Severe congenital hypothyroidism due to a homozygous mutation of the betaTSH gene.

Isolated TSH deficiency leading to hypothyroidism seems to be a rare condition, escaping the diagnosis by neonatal screening programs, which are based on the primary determination of TSH. This is the first report of a case with an autosomal recessive TSH defect caused by a homozygous mutation of the betaTSH gene that was diagnosed in the early neonatal period. Hypothyroidism in the first child of apparently unrelated parents was suspected because of the classical symptoms of congenital hypothyroidism, which were fully expressed already on the 11th day of life. Routine neonatal TSH-screening on the 4th day of life had been normal, but subsequent determination of serum thyroid hormone levels revealed almost undetectable levels and thyroid hormone substitution was immediately started. Because there was no indication for other pituitary hormone deficiencies, sequence analysis of the betaTSH gene was initiated. A homozygous T deletion in codon 105 was found resulting in a change of a highly conserved cysteine to valine followed by eight altered amino acids and a premature stop codon due to the frame-shift. This altered betaTSH is a biologically inactive peptide. Because of the early development of severe symptoms, it is possible that this altered TSH suppresses the physiologic constitutive activity of the unliganded TSH receptor. Rapid molecular diagnosis in this patient clarified the diagnosis without additional endocrine and imaging studies and it is concluded, that symptoms of hypothyroidism in the neonatal period should result always in an immediate comprehensive work-up of thyroid function including molecular genetic studies irrespective of the screening result.     

Cytochrome c oxydase-deficient Leigh syndrome with homozygous mutation in SURF1 gene]

Leigh syndrome is a heterogeneous disorder, usually due to a defect in oxidative metabolism. Mutations in SURF1 gene have been identified in patients with cytochrome c oxidase deficiency. We report a homozygous splice site deletion [516-2_516-1delAG] in a young girl presenting with cytochrome c oxidase-deficient Leigh syndrome. Identification of molecular defect is indispensable for genetic counselling and prenatal diagnosis.     

Brain malformations associated to Aldh7a1 gene mutations: Report of a novel homozygous mutation and literature review

Background

The ALDH7A1 gene is known to be responsible for autosomal recessive pyridoxine-dependent epilepsy (OMIM 266100). The phenotypic spectrum of ALDH7A1 mutations is very heterogeneous ranging from refractory epilepsy and neurodevelopmental delay, to multisystem neonatal disorder.

Factors associated with lowered intelligence in homozygous sickle cell disease.

The intelligence quotient (IQ) of 60 patients with homozygous sickle cell (SS) disease and 60 age and sex matched controls with a normal haemoglobin (AA) genotype aged 15-18 years, followed up in a cohort study from birth, was assessed by the Wechsler intelligence scales for children or for adults. IQ appeared to be normally distributed in both genotypes but mean values in SS disease were 5.6 points (95% confidence interval (CI) 1.0 to 10.2) lower than in AA controls (p = 0.016). The difference occurred in both verbal (5.5 points, p = 0.017) and performance (5.0 points, p = 0.044) subscales of the IQ score and the IQ defect in SS disease was associated with a significantly lower attention factor score (p = 0.005) but not with other factor scores. The genotype difference in IQ was not accounted for by differences in parental occupational level, school absenteeism, or school drop out, or reported activity level. In SS disease, IQ was not related to mean steady state haemoglobin, fetal haemoglobin, or mean cell haemoglobin concentration, or clinical severity as judged by the frequency of painful crises, hospital admission, or sick visits. IQ, at age 15-18 years, correlated with the patients'' height at all ages from 1 to 10 years (partial correlations increasing from 0.14 (p = 0.15) at age 1 to 0.27 (p = 0.004) at age 10). Adjusting for height reduced the mean genotype difference in IQ to 5.5 (95% CI 0.6 to 10.3) points at age 1 and to 2.6 points (95% CI to -2.3, 7.5) at age 10. Prepubertal height therefore accounted for much of the genotype difference in IQ. It is speculated that early factors, possible nutritional, contribute to both impaired growth and mental development in sickle cell disease.     

Congenital hypothyroidism caused by a novel homozygous mutation in the thyroglobulin gene

Congenital hypothyroidism (CH) due to thyroglobulin (TG) deficit is an autosomal recessive disease (OMIM #274700) characterized by hypothyroidism, goiter, low serum TG, and a negative perchlorate discharge test. The aim of this study was to perform the genetic analysis of the TG gene in two sisters born from consanguineus parents and affected by CH and low serum TG levels. The index patient and her sister were identified at neonatal screening for CH and treated with L-thyroxine (L-T4). After discontinuation of L-T4 therapy, hypothyroidism was confirmed, serum TG was undetectable, and no organification defect after ¹²³I scintigraphy and perchlorate test was shown; thyroid ultrasound showed a eutopic gland of normal size. DNA was extracted from peripheral white blood cells of the two sisters and the father. All 48 exons of TG gene were amplified by polymerase chain reaction and subjected to direct sequencing. A novel homozygous point mutation in exon 10 of TG gene was identified in the patient and her sister. The mutation determined a stop codon at position 768 (R768X) resulting in an early truncated protein or in the complete absence of the protein. The father (euthyroid) was heterozygous carrier of the mutation. Conclusion: Genetic analysis of TG gene was performed in two sisters affected by CH. A novel point mutation of the TG gene determining a stop codon at position 768 of the protein was identified. The early truncated nonfunctioning protein or the absence of the protein due to the premature degradation of abnormal mRNA may be responsible of the observed phenotype.     

