Cytogenetic abnormalities and TP53 and RAS gene profiles of childhood acute lymphoblastic leukemia in Morocco.

BACKGROUND: Recurrent genetic abnormalities affecting pivotal signaling pathways are the hallmark of childhood acute lymphoblastic leukemia (ALL). The identification of these aberrations remains clinically important. Therefore, we sought to determine the cytogenetic profile and the mutational status of TP53 and RAS genes among Moroccan childhood cases of ALL. METHODS: In total, 35 patients with childhood ALL were enrolled in the study. The diagnosis and treatment were established in the Pediatric Hematology and Oncology Center at the Children's Hospital of Rabat. Chromosome banding analysis and fluorescence in situ hybridization were used to detect genetic aberrations. Blood samples were screened for TP53 and RAS mutations using Sanger sequencing. RESULTS: Of the 35 cases, 30 were B-lineage ALL (85.7 %). Moreover, a male predominance was observed. Cytogenetic analysis revealed chromosomal anomalies in 27 cases (77.1 %). The most frequent aberrations were high hyperdiploidy and BCR/ABL rearrangement. Interestingly, we found the rare t(15;16) and the t(8;14), which are uncommon translocations in pediatric B-ALL. The mutational analysis revealed Pro72Arg (rs1042522:C > G) and Arg213Arg (rs1800372:A > G) in TP53. In correlation with cytogenetic data, rs1042522:C > G showed a significant association with the occurrence of chromosomal translocations (p = 0.04). However, no variant was detected in NRAS and KRAS genes. CONCLUSION: Our findings emphasize the significance of detecting chromosomal abnormalities as relevant prognostic markers. We also suggest a low occurrence of genetic variants among Moroccan children with ALL.

Moroccan Experience of Targeted Screening for Inborn Errors of Metabolism by Tandem Mass Spectrometry.

BACKGROUND: Expanded newborn screening using tandem mass spectrometry (MS/MS) for inborn errors of metabolism (IEM), such as organic acidemias (OAs), fatty acid oxidation disorders (FAODs), and amino acid disorders (AAs), is increasingly popular but has not yet been introduced in Africa. With this study, we aim to establish the disease spectrum and frequency of inborn errors of OAs, FAODs, and AAs in Morocco. METHODS: Selective screening was performed among infants and children suspected to be affected with IEM between 2016 and 2021. Amino acids and acylcarnitines spotted on filter paper were analyzed using MS/MS. RESULTS: Out of 1178 patients with a clinical suspicion, 137 (11.62%) were diagnosed with IEM, of which 121 (88.3%) patients suffered from amino acids disorders, 11 (8%) were affected by FAOD, and 5 (3.7%) by an OA. CONCLUSIONS: This study shows that various types of IEM are also present in Morocco. Furthermore, MS/MS is an indispensable tool for early diagnosis and management of this group of disorders.

Coeliac disease hidden by cryptogenic hypertransaminasaemia in children: a case report.

Celiac disease is a chronic immune-mediated multisystem disorder that may affect several organs. Isolated hypertransaminasemia, with mild or nonspecific histologic changes in the liver biopsy, also known as "celiac hepatitis", is the most frequent presentation of liver injury in celiac disease. Both, histologic changes and liver enzymes reverse to normal after treatment with a gluten-free diet in most patients. Here we report the case of a young boy presenting with asymptomatic and persistent hypertransaminasemia whose etiologic investigation led to the diagnosis of celiac disease that resolved with dietary treatment alone. This case emphasizes the need to screen Celiac disease in patients with cryptogenic hypertransaminasemia, irrespective of the existence of gastrointestinal symptoms. It also exemplifies a particular situation in which a liver biopsy is useful to establish the diagnosis of celiac hepatitis.

Vitamin B12 deficiency: case report and review of literature.

