Malformations of cortical development: clinical spectrum in a series of 101 patients and review of the literature (Part I)

Patients with malformations of cortical development (MCD) present with a wide spectrum of clinical manifestations ranging from asymptomatic cases to those with epilepsy and neurodevelopmental problems. Thorough clinical delineation of patients with MCD may provide clues for future phenotype-genotype correlation studies. We studied clinical features of patients with MCD, including developmental risk factors and family history. We evaluated 10 patients with MCD at Hacettepe University Children's Hospital, Department of Pediatric Neurology. All patients underwent neurological evaluation with detailed medical and family history, and neuropsychological evaluation. Routine EEG and MRI were obtained. The patients were between 1 month and 19 years of age (mean: 6.1 +/- 4.4 years). Fifty-four patients were diagnosed with polymicrogyria (PMG), 23 patients with lissencephaly, 12 patients with schizencephaly, and 12 patients with heterotopia. Parents were relatives in 31.7% of the cases; consanguinity was most common in patients with lissencephaly and other MCDs with diffuse/bilateral involvement. Initial clinical presentation was seizures in 61.4% of the cases, developmental delays in 12.9%, and microcephaly in 9.9%. Neurological evaluation revealed most severe abnormalities in patients with lissencephaly, and relatively better outcome in patients with heterotopias. Cognitive functions were better in patients with heterotopias compared to other groups. Overall, 71.3% of patients ha epilepsy. In conclusion, initial presentation and clinical course of patients with MCD are variable and seem to be correlated with the extent of cortical involvement. Epilepsy and mental retardation are the most common problems. The most severe clinical outcome was seen in patients with lissencephaly.     

Two years of growth hormone treatment in the first growth hormone deficient patient with cerebrofaciothoracic dysplasia

We recently reported two siblings, a sister and a brother, with intrauterine growth retardation, microcephaly, short stature, mental retardation, facial dysmorphism and multiple costovertebral malformations. These features fit most with the diagnosis of cerebrofaciothoracic dysplasia, or Pascual-Castroviejo syndrome. The second sibling, our index patient, presented also with cleft palate and growth hormone (GH) deficiency, suggesting that endocrinological assessment should be performed in short patients with this syndrome, especially if midline defects are present. We present the results of 2 years GH treatment of this first GH deficient patient with cerebrofaciothoracic syndrome and compare the results to those observed in other genetic syndromes with GH deficiency.     

Severe feeding problems and congenital laryngostenosis in a patient with 3q23 deletion

Common clinical features of patients with 3q23 deletion include the phenotype of BPES (blepharophimosis, ptosis, epicanthus inversus and telecanthus syndrome), growth and mental retardation, microcephaly, ear and nose dysmorphism and joint and digit abnormalities. We report on a 3-year-old girl with the phenotype of BPES, mental retardation, facial dysmorphism and camptodactyly. In addition, she had a congenitally small larynx and severe, chronic feeding difficulties. Chromosome studies revealed an interstitial deletion in the long arm of chromosome 3: del(3)(q23-q25) Conclusion Congenital laryngostenosis and severe feeding problems may be part of the clinical syndrome caused by chromosome 3q23 deletion. Received: 28 January 1997 / Accepted: 25 February 1997     

Rare manifestations of Neu-Laxova syndrome

Neu-Laxova syndrome is a rare lethal congenital disorder involving multiple systems. Intrauterine growth retardation, ichthyosis, microcephaly, abnormal facial findings and limb contractures are its key features. We present a stillborn female baby of 1.5 kg with characteristic features including growth retardation, microcephaly, severe ectropion, micrognathia, flattened nose, eclabion, large ears, puffy hands and feet. In addition to these features, lissencephaly, severely hypoplastic cerebrum and corpus callossum, Dandy-Walker malformation, Transposition of Great Vessels and hepatomegaly were noted at autopsy. The patient was born at 38 weeks of gestation to consanguineous (second degree) Indian parents. The mother was 26 year old second gravida with lack of prenatal followup. Therefore, the condition was diagnosed postnatally. Because of the autosomal recessive inheritence of Neu-Laxova syndrome, in countries with high rates of consanguineous marriage, serial prenatal ultrasound examinations with genetic counseling should be performed on pregnant women at high risk to offer termination of affected pregnancies.     

