Protocol for multi-site randomized trial of inpatient palliative care for patients with hematologic malignancies undergoing hematopoietic stem cell transplantation.

BACKGROUND: Patients with hematologic malignancies undergoing hematopoietic stem cell transplantation (HSCT) commonly experience debilitating physical and psychological symptoms during a 3-4-week-hospitalization. During hospitalization, caregivers (i.e., family and friends) also endure immense emotional stress as they witness their loved one struggle with HSCT toxicities. Yet interventions to improve quality of life (QOL) and reduce psychological distress during HSCT are limited. METHODS: We are conducting a multi-site randomized controlled trial of inpatient integrated palliative and transplant care versus usual care in 360 patients hospitalized for HSCT and their caregivers at three academic centers. Intervention participants meet with a palliative care clinician at least twice weekly during the HSCT hospitalization to address their physical and psychological symptoms. Patients assigned to usual care receive all supportive care measures provided by the HSCT team and could be seen by palliative care upon request. We assess patient QOL (Functional Assessment of Cancer Therapy (FACT) - Bone Marrow Transplant), depression and anxiety symptoms (Hospital Anxiety and Depression Scale), post-traumatic stress (PTSD) symptoms (PTSD checklist), symptom burden (Edmonton Symptom Assessment Scale), and fatigue (FACT-Fatigue) as well as caregiver-reported outcomes at baseline, 2 weeks, 3-months, 6-months, and 12-months post-HSCT. The primary endpoint is to compare QOL at week-2 during HSCT hospitalization between the two groups when patients typically experience their QOL nadir during HSCT. CONCLUSIONS: This multi-site trial will define the role of palliative care for improving QOL and care for patients with hematologic malignancies undergoing HSCT and their caregivers.

Is soy protein effective in reducing cholesterol and improving bone health?

Hyperlipidemia associated with cardiovascular health, and bone loss with regard to osteoporosis contribute to increased morbidity and mortality and are influenced by diet. Soy protein has been shown to reduce cholesterol levels, and its isoflavones may improve bone health. The objective of this study was to determine the effects of soy protein on lipid profiles and biomarkers of bone metabolism and inflammation. Ninety men and women (aged 27-87) were randomly assigned to consume 40 g of soy or casein protein daily for three months. Both soy and casein consumption significantly reduced bone alkaline phosphatase (P = 0.011) and body fat % (P < 0.001), tended to decrease tartrate-resistant acid phosphatase (P = 0.066), and significantly increased serum insulin-like growth factor-I (IGF-1) (P < 0.001), yet soy increased IGF-1 to a greater extent (P = 0.01) than casein. Neither treatment affected total cholesterol, HDL cholesterol, LDL cholesterol, or C-reactive protein. These results demonstrate that daily supplementation of soy and casein protein may have positive effects on indices of bone metabolism and body composition, with soy protein being more effective at increasing IGF-1, an anabolic factor, which may be due to soy isoflavones' role in upregulating Runx2 gene expression, while having little effect on lipid profiles and markers of inflammation.

The effects of supplemental vitamin E on hematological parameters in a rat model of ovarian hormone deficiency.

OBJECTIVE: Menopause is associated with adverse changes in hematological parameters. Although the antioxidative and anti-inflammatory properties of vitamin E have been previously demonstrated, the effects of vitamin E on hematopoietic parameters are not well-documented. This study investigated the effects of supplemental vitamin E on hematological parameters in a rat model of ovarian hormone deficiency. METHODS: Twelve-month-old female Sprague-Dawley rats were either sham-operated (Sham) or ovariectomized (Ovx). Animals were randomly divided among five treatment groups (n = 12/group) as follows: Sham; Ovx; Ovx + 300, Ovx + 525, or Ovx + 750 mg/kg diet of vitamin E for 100 days. RESULTS: Compared with Sham, ovariectomy increased leukocyte subpopulation counts including lymphocytes (2.01 × 10/mm; 95% confidence interval [CI] 0.11, 4.03; P = 0.03), monocytes (0.35 × 10/mm; 95% CI 0.60, 0.11; P = 0.01), neutrophils (0.72 × 10/mm; 95% CI 0.26, 1.19; P = 0.01), eosinophils (0.07 × 10/mm; 95% CI 0.12, 0.30; P = 0.00), and basophils (0.13 × 10/mm; 95% CI 0.04, 0.21; P = 0.02). Medium dose (MD) (-0.26 × 10/mm; 95% CI -0.47, -0.05; P = 0.007) and high dose (HD) (-0.22 × 10/mm; 95% CI -0.43, -0.01; P = 0.037) supplemental vitamin E attenuated Ovx-induced increases in monocyte counts. Low dose (LD) (-0.55 × 10/mm; 95% CI -0.95, -0.15; P = 0.003), MD (-0.61 × 10/mm; P = 0.001), and HD (-0.54 × 10/mm; 95% CI -0.95, -0.14; P = 0.004) supplemental vitamin E attenuated Ovx-induced increases in neutrophil counts. LD (-0.05 × 10/mm; 95% CI -0.08, -0.11; P = 0.006), MD (-0.05 × 10/mm; 95% CI -0.08, -0.11; P = 0.005), and HD (-0.05 × 10/mm; 95% CI -0.09, -0.01; P = 0.004) supplemental vitamin E also attenuated the Ovx-induced increase in eosinophil counts. Only LD (-0.09 × 10/mm; 95% CI -0.17, -0.02; P = 0.009) supplemental vitamin E attenuated the Ovx-induced increase in basophil counts. The remaining hematological parameters assessed were not significantly affected by ovariectomy or supplemental vitamin E. CONCLUSION: These findings suggest that vitamin E in the form of α-tocopherol acetate may provide protection against ovarian hormone deficiency-associated adverse changes in hematological parameters.

