Lesch-Nyhan disease in a 20-year- old man incorrectly described as developing 'cerebral palsy' after general anaesthesia in infancy

Lesch-Nyhan disease (LND) is a rare X-linked recessive genetic disorder caused by a deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT) enzyme. The classic clinical condition is characterized by cognitive impairment, hypotonia at rest, choreoathetosis, hyperuricaemia and the hallmark symptom of severe and involuntary self-mutilation. We describe a man with LND who was initially thought to have suffered from a dyskinetic cerebral palsy after an uncomplicated inguinal herniorrhaphy under general anaesthesia at 5 1/2 months of age. In the absence of overt self-injurious behaviour, the diagnosis was not considered for nearly two decades. The diagnosis of LND was established at 20 years of age through clinical review, biochemical examinations and molecular analysis. HPRT haemolysate activity was 7.6% of the normal control, suggesting that he had a milder variant of the disease. Mutation analysis of the HPRT gene revealed a novel missense mutation, c.449T > G in exon 6 (p.V150G). Cascade testing of family members revealed that the mother was heterozygous for the mutation but two siblings (a brother and a sister) did not carry the sequence mutation. Whether the onset of neurological abnormalities in this particular case can be attributed to the general anaesthesia is discussed.     

G-33A mutation in the promoter region of thrombomodulin gene and its association with coronary artery disease and plasma soluble thrombomodulin levels

Thrombomodulin is an endothelial glycoprotein that decreases thrombin activity and activates protein C. A recent study has shown that G-33A promoter mutation of the thrombomodulin gene occurs particularly in Asians. In this study, we analyzed the distribution of G-33A mutation in the promoter region of the thrombomodulin gene in the Chinese population and determined whether the mutation might be a risk for coronary artery disease (CAD). In addition, the influence of this mutation on plasma soluble thrombomodulin levels in patients with CAD was also examined. We studied 320 consecutive patients (mean age 63 years; 73% men) with CAD and 200 age- and sex-matched control subjects. Screening for thrombomodulin G-33A promoter mutation was conducted using polymerase chain reaction, single-strand conformation polymorphism, and direct deoxyribonucleic acid sequencing. The frequency of the G-33A mutation (GA+AA genotypes) was significantly higher in the CAD group (23.8% vs 15.5%, odds ratio [OR] 1.70, p = 0.031). Multiple logistic regression analysis showed that the mutation was an independent risk factor (OR 1.81, p = 0.016) for CAD, as was hypertension (OR 1.44, p = 0.040), diabetes mellitus (OR 2.50, p <0.001), and smoking (OR 2.15, p <0.001). In CAD patients with GG genotype, the soluble thrombomodulin level increased with the extent of CAD (36 +/- 15 vs 47 +/- 18 vs 55 +/- 36 ng/ml in 1-, 2-, or 3-vessel CAD, p <0.001). However, in CAD patients with G-33A mutation, there was no difference between the levels of soluble thrombomodulin (39 +/- 17 vs 37 +/- 15 vs 42 +/- 18 ng/ml, p = NS) in 1-, 2-, or 3-vessel CAD. Our observations suggest that there is a significant association of the G-33A mutation in thrombomodulin gene with CAD, and this mutation may influence the soluble thrombomodulin levels in patients with CAD.     

Lesch–Nyhan disease in a 20-year- old man incorrectly described as developing ‘cerebral palsy’ after general anaesthesia in infancy

Summary  Lesch–Nyhan disease (LND) is a rare X-linked recessive genetic disorder caused by a deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT) enzyme. The classic clinical condition is characterized by cognitive impairment, hypotonia at rest, choreoathetosis, hyperuricaemia and the hallmark symptom of severe and involuntary self-mutilation. We describe a man with LND who was initially thought to have suffered from a dyskinetic cerebral palsy after an uncomplicated inguinal herniorrhaphy under general anaesthesia at 5 1/2 months of age. In the absence of overt self-injurious behaviour, the diagnosis was not considered for nearly two decades. The diagnosis of LND was established at 20 years of age through clinical review, biochemical examinations and molecular analysis. HPRT haemolysate activity was 7.6% of the normal control, suggesting that he had a milder variant of the disease. Mutation analysis of the HPRT gene revealed a novel missense mutation, c.449T > G in exon 6 (p.V150G). Cascade testing of family members revealed that the mother was heterozygous for the mutation but two siblings (a brother and a sister) did not carry the sequence mutation. Whether the onset of neurological abnormalities in this particular case can be attributed to the general anaesthesia is discussed. Electronic supplementary material  Supplementary material is available for this article at Communicating editor: Robert Steiner     

