Epidemiological profile of common haemoglobinopathies in Arab countries.

Haemoglobinopathies including the thalassemias and sickle cell disease are known to be prevalent inherited disorders in most Arab countries with varying prevalence rates and molecular characterisation. ß-thalassemia is encountered in polymorphic frequencies in almost all Arab countries with carrier rates of 1-11 % and a varying number of mutations. The most widespread mutation in Lebanon, Egypt, Syria, Jordan, Tunisia and Algeria is the IVS-I-110 (G>A). In the Eastern Arabian Peninsula, the Asian Indian mutations (IVS-I-5 (G>C), codons 8/9 (+G) and IVS-I (-25 bp del)) are more common. The α-thalassemias are encountered in the majority of Arab countries in frequencies ranging from 1 to 58 % with the highest frequencies reported from Gulf countries. The (-α(3.7)) mutation is the most frequent followed by the non-deletional α2 polyadenylation signal mutation (AATAAA>AATAAG) and the α2 IVS1 5-bp deletion. The rates of sickle cell trait in Arab countries range from 0.3 to 30 %, with the Benin, the Arab-Indian and the Bantu haplotypes constituting the bulk of the haplotypes, leading to two major phenotypes; a mild one associated with the Arab-Indian and a severe one with the Benin and Bantu haplotypes. Public health approaches targeting prevention of haemoglobinopathies in Arab countries include newborn screening for sickle cell disease, and premarital screening for carriers of ß-thalassemia and sickle cell disease. These services are still patchy and inadequate in many Arab countries recommending the upgrade of these services with strengthening of the education and training of health care providers and raising public awareness on the feasibility of prevention and care for haemoglobinopathies.

Consanguinity and reproductive health among Arabs.

Consanguineous marriages have been practiced since the early existence of modern humans. Until now consanguinity is widely practiced in several global communities with variable rates depending on religion, culture, and geography. Arab populations have a long tradition of consanguinity due to socio-cultural factors. Many Arab countries display some of the highest rates of consanguineous marriages in the world, and specifically first cousin marriages which may reach 25-30% of all marriages. In some countries like Qatar, Yemen, and UAE, consanguinity rates are increasing in the current generation. Research among Arabs and worldwide has indicated that consanguinity could have an effect on some reproductive health parameters such as postnatal mortality and rates of congenital malformations. The association of consanguinity with other reproductive health parameters, such as fertility and fetal wastage, is controversial. The main impact of consanguinity, however, is an increase in the rate of homozygotes for autosomal recessive genetic disorders. Worldwide, known dominant disorders are more numerous than known recessive disorders. However, data on genetic disorders in Arab populations as extracted from the Catalogue of Transmission Genetics in Arabs (CTGA) database indicate a relative abundance of recessive disorders in the region that is clearly associated with the practice of consanguinity.

First report of clinical, functional, and molecular investigation of chronic granulomatous disease in nine Jordanian families.

INTRODUCTION: Chronic granulomatous disease is a rare inherited immunodeficiency syndrome caused by mutations in four genes encoding essential nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex components. MATERIAL AND METHODS: Clinical, functional, and molecular investigations were conducted in 15 Jordanian CGD patients from nine families. RESULTS AND DISCUSSION: Fourteen patients were children of consanguineous parents and suffered from autosomal recessive (AR) CGD forms with mutations in the CYBA, NCF1, and NCF2 genes encoding p22phox, p47phox, and p67phox proteins, except for one patient in whom the mutation's location was not found. One patient had an extremely rare X(+)CGD subtype resulting from a novel missense mutation (G1234C) in exon 10 of CYBB. We found a genetic heterogeneity in the Jordanian families with a high frequency of rare ARCGD, probably because consanguineous marriages are common in Jordan. No clear correlation between the severity of the clinical symptoms and the CGD types could be established.

Male transient hip osteoporosis: are physicians at a higher risk?

