reviewed. Review revealed 60 children with cryptogenic epilepsy: 32 (53.3%) males, 11 (18.3%) prior febrile seizure, 9 (15.0%) developmental delay at onset, and 38 (63.3%) placement in regular classes. Twenty-two (35.7%) had generalized seizures. Mean follow-up after initiating antiepileptic medication was 53 months (range 24-128 months). Four (6.7%) were intractable; 4 (6.7%) had very poor outcomes; 8 (13.3%) had poor outcomes; 44 (73.3%) were well controlled. Sixteen (26.7%) and 31 (51.7%) had seizure recurrence within the last 12 and 24 months, respectively. Twenty-nine (48.3%) were seizure-free for at least 24 months. Factors associated with a poor outcome include seizure recurrence in the 6- to 12-month interval after therapy initiation (P = 0.006) and developmental delay at onset (P = 0.023). This case series suggests that children with cryptogenic epilepsy tend to have a favorable outcome. Seizure recurrence in the first months after therapy initiation and developmental delay apparent at onset are predictive of poor outcome.

Adolescent↗

PubMed2005

Developmental, cognitive, and neuropsychological functioning in preschool-aged foster children: associations with prior maltreatment and placement history.

Although young children in foster care are at high risk for developmental delays and subsequent academic, social, and behavioral difficulties, many do not receive services for delays. We sought to explicate the types of developmental delays observed in young children (ages 3-6 years) in foster care and how placement and maltreatment experiences for these children were associated with such delays. Physical growth, neuropsychological functioning, executive functioning, language, and general cognitive functioning were compared for a sample of 99 foster children and 54 nonmaltreated, same-aged children from comparable socioeconomic status backgrounds. The foster children showed developmental lags on measures of height, head circumference, visuospatial functioning, language, and general cognitive functioning. A history of neglect was negatively associated with functioning in a number of domains; surprisingly, the number of maltreatment types experienced was positively associated with functioning. Placement history was generally not associated with scores in the various developmental domains. We discuss the need to screen and evaluate preschoolers and possible methods for doing so.

Child↗

PubMed2002

Adverse outcomes in primary hemophagocytic lymphohistiocytosis.

PURPOSE: Hemophagocytic lymphohistiocytosis (HLH) is a rare condition characterized by abnormal proliferation of macrophages. Although the mortality rate in children diagnosed with primary HLH is high, little has been described about the nature of adverse events. This review evaluates unfavorable events in children with primary HLH to suggest methods of improving outcomes. METHODS: Charts of patients who met diagnostic criteria for primary HLH at the Hospital for Sick Children between January 1985 and June 2000 were retrospectively reviewed. The primary outcome measure was an adverse event, defined as death, the subsequent diagnosis of malignancy, or developmental delay. RESULTS: Twenty children were diagnosed with primary HLH. The median age at diagnosis was 6.5 months (range 1-78 months). Nineteen children received chemotherapy and two underwent matched sibling donor bone marrow transplantation. Of the 20 children, 12 (60%) died. These deaths were attributed to progressive HLH in 4 cases and invasive infection in 8 cases. These infections consisted of disseminated cytomegalovirus infection (n = 1), sepsis (n = 1), and invasive fungal infections (n = 6). Eight children survived. Two were subsequently diagnosed with malignancy. Two others were found to have significant developmental delay. CONCLUSIONS: The overall mortality rate was 60% in our series of 20 children with primary HLH; 50% of deaths were directly attributable to invasive fungal infection. Developmental delay and the diagnosis of malignancy are important events in this cohort.

Cerebrospinal Fluid↗

PubMed2006

Refractive eye surgery in treating functional amblyopia in children.

PURPOSE: While excimer laser refractive surgery is recommended and highly successful for correcting refractive errors in adults, its use in children has not been extensively exercised or studied. We report our experience treating children with amblyopia due to high anisometropia, high astigmatism, high myopia and with associated developmental delay. SETTING: Review of patient records of our refractive clinic. METHODS: A retrospective review was made of all 11 children with stable refractive errors who were unsuccessfully treated non-surgically and then underwent corneal refractive surgery and in one case, lenticular surgery. Seven had high myopic anisometropia, 2 had high astigmatism, and two had high myopia--one with Down's Syndrome and one with agenesis of the corpus callosum. RESULTS: The surgical refractive treatment eliminated or reduced the anisometropia, reduced the astigmatic error, improved vision and improved the daily function of the children with developmental delay. There were no complications or untoward results. CONCLUSIONS: Refractive surgery is safe and effective in treating children with high myopic anisometropia, high astigmatism, high myopia and developmental delay due to the resulting poor vision. Surgery can improve visual acuity in amblyopia not responding to routine treatment by correcting the refractive error and refractive aberrations.

