Maha M. Eid

A homozygous mutation in RNU4ATAC as a cause of microcephalic osteodysplastic primordial dwarfism type I (MOPD I) with associated pigmentary disorder

The designation microcephalic osteodysplastic primordial dwarfism (MOPD) refers to a group of autosomal recessive disorders, comprising microcephaly, growth retardation, and a skeletal dysplasia. The different types of MOPD have been delineated on the basis of clinical, radiological, and genetic criteria. We describe two brothers, born to healthy, consanguineous parents, with intrauterine and postnatal growth retardation, microcephaly with abnormal gyral pattern and partial agenesis of corpus callosum, and skeletal anomalies reminiscent of those described in MOPD type I. This was confirmed by the identification of the homozygous g.55G > A mutation of RNU4ATAC encoding U4atac snRNA. The sibs had yellowish‐gray hair, fair skin, and deficient retinal pigmentation. Skin biopsy showed abnormal melanin function but OCA genes were normal. The older sib had an intracranial hemorrhage at 1 week after birth, the younger developed chilblains‐like lesions at the age 2½ years old but analysis of the SAMHD1 and TREX1 genes did not show any mutations. To the best of our knowledge, vasculopathy and pigmentary disorders have not been reported in MOPD I.

Muenke syndrome with pigmentary disorder and probable hemimegalencephaly: An expansion of the phenotype

We describe a 2‐year‐old boy born to healthy, consanguineous parents. He had craniofacial asymmetry with left frontal bossing, midface hypoplasia, proptosis, and low‐set ears. In addition, he had curly, light hair, and oval hypomelanotic patches in the abdomen, lower limbs and back and one hyperpigmented patch in the groin without acanthosis nigricans. Cranial three‐dimensional CT scan showed right‐coronal, sagittal, and lambdoid suture synostoses. His cranial MRI at 2‐months of age showed left hemimegalencephaly, hypoplasia of corpus callosum, and an abnormal configuration of hippocampus. In spite of these cranial findings, he had mild developmental delay and his neurological examination showed symmetric strength, tone and reflexes. Apart from febrile seizures, there was no history of epilepsy. The proband developed asymmetric hydrocephalus at the age of 18 months that required third ventriculostomy. Post‐operative cranial MRI showed Chiari I‐ like malformation and asymmetry of cerebral hemispheres but less dysplastic cerebral cortex. Mutation analysis of FGFR3 showed a c.749C > G, p.Pro250Arg substitution. To the best of our knowledge, these manifestations have not been reported in patients with Muenke syndrome.

Ectodermal abnormalities in patients with Kabuki syndrome.

Abstract:  Kabuki syndrome (KS) is extensively described in the literature and characterized by a typical facial gestalt in combination with postnatal short stature, hypotonia, joint laxity, developmental delay, persistent fetal fingertip pads, and an ever‐growing group of congenital abnormalities. In this study, we focus on some ectodermal manifestations that we have observed. We studied seven patients who fulfilled the clinical criteria for KS and undertook a detailed clinical, dental, cytogenetic, and immunoglobulin assessments. In addition, microscopic hair examinations were performed on all patients and compared with matched control patients. All patients had receding of the anterior hair line, but five had evident sparse frontal scalp hair. They all showed peculiar similar microscopic hair abnormalities in the form of twisting of the hair shafts, irregularity of the diameter of the hair, and trichorrhexis nodosa. In addition, hypoplastic nails, café‐au‐lait patches, and missing upper lateral incisors were observed in 57.1%, 28.6%, and 14.3% of the patients, respectively. Variable orodental anomalies were seen in all the patients with an everted lower lip found in four patients (57.1%). This report provides further evidence that some cases of KS have ectodermal involvement.

De Novo Mutation in ABCC9 Causes Hypertrichosis Acromegaloid Facial Features Disorder

A 13‐year‐old Egyptian girl with generalized hypertrichosis, gingival hyperplasia, coarse facial appearance, no cardiovascular or skeletal anomalies, keloid formation, and multiple labial frenula was referred to our clinic for counseling. Molecular analysis of the ABCC9 gene showed a de novo missense mutation located in exon 27, which has been described previously with Cantu syndrome. An overlap between Cantu syndrome, acromegaloid facial syndrome, and hypertrichosis acromegaloid facial features disorder is apparent at the phenotypic and molecular levels. The patient reported here gives further evidence that these syndromes are an expression of the ABCC9‐related disorders, ranging from hypertrichosis and acromegaloid facies to the severe end of Cantu syndrome.

Expanding the mutation and clinical spectrum of Roberts syndrome

Roberts syndrome and SC phocomelia syndrome are rare autosomal recessive genetic disorders representing the extremes of the spectrum of severity of the same condition, caused by mutations in ESCO2 gene. We report three new patients with Roberts syndrome from three unrelated consanguineous Egyptian families. All patients presented with growth retardation, mesomelic shortening of the limbs more in the upper than in the lower limbs and microcephaly. Patients were subjected to clinical, cytogenetic and radiologic examinations. Cytogenetic analysis showed the characteristic premature separation of centromeres and puffing of heterochromatic regions. Further, sequencing of the ESCO2 gene identified a novel mutation c.244_245dupCT (p.T83Pfs*20) in one family besides two previously reported mutations c.760_761insA (p.T254Nfs*27) and c.764_765delTT (p.F255Cfs*25). All mutations were in homozygous state, in exon 3. The severity of the mesomelic shortening of the limbs and craniofacial anomalies showed variability among patients. Interestingly, patient 1 had abnormal skin hypopigmentation. Serial fetal ultrasound examinations and measurements of long bones diagnosed two affected fetuses in two of the studied families. A literature review and case comparison was performed. In conclusion, we report a novel ESCO2 mutation and expand the clinical spectrum of Roberts syndrome.