Clinical heterogeneity of PLA2G6-related Parkinsonism: analysis of two Saudi families.

BACKGROUND: Recessive mutations in PLA2G6 have been associated with different neurodegenerative disorders, including infantile neuroaxonal dystrophy, neurodegeneration with brain iron accumulation and more recently, early-onset dystonia parkinsonism. METHOD: Targeted-next generation sequencing using a custom Neurology panel, containing 758 OMIM-listed genes implicated in neurological disorders, was carried out in two index cases from two different Saudi families displaying early-onset levodopa-responsive Parkinsonism with pyramidal signs and additional clinical features. The detected mutations were verified in the index cases and available family members by direct sequencing. RESULTS AND CONCLUSION: We identified a previously described PLA2G6 homozygous p.R741Q mutation in three affected and two asymptomatic individuals from two Saudi families. Our finding reinforces the notion of the broadness of the clinical spectrum of PLA2G6-related neurodegeneration.

Genetic spectrum of Saudi Arabian patients with antenatal cystic kidney disease and ciliopathy phenotypes using a targeted renal gene panel.

BACKGROUND: Inherited cystic kidney disorders are a common cause of end-stage renal disease. Over 50 ciliopathy genes, which encode proteins that influence the structure and function of the primary cilia, are implicated in cystic kidney disease. METHODS: To define the phenotype and genotype of cystic kidney disease in fetuses and neonates, we correlated antenatal ultrasound examination and postnatal renal ultrasound examination with targeted exon sequencing, using a renal gene panel. A cohort of 44 families in whom antenatal renal ultrasound scanning findings in affected cases included bilateral cystic kidney disease, echogenic kidneys or enlarged kidneys was investigated. RESULTS: In this cohort, disease phenotypes were severe with 36 cases of stillbirth or perinatal death. Extra renal malformations, including encephalocele, polydactyly and heart malformations, consistent with ciliopathy phenotypes, were frequently detected. Renal gene panel testing identified causative mutations in 21 out of 34 families (62%), where patient and parental DNA was available. In the remaining 10 families, where only parental DNA was available, 7 inferred causative mutations were found. Together, mutations were found in 12 different genes with a total of 13 novel pathogenic variants, including an inferred novel variant in NEK8. Mutations in CC2D2A were the most common cause of an antenatal cystic kidney disease and a suspected ciliopathy in our cohort. CONCLUSIONS: In families with ciliopathy phenotypes, mutational analysis using a targeted renal gene panel allows a rapid molecular diagnosis and provides important information for patients, parents and their physicians.

Parkinson's Disease in Saudi Patients: A Genetic Study.

Parkinson's disease (PD) is one of the major causes of parkinsonism syndrome. Its characteristic motor symptoms are attributable to dopaminergic neurons loss in the midbrain. Genetic advances have highlighted underlying molecular mechanisms and provided clues to potential therapies. However, most of the studies focusing on the genetic component of PD have been performed on American, European and Asian populations, whereas Arab populations (excluding North African Arabs), particularly Saudis remain to be explored. Here we investigated the genetic causes of PD in Saudis by recruiting 98 PD-cases (sporadic and familial) and screening them for potential pathogenic mutations in PD-established genes; SNCA, PARKIN, PINK1, PARK7/DJ1, LRRK2 and other PD-associated genes using direct sequencing. To our surprise, the screening revealed only three pathogenic point mutations; two in PINK1 and one in PARKIN. In addition to mutational analysis, CNV and cDNA analysis was performed on a subset of patients. Exon/intron dosage alterations in PARKIN were detected and confirmed in 2 cases. Our study suggests that mutations in the ORF of the screened genes are not a common cause of PD in Saudi population; however, these findings by no means exclude the possibility that other genetic events such as gene expression/dosage alteration may be more common nor does it eliminate the possibility of the involvement of novel genes.

