Lingual thyroid in two natural brothers

Tc99m scanning because of hypothyroidism revealed a lingual thyroid in two natural brothers who had no family history of thyroid disease. No thyroid tissue was found in the neck. Further development under substitution therapy with levothyroxine was normal. The diagnosis of this rare disease in two natural brothers suggests that lingual thyroid may be inherited.     

Education and management of patients with familial adenomatous polyposis. Are we making progress? A case report

A 25-year-old male patient was admitted to our clinic for abdominal pain, diarrhea, intermittent rectal bleeding and weight loss. The family history revealed two deaths due to colorectal cancer (maternal grandmother and patient's mother). The colonoscopy showed hundreds of polyps throughout the colon, and an ulcerative rectosigmoidian tumor. The diagnosis was Familial Adenomatous Polyposis (FAP). Colectomy with ileorectal anastomosis was performed. Histopathological diagnosis revealed moderately differentiated adenocarcinoma. Adjuvant chemotherapy was carried out. The patient had three brothers, without clinical symptoms. They had a colonoscopic examination for screening. Two of them were diagnosed with adenomatous polyposis - the first with classic FAP and the other one with the attenuated type (AFAP). The diagnosis of FAP can be made on the basis of either clinical or genetic criteria. When the family history, clinical features, and pathological findings are classic, the diagnosis is straightforward. Screening and prophylactic surgery are effective to prevent colorectal cancer in patients with FAP. Lifelong regular surveillance is necessary to detect and manage extracolonic lesions.     

Primary sclerosing cholangitis in two brothers: report of a family with special emphasis on molecular HLA and MICA genotyping

Immune mechanisms play a role in the pathogenesis of primary sclerosing cholangitis (PSC), as suggested by its association with certain HLA haplotypes. Genetic predisposition is supported by its occurrence in families, but data are scarce. Our aim is to report on two brothers with PSC, and to investigate HLA and MICA alleles in this family. The clinical, biochemical, radiological, and pathological findings in two brothers with PSC as well as in their sister and parents were reviewed. Molecular genotyping of HLA class II and MICA alleles was performed in all five family members. In two brothers, p-ANCA positive PSC was found. The youngest also had ulcerative colitis, and had evolved into cirrhosis at the age of 17 years. Their mother had positive p-ANCA and mild cholestatic changes. Their father and sister were unaffected. Both brothers were homozygous for the MICA*00801 allele, and were positive for the susceptibility HLA haplotypes DR3-DQ2 and DR6-DQ6. Their unaffected father and sister both carried the protective DR4 allele. The presence of PSC in two brothers, and the distribution of HLA haplotypes and MICA alleles, adds supportive evidence for an immunogenetic origin of PSC.     

Familial dissecting aortic aneurysm]

A family is described in which two brothers (44 and 48 years old) had aortic dissecting aneurysms (the first one died, the other one underwent surgical treatment and is still living) in the absence of clinical features of Marfan syndrome and of systemic hypertension. Two of the six living siblings have aortic dilation on echocardiography. Histologic examination of the aortic wall at autopsy or surgery revealed a loss of elastic fibers, deposition of mucopolysaccaride-like material and medionecrosis. We can postulate a genetically-determined disease of connective tissue usually described as "Marfan's forme fruste".     

Familial thrombocytosis as a recessive, possibly X-linked trait in an Arab family

Familial thrombocytosis (FT) has previously been described as an autosomal-dominant disorder with manifestations similar to those of sporadic essential thrombocythaemia. We studied an Arab family consisting of four brothers, aged 4-8 years, who had either sustained markedly elevated (> 1000 x 109/l) or moderately elevated (> 500 x 109/l) platelet counts, two healthy sisters and their parents who had normal platelet counts. The four brothers with FT had normal plasma thrombopoietin levels and are currently not presenting with any thrombotic or haemorrhagic complications. Mutation analysis at the thrombopoietin gene (THPO) of the affected family members failed to detect the intron 3 G-->C splice mutation that had been described as causing FT. In addition, segregation analysis using a polymorphic CA marker revealed completely discordant THPO alleles among the affected brothers. We postulate the existence of a new locus for FT whereby the disease is transmitted as a recessive, possibly X-linked trait.     

