Circumferential skin creases Kunze type (CSC-KT) is a specific congenital entity with an unknown genetic cause. The disease phenotype comprises characteristic circumferential skin creases accompanied by intellectual disability, a cleft palate, short stature, and dysmorphic features. Here, we report that mutations in either MAPRE2 or TUBB underlie the genetic origin of this syndrome. MAPRE2 encodes a member of the microtubule end-binding family of proteins that bind to the guanosine triphosphate cap at growing microtubule plus ends, and TUBB encodes a β-tubulin isotype that is expressed abundantly in the developing brain. Functional analyses of the TUBB mutants show multiple defects in the chaperone-dependent tubulin heterodimer folding and assembly pathway that leads to a compromised yield of native heterodimers. The TUBB mutations also have an impact on microtubule dynamics. For MAPRE2, we show that the mutations result in enhanced MAPRE2 binding to microtubules, implying an increased dwell time at microtubule plus ends. Further, in vivo analysis of MAPRE2 mutations in a zebrafish model of craniofacial development shows that the variants most likely perturb the patterning of branchial arches, either through excessive activity (under a recessive paradigm) or through haploinsufficiency (dominant de novo paradigm). Taken together, our data add CSC-KT to the growing list of tubulinopathies and highlight how multiple inheritance paradigms can affect dosage-sensitive biological systems so as to result in the same clinical defect.

In the areas with a high prevalence of tuberculosis and confirmatory investigations are inadequately available, treatment may be initiated, based on strong clinical diagnosis and supportive investigations. In such situations, it is the response to therapy that indirectly proves the diagnosis.

BackgroundCystic fibrosis is rare in Tunisia. Its diagnosis requires experienced specialists. Its prognosis is poor in developing countries.ObjectivesTo study the epidemiologic, clinical, genetic features and the therapeutic challenges of cystic fibrosis in Tunisian children.MethodsCovering a period of 21 years, this retrospective study included all patients with a definite diagnosis of cystic fibrosis from the Pediatrics Department B of The Children's Hospital of Tunis.ResultsData from 32 children (14 boys and 18 girls) were collected. The diagnosis was made during the first year of life in 28 cases. Meconium ileus was found in 5 cases, respiratory manifestations in 22 cases, chronic diarrhea in 19 cases, faltering growth in 17 cases and a pseudo Barter syndrome in 2 cases. The sweat chloride test was positive in all cases. The most frequent mutation was F508del (56% of cases). Respiratory complications marked the outcome. Among our 32 patients, 15 patients (50%) died at an average age of 5 years and 3 months, mainly due to respiratory failure. The mean age of the surviving patients was 5 years.ConclusionCystic fibrosis prognosis is poor in our series compared to developed countries due to the longer diagnostic delay and the limited therapeutic options.

We describe a combination of multiple congenital anomalies, a severe psychomotor retardation and seizures in a 9-year-old Tunisian boy with circumferential ringed skin creases. He had symmetrical circumferential skin creases on arms, legs, and penis. Craniofacial anomalies included: an elongated face, tight forehead, hypertelorism, bilateral epicanthic folds, upslanting palpebral fissures, microphthalmia, convergent strabismus, wide nasal bridge, aberrant teeth, dental caries, and low-set posteriorly rotated ears with overfolded thick helices. He had also ureterocele, hypospadias, and others anomalies. The magnetic resonance imaging of the brain showed hypoplastic vermis, hypoplastic corpus callosum, and dilatation of ventricles. Chromosomal analysis revealed a normal male karyotype with 46,XY. Skin biopsy was normal. To the best of our knowledge, this combination of anomalies has not been reported and this case may be a unique syndrome.

Wolman disease is an ultrarare lysosomal storage disease caused by a mutation in the LIPA gene. The clinical features of Wolman disease include early onset of vomiting, diarrhea, failure to thrive, hepatosplenomegaly, and bilateral adrenal calcification. We report the case of a 3-month-old infant who presented clinical features of hemophagocytic lymphohistiocytosis. Genetic sequence analysis of the LIPA gene revealed homozygous mutation c.153 C>A (p.Tyr51*). The parents were heterozygous for this mutation. Prenatal diagnosis has been carried out in the next pregnancy. To our knowledge, this mutation has never been reported before, and this is an unusual case of secondary hemophagocytic lymphohistiocytosis complicating Wolman disease.