Vitamin B12 deficiency in early childhood is an important cause of neurodevelopmental delay and regression. Most of these cases occur in exclusively breast-fed infants of deficient mothers. Symptoms and signs of vitamin B12 deficiency appear between the ages of 2 to 12 months and include vomiting, lethargy, failure to thrive, hypotonia, and arrest or regression of developmental skills. Approximately one half of this cases exhibit abnormal movements, variously described as tremors, twitches, chorea, or myoclonus. Urinary concentrations of methylmalonic acid and homocysteine are characteristically elevated in vitamin B12 deficiency. Hyperglycinuria is sometimes present. The early diagnosis and treatment of vitamin B12 deficiency is crucial for significant neurological impairment and long-term prognosis. Treatment with vitamin B12 corrects these metabolic abnormalities very rapidly (within a few days). Vitamin B12 supplementation of pregnant women may prevent neurological and neuroradiological findings of the infants. Because of the importance of vitamin B12 in the development of the foetal and neonatal brain, vegetarian and vegan mothers should be aware of the severe and not fully-reversible damages caused by insufficient nutritional intake of vitamin B12 during pregnancy and lactation. Therefore, efforts should be directed to prevent its deficiency in pregnant and breastfeeding women on vegan diets and their infants. It is also important to take the nutritional history of both infants and their mothers for the early prevention and treatment. Here an interesting case of vitamin B12 deficiency in a 10-month-old boy presented with psychomotor regression, hypotonia and lethargy.

Congenital hepatic fibrosis: case report and review of literature.

Congenital hepatic fibrosis (CHF) is a rare autosomal recessive disease derived from biliary dysgenesis secondary to ductal plate malformation; it often coexists with Caroli's disease, von Meyenburg complexes, autosomal dominant polycystic kidney disease (ADPKD), and autosomal recessive polycystic kidney disease (ARPKD). Although CHF was first named and described in detail by Kerr et al. in 1961. Its pathogenesis still remains unclear. The exact incidence and prevalence are not known, and only a few hundred patients with CHF have been reported in the literature to date. However, with the development of noninvasive diagnostic techniques such as ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI), CHF may now be more frequently detected. Anatomopathological examination of liver biopsy is the gold standard in diagnosis of CHF. Patients with CHF exhibit variable clinical presentations, ranging from no symptoms to severe symptoms such as acute hepatic decompensation and even cirrhosis. The most common presentations in these patients are splenomegaly, esophageal varices, and gastrointestinal bleeding due to portal hypertension. In addition, in younger children, CHF often is accompanied by renal cysts or increased renal echogenicity. Great variability exists among the signs and symptoms of the disease from early childhood to the 5th or 6th decade of life, and in most patients the disorder is diagnosed during adolescence or young adulthood. Here, we present two cases of congenital hepatic fibrosis in 2-years-old girl and 12-year-old male who had been referred for evaluation of an abdominal distension with persistent hyper-transaminasemia and cholestasis, the diagnostic was made according to the results of medical imaging (CT or MRI), a liver biopsy, and genetic testing.

Clinical and Immunological Features of 96 Moroccan Children with SCID Phenotype: Two Decades' Experience.

Severe combined immunodeficiency (SCID) is a heterogeneous group of primary immunodeficiency diseases (PIDs) characterized by a lack of autologous T lymphocytes. This severe PID is rare, but has a higher prevalence in populations with high rates of consanguinity. The epidemiological, clinical, and immunological features of SCIDs in Moroccan patients have never been reported. The aim of this study was to provide a clinical and immunological description of SCID in Morocco and to assess changes in the care of SCID patients over time. This cross-sectional retrospective study included 96 Moroccan patients referred to the national PID reference center at Casablanca Children's Hospital for SCID over two decades, from 1998 to 2019. The case definition for this study was age < 2 years, with a clinical phenotype suggestive of SCID, and lymphopenia, with very low numbers of autologous T cells, according to the IUIS Inborn Errors of Immunity classification. Our sample included 50 male patients, and 66% of the patients were born to consanguineous parents. The median age at onset and diagnosis were 3.3 and 6.5 months, respectively. The clinical manifestations commonly observed in these patients were recurrent respiratory tract infection (82%), chronic diarrhea (69%), oral candidiasis (61%), and failure to thrive (65%). The distribution of SCID phenotypes was as follows: T-B-NK+ in 44.5%, T-B-NK- in 32%, T-B+NK- in 18.5%, and T-B+NK+ in 5%. An Omenn syndrome phenotype was observed in 15 patients. SCID was fatal in 84% in the patients in our cohort, due to the difficulties involved in obtaining urgent access to hematopoietic stem cell transplantation, which, nevertheless, saved 16% of the patients. The autosomal recessive forms of the clinical and immunological phenotypes of SCID, including the T-B-NK+ phenotype in particular, were more frequent than those in Western countries. A marked improvement in the early detection of SCID cases over the last decade was noted. Despite recent progress in SCID diagnosis, additional efforts are required, for genetic confirmation and particularly for HSCT.