Outcome of children of alcoholic mothers (study of 105 cases followed to adult age) and various prophylactic findings]

Thirty years after recognition of the fetal alcohol syndrome, a study of 105 affected individuals who reached adulthood provides insight into the long-term outcome of this condition. The typical facial dysmorphism undergoes odd changes, often with a long face and a bulky nose and chin, in contrast to the appearance of affected infants. The growth failure becomes slightly less marked. The malformations, which occur in 3/4 of severe forms, increase the disability although function is sometimes better than expected. In contrast, the microcephaly becomes more pronounced. This explains the psychic disorders which are the main prognostic factor: mental retardation in the most severely affected patients or severe learning disabilities and, in every case, behavior disorders and marked instability. Similar disorders are often found in siblings with no apparent dysmorphism underlining the extent of the problem and the urgent need for prophylaxis. Some of the observations made in adults, confronted to embryologic data, lead to useful inferences with respect to prophylaxis.     

Medulloblastoma with adverse reaction to radiation therapy in nijmegen breakage syndrome

A 3-year-old child with microcephaly, facial dysmorphism, growth retardation, and developmental delay was diagnosed with medulloblastoma. Craniospinal irradiation resulted in severe radiation-induced dermatitis and gastroesophagitis, unresponsive to further medical therapy. Colony survival assay on the patient's transformed lymphocytes revealed a high degree of radiosensitivity ex vivo. The presence of radiation sensitivity, both clinically and ex vivo, in association with microcephaly and growth retardation, prompted a diagnostic workup for Nijmegen breakage syndrome. The patient was confirmed to have a compound heterozygote genotype for the common founder mutation of NBS1 675del5 in exon 6, and 1142delC in exon 10. Because irradiation is an important component of therapy for brain tumors, caution should be exercised in cancer patients with associated microcephaly and growth retardation, as they may turn out to have the rare diagnosis of Nijmegen breakage syndrome.     

Malformations of cortical development and epilepsy: evaluation of 101 cases (part II)

Malformations of cortical development (MCD) form a spectrum of lesions produced by insult to the developing neocortex. Clinical presentation and electrophysiologic findings of MCD are variable and depend on the affected cortical area. We evaluated epilepsy, EEG, and response to antiepileptic treatment in patients with MCD with respect to the neuroimaging findings. We studied 101 patients, ranging between 1 month and 19 years of age. Fifty-four patients were diagnosed with polymicrogyria (PMG), 23 patients with lissencephaly, 12 patients with schizencephaly, and 12 patients with heterotopia. With regards to epilepsy and seizure type, 72/101 (71.3%) patients had epilepsy, and 62/101 (61.4%) patients presented with seizures. Overall, 32.7% of patients had generalized seizures, and 25.7% had complex partial seizures. Mean age at the onset of seizures was 2.7 +/- 3.4 years. The onset of epilepsy tended to be younger in patients with lissencephaly and older in patients with heterotopias. Of the cases, 79.2% had abnormal EEG (56.3% with epileptiform abnormality, 22.9% with non-epileptiform abnormality). EEG was abnormal in 44.9% (13/29) of the cases without epilepsy. EEG showed bilateral synchronous and diffuse epileptiform discharges in 90% of patients with lissencephaly. Patients with schizencephaly had mostly focal epileptiform discharges. Heterotopia cases had a high rate of EEG abnormalities (72.7%). Patients with PMG had epileptiform abnormality in 59.5% of the cases. Patients with heterotopias and PMG achieved better seizure control in comparison with the other groups. In conclusion, epilepsy is the most common problem in MCD. Epilepsy and EEG findings of patients with MCD are variable and seem to be correlated with the extent of cortical involvement.     