SUMMARY: Data of 17 male patients with a final diagnosis of transient osteoporosis (TO) of the hip seen at the radiology department of a university hospital over a period of 7 years were retrospectively studied. Comparison of the proportion of doctors among TO cases with that among other hip joint pathologies revealed a significant difference. PURPOSE: The objective of this study is to present clinical and radiological findings of hip TO and to assess the association of the condition with patients' occupation. MATERIALS AND METHODS: Data of 17 male patients with a final diagnosis of transient osteoporosis of the hip seen at the radiology department of a university hospital over a period of 7 years were retrospectively studied. RESULTS: The diagnosis of transient hip osteoporosis was in accordance with the published literature for clinical, imaging findings, and laboratory results. Among the 17 cases of male transient hip osteoporosis, 65% were physicians and 12% were commercial pilots. Comparison of the proportion of doctors among TO cases with that among other hip joint pathologies revealed a significant difference. Abnormal low hormone levels of testosterone and 25-cholicalciferol (vitamin D) were detected in three and two patients, respectively. CONCLUSION: The preponderance of physicians among patients with transient hip osteoporosis has not been previously reported. Etiological contribution of endocrine pathology and type of occupation to the causation of transient osteoporosis merits further research.

Clinical and inheritance profiles of hyperekplexia in Jordan.

Hyperekplexia is a rare nonepileptic disorder characterized by excessive startle response to acoustic, visual, or other stimuli. Patients with hyperekplexia are often misdiagnosed as having epilepsy. The presentation modalities, phenotypes, and the modes of inheritance among patients with hyperekplexia from 9 Jordanian families are described. All families were referred with the preliminary diagnosis of uncontrolled seizures with onset of the disease in the neonatal period and with variable and atypical presenting features. The inheritance profile in 4 families was compatible with autosomal recessive and in 1 family with autosomal dominant inheritance. Four families showed sporadic cases of hyperekplexia. This is the first report of a series of patients with hyperekplexia from Jordan. The clinical manifestations show atypical features that have not been previously reported, pointing to the probable broader clinical spectrum of this entity. Recognition of the syndrome allows for prompt proper management and provision of genetic counseling.

Consanguinity and genetic disorders. Profile from Jordan.

OBJECTIVE: With 20-30% of all marriages occurring between first cousins, increasing attention in Jordan is now given to role of consanguinity in the occurrence of genetic diseases. The objective of this study is to define the specific categories of genetic disorders associated with consanguineous marriages. METHODS: Etiological categories and consanguinity rates were studied among 623 families with genetic syndromes, congenital anomalies or mental retardation, or both, seen at the National Center for Diabetes, Endocrinology and Genetics for the period August 2002 to August 2006. Comparisons were made for first cousin marriage rates in the study group and that for the general population. RESULTS: First cousin marriages constituted 69%, 22% and 41.7% of marriages among families with autosomal recessive conditions (group 1), dominant, X-linked and chromosomal conditions (group 2) and sporadic undiagnosed conditions (group 3) respectively. The differences in rates of first cousin matings versus non-consanguineous matings were highly significant when comparing known figures in the general population with group 1 and 3, but not significant with group 2. CONCLUSION: Two messages to the public and health care personnel regarding consanguinity can be derived from this study. The first message is that among genetic disorders, only autosomal recessive disorders are strongly associated with consanguinity. The second message is that approximately 30% of sporadic undiagnosed cases of mental retardation, congenital anomalies and dysmorphism may have an autosomal recessive etiology with risks of recurrence in future pregnancies.

Severe hypertelorism, midface prominence, prominent/simple ears, severe myopia, borderline intelligence, and bone fragility in two brothers: new syndrome?

We report on two brothers, born to double first cousin Jordanian Arab parents, with a syndrome comprising severe hypertelorism with upslanted palpebral fissures, brachycephaly, abnormal ears, sloping shoulders, enamel hypoplasia, and osteopenia with repeated fractures. Both have severe myopia, mild to moderate sensori-neural hearing loss and borderline intelligence. Results of chromosome analysis were normal as was a FISH assay for subtelomeric rearrangements. The father has mild hypertelorism but the family history is otherwise unremarkable. We think that this represents a previously unrecognized autosomal or X-linked recessive syndrome.

Hereditary multiple exostoses with pseudoaneurysm.

A 16-year-old male patient with hereditary multiple exostoses (HME) was found to have a pseudoaneurysm of the left popliteal artery caused by osteochondroma in the lower femur. The diagnosis was confirmed by ultrasound, magnetic resonance imaging and magnetic resonance angiography without the need to perform an angiogram. The osteochondroma was excised and the popliteal artery was repaired with a saphenous graft. Vascular complications are extremely rare in HME, pseudoaneurysm being the most common and mostly located in the popliteal artery. This complication should be considered in young HME patients with a mass at the knee region. The radiological spectrum of investigations allows the diagnosis of this complication with proper and less invasive management procedures for the patient.