Clinical features of SMARCA2 duplication overlap with Coffin–Siris syndrome

Coffin–Siris syndrome is a rare congenital malformation and intellectual disability syndrome. Mutations in at least seven genes have been identified. Here, we performed copy number analysis in 37 patients with features of CSS in whom no causative mutations were identified by exome sequencing. We identified a patient with a 9p24.3–p22.2 duplication and another patient with the chromosome der(6)t(6;9)(p25;p21)mat. Both patients share a duplicated 15.8‐Mb region containing 46 protein coding genes, including SMARCA2. Dominant negative effects of SMARCA2 mutations may contribute to Nicolaides–Baraitser syndrome. We conclude that their features better resemble Coffin–Siris syndrome, rather than Nicolaides–Baraitser syndrome and that these features likely arise from SMARCA2 over‐dosage. Pure 9p duplications (not caused by unbalanced translocations) are rare. Copy number analysis in patients with features that overlap with Coffin–Siris syndrome is recommended to further determine their genetic aspects.

Identification of a novel homozygous ALX4 mutation in two unrelated patients with frontonasal dysplasia type-2

We report two unrelated boys with frontonasal dysplasias type‐2 (FND‐2) who shared an identical novel homozygous ALX4 mutation c.291delG (p.Q98Sfs*83). Both patients presented with a large skull defect but one had bilateral parietal meningocele‐like cysts that lie along with the bony defect and increased in size with age. Scalp alopecia, hypertelorism, and clefted alae nasi were also detected in both of them. Furthermore, impalpable gonads were noted, being unilateral in one and bilateral in the other. Neuroimaging showed small dysplastic occipital lobes with dysgyria and midline subarachnoid cyst. Additional dysplastic corpus callosum and small cerebellar vermis were observed in one patient. Parietal foramina were noted in the parents of one patient. Our findings highlight the dosage effect of ALX4 and underscore the challenges of prenatal genetic counseling. Further, the indirect role of ALX4 in the development of the occipital lobe and posterior fossa is discussed.

De Novo 17q24.2-q24.3 microdeletion presenting with generalized hypertrichosis terminalis, gingival fibromatous hyperplasia, and distinctive facial features.

Generalized hypertrichosis is a feature of several genetic disorders, and the nosology of these entities is still provisional. Recent studies have implicated chromosome 17q24.2–q24.3 microdeletion and the reciprocal microduplication in a very rare form of congenital generalized hypertrichosis terminalis (CGHT) with or without gingival hyperplasia. Here, we report on a 5‐year‐old Egyptian girl born to consanguineous parents. The girl presented with CGHT and gingival hyperplasia for whom we performed detailed clinical, pathological, and molecular studies. The girl had coarse facies characterized by bilateral epicanthic folds, thick and abundant eyelashes, a broad nose, full cheeks, and lips that constituted the distinctive facial features for this syndrome. Biopsy of the gingiva showed epithelial marked acanthosis and hyperkeratosis with hyperplastic thick collagen bundles and dense fibrosis in the underlying tissues. Array analysis indicated a 17q24.2–q24.3 chromosomal microdeletion. We validated this microdeletion by real‐time quantitative PCR and confirmed a perfect co‐segregation of the disease phenotype within the family. In summary, this study indicates that 17q24.2–q24.3 microdeletion caused CGHT with gingival hyperplasia and distinctive facies, which should be differentiated from the autosomal recessive type that lacks the distinctive facies.

Epilepsy and autistic manifestations in an Egyptian child with ring 14

BackgroundRing chromosomes are rare chromosomal disorders. Patients carrying a ring chromosome have different phenotypes depending on the degree of structural rearrangement. Subject and methodsWe observed an 8-year-old patient attending the clinic for autistic disorders. By cytogenetic analysis, we identified a de-novo ring chromosome 14. ResultsOur patient had a rare condition of developmental delay, behavioral hyperactivity, anxiety, and autistic traits in addition to severe drug-resistant epilepsy, indicating that these features might be part of a syndromic condition. In comparison with other ring 14 patients, the neurological features seen in this patient were extremely severe, in addition to having low-functioning autism. ConclusionWe believe that chromosome 14qter can have a role in the etiology of autism; therefore, cytogenetic analysis should be considered in autistic children.

Nonmosaic partial duplication 12p: clinical and cytogenetic findings and review of the literature 12p duplication

We report on a male patient with de-novo pure partial trisomy 12p syndrome besides Robertsonian translocation. The patient had characteristic dysmorphic features such as low-set ear, a high forehead, flat occiput, long philtrum, and nystagmus. He also suffers from intellectual disabilities, seizures, hypotonia, and developmental delay. He has normal anthropometric measurements, and normal height, weight, and skull circumference. A cytogenetic study using the G-banding technique showed 45,XY, add (12)(p12.3), t(13;14)(q10q10). Karyotyping of the parents was performed, which indicated a normal result for the father and 45, XX, t(13;14)(q10;q10) for the mother. The fluorescence in-situ hybridization technique was performed for the patient using whole-chromosome paint 12 and subs telomere 12p. It showed that the add segment on chromosome 12p was derived from chromosome 12 and that 12p subtelomere was inverted and duplicated. Thus, the karyotype is 45, XY, dup (12)(p ter-p12.3), t(13;14)(q10q10). Comparison of the clinical and the cytogenetic findings of our patient with previously reported dup (12p) in the literature was carried out for better characterization and understanding of the phenotypic and cytogenetic relationship.