Microcephaly, sensorineural deafness and Currarino triad with duplication–deletion of distal 7q

Currarino syndrome (CS) is a peculiar form of caudal regression syndrome [also known as autosomal dominant sacral agenesis (OMIM no. 176450)] characterised by (1) partial absence of the sacrum with intact first sacral vertebra, (2) a pre-sacral mass and (3) anorectal anomalies (Currarino triad). We studied a 3-year-old girl with Currarino triad who had additional systemic features and performed array comparative genomic hybridisation to look for chromosomal abnormalities. This girl had the typical spectrum of anomalies of the CS including (a) partial sacral agenesis (hemisacrum with remnants of only sacral S1–S2 vertebrae and a residual S3 vertebral body) associated with complete coccygeal agenesis, (b) pre-intrasacral dermoid, (c) intra-dural lipoma, (d) ectopic anus and (e) tethered cord. She had, in addition, pre- and post-natal growth impairment (<3rd percentile), severe microcephaly (<?3 SD) with normal gyration pattern and lack of cortical thickening associated with a hypoplastic inferior vermis, facial dysmorphism, sensorineural deafness and decreased serum levels of IGF-1. A de novo 10.3-Mb duplication of 7q34–q35 and an 8.8-Mb deletion on 7q36 were identified in this patient. The Homeobox HLXB9 (CS) gene is contained within the deletion accounting for the CS phenotype including microcephaly. The spectrums of associated abnormalities in the IGF-1 deficiency growth retardation with sensorineural deafness and mental retardation syndrome (OMIM no. 608747) are discussed. To the best of our knowledge, this is the first reported case of a patient with distal 7q chromosomal imbalance and features of CS triad (including microcephaly) and the first documented case of a patient with normal gyration pattern microcephaly. The spectrum of associated anomalies in this newly recognised phenotype complex consists of growth failure, typical facial anomalies with additional (previously unreported) nervous system abnormalities (e.g. sensorineural deafness) and somatomedin C deficiency.     

3-M syndrome in two sisters

3-M syndrome is a rare, autosomal recessive dwarfing syndrome characterized by prenatal growth restriction, facial dysmorphism and absence of both microcephaly and mental retardation. The term 3-M syndrome originates from the common initial of the first three authors of the first report. The diagnosis is established by a combination of clinical history, clinical examination and radiographic findings. The present report shows two sisters whose facial features were slightly different from those usually reported. In addition, they presented with small nails and abnormal dermatoglyphics. The present report expands the phenotypic spectrum of 3-M syndrome.     

母源性苯丙酮尿症的临床特征与干预

母源性苯丙酮尿症是由于苯丙酮尿症孕妇在孕前及孕中苯丙氨酸水平持续升高导致的综合征,其表现为小头及面部畸形、先天性心脏病、智力低下和行为及情感异常.合理控制苯丙酮尿症孕妇血苯丙氨酸水平并保持在120～360μmol/L,能够降低和避免胎儿畸形不良结局的发生.母源性苯丙酮尿症应倡导三级干预.     

Partielle Trisomie 11q23–q25

Background. Report of a 21 month old female patient with a partial trisomy 11q23–q25 (and a deletion 11q24.3), which is not due to a chromosomal translocation in one of the parents, but represents a new duplication of that segment of chromosome 11. This is a very rare event. Case report. The patient's clinical symptoms consist of a typical dysmorphism of facial structures, muscle hypotonia, severe psychomotor and mental retardation, microcephaly and signs of abnormal brain structure, hearing loss, hypothyroidism, recurrent infections of the respiratory, alimentary and urinary tract, vesico-ureteral reflux and hydronephrosis, growth retardation and especially several important defects in the respiratory tract, visible in flexible brochoscopy, which were not reported before. In the neonatal period and during the first year treatment for apnoe, hypoglycemia, transient thrombocytopenia and a convulsive disorder was necessary. Prenatal diagnosis. Given the specific chromosomal changes, a prenatal diagnosis would be possible in future pregnancies, although the recurrence risk should be very low, considering the normal chromosomal findings in the parents.     

