Azmy M. Al-Hadidy

Griscelli syndrome type 2: a rare and lethal disorder.

Griscelli syndrome is a rare autosomal recessive disorder. It is characterized by pigment dilution and variable immune deficiency leading to increased susceptibility to certain infections and a tendency to develop a life-threatening hemophagocytic syndrome known as the accelerated phase. Griscelli syndrome is now classified into 3 types based on the genetic and molecular features. Primary neurological presentation without the accelerated phase is rare in type 2. In this article, the authors report a boy who was presented with seizures and diffuse white matter involvement unaccompanied by the other features of the accelerated phase. Mutation analysis in family members revealed the presence of a missense mutation in Rab27a gene. In addition to the rare presentation, this is the first case of Griscelli syndrome to be reported from Jordan.

Hereditary Multiple Exostoses with Pseudoaneurysm

A 16-year-old male patient with hereditary multiple exostoses (HME) was found to have a pseudoaneurysm of the left popliteal artery caused by osteochondroma in the lower femur. The diagnosis was confirmed by ultrasound, magnetic resonance imaging and magnetic resonance angiography without the need to perform an angiogram. The osteochondroma was excised and the popliteal artery was repaired with a saphenous graft. Vascular complications are extremely rare in HME, pseudoaneurysm being the most common and mostly located in the popliteal artery. This complication should be considered in young HME patients with a mass at the knee region. The radiological spectrum of investigations allows the diagnosis of this complication with proper and less invasive management procedures for the patient.

Is autosomal recessive Silver–Russel syndrome a separate entity or is it part of the 3-M syndrome spectrum?†‡

Intrauterine growth retardation (IUGR) is a nonspecific finding that occurs in approximately 0.17% of all live‐births. However, IUGR can also be a significant feature of many recognized genetic syndromes including Silver–Russel syndrome (SRS), Three M syndrome (3‐M), Dubowitz syndrome, and Mulibrey nanism. Differentiation of 3‐M syndrome from autosomal recessive SRS has been difficult because of the phenotypic variability of the latter. Limb length asymmetry is seen in over half of those with autosomal recessive SRS, but not in individuals with 3‐M syndrome. Characteristic radiologic findings of 3‐M syndrome are not present in SRS. We used single nucleotide polymorphism (SNP) microarrays to investigate the cause of phenotypic features of SRS that shows autosomal recessive inheritance in three consanguineous families, two from United Arab Emirates (UAE), and one from Jordan. The mapped regions contained CUL7 and OBSL1, the genes that have recently been shown to cause 3‐M syndrome. Subsequently, direct DNA sequencing of CUL7 and OBSL1 genes revealed novel mutations in both genes including two mutations in OBSL1 [c.1119G>C (p.W373C) and c.681_682delinsTT (p.Q228X)], and a nonsense mutation in CUL7 [c.203G>A (p.W68X)]. In addition, a six nucleotide deletion in CUL7 [c.649_654delAGCCGC (p.217_218delSR)] was found in a consanguineous family from UAE that had the typical features of 3‐M. As a result of these findings, we question the identity of the autosomal recessive SRS and suggest that all apparently recessive SRS families should be tested for mutations in CUL7 and OBSL1.

Cenani-Lenz syndactyly with facial dysmorphism, hypothyroidism, and renal hypoplasia: a case report.

Clinical summary and investigations A female child with Cenani–Lenz syndactyly (CLS) is described. The proband showed bilateral malformations of the hands and feet. The patient also had a prominent forehead, deep-set eyes, low-set ears, retrognathia, higharched narrow palate, a short-beaked nose, and high nasal bridge, (Fig. 1). The hands showed a complex syndactyly and disorganization of the fingers, which could not be identified individually (Figs 2, 3). The feet showed partial disorganization of the toes and partial syndactyly (Fig. 4). The karyotype was 46, XX. The proband had normal developmental milestones and cognitive abilities. Laryngomalacia was diagnosed in infancy. Although there were no clinical criteria of hypothyroidism, thyroid functions testing at 8 months of age showed a higher than normal thyroid-stimulating hormone level of 6.2, and a repeat at 9 months of 7.89 mU/l (N = 0.47–5.01), T4 of 12.55 pmol/l (N = 9.1–23.6), and T3 of 4.36 pmol/l (N = 2.58–5.44). Taking her young age into consideration, no further investigations were carried out at the endocrine clinic; she was diagnosed as having primary hypothyroidism and started on thyroxin with regular follow-up. Abdominal ultrasonography showed that the right kidney was hypoplastic and ectopic. Radiography of pelvis showed bilateral coxa valga and dysgenesis of the hip joints. The right hand showed fusion of all metacarpal bones into one mass, with broad, fused, disorganized phalanges and reduction of digital rays. The phalanges of the dorsiflexed little finger were seen overlying the phalanges of the adjacent fused digit. The left hand showed three separate metacarpals with fusion and disorganization of the phalanges and reduction of the digital rays (Fig. 5). Fig. 1

