Misdiagnosis of Tracher-Collins Syndrome Initially Attributed to Drug Teratogenicity: A Moroccan Case Report.

Background: Treacher Collins syndrome (TCS) is a rare congenital disorder of craniofacial development characterized by numerous developmental anomalies that are restricted to the head and neck. Most TCS cases are inherited in an autosomal dominant manner. The diagnosis of TCS relies on clinical and radiographic findings. The four genes involved in TCS are TCOF1, POLR1D, POLR1C, and POLR1B. Case presentation: In this report, we present the case of a 7-year-old Moroccan boy who exhibited distinctive dysmorphic features, including coloboma and zygomatic bone hypoplasia. Upon genetic analysis, a mutation in the TCOF1 gene was identified, conclusively confirming the presence of Treacher Collins Syndrome. It is worthy that the correct etiological diagnosis was significantly delayed due to the initial misperception that the observed malformation syndrome was a result of drug teratogenicity. Conclusions: This case highlights the importance of seeking pharmacovigilance advice if any adverse event occurs following medication use. Furthermore, requesting a genetic consultation to establish a confirmed etiological diagnosis for any malformation syndrome can significantly reduce the protracted social and psychological suffering that patients and their families may endure.

Clinical and molecular findings in a Moroccan family with Jervell and Lange-Nielsen syndrome: a case report.

BACKGROUND: Jervell and Lange-Nielsen syndrome (Online Mendelian Inheritance in Man 220400) is a rare autosomal recessive cardioauditory ion channel disorder that affects 1/200,000 to 1/1,000,000 children. It is characterized by congenital profound bilateral sensorineural hearing loss, a long QT interval, ventricular tachyarrhythmias, and episodes of torsade de pointes on an electrocardiogram. Cardiac symptoms arise mostly in early childhood and consist of syncopal episodes during periods of stress, exercise, or fright and are associated with a high risk of sudden cardiac death. Jervell and Lange-Nielsen syndrome is caused by homozygous or compound heterozygous mutations in KCNQ1 on 11p15.5 or KCNE1 on 1q22.1-q22.2. CASE PRESENTATION: We report the case of a 10-year-old Moroccan boy with congenital hearing loss and severely prolonged QT interval who presented with multiple episodes of syncope. His parents are first-degree cousins. We performed Sanger sequencing and identified a homozygous variant in KCNQ1 (c.1343dupC, p.Glu449Argfs*14). CONCLUSIONS: The identification of the genetic substrate in this patient confirmed the clinical diagnosis of Jervell and Lange-Nielsen syndrome and allowed us to provide him with appropriate management and genetic counseling to his family. In addition, this finding contributes to our understanding of genetic disease in the Moroccan population.

Clinical and molecular findings in three Moroccan families with distal renal tubular acidosis and deafness: Report of a novel mutation of ATP6V1B1 gene.

BACKGROUND: Primary distal renal tubular acidosis (dRTA) is a rare genetic condition characterized by an impaired acid excretion by the intercalated cells in the renal collecting duct. Recessive forms of this disease are caused by mutations in tow major genes: ATP6V1B1 and ATP6V0A4. Causal mutations in ATP6V1B1 gene are classically associated with early sensorineural hearing loss, however cases of tubular acidosis with early deafness have also been described in patients with mutations in the ATP6V0A4 gene. METHODS: The phenotype and genotype of three Moroccan consanguineous families with dRTA and deafness were assessed. Molecular analysis was performed by PCR amplification and direct sequencing of exon 12 of ATP6V1B1 gene. RESULTS: A novel c.1169dupC frameshift mutation of ATP6V1B1 gene was identified in one family and the c.1155dupC North African mutation in the tow other families. DISCUSSION AND CONCLUSION: In this report, we propose first line genetic testing based on screening of these two mutations both located in exon 12 of ATP6V1B1 gene in Moroccan patients with recessive form of dRTA associated to precocious hearing loss. Molecular diagnosis of dRTA leads to appropriate treatment and prevention of renal failure in affected individuals and to provide genetic counseling for families at risk.

Clinical and molecular report of novel GALC mutations in Moroccan patient with Krabbe disease: case report.

BACKGROUND: Krabbe disease (KD) or globoid cell leukodystrophy is an autosomal recessive lysosomal disorder, which affects metabolic and neurologic systems. This pathology has different forms. Infantile onset is about 85% to 90% of individuals with Krabbe disease. Disorder's onset is characterized, in early childhood, by hyperirritability, psychomotor deterioration associated to episodes of fever. To date, all reported cases have been attributed to mutations in galactosylceramidase gene (GALC gene) that encodes an enzyme which degrades galactosyl-sphingolipids (galactosylceramide, psychosine), essential in myelin production. A child compounded with two new mutations in the GALC gene was detected. CASE PRESENTATION: An eleven month old male child of Moroccan origin presented to our genetic consultation with severe symptoms that included hypotonia, fever, vision loss and feeding difficulties. He was suffering from the 4th month of life. Krabbe disease was suspected. Galactocerebrosidase deficiency was confirmed by biochemical analysis. DNA sequencing revealed a novel heterozygous compound mutation in GALC gene. The child was compounded with two mutations c.860G > A; p.Cys287Tyr and c.1622G > A; p.Trp541*. CONCLUSION: These new mutations could affect GALC structure and therefore its function. The identification of these mutations and their associated phenotypes are important to predict the prognosis and to confer to families an adequate genetic counseling.

