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Vitamin D deficiency remains a major cause of rickets worldwide. Nutritional factors are the major cause and less commonly, inheritance causes. Recently, CYP2R1 has been reported as a major factor for 25-hydroxylation contributing to the inherited forms of vitamin D deficiency. We conducted a prospective cohort study at King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia, to review cases with 25-hydroxylase deficiency and describe their clinical, biochemical, and molecular genetic features. We analyzed 27 patients from nine different families who presented with low 25-OH vitamin D and not responding to usual treatment. Genetic testing identified two mutations: c.367+1G>A (12/27 patients) and c.768dupT (15/27 patients), where 18 patients were homozygous for their identified mutation and 9 patients were heterozygous. Both groups had similar clinical manifestations ranging in severity, but none of the patients with the heterozygous mutation had hypocalcemic manifestations. Thirteen out of 18 homozygous patients and all the heterozygous patients responded to high doses of vitamin D treatment, but they regressed after decreasing the dose, requiring lifelong therapy. Five out of 18 homozygous patients required calcitriol to improve their biochemical data, whereas none of the heterozygous patients and patients who carried the c.367+1G>A mutation required calcitriol treatment. To date, this is the largest cohort series analyzing CYP2R1-related 25-hydroxylase deficiency worldwide, supporting its major role in 25-hydroxylation of vitamin D. It is suggested that a higher percentage of CYP2R1 mutations might be found in the Saudi population. We believe that our study will help in the diagnosis, treatment, and prevention of similar cases in the future.

Mutant alleles of CDH23, a gene that encodes a putative calcium-dependent cell-adhesion glycoprotein with multiple cadherin-like domains, are responsible for both recessive DFNB12 nonsyndromic hearing loss (NSHL) and Usher syndrome 1D (USH1D). The encoded protein cadherin 23 (CDH23) plays a vital role in maintaining normal cochlear and retinal function. The present study&rsquo, s objective was to elucidate the role of DFNB12 allelic variants of CDH23 in Saudi Arabian patients. Four affected offspring of a consanguineous family with autosomal recessive moderate to profound NSHL without any vestibular or retinal dysfunction were investigated for molecular exploration of genes implicated in hearing impairment. Parallel to this study, we illustrate some possible pitfalls that resulted from unexpected allelic heterogeneity during homozygosity mapping due to identifying a shared homozygous region unrelated to the disease locus. Compound heterozygous missense variants (p.(Asp918Asn), p.(Val1670Asp)) in CDH23 were identified in affected patients by exome sequencing. Both the identified missense variants resulted in a substitution of the conserved residues and evaluation by multiple in silico tools predicted their pathogenicity and variable disruption of CDH23 domains. Three-dimensional structure analysis of human CDH23 confirmed that the residue Asp918 is located at a highly conserved DXD peptide motif and is directly involved in &ldquo, Ca2+&rdquo, ion contact. In conclusion, our study identifies pathogenic CDH23 variants responsible for isolated moderate to profound NSHL in Saudi patients and further highlights the associated phenotypic variability with a genotypic hierarchy of CDH23 mutations. The current investigation also supports the application of molecular testing in the clinical diagnosis and genetic counseling of hearing loss.

Larsen syndrome is characterized by the dislocation of large joints and other less consistent clinical findings. Heterozygous FLNB mutations account for the majority of Larsen syndrome cases, but biallelic mutations in CHST3 and B4GALT7 have been more recently described, thus confirming the existence of recessive forms of the disease. In a multiplex consanguineous Saudi family affected by severe and recurrent large joint dislocation and severe myopia, we identified a homozygous truncating variant in GZF1 through a combined autozygome and exome approach. Independently, the same approach identified a second homozygous truncating GZF1 variant in another multiplex consanguineous family affected by severe myopia, retinal detachment, and milder skeletal involvement. GZF1 encodes GDNF-inducible zinc finger protein 1, a transcription factor of unknown developmental function, which we found to be expressed in the eyes and limbs of developing mice. Global transcriptional profiling of cells from affected individuals revealed a shared pattern of gene dysregulation and significant enrichment of genes encoding matrix proteins, including P3H2, which hints at a potential disease mechanism. Our results suggest that GZF1 mutations cause a phenotype of severe myopia and significant articular involvement not previously described in Larsen syndrome.

Hereditary sensory autonomic neuropathy type IV (HSAN-IV) is a rare autosomal recessive disorder that usually begins in infancy and is characterized by anhidrosis, insensitivity to noxious stimuli leading to self-mutilating behavior, and intellectual disability. HSAN-IV is caused by mutations in the neurotrophic tyrosine kinase receptor type 1 gene, NTRK1, encoding the high-affinity receptor of nerve growth factor (NGF) which maps to chromosome 1q21-q22. Patients with HSAN-IV lack all NGF-dependent neurons, the primary afferents and sympathetic postganglionic neurons leading to lack of pain sensation and the presence of anhidrosis, respectively. Herein, we report nine patients from nine unrelated families with HSAN-IV due to various mutations in NTRK1, five of which are novel. These are three missense and two nonsense mutations distributed in various domains of NTRK1 involved in binding of NGF. The affected patients had variable intellectual deficits, and some had delayed diagnosis of HSAN-IV. In addition to being the first report of HSAN-IV from the Arabian Peninsula, this report expands the mutational spectrum of patients with NTRK1 mutations and provides further insights for molecular and clinical diagnosis.

Background Van Den Ende-Gupta Syndrome (VDEGS) is an extremely rare autosomal recessive syndrome with less than 20 reported families (approximately 40 patients) in the worldwide literature. Case presentation We have assessed one consanguineous Saudi family with typical features of VDEGS. Two siblings were affected with almost identical features; including blepharophimosis, arachnodactyly, flexion contractures of the elbows, camptodactyly, slender ribs, hooked lateral clavicular ends, and bilateral radial head dislocations. Both patients had several unusual features; including joint laxity, flat feet, recurrent patellar dislocations, and bilateral short distal ulnae. Full sequencing of SCARF2 revealed a homozygous mutation c.773G > A (p. Cys258Tyr) in both affected children. The parents (both with no abnormalities) were heterozygous for the same mutation. Conclusion Joint laxity, recurrent patellar dislocations, and short distal ulnae should be included as part of the clinical spectrum of VDEGS.

