Marshall syndrome: further evidence of a distinct phenotypic entity and report of new findings.

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.

Smith-Lemli-Opitz syndrome among Arabs.

Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder of variable presentation caused by the deficiency of the 3ß- 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.

Infantile systemic hyalinosis: a fatal disorder commonly diagnosed among Arabs.

We retrospectively reviewed 19 patients (11 male, 8 female) with infantile systemic hyalinosis (ISH) seen at a tertiary care hospital. Fifteen patients (83.3%) presented in the neonatal period. The referral diagnosis was inaccurate in 14 patients (73.7%). Thirteen patients were products of first-degree cousin marriages (68%) and 5 families had more than one affected child. All patients had painful joint contractures and typical mucocutaneous changes (hyper-pigmented sclerodermatous skin over the knuckles and malleoli, gingival hyperplasia, subcutaneous and perianal fleshy nodules). Growth failure was noted in all of them and 39% had profuse diarrhea, 72% had low serum albumin. Radiological findings included osteopenia, periosteal reaction and osteolytic lesions. Tissue biopsy was consistent with the diagnosis in the 8 patients who had the biopsies. Despite aggressive management with physiotherapy and different medications (including NSAIDs, penicillamine and methotrexate), the disorder was progressive and none of them showed improvement. 16 patients died with a mean age of 11 months and only 3 are alive with a mean age of 20 months. This report represents the largest series of ISH. Our data suggests that ISH is a commonly diagnosed disorder in Saudi Arabia and among Arabs.

Endocrine sequelae of childhood craniopharyngioma.

The endocrine sequelae of 62 children with craniopharyngioma were studied retrospectively. These patients were followed for a median duration of 3 years (range 1 to 10 years). Eighteen patients had a long-term follow-up for more than 5 years (range 5 to 10 years). Complete surgical resection was achieved in 30 patients and 32 patients had residual tumor. Twenty-five patients had recurrence or progression of the residual tumor and were treated with radiotherapy. Presenting complaints suggestive of endocrinopathy were infrequent. The most common presenting symptoms were headache, nausea and vomiting, followed by growth failure. Pre-operatively, growth hormone deficiency was the most commonly encountered pituitary hormonal deficiency; however postoperatively, most children had diabetes insipidus. Multiple pituitary hormonal deficiencies were more frequently observed in children treated with extensive radical surgery than in those treated with conservative surgery and radiotherapy. The endocrine morbidity associated with craniopharyngioma and its different management modalities remains high; however, it is manageable with appropriate hormonal replacement therapy.

Cytogenetic diagnosis of fragile X syndrome: study of 305 suspected cases in Saudi Arabia.

BACKGROUND: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: The frequency of fragile X positive cases found in this study is similar to other reports of fragile X syndrome in preselected patients.

X-linked adrenoleukodystrophy. The Saudi experience.

OBJECTIVES: To evaluate the clinical, biochemical, neuroradiological, and neurophysiological findings of patients with X-linked adrenoleukodystrophy. METHODS: Retrospective study evaluating the data of 10 X-linked adrenoleukodystrophy patients diagnosed at King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. RESULTS: The common presenting symptoms were deterioration in school performance, vision and hearing, behavioral changes, and seizures. Eight patients survived 1-4 years and one patient 12 years after the initial presentation, while one patient expired. Six patients had the childhood form, 3 had the adolescent form and one had the adrenomyeloneuropathy form. Six are in an advanced stage of the disease and 3 have mild to moderate spasticity. All except 2 manifested moderate to severe dementia with variable degrees of visual loss. Decreased hearing and features of adrenal insufficiency were seen in 7 patients. Very long chain fatty acids were significantly increased in seven and mildly elevated in 2 patients, however the C26 to C22 ratio was increased in all. The characteristic high-signal intensity of parieto-occipital white matter on brain magnetic resonance imaging T2-weighted images was observed in all patients. Two patients had functional study of the brain, which showed hypometabolic activity in gray and white matter of the occipital lobes. Various neurophysiological abnormalities were detected. The response to different treatment modalities was not promising. CONCLUSION: The disease is more common than had been previously recognized due to phenotypic variability and a wide spectrum of presentations. This report describes various aspects of this disorder and emphasizes the importance of early identification and treatment of asymptomatic but biochemically affected individuals, since all current therapeutic approaches are disappointing if overt neurological abnormalities have been already developed.

X-linked adrenoleukodystrophy. The Saudi experience.

