Child Of Unrelated Parents Research Articles

Chromatin remodeling dysfunction extends the etiological spectrum of schizophrenia: a case report

BackgroundThe role of deleterious copy number variations in schizophrenia is well established while data regarding pathogenic variations remain scarce. We report for the first time a case of schizophrenia in a child with a pathogenic mutation of the chromodomain helicase DNA binding protein 2 (CHD2) gene.Case presentationThe proband was the second child of unrelated parents. Anxiety and sleep disorders appeared at the age of 10 months. He presented febrile seizures and, at the age of 8, two generalized tonic-clonic seizures. At the age of 10, emotional withdrawal emerged, along with a flat affect, disorganization and paranoid ideation, without seizures. He began to talk and giggle with self. Eventually, the patient presented daily auditory and visual hallucinations. The diagnosis of childhood onset schizophrenia (DSM V) was then evoked. Brain imaging was unremarkable. Wakefulness electroencephalography showed a normal background and some bilateral spike-wave discharges that did not explain the psychosis features. A comparative genomic hybridization array (180 K, Agilent, Santa Clara, CA, USA) revealed an 867-kb 16p13.3 duplication, interpreted as a variant of unknown significance confirmed by a quantitative PCR that also showed its maternal inheritance. Risperidone (1,5 mg per day), led to clinical improvement. At the age of 11, an explosive relapse of epilepsy occurred with daily seizures of various types. The sequencing of a panel for monogenic epileptic disorders and Sanger sequencing revealed a de novo pathogenic heterozygous transition in CHD2 (NM_001271.3: c.4003G > T).ConclusionsThis case underlines that schizophrenia may be, sometimes, underpinned by a Mendelian disease. It addresses the question of systematic genetic investigations in the presence of warning signs such as a childhood onset of the schizophrenia or a resistant epilepsy. It points that, in the absence of pathogenic copy number variation, the investigations should also include a search for pathogenic variations, which means that some of the patients with schizophrenia should benefit from Next Generation Sequencing tools. Last but not least, CHD2 encodes a member of the chromodomain helicase DNA-binding (CHD) family involved in chromatin remodeling. This observation adds schizophrenia to the phenotypic spectrum of chromodomain remodeling disorders, which may lead to innovative therapeutic approaches.

NOVEL DAX-1 (NR0B1) MUTATION IN A THAI BOY WITH X-LINKED ADRENAL HYPOPLASIA CONGENITA (AHC): A FIRST REPORT

Background:Adrenal hypoplasia congenita (AHC) is a rare inherited disorder of adrenal development resulting in hypoplasia of adrenal gland and inability to produce glucocorticoids, mineralocorticoids and sex steroids. X-linked AHC is the most common form and is caused by mutation of the DAX1 gene. Here we report a case of 4-year-old Thai boy with X-linked AHC, the first case of genetically confirmed novel DAX1 mutation in Thailand. Patient and Method:A 4-year-old Thai boy presented with fever and vomiting for 3 days. He was the fifth child of unrelated parents. The past medical history was unremarkable except his skin had been progressively more pigmented since early infancy. Physical examination revealed normal genital development and addisonian hyperpigmentation which prominent at skin crease, gum and knuckles. Laboratory investigations showed hyponatremia, hyperkalemia, and hypochloremia. Hormonal evaluation revealed low baseline cortisol level which is not rising after 250 mg ACTH stimulation test. ACTH level and plasma renin activity were elevated. A diagnosis of X-linked AHC was established. Glucocorticoid and mineralocorticoid replacement therapy were initiated. Molecular analysis by direct DNA sequencing of the DAX1 gene was performed in the patient and family members. Result:Mutation analysis revealed a novel hemizygous GG deletion (c.1148_1149delGG) resulting in a premature termination codon at the position 387 (p.Gly383Aspfs*5). This frameshift mutation was predicted to encode a truncated DAX1 protein missing a portion of ligand binding domain. The mutation identified in our proband was inherited from his carrier mother. Conclusion:We report a case of classical X-linked AHC with established a novel frameshift mutation in the DAX1 gene. Genetic analysisis important not only for diagnostic confirmation in the index case but also for carrier detection in his mother which provided a proper management and appropriate genetic counseling for this famity.

Spinal cord infarction in a sick neonate from predominant haemorrhagic aetiology: a case report.