A common mutation in the surfactant protein C gene associated with lung disease

OBJECTIVE: To determine the contribution of the surfactant protein C (SP-C) I73T mutation to lung disease. STUDY DESIGN: Genomic DNA was obtained from 116 children with interstitial lung disease (ILD) or chronic lung disease of unclear cause and from 166 control subjects and was screened for the I73T mutation using an allele-specific polymerase chain reaction assay. RESULTS: The I73T mutation was found on 7 of 232 SP-C alleles from 7 unrelated children with ILD but was not found on 332 control SP-C alleles ( P < .01, Fisher exact test). The I73T mutation segregated with lung disease in one kindred with familial ILD. The I73T mutation was found in an asymptomatic parent from two different families with affected children consistent with variable penetrance, but it was not found in either asymptomatic parent of two other unrelated affected children consistent with a de novo mutation. Analysis of single nucleotide polymorphisms indicated diverse genetic backgrounds of the I73T alleles. Immunohistochemical analysis of lung tissue from an infant with the I73T mutation demonstrated normal staining patterns for proSP-B, SP-B, and proSP-C. CONCLUSIONS: These findings support the hypothesis that the I73T mutation predisposes to or causes lung disease.     

UGT1A1基因G71R突变与新生儿不明原因严重高胆红素血症相关

目的探讨尿苷二磷酸葡萄糖醛酸转移酶1A1(UGT1A1)基因G71R突变与新生儿严重高胆红素血症的相关性。方法采用病例对照研究的方法,病例组为复旦大学附属儿科医院(我院)收治的不明原因严重高胆红素血症(血清总胆红素水平≥342μmol·L-1)新生儿,采用PCR对外周血UGT1A1基因进行检测。对照组为我院新生儿出生缺陷生物样本数据库中血清总胆红素水平221μmol·L-1病例。病例组及对照组新生儿均要求胎龄≥35周,出生体重≥2 500 g。结果病例组和对照组各65例。UGT1A1 G71R是病例组中最常见的突变类型(73.8%,48/65)。对照组UGT1A1 G71R突变位点与既往Meta分析中提取的中国健康新生儿对比,在基因型分布及等位基因频率上差异均无统计学意义(P0.05)。病例组和对照组UGT1A1基因G71R突变中A等位基因频率分别为0.5和0.15,差异有统计学意义(P0.001),把握度为0.993。与携带G/G基因型新生儿相比,UGT1A1 G71R突变(A/A+G/A基因)可增加新生儿严重高胆红素血症的发病风险(OR=7.373,95%CI:3.395~16.008),把握度为1.0。结论 UGT1A1基因G71R突变与新生儿不明原因严重高胆红素血症相关。     

Hypothyroidism in siblings due to a homozygous mutation of the TSH-beta subunit gene

We report two American sisters of Scottish-Irish ancestry with isolated thyrotropin (TSH) deficiency. The diagnosis of central congenital hypothyroidism was based on low levels of TSH and free thyroxine. Sequencing of the TSH-beta subunit gene revealed a homozygous single nucleotide deletion in codon 105, producing a frame shift and resulting in inactive TSH. This mutation has previously been reported in a Brazilian family, two German families, and a Belgian family. Our case, along with a review of the other reports, supports the theory that this mutation may be a common cause of isolated TSH deficiency.     

Permanent neonatal diabetes caused by a homozygous nonsense mutation in the glucokinase gene

Abstract:  Glucokinase deficiency is an unfrequent cause of permanent neonatal diabetes (PND), as only seven patients have been reported, either homozygous for a missense or frameshift mutation or compound heterozygous for both of them. We report here the first known case caused by a homozygous nonsense mutation (Y61X) in the glucokinase gene ( GCK ) that introduces a premature stop codon, generating a truncated protein that is predicted to be completely inactive as it lacks both the glucose- and the adenosine triphosphate-binding sites. The proband, born to consanguineous parents, was a full-term, intra-uterine growth-retarded male newborn who presented with a glycaemia of 129 mg/dL (7.16 mmol/L) on his second day of life, increasing thereafter up to 288 mg/dL (15.98 mmol/L) and 530 mg/dL (29.41 mmol/L) over the next 24 h, in the face of low serum insulin (<3 μIU/mL; <20.83 pmol/L). He was put on insulin on the third day of life. Insulin has never been discontinued since then. The patient was tested negative for anti-insulin and islet cell antibodies at age 5 months. His father had non-progressive, impaired fasting glucose for several years. The mother was found to be mildly hyperglycaemic only when her glucose was checked after the child was diagnosed. In conclusion, biallelic GCK loss should be considered as a potential cause of PND in children born to consanguineous parents, even if they are not known to be diabetic at the time of PND presentation.     

