Presence Of Parental Consanguinity Research Articles

Cisplatin-induced bone marrow failure in an adult patient with Fanconi anemia.

Fanconi anemia (FA) is a genetic disorder characterized by bone marrow failure typically developing in the first decade of life, congenital abnormalities, and an increased predisposition to malignancy. However, patients with FA can remain undiagnosed until adulthood and present with solid organ malignancies. Due to impaired DNA repair mechanisms, patients with FA are highly susceptible to severe bone marrow toxicity when treated with cisplatin. A 38-year-old woman, diagnosed with locally advanced squamous cell carcinoma (SCC) of the uterine cervix, underwent treatment with weekly cisplatin concurrent with radiotherapy. After the second week of cisplatin treatment, she presented with severe pancytopenia. The prolonged and severe pancytopenia following cisplatin and radiation, along with cervical SCC in the absence of risk factors and the presence of parental consanguinity, raised the possibility of FA as the underlying cause. Whole exome sequencing revealed a homozygous FANCI c.668A > C (p.Lys223Thr) missense variant confirming the diagnosis of FA. The pancytopenia exhibited a protracted course, necessitating admission and supportive treatment with antibiotics, red blood cell and platelet transfusions, as well as filgrastim and eltrombopag. Eventually, the pancytopenia improved after approximately 40 days of hospitalization. SCC of the head and neck or gynecologic organs in a young adult without known risk factors should prompt consideration of FA. Cisplatin should be avoided in patients with FA.

Analysis of disease characteristics of a large patient cohort with congenital generalized lipodystrophy from the Middle East and North Africa

BackgroundCongenital generalized lipodystrophy (CGL) is a rare inherited disease characterized by a near-total absence of adipose tissue and is associated with organ system abnormalities and severe metabolic complications. Here, we have analyzed the disease characteristics of the largest CGL cohort from the Middle East and North Africa (MENA) who have not received lipodystrophy-specific treatment.MethodsCGL was diagnosed clinically by treating physicians through physical assessment and supported by genetic analysis, fat loss patterns, family history, and the presence of parental consanguinity. Data were obtained at the time of patient diagnosis and during leptin-replacement naïve follow-up visits as permitted by available medical records.ResultsData from 43 patients with CGL (37 females, 86%) were collected from centers located in eight countries. The mean (median, range) age at diagnosis was 5.1 (1.0, at birth–37) years. Genetic analysis of the overall cohort showed that CGL1 (n = 14, 33%) and CGL2 (n = 18, 42%) were the predominant CGL subtypes followed by CGL4 (n = 10, 23%); a genetic diagnosis was unavailable for one patient (2%). There was a high prevalence of parental consanguinity (93%) and family history (67%) of lipodystrophy, with 64% (n = 25/39) and 51% (n = 20/39) of patients presenting with acromegaloid features and acanthosis nigricans, respectively. Eighty-one percent (n = 35/43) of patients had at least one organ abnormality; the most frequently affected organs were the liver (70%, n = 30/43), the cardiovascular system (37%, n = 16/43) and the spleen (33%, n = 14/43). Thirteen out of 28 (46%) patients had HbA1c > 5.7% and 20/33 (61%) had triglyceride levels > 2.26 mmol/L (200 mg/dl). Generally, patients diagnosed in adolescence or later had a greater severity of metabolic disease versus those diagnosed during childhood; however, metabolic and organ system abnormalities were observed in a subset of patients diagnosed before or at 1 year of age.ConclusionsThis analysis suggests that in addition to the early onset of fat loss, family history and high consanguinity enable the identification of young patients with CGL in the MENA region. In patients with CGL who have not received lipodystrophy-specific treatment, severe metabolic disease and organ abnormalities can develop by late childhood and worsen with age.

Implications of ACMG guidelines to identify high-risk acute lymphoblastic leukemia patients with hereditary cancer susceptibility syndromes (HCSS) in a highly consanguineous population