Spinal cord injuries in new born infants following a traumatic delivery or umbilical cord catheterisation due to thromboembolism are well known. Cases with atraumatic acute onset of neonatal paraplegia have also been described in preterm babies or babies born small for gestational age with a stormy postnatal course related to ischaemic aetiology. We describe a rare case of infarction of the spinal cord from a predominant haemorrhagic aetiology. A term female baby, first child of unrelated parents, was born by normal vaginal delivery. She had meconium aspiration at birth, leading to severe respiratory distress, requiring neonatal intensive care admission. At 2 weeks, she developed new flaccid paraplegia. MRI scan of the spine showed haemorrhagic infarction of the spinal cord from the level of thoracic inlet, vertebral level C7-T1. A follow-up MRI scan at 11 months revealed severe atrophy of the cord distal to C6. At 3 years of age, she had good upper-limb function, diaphragmatic breathing and flaccid paralysis of lower limbs. In an acutely unwell term infant with symptoms of paralysis or spinal cord damage, haemorrhagic infarction needs to be considered in the differential diagnosis. To our knowledge, this is the first reported case of spinal cord injury in a term infant with a haemorrhagic lesion, and it helps to understand the pathogenesis of nontraumatic insult.

Further characterization of acro-renal-uterine-mandibular syndrome

List of key featuresEctrodactylyMicrognathiaMandibular hypoplasiaCleft palateRenal anomaliesCase reportThe proposita is the only child of unrelated parents. Her mother had untreated vitiligo. She had no antenatal problems and was not exposed to any known teratogens. The child was delivered at full t

Sevoflurane in anaesthetic management of a patient with methylmalonic acidaemia

Sevoflurane in anaesthetic management of a patient with methylmalonic acidaemia

Shwachman-Diamond syndrome in a child presenting with cystic fibrosis-type symptoms and a false-positive sweat test

A six-month-old Caucasian boy was referred by his general practitioner with concerns regarding poor weight gain and poor feeding. He was the second child of unrelated parents. His mother was Italian and his father English. His older brother, aged 5 years, was known to be egg allergic but well in other respects. There was no other family history of note. He was born following a normal pregnancy and there were no initial neonatal concerns. Birth weight was 3.86 kg (75th centile). He was breast-fed for the first four months, after which he was fed on standard formula. From 14 weeks of age his weight started to falter from the 75th to the 9th centile. He had only received his first immunization at two months of age due to parental concerns regarding his health. There had been no developmental concerns. On his first review he had appeared quite irritable on feeding and the question of cow's milk protein intolerance was raised. His feed was therefore changed to a hydrolysed formula and a dietitian reviewed him. On review three weeks later he was found to be chesty and wheezy, but with no chest deformity. He was pale and thin. His stools were noted to be fatty, loose and offensive and his weight gain had not significantly improved. From his initial blood tests he was noted to have a raised alanine aminotransferase (ALT) concentration of 73 U/L (reference range 0–45 U/L) and a borderline low neutrophil count of 1.9 × 109/L (reference range 1.5–8 × 109/L). The results of other initial investigations, performed as part of a failure-to-thrive screen, were unremarkable, including immunoglobulin E (IgE), radioallergosorbent test (RAST) to cow's milk protein, thyroid function tests, urine and faecal microbiology, coeliac screen, faecal reducing substances and amino and organic acids. Abdominal ultrasound scan was also normal. Given the concerns regarding his poor weight gain, loose offensive stools and malabsorption, a sweat test and faecal elastase level were requested. His sweat test was reported as positive (chloride 75 mmol/L). Sodium levels were not measured. Sweat volume of at least 30 μL was collected using the Macroduct sweat collection system. Faecal elastase level was significantly low (<15 IU). His chest X ray was normal. A diagnosis was made of cystic fibrosis (CF) with pancreatic insufficiency. His parents were counselled regarding the diagnosis and he was started on prophylactic amoxicillin and clavulanic acid, as well as pancreatic enzyme and vitamin supplementation. Genotyping was requested and he was referred to a tertiary centre for joint care. Over the next weeks he started to gain weight, although not as much as would have been expected. His stools were less oily. Genotyping failed to show any CF mutations both on routine analysis and on extended testing. His parents became increasingly concerned that the diagnosis was incorrect. Their concerns were initially raised as they felt he did not taste salty, but were compounded by the fact that a mutation was not isolated. A repeat sweat test was sent and reported as negative (chloride 5 mmol/L). A third sweat test was also negative (8 mmol/L). Repeat faecal elastase level was still <15 IU/g, confirming pancreatic insufficiency. Following these two negative sweat tests an alternative diagnosis was sought, in particular Shwachman-Diamond syndrome (SDS). Genotyping was requested and he was found to be homozygous for 258+2T>2C, the genetic mutation for SDS. His parents were both heterozygous. A final diagnosis was therefore made of SDS and he was referred to a tertiary centre for further management.