What about the treatment of asymptomatic forms of congenital malaria: case report and review of the literature.

We report in this manuscript a case of newborn baby with asymptomatic form of congenital malaria; the screening of the peripheral blood smear of the baby after a positive result in the mother allowed the diagnosis. The authors were permitted through this case to discuss the therapeutic possibility in these cases.

Congenital hyperinsulinsim: case report and review of literature.

Neonatal hypoglycemia (NH) is one of the most common abnormalities encountered in the newborn. Hypoglycemia continues to be an important cause of morbidity in neonates and children. Prompt diagnosis and management of the underlying hypoglycemia disorder is critical for preventing brain damage and improving outcomes. Congenital hyperinsulinism (CHI) is the most common and severe cause of persistent hypoglycemia in neonates and children, it represents a group of clinically, genetically and morphologically heterogeneous disorders characterised by dysregulation of insulin secretion from pancreatic ß-cells. It is extremely important to recognize this condition early and institute appropriate management to prevent significant brain injury leading to complications like epilepsy, cerebral palsy and neurological impairment. Histologically, CHI is divided mainly into two types focal and diffuse disease. The diffuse form is inherited in an autosomal recessive (or dominant) manner whereas the focal form is sporadic in inheritance and is localized to a small region of the pancreas. Recent discoveries of the genetic causes of CHI have improved our understanding of the pathophysiology, but its management is complex and requires the integration of clinical, biochemical, molecular, and imaging findings to establish the appropriate treatment according to the subtype. Here we present a case of sever congenital hyperinsulinism in a girl admitted for lethargy, irritability and general seizures accompanied with profound hypoglycemia, in spite of aggressive medical treatment, she died because of sever congenital hyperinsulinism diazoxide unresponsive.

Nijmegen breakage syndrome: case report and review of literature.

Nijmegen Breakage Syndrome (NBS) is a rare autosomalrecessive DNA repair disorder characterized by genomic instability andincreased risk of haematopoietic malignancies observed in morethan 40% of the patients by the time they are 20 years old. The underlying gene, NBS1, is located on human chromosome 8q21 and codes for a protein product termed nibrin, Nbs1 or p95. Over 90% of patients are homozygous for a founder mutation: a deletion of five base pairs which leads to a frame shift and protein truncation. Nibrin (NBN) plays an important role in the DNA damage response (DDR) and DNA repair. DDR is a crucial signalling pathway in apoptosis and senescence. Cardinal symptoms of Nijmegen breakage syndrome are characteristic: microcephaly, present at birth and progressive with age, dysmorphic facial features, mild growth retardation, mild-to-moderate intellectual disability, and, in females, hypergonadotropic hypogonadism. Combined cellular and humoral immunodeficiency with recurrent sino-pulmonary infections, a strong predisposition to develop malignancies (predominantly of lymphoid origin) and radiosensitivity are other integral manifestations of the syndrome. The diagnosis of NBS is initially based on clinical manifestations and is confirmed by genetic analysis. Prenatal molecular genetic diagnosis is possible if disease-causing mutations in both alleles of the NBN gene are known. No specific therapy is available for NBS; however, hematopoietic stem cell transplantation may be one option for some patients. Prognosis is generally poor due to the extremely high rate of malignancies. We present here a case of Nijmegen breakage syndrome associated with Hodgkin lymphomas and Combined variable immunodeficiency.

Prevalence and risk factors for latent tuberculosis infection among healthcare workers in Morocco.