BackgroundHereditary cancer susceptibility syndrome (HCSS) contributes to the cancer predisposition at an early age, therefore, identification of HCSS has found to be crucial for surveillance, managing therapeutic interventions and refer the patients and their families for genetic counselling. The study aimed to identify ALL patients who meet the American College of Medical Genetics (ACMG) criteria and refer them for the genetic testing for HCSS as hereditary leukemia and hematologic malignancy syndrome, and to elucidate the significance of high consanguinity with the prevalence of inherited leukemia in Pakistani population.MethodsA total of 300 acute lymphoblastic leukemia patients were recruited from the Children’s Hospital, Lahore, Pakistan from December 2018 to September 2019. A structured self-reporting questionnaire based on family and medical history of the disease was utilized for the data collection.ResultsIn our cohort, 60.40% of ALL patients were identified to meet ACMG criteria. Among them, a large number of patients (40.65%) solely fulfil the criteria due to the presence of parental consanguinity. However, parental consanguinity showed protective impact on the onset at early age of disease [OD = 0.44 (0.25–0.77), p-value = 0.00] while, a family history of cancer increased the risk of cardiotoxicity [OD = 2.46 (1.15–5.24), p-value = 0.02]. Parental consanguinity shows no significant impact on the family history of cancer and the number of relatives with cancer.ConclusionsMore than 50% of the ALL patients were considered the strong candidates’ for genetic testing of HCSS in the Pakistani population, and parental consanguinity was the leading criteria fulfilled by the individuals when assessed through ACMG guidelines. Our study suggests revisiting ACMG guidelines, especially for the criterion of parental consanguinity, and formulating the score based criteria based on; genetic research, the toxicology profile, physical features, personal and family history of cancer for the identification of patients for the genetic testing.

Persistent Mullerian duct syndrome in two brothers from a Saudi family with a homozygous variant in the AMHR2 gene

Persistent Mullerian duct syndrome (PMDS) is a rare disease characterized by normal virilization and XY genotype including failure of Mullerian duct regression. In this article, we report two cases of PMDS in Saudi patients with a pathogenic homozygous variant in the AMHR2 gene and review the literature. PMDS should be taken into consideration in all cases of bilateral cryptorchidism. Laparoscopy is the elective procedure for the diagnosis of this disease, and laparoscopic surgery for orchidopexy of intra-abdominal testes is the intervention of choice. It remains unclear at present whether the anti-Mullerian hormone is necessary to maintain normal testicular function. Early surgical intervention is important to reduce the risk of malignancy. The patient and his family should be completely informed about the diagnosis, the surgical options, and the need for long-term follow-up. A genetic cause can be strongly suggested in the presence of parental consanguinity.

Nörofibromatozis tip 1 tanılı hastalarda nöroradyolojik bulguların kognitif fonksiyonlara etkisi

Amaç: Bu çalışmada, Nörofibromatozis Tip 1 (NF1) tanısıyla takip edilen çocukların klinik ve radyolojik bulgularının değerlendirilmesi, kognitif fonksiyonlara etki eden faktörlerin araştırılması amaçlandı. Gereç ve Yöntem: Bu çalışmaya 2 Çukurova Üniversitesi Tıp Fakültesi Çocuk Nöroloji Polikliniğinde NF1 tanısı alan, en az 1 yıllık izlemi olan 53 hasta alındı. Hastaların yaşı, cinsiyet dağılımı, aile öyküsü varlığı, anne-baba arasında akrabalık varlığı, zeka testleri, öğrenme güçlüğü, motor gerilik varlığı, otizm varlığı, dikkat eksikliği ve hiperaktivite bozukluğu varlığı, davranış bozukluğu varlığı, nörogörüntüleme bulguları, nöbet öyküleri, kullandığı antiepileptik ilaç sayıları açısından retrospektif olarak değerlendirildi.Bulgular: Hastaların 27’si (%50.9) kız, 26’sı (%49.1) erkekti. Yirmiyedisi (%50.9) herediter, 26’sı (%49.1) sporadik geçişliyken, herediter olanların 8’i (%29.6) anneden, 19’u (%70.4) babadan geçişli idi. Serebral manyetik rezonans görüntülemede (MRG) T2 hiperintensitesi varlığı ile hastaların kız cinsiyette olması, makrosefali varlığı ve mental retardasyon varlığı arasında istatistiksel olarak anlamlı bir ilişki saptandı. Ayrıca otizm varlığı ve dikkat eksikliği hiperaktivite bozukluğu ile mental retardasyon arasında önemli bir ilişki saptandı.Sonuç: Klinik ve radyolojik olarak bazı bulgular arasında ilişki varlığı saptansa da oluş mekanizmaları bilinmemekle birlikte, makrosefali gibi tanı kriterleri içinde yer almayan ancak NF1’li hastalarda aydınlatılmayı bekleyen birliktelikler mevcuttur.

Risk factors associated with epilepsy development in children with cerebral palsy.