Afibrinogenaemia Resulting from a Novel Putative Splicing Mutation, and Evidence for Tissue Specific Expression of FGAα RNA.

Congenital afibrinogenaemia is a rare autosomal recessive disorder characterised by the complete absence of fibrinogen in plasma. Fibrinogen is predominantly produced in hepatocytes from 3 homologous polypeptide chains (Aα, Bβ, γ) which assemble to form a hexameric structure. The genes that encode the 3 polypeptides (FGAα, FGBβ, FGγ) are clustered in an approximately 50kb region on chromosome 4q28-q31. Defects in each of the 3 genes have been implicated in afibrinogenaemia, and encompass missense and nonsense mutations, insertions, small and gross deletions and splicing defects.We present a case of congenital afibrinogenaemia, diagnosed in a neonate, the only child of unrelated parents. Sequence analysis of the FGAα, FGBβ and FGγ genes identified a single, novel, homozygous nucleotide substitution (T→A) at IVS1 -19 of the FGAα gene. Both parents genotyped as heterozygous for this variant. Analysis of ~100 normal alleles failed to detect this change, thereby excluding it as a common polymorphism. Using splice prediction software, the IVS1 acceptor splice site is undetected, reflecting poor agreement with acceptor consensus sequences. The mutation presented here, results in the creation of a preferential acceptor splice site (Spliceview score of 77). It has been previously reported (Catia et al, 2003) that intron 1 is preferentially the last intron of the FGAα gene to be spliced, and it may be that the wild type exon 1-intron 1- exon 2- exon 3- exon 4 - exon 5 intermediate presents a better substrate to the spliceosome. If we accept this predicted splicing order the mutation described in this study will not affect expression. Instead, the resulting incorporation of 19 intronic bases will result in a premature termination sequence (TGA) and a truncated protein.RNA work was undertaken to attempt to demonstrate these findings. However, RNA extracted from peripheral blood leukocytes from both parents failed to amplify for even the normal allele of FGAα (using primers located in exons 1and 5). Integrity of the samples was demonstrated by amplification of F8 RNA. To investigate this further, we tested a panel of commercially available RNAs from various tissues. RNA derived from liver, heart, spleen and kidney cells produced the expected product, with much higher yields being seen with liver cells, while RNA from brain cells and leukocytes failed to yield any product at all. Tissue specific expression has previously been described for FGγ RNA.In summary: This case study has identified a novel splice site mutation in the FGAα gene which is predicted to result in the introduction of a premature termination sequence at the newly created codon -1. This could not be confirmed due to the previously unreported discovery that FGAα RNA is not expressed in peripheral leukocytes.

P0574 LONG TERM FOLLOW UP OF CONGENITAL DISORDERS OF GLYCOSYLATION TYPE I OR CDG I SYNDROME

Introduction: Congenital disoders of glycosylation (CDG), or carbohydrate deficient glycoprotein syndromes, form a rapidly growing group of autosomal recessive inherited disorders characterised by defects affecting the glycosylation of proteins. Fourteen CDG are identified, the most frequent is CDG Ia due to a defect in phosphomannomutase. Most CDG Ia are multisystem diseases that include severe brain involvement, early failure to thrive and feeding difficulties. Methods: We report the clinical, biological and molecular analysis of a CDG Ia patient detected by western blotting of serum glycoproteins at age 19. He was the first child of unrelated parents and was born in 1980. At age 1 month, he presented with generalised oedema, diarrhoea which started at the first feeding and anorexia. Neonatal hypotonia, nystagmus, psychomotor retardation were also present as well as inverted nipples, facial dysmorphia and lipodystrophia. Weight was 4.9kg and height 62 cm at age 7 months. Seizures started during the second year of life. At age 16, he developed a thrombosis of the left external iliac artery and the left lower limb. At age 23, he is on anormal diet, has no diarrhoea and his liver function is normal. He is unable to walk without support and receives daily heparin, phenobarbital and valproic acid. Results: Hypoproteinemia <45g/l and hypoalbuminemia were attributed to protein losing enteropathy and lymphangiectasy at 1 month of age and persisted during the first 2 years. Transaminases were elevated and severe portal fibrosis was seen on a liver biopsy at age 1. Thrombocytopenia is permanent. Coagulopathy was noted at 2 months and 10 years: PTT 25%, TCK 180, factor IX 7%. The level of antithrombin III is <5%. Cerebellar atrophy was detected on CT scan at age 2 years. Phosphomannose activity is severely decreased: 0.5 U/g prot (N>3.4). Mutation analysis of the PMM gene identified 2 mutations on the maternal allele (P20S and IVS1 + 1G->T) and a different mutation on the paternal allele (I132T). Conclusion: It is concluded that CDG Ia is a multisystem disease with severe gastrointestinal and hepatic manifestations during the first years of life. After childhood, CDG Ia has no longer digestive symptoms and becomes a non-progressive neurologic disease with peripheral neuropathy, mental retardation and seizures and a thrombotic predisposition due to decreased levels of major coagulation inhibitors, particularly as a result of impaired glycosylation of antithrombin III. A study of ten French adolescents and adult patients with CDG I is ongoing in Paris and coordinated by N Seta.

