Mild Developmental Delay Research Articles

Parathyroid adenomas – a cluster of boys

Primary hyperparathyroidism is rare in children and adolescents, representing 1% of all cases, with a slight female preponderance [1-3]. 3-5% of cases are hereditary and may represent the initial clinical manifestation of multiple endocrine neoplasia type 1 (MEN1). Over the last 30 years, ten cases of primary hyperparathyroidism have presented to our hospital, all aged 11-14 years, with nine cases being male, and eight cases over the last six years. Presenting features included headache and blurred vision in five patients, abdominal pain and nausea (in three), renal calculi (in four), generalized bone pain (in three) and two asymptomatic. One patient had received radiation for acute lymphoblastic leukaemia. Other history included ADHD (in one patient), mild developmental delay (in one), depression (in one) and fine motor difficulties (in one). No patients had a significant family history. Peak corrected calcium level ranged between 3.12-3.65 mmol/L (2.1-2.65), peak PTH level 6.9-154 pmol/L (1-7), and urine calcium creatinine ratio 0.47-2.76mM/mM (0.04-0.7). Serum alkaline phosphatase was 212-549U/L (80-355), and normal in three of the renal calculi patients. Bony changes were seen in three patients, with flaring of clavicles and widening of epiphyses, decreased phalangeal cortical density and osteopenia. 25-OH calciferol was low at 27-39nmol/L (>50) in 3 of 7 patients in whom it was measured. Thyroid ultrasound detected suspicious lesions in seven patients and was normal in three patients. Sestamibi scan was negative for three patients (with one ectopic gland) and indicated a single overactive gland in seven patients. All patients had a positive result from at least one modality. All patients underwent surgical resection, with a single benign parathyroid adenoma identified in each case. The only significant post-operative issues were initial hypocalcaemia (lowest cCa 1.8mmol/L) in eight patients, requiring management with calcitriol and elemental calcium. There was normalisation of calcium over several weeks post-operatively, with gradual weaning of supplementation required. In all, post-operative PTH level was suppressed. MEN1 screening has been negative for all patients. This case series illustrates the difficulties involved in the diagnosis of parathyroid adenoma in children, requiring both scintigraphy and ultrasound. Scintigraphy has been reported in the literature to have 88% sensitivity, lower in our case series, compared to 78% sensitivity for ultrasound [4]. The gender mix of our cases differs significantly from other reported case series, being predominantly male [3,5] and there is a suggestion of increasing incidence over recent years.

Hippocampal neuron populations are reduced in vervet monkeys with fetal alcohol exposure.

Prenatal exposure to beverage alcohol is a major cause of mild mental retardation and developmental delay. In nonendangered alcohol-preferring vervet monkeys, we modeled the most common nondysmorphic form of fetal alcohol syndrome disorder with voluntary drinking during the third trimester of pregnancy. Here, we report significant numerical reductions in the principal hippocampal neurons of fetal alcohol-exposed (FAE) offspring, as compared to age-matched, similarly housed conspecifics with isocaloric sucrose exposure. These deficits, particularly marked in CA1 and CA3, are present neonatally and persist through infancy (5 months) and juvenile (2 years) stages. Although the volumes of hippocampal subdivisions in FAE animals are not atypical at birth, by age 2, they are only 65–70% of those estimated in age-matched controls. These data suggest that moderate, naturalistic alcohol consumption during late pregnancy results in a stable loss of hippocampal neurons and a progressive reduction of hippocampal volume. © 2015 The Authors. Developmental Psychobiology Published by Wiley Periodicals, Inc. Dev Psychobiol 57:470–485, 2015.