A case of male pseudohermaphroditism due to 17 alpha-hydroxylase deficiency and hormonal profiles in the nuclear family

A genetic male with 17 alpha-hydroxylase deficiency is described. The patient, raised as a female, was seen at 17 yr of age for impuberism. She presented all the features of the classical severe form of the disease: complete female phenotype; hypertension; hypokalemia; elevated levels of plasma progesterone, 11-deoxycorticosterone, corticosterone (B), and ACTH; and suppression of renin and aldosterone production. Levels of 17-hydroxyprogesterone, 17-hydroxypregnenolone, and all androgens were barely detectable. Hormone steroid patterns were determined in basal conditions and after acute ACTH stimulation in the parents and the two unaffected brothers in order to identify the heterozygotes. Subtle abnormalities in B and aldosterone secretion were observed in the male members of the family. On the basis of an increased ratio of B to aldosterone the two brothers were assumed to be heterozygotes. The mother had normal basal and stimulated levels of B, deoxycorticosterone, and aldosterone. In the parents and two brothers the progesterone responses to ACTH were exaggerated. The most striking finding in the father and both brothers was the observation of increased basal plasma 17-hydroxyprogesterone, unresponsive to ACTH stimulation, suggesting a partial Leydig cell 17,20-lyase deficiency in the male heterozygotes of this family. This study shows that a short ACTH test can help to identify the heterozygotes in affected families, but the abnormalities found are more heterogeneous than previously suggested.     

Hereditary antithrombin iii deficiency and thromboembolic disease

Two teenage brothers with recurrent thromboembolic disease were found to have antithrombin III deficiency. A family study spanning four generations revealed a total of 10 members with antithrombin III deficiency. Five of the 10 affected family members have had thrombotic problems. Antithrombin III deficiency was documented by coagulation assays measuring heparin cofactor, anti-Factor Xa, and progressive antithrombin activity; the level of antithrombin III antigenic material measured by immunoelectrophoresis was low in subjects with abnormal coagulation assays. The clinical features which may lead one to suspect the hereditary hypercoagulable condition of antithrombin III deficiency are reviewed.     

Impaired catabolism of very low-density lipoprotein-triglyceride in a family with primary hypertriglyceridemia

In this report, kinetic studies of plasma very low-density lipoprotein-triglyceride (VLDL-TG) were examined in five brothers (three affected and two unaffected) from a family with primary hypertriglyceridemia. Synthesis and catabolism of VLDL-TG were studied by in vivo labelling of plasma TG with 3H-glycerol, and multicompartmental analysis of the plasma die-away curves. Results of the kinetic studies revealed the following information: (1) one brother, who had the highest plasma TG level and was obese, had both overproduction and a reduced fractional catabolic rate (FCR) of VLDL-TG; (2) second brother, who had moderate hypertriglyceridemia, had a low FCR and high-normal synthesis of VLDL-TG; (3) a third, who had only mildly elevated TG, had a low FCR and normal synthesis of VLDL-TG; and (4) the two normolipidemic brothers had neither overproduction nor decreased FCR of VLDL-TG. The composition of the soluble apoproteins of VLDL was normal. The apoprotein E phenotypes were E4/3 in four brothers, and E3/2 in the fifth. We have reached the following conclusions regarding this family: (1) the common kinetic abnormality of VLDL-TG metabolism in the hypertriglyceridemic brothers was a low clearance of VLDL-TG; (2) impaired catabolism of VLDL could not be explained by the apoprotein C or E patterns; and (3) the most severe hypertriglyceridemia occurred when the decreased FCR was present in conjunction with VLDL-TG overproduction due to obesity. Thus, a moderate defect in catabolism of plasma TG appears to be responsible for one familial form of primary hypertriglyceridemia.     

Congenital long QT syndrome with compound mutations in the KCNH2 gene

Congenital long QT syndrome is a genetic disorder encompassing a family of mutations that can lead to aberrant ventricular electrical activity. We report on two brothers with long QT syndrome caused by compound mutations in the KCNH2 gene inherited from parents who had no prolonged QT interval on electrocardiography. The proband had syncope, and his elder brother suffered from ventricular fibrillation. Genetic testing revealed that both brothers had multiple mutations in the KCNH2 gene, including a missense mutation of C1474T (exon 6) as well as a frameshift/nonsense mutation, resulting from the insertion of 25 nucleotides, which caused an altered amino acid sequence beginning at codon 302 and a premature termination codon (i.e., TAG) at codon 339 (exon 4). Family genetic screening found that their father had the same frameshift mutation, and their mother and sister had the same missense mutation, in the KCNH2 gene. However, these other family members were asymptomatic, with normal QT intervals on electrocardiography. These results suggest that compound mutations in the KCNH2 gene inherited independently from the parents made the phenotypes of their sons more severe.     