Increased prevalence of latent tuberculosis infection (LTBI) has been observed among high-risk populations such as healthcare workers (HCWs). The results may depend on the method of LTBI assessment, interferon-gamma release assay (IGRA) and/or tuberculin skin test (TST). Here, we investigated the prevalence and risk factors for LTBI assessed by both IGRAs and TST in HCWs living in Morocco, a country with intermediate tuberculosis (TB) endemicity and high BCG vaccination coverage. HCWs were recruited in two Moroccan hospitals, Rabat and Meknes. All the participants underwent testing for LTBI by both IGRA (QuantiFERON-TB Gold In-Tube, QFT-GIT) and TST. Different combinations of IGRA and TST results defined the LTBI status. Risk factors associated with LTBI were investigated using a mixed-effect logistic regression model. The prevalence of LTBI among 631 HCWs (age range 18-60 years) varied from 40.7% (95%CI 36.9-44.5%) with QFT-GIT to 52% (95%CI 48.2-56.0%) with TST using a 10 mm cut-off. The highest agreement between QFT-GIT and TST (κ = 0.50; 95%CI 0.43-0.56) was observed with the 10 mm cut-off for a positive TST. For a definition of LTBI status using a double positive result for both QFT-GIT and TST, significant associations were found with the following risk factors: being male (OR = 2.21; 95%CI 1.40-3.49; p = 0.0007), belonging to age groups 35-44 years (OR = 2.43; 95%CI 1.45-4.06; p = 0.0007) and even more 45-60 years (OR = 4.81; 95%CI 2.72-8.52; p = 7.10-8), having a family history of TB (OR = 6.62; 95%CI 2.59-16.94; p = 8.10-5), and working at a pulmonology unit (OR = 3.64; 95%CI 1.44-9.23; p = 0.006). Smoking was associated with LTBI status when defined by a positive QFT-GIT result (OR = 1.89; 95%CI 1.12-3.21; p = 0.02). A high prevalence of LTBI was observed among HCWs in two Moroccan hospitals. Male gender, increased age, family history of TB, and working at a pulmonology unit were consistent risk factors associated with LTBI.

A three-year-old boy with hypodipsic hypernatremia syndrome.

We describe a three-year-old boy who had a growth and psychomotor retardation associated with inappropriate lack of thirst and vasopressin secretion in the presence of chronic plasma hyperosmolarity. Computed brain tomography revealed bilateral supratentorial sub-ependymal and cortical calcifications. Dissociation in the plasma vasopressin response to osmotic change was demonstrated in this patient. Treatment with a vasopressin analogue, desamino-D-arginine vasopressin (DDAVP) and forced intake of water restored plasma osmolality and serum sodium levels to normal.

[Pycnodysostosis: about a case]. / Pycnodysostose: à propos d'un cas.

Pycnodysostosis is a very rare genetic disease of the bone characterized by osteocondensation associated with dysmorphic syndrome and growth retardation. This study aims to highlight the phenotypic abnormalities, the radiological signs, the therapeutic and evolutionary features of pycnodysostosis in a 11-year old child. The child was referred by his dentist for clinical evaluation. He was born to first-degree consanguineous parents and had recurrent spontaneous fractures since the age of 3 years. Clinical examination showed dysmorphic syndrome characterized by frontal hump, persistent anterior fontanelle, micrognathia, finger deformities, dental malposition, curved nails, asymmetric chest, lumbar spine scoliosis with severe growth retardation (-4DS). Skeletal X-rays showed bony densification of the skull base, persistent anterior fontanelle, dental malposition, diaphysometaphyseal densification of the long bones mainly at the level of the lower limbs with malunions and tapered phalanges of the hands. Bone densitometry was normal. The diagnosis of pycnodysostosis was retained based on the clinical and radiological signs. Genetic counselling was proposed to the family as well as dental and orthopaedic treatment. Pycnodysostosis is a rare disorder; diagnosis is sometimes difficult and delayed posing diagnostic problem due to its resemblance with osteoporosis. Treatment is essentially based on fractures and dental caries prevention.