Personality Disorders in a Developmental Delay Population

Introduction: Determine the prevalence of personality disorders in an inpatient developmental delay population. Objectives Find individual-biological-social factors that may be associated with personality disorder. Methods: A cross-sectional study of 14 patients admitted to a Spanish developmental delay unit. Standard procedures were followed in all the measurements (i.e., socio-demographics, etc) as well as in the evaluation of developmental delay, Axis I and Axis V. Results As expected all patietns have been diagnosed with developmental delay while the 64% were males. The 50% of them had diagnosed with mild developmental delay, 43% with moderate and 7% with severe symptoms. The mean age was 31.14±9.65 years and the mean hospitalization in the unit was 29.36±18.96 months. The mean Axis V score (0-100) among the 14 patients was 45.07±11. Among the patients, the highest prevalence of Axis I disorders, had other disorders (64%), followed by impulse control disorders (43%), psychoses (21%), mood disorders (14%) and substance abuse (7%). The 29% of the sample have been diagnosed with personality disorder, and specifically the 50% was diagnosed as Cluster B. There was a significant difference on personality disorder Cluster B among males and females (0% vs 40%, p=0.04). Moreover a strong association among female gender and personality disorder Cluster B was evaluated (r= −0.54, p=0.04). Conclusions: More than the half of the patients had diagnosed with mild and moderate symptoms of developmental delay. Among them, the personality disorder Cluster B, seems to be related wtih the female gender.

15q11.2 microdeletion (BP1–BP2) and developmental delay, behaviour issues, epilepsy and congenital heart disease: A series of 52 patients

Proximal region of chromosome 15 long arm is rich in duplicons that, define five breakpoints (BP) for 15q rearrangements. 15q11.2 microdeletion between BP1 and BP2 has been previously associated with developmental delay and atypical psychological patterns. This region contains four highly-conserved and non-imprinted genes: NIPA1, NIPA2, CYFIP1, TUBGCP5. Our goal was to investigate the phenotypes associated with this microdeletion in a cohort of 52 patients.This copy number variation (CNV) was prevalent in 0.8% patients presenting with developmental delay, psychological pattern issues and/or multiple congenital malformations. This was studied by array-CGH at six different French Genetic laboratories. We collected data from 52 unrelated patients (including 3 foetuses) after excluding patients with an associated genetic alteration (known CNV, aneuploidy or known monogenic disease).Out of 52 patients, mild or moderate developmental delay was observed in 68.3%, 85.4% had speech impairment and 63.4% had psychological issues such as Attention Deficit and Hyperactivity Disorder, Autistic Spectrum Disorder or Obsessive-Compulsive Disorder. Seizures were noted in 18.7% patients and associated congenital heart disease in 17.3%. Parents were analysed for abnormalities in the region in 65.4% families. Amongst these families, ‘de novo’ microdeletions were observed in 18.8% and 81.2% were inherited from one of the parents. Incomplete penetrance and variable expressivity were observed amongst the patients.Our results support the hypothesis that 15q11.2 (BP1–BP2) microdeletion is associated with developmental delay, abnormal behaviour, generalized epilepsy and congenital heart disease. The later feature has been rarely described. Incomplete penetrance and variability of expression demands further assessment and studies.

Holoprosencephaly: a survey of the entity, with embryology and fetal imaging.

Structural malformations of the brain are an important cause of childhood mortality and morbidity, with the latter having long-term financial and psychosocial implications for the affected child and family. Holoprosencephaly (HPE) is a severe brain malformation characterized by abnormal cleavage of the prosencephalon in the 5th gestational week. Aprosencephaly and atelencephaly occur earlier because of failure in the formation of the prosencephalon and telencephalon, respectively. The HPE holoprosencephaly spectrum classically includes alobar, semilobar, and lobar forms, although there are no clear-cut defining features. The middle interhemispheric variant (MIH), also known as syntelencephaly, is classified as a variant of HPE holoprosencephaly with midline interhemispheric fusion. Other conditions sometimes included in the spectrum of HPE holoprosencephaly include septo-optic dysplasia (SOD); "minimal" HPE holoprosencephaly , which is associated with subtle craniofacial malformations and mild developmental delay; and microform HPE holoprosencephaly , which by definition excludes brain involvement. The focus of this article will be on the spectrum of findings visible in fetal manifestation of the HPE holoprosencephaly spectrum. Brain embryology; the imaging characteristics, epidemiology, and embryology of HPE; and the more common associated anomalies, particularly those of the face ("the face predicts the brain") are reviewed. Recognition of these anomalies is important for accurate parental counseling, since the prognosis is poor but not invariably lethal; children with the milder forms may live well into their teens with severe developmental delays, endocrine dysfunction, and disrupted homeostasis. Available data on outcome in surviving children are summarized. Illustrative fetal ultrasonographic and magnetic resonance images are presented with clinical, autopsy, and postnatal imaging correlation.