Adolescent↗

PubMedDate not supplied

A clinical study of infants presenting to a mental retardation clinic.

Early detection has a central role in the prevention and management of mental retardation. The purpose of this present study is to delinerate the characteristics of developmentally delayed infants and their families attending Mental Retardation Clinic. The sample consisted of 101 infants who were registered in Mental Retardation Clinic of NIMHANS, Bangalore in 1988 constituting 12.5% of total registrations. Data was collected from case records. Majority of subjects were males, first or second born, 7 months or older, from a consanguineous lower or middle class family. Along with developmental delay, 60% had other complaints. Medical problems were reported in about half of the subjects and most had abnormalities on physical examination. Aetiology was discernible in 77.1%. Majority had associated physical disorder such as cerebral palsy, seizures and hearing and/or visual impairment. Around 17% came for follow-up thrice or more, 43% dropped out after work-up. The main conclusions are that; (i) certain socio-demographic, personal and clinical variables influence treatment seeking, and (ii) developmental delay recognised in infancy tends to be associated with clear aetiologic factors and significant medical/neurologic problems.

Cerebral Palsy↗

PubMed2000

Developmental problems and interactions between mothers and prematurely born children.

This study explored how the developmental status of 49 3-year-old prematurely born children related to the interactions between these children and their mothers. Two 2-hour observations of mother-child interactions, the Home Observation for Measurement of the Environment (HOME) inventory, a developmental assessment, and Nursing Child Assessment Teaching Scale (NCATS) were scored when the child was 3 years corrected age. The effects of specific developmental problems (cognitive, language, and attention) were examined by comparing subgroups with and without these problems. Children with normal IQs spent less time not playing and scored higher on the NCATS than children with low IQs. Mothers of children with normal IQs scored higher on provision of play materials on the HOME. The mothers of children with language concerns interacted less, talked less, were more negative, and scored lower on the HOME and NCATS than mothers of the children with normal language abilities. Children with attention problems were more active than children with normal attention spans. These findings suggest that mother-child interactions might be useful for identifying children at risk for developmental delay and that interventions with preschool children with developmental delays will probably be more effective if their mothers are helped to provide a more appropriate social environment.

Adult↗

PubMed1994

Sotos syndrome: a study of the diagnostic criteria and natural history.

Seventy-nine patients with a provisional diagnosis of Sotos syndrome were clinically assessed, and their photographs between the ages of 1 and 6 years evaluated. These photographs, together with photographs of first degree relatives, also at ages 1 to 6 years, were reviewed by four clinical geneticists. Forty-one probands (but no first degree relatives) were identified in whom the facial gestalt was thought to be characteristic of Sotos syndrome. Comparison of anthropometric measurements, bone age, and developmental delay in these 41 probands showed marked differences between them and the remaining 38 probands, and allowed the formulation of guidelines for the diagnosis of Sotos syndrome. Length was identified as the most significantly increased prenatal parameter. In childhood occipitofrontal head circumference (OFC), height, and weight were all increased. OFC remained above the 97th centile in all but one case throughout childhood and adulthood, whereas height and weight had a tendency to return towards the mean. This 'normalisation' was more pronounced in females and was probably related to their early puberty. Early developmental delay and an advanced bone age, seen in 100% and 84% respectively of study cases, may be invariable in Sotos syndrome, but selection bias and limited data prevented confirmation of this supposition. The authors suggest that facial gestalt, growth pattern, bone age, and developmental delay are the major diagnostic criteria. Using these criteria, no affected first degree relatives were identified. There were few long term medical complications in the probands, but behavioural difficulties caused considerable parental concern.

Abnormalities, Multiple↗

PubMed2000

Early postnatal (<96 hours) corticosteroids for preventing chronic lung disease in preterm infants.