Marshall syndrome and type II Stickler syndrome are caused by mutations in COL11A1, which codes for the proα1chain of collagen XI. Collagen XI is a minor fibrillar collagen co-expressed with collagen II in cartilage and the vitreous of the eye. Characteristic features of Marshall syndrome include midfacial hypoplasia, high myopia, and sensorineural-hearing deficit. Deletions, insertions, splice site, and missense mutations in COL11A1 have been identified in Stickler syndrome and Marshall syndrome patients. In this study, we describe the clinical presentations of seven patients with Marshall syndrome from three unrelated Saudi families, inherited as autosomal dominant (two families) and autosomal recessive (one family). Cardinal clinical features of Marshall syndrome are manifested in all patients. One patient had ectodermal abnormalities. Mutations (c.2702G > A in exon 34,IVS50 + 1G > A, and IVS50 + lG > C) were identified in COL11A1 in affected members. Interestingly, the first report of autosomal recessive Marshall syndrome was from Saudi Arabia caused by the same mutation (c.2702G > A, p.Gly901Glu) as in one of our families. This study depicts detailed phenotypic and genetic description of dominant and recessive forms of Marshall syndrome due to COL11A1 mutations.

Four children are described from three Saudi Arabian families suffering from osteopetrosis, distal renal tubular acidosis and cerebral calcification associated clinically with mental retardation, stunted growth, abnormal teeth and a similar facial appearance. The syndrome is inherited as an autosomal recessive. The growth retardation is attributed to renal tubular acidosis but no metabolic link is evident between its other major features, and the fundamental defect is unknown. The disorder is radiologically indistinguishable from the classical recessive (malignant) and dominant (benign) forms of osteopetrosis but its other characteristics establish it as a separate disease entity.

Canavan disease, caused by a deficiency of aspartoacylase, is one of the most common cerebral degenerative diseases of infancy. The aims of this study were to identify the mutations associated with Canavan disease in Saudi Arabia and to identify differentially expressed genes likely to contribute to the development of this disease.Polymerase chain reaction, long polymerase chain reaction, multiplex ligation-dependent probe amplification, sequencing, array comparative genomic hybridization (aCGH), and global gene expression profiling were used to determine putative mutations and likely gene signatures in cultured fibroblasts of patients from Saudi Arabia.One novel and one known large deletion and two previously known mutations (IVS4 + 1GT and G27R) were identified. Compared with controls, 1440 genes were significantly modulated in Canavan patients (absolute fold change [FC]or =4). Genome-wide gene expression profiling results indicated that some genes, involved in apoptosis, muscle contraction and development, mitochondrial oxidation, inflammation and glutamate, and aspartate metabolism, were significantly dysregulated.Our findings indicate that the presence of muscle weakness and hypotonia in patients may be associated with the dysregulated gene activities of cell motility, muscle contraction and development, actin binding, and cytoskeletal-related activities. Overall, these observations are in accordance with previous studies performed in a knockout mouse model.

Various degrees of bone marrow aplasia have been described in association with distinctive congenital anomalies such as the Fanconi Pancytopenia Syndrome (F.P.S.), Thrombocytopenia Absent Radii Syndrome (T.A.R. Syndrome) the Aase Syndrome and Diamond-Blackfan Anemia. This case report describes a child with pancytopenia and several dysmorphic features which have never collectively been described in any of the bone marrow aplasia syndromes listed above. In this paper, we report a constellation of dysmorphic features and pancytopenia which may constitute a new syndrome.

Purpose The purpose of the study was to identify the spectrum of disease characteristics of pheochromocytoma in children. Methods Records of 21 consecutive children diagnosed with pheochromocytoma were reviewed. Patients' age, sex, presentation, associated conditions, diagnostic and imaging modalities used, preoperative preparation, operative details, outcome, and follow-up were recorded. Results The study included 21 children. Patients were diagnosed clinically and confirmed by biochemical tests. Tumors were localized by imaging studies and all were confirmed pathologically. Patients included 17 with adrenal and 4 with extra-adrenal tumors including 1 in the urinary bladder. Seventeen had sporadic and 4 had familial pheochromocytoma. Associated manifestations were the predominant features in 1 of the 4 patients with familial pheochromocytoma. The patient with bladder pheochromocytoma presented with gross hematuria. Hypertension and visual disturbances were prominent findings in the other patients with sporadic form. Two patients (1 sporadic and 1 familial) had malignant pheochromocytoma. One patient with benign pheochromocytoma had multiple recurrences in chromaffin-containing sites. All patients were treated surgically. Seventeen patients were treated preoperatively with alpha-adrenergic blockade. Two patients continued to have significant visual disturbances. One patient with malignant pheochromocytoma died of the disease, and 1 with recurrent pheochromocytoma had neurologic consequences. Conclusions Pheochromocytoma in children has unique characteristics. To our knowledge, this series is one of the largest reports of adrenal pheochromocytoma in children. It also reflects the spectrum of pheochromocytoma in this age group.