Engrafted maternal T cells in human severe combined immunodeficiency: Evidence for a T H2 phenotype and a potential role of apoptosis on the restriction of T-cell receptor variable β repertoire

1. Street MD, Donovan GR, Baldo BA, Sutherland S. Immediate allergic reactions to Myrmecia ant stings; immunochemical analysis of Myrmecia venoms. Clin Exp Allergy 1994;24:590-7. 2. Donovan GR, Baldo BA, Sutherland S. Molecular cloning and characterisation of a major allergen (Myr p 1) from the venom of the Australian jumper ant. Biochim Biophys Acta 1993;1171:272-80. 3. Weiner JM, Baldo BA, Donovan GR, Sutherland SK. Allergy to jumper ant (Myrmecia pilosula) stings in south-eastern Australia [abstract]. Ann Allergy Asthma Immunol 1995;74:60. 4. Stuckey M, Cobain T, Sears M, Cheney J, Dawkins RL. Bee venom hypersensitivity in Busselton [letter]. Lancet 1982;2:41.

A NEW TYPE OF INHERITED GROWTH HORMONE DEFICIENCY: A COMPOUND HETEROZYGOTE OF A 6.7 KB DELETION, INCLUDING THE GH-1 GENE, AND TWO BASE DELETION IN THE THIRD EXON OF THE GH-1 GENE

The genomic DNA in a patient with severe growth retardation was analysed and a new type of mutation, a compound heterozygous mutaion, was found in her GH-1 gene. The patient was a 13 years old girl, a first child of unrelated parents and born by normal delivery. She had been diagnosed as growth hormone deficiency at the age of 8 years 11 months. Her height and weight were 86.1 cm (−7.8SD) and 10.2 kg (−3.4SD), respectively. She has been treated with exogenous hGH successfully over years without producing antibody against hGH by now. The genomic DNA of this patient and her parents were analyzed by polymerase chain reaction followed by restriction enzyme digestion as reported by Vneneak-jones et al. and the existence of 6.7 kb deletion including whole GH-1 gene was found in one allele of the patient and her father but not in her mother. The sequence analysis of this family revealed the 2 bp deletion in exon 3 of GH-1 gene in the patient and her mother but not in her father. A termination codon at the position of amino acid residue 132 in exon 4 was assumed to be introduced through this mutation. These results might suggest the new type of inherited GH-1 gene deficiency caused by heterozygous mutation in GH-1 gene.

Insulin-Dependent Diabetes Mellitus in Children: Familial and Clinical Patterns in Riyadh

Type I diabetes mellitus is probably common in Saudi Arabia, but only a small amount of information on the disease is available and most cases reported so far have been type II diabetes mellitus. Type I diabetes was diagnosed in 110 children who were followed at Suleimania Children's Hospital over a five-year period (1985-1989). Saudis represented 74.5% (82/110) of the patients, and 53.6% (59/110) were female. Consanguinity existed in 42.7% (47/110) of the parents. A first-degree family history was positive for insulin-dependent diabetes mellitus in 28.1% (31/110). Mean age at onset was 5.87 years, which is low compared with other ages cited in the literature. Thirty-three patients (30%) were below three years of age at onset. The most common clinical sign was diabetic ketoacidosis, which was seen in 67.2% (74/110). Duration of symptoms before diagnosis ranged from two days to more than two months, with a mean of 18.2 days. Partial remission was seen in 30.9% (34/110). This low percentage is probably due to the young age distribution at onset and perhaps to a different pattern of severity of the disease in our community. Further studies, including opening a local registry, are needed for confirming the incidence and characteristics of the disease in Saudi Arabia.