A familial occurrence of allergic bronchopulmonary aspergillosis.

A family was recently studied in which two brothers with identical HLA serotypes had allergic bronchopulmonary aspergillosis. One of the two had a normal bronchogram. A field investigation of the family residence showed that a barn was the probable source of the organism causing disease in these patients. Immunologic characterization of the family members showed a broad spectrum of response to the environmental exposure.     

Hereditary combined deficiency of clotting factors V and VIII with involvement of von Willebrand factor

A family is described in which two brothers, with a significant haemorrhagic disorder, are affected by combined factor V/VIII deficiency. In one of these patients an abnormal decrease of von Willebrand factor was also observed. Family studies suggest that both of the brothers are homozygous for a recessive gene. Normal laboratory results were found in eight other family members although seven of them had reported a mild bleeding tendency. The results indicate that hereditary combined factor V/VIII deficiency is a heterogeneous disorder and that defects of von Willebrand factor might be involved in the aetiology of the disease in some families.     

Familial pulmonary Mycobacterium avium complex disease

We report two Japanese families affected by pulmonary Mycobacterium avium complex (MAC) disease, involving an older brother and younger sister in one family and two brothers in the second family. We investigated whether defects in the natural resistance-associated macrophage protein gene (NRAMP1) underlay susceptibility to MAC in these cases. All of the patients had computed tomographic findings of peripheral nodules and bronchiectasis. Pulse-field gel electrophoresis patterns of mycobacterial genomic DNA restriction fragments revealed that none of the MAC strains isolated from the patients was epidemiologically related to any of the others. Direct sequencing of the complementary DNA of the patients' NRAMP1 revealed a nonconservative missense mutation at codon 419 in one patient, which was heterozygous and was not seen in his affected sibling. No variations similar to those found in mice that show susceptibility to MAC were found. The results suggest an underlying genetic defect in host defense rather than exposure to an unusually virulent strain of MAC as the pathogenetic factor in MAC disease; however, alterations in the coding region of NRAMP1 do not appear to explain the susceptibility to MAC.     

Anomalous coronary arteries: a familial clustering

We present two brothers with anomalous origin of left coronary artery from the right sinus of Valsalva. Screening of other members of the family revealed no coronary artery anomalies. The likelihood of finding such a rare anomaly in two members of a family by chance alone is extremely small; extensive review of the literature found only three other reports of such familial association.     

Pachydermoperiostosis, hypertrophic gastropathy, and peptic ulcer

Two brothers with pachydermoperiostosis, an autosomal dominant syndrome characterized by digital clubbing, periosteal new bone formation, coarse facial features with thick, furrowed, and oily skin, presented in their twenties with severe complicated duodenal ulcer disease requiring multiple operations. Their father and one paternal uncle also had pachydermoperiostosis and a past history of ulcer dyspepsia. The mother, one sister, two maternal aunts, and one other paternal uncle were healthy. Both brothers had giant hypertrophic gastritis (Ménétrier's disease). Their pentagastrin-stimulated acid output and fasting and meal-stimulated serum gastrin levels were normal, but their serum pepsinogen I and II levels were markedly elevated. The father had hypochlorhydria and a low serum pepsinogen I/II ratio, suggesting atrophic gastritis. This family study raises the possibility that pachydermoperiostosis, hypertrophic gastropathy, and peptic ulcer may be genetically related.     