Multiple displacement amplification (MDA) is a technique used in the amplification of very low amounts of DNA and reported to yield large quantities of high-quality DNA. We used MDA to amplify the whole genome directly from a single cell. The most common techniques used in PGD are PCR and fluorescent in-situ hybridization (FISH). There are many limitations to these techniques including, the number of chromosomes diagnosed for FISH or the quality of DNA issued from a single cell PCR. This report shows, for the first time, use of MDA for single cell whole genome amplification. A total of 16 short tandem repeats (STRs) were amplified successfully with a similar pattern to the genomic DNA. Furthermore, allelic drop out (ADO) derived from MDA was assessed in 40 single cells by analysing (i) heterozygosity for a known beta globin mutation (IVSI-5 C-G) and by studying (ii) the heterozygous loci present in the STRs. ADO turned out to be 10.25% for the beta globin gene sequencing and 5% for the fluorescent PCR analysis of STRs. Moreover, the amplification accuracy of MDA permitted the detection of trisomy 21 on a single cell using comparative genome hybridization-array. Altogether, these data suggest that MDA can be used for single cell molecular karyotyping and the diagnosis of any single gene disorder in PGD.

A newborn with ambiguous genitalia needs prompt evaluation to detect life-threatening conditions (e.g., salt-losing crisis in congenital adrenal hyperplasia [CAH]) and gender assignment. Sex assignment in these children continues to be a challenging diagnostic and therapeutic problem. We studied the causes and characteristics of ambiguous genitalia in children who were referred to a cytogenetic laboratory.We retrospectively reviewed a total of 120 medical records of patients with a primary indication of ambiguous genitalia that were referred to the cytogenetic lab for karyotyping during the period of 1989 to 1999. Diagnosis was based on a clinical impression from the primary physician, who was primarily a staff pediatrician, endocrinologist and/or pediatric urologist.CAH was the underlying cause of ambiguous genitalia in 41 of 63 patients with ambiguity due to endocrine causes; 39 of these patients showed a 46,XX karyotype and 2 cases were 46,XY (both the 46,XY patients had 3 beta-hydroxylase deficiency). In 57 patients, ambiguous genitalia were due to congenital developmental defects. The most common endocrine case of ambiguous genitalia was 21-OH deficiency. Seven patients were classified as idiopathic with six showing the 46,XY and one the 46,XX karyotype. Gender was reassigned at birth or at diagnosis in 15 patients.The etiology of ambiguous genitalia is variable. The physician managing these families could minimize the trauma of having a child with unidentified sex by providing appropriate genetic counseling so that the parents can make an early decision. Prenatal DNA testing in at-risk families should be considered and appropriate therapy offered to minimize or prevent genital ambiguity.

Recently, Tompson et al 1 described the use of autozygosity mapping and expression studies to identify compound heterozygous mutations (c.2386G>C/c.3943G>T; c.1786dupG/c.3124G>A) in the COL11A1 gene in two unrelated patients as a cause of fibrochondrogenesis (MIM 228520). They concluded that fibrochondrogenesis, a short-limbed skeletal dysplasia, represents the most severe end of a spectrum of disorders caused by a COL11A1 defect to date.1 Subsequently, dominant and recessive forms of fibrochondrogenesis resulting from mutations at a second locus, COL11A2 , were described.2 Mutations in these two genes along with COL2A1 were previously reported to cause autosomal dominant forms of Stickler (MIM 604841) and Marshall syndromes (MIM 154780).3–5 COL9A1 and COL9A2 defects, on the other hand, were identified as causing forms of Stickler syndrome with an autosomal recessive inheritance pattern.6 7 Here we report the first evidence that adds COL11A1 defect as a cause of Marshall syndrome with a recessive mode of inheritance. The proband is a Saudi boy born at term after an uneventful pregnancy to consanguineous parents. He was referred to us at the age of 16 months because of mild motor, speech delay, and dysmorphic facial features (figure 1 A,B). He had ocular hypertelorism with midface hypoplasia and a broad, flat nasal bridge, anteverted nares, and long philtrum. He also had sparse lusterless scalp hair. He had normal palate, teeth, nails, and skin with normal hidrosis. Ophthalmological examination showed progressive high myopia (−12 Diopters), iridodenesis and subluxation of lenses nasally with loss of zonules temporally resulting …

The syndrome of congenital hypoparathyroidism, mental retardation, facial dysmorphism and extreme growth failure (HRD or Sanjad-Sakati syndrome; OMIM 241410) is an autosomal recessive disorder reported almost exclusively in Middle Eastern populations. A similar syndrome with the additional features of osteosclerosis and recurrent bacterial infections has been classified as autosomal recessive Kenny-Caffey syndrome (AR-KCS; OMIM 244460). Both traits have previously been mapped to chromosome 1q43-44 (refs 5,6) and, despite the observed clinical variability, share an ancestral haplotype, suggesting a common founder mutation. We describe refinement of the critical region to an interval of roughly 230 kb and identification of deletion and truncation mutations of TBCE in affected individuals. The gene TBCE encodes one of several chaperone proteins required for the proper folding of alpha-tubulin subunits and the formation of alpha-beta-tubulin heterodimers. Analysis of diseased fibroblasts and lymphoblastoid cells showed lower microtubule density at the microtubule-organizing center (MTOC) and perturbed microtubule polarity in diseased cells. Immunofluorescence and ultrastructural studies showed disturbances in subcellular organelles that require microtubules for membrane trafficking, such as the Golgi and late endosomal compartments. These findings demonstrate that HRD and AR-KCS are chaperone diseases caused by a genetic defect in the tubulin assembly pathway, and establish a potential connection between tubulin physiology and the development of the parathyroid.

Fragile X syndrome is the most common cause of inherited mental retardation. Patients with fragile X syndrome show variable mental disability, typical long and narrow facial appearance with large ears and prominent fontanelle and frequent macro-orchidism. It is generally associated with a fragile site at Xq 27.3, which can be observed in the metaphase chromosome following selective culture conditions. At the molecular level, the fragile X syndrome is associated with an amplification of CGG repeat sequence of the FMR1 gene. The prevalence estimates are reported as one per 1500 males and one per 2500 females. Estimated prevalence rates of fragile X syndrome in different ethnic groups range from 0.4-0.8 per 1000 in males and 0.2-0.6 per 1000 in females. In this study, we have determined the frequency of fragile X-positive cases in 305 preselected patients.Three hundred and five Saudi patients with mental retardation/developmental delay/clinical suspicion of fragile X syndrome were screened for fragile X chromosome by cytogenetic methods. The majority of patients (95.59%) screened were under the age of 20 years.Two hundred and ninety-nine patients (98.03%) were in the category of mild to moderate mental retardation. Twenty-four males (7.86%) and two females (0.65%) were found to express fragile X site at q27.3. The frequency of fragile X-positive cells in males ranged between 7% and 58% (mean 26+/-13.11), while in the females it was between 14% and 21% (mean 12.5+/-35), respectively.The frequency of fragile X positive cases found in this study is similar to other reports of fragile X syndrome in preselected patients.