BACKGROUND: Chronic lung disease (CLD) remains a major problem in neonatal intensive care units. Persistent inflammation in the lungs is the most likely underlying pathogenesis. Corticosteroids have been used to either prevent or treat CLD because of their potent anti-inflammatory effects. OBJECTIVES: To determine if postnatal corticosteroid treatment is of benefit in the prevention of chronic lung disease (CLD) in the preterm infant. This review examines the outcome of trials where preterm infants at risk of CLD were given postnatal steroids within 96 hours after birth. SEARCH STRATEGY: Randomised controlled trials of postnatal corticosteroid therapy were sought from the Oxford Database of Perinatal Trials, the Cochrane Controlled Trials Register, Medline, hand searching paediatric and perinatal journals, examining previous review articles and information received from practising neonatologists. SELECTION CRITERIA: Randomised controlled trials of postnatal corticosteroid treatment within 96 hours of birth (early) in high risk preterm infants were selected for this review. DATA COLLECTION AND ANALYSIS: Data regarding clinical outcomes including mortality, failure to extubate, pulmonary air leak, survival without chronic lung disease, CLD defined at 28 days postnatal age and 36 weeks post menstrual age, patent ductus arteriosus (PDA), severe intraventricular hemorrhage (IVH), infection, hyperglycaemia, hypertension, severe retinopathy of prematurity (ROP), necrotizing enterocolitis (NEC), gastrointestinal bleeding and longterm outcome were abstracted and analysed using Revman 4.0.4. MAIN RESULTS: Fifteen randomised controlled trials of early postnatal corticosteroid treatment of preterm babies at risk of developing CLD were identified. A meta-analysis of these trials demonstrates benefits as regards earlier extubation, decreased risks of CLD at both 28 days and 36 weeks, death or CLD at 28 days, and PDA. There was an almost significant reduction in the risk of pulmonary air leak and in death or CLD at 36 weeks in the babies treated with early corticosteroids. There were no differences in the rates of neonatal mortality, infection, severe ROP, severe IVH, NEC and pulmonary haemorrhage. Gastrointestinal bleeding and intestinal perforation were important adverse effects and the risks of hyperglycaemia and hypertension were also increased. Several adverse neurological effects were found at follow-up examinations of survivors treated with early steroids: abnormal neurological examination, cerebral palsy and developmental delay. REVIEWER'S CONCLUSIONS: The benefits of early postnatal corticosteroid treatment (< 96 hours) may not outweigh the known or potential adverse effects of this treatment. Gastrointestinal effects early in the neonatal period and neurological effects seen at follow-up mean that current use of early postnatal steroids needs to be reconsidered. There is a compelling need for the long term follow-up and reporting of late outcomes, especially neurologic and developmental outcomes, among surviving infants who participated in all randomized trials of early postnatal corticosteroid treatment. The role of inhaled steroids remains to be elucidated.

Anti-Inflammatory Agents↗

PubMed1985

Chromosomal abnormalities associated with congenital contractures (arthrogryposis).

In a study of 350 patients with multiple congenital contractures (arthrogryposis), 80 (23%) patients had mental retardation or were developmentally delayed. Out of that group of 80 patients, 13 (16%) were found to have abnormal karyotypes. Two of the thirteen had a family history of chromosomal abnormalities without congenital contractures, therefore, 11 patients had chromosomal anomalies which appeared to be associated with the congenital contractures. Five of the eleven (45%) had chromosome mosaicism, three of those had tissue mosaicism. Two had abnormal skin fibroblast cell lines and normal peripheral leukocyte chromosome studies and one had a normal bone marrow karyotype with abnormal peripheral leukocyte chromosome studies. Chromosome studies were done in these patients with congenital contractures because of developmental delay and multisystem involvement, or recognition of clinical features typical of a chromosomal syndrome. We recommend first lymphocyte; and if those are normal, then fibroblast studies be done on all patients with multiple joint contractures and developmental delay, particularly if unusual facial features or multisystem abnormalities are present.

Abnormalities, Multiple↗

PubMed1983

Maternal and child characteristics associated with mothers' perceptions of their high risk/developmentally delayed infants.

Mothers of 46 high risk infants, many of whom were developmentally delayed, were visited in their homes at approximately 9 months post-expected-date-of-delivery. The Perception of Baby Temperament (PBT) scales and the Profile of Mood States were administered and an observation of infant, parent, and parent-infant behavior was made. Infants were most likely to receive higher PBT scores on more than one scale if their mothers were more highly educated and reported lesser degrees of depression and anxiety. Infants who were perceived as more active and approaching by their mothers tended to be rated as more responsive by the observer and to show less developmental delay. Mothers who rated their infants as more active tended to show greater responsiveness to the infant and to participate in reciprocal activities with the infant more frequently during the home visit. These findings demonstrate that mothers' perceptions of high risk/developmentally delayed infant temperament are associated with similar categories of variables found to correlate with maternal perceptions of developmentally normal infant temperament.

Adaptation, Psychological↗

PubMed1999

An open, nonrandomized clinical comparative study evaluating the effect of epilepsy on learning.