5例炎症性肠病患者的家系调查及其与遗传易感关系分析

目的 探讨我国炎症性肠病患者的遗传易感倾向.方法 在广泛进行流行病学调查的基础上,采用系谱分析方法,对5例具有家族聚集现象的炎症性肠病患者家系进行病史、临床表现、X线、结肠镜及病理组织学检查、治疗状况、家族成员死亡原因、有无近亲结婚史等的详细调查.结果 2个克罗恩病家族分别有兄弟、母子患病;3个溃疡性结肠炎家族分别有姐弟、母子和祖孙三人患病.患者的一级亲属更易受累,同胞受累最多见,其特点是发病年龄较早、后代发病年龄早且病情重.男女均可发病,患病类型相同,病变部位相似.结论 该调查中的炎症性肠病患者存在着遗传易感倾向,发病人数少,推测可能为多基因遗传或常染色体隐性遗传.     

Alterations of the X-linked lymphoproliferative disease gene SH2D1A in common variable immunodeficiency syndrome

X-linked lymphoproliferative (XLP) disease is a primary immunodeficiency caused by a defect in the SH2D1A gene. At least 3 major manifestations characterize its clinical presentation: fatal infectious mononucleosis (FIM), lymphomas, and immunoglobulin deficiencies. Common variable immunodeficiency (CVID) is a syndrome characterized by immunoglobulin deficiency leading to susceptibility to infection. In some patients with CVID, a defective btk or CD40-L gene has been found, but most often there is no clearly identified etiology. Here, 2 unrelated families in whom male members were affected by CVID were examined for a defect in the XLP gene. In one family previously reported in the literature as having progressive immunoglobulin deficiencies, 3 brothers were examined for recurrent respiratory infections, whereas female family members showed only elevated serum immunoglobulin A levels. A grandson of one of the brothers died of a severe Aspergillus infection secondary to progressive immunoglobulin deficiency, FIM, aplastic anemia, and B-cell lymphoma. In the second family, 2 brothers had B lymphocytopenia and immunoglobulin deficiencies. X-linked agammaglobulinemia syndrome was excluded genetically, and they were classified as having CVID. The occurrence of FIM in a male cousin of the brothers led to the XLP diagnosis. Because the SH2D1A gene was found altered in both families, these findings indicate that XLP must be considered when more than one male patient with CVID is encountered in the same family, and SH2D1A must be analyzed in all male patients with CVID. Moreover, these data link defects in the SH2D1A gene to abnormal B-lymphocyte development and to dysgammaglobulinemia in female members of families with XLP disease.     

Wilson's disease with concomitant beta thalassaemia and factor V deficiency

A case of late presentation of Wilson's disease in a female with a thalassaemic trait is reported in whom diagnosis of Factor V deficiency was made. Despite ignoring the disease for years the patient had compensated cirrhosis. She had a dramatic family history of Wilson's disease affecting at least two brothers and two sisters. Moreover, her haematologic problems were not clinically revealed until diagnosis had been made on the basis of suspicions arising from laboratory results. The therapy of choice for hepatolenticular degeneration was not feasible due to the patient's refusal. Zinc salts were, therefore, administered. To our knowledge the association of such rare genetic disorders has not been reported.     

Erythrocyte lipids in triose-phosphate isomerase deficiency.

Marked hypoalphalipoproteinemia was found together with relatively low serum cholesterol, triacylglycerol, and LDL levels in a triose-phosphate isomerase (TPI; D-glyceraldehyde-3-phosphate ketol-isomerase, EC 5.3.1.1)-deficient Hungarian family, especially in the two compound-heterozygote brothers. Apart from a slight increase in palmitic and stearic acids together with a slight decrease in oleic and linoleic acids, no other changes were found in the fatty acid composition of the erythrocyte phospholipids. Anisotropy measurements with n-(9-anthroyloxy) stearic and -palmitic acid fluorophores revealed increased motional freedom of the fatty acid chains in the external lipid layers of the intact erythrocytes from all members of the TPI-deficient family as compared with normal age-matched controls. This asymmetric increase in membrane fluidity was found to be significantly higher in the propositus than in his compound-heterozygote brother without any neurological disorders. The change in membrane fluidity may result from as-yet-unresolved aspects of the lipid composition of the plasma membrane. Our findings that the differences between the TPI-deficient individuals and normal controls and the differences between the two compound-heterozygote brothers were all absent in the phospholipid extracts of the same erythrocytes favor the assumption that the increased motional freedom of the fatty acid chains in the external surface of the bilayer is caused by the binding of the mutant TPI molecule to the N-terminal sequence of band 3 protein.