The Sanjad-Sakati syndrome (SSS; MIM241410), an autosomal recessive trait characterized by congenital hypoparathyroidism, growth and mental retardation, seizures, and a characteristic physiognomy, was recently linked to chromosome area 1q42-q43. SSS resembles the autosomal recessive form of Kenny-Caffey syndrome (KCS; MIM244460), with similar manifestations but lacking osteosclerosis. Since KCS was recently linked to the region 1q42-q43, the possibility that this disorder is allelic with SSS was considered. Eight Sanjad-Sakati families from Saudi Arabia were genotyped with polymorphic short tandem repeat markers from the SSS/KCS critical region. A maximum multipoint LOD score of 14.32 was obtained at marker D1S2649, confirming linkage of SSS to the same region as autosomal recessive KCS. Haplotype analysis refined the critical region to 2.6 cM and identified a rare haplotype present in all the SSS disease alleles, indicative of a common founder. In addition to the assignment of the Saudi SSS and Kuwaiti KCS syndromes to overlapping genetic intervals, comparison of the haplotypes unexpectedly demonstrated that the diseases shared an identical haplotype. This finding, combined with the clinical similarity between the two syndromes, suggests that the two conditions are not only allelic but are also caused by the same ancestral mutation.

Pyroglutamic aciduria (5-oxoprolinuria) is a rare autosomal recessive disorder caused by either glutathione synthetase deficiency (GSSD) or 5-oxoprolinase deficiency. GSSD results in low glutathione levels in erythrocytes and may present with hemolytic anemia alone or together with pyroglutamic aciduria, metabolic acidosis, and CNS damage. Five patients with pyroglutamic aciduria were studied. All presented with hemolytic anemia and metabolic acidosis. Two (brothers) also had Fanconi nephropathy, which is not seen in pyroglutamic aciduria. Molecular analyses of the GSS gene was performed in 3 patients. RT-PCR and heteroduplex analysis identified a homozygous deletion in 1 patient and a homozygous mutation in 2 others (brothers with Fanconi nephropathy). Sequencing of glutathione synthetase (GSS) cDNA from the first patient showed a 141-bp deletion corresponding to the entire exon 4, whilst the corresponding genomic DNA showed a G491 --> A homozygous splice site mutation. Sequencing of GSS cDNA from the Fanconi nephropathy patients showed a C847 --> T [ARG283 --> CYS] mutation in exon 9.

The aim of this report is to describe four cases of non-autoimmune diabetes that presented in infancy. Three had transient neonatal diabetes mellitus (TNDM) with diabetic ketoacidosis at onset, followed by complete remission after several months of insulin treatment. While the fourth case was initially diagnosed as TNDM, she had renal, hepatic and pancreatic dysplasia. These cases illustrate that diabetes in infants can be difficult to diagnose and that patients with TNDM can have a recurrence of diabetes several years later.

We have analyzed the GH receptor (GHR) gene in four individuals with Laron syndrome, and a missense mutation was identified for each patient in the extracellular domain of the GHR (D152H, I153T, Q154P, and V155G). The D152H mutation was previously reported. We have reproduced the three novel mutations in the GHR complementary DNA and analyzed their consequences in human 293 transfected cells. In cells expressing the I153T and V155G mutants, binding of [125I]human GH at the cell surface was very low, whereas binding to total membrane fractions was much less affected, suggesting impaired cell surface expression. Binding assays with cells expressing the Q154P mutant revealed severe defects both at the cell surface and in total particulate membrane fractions. Immunofluorescence experiments confirmed that cell surface expression of the three mutants was altered, and colocalization studies suggested that most of the mutant receptors are retained in the endoplasmic reticulum. Endoglycosidase H resistance tests a...

By using fluorescence in situ hybridization (FISH), we demonstrate a case of monosomy 21 to result from an unbalanced translocation involving the short arm of chromosome 5 and the long arm of chromosome 21. Our case is compared to 3 similar cases of t(5p;21q) reported recently, which were also originally diagnosed as monosomy 21. The breakpoint on chromosome 5 in these cases occurred in the p13–p15 region, whereas the breakpoint on chromosome 21 was in the q21–q22 region. Comparison of the clinical findings in these patients demonstrated great similarities. Furthermore, a strong correlation between the clinical manifestations of these patients with cridu-chat syndrome patients was also noted. We suggest that cases with unbalanced t(5p;21q) represent a distinct syndrome which can be grouped under a new category of “5p/21q deletion syndrome.” Am. J. Med. Genet. 70:174–178, 1997. © 1997 Wiley-Liss, Inc.