The first activating TSH receptor mutation in transmembrane domain 1 identified in a family with nonautoimmune hyperthyroidism

Sporadic and familial nonautoimmune hyperthyroidism are very rarely occurring diseases. Within the last years constitutively activating TSH receptor mutations were identified as one possible pathomechanism. Except for S281N in the extracellular N-terminal domain, all other germline mutations are located in the transmembrane domains 2, 3, 5, 6, and 7 of the TSH receptor, whereas no mutation was reported in transmembrane domains 1 and 4 to date. Here we report the first family with a constitutively active TSHR mutation in transmembrane domain 1 resulting in a substitution of the conserved Gly(431) for Ser. This mutation was found in the investigated patient, his father, and the paternal grandmother. As known from other familial cases of nonautoimmune hyperthyroidism, the age of onset of the disease was variable, ranging from early childhood in the patient and his father to adolescence in the grandmother. Functional characterization of this mutation showed a constitutive activation of the G(s)/adenylyl cyclase system. Moreover, this germline mutation also activates the G(q/11)/phospholipase C pathway. The importance of Gly(431) for receptor quiescence is supported further by introduction of other mutations at this position, all leading to constitutive receptor activity. Our data show now that constitutively activating mutations can be found in the entire transmembrane domain region of the TSH receptor, indicating the important role of all parts of the transmembrane domain region for maintaining the inactive receptor conformation.     

Risk for subsequent venous thromboembolic complications in carriers of the prothrombin or the factor V gene mutation with a first episode of deep-vein thrombosis

Carriers of a mutation in the prothrombin (clotting factor II) or factor V gene have a 2- to 4-fold greater risk for venous thromboembolism than subjects without the mutations. Whether both mutations also predispose to recurrent venous thromboembolism is unclear. Outpatients who had a first episode of proven symptomatic deep-vein thrombosis and a long-term follow-up were studied. The outcome measure was the cumulative incidence of confirmed venous thromboembolic complications. Two hundred fifty-one patients were enrolled in the study. Mean duration of follow-up was 8.3 years. The prothrombin gene mutation was demonstrated in 27 patients (prevalence, 10.8%; 95% CI, 6.9 to 14.6), and the factor V gene mutation was demonstrated in 41 patients (prevalence, 16.3%; 95% CI, 11.8 to 20.9). The cumulative incidence of venous thromboembolic complications after 10 years was 61.3% (95% CI, 35.7 to 87.9), and the hazard ratio was 2.4 (95% CI, 1.3 to 4.7; P =.004) in patients with the prothrombin gene mutation); the cumulative incidence of venous thromboembolic complications after 10 years was 55.2% (95% CI, 36.4 to 74.0), and the hazard ratio was 2.4 (95% CI, 1.4 to 4.1; P =.001) in patients with the factor V gene mutation. In comparison, the cumulative incidence of venous thromboembolic complications after 10 years was 23.1% (95% CI, 16.2 to 30.1) in patients without the mutations. Prothrombin and factor V gene mutations occur frequently in patients with venous thrombosis and are associated with an increased risk for recurrent venous thromboembolic complications.     

Menetrier's disease presenting as an acute protein-losing gastroenteropathy in a 27-year-old man with Gaucher disease

OBJECTIVES: To describe a unique case of a young man with Gaucher disease who was diagnosed with Menetrier's disease. BACKGROUND: After an acute episode of severe gastritis, the patient developed hypoalbuminemia and protein-losing gastroenteropathy, and became unwell. STUDY: Endoscopy revealed an abnormal stomach, with rigid, thickened folds covered with viscous greyish exudates. Superficial biopsies revealed foveolar hyperplasia, acute and severe gastritis with massive inflammatory infiltrate of neutrophils in the lamina propria with pit abscess formation. Tissue cultures for Helicobacter pylori were negative. RESULTS: Snare deep particle biopsy revealed the typical features of Menetrier's disease. Enzyme replacement therapy for Gaucher disease was started. CONCLUSION: This case poses a dilemma because the patient improved spontaneously, and as such is dissimilar to other adults who develop Menetrier's disease because of an infection; it is hoped that he may also not be at risk of the potential malignancies that are correlated with adult Menetrier's disease. The value of enzyme treatment is considered.     