A Patient with Septo-Optic Dysplasia Accompanying with Central Precocious Puberty

Septo-Optic Dysplasia (SOD) is a heterogeneous condition defined by any combination of i) optic nerve hypoplasia, ii) hypopituitarism, and iii) midline brain anomalies such as agenesis of the corpus callosum and absence of the septum pellucidum. We encountered a Japanese girl with optic nerve hypoplasia, growth failure, precocious puberty, and mild developmental delay. Her optic nerve hypoplasia was diagnosed at 4 months of age. Thereafter, she showed growth failure from infancy. Gradual breast development was noticed from 6 years of age. Therefore, she was referred to us at 9.2 years of age. Endocrinological investigations demonstrated deficiencies in growth hormone, adrenocorticotropic hormone, and cortisol. However, serum levels of luteinizing hormone, follicle stimulating hormone, and estradiol were increased to pubertal levels. Brain MRI revealed bilateral optic nerve hypoplasia, a normal anterior pituitary lobe, an invisible pituitary stalk, and an invisible posterior lobe. Based on these findings, she was diagnosed as having SOD with growth hormone deficiency, secondary adrenal insufficiency, and central precocious puberty. Replacement of hydrocortisone, recombinant growth hormone replacement, and suppression therapy by gonadotropin releasing hormone analog were initiated. Her growth rate and physical activity were improved after treatment. While SOD is rare, children with optic nerve hypoplasia should be carefully checked for symptoms of pituitary hormone deficiency. Timely diagnosis of endocrine deficits could reduce the morbidity of patients with SOD.

Recessive loss-of-function mutations in AP4S1 cause mild fever-sensitive seizures, developmental delay and spastic paraplegia through loss of AP-4 complex assembly.

We report two siblings with infantile onset seizures, severe developmental delay and spastic paraplegia, in whom whole-genome sequencing revealed compound heterozygous mutations in the AP4S1 gene, encoding the σ subunit of the adaptor protein complex 4 (AP-4). The effect of the predicted loss-of-function variants (p.Gln46Profs*9 and p.Arg97*) was further investigated in a patient's fibroblast cell line. We show that the premature stop mutations in AP4S1 result in a reduction of all AP-4 subunits and loss of AP-4 complex assembly. Recruitment of the AP-4 accessory protein tepsin, to the membrane was also abolished. In retrospect, the clinical phenotype in the family is consistent with previous reports of the AP-4 deficiency syndrome. Our study reports the second family with mutations in AP4S1 and describes the first two patients with loss of AP4S1 and seizures. We further discuss seizure phenotypes in reported patients, highlighting that seizures are part of the clinical manifestation of the AP-4 deficiency syndrome. We also hypothesize that endosomal trafficking is a common theme between heritable spastic paraplegia and some inherited epilepsies.

TRNT1 missense mutations define an autoinflammatory disease characterized by recurrent fever, severe anemia, and b-cell immunodeficiency

We observed a syndrome characterized by recurrent fever, severe anemia, gastrointestinal symptoms, and a spectrum of immunologic and neurologic symptoms in five children from four unrelated families. Neurologic manifestations ranged from mild developmental delay to nystagmus, spasticity, optic nerve atrophy, and sensorineural hearing loss. Sideroblastic anemia was identified by bone marrow biopsies in two of the children.

Functional characterization of obesity-associated variants involving the α and β isoforms of human SH2B1.