OBJECTIVE: To evaluate the clinical, biochemical, neuroradiological, and neurophysiological findings of patients with X-linked adrenoleukodystrophy. METHODS: Retrospective study evaluating the data of 10 X-linked adrenoleukodystrophy patients diagnosed at King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. RESULTS: The common presenting symptoms were deterioration in school performance, vision and hearing, behavioral changes, and seizures. Eight patients survived 1-4 years and one patient 12 years after the initial presentation, while one patient expired. Six patients had the childhood form, 3 had the adolescent form and one had the adrenomyeloneuropathy form. Six are in an advanced stage of the disease and 3 have mild to moderate spasticity. All except 2 manifested moderate to severe dementia with variable degrees of visual loss. Decreased hearing and features of adrenal insufficiency were seen in 7 patients. Very long chain fatty acids were significantly increased in seven and mildly elevated in 2 patients, however the C26 to C22 ratio was increased in all. The characteristic high-signal intensity of parieto-occipital white matter on brain magnetic resonance imaging T2-weighted images was observed in all patients. Two patients had functional study of the brain, which showed hypometabolic activity in gray and white matter of the occipital lobes. Various neurophysiological abnormalities were detected. The response to different treatment modalities was not promising. CONCLUSION: The disease is more common than had been previously recognized due to phenotypic variability and a wide spectrum of presentations. This report describes various aspects of this disorder and emphasizes the importance of early identification and treatment of asymptomatic but biochemically affected individuals, since all current therapeutic approaches are disappointing if overt neurological abnormalities have been already developed.

Clinical, biochemical, and molecular characterization of patients with glutathione synthetase deficiency.

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.

Sanjad-Sakati and autosomal recessive Kenny-Caffey syndromes are allelic: evidence for an ancestral founder mutation and locus refinement.

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.

Use of FISH technique in the diagnosis of chromosomal syndromes.

Major chromosome abnormalities are present in 0.65% of all neonates. Fluorescent in situ hybridization (FISH) is useful in diagnosing microdeletion syndromes that would otherwise be difficult to diagnose using standard cytogenetics. In this study, we used FISH analysis in the laboratory diagnosis of 4 patients with Prader-Willi Syndrome [del(15)(q11.2q12)], 4 patients with DiGeorge syndrome [del(22)(q11.2q11.23)] and 4 patients with Williams syndrome [del(7)(q11.23q11.23)]. High-resolution chromosome analysis in all these patients was either normal or inconclusive but all the syndromes were confirmed using FISH. We recommend cytogenetic analysis should always be supplemented with FISH to diagnose all cases suspected of a microdeletion syndrome.

Use of FISH technique in the diagnosis of chromosomal syndromes

Major chromosome abnormalities are present in 0.65% of all neonates. Fluorescent in situ hybridization [FISH] is useful in diagnosing microdeletion syndromes that would otherwise be difficult to diagnose using standard cytogenetics. In this study, we used FISH analysis in the laboratory diagnosis of 4 patients with Prader-Willi Syndrome [del[15][q11.2q12]], 4 patients with DiGeorge syndrome [del[22][q11.2q11.23]] and 4 patients with Williams syndrome [del[7][q11.23q11.23]]. High-resolution chromosome analysis in all these patients was either normal or inconclusive but all the syndromes were confirmed using FISH. We recommend cytogenetic analysis should always be supplemented with FISH to diagnose all cases suspected of a microdeletion syndrome

Four contiguous amino acid substitutions, identified in patients with Laron syndrome, differently affect the binding affinity and intracellular trafficking of the growth hormone receptor.

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 also indicated that the majority of I153T and V155G GHRs are trapped in the endoplasmic reticulum. Thus, mutations on contiguous amino acids of the GHR result in various defects. The I153T, Q154P, and V155G mutations mainly affect intracellular trafficking and binding affinity of the receptor, whereas the D152H mutation affects receptor expression, dimerization, and signaling.

Different faces of non-autoimmune diabetes of infancy.

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.

Wolman's disease: The King Faisal Specialist Hospital and Research Centre experience.

BACKGROUND: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Gender reversal in 46XX congenital virilizing adrenal hyperplasia.

OBJECTIVE: To review the results of gender reversal in six patients with 46XX congenital virilizing adrenal hyperplasia (CVAH). PATIENTS AND METHODS: Fifty-one patients with 46XX CVAH were seen in an 8 year period; 45 were managed by conventional feminizing genitoplasty, but six underwent gender reversal and were managed as males. The clinical decision for gender reversal was made after appropriate counselling and was based primarily on parental choice, this being influenced significantly by a delayed diagnosis in four patients. Surgical management consisted of gonadectomy, excision of Müllerian structures and staged hypospadias repair/ chordee correction in four patients, and circumcision in two completely masculinized children. RESULTS: All six boys are well adjusted to their gender of rearing, with ages ranging from 3 years to 16.5 years (mean 8.5) at the time of review. Two children have normal penises and four have a satisfactory result after two-stage repair of hypospadias/chordee. CONCLUSION: Most patients with 46XX CVAH are preferably raised as females and require a feminizing genitoplasty. However, the clinical decision may be influenced by many factors, including delay in diagnosis, social bias and the premium on male rearing in certain communities. When male rearing is chosen, early gonadectomy and excision of Müllerian structures, together with staged hypospadias repair, gives satisfactory results.

A case of presumptive monosomy 21 re-diagnosed as unbalanced t(5p;21q) by FISH and review of literature.

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."