Parvovirus associated aplastic crisis in homozygous sickle cell disease.

Aplastic crises in homozygous sickle cell disease in Jamaica predominantly affect children and occur in epidemics. Of 67 cases in a cohort study of 314 children with homozygous sickle cell disease, 62 were attributable to human parvovirus infection. Affected children were aged 0.5-12.5 years, and the incidence rose to 28% by 10 years. No recurrences were seen. Symptoms and signs on presentation were attributable to the viraemia and acute anaemia. Asymptomatic thrombocytopenia was common. Blood transfusion was given in 54 cases (87%). Thirty eight children (61%) were admitted to hospital, 16 of whom were extremely ill on presentation and one of whom died soon after admission. Twenty four (39%) were managed as outpatients, 16 of whom were transfused. Parvovirus associated aplastic crisis is a self limited condition with excellent prognosis if diagnosed promptly and managed appropriately.     

Aarskog-Scott syndrome: a novel mutation in the FGD1 gene associated with severe craniofacial dysplasia

Aarskog syndrome (AAS) is an X-linked human disease that affects the skeletal formation and embryonic morphogenesis and is caused by mutations in the FGD1 gene. Patients typically show distinctive skeletal and genital developmental abnormalities, but a broad spectrum of clinical phenotypes has been observed. We report here on the clinical and molecular analysis of a family that reveals a novel FGD1 mutation in a 9-year-old boy displaying extreme craniofacial dysplasia associated with attention deficit hyperactivity disorder. Sequencing of FGD1 revealed a novel mutation in exon 7 at position c.1468 C > T in the index patient, leading to a stop codon in the highly conserved RhoGEF gene domain. His mother and maternal grandmother were also found to be heterozygous for this FGD1 mutation. Conclusion: Our results identify a novel mutation of FDG1 in a family with Aarskog syndrome and underscore the phenotypical variability of this condition.     

A case of Walker-Warburg syndrome resulting from a homozygous POMT1 mutation.

Walker--Warburg syndrome (WWS), the most severe alpha-dystroglycanopathy, is characterized by brain and eye anomalies, and congenital muscular dystrophy (CMD). So far at least four genes (POMT1, POMT2, Fukutin, and FKRP gene) have been implicated in WWS, accounting for about 30% of all cases. We report a male patient with WWS resulting from a homozygous nonsense mutation (R514X) in the POMT1 gene. The patient had congenital hydrocephalus which was detected at 29 weeks of gestation. A brain MRI obtained after birth revealed type II lissencephaly, hydrocephalus, and pontocerebellar hypoplasia. The case also exhibited severe ocular malformations and muscular hypotonia due to CMD.     

A case of anorexia nervosa with hyperbilirubinaemia in a patient homozygous for a mutation in the bilirubin UDP-glucuronosyltransferase gene

Gilbert syndrome was diagnosed in a girl with anorexia nervosa and unconjugated hyperbilirubinaemia. Since the patient was starved and hyperbilirubinaemic, the loading test was not used for the diagnosis but analysis of the bilirubin UDP-glucuronosyltransferase gene (UGT1A1) instead. The patient was homozygous for a missense mutation that replaced guanine with adenine at nucleotide number 211 (211G→A: G71R). The unconjugated hyperbilirubinaemia was apparently induced by the fasting state. Homozygous missense mutations of the gene have been generally recognized as responsible for Crigler-Najjar syndrome type II; the results obtained here, however, confirm that Gilbert syndrome may also be caused by a homozygous missense mutation of UGT1A1. Conclusion Since anorexia nervosa patients are in a fasting state, they may show moderate unconjugated hyperbilirubinaemia if they have Gilbert syndrome. Gene analysis of such cases will rule out hepatic damage. Homozygous missense mutations of the bilirubin-UDP-glucuronosyltransferase gene cause not only Crigler-Najjar syndrome type II but also Gilbert syndrome. Received: 18 August 1998 / Accepted: 3 December 1998     

A neonate with homozygous protein C deficiency with a homozygous Arg178Trp mutation

Homozygous protein C deficiency affects approximately 1/400,000 to 1/1,000,000 live births. Homozygous protein C deficiency is associated with catastrophic and fatal purpura fulminans-like or thrombotic complications and disseminated intravascular coagulation. In the present patient, genetic study revealed Arg178Trp, a mutation found widely in European population; but this is the first case of homozygous Arg178Trp mutation who suffered from catastrophic purpura fulminans phenotype.