We have previously reported rare variants in sarcoma (Src) homology 2 (SH2) B adaptor protein 1 (SH2B1) in individuals with obesity, insulin resistance, and maladaptive behavior. Here, we identify 4 additional SH2B1 variants by sequencing 500 individuals with severe early-onset obesity. SH2B1 has 4 alternatively spliced isoforms. One variant (T546A) lies within the N-terminal region common to all isoforms. As shown for past variants in this region, T546A impairs SH2B1β enhancement of nerve growth factor-induced neurite outgrowth, and the individual with the T546A variant exhibits mild developmental delay. The other 3 variants (A663V, V695M, and A723V) lie in the C-terminal tail of SH2B1α. SH2B1α variant carriers were hyperinsulinemic but did not exhibit the behavioral phenotype observed in individuals with SH2B1 variants that disrupt all isoforms. In in vitro assays, SH2B1α, like SH2B1β, enhances insulin- and leptin-induced insulin receptor substrate 2 (IRS2) phosphorylation and GH-induced cell motility. None of the variants affect SH2B1α enhancement of insulin- and leptin-induced IRS2 phosphorylation. However, T546A, A663V, and A723V all impair the ability of SH2B1α to enhance GH-induced cell motility. In contrast to SH2B1β, SH2B1α does not enhance nerve growth factor-induced neurite outgrowth. These studies suggest that genetic variants that disrupt isoforms other than SH2B1β may be functionally significant. Further studies are needed to understand the mechanism by which the individual isoforms regulate energy homeostasis and behavior.

Neurocutaneous Melanosis: An Illustrative Patient

We present a newborn with an unremarkable birth history who presented with a giant congenital melanocytic nevus with a “bathing trunk” distribution, accompanied by multiple satellite nevi (Fig 1). Cranial magnetic resonance imaging revealed multiple hyperintense lesions of the brain parenchyma and leptomeninges (Fig 2), confirming the diagnosis of neurocutaneous melanosis. At 13 months, he developed a partial seizure with secondary generalization. He had been asymptomatic until then. Antiepileptic treatment with valproic acid was started. Subsequently he has had occasional seizures that have required antiepileptic readjustment but has otherwise been well. Currently he is 3 years of age and has been seizure-free for 18 months with only mild developmental delay and no apparent progression of his neurocutaneous melanosis. Discussion Congenital melanocytic nevi are proliferations of benign melanocytes that arise during embryogenesis. Neurocutaneous melanosis is a complication of congenital melanocytic nevi and consists of proliferation of melanocytes in the central nervous system and leptomeninges as well as in the skin. It occurs in 2.5-45% of patients with congenital melanocytic nevi, 1 and the risk factors include large congenital melanocytic nevus, multiple satellite nevi, and more than two medium-sized congenital melanocytic nevi. 2-4 Neurocutaneous melanosis can be either symptomatic (3-10% of infants and children with congenital melanocytic nevi 2 ) or asymptomatic. Symptoms usually present in the first 2 years of life as developmental delay and/or seizures, 2 and the prognosis of symptomatic individuals is poor. Neurocutaneous melanosis is best

Unexpected exome sequencing result: De novo TRPS1 mutation in an infant with infantile scoliosis, mild developmental delay, and history of consanguinity

Unexpected Exome Sequencing Result: De Novo TRPS1 Mutation in an Infant With Infantile Scoliosis, Mild Developmental Delay, and History of Consanguinity Ian Casci, William Accousti, and Yves Lacassie* Department of Genetics, LSU Health Sciences Center, New Orleans, Louisiana Department of Orthopedics, LSU Health Sciences Center and Children’s Hospital, New Orleans, Louisiana Department of Pediatrics, Division of Genetics, LSU Health Sciences Center and Children’s Hospital, New Orleans, Louisiana

Optic Atrophy and a Leigh-Like Syndrome Due to Mutations in the C12orf65 Gene

Combined oxidative phosphorylation deficiency type 7 (COXPD7) is a rare disorder of mitochondrial metabolism that results in optic atrophy and Leigh syndrome-like disease. We describe 2 siblings with compound heterozygous mutations in the recently identified C12orf65 gene who presented with optic atrophy and mild developmental delays and subsequently developed bilateral, symmetric lesions in the brainstem reminiscent of Leigh syndrome. Repeat neuroimaging demonstrated reversibility of the findings in 1 sibling and persistent metabolic stroke in the other. This article highlights the phenotypic manifestations from a novel mutation in the C12orf65 gene and reviews the clinical presentation of the 5 other individuals reported to date who carry mutations in this gene.