The association of microtia, midface hypoplasia, micrognathia, lower limb arthrogryposis, absent patella, and cryptorchidism was first described by Meier et al. [1959]. Gorlin et al. [1975] reported remarkably similar findings in a male patient associated with short stature. Boles et al. [1994], reporting on two sisters and reviewing six previously described patients, suggested the eponym Meier-Gorlin syndrome (MGS), which includes the triad of preand postnatal growth retardation, bilateral microtia, and patellar aplasia/ hypoplasia. Ear-patella-short stature syndrome (MGS) has become one of the increasingly recognized disorders and to date, at least cases of 35 patients have been published [Meier et al., 1959; Gorlin et al., 1975; Hurst et al., 1988; Cohen et al., 1991; Boles et al., 1994; Lacombe et al., 1994; Buebel et al., 1996; Teebi and Gorlin, 1997; Fryns, 1998; Loeys et al., 1999; Verhallen et al., 1999; Terhal et al., 2000; Bongers et al., 2001; Cohen et al., 2002; Feingold, 2002; Shalev and Hall, 2003; Dudkiewicz and Tanzer, 2004]. We observed a new patient with a previously unrecognized finding. The patient is the third child born to nonconsanguineous phenotypically normal parents who belong to the same endogamous tribe in Saudi Arabia. She was born normally at 36-week gestation and weighed 2.8 kg. Soon after birth, she developed severe respiratory distress that needed immediate intensive care. The patient was referred to King Faisal Specialist Hospital andResearchCenterwhere shewas diagnosedwith congenital left upper lobar emphysema, with generalized minimal emphysematous changes. In addition, she was noted to have microtia, micrognathia, and small-beaked nose. She underwent left upper lobectomy in the first week of life, and subsequently she had surgical resection of right middle lobe. Histopathological report indicated markedly dilated alveolar spaces. The patient’s general condition improved thereafter, though she still has hyperreactive airway disease. Chest radiographs showed variable infiltrateswith small thymus.One of the films showed soft tissue density posterior to the lower end of the sternum, suggestive of Morgagni hernia. Thyroid function tests, random GH and IGF-1 performed in early life were all unremarkable. Somatomedin C (IGF-1) and random growth hormone (rGH) at 20 months of age showed 6.7 mU/L and 37 MCG/L, respectively. Same tests, repeated at age 6, showed IGF-1 at 87 mg/L (normal: 82–262 mg/L) and rGH at 0.76mU/L (normal: 0–13 mU/L). GH stimulation test with Clonidine was safely performed in day and the patient was given an oral dose of Clonidine of 50 mg. Overall result showed definite GH deficiency (Table I). The patient was then started on recombinant GH on a weekly basis. The patient’s motor and mental developments were within normal since the age of 21⁄2years. Currently, she is 10 years old, doing well at normal school. Her most recent evaluation showed an apparently intelligent girl with OFC 49cm (

Purpose Most patients diagnosed with malignant osteopetrosis die during infancy or early childhood from hemorrhage and infection due to bone marrow failure. Allogeneic bone marrow transplantation (BMT) has been reported to provide curative therapy for this disorder. We report our experience with eight patients with malignant osteopetrosis who underwent BMT. Patients and Methods Between May 1987 and August 1992, eight children with malignant osteopetrosis underwent allogeneic BMT. Median age at BMT was 9 months (range, 2–36 months). Six patients received marrow from HLA-identical sibling donors, one from phenotypically matched father, and one from a one antigen mismatched father. BMT conditioning for all patients was busulfan 16 mg/kg and cyclophosphamide 200 mg/kg each administered over 4 days. Graft versus host disease (GVHD) prophylaxis included cyclosporin A in six patients or cyclosporin A and methotrexate in two patients. Results Six patients, including those who received bone marrow from their father's, engrafted as documented by bone marrow biopsy showing an increase in osteoclasts in all cases and by chromosomal analysis in four patients. Two patients died without engraftment. Three out of six patients engrafted are alive and well at the follow-up of 48, 63, and 81 months. Serum calcium, alkaline, and acid phosphatase levels normalized within 2 months. These patients have full bone marrow reconstitution. Serial radiologic studies revealed bone marrow remodelling and a new nonsclerotic bone formation. Vision improved dramatically in the youngest patient. Conclusion BMT offers cure to patients with malignant osteopetrosis with reconstitution of bone marrow and correction of metabolic disturbances. In our experience, reversibility in neurosensory deficit is possible when BMT is done at an early age.

Two families with familial isolated GH deficiency (IGHD) were studied, type II (autosomal dominant) and type I (autosomal recessive), whose GH1 genes exhibit cosegregation with IGHD. DNA sequencing of the GH1 genes of the first family (IGHD II) demonstrated heterozygosity for a T-->C transition in the sixth base of the donor splice site of intron III. The GH1 gene mutation in the second family (IGHD I) was found, in a previous study, to be a G-->C transversion altering the first base of the donor splice site of intron IV. Interestingly, analysis of the transcripts derived from the mutant IGHD II allele revealed that the sequences corresponding to exon III were absent due to an exon skip that causes the loss of amino acids 32-71 from the mature GH protein. In contrast, the IGHD I mutation activates a cryptic donor splice site 73 bases upstream of the normal exon IV donor splice site causing loss of amino acids 103-126 of exon IV followed by a reading frameshift and synthesis of 94 novel amino acids before chain termination 88 nucleotides downstream of the normal GH stop codon. It is hypothesized that, because of the loss of protein sequences derived from exons IV and V, the IGHD I mutation products are not transported to secretory granules and thus cannot perturb secretion of the normal monomeric GH protein. In contrast the T-->C IGHD II mutant allele product retains these sequences and is transported to secretory granules where it can interact with the normal allele product producing a dominant-negative effect at the protein level.