Pituitary enlargement in patients with primary hypothyroidism.

OBJECTIVE: To assesses the frequency and degree of pituitary hyperplasia in patients with primary hypothyroidism, the association of pituitary enlargement with disease severity, and the response to treatment. METHODS: Between April 2002 and August 2004 at the National Center for Diabetes, Endocrinology and Genetics in Amman, Jordan, 53 patients (49 female and 4 male subjects) with primary hypothyroidism and serum thyrotropin (thyroid-stimulating hormone or TSH) levels of > or = 50 microIU/mL were encountered. Initial and follow-up investigations included thyroid function tests, serum prolactin levels, and magnetic resonance imaging (MRI) of the pituitary. Visual field examination was requested for all patients with pituitary enlargement (and adequately completed in 24). RESULTS: Pituitary enlargement on MRI was found in 37 of the 53 patients (70%), with 31 of the 37 patients (84%) having TSH levels of > or = 100 microIU/mL. After thyroxine treatment, 85% of the patients with pituitary enlargement who underwent a follow-up MRI showed a decrease in size of the gland. About half of the patients were referred to our facility with the diagnosis of hypothyroidism; presenting features in the rest of the patients included galactorrhea, menstrual irregularities, learning disability, short stature, precocious puberty, ovarian hyperstimulation syndrome, headaches, visual field defects, and dry ichthyotic skin. CONCLUSION: The association between pituitary gland enlargement and primary hypothyroidism should be kept in mind when pituitary hyperplasia is detected on MRI, before unwarranted and drastic interventions are initiated.

Cockayne syndrome in 2 siblings.

Cockayne syndrome is a rare autosomal recessive condition characterized by growth failure and multisystem progressive degeneration. We report and describe this syndrome in a Jordanian brother and sister with Cockayne syndrome with first cousin parents. Clinical features included short stature, cachectic senile look, neurological deterioration, photosensitivity, mental retardation, hearing impairment and carious teeth. The phenotype is compatible with a mild variant of type I Cockayne syndrome. They showed an exaggerated response to growth hormone provocation test, with slightly elevated basal insulin-like growth factor 1 levels. The radiological findings of thinning of ribs and slender femora with narrow medullary canals have not previously been reported in this syndrome. We discuss the implications of these findings.

Clinical and inheritance profiles of Kallmann syndrome in Jordan.

BACKGROUND: Proper 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. SUBJECTS: Over 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. RESULTS: The 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.

Parental decisions following the prenatal diagnosis of sex chromosome abnormalities.

OBJECTIVE: To report parental decisions regarding pregnancy termination following the prenatal diagnosis of a sex chromosome abnormality (SCA) in the fetus. METHODS: Retrospective collection of data from records of 61 families receiving genetic counseling after prenatal diagnosis of a sex chromosome abnormality in the fetus in the Division of Medical Genetics, University Hospital of Geneva during the time period 1980-2001. RESULTS: Among 61 couples with a prenatal diagnosis of a sex chromosome abnormality (SCA), 44 couples (72.1%) decided to terminate pregnancy. Pregnancy termination rates were 100, 73.9, 70, 50 and 42.9% for Turner syndrome, Klinefelter syndrome, 47,XXX females, 47,XYY males, and mosaic cases, respectively. In all 11 cases with a fetal abnormality seen on ultrasound, pregnancy was terminated. Termination rates were higher among couples with a higher mean number of previous children. Maternal age and year of test did not influence parental decisions. CONCLUSIONS: Parental decision to terminate a pregnancy for a fetus with a SCA varied by type of sex chromosome abnormality, by presence of fetal ultrasound anomalies, and by the mean number of previous children.

Familial monozygotic twinning: report of an extended multi-generation family.

Thirteen sets of monozygotic (MZ) twins from an extended multi-generation family are reported. Zygosity was determined by interviewing families for overall physical similarity and by assessment of facial photographs. A hypothetical gene was traced back five generations to a common grandfather. Familial monozygotic twinning in this pedigree is compatible with autosomal dominant inheritance with reduced penetrance. Other plausible mechanisms of inheritance are discussed.