Epilepsy is one of the most common and important comorbidity among patients with cerebral palsy (CP). The purpose of this study was to determine the risk factors predicting the development of epilepsy considering prenatal, perinatal, and natal characteristics; associated impairments; and cranial imaging findings in our patient population with cerebral palsy at a tertiary center in Istanbul, Turkey. This retrospective study consisted of 234 children aged between 3 and 18years of age. Children were divided into two groups as CP patients with epilepsy (126 patients) and CP patients without epilepsy (108 patients). Demographic features and clinical and cranial magnetic resonance imaging (cMRI) findings were compared between the two groups. Presence of family history of epilepsy, history of neonatal seizure especially in the first 72h of life, quadriplegic type of CP, severe degree of gross motor function and fine motor disorders, and moderate to severe mental retardation or psycho-social developmental delay were determined as risk factors for the development of epilepsy in CP patients. Also, an increased risk of epilepsy was detected in term infants and appropriate for gestational age (2500-4000g) infants. On the other hand, presence of parental consanguinity, being born from a primiparous mother, age of mother at birth, mode of delivery, presence of multiple gestation and labor problems, history of follow-up in neonatal intensive care unit and intubation, and cMRI findings were not significant risk factors for the development of epilepsy in CP. Predicting epilepsy development by determining the risk factors in patients with CP might be useful because knowing the risk factors could provide close follow-up of these patients for epilepsy.

Biallelic loss of EEF1D function links heat shock response pathway to autosomal recessive intellectual disability.

Intellectual disability (ID) is a genetically heterogeneous neurodevelopmental disorder characterised by significantly impaired intellectual and adaptive functioning. ID is commonly syndromic and associated with developmental, metabolic and/or neurological findings. Autosomal recessive ID (ARID) is a significant component of ID especially in the presence of parental consanguinity. Several ultra rare ARID associated variants in numerous genes specific almost to single families have been identified by unbiased next generation sequencing technologies. However, most of these new candidate ARID genes have not been replicated in new families due to the rarity of associated alleles in this highly heterogeneous condition. To determine the genetic component of ARID in a consanguineous family from Turkey, we have performed SNP-based linkage analysis in the family along with whole exome sequencing (WES) in an affected sibling. Eventually, we have identified a novel pathogenic variant in EEF1D, which has recently been recognised as a novel candidate gene for ARID in a single family. EEF1D encodes a ubiquitously expressed translational elongation factor functioning in the cytoplasm. Herein, we suggest that the loss of function variants exclusively targeting the long EEF1D isoform may explicate the ARID phenotype through the heat shock response pathway, rather than interfering with the canonical translational elongation.

Primer immun yetersizliklerin tanısında farkındalığı arttıracak klinik özelliklerin değerlendirilmesi

Objective: Each step effective on the emergence of immune response creates a potential for primary immune deficiency disease (PID). From the year 1952 on when X-linked agammaglobulinemia was described firstly, more than 150 cases with PID have been defined. Although as a common finding most of the patients manifest predisposition to infections, controversies exist about the choice of laboratory tests, and candidate patients. Materials and Methods: The study group consisted of 100 children aged between 2008-2009 who applied to our hospital with complaints of recurrent or deep-seated infection and had at least one of the 10 PID warning signs reported by the Jeffrey Model Foundation Medical Advisory Board. Study forms contained questions regarding the patient’s age, gender, immunization status, diet, age at onset of complaints, presence of parental consanguinity and other demographic features. Results: Twenty-five of 100 patients were diagnosed with PID, while the remaining 75 were found to be normal. There was a significant difference between PID and nonPID groups in ≥ 2 out of 10 warning signs: >2 sinus infections, ≥2 pneumonias and requirement for IV antibiotic use for the recovery from infection (p<0.05). While consanguinity and formula feeding were more frequently seen in group of PID, while age distribution, gender and immunization history were similar between two groups (p>0.05). Conclusion: While 10 warning signs determined by the Jeffrey Model Foundation are important for screening of immunodeficiencies, they are not sufficient on their own. Gathering additional information on consanguinity, diet and age, a detailed physical examination and basic laboratory analyses will facilitate early diagnosis of PID.

Genealogical and molecular analysis of a family-based cohort of congenital heart disease patients from the São Miguel Island (Azores, Portugal)

Background: Congenital heart disease (CHD) is one common birth malformation, accounting for ∼30% of total congenital abnormalities.Aim: Considering the unknown role of consanguinity in causing CHD, this study hypothesised that consanguineous unions and/or familial aggregation may be frequent in the Azorean Island of São Miguel (Portugal). To that end, a retrospective observational study was performed based on genealogical and molecular analyses.Subjects and methods: The study enrolled 112 CHD patients from São Miguel Island, which allowed the assessment of type of family (simplex or multiplex), parental consanguinity and grandparental endogamy. Based on 15 STR markers, inbreeding coefficients (FIS) in the CHD cohort and healthy control group (n = 114) were estimated.Results: Multiplex families were 37.6% (n = 41/109), a rate considerably higher than previously described in the literature (< 15%). Moreover, 9.2% (n = 10/109) of the CHD families were consanguineous, mostly derived from third cousin unions, and 20.2% (n = 22/109) presented full grandparental endogamy. Higher FIS values were found in patients with parental consanguinity (0.0371) and patent ductus arteriosus (0.0277).Conclusion: This study analysed several genealogical and genetic features related with CHD, revealing the presence of parental consanguinity and extensive familial aggregation in the CHD patients from São Miguel Island.