Combined hypothalamic-pituitary-gonadal defect in a hypogonadic man with a novel mutation in the DAX-1 gene.

We have studied a 20-yr-old male patient with adrenal hypoplasia congenita and hypogonadotropic hypogonadism (HH) due to a C to A transversion at nucleotide 825 in the DAX-1 gene, resulting in a stop codon at position 197. The same mutation was detected in his affected first cousin (adrenal hypoplasia congenita and HH) and in a heterozygous state in their carrier mothers. The patient had had acute adrenal insufficiency at the age of 2 yr and 6 months, bilateral cryptorchidism corrected surgically at the age of 12 yr, and failure of spontaneous puberty. Plasma testostereone (T) was undetectable (<0.30 nmol/L), gonadotropin levels were low (LH, <0.4 IU/L; FSH, 1.5 IU/L) and not stimulated after i.v. injection of 100 microg GnRH. The endogenous LH secretory pattern was apulsatile, whereas free alpha-subunit (FAS) levels depicted erratic pulses, suggesting an incomplete deficiency of hypothalamic GnRH secretion. During i.v. pulsatile GnRH administration (10 microg/pulse every 90 min for 40 h), each GnRH pulse induced a LH response of low amplitude (0.54 +/- 0.05 UI/L), whereas mean LH (0.45 +/- 0.01 IU/L) and FAS (63 +/- 8 mU/L) levels remained low. Amplitude of LH peaks (0.83 +/- 0.09 IU/L), mean LH (0.53 +/- 0.02 IU/L), and FAS (161 +/- 18 mU/L) levels increased (P < 0.01), whereas the T concentration remained low (0.75 nmol/L) when the pulsatile GnRH regimen was raised to 20 microg/pulse for a 40-h period, suggesting a partial pituitary resistance to GnRH. Thereafter, plasma T levels remained in prepubertal value after three daily im injections of 5000 IU hCG (3.6 nmol/L) and after 1-yr treatment with weekly i.m. injections of 1500 IU hCG (1.2 nmol/L), implying Leydig cell resistance to hCG. The patient had a growth spurt, bone maturation, progression of genital and pubic hair stages, and normalization of plasma T level (15.8 nmol/L) after a 12-month treatment with twice weekly injections of hCG and human menopausal gonadotropin (75 IU International Reference Preparation 2) preparations, suggesting that, in presence of FSH, a Sertoli cell-secreted factor stimulated Leydig cell production of T. In conclusion, we report a novel mutation in the DAX-1 gene in patients with AHC and HH. Our results suggest that the hypogonadism is due to a combined hypothalamic-pituitary-gonadal defect and imply that the DAX-1 gene may play a critical role in human testicular function.     

A novel mutation in the preprovasopressin gene identified in a kindred with autosomal dominant neurohypophyseal diabetes insipidus

Autosomal dominant neurohypophyseal diabetes insipidus (ADNDI) is a defect in free water conservation caused by mutations in the single gene that encodes both vasopressin (VP) and its binding protein, neurophysin II (NP II). Most of the human mutations in this gene have been in the portion encoding the NP molecule; the resultant abnormal gene products are believed to cause cellular toxicity as improperly folded precursor molecules accumulate in the endoplasmic reticulum. We identified a new American kindred with ADNDI and found a novel mutation in the VP molecule. A 78-yr-old man was noted to have hypotonic polyuria and plasma hyperosmolarity; the urinary concentration defect was reversed by administration of VP. His symptomatology dated to childhood, and his family history was consistent with autosomal transmission of the polyuric syndrome, with affected members in three generations, including several females. Affected individuals were found to be heterozygous for a 3-bp deletion in exon 1 of arginine VP (AVP)-NP II, predicting a deletion of phenylalanine 3 (known to be critical for receptor binding) in the VP nonapeptide. Neuro 2A cells stably transfected with the mutant AVP-NP construct showed increased rates of apoptosis as assessed by flow cytometric methods. These observations support the concept that cellular toxicity of abnormal AVP-NP gene products underlies the development of ADNDI, and the data further demonstrate that mutations affecting the AVP moiety can result in initiation of these pathological processes.     

