Ibrahim A. Alorainy

Homozygous HOXA1 mutations disrupt human brainstem, inner ear, cardiovascular and cognitive development

We identified homozygous truncating mutations in HOXA1 in three genetically isolated human populations. The resulting phenotype includes horizontal gaze abnormalities, deafness, facial weakness, hypoventilation, vascular malformations of the internal carotid arteries and cardiac outflow tract, mental retardation and autism spectrum disorder. This is the first report to our knowledge of viable homozygous truncating mutations in any human HOX gene and of a mendelian disorder resulting from mutations in a human HOX gene critical for development of the central nervous system.

The Clinical Spectrum of Homozygous HOXA1 Mutations

We describe nine previously unreported individuals from six families who have homozygous mutations of HOXA1 and either the Bosley–Salih–Alorainy syndrome (BSAS) or the Athabascan brainstem dysgenesis syndrome (ABDS). Congenital heart disease was present in four BSAS patients, two of whom had neither deafness nor horizontal gaze restriction, thus raising the possibility that cardiovascular malformations might be a clinically isolated, or relatively isolated, manifestation of homozygous HOXA1 mutations. Two ABDS probands had relatively mild mental retardation. These individuals blur the clinical distinctions between the BSAS and ABDS HOXA1 variants and broaden the phenotype and genotype of the homozygous HOXA1 mutation clinical spectrum.

Clinical characterization of the HOXA1 syndrome BSAS variant.

Background: The Bosley-Salih-Alorainy syndrome (BSAS) variant of the congenital human HOXA1 syndrome results from autosomal recessive truncating HOXA1 mutations. We describe the currently recognized spectrum of ocular motility, inner ear malformations, cerebrovascular anomalies, and cognitive function. Methods: We examined nine affected individuals from five consanguineous Saudi Arabian families, all of whom harbored the same I75-I76insG homozygous mutation in the HOXA1 gene. Patients underwent complete neurologic, neuro-ophthalmologic, orthoptic, and neuropsychological examinations. Six individuals had CT, and six had MRI of the head. Results: All nine individuals had bilateral Duane retraction syndrome (DRS) type 3, but extent of abduction and adduction varied between eyes and individuals. Eight patients were deaf with the common cavity deformity of the inner ear, while one patient had normal hearing and skull base development. Six had delayed motor milestones, and two had cognitive and behavioral abnormalities meeting Diagnostic and Statistical Manual of Mental Disorders–IV criteria for autism spectrum disorder. MRI of the orbits, extraocular muscles, brainstem, and supratentorial brain appeared normal. All six appropriately studied patients had cerebrovascular malformations ranging from unilateral internal carotid artery hypoplasia to bilateral agenesis. Conclusions: This report extends the Bosley-Salih-Alorainy syndrome phenotype and documents the clinical variability resulting from identical HOXA1 mutations within an isolated ethnic population. Similarities between this syndrome and thalidomide embryopathy suggest that the teratogenic effects of early thalidomide exposure in humans may be due to interaction with the HOX cascade.

Ossification of the ligament flavum

A total of 82 patients who underwent spinal computed tomographic scan, in an 8-month period at the King Khalid University Hospital, Riyadh, Saudi Arabia, were analyzed for age, sex, the presence/absence, site, and type of ossification of the ligamentum flavum (OLF) as well as associated diseases. The OLF was radiographically present (bilaterally or unilaterally) as linear (74.5%) or nodular types (25.5%). The linear type was especially seen at the inner aspects of the ligamentum flavum. OLF was present in 35.4% of patients, and was seen at single and multiple levels in 51% and 41% of them, respectively. OLF was identified in a total of 47 levels in the study group and was associated with other disease in the spine in 38 (81%) of these levels. In none of the patients was OLF the cause of myelopathy. The incidence of OLF and its pathogenesis and significance are discussed. This paper is the first report of OLF from the Middle East. OLF in this part of the world is usually asymptomatic.

Brain stem and cerebellar findings in joubert syndrome

Joubert syndrome is often missed clinically and radiologically if not enough attention is paid to its subtle and variable clinical presentation and the imaging findings in the posterior fossa. The purpose of this paper is to illustrate the brain stem and cerebellar imaging findings in Joubert syndrome. Awareness of the clinical and neuroimaging findings in Joubert syndrome and maintenance of a high index of suspicion are essential to correctly diagnose this rare congenital malformation.

Pai syndrome: a report of a case and review of the literature

Pai syndrome is a rare congenital disorder first described in 1987. The main clinical features of the syndrome include median cleft of the upper lip, intra-cranial lipoma, and cutaneous polyps. Only four cases have been described previously. This is the fifth who is a twin of Arabian descent to be reported. Full description of the clinico-pathological features and a review of the relevant medical literature is presented. To the best of our knowledge, this is the first case of Pai syndrome in a twin in the English literature.

