Nadim Jarrah

Bleeding tendency in Wolfram syndrome: a newly identified feature with phenotype genotype correlation

Abstract Wolfram syndrome (WS) is a recessively inherited disorder associated with recognised clinical features. Bleeding tendency was noticed in some of our patients, although this has not been reported before. We therefore studied this problem in all our WS patients and tried to postulate a possible pathogenesis. At the same time, a genetic linkage study provided evidence of locus heterogeneity of this syndrome and showed that the majority of our patients belong to the second WS locus identified in that study. Our study group consisted of 13 WS patients, belonging to WSF2 locus (group I). Controls consisted of 4 healthy siblings of WS patients (group II) and 7 diabetics who do not have WS (group III). Relevent clinical data were obtained, and a coagulation screen was carried out for all groups. All individuals in the three study groups have normal platelet count, thrombin time (TT), prothrombin time (PT), activated partial thromboplastin time (aPTT), clot retraction, Factor VIII activity (FVIIIc) and von Willebrand factor antigen (vWAg). Eleven of the WS patients have prolonged template bleeding time (BT) compared with both control groups. Patients with WS have a longer BT (mean 9.6 min, 95% CL 8.61–10.53 min) than the siblings group (mean 6.75 min, 95%CL 5.52–7.98 min) and the diabetic group (mean 5.49 min, 95%CL 4.56–6.42 min). The differences between the study group and controls are statistically significant, p=0.02 and 0.0002, respectively. In the three groups, platelet aggregation studies were normal using adenosine diphosphate (ADP), ristocetin and epinephrine. Aggregation with collagen was either absent or impaired, with failure of secondary wave being noticed in 11 of the WS patients (85%) and normal in the control groups. The pathogenesis of this problem is not known, but could be due to an inhibitory effect of vWAgII, deficiency of thrombospondin or a defect in the platelet membrane GPIa/IIa. Bleeding diathesis is a new additional feature to the clinical spectrum of WS, which is probably a feature of the disorder WFS2 and not WFS1, as bleeding has never been reported in the latter. This provides further evidence for the phenotypic and genotypic heterogeneity of this complex disorder and may provide clues to the search for the second gene responsible for this phenotype.

Familial disorder of sex determination in seven individuals from three related sibships

Abstract In humans, the sex of an individual is determined by the Y-chromosome-related SRY gene, which causes the differentiation of the undifferentiated gonads into testicular tissue. True hermaphrodites without a Y chromosome and XX males represent a sex determination error in which testicular tissue develops despite the absence of the SRY gene. Familial forms of XX true hermaphrodites and XX males exist in the literature, which also contains the two forms co-existing in the same family. In this report, we present a large family with seven affected individuals with phenotypes ranging from XX male to XX true hermaphrodite with predominance of female characteristics. We suggest that XX maleness and XX true hermaphroditism represent a continuum of the same disorder. We speculate on the mode of inheritance of this disorder in this particular family.

Clinical and inheritance profiles of Kallmann syndrome in Jordan

BackgroundProper management of patients with Kallmann syndrome (KS) allows them to attain a normal reproductive health. The purpose of this study is to demonstrate the presentation modalities, phenotypes and the modes of inheritance among 32 patients with Kallmann syndrome in Jordan. Recognition of the syndrome allows for prompt proper management and provision of genetic counselling.SubjectsOver a period of five years (1999–2004), the clinical and inheritance profiles of 26 male and 6 female patients with Kallmann syndrome from 12 families were evaluated at the National Center for Diabetes, Endocrinology and Genetics in Jordan.ResultsThe patients belonged to twelve Jordanian and Palestinian families and their age at presentation ranged from 4 – 46 years. Nine boys aged 4–14 years presented with cryptorchidism and microphallus, all other males presented with delayed puberty, hypogonadism and/or infertility. The main presentation among six female patients was primary amenorrhea. Intrafamilial variability in clinical phenotype was specifically evident for renal abnormalities and sensorineural hearing impairment. Familial KS was diagnosed in 27 patients belonging to five families with the X-linked mode of inheritance and two families with the autosomal recessive mode of inheritance.Conclusions(1) the majority of cases in this study represented the X-linked form of KS, which might point to a high prevalence of Kal 1 gene in the population. (2) Genetic counselling helps these families to reach a diagnosis at an early age and to decide about their reproductive options. (3) Children presenting with cryptorchidism and microphallus in our population should be investigated for KS.

TERTIARY HYPERPARATHYROIDISM AFTER HIGH-DOSE PHOSPHATE THERAPY IN ADULT-ONSET HYPOPHOSPHATEMIC OSTEOMALACIA

OBJECTIVE To describe a case of adult-onset hypophosphatemic osteomalacia treated with orally administered phosphate and complicated by tertiary hyperparathyroidism. METHODS We present pertinent clinical, radiologic, and laboratory details of the study patient for a period of more than 20 years and discuss the few reported cases of tertiary hyperparathyroidism attributable to prolonged phosphate therapy. RESULTS A 49-year-old Jordanian man, who had been diagnosed at age 26 years as having sporadic adult-onset hypophosphatemic vitamin D-resistant osteomalacia, presented with severe right hip pain, severe osteopenia with lytic bone lesions, and hypercalcemia after prolonged oral treatment with phosphate and vitamin D. These clinical, radiologic, and biochemical findings, in conjunction with a very high serum parathyroid hormone level, indicated the diagnosis of tertiary hyperparathyroidism, which was substantiated histopathologically. CONCLUSION Physicians should be aware of the potential for development of tertiary hyperparathyroidism in patients receiving prolonged oral phosphate therapy.

A CASE OF WOLFRAM SYNDROME IN TRIPLETS: SOME NEWLY RECOGNIZED FEATURES

We report here the occurrence of Wolframsyndrome in triplets, two of whom are identical females.We also describe a previously unreported gastrointestinalfinding and the presence of urinary tract dilatation, despitethe absence of diabetes insipidus.Patients and MethodsThe triplets, one male and two females, were conceivednaturally to normal healthy parents who are first cousins.There was a family history of similar conditions amongsiblings, although this was not clearly stated by the family.