Inferior vermian hypoplasia – preconception, misconception

Inferior vermian hypoplasia – preconception, misconception

Absence of skeletal anomalies in siblings with a maternally inherited 12q13.13‐q13.2 microdeletion partially involving the HOXC gene cluster

Microdeletions (12q13.13-q13.2) involving the HOXC gene cluster are rare. Only three patients with this contiguous deletion have been reported, all resulting in phenotypic features that include skeletal anomalies, facial dysmorphism, and intellectual disability. The deletion of the HOXC gene cluster is thought to result in skeletal anomalies in these patients. We report on siblings with a 969 kb deletion in the 12q13.13-q13.2 region detected by array comparative genomic hybridization (aCGH). This deletion spans seven of nine HOXC cluster genes. FISH analysis confirmed the siblings and mother were carriers of the 12q13.13-q13.2 deletion. Although minor facial dysmorphic features were present in both siblings, no skeletal anomalies were present in the siblings or the mother. The proband had autistic-like features and mild developmental delay, while the sibling and mother are of normal intelligence. The absence of skeletal anomalies in our family suggests that deletion of the entire HOXC gene cluster may be required to result in an abnormal skeletal phenotype, or those skeletal anomalies in previously reported patients may be attributed to other genes within the deletion interval.

Siblings with fucosidosis

Fucosidosis is a rare lysosomal storage disorder due to deficiency of fucosidase enzyme, with around 100 cases reported worldwide. Here, we describe the clinical and imaging features in two siblings with fucosidosis. An 8-year-old girl presented with global developmental delay, followed by regression of acquired milestones from 3 years of age with bipyramidal, extrapyramidal involvement, coarse facies, telangiectatic lesions, dysostosis multiplex, characteristic magnetic resonance imaging finding along with undetectable levels of the fucosidase activity, which confirmed the diagnosis. Younger sibling has mild developmental delay with autistic traits with no neuroregression until now. He also has undetectable level of fucosidase enzyme activity and is being considered for stem cell transplantation. New case reports would expand the clinical spectrum, early diagnosis and help formulating appropriate therapy. Early diagnosis is crucial and hence sibling screening can be done, and those in the presymptomatic stage can undergo hematopoietic stem cell transplantation, which is potentially curable.

Clinical variability in neurohepatic syndrome due to combined mitochondrial DNA depletion and Gaucher disease

A 1-year-old girl born to consanguineous parents presented with unexplained liver failure, leading to transplantation at 19months. Subsequent partial splenectomy for persistent cytopenia showed the presence of foamy cells, and Gaucher disease was confirmed by homozygosity for the p.Leu483Pro mutation in the GBA gene. She was treated by enzyme replacement therapy (ERT). Clinical follow-up showed mild developmental delay, strabismus, nystagmus and oculomotor apraxia. Biochemical studies revealed multiple respiratory chain deficiencies and a mosaic pattern of deficient complex IV immunostaining in liver and fibroblast. Molecular analysis identified a mtDNA depletion syndrome due to the homozygous p.Pro98Leu mutation in MPV17. A younger sister unaffected by mtDNA depletion, presented with pancytopenia and hepatosplenomegaly. ERT for Gaucher disease resulted in visceral normalization without any neurological symptom. A third sister, affected by both conditions, had marked developmental delay, strabismus and ophthalmoplegia but no liver cirrhosis. In conclusion, intrafamilal variability occurs in MPV17-related disease. The combined pathological effect of Gaucher and mitochondrial diseases can negatively impact neurological and liver functions and influence the outcome in consanguineous families. The immunocytochemical staining of OXPHOS protein in tissues and cultured cells is a powerful tool revealing mosaic pattern of deficiency pointing to mtDNA-related mitochondrial disorders.