Women with osteoarthritis have elevated synovial fluid levels of insulin-like growth factor (IGF)-1 and IGF-binding protein-3.

The present study explores the possible connection between synovial fluid concentrations of insulin like growth factor (IGF-1), IGF-binding protein (IGFBP-3), leptin, and C-reactive protein (CRP) in osteoarthritis (OA). Synovial fluid specimens were obtained from a total of thirty-four individuals with and without OA. Protein-normalized measurements of IGF-1, IGFBP-3, and leptin concentrations in synovial fluid showed significantly (P < 0.05) elevated levels in women with knee OA but not in men. This study provides initial evidence that protein normalized IGF-1 and IGFBP-3 and leptin levels increase in synovial fluid of women but not in men with OA versus those without OA.

Effects of vitamin e on bone biomechanical and histomorphometric parameters in ovariectomized rats.

The present study examined the dose-dependent effect of vitamin E in reversing bone loss in ovariectomized (Ovx) rats. Sprague-Dawley rats were either Sham-operated (Sham) or Ovx and fed control diet for 120 days to lose bone. Subsequently, rats were divided into 5 groups (n = 12/group): Sham, Ovx-control, low dose (Ovx + 300 mg/kg diet; LD), medium dose (Ovx + 525 mg/kg diet; MD), and high dose (Ovx + 750 mg/kg diet; HD) of vitamin E and sacrificed after 100 days. Animals receiving MD and HD of vitamin E had increased serum alkaline phosphatase compared to the Ovx-control group. Bone histomorphometry analysis indicated a decrease in bone resorption as well as increased bone formation and mineralization in the Ovx groups supplemented with MD and HD of vitamin E. Microcomputed tomography findings indicated no effects of vitamin E on trabecular bone of fifth lumbar vertebrae. Animals receiving HD of vitamin E had enhanced fourth lumbar vertebra quality as evidenced by improved ultimate and yield load and stress when compared to Ovx-control group. These findings demonstrate that vitamin E improves bone quality, attenuates bone resorption, and enhances the rate of bone formation while being unable to restore bone density and trabecular bone structure.

Soy protein with or without isoflavones failed to preserve bone density in gonadal hormone-deficient male rat model of osteoporosis.

Soy with its isoflavones has been shown to positively influence bone mineral density in female ovariectomized rats; hence, we hypothesized a similar effect in orchidectomized (ORX) male rats. Forty male Sprague-Dawley rats, aged 95 days, were divided into 4 groups and were either sham operated (Sham) or ORX. The ORX groups were fed a soy protein-based diet (SOY), an isoflavone-depleted soy protein diet (SOY-), or a casein based diet for 65 days after surgery. Orchidectomy increased the rate of bone turnover, resulting in reduced bone mineral density and bone mineral content by 3.5% and 14%, respectively, and compromised biomechanical properties. The mean femoral length of ORX animals was also significantly shorter than Sham animals, but ORX rats that were fed SOY diet did not experience this reduction in bone length, implicating a role for soy protein in bone growth (4.02 ± 0.02, 3.93 ± 0.01, 3.99 ± 0.02, 3.91 ± 0.01 for Sham, ORX, SOY, SOY-, respectively). The SOY and SOY- positively influenced the biomechanical properties of bone such as yield and ultimate force, the measures of bone elasticity, and plasticity. In terms of bone histomorphometry, the data indicate that SOY- tends to reduce ORX-induced increase in bone turnover as evidenced by suppressed bone formation rate/mineralized surface by about 9%. Overall, our results indicated that soy protein, regardless of its isoflavone content, was unable to prevent the ORX-induced femoral decrease in bone density and mineral content. However, soy may enhance the quality of bone as indicated by increased yield force.

A missense mutation in PIK3R5 gene in a family with ataxia and oculomotor apraxia.