Molecular and neurological characterizations of three Saudi families with lipoid proteinosis

BackgroundLipoid proteinosis is a rare autosomal recessive disease characterized by cutaneous and mucosal lesions and hoarseness appearing in early childhood. It is caused by homozygous or compound heterozygous mutations in the ECM1 gene. The disease is largely uncharacterized in Arab population and the mutation(s) spectrum in the Arab population is largely unknown. We report the neurologic and neuroradiologic characteristics and ECM1 gene mutations of seven individuals with lipoid proteinosis (LP) from three unrelated consanguineous families.MethodsClinical, neurologic, and neuro-ophthalmologic examinations; skin histopathology; brain CT and MRI; and sequencing of the fullECM1 gene.ResultsAll seven affected individuals had skin scarring and hoarseness from early childhood. The two children in Family 1 had worse skin involvement and worse hoarseness than affected children of Families 2 and 3. Both children in Family 1 were modestly mentally retarded, and one had typical calcifications of the amygdalae on CT scan. Affected individuals in Families 2 and 3 had no grossneurologic, neurodevelopmental, or neuroimaging abnormalities. Skin histopathology was compatible with LP in all three families. Sequencing the full coding region of ECM1 gene revealed two novel mutationsin Family 1 (c.1300-1301delAA) and Family 2 (p.Cys269Tyr) and in Family 3 a previously described 1163 bp deletion starting 34 bp into intron 8.ConclusionsThese individuals illustrate the neurologic spectrum of LP, including variable mental retardation, personality changes, and mesial temporal calcificationand imply that significant neurologic involvement may be somewhat less common than previously thought. The cause of neurologic abnormalities was not clear from either neuroimaging or from what is known about ECM1 function. The severity of dermatologic abnormalities and hoarseness generally correlated with neurologic abnormalities, with Family 1 being somewhat more affected in all spheres than the other two families. Nevertheless, phenotype-genotype correlation was not obvious, possibly because of difficulty quantifying the neurologic phenotype and because of genetic complexity.

Ophthalmologic abnormalities in a de novo terminal 6q deletion

Purpose: To correlate the clinical phenotype with the genotype of a boy with a terminal deletion of chromosome 6q and to compare these observations to previous reports of 6q deletions and review of the literature. Methods: Careful clinical evaluation, conventional cytogenetic analysis on GTG-banded chromosomes and 244K array CGH analysis. Results: This 14 year old Saudi boy had modest mental retardation, seizures, microcephaly, cortical dysplasia, a non-comitant esotropia, impersistent eccentric gaze, congenital nystagmus, thick corneas, and substantial myopia. He had a de novo 10.79 Mb deletion on chromosome 6 from 6q25.3 to 6qter. The deleted region extended from nucleotide 159929512 to 170723629 and encompassed 87 genes. Eleven genes remained within the proband’s deleted region after excluding genes located in deleted areas reported in phenotypically normal individuals. Among those 11 genes, only the TBP (TATA box binding protein) gene has been associated with any symptom or sign observed in our patient. Conclusions: This boy had clinical features similar to patients reported with the 6q terminal deletion syndrome. In addition, he had an unusual ocular motility pattern and thick corneas, features that may be more common than previously recognized. Deleted genes in this area of chromosome 6 may contribute to ophthalmic abnormalities in addition to mental retardation.

Xq26.3 microdeletion in a male with wildervanck syndrome

ABSTRACT Background: Wildervanck Syndrome (WS; cervico-oculo-acoustic syndrome) consists of Duane retraction syndrome (DRS), the Klippel-Feil anomaly, and congenital deafness. It is much more common in females than males and could be due to an X-linked mutation that is lethal to hemizygous males. We present the genetic evaluation of a male with WS and his family. Materials and Methods: Clinical evaluation and neuroimaging, sequencing of candidate genes, and array comparative genomic hybridization. Results: The patient had bilateral type 1 DRS, fusion of almost the entire cervical spine, and bilateral severe sensorineural hearing loss due to bilateral cochlear dysplasia; he also had congenital heart disease requiring surgery. His parents were unrelated, and he had eight unaffected siblings. The patient had no mutation found by Sanger sequencing of HOXA1, KIF21A, SALL4, and CHN1. He had a 3kB deletion in the X-chromosome at Xq26.3 that was not found in his mother, one unaffected sibling, or 56 healthy controls of matching ethnicity. This deletion encompassed only one gene, Fibroblast Growth Factor Homologous Factor 13 (FGF13), which encodes a 216-amino acid protein that acts intracellularly in neurons throughout brain development. Conclusions: Analysis of this patient’s phenotype and genotype open the possibility that X-chromosome deletions may be a cause of WS with larger deletions being lethal to males and that FGF13 mutations may be a cause of WS.

Partial chromosome 7 duplication with a phenotype mimicking the HOXA1 spectrum disorder.

Purpose: To evaluate possible monogenic and chromosomal anomalies in a patient with bilateral Duane retraction syndrome and hearing impairment resulting in a phenotype resembling the HOXA1 spectrum disorder. Methods: Sequencing HOXA1 and performing high resolution array comparative genomic hybridization (arrayCGH). Results: The proband had bilateral Duane retraction syndrome (DRS) with severe hearing loss bilaterally and an absent right vertebral artery, mimicking the major features of the Bosley-Salih-Alorainy variant of the HOXA1 spectrum. However, he also had developmental delay, mild mental retardation, and seizures. His parents were not related, but his father had milder sensorineural hearing loss bilaterally, and two paternal uncles and a paternal cousin had seizures. Neuroimaging revealed moderate maldevelopment of inner ear bony anatomy bilaterally. HOXA1 sequencing was normal, but arrayCGH revealed a small partial duplication of chromosome 7 encompassing only the PTPRN2 gene (protein tyrosine phosphatase, receptor type, N polypeptide 2) that was not present in his parents, an unaffected brother, or 53 normal ethnically-matched individuals. Conclusions: PTPRN2 is not yet linked to a genetic syndrome, although its expression has been identified in the adult human brain, in certain tumors, and in association with type 1 diabetes mellitus. The phenotype of this patient is strikingly similar to, but not identical to, that of the HOXA1 spectrum disorder. The findings in this patient raise the possibility that PTPRN2 may be active during early development of the human brainstem and that its overexpression may cause bilateral DRS with hearing loss as occurs in patients with homozygous HOXA1 mutations.