Hereditary Fructose Intolerance in the Vomiting Infant

Hereditary fructose intolerance is one of numerous entities included in the differential diagnosis of vomiting in infancy. Caused by a deficiency of fructose-1-aldolase, it is inherited as an autosomal recessive trait.1 The symptoms are often subtle and may be confused with more common disorders such as gastroesophageal reflux, milk protein allergy, or improper feeding practices. The following case emphasizes the need to consider the diagnosis of hereditary fructose intolerance in the vomiting infant. CASE REPORT A 9-week-old male infant was admitted with vomiting that was unresponsive to outpatient management. The first child of unrelated parents, he was born full term, with a birth weight of 4.1 kg, after an uncomplicated pregnancy and delivery.

The radiology of Coffin–Lowry syndrome

The Coffin–Lowry syndrome is a rare disorder inherited as an X-linked condition, affecting men much more severely than women. The characteristics are mental retardation, skeletal abnormalities with short stature, hypermobile joints, loose skin, tapering fingers and dysmorphic facial features. The proband was referred for genetic assessment at the age of 15 years because of developmental delay with dysmorphic features. He was the first child of unrelated parents, and had a younger sister. His mother was said to be mildly educationally subnormal, but she came from a family of highly educated people, and there was no other family history of retardation (Fig. 1). His sister (aged 16 years) was of normal intelligence and had no dysmorphic features. The proband was induced at 36 weeks gestation because of placenta praevia in an otherwise normal pregnancy, and was healthy at birth (birth weight 5 lb 2 oz). His milestones were delayed, sitting at 18 months and only walking at 3 years of age, and making no meaningful sounds until the age of 2 years. He went into residential care for the moderately to severely retarded from 5 years of age, at which time he only had two or three words of speech. In his early teens he developed epilepsy in the form of “drop attacks”, which caused him to fall backwards to the ground; he would rise immediately afterwards.

先天性無舌症の１例

Congenital aglossia is a rare tongue anomaly. There were 16 cases reported in Japan of which only one was an adult case.Recently we experienced a congenital aglossia case. The patient, a 20-year-old female, is the youngest of two children of unrelated parents, aged 32 (father) and 28 (mother). The patient's mother had a drugless normal pregnancy and normal delivery. The patient had sucking difficulty, but no treatment such as nasal feeding.Intraorally, a small extruded mass was recognized from the floor of the mouth. Both of the maxillary and the mandibular arches were very narrow, and three incisors of the mandible were congenitally missing. Radiographically, the existance of hyoid bone, submandibular, salivary gland and suprahyoid muscles were suggested by computed radiography and computed tornography. However, the patient had almost normal taste and clear pronunciation.

Hypertension, hypokalemia and retarded growth in a 17 month-old boy with 11β hydroxysteroid-dehydrogenase deficiency

A 17 month old boy, the first child of unrelated parents, presented with polydipsia, lack of appetite and failure to thrive. Blood pressure was 150/100 mmHg. He had hypokalemia (2.6 mEq/1), suppressed renin activity (0.4 ng/ml/hr) and low plasma aldosterone level (2 ng/100 ml). Urinary 11β-hydroxy-steroids were increased relative to 11 oxosteroids (THF: 110, THE 8 μg/day; ratio 13.8. Control ratio 0.4) indicating 11 β-hydroxysteroid-dehydrogenase deficiency. Both parents were normal. The hypertension and hypokalemia were unresponsive to spironolactone. Dexamethason treatment did not influence the hypokalemia and even increased blood pressure. Triamterene (3 × 25 mg) normalised serum potassium, but addition of furosemide (2 × 10 mg) was required for normalisation of blood pressure. This treatment resulted in catch up growth (from -3.6 SD to -1.8 SD for height). This is the youngest patient known with this syndrome. Unlike the other cases (Ulick et all. J.C.E.M., 49: 757, 1979) he did not respond to triamterene alone. Also the growth retardation and catch up growth after treatment is documented for the first time.

Can the de Lange Syndrome Always Be Diagnosed at Birth?

The comment "... The children are diagnosable at birth. This resemblance to one another is as striking to us as the resemblance of mongols to each other"1 holds true for most, but not all cases of the de Lange syndrome.2,3 This paper will describe a patient who at the age of 9 months had features suggestive of Turner's syndrome, and at the age of 21 months had the typical appearance of the de Lange syndrome. Case Report The patient, a Caucasian female, was the third child of unrelated parents who were 28 and 30 years old respectively when she was born January 29, 1968.