Autosomal recessive ataxias are heterogeneous group of disorders characterized by cerebellar atrophy and peripheral sensorimotor neuropathy. Molecular characterization of this group of disorders identified a number of genes contributing to these overlapping phenotypes. Ataxia with oculomotor apraxia type 2 (AOA2) is an autosomal recessive form of ataxia caused by mutations in the SETX gene. We report on a consanguineous family with autosomal recessive inheritance and clinical characteristics of AOA2, and no mutations in the SETX gene. We mapped the AOA locus in this family to chromosome 17p12-p13. Sequencing of all genes in the refined region identified a homozygous missense mutation in PIK3R5 that was absent in 477 normal controls. Our characterization of the PIK3R5 protein and findings suggest that it may play a role in the development of the cerebellum and vermis.

Infantile esotropia could be oligogenic and allelic with Duane retraction syndrome.

PURPOSE: To describe phenotyping and linkage analysis results for available members from a consanguineous nuclear family with hereditary congenital strabismus. METHODS: Both parents and all 12 children underwent clinical examination. Available affected and several unaffected family members had venous blood sampling for DNA extraction and 10K single nucleotide polymorphism (SNP) genotyping (Affymetrix Gene Chip® Human). Multipoint logarithm of the odds (LOD) score calculations were performed assuming an autosomal recessive mode of inheritance with 100% penetrance and disease allele frequency of 0.01%. RESULTS: Three children had non-syndromic large-angle infantile esotropia without significant hyperopia. A fourth child had left esotropic Duane retraction syndrome. A fifth child who had esotropia in the setting of prematurity and childhood poliomyelitis was excluded from the analysis. A sixth child had keratoconus and was excluded. Both parents and the remaining 6 children had no significant orthoptic or ophthalmic findings. Using linkage analysis including the 4 esotropic children, disease loci were mapped to regions on chromosomes 3p26.3-26.2 and 6q24.2-25.1 using multipoint linkage analysis with LOD scores of 3.18 and 3.25 respectively. Linkage to these regions persisted when the esotropic Duane retraction syndrome patient was excluded from the linkage analysis (LOD scores of 2.00 and 2.32, respectively). CONCLUSIONS: Non-syndromic infantile esotropia could be related to susceptibility loci on chromosomal regions 3p26.3-26.2 and 6q24.2-25.1 and may share alleles that underlie Duane retraction syndrome.

Prolonged pursuit by optokinetic drum testing in asymptomatic female carriers of novel FRMD7 splice mutation c.1050 +5 G>A.

OBJECTIVE: To determine the genotype underlying suspected X-linked infantile nystagmus in a family and to correlate genotype with clinical examination in potential female carriers. METHODS: Ophthalmic examination (ophthalmic, orthoptic, optokinetic [OKN] drum, and electrophysiologic when possible) and candidate gene analysis. RESULTS: Two affected brothers had infantile nystagmus with no evidence of associated visual or neurological disease. The symptomatic maternal aunt had infantile nystagmus in addition to congenital fibrosis of the extraocular muscles (CFEOM) (bilateral hypotropia, exotropia, ptosis, almost complete ophthalmoplegia, and poorly reactive pupils). A sister, the mother, and the maternal grandmother-all 3 of whom were asymptomatic-had delayed corrective saccades (prolonged pursuit) during OKN drum testing.A brother and the father­both of whom were asymptomatic­had unremarkable examination findings [corrected]. A FRMD7 splice variant (c.1050 + 5 G>A) was identified in the 2 affected brothers and in the 3 asymptomatic women only. Allele sharing analysis further confirmed that the aunt's phenotype was not related to the FRMD7 variant, which was absent in 246 ethnic controls. Her phenotype was also not related to mutation in known CFEOM genes (KIF21A, PHOX2A, TUBB3). CONCLUSIONS: Prolonged pursuit responses during OKN drum testing in asymptomatic female carriers is consistent with the concept of infantile nystagmus being an abnormally increased pursuit oscillation. Further studies are required to determine the reproducibility of this potential female carrier sign. Rather than being FRMD7 related, nystagmus in the maternal aunt represented a second disease in this family, likely related to CFEOM. CLINICAL RELEVANCE: Clinicians can use the OKN drum to assess obligate female carriers in a family suspected of having X-linked nystagmus.

Potential linkage of different phenotypic forms of childhood strabismus to a recessive susceptibility locus (16p13.12-p12.3).