Five infants from 3 families, one Egyptian, two Yemeni, are described with a progressive encephalopathy, four of whom have been studied in detail. All patients showed vascular lesions of the skin, characterized by waxing and waning petechiae and ecchymoses. Acrocyanosis was present in three patients. All patients showed retinal lesions characterized by tortuous veins. Protracted diarrhea was not a consistent finding, although they had metabolic crisis in association with diarrhea. They did not show failure to thrive. The neurologic symptoms were indicative of a progressive pyramidal tract disease. Three patients died following sudden emergence of severe basal ganglia, putaminal and head of caudate lesions. In one patient the CT changes in brain were suggestive of infarction. The patients who died manifested pulmonary congestion, or wet lung, and respiratory difficulties during the terminal stage of the disease. In all patients before and during the terminal event, mild-to-moderate hematuria, and in two RBC in CSF, was observed. In one patient there was mild hemoperitoneum at the terminal event. The urine organic acids indicated increased excretion of ethylmalonic, methylsuccinic, glutaric, and adipic acids. The patients invariably showed lactic acidosis, but no ketosis, during and in between the acidotic attacks of the disease. The acylcarnitine profile in blood of two patients showed a pronounced increase in C4 and C5 carnitine esters. In three patients, biopsies from petechiae indicated absence of an immune event, showing only fresh hemorrhage. An immunologic study in one patient was normal for the suppressor:cytotoxic lymphocyte ratio and concentration of interleukin-2 receptor during and in between hemorrhagic attacks. The cytochrome c oxidase activity in fibroblasts was normal. The rate of oxidation of glucose, leucine, isoleucine, valine, propionate and butyrate by fibroblasts was normal. The disease is not responsive to treatment with riboflavin, ascorbic acid, vitamin E, glycine, or carnitine. One patient remained stable on prolonged large doses of methylprednisolone. The biochemical defect leading to ethylmalonic aciduria in this disease remains unknown.

A 5 1/2-year-old Saudi Arabian girl presented with a syndrome of intrauterine growth retardation, minor anomalies, hypoparathyroidism, and growth hormone deficiency. She was the product of a consanguineous mating. Her minor anomalies and delayed development were similar to findings in a previously reported Saudi Arabian patients with hypoparathyroidism and growth deficiency. There were substantial differences in findings from a series of Kuwaiti children. Parathyroid hormone was undetectable, but the renal response to infused parathyroid hormone was normal, indicating primary hypoparathyroidism. In response to arginine stimulation, her GH rose to 5.8 ng/ml (5.8 micrograms/L) (nl10), and to 2.3 ng/ml (2.3 micrograms/L) after L-dopa. Following clonidine it rose to 15 ng/ml (15 micrograms/L) at 120 minutes. She responded normally to infusions of GHRH (GH rose to 22 ng/ml (22 micrograms/L) at 75 minutes) and TRH (TSH rose to 37 mu u/ml, 37 mIU/L). On treatment with recombinant human growth hormone, she showed an increase in height and weight. Hypocalcemia was well controlled with supplemental 1-alpha-cholecalciferol.

The clinical and biochemical findings in three patients with glutaric aciduria Type 1 (GAT1) are presented. They had a normal postnatal period of three to 14 months. They developed sudden and severe encephalopathy following an infection or trauma (patient 3) that gradually progressed to severe dystonia, choreoathetosis, spastic quadriplegia and mental retardation. Neuroradiologic studies of the brain revealed white matter disease and frontotemporal lobe hypoplasia. The urine findings by gas chromatography/mass spectrometry (GC)/(MS) were characteristic of GAT1. Since GAT1 is an organic acidemia without intermittent acidotic attacks, but primarily manifests with progressive encephalopathy, it is important to recognize the potential of its existence among handicapped children in chronic care facilities. The good clinical response in two of the patients urges early diagnosis in subsequent newborn siblings of the families with the disease. The diagnosis of three patients in less than two years indicates the need for neonatal screening for the recognition of this disease, among other treatable metabolic diseases, in Saudi Arabia.

Objective: Genomic duplications that lead to autism and other human diseases are interesting pathological lesions since the underlying mechanism almost certainly involves dosage sensitive genes. We aim to understand a novel genomic disorder with profound phenotypic consequences, most notably global developmental delay, autism, psychosis, and anorexia nervosa. Methods: We evaluated the affected individuals, all maternally related, using childhood autism rating scale (CARS) and Vineland Adaptive scales, magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) brain, electroencephalography (EEG), electromyography (EMG), muscle biopsy, high-resolution molecular karyotype arrays, Giemsa banding (G-banding) and fluorescent in situ hybridization (FISH) experiments, mitochondrial DNA (mtDNA) sequencing, X-chromosome inactivation study, global gene expression analysis on Epstein-Barr virus (EBV)-transformed lymphoblasts, and quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Results: We have identified a novel Xq12–q13.3 duplication in an extended family. Clinically normal mothers were completely skewed in favor of the normal chromosome X. Global transcriptional profiling of affected individuals and controls revealed significant alterations of genes and pathways in a pattern consistent with previous microarray studies of autism spectrum disorder patients. Moreover, expression analysis revealed copy number–dependent increased messenger RNA (mRNA) levels in affected patients compared to control individuals. A subset of differentially expressed genes was validated using qRT-PCR. Interpretation: Xq12–q13.3 duplication is a novel global developmental delay and autism-predisposing chromosomal aberration; pathogenesis of which may be mediated by increased dosage of genes contained in the duplication, including NLGN3, OPHN1, AR, EFNB1, TAF1, GJB1, and MED12. ANN NEUROL 2012

Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder of variable presentation caused by the deficiency of the 3β- hydroxycholesterol Δ(7) - reductase. Over the past 10 years, our biochemical laboratory has screened 191 plasma samples for possible SLOS, measuring the plasma cholesterol and 7-dehydrocholesterol using gas chromatography-mass spectrometry (GC-MS). The SLOS was confirmed in only five Arab patients with growth retardation, global developmental delay, dysmorphic features, and 2-3 toe syndactyly, among other findings. All cases represented moderate to severe form of SLOS. One patient had a unique cardiovascular malformation (cor triatriatum with significant obstruction of the right pulmonary veins). Two previously reported N287K (861 C>A) and R352Q (1055 G>A) and a novel R352L (1055 G>T) mutations were identified in the DHCR7 gene in these patients. The paper sheds light on this rare disease among Arabs and reviews all reported SLOS cases in the Arab population.