Children with epilepsy, as a group, have a greater risk for developing learning problems as comorbid disorders. It is unknown which factors contribute to the development of such learning problems; therefore, our current knowledge does not allow the prediction of educational delay in an individual child with epilepsy. This study aimed at excluding as many factors as possible that could interfere with the analysis of the impact of epilepsy on learning. From patients referred to us in 1997 (N = 123), children were included with mild global learning impairment, defined as educational delay between 6 months and 1 year and no other apparent reason for learning impairment except for epilepsy (ie, excluding children with dyslexia, attention-deficit hyperactivity disorder, or mental handicap). A total of 44 patients fulfilled this criterion: 31 also had epilepsy (experimental group); the remaining 13 patients with similar mild learning impairment but without epilepsy were used as controls. In the experimental group two subgroups were distinguished on the basis of onset of learning impairment: in group A (n = 17) the learning problems are not unexpected as they were preceded by mild developmental delay; in group B (n = 14) the problems are unexpected and had a sudden onset. The two experimental groups differed from the control group on a number of variables, such as gender and the incidence of perinatal complications. More differences have been found between the two experimental groups: group B is selected from a larger group: all children with mild global learning impairment with sudden onset. In this group considerably more children with epilepsy have been found compared to the children with developmental delay; moreover the epilepsy is more often characterized in these children as "unexpected," that is, there was no previous established diagnosis of epilepsy, the symptoms were mostly unclear and behavioral in make-up (attentional lapses, etc); the electroencephalogram plays a much greater role in the diagnosis in this group, especially in demonstrating seizures; finally, the children in this group more frequently have neuropsychologic impairment. Children with epilepsy can have mild global learning difficulties, especially in the period after the onset of seizures. This group can be divided in a group with "trait-dependent learning difficulties," that is learning difficulties based on developmental delay, and a group with "state-dependent learning difficulties." The focus in our study was on this latter group, consisting of children with sudden and unexpected decline of results in school. The crucial finding in this group is the relatively frequent demonstration of difficult-to-detect seizures, demonstrating that an uncontrolled epilepsy can cause a decline in school results even when the seizures are of short duration and have subtle symptoms.

Attention Deficit Disorder with Hyperactivity↗

PubMed2026

WWOX-related developmental and epileptic encephalopathy (WOREE): A case series of seven patients from Argentina.

PURPOSE: WWOX-related developmental and epileptic encephalopathy (WOREE) is a rare autosomal recessive disorder caused by biallelic pathogenic WWOX variants, characterized by very early-onset epilepsy, profound developmental delay, and progressive brain abnormalities. Detailed electroclinical descriptions remain limited. METHODS: We conducted a retrospective study of seven patients with pathogenic/likely pathogenic WWOX variants. Clinical features, seizure evolution, EEG findings, brain MRI, and genetic data were reviewed. Epilepsy syndromes were classified according to International League against Epilepsy (ILAE) criteria. Variants were identified through next-generation sequencing and interpreted following American College of Medical Genetics and Genomics (ACMG) guidelines. RESULTS: Median seizure onset was 3 months (range 2-6). Five patients presented with focal seizures evolving to infantile epileptic spasms syndrome (IESS), while two had IESS at onset. Epilepsy was drug-resistant in all. Developmental delay was evident from birth with generalized hypotonia, acquired microcephaly, and impaired visual attention. Four patients had dysmorphic features. During the IESS period, EEG showed hypsarrhythmia in six patients and a severely disorganized encephalopathic background that did not strictly fulfill the criteria for hypsarrhythmia in one. Brain MRI revealed abnormalities in all patients, including frontotemporal atrophy and corpus callosum hypoplasia; delayed myelination was observed in one case. Eight pathogenic/likely pathogenic WWOX variants were found; including one novel variant (NM_016373.4:c.571C>T, p.(Gln191*)). The recurrent splice-site variant NM_016373.4:c.107+1G>A was identified in five patients, suggesting a possible regional founder effect. CONCLUSION: WOREE shows a recognizable electroclinical and neuroimaging profile with early drug-resistant epilepsy and profound developmental delay. Recognition of this pattern may facilitate early diagnosis and targeted genetic testing, particularly in populations with recurrent variants.

Developmental and epileptic encephalopathy↗

PubMed1997

Inherited interstitial duplications of proximal 15q: genotype-phenotype correlations.

We present the cytogenetic, molecular cytogenetic, and molecular genetic results on 20 unrelated patients with an interstitial duplication of the proximal long arm of chromosome 15. Multiple probes showed that the Prader-Willi/Angelman critical region (PWACR) was included in the duplication in 4/20 patients, each ascertained with developmental delay. The duplication was also found in two affected but not in three unaffected sibs of one of these patients. All four probands had inherited their duplication from their mothers, three of whom were also affected. Two of the affected mothers also carried a maternally inherited duplication, whereas the duplication in the unaffected mother and in an unaffected grandmother was paternal in origin, raising the possibility of a parental-origin effect. The PWACR was not duplicated in the remaining 16 patients, of whom 4 were referred with developmental delay. In the 14 families for which parental samples were available, the duplication was inherited with equal frequency from a phenotypically normal parent, mother or father. Comparative genomic hybridization undertaken on two patients suggested that proximal 15q outside the PWACR was the origin of the duplicated material. The use of PWACR probes discriminates between a large group of duplications of no apparent clinical significance and a smaller group, in which a maternally derived PWACR duplication is consistently associated with developmental delay and speech difficulties but not with overt features of either Prader-Willi syndrome or Angelman syndrome.

Adult↗