Mild developmental delay and obesity in two patients with mosaic 1p36 deletion syndrome

We identified mosaic 1p36 deletions in two patients with developmental delay, distinctive features, and obesity, who can walk alone and communicate with others. Thus, their neurological defects are milder than those in typical patients with 1p36 deletion syndrome because most patients with 1p36 deletion cannot acquire expressive language. Chromosomal microarray testing revealed 3.0 and 4.5 Mb aberrations in the subtelomeric region of the short arm of chromosome 1. Mean signal ratios of the identified aberrations were -0.4 and -0.5, indicating mosaicism, which was confirmed by fluorescence in situ hybridization analysis with a mosaic ratio of 70% and 77%, respectively. Previous studies demonstrated that deletion of the distal 2-3 Mb region would be responsible for hyperphagia and obesity seen in patients. On the other hand, the severity of the neurological defect often correlates with the size of the terminal deletion of 1p36, and patients with larger deletions of 1p36 would usually show severely impaired developmental milestones and be immobile and aphasic. In such cases, hyperphagia and obesity could be clinically masked. In this study, two patients with mosaic deletions of 1p36 showed obesity as a consequence of hyperphagia. This study suggests that patients with 1p36 deletion would be at risk for hyperphagia and obesity when they have both risk factors, that is, (1) deletions including the 2-3 Mb critical region and (2) milder phenotypes that allow them to reach food on their own and to overeat.

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Introduction: Dexmedetomidine is a selective alpha adrenergic agonist with high alpha2 receptor affinity that is used for sedation, analgesia, and as an anxiolytic. While the Food and Drug Association approved the use of Dexmedetomidine in the adult intubated population for less than 24 hours or for adult patients undergoing surgery or a procedure, it is being more widely used for longer periods of time in pediatric intensive care units. The common side effects noted with dexmedetomidine are bradycardia, hypotension, and hypertension which are all dose related. While rare, the most common withdrawal symptoms include agitation, irritability, headache, and rebound hypertension which occur occasionally following abrupt cessation of the medication. Posterior reversible encephalopathy (PRES), also known as reversible posterior leukoencephalopathy syndrome or hypertensive encephalopathy is a clinical condition presenting secondary to acute hypertension that results in neurologic symptoms including headaches, seizures, altered sensorium, and loss of vision. It is diagnosed via these clinical findings coupled with characteristic MRI changes that are typically reversible. We report the first case of posterior reversible encephalopathy syndrome after a hypertensive crisis likely precipitated by dexmedetomidine withdrawal. An 11 year old female with sickle cell disease was admitted in extremis with hypoxemia, shock and acute chest. She was emergency resuscitated and intubated, and then received both red cell transfusion and exchange transfusion. After 8 days of intubation, and 7 days of dexmedetomidine (dose range 0.8 to 1.5 mcg/kg/hour) infusion and 8 days of fentanyl (dose range from 1 mcg/kg/hour to 2.2 mcg/kg/hour) infusion, she was successfully extubated and her infusions were discontinued without a tapering dose. She was started on intermittent fentanyl and midazolam for potential withdrawal. 12 hours after extubation, she was hypertensive to 160s/90s. She became agitated and combative, and progressed to altered mental status. To treat her hypertension, she was given fentanyl, midazolam, and clonidine and eventually started on a nicardipine infusion. Fentanyl and dexmedetomidine infusions were reinstituted after reintubation, which was 24 hours after initial extubation. Following reintubation, she developed 2 general tonic-clonic seizures, which responded to levetiracetam and midazolam infusions. A head CT was negative, but her head MRI was consistent with posterior reversible encephalopathy syndrome. She had aggressive blood pressure control and seizure management, and slowly improved. After an additional 5 days of intubation and blood pressure control, she was eventually extubated. After extubation for the second time, she was slowly weaned off all infusions and transitional to oral medications over the next 4 days. On day 20 of admission, she was transferred to the general wards and continued her oral blood pressure medications. She was on weaning doses of clonidine and amlodipine at discharge on day 31 of hospital stay. She was functioning at her baseline status with mild developmental delay working with Physical therapy and Occupational therapy at the time of discharge from the hospital. There are other reports of dexmedetomidine withdrawal, but mainly related to agitation and self-limited rebound hypertension. We believe this to be the first case of posterior reversible encephalopathy from dexmedetomidine withdrawal, and want others to be aware of this potential complication.

