A novel PAX1 null homozygous mutation in autosomal recessive otofaciocervical syndrome associated with severe combined immunodeficiency.

Otofaciocervical syndrome (OFCS) is a rare disorder characterized by facial anomalies, cup-shaped low-set ears, preauricular fistulas, hearing loss, branchial defects, skeletal anomalies, and mild intellectual disability. Autosomal dominant cases are caused by deletions or point mutations of EYA1. A single family with an autosomal recessive form of OFCS and a homozygous missense mutation in PAX1 gene has been described. We report whole exome sequencing of 4 members of a consanguineous family in which 2 children, showing features of OFCS, expired from severe combined immunodeficiency (SCID). To date, the co-occurrence of OFCS and SCID has never been reported. We found a nonsense homozygous mutation in PAX1 gene in the 2 affected children. In mice, Pax1 is required for the formation of specific skeletal structures as well as for the development of a fully functional thymus. The mouse model strongly supports the hypothesis that PAX1 depletion in our patients caused thymus aplasia responsible for SCID. This report provides evidence that bi-allelic null PAX1 mutations may lead to a multi-system autosomal recessive disorders, where SCID might represent the main feature.

9q31.1q31.3 deletion in two patients with similar clinical features: a newly recognized microdeletion syndrome?

Interstitial deletions of the long arm of chromosome 9 are rare and most patients have been detected by conventional cytogenetic techniques. Disparities in size and localization are large and no consistent region of overlap has been delineated. We report two similar de novo deletions of 6.3 Mb involving the 9q31.1q31.3 region, identified in two monozygotic twins and one unrelated patient through array-CGH analysis. By cloning the deletion breakpoints, we could show that these deletions are not mediated by segmental duplications. The patients displayed a distinct clinical phenotype characterized by mild intellectual disability, short stature with high body mass index, thick hair, arched eyebrows, flat profile with broad chin and mild prognathism, broad, and slightly overhanging tip of the nose, short neck with cervical gibbus. The twin patients developed a metabolic syndrome (type 2 diabetes, hypercholesterolemia, vascular hypertension) during the third decade of life. Although long-term follow-up and collection of additional patients will be needed to obtain a better definition of the phenotype, our findings characterize a previously undescribed syndromic disorder associated with haploinsufficiency of the chromosome 9q31.1q31.3 region.

Xq28 duplications including MECP2 in five females: Expanding the phenotype to severe mental retardation.

Duplications leading to functional disomy of chromosome Xq28, including MECP2 as the critical dosage-sensitive gene, are associated with a distinct clinical phenotype in males, characterized by severe mental retardation, infantile hypotonia, progressive neurologic impairment, recurrent infections, bladder dysfunction, and absent speech. Female patients with Xq duplications including MECP2 are rare. Only recently submicroscopic duplications of this region on Xq28 have been recognized in four females, and a triplication in a fifth, all in combination with random X-chromosome inactivation (XCI). Based on this small series, it was concluded that in females with MECP2 duplication and random XCI, the typical symptoms of affected boys are not present. We present clinical and molecular data on a series of five females with an Xq28 duplication including the MECP2 gene, both isolated and as the result of a translocation, and compare them with the previously reported cases of small duplications in females. The collected data indicate that the associated phenotype in females is distinct from males with similar duplications, but the clinical effects may be as severe as seen in males.

Early-onset seizure variant of Rett syndrome: definition of the clinical diagnostic criteria.

BACKGROUND: Rett syndrome is a severe neurodevelopmental disorder affecting almost exclusively females. Among Rett clinical variants, the early-onset seizure variant describes girls with early onset epilepsy and it is caused by mutations in CDKL5. METHODS: Four previously reported girls and five new cases with CDKL5 mutation, ranging from 14 months to 13 years, were evaluated by two clinical geneticists, classified using a severity score system based on the evaluation of 22 different clinical signs and compared with 128 classic Rett and 25 Zappella variant MECP2-mutated patients, evaluated by the same clinical geneticists. Clinical features were compared with previously described CDKL5 mutated patients. Both the statistical and the descriptive approach have been used to delineate clinical diagnostic criteria. RESULTS: All girls present epilepsy with onset varying from 10 days to 3 months. Patients may present different type of seizures both at onset and during the whole course of the disease; multiple seizure types may also occur in the same individual. After treatment with antiepileptic drugs patients may experience a short seizure-free period but epilepsy progressively relapses. Typical stereotypic hand movements severely affecting the ability to grasp are present. Psychomotor development is severely impaired. In the majority of cases head circumference is within the normal range both at birth and at the time of clinical examination. CONCLUSION: For the practical clinical approach we propose to use six necessary and eight supportive diagnostic criteria. Epilepsy with onset between the first week and 5 months of life, hand stereotypies, as well as severe hypotonia, are included among the necessary criteria.

A 9.3 Mb microdeletion of 3q27.3q29 associated with psychomotor and growth delay, tricuspid valve dysplasia and bifid thumb.

We describe a de novo 3q27.3q29 deletion in a 2.5-year-old female patient with developmental and growth delay, dysmorphic facial features, mild tricuspid valve dysplasia, bifid thumb, clinodactyly of the 2nd toe bilaterally and scoliosis. The deletion overlaps for about 1Mb with the 1.6Mb region commonly deleted in patients with 3q29 microdeletion syndrome. The phenotype of the two syndromes is not completely overlapping, though the most important clinical features, such as mental retardation and microcephaly, occur in both. This suggests that the deletion in our patient causes a distinct clinical phenotype, not described previously. In the deleted region there are 47 annotated genes. Among them, seven are of particular interest for correlation with clinical features of the patient. Two genes, OPA1 and CCDC50, responsible for autosomal dominant optic atrophy and deafness, respectively, may be important for the correct follow-up of the patient.