Brachydactyly type B1: report of a family with de novo ROR2 mutation

To the Editor: Brachydactyly type B1 (BDB1, MIM 113000) is the most severe form of the inherited brachydactylies, with hypoplasia/aplasia of nails and distal phalanges and hypoplasia of middle phalanges of fingers II–V. The feet are similarly, but more mildly, affected (1, 2). A characteristic facial appearance of hypertelorism, down-slanting palpebral fissures, short philtrum and a prominent nose with a bulbous tip is sometimes seen (3–7). BDB1 is dominantly inherited, with a defect in the ROR2 gene located on chromosome 9q22 (4, 5, 8). New mutations in the ROR2 gene are rare, and only five families segregating a classic de novo BDB1 phenotype have been reported (1, 5, 8), among which two de novo ROR2 mutations were described (Table 1). Our family represents the sixth reported case with de novo BDB1 phenotype and the third de novo ROR2 mutation. The proband (case 1) is a 29-year-old Jordanian man with non-consanguineous parents. He is married to his matrilineal first cousin and has a healthy, similarly affected 3-year-old son (case 2). The hands in both case 1 and 2 showed marked shortening of fingers II–V with nails absent and normal thumbs. In case 2, fingers III– V showed bulbous finger tips (Fig. 1a,c). Feet in both cases showed mild shortening of toes II–V with hypoplastic nails and normal first toes (Fig. 1b,d). Case 1 showed the specific facial features of BDB1, with prominent nose, high nasal bridge, hypoplastic alae nasi, and high arched palate. Hand and feet radiographs in cases 1 and 2 are presented in Fig. 1. Radiographs of hands and feet of parents and three siblings of the proband have excluded aplasia/hypoplasia of fingers and toes. Screening of the mutation hotspots in the ROR2 gene was performed at the Molecular Genetics Laboratory, Churchill Hospital at Oxford by sequencing the coding regions and intron–exon boundaries of exons 8 and 9. These relate to the flanking regions of the tyrosine kinase domain of the protein. The proband was found to have a distal mutation, a 2265C.A substitution in exon 9 resulting in an exchange of Tyr for a termination codon at residue 755 (Y755X), which is predicted to cause premature termination of translation. The diagnosis of this family conforms with BDB1, where there is a pattern of symmetric hypoplasia/aplasia of the terminal phalanges of fingers II–V and to a lesser extent of the toes, with specific facial features (1–7). This pattern differs from that of Cooks syndrome (MIM 106995), a rare syndrome described in two families, with involvement of thumbs and great toes (9, 10). de Ravel et al. proposed that a subgroup of individuals with BDB1 and distinct facies might be identical to individuals with Cooks syndrome (6). Mutations in ROR2 can result in either of two distinct skeletal disorders depending on the location and nature of the mutation; homozygous loss-of-function mutations spread throughout the gene cause recessive Robinow syndrome (MIM 268310), whereas gain-of-function mutations, not haploinsufficiency, cause BDB1 (1, 8). Up to date, only eight mutations have been reported to cause the BDB1 phenotype (Table 1). A genotype–phenotype correlation between the distal and the proximal mutations in the ROR2 gene was detected, with distal gene mutations being less variable and more severe. The clinical picture seen in the proband is of the severe type and is consistent with the clinical features of previously reported patients with the distal (Y755X) mutation (1, 8). Up to date, new mutations have been arising only in the distal stretch of the gene, which may be related to a very specific gain-of-function effect that is critically dependent on position. Mutations may occur across the whole gene at the same rate but they cause recessive Robinow syndrome, are silent changes or could possibly be embryonic lethal. It is only a very small subset in a particular region that cause BDB1 and hence the rarity of the phenotype.