Report of the First Clinical Case of a Moroccan Kabuki Patient with a Novel MLL2 Mutation.

Kabuki syndrome (also known as Niikawa-Kuroki syndrome) is a rare autosomal disorder, characterized by an unusual face, short stature, skeletal, visceral and dermatoglyphic abnormalities, cardiac anomalies, mental retardation, and immunological defects. Point mutations and large intragenic deletions and duplications of the mixed lineage leukemia 2 (MLL2) and exons deletions of lysine demethylase 6A (-KDM6A) genes have been identified as its underlying causes. We report on the first description of a Moroccan Kabuki syndrome patient with typical facial features, developmental delay, finger pads, and other anomalies carrying a novel splice site mutation in the MLL2 gene that produces a truncated and likely pathogenetic form of MLL2 protein.

Non-association of Crohn's disease with NOD2 gene variants in Moroccan patients.

UNLABELLED: Crohn's disease is a chronic inflammatory bowel disease, with multifactorial traits, that can involve any part of the gastrointestinal tract. In recent years, a dozen genome-wide association scan and meta-analysis were published bringing the number of susceptibility alleles to more than 30 variations. However, the major susceptibility gene for Crohn's disease is NOD2, located on proximal 16q, which is involved in the innate immune response. Three main variants of this gene: two single nucleotide polymorphisms p.Arg702Trp and p.Gly908Arg substitutions and frameshift polymorphism p.Leu1007fsinsC are involved in susceptibility to Crohn's disease. There is no data about the frequency of these allelic variants in Moroccan patients with Crohn's disease. The aim of our study is to genotype the NOD2 gene to assess the involvement of these three variants in susceptibility to Crohn's disease for Moroccans. METHODS: We carried out genotyping for the three variants p.Arg702Trp, p.Gly908Arg and p.Leu1007fsinsC of NOD2 gene using PCR-sequencing among 101 Moroccan patients with Crohn's disease and 107 healthy controls. RESULTS: The three main variants of NOD2 gene were present in Moroccan patients with no significant difference compared to controls. CONCLUSION: This preliminary study shows no evidence association of NOD2 gene with Crohn's disease in the Moroccan population.

[Spinal muscular atrophy: frequent cause of congenital hypotonia in Morocco]. / L'amyotrophie spinale infantile : cause fréquente des hypotonies congénitales au Maroc.

INTRODUCTION: Congenital hypotonia is a non specific symptom frequently seen in newborns and infants, and whose etiological diagnosis is often difficult due to the lack of specialized and affordable explorations. Childhood-onset proximal spinal muscular atrophy (SMA) is an autosomal recessive disorder caused by degeneration of the anterior horn cells of the spinal cord, leading to progressive paralysis with muscular atrophy. In more than 95% of the cases, it results from deletion of exon 7 of the SMN gene localized on 5q13, easily identified by molecular biology. OBJECTIVE: To determine the prevalence of the deletion of exon 7 of the SMN gene in congenital hypotonia with an unknown cause in Morocco. PATIENTS AND METHODS: We investigated the deletion of exon 7 of the SMN gene in 87 newborns and infants with congenital hypotonia. The cause of congenital hypotonia could not be determined in 60 of them, while 27 had electrophysiological evidence for an involvement of the anterior horn cells. RESULTS: The homozygous deletion of the SMN gene was detected in 23 of the newborns with unknown cause for hypotonia (38%) and in 21 of the infants whose electromyogram suggested infantile spinal amyotrophy (78%). CONCLUSION: This study underlines the advantages of a systematic search for the deletion of exon 7 of the SMN gene in every infant suffering from congenital hypotonia due to an unknown cause, particularly when the child's vital prognosis is at stake. This genetic test, easily implemented, should be systematically proposed after an attentive clinical evaluation in countries where the etiological diagnosis of congenital hypotonia is not systematic.

[The mutation 35delG of the gene of the connexin 26 is a frequent cause of autosomal-recessive non-syndromic hearing loss in Morocco]. / La mutation 35delG du gène de la connexine 26, une cause fréquente des surdités non syndromiques autosomiques récessives au Maroc.

UNLABELLED: Mutations of the connexin 26 gene, GJB2, are the most common cause of non syndromic autosomal-recessive hearing loss. One of the GJB2 mutations, the 35delG, is recurrent in European and Mediterranean populations with allelic frequency of at least 70% in patients with hearing loss caused by GJB2 impairment. OBJECTIVES: To determine the prevalence of the 35delG mutation in non-syndromic autosomal-recessive deafness in Morocco. PATIENTS AND METHODS: We looked for the 35delG mutation among 25 non-related Moroccan children suffering from an autosomal recessive hearing loss. A screening for GJB2 mutations, and then a search for GJB6 deletions were carried out among patients who do not bear the 35delG. RESULTS: Twelve patients were homozygous for the 35delG mutation. This mutation was responsible for almost half of the hearing loss among our patients (48%). There was no other GJB2 or GJB6 mutation among 13 patients. CONCLUSION: This study underlines the advantages of a systematic search for this mutation among deaf children when environmental causes are considered irrelevant. The identification of this genetic anomaly signs the etiologic diagnosis of deafness, which allows a relevant genetic advice, and a better treatment of patients.