Proximal 3p Deletion: Case Report and Review of the Literature

A boy with severe growth and psychomotor retardation, facial dysmorphism, a large atrial septal defect, limitation of joint movement and hearing impairment is described. High-resolution banding chromosome analysis showed interstitial deletion of the proximal segment of chromosome 3: 46, XY, del(3)(p12p14.2) de novo. The deleted chromosome 3 was of paternal origin as judged from Q-banding polymorphisms. Delineation of proximal 3p deletion syndrome is proposed by summarizing the clinical and cytogenetical findings of the present and previously reported five patients.     

Primary microcephaly in Hungary: epidemiology and clinical features

Aim: To describe the population‐based epidemiological characteristics and clinical features of primary microcephaly in Hungary. Methods: A retrospective survey of patients born with microcephaly in a region (Dél‐Alföld – South Great Plain) in Hungary between July 1, 1992 and June 30, 2006 was performed. Patients with microcephaly and without any environmental or obstetric risk factors and/or dysmorphism (primary microcephaly) were included in the study. The birth prevalence of primary microcephaly per 10 000 live births was calculated. Results: Ten patients (8 girls and 2 boys) were found with primary microcephaly among 185 486 live births, which corresponds to a birth prevalence of 0.54 per 10 000 live births (95% confidence interval: 0.20–0.87). Developmental delay and intellectual disability were the main clinical features. Dyskinesia was seen in one and epilepsy was diagnosed in two patients. The MRI revealed simplified gyral pattern in all patients. Conclusion: Primary microcephaly is a very rare brain malformation, although the birth prevalence found in this survey is slightly higher than the few figures published earlier. As more and more genes and mutations responsible for primary microcephaly are discovered, the ascertainment of these rare cases is mandatory to provide the parents with genetic counselling.     

Hypoparathyroidism-retardation-Dysmorphism (HRD) syndrome--a review

Hypoparathyroidism, retardation, and dysmorphism (HRD) is a newly recognized genetic syndrome, described in patients of Arab origin. The syndrome consists of permanent congenital hypoparathyroidism, severe prenatal and postnatal growth retardation, and profound global developmental delay. The patients are susceptible to severe infections including life-threatening pneumococcal infections especially during infancy. The main dysmorphic features are microcephaly, deep-set eyes or microphthalmia, ear abnormalities, depressed nasal bridge, thin upper lip, hooked small nose, micrognathia, and small hands and feet. A single 12-bp deletion (del52-55) in the second coding exon of the tubulin cofactor E (TCFE) gene, located on the long arm of chromosome 1, is the cause of HRD among Arab patients. Early recognition and therapy of hypocalcemia is important as is daily antibiotic prophylaxis against pneumococcal infections.     

FISH investigation of 22q11.2 deletion in patients with immunodeficiency and/or cardiac abnormalities

DiGeorge anomaly/velocardiofacial syndrome (DG/VCFS), called 22q11.2 deletion syndrome in general, is the most common chromosomal deletion syndrome found in humans. Typical facial features, palatal defects, conotruncal abnormalities of the heart, aplasia/hypoplasia of the parathyroid glands and of thymus are characteristics of this syndrome. Deletions of chromosome 22q11.2 (del22q11.2) are the leading causes of DG7VCFS. We report on a systematic search by fluorescence in situ hybridization (FISH) for deletions of chromosomes 22q11.2 in patients with a clinical suspicion or diagnosis of DG/VCFS. Using FISH we studied a series of 43 patients with suspected DG/VCFS. In this study, a total of 43 patients were investigated for the presence of a 22q11.2 deletion over a two-year period. Del22q11.2 was detected in 5 of the 43 patients tested. All patients with deletion had hypocalcemia, 80% had cardiac defects, 40% had facial dysmorphism, 40% had immunodeficiency , and 20% had otolaryngeal abnormalities. Chromosome 22q11.2 deletion is a relatively common condition and is readily diagnosed by FISH. We suggest that FISH analysis of 22q11.2 deletion should be performed in the presence of combined of hypocalcemia and congenital cardiac malformations, with or without any characteristics of the disease. This may facilitate an early diagnosis in such patients.     