Myelopathy Associated with Age-Related Cervical Disc Herniation: A Retrospective Review of Magnetic Resonance Images

BACKGROUND Cervical intervertebral disc herniation can lead to myelopathy. Aging is an established variable related to spondylotic myelopathy. Studying this association will help in controlling the increase in spondylotic myelopathy with age. OBJECTIVES To study the association between cervical disc level, its direction, and the frequency of myelopathy with age, and to assess the epidemiology of age-related cervical disc herniation and myelopathy. DESIGN Retrospective review of magnetic resonance (MR) images. SETTING Tertiary referral hospital. PATIENTS AND METHODS We studied the MR images of adults patients (>18 years of age) referred to our department between 2001 and 2012 for suspected cervical spondylopathy. The direction and severity of herniation and the presence of myelopathy was determined for spinal levels C2 to C7. MAIN OUTCOME MEASURE(S) Relationship between age-related cervical disc herniation and myelopathy. RESULTS We studied 6584 patient MR images, which included 2402 males (39.1%) and 3737 females (60.9%). The frequency of myelopathy increased with age from 0.6% in patients <20 years of age, reaching 9.1% in patients >70 years of age. The most common level affected by myelopathy was C5–C6. In elderly patients (>60 years), the C3–C4 level became the predominant level affected by myelopathy. Likewise, the frequency of central disc herniation increased significantly (P<.001) with age at all cervical levels. Furthermore, upper cervical levels showed a higher frequency of central disc herniation than lower cervical levels in the elderly. CONCLUSION The increased frequency of central disc herniation with age suggest an important, and probably a cause-effect relationship, between herniation and myelopathy. LIMITATIONS We were unable to access clinical data or electrophysiological studies to correlate with MR image findings.

Sporadic Lateral Ventricular Hemangioblastoma presenting with Intraventricular and Subarachnoid Haemorrhage

Intraventricular hemangioblastoma (HB) is very rare; few cases of intraventricular HB have been reported in the literature, either sporadically or in association with von Hippel-Lindau disease. Furthermore, the incidence of ventricular haemorrhage from HB seems to be uncommon. We report a unique case of sporadic HB of the right lateral ventricle presenting with intratumoural and intraventricular haemorrhage in addition to multifocal intracranial superficial siderosis, indicating the presence of a subarachnoid haemorrhage (SAH) as well. Such a combination has not been reported before. In the future, the detection of an intraventricular mass in association with ventricular haemorrhage, with or without SAH, should include HB as a differential diagnosis, particularly when the imaging appearances are not typical of the more common intraventricular tumours.

Brucellosis presenting as myelofibrosis: First case report

We describe the case of a 29-year-old woman who presented with pancytopenia and myelofibrosis. Brucella melitensis was identified in her blood. The patient recovered completely with doxycycline and rifampin. A repeat bone marrow biopsy showed hypercellularity without myelofibrosis. Bone marrow findings in cases of pancytopenia due to brucellosis reveal normocellularity, hypercellularity, hemophagocytosis, or granuloma. To our knowledge this is the first report of brucellosis causing myelofibrosis. Brucellosis should be considered as a possible cause of myelofibrosis in endemic areas.

Congenital pseudoarthrosis associated with venous malformation

Congenital pseudoarthrosis is a pathologic entity that may be isolated, or may be associated with neurofibromatosis. We report the case of a 3-year-old female with congenital pseudoarthrosis involving the right tibia and fibula. Magnetic resonance imaging (MRI) and complementary magnetic resonance angiogram (MRA) revealed a lobulated mass with vivid enhancement, which led to the diagnosis of venous malformation. This is the first report of congenital pseudoarthrosis caused by the presence of a vascular malformation.

Isolated Bilateral Lacrimal Gland Agenesis

A 5-year-old boy presented to the ophthalmology department complaining of absent tearing while crying. Slit-lamp examination showed decreased tear margin film with normal punctae. Orbit magnetic resonance imaging was done and showed bilateral absent lacrimal glands. This is the third case of isolated bilateral lacrimal gland agenesis in the literature. [J Pediatr Ophthalmol Strabismus. 2016;53:e35-e38.].