A clinical study of patients with pericentromeric deletion and duplication within 16p12.2–p11.2

The short arm of chromosome 16 is rich in segmental duplications that result in chromosomal rearrangements through non-allelic homologous recombination. Several syndromes resulting from microdeletions or microduplications in this region have been reported. The chromosome 16p12.2-p11.2 deletion syndrome, 7.1- to 8.7-Mb [OMIM#613604] is characterized by minor facial anomalies, feeding difficulties, a significant delay in speech development, and recurrent ear infections. Reciprocal duplications of 16p12.2-p11.2 have been reported in some patients with autism. We identified a patient with a 16p12.2-p11.2 deletion and a patient with a 16p12.2-p11.2 duplication using oligonucleotide SNP array. The patient with the deletion showed severe developmental delay without autism. The patient with the deletion shared clinical features with previously reported patients. The patient with the duplication showed mild developmental delay and autism. She had dysmorphic features including a round face, a large mouth, and relative macrocephaly. We reviewed the reports of the two syndromes and compared the clinical manifestations. The 16p12.2-p11.2 duplication syndrome is a new syndrome with autism spectral disorders and dysmorphic features.

Megalencephalic Leukoencephalopathy with Subcortical Cysts = إعتلال و تضخم بيضاء الدماغ مع تكيسات تحت قشرة المخ

Megalencephalic leucoencephalopathy with subcortical cysts (MLC) is a genetic degenerative disease of the white matter of the brain. The white matter degenerates and swells, resulting in patients with large head sizes. Cysts are also seen in white matter.1 Children with MLC usually present in the first year of life, though some discrepancy has been reported in their clinical course.1 MLC is a rare neurodegenerative disorder and is reported here for the first time in two siblings in Oman. Two children of consanguineous parents presented in 2004, a girl (A), currently 19 years of age, and a boy (T), currently 11 years. Their main complaint was mild developmental delay and the large head size, the latter noted by the parents during the first year of life, compared to their siblings. The patients gained initial milestones normally but after the first year had difficulty walking. Over time there was an increase in spasticity and weakness of the limbs. At the time of writing, neither child could walk or sit unsupported. The elder sibling (A) had eating difficulties and was fed through a nasogastric tube. She could understand simple commands but had difficulty in speaking. The younger sibling (T) was still able to eat with assistance and had preserved speech. However, he had recently developed gastrooesophageal reflux. Neither sibling had a history of seizures. The other 6 children in the family (3 sons and 3 daughters) were normal; there was no family history of similar or other neurologic conditions in the past two to three generations. In 2004, upon examination at presentation, there was macrocephaly in both patients. The head circumference of patient T was 58 cm at 4 years of age and 59 cm in patient A at 11 years; both measurements are well above the 97th percentile for their ages. The cranial nerves and language were normal. Bipyramdial signs were noted in the upper and lower limbs. There was spasticity in lower limbs with upgoing plantar responses. Although the upper limb muscles were wasted, the power was normal (Medical Research Council grade 5), with brisk deep tendon reflexes. Routine blood and metabolic investigations were normal. Electroencephalography and visual evoked potentials were not performed, as there were no seizures or visual abnormalities. A magnetic resonance imaging (MRI) brain scan revealed bilateral white matter diffuse changes with subcortical cysts [Figure 1]. A diagnosis of MLC was made after consultation with an expert.1,2 Although the diagnosis was clinically certain, there was no genetic confirmation. Recently, MLC1 gene sequencing revealed a homozygous c.432+1G>A mutation. The mutation is predicted to cause aberrant splicing, and it was not found in more than 400 control chromosomes; features which suggest the likely pathogenicity of this mutation.1 Both patients were severely handicapped and on symptomatic treatment only, not yet having developed seizures. Patient A was bedridden and on nasogastric feeding. Figure 1. A to C. A: Axial magnetic resonance images (T2-weighted) of patient T, showing diffuse white matter swelling and hyperintensity (arrows). B: Axial fluid liquid attenuation inversion recovery (FLAIR) image showing subcortical cysts in the frontal region (arrows). ...