A Japanese boy with Young-Simpson syndrome

In 1987 Young and Simpson reported a child with hypothyroidism, a congenital heart disease, severe mental retardation and striking facial dysmorphism, including microcephaly, blepharophimosis, bulbous nose, thin lip, low-set ears and micrognathia. This study presents an 8-month-old boy with virtually identical features to those in Young and Simpson's original case. The patient is a sporadic case and his parents are unrelated and phenotypically normal, hence the family data corresponds to any mode of inheritance. This is the first male case reported in the world and the first in Orientals.     

De novo interstitial deletion of the long arm of chromosome 2 in a malformed newborn with a karyotype: 46,XY,del(2)(q12q14)

A male neonate with severe malformations, including facial dysmorphism, a short neck, postaxial-hexadactyly of the toes, congenital heart disease, hydronephrosis, imperforate anus and agenesis of corpus callosum, is described. His karyotype was 46,XYdel(2)(q12q14).     

A new syndrome of congenital hypoparathyroidism,severe growth failure,and dysmorphic features.

Twelve infants (six boys, six girls) with severe hypocalcaemic tetany or convulsions were seen over a three year period. Nine patients were symptomatic in the newborn period. Their hypocalcaemia was associated with hyperphosphataemia and very low concentrations of immunoreactive parathyroid hormone. None of the babies suffered from congenital cardiac disease. Cell mediated immunity, measured in five patients, was normal. There were no chromosomal abnormalities but all patients shared several dysmorphic features including deep set eyes, microcephaly, thin lips, beaked nose tip, external ear anomalies, micrognathia, and depressed nasal bridge. Mental retardation of varying degree was found in all patients. All had severe intrauterine and postnatal growth retardation. Four patients have died. The remaining eight patients are on treatments with vitamin D and calcium supplements with no change in their growth pattern. We believe that this association of congenital hypoparathyroidism with severe growth failure and dysmorphism represents a new syndrome.     

Combination of Miller–Dieker syndrome and VACTERL association causes extremely severe clinical presentation

We report a Japanese boy, who showed overlapping clinical features of Miller–Dieker syndrome (lissencephaly and facial dysmorphism) and vertebral defect, anal atresia, cardiac malformation and limb anomalies (VACTERL) association. The overall clinical presentation was much more severe than that normally associated with each disorder, and the infant died on day 100 of life despite aggressive therapy. Fluorescence in situ hybridization using a commercially available LIS1 probe failed to detect a deletion, but chromosomal microarray analysis detected a 2.50-Mb microdeletion in 17p13.3 which involved partially the LIS1 gene, and thus was compatible with Miller–Dieker syndrome. It may represent an example of a combination of two congenital disorders with blended phenotypes explaining unexpectedly severe phenotypes occurring with known chromosomal rearrangements. Conclusion: We report the first case of a combination of Miller–Dieker syndrome and VACTERL association with an unusually severe phenotype.     

Miller‐Dieker Syndrome with unbalanced translocation 45, X,psu dic(17;Y)(p13;p11.32) detected by fluorescence in situ hybridization and G‐banding analysis using high resolution banding technique

Lissencephaly is one of the central nervous system anomalies of Miller‐Dieker Syndrome (MDS). Fetuses with lissencephaly have an abnormal smooth brain with fewer folds and grooves that will be detected by ultrasounds or fetal magnetic resonance imaging (MRI) after 30 weeks of gestation. We report a fetus with lissencephaly diagnosed as Miller‐Dieker Syndrome postnatally. G banded chromosome analysis revealed 45,X,psu dic(17;Y)(p13;p11.32).ish dic (17;Y)(LIS1‐,RARA+, SRY+, DYZ3+) by G‐banding analysis using high resolution banding technique. Fetal delayed cortical development will be the findings to perform further investigations including fluorescence in situ hybridization analysis for MDS, a 17p13.3 microdeletion syndrome, pre/postnatally. This will be the first case of MDS with unbalanced translocation between deleted short arm of chromosome 17 and Y chromosome.