PURPOSE: To perform linkage analysis on an inbred family with members who exhibit different phenotypic forms of childhood strabismus. METHODS: Prospective clinical examination and linkage analysis. RESULTS: three of the ten siblings and their cousin each had a different phenotypic form of childhood strabismus: infantile esotropia with convergence excess, esotropia associated with anisometropic amblyopia, unilateral esotropic Duane syndrome, and monocular elevation deficiency. Linkage analysis for the four strabismic individuals, an unaffected sibling, and the unaffected parents identified a single disease locus on chromosome 16p13.12-p12.3 (Ensembl cytogenetic band) with a 2.5 maximum logarithm of odds score. The region is 6 MB in size and comprises 80 genes. DISCUSSION: Linkage analysis in this unique family suggests that childhood strabismus can be recessive and that different phenotypic forms of childhood strabismus can share the same underlying genotype.

The optic nerve head in congenital fibrosis of the extraocular muscles.

OBJECTIVE: Optic nerve head abnormalities have been reported in some patients with congenital fibrosis of the extraocular muscles (CFEOM). This study prospectively assesses optic nerve head appearance in a consecutive CFEOM cohort. METHODS: All patients with CFEOM referred between 2006 and 2010 and who were mature enough to cooperate with fundus photography were included. Fundus photographs were reviewed with attention to optic nerve head features (eg, cupping >0.6, asymmetric cupping >0.3, optic nerve hypoplasia). Interested participants had CFEOM candidate gene analysis (KIF21A, TUBB3, PHOX2A) for genetic counseling purposes. RESULTS: Ten CFEOM patients (five CFEOM1, five CFEOM3, age range 5-23 years) from eight families (all consanguineous but one) participated. All 10 patients had notable disc excavation (5) or optic nerve hypoplasia (5). CFEOM candidate gene analysis was performed in all patients and revealed a heterozygous p.R954W KIF21A mutation only in the patient who was not from a consanguineous family. CONCLUSIONS: Our observations suggest the optic nerve head can be affected by the orbital dysinnervation that occurs in CFEOM. Because careful clinical optic nerve head assessment is difficult in young patients with CFEOM and associated large angle incomitant strabismus, optic nerve head abnormalities may be under-diagnosed. The absence of mutations in known CFEOM genes in our cohort of consanguineous families suggests further genetic heterogeneity of this group of conditions.

Clinical and molecular characterization of ataxia with oculomotor apraxia patients in Saudi Arabia.

BACKGROUND: Autosomal recessive ataxias represent a group of clinically overlapping disorders. These include ataxia with oculomotor apraxia type1 (AOA1), ataxia with oculomotor apraxia type 2 (AOA2) and ataxia-telangiectasia-like disease (ATLD). Patients are mainly characterized by cerebellar ataxia and oculomotor apraxia. Although these forms are not quite distinctive phenotypically, different genes have been linked to these disorders. Mutations in the APTX gene were reported in AOA1 patients, mutations in SETX gene were reported in patients with AOA2 and mutations in MRE11 were identified in ATLD patients. In the present study we describe in detail the clinical features and results of genetic analysis of 9 patients from 4 Saudi families with ataxia and oculomotor apraxia. METHODS: This study was conducted in the period between 2005-2010 to clinically and molecularly characterize patients with AOA phenotype. Comprehensive sequencing of all coding exons of previously reported genes related to this disorder (APTX, SETX and MRE11). RESULTS: A novel nonsense truncating mutation c.6859 C > T, R2287X in SETX gene was identified in patients from one family with AOA2. The previously reported missense mutation W210C in MRE11 gene was identified in two families with autosomal recessive ataxia and oculomotor apraxia. CONCLUSION: Mutations in APTX , SETX and MRE11 are common in patients with autosomal recessive ataxia and oculomotor apraxia. The results of the comprehensive screening of these genes in 4 Saudi families identified mutations in SETX and MRE11 genes but failed to identify mutations in APTX gene.

Lack of KIF21A mutations in congenital fibrosis of the extraocular muscles type I patients from consanguineous Saudi Arabian families.

PURPOSE: Congenital fibrosis of the extraocular muscles type I (CFEOM1), the most common CFEOM worldwide, is characterized by bilateral ptotic hypotropia, an inability to supraduct above the horizontal midline, horizontal strabismus (typically exotropia), and ophthalmoplegia with abnormal synkinesis. This distinct non-syndromic phenotype is considered autosomal dominant and is virtually always from heterozygous missense mutations in kinesin family member 21A (KIF21A). However, there are occasional KIF21A-negative cases, opening the possibility for a recessive cause. The objective of this study is to explore this possibility by assessing CFEOM1 patients exclusively from consanguineous families, who are the most likely to have recessive cause for