Lymphocytic hypophysitis in a man presenting with hypercalcemia

A 59-year-old man with a 30-year history of type 2 diabetes mellitus presented with fatigue, confusion, and weight loss over a 3-month period. He was found to be hypercalcemic (11.8 mg/dL) and dehydrated, and his hypercalcemia improved with intravenous fluids. While in the hospital, he developed hyponatremia, hypoglycemia, and hypotension. He was found to have a subnormal cortisol level of 2.3 microg/dL at baseline, which increased to only 5.6 microg/dL 60 minutes after a 250-microg corticotropin intravenous stimulation test. The patient developed pneumonia and adult respiratory distress syndrome and died of an acute myocardial infarction. During the autopsy, he was found to have lymphocytic hypophysitis with a severe reduction in corticotropin-producing anterior pituitary cells. No malignancy was identified at autopsy. He is the first male patient to be described in the literature who presented with hypercalcemia caused by lymphocytic hypophysitis.     

Addison disease as first manifestation in one patient with adrenoleukodystrophy and identification of a novel ABCD1 gene mutation

正Objective To identify the clinical manifestations,imaging findings,and genetic mutation characteristics in a rare case of adrenoleukodystrophy (ALD) with adrenocortical dysfunction (Addison's disease) as the first manifestation.Methods The clinical data of the proband and his family members were comprehensively collected,and ABCD1 gene sequencing was meticulously performed for the proband and his mother using high throughput sequen-     

A novel splice site mutation of the MEN1 gene identified in a patient with primary hyperparathyroidism

Heterozygous germline mutation of the tumor suppressor gene MEN1 is responsible for multiple endocrine neoplasia type 1 (MEN1), a familial cancer syndrome characterized by pituitary, parathyroid and enteropancreatic tumors. Various mutations have been identified throughout the entire gene region in patients with MEN1 and its incomplete forms often manifested as familial isolated hyperparathyroidism and apparently sporadic parathyroid tumor. Mutation analysis of the MEN1 gene is a powerful tool for the early diagnosis of MEN1; however, the clinical significance of the identified mutations is not always obvious. In this study, a previously unreported missense MEN1 mutation, c.824G>T was identified in a patient with primary hyperparathyroidism and evaluated for its pathogenicity. This mutation was predicted to generate a putative missense menin protein, R275M. A stability test of the menin protein demonstrated that the stability of R275M mutant was reduced only slightly as compared with wild type menin, and therefore could not preclude the possibility that it was a rare benign polymorphism. However, further analysis of leukocyte mRNA and minigene experiments indicated that the mutant c.824G>T allele gives rise to abnormally spliced menin mRNA, and thereby confirmed that c.824G>T mutation is causative for MEN1. Thus, leukocyte mRNA analysis has been demonstrated useful to identify a splicing mutation of the MEN1 gene.     

Identification and characterization of a thrombomodulin gene mutation coding for an elongated protein with reduced expression in a kindred with myocardial infarction

Thrombomodulin is an endothelial cell receptor for thrombin. It functions as a natural anticoagulant by greatly accelerating activation of protein C by thrombin. Using a direct gene screening strategy we identified a frameshift insertion mutation, insT 1689, in the thrombomodulin gene of a patient with myocardial infarction. The mutation predicts an elongated gene product because of substitution of the 12 C-terminal amino acids by 61 abnormal residues. Pedigree analysis showed that the mutation was also likely to have been present in a sibling who had had fatal myocardial infarction. Carriers of the mutant allele express significantly lower amounts of thrombomodulin on the surface of their monocytes detected by flow cytometry and have lower levels of soluble thrombomodulin in plasma. Wild type and the mutant thrombomodulin were expressed in COS-7 cells. Cellular distribution of the expressed proteins was evaluated by immunofluorescence microscopy, which showed reduced cell surface expression and intense juxtanuclear localization of the abnormal protein. This suggests impaired translocation through the endoplasmic reticulum/Golgi apparatus. Cells expressing abnormal thrombomodulin had reduced ability ( approximately 2.5-fold) to accelerate the thrombin mediated activation of protein C. This is the first demonstration of reduced expression arising from a natural thrombomodulin gene mutation. The results provide support for the suggestion that gene mutation of thrombomodulin may be important in the pathogenesis of some cases of occlusive thrombotic disease. (Blood. 2000;95:569-576)