Sixty-eight Saudi children, 17 to 19 months of age, were enrolled in a study to evaluate the safety and immunogenicity of Hemophilus influenzae type B capsular polysaccharide diphtheria toxoid (PRP-D) conjugate vaccine. Adverse reactions to the vaccine were determined through a questionnaire administered to the parents. Local and systemic reactions to the vaccine were mild and resolved within 24 to 48 hours. PRP antibody levels were measured prior to and one to two months following immunization. PRP antibody levels in the pre-immunization sera of 77% of subjects were below the level associated with immediate protection (>/=0.15 microg/ml), and 88% were below the level associated with long-term protection (>/=1 microg/ml) from Hemophilus influenzae type B (HIB) disease. After one dose of PRP-D vaccine, 100% of recipients achieved antibody levels of >/=0.15 microg/ml, and 85% achieved levels of >/=1 microg/ml. The geometric mean level of antibody after immunization (5.66 microg/ml) was significantly higher than that before immunization (0.098 microg/ml). All subjects had a twofold or greater increase in antibody level in response to the vaccine. We conclude that PRP-D is a safe and highly immunogenic vaccine in this age group of Saudi children.

The GH1 genes of probands of two families with familial isolated GH deficiency (IGHD) were sequenced. Double stranded sequencing of the polymerase chain reaction (PCR) amplification products from genomic DNA of two affected cousins in a consanguineous Turkish family revealed a G--A transition in the 20th codon of the GH1 signal peptide. This substitution converts a TGG (Trp) to a TAG (stop) codon and generates a new AluI recognition site. PCR amplification of the GH1 alleles of family members, followed by AluI digestion, revealed that the G--A transition segregated with the IGHD phenotype. In a Saudi Arabian family, a G--C transversion was found that alters the first base of the donor splice site of intron IV. This substitution should perturb mRNA splicing, resulting in an altered protein product which should be unstable or bioinactive. This transversion also destroys an HphI site, which was used to assay samples from relatives. Digestion of PCR amplification products with HphI demonstrated cosegregation of the G--C transversion with IGHD. These results demonstrate that familial IGHD is a heterogeneous disease that perturbs different steps in the expression of the GH1 gene.

The 23rd of September 1932 marks in history the foundation of modern Saudi Arabia, when a royal decree affirmed the unity of the nation and named the country the Kingdom of Saudi Arabia (KSA). Spreading over 2,150,000 km2, KSA occupies almost 80% of the Arabian Peninsula. It is surrounded by the Red Sea on the west and the Arabian Gulf on the east; the coastlines of which stretch more than 2,300 km. Along the Red Sea lies Tihama coastal plain, to the east of which is the chain of Sarawat Mountains that extend beyond the southern and northern borders of Saudi Arabia. In the central part of the country lies the Najd plateau where the capital city, Riyadh, is located. Deserts cover more than half the total area of Saudi Arabia; the largest is the Empty Quarter in the Eastern Province (Saudi Geographical Society).

We describe eight patients with multiple sulfatase deficiency (MSD, or Austin's disease) who differ phenotypically from classic neonatal-, childhood-, or juvenile-onset MSD. The age of onset was in childhood. The patients presented with somatic and facial features of mucopolysaccharidosis reminiscent of Maroteaux-Lamy and Morquio syndromes. They differed from classic MSD by the presence of corneal cloudiness, macrocephaly, severe dysostosis multiplex, and gibbus and the absence of ichthyosis, retinal degeneration, severe deafness, severe mental retardation, and dementia. The main neurologic presentation was cervical cord compression due to axis abnormalities. Despite neuroradiologic evidence of white-matter changes, neurologic presentation was not like metachromatic leukodystrophy. The sulfatase deficiencies were more marked than in the classic juvenile form of MSD, but less marked than in the classic childhood-onset form of MSD. Steroid sulfatase activity was spared except in one patient. This Saudi variant of MSD accounts for 5% of all lysosomal storage diseases in the Cell Repository Registry of our Inborn Errors of Metabolism Laboratory. (J Child Neurol 1992;7(Suppl):S12-S21.)

Twelve infants (six boys, six girls) with severe hypocalcaemic tetany or convulsions were seen over a three year period. Nine patients were symptomatic in the newborn period. Their hypocalcaemia was associated with hyperphosphataemia and very low concentrations of immunoreactive parathyroid hormone. None of the babies suffered from congenital cardiac disease. Cell mediated immunity, measured in five patients, was normal. There were no chromosomal abnormalities but all patients shared several dysmorphic features including deep set eyes, microcephaly, thin lips, beaked nose tip, external ear anomalies, micrognathia, and depressed nasal bridge. Mental retardation of varying degree was found in all patients. All had severe intrauterine and postnatal growth retardation. Four patients have died. The remaining eight patients are on treatments with vitamin D and calcium supplements with no change in their growth pattern. We believe that this association of congenital hypoparathyroidism with severe growth failure and dysmorphism represents a new syndrome.

Hypogonadism, alopecia, diabetes mellitus, mental retardation, and extrapyramidal syndrome (also referenced as Woodhouse-Sakati syndrome) is a rare autosomal recessive multisystemic disorder. We have identified a founder mutation consisting of a single base-pair deletion in C2orf37 in eight families of Saudi origin. Three other loss-of-function mutations were subsequently discovered in patients of different ethnicities. The gene encodes a nucleolar protein of unknown function, and the cellular phenotype observed in patient lymphoblasts implicates a role for the nucleolus in the pathogenesis of this disease. Our findings expand the list of human disorders linked to the nucleolus and further highlight the developmental and/or maintenance functions of this organelle.

We report on four siblings (three males, one female) born to first cousin Arab parents with the constellation of distal renal tubular acidosis (RTA), small kidneys, nephrocalcinosis, neurobehavioral impairment, short stature, and distinctive facial features. They presented with early developmental delay with subsequent severe mental, behavioral and social impairment and autistic-like features. Their facial features are unique with prominent cheeks, well-defined philtrum, large bulbous nose, V-shaped upper lip border, full lower lip, open mouth with protruded tongue, and pits on the ear lobule. All had proteinuria, hypercalciuria, hypercalcemia, and normal anion-gap metabolic acidosis. Renal ultrasound examinations revealed small kidneys, with varying degrees of hyperechogenicity and nephrocalcinosis. Additional findings included dilated ventricles and cerebral demyelination on brain imaging studies. Other than distal RTA, common causes of nephrocalcinosis were excluded. The constellation of features in this family currently likely represents a possibly new autosomal recessive syndrome providing further evidence of heterogeneity of nephrocalcinosis syndromes.