Is parental consanguinity associated with reduced ovarian reserve?

This observational study assessed whether women descending from consanguineous unions have reduced ovarian reserve compared with daughters of non-consanguine couples. Two hundred and ninety-one women (≤39 years) were treated in a tertiary care centre in Kuwait. Women underwent a complete anamnesis, including an evaluation of the possible presence of parental consanguinity, transvaginal ultrasound on day 2/3 of the cycle to obtain the antral follicle count (AFC), determination of serum concentrations of FSH, LH, oestradiol and in case of low ovarian reserve (AFC < 9) anti-Müllerian hormone (AMH). The median AFC of non-consanguineous daughters was 11, while daughters from consanguineous parents displayed a significantly lower median AFC (7; P < 0⋅0001). FSH was slightly higher in the consanguineous patients, while LH and oestradiol concentrations did not vary between groups. In total, 29.9% of consanguineous patients had an AFC ≥ 9, compared with 63.9% of non-consanguineous patients. Consanguineous patients did not exhibit an age-dependent AFC-decline and displayed reduced AFC and AMH concentrations. The multivariate analysis revealed female consanguinity, as well as surgical history in non-consanguineous women, as strong positive predictors of low ovarian reserve. Parental consanguinity is strongly associated with reduced ovarian reserve. Future studies should evaluate a possible association between parental consanguinity and infertility.

Cystinosis Presenting with Findings of Bartter Syndrome - Case Report

A five-year-old boy was referred to our pediatric clinic for evaluation of failure to thrive, headache, intermittent high fever, restlessness, polyuria, and polydipsia. His weight and height measurements were under the 3rd percentile. Clinical findings consisted of frontal bossing, carious teeth, O-bain deformity of the lower extremities, and moderate dehydration. The presence of metabolic alkalosis, hypokalemia, hypochloremia, and high renin and aldosterone levels were suggestive of Bartter syndrome and a treatment regimen for Bartter syndrome was started. At follow-up, the polyuria and hyponatremia were found to persist. A reassessment of the patient revealed findings consistent with proximal renal tubular acidosis such as metabolic acidosis with a high urinary pH, proteinuria, aminoaciduria with phosphaturia and hypercalciuria. Based on the presence of parental consanguinity as well as polyuria, proteinuria, low tubular reabsorption of phosphorus, generalized aminoaciduria, light yellow skin and hair color, the probable diagnosis of cystinosis was established and was confirmed by slit-lamp examination of the cornea showing cystine crystal deposition. Our case is a good example demonstrating that development of metabolic alkalosis does not exclude cystinosis and that all findings of the patient should be thoroughly evaluated.Conflict of interest:None declared.

Evidence for a major gene in familial anencephaly

A 21-year-old white woman sought counseling after the birth of two consecutive anencephalic male fetuses with complete rachischisis and discordant renal dysplasia. The presence of parental consanguinity prompted reconsideration of recessive inheritance. The segregation ratio from 23 additional consanguineous cases was compared with that observed in 294 presumably nonconsanguineous families previously reported. Using classical segregation analysis, the segregation ratios in the non-sporadic cases were consistent with a major autosomal recessive locus in both populations.

Primary hypomagnesaemia. A case report and literature review.

A case of primary hypomagnesaemia with secondary hypocalcaemia in an Arab girl of consanguineous parents is reported. She presented at the age of 3 weeks with generalised convulsions, was treated with magnesium supplements and followed up for 5 years during which she showed normal physical and psychomotor development. In view of the striking male preponderance among the reported cases and the presence of parental consanguinity in a few, the inheritance is discussed and genetic heterogeneity is suggested.

Clinical and pathological features of an autosomal recessive neuropathy

Two siblings are described, ages 49 and 45 years, having a distinct hereditary motor and sensory neuropathy (HMSN) with severe peroneal nerve involvement. The neuropathic symptoms began in childhood. Both patients have sensorineural deafness. The proband was found to have a cardiac conduction abnormality in the absence of known ischemic heart disease. Electrodiagnostic studies were consistent with a demyelinating peripheral neuropathy. The presence of parental consanguinity and absence of affected individuals in succeeding or preceding generations suggested that the sensorimotor neuropathy in this family is inherited in an autosomal recessive manner. The sural nerve of the proband had significant loss of myelinated fibers and demyelination but few regenerating myelinated fibers and no onion-bulbs. The pathological findings, while nonspecific, are not characteristic of the hypertrophic, neuronal or intermediate types of HMSN.