Wolman's disease is a rare autosomal recessive lysosomal storage disease. A recent review indicates that approximately 50 patients have been reported in the world. Reports of patients from the Arabian peninsula are rare due to lack of awareness among pediatricians.We retrospectively reviewed the clinical, radiological, biochemical and histopathological findings of four Saudi patients diagnosed with Wolman's disease at King Faisal Specialist Hospital and Research Centre. The diagnosis was confirmed by deficient acid lipase activity in the leukocytes and fibroblasts, which was measured using 4-methylumbelliferyl palmitate.All patients were failing to thrive with progressive hepatosplenomegaly. Abdominal x-ray revealed calcifications which were confirmed on abdominal CT scan. Peripheral blood film showed vacuolated lymphocytes and the bone marrow aspiration showed foamy histiocytes. Liver biopsy in one patient showed marked steatosis and elliptical empty clefs predominantly in the Kupffer cells, indicating cholesterol storage in the reticulo-endothelial cells. The acid lipase activity was less than 6% in all patients.In all suspected cases of Wolman's disease, a plain abdominal x-ray should be obtained to check for the typical pattern of adrenal calcification characteristic of the disease, especially in any young infant with failure to thrive and progressive hepatosplenomegaly.

In this paper, we address the preventive health aspects of genetic problems in the Middle East and provide guidelines to prioritize preventive strategies. Applications of various novel genetic techniques such as comprehensive neonatal screening, high throughput heterozygote detection, preimplantation genetic diagnosis, Affymetrix systems, the NanoChip system and a new way of sensitive karyotyping for single-cell chromosome abnormalities are discussed. In conclusion, from the various genetic techniques available, each country should adopt strategies most suitable to its genetic needs and should prioritize the programs to be used in prevention.

Objective The hereditary syndrome of multiple congenital intraspinal cysts associated with distichiasis, lymphedema and other congenital deformities is extremely rare. Modern imaging techniques have promoted the non-invasive diagnosis of spinal pathology and paved the way for better surgical planning. We reviewed the clinical data, imaging studies and treatment outcomes of a 12-year-old boy with this syndrome. Clinical Presentation Progressive spastic paraparesis with signs of spinal cord compression leading to frequent falls. This was associated with bilateral double row of eyelashes and pretibial edema. The MRI of thoracic spine depicted two large elongated extradural lesions extending from D5-D10 with signal intensity compatible with cerebrospinal fluid leading to severe compression of the spinal cord dorsally. Treatment Laminotomy and complete microsurgical excision of the cysts resulted in a fast and full clinical recovery of his neurological deficit. Conclusion Type I congenital intraspinal cysts is a rare etiology of cord compression syndrome and may be associated with distichiasis, lymphedema and other congenital deformaties. It has several characteristics, which include the higher incidence in thoracic spine and younger age group, disproportional sever motor deficit as compared with sensory disturbances and the excellent clinical recovery following successful surgical treatment.

To describe the long term clinical, biochemical and radiological features of 35 Saudi Arabian children with carbonic anhydrase II deficiency syndrome who have been followed at King Faisal Specialist Hospital and Research Center, Riyadh since 1979.The records of these patients were retrospectively evaluated. The diagnosis was based on the clinical and the radiological evidence of the disease. Carbonic anhydrase II level was measured in 9 patients.Clinically, these patients had typical facial features, growth failure and varying degrees of psychomotor retardation. Biochemically, all children had renal tubular acidosis that was of distal type in the majority of them. Radiologically, this syndrome was characterized by metyphyseal osteopetrosis and intracranial calcification that was progressive in 2 patients. Five patients were blind secondary to optic nerve entrapment and 2 patients developed anemia and secondary erythropoesis due to bone marrow involvement. Nineteen patients had attained the final adult height; the mean adult height was 146 cm (-3 standard deviation) in 11 females and 152 cm (-4 standard deviation) in 8 males. Two patients were married and had clinically and radiologically normal children.The syndrome of carbonic anhydrase II deficiency is usually benign in nature and compatible with long term survival, however it can progress and involve the cranial nerves. Close clinical and neurological assessment of these patients is mandatory to early detect and manage potential serious complications.

Editor—Over the past 12 years, 26 patients with an unusual syndrome of congenital hypoparathyroidism associated with severe prenatal and postnatal growth retardation and a pattern of facial anomalies have been seen at the King Faisal Specialist Hospital and Research Centre, Saudi Arabia.1 2 The disorder has been listed by McKusick in OMIM as “hypoparathyroidism-retardation-dysmorphism syndrome; HRD” as entry 241410. Recently, Parvari et al 3 reported the assignment of the gene for this disorder to chromosome 1 at 1q42-43. Their report was based on a study of consanguineous Bedouin families from Israel and their linkage analysis was based on homozygosity by descent.4 This reports describes a study of three consanguineous Saudi families, which yielded results consistent with the 1q42-43 location of the responsible gene. Blood samples were collected and DNA …

Hyperinsulinism and hyperammonaemia L . Al-Shamsan1, M. Al-Essa2, A. Al-Mutair2, A. Al-Ashwal2, N. Sakati2 and P. T . Ozand2,3* 1 Department of Pediatrics, King Fahad National Guard Hospital, Riyadh ; 2 Department of Pediatrics, King Faisal Specialist Hospital and Research Centre ; 3 Department of Biological and Medical Research, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia * Correspondence : Section of Inborn Errors of Metabolism, Department of Pediatrics, King Faisal Specialist Hospital and Research Centre, PO Box 3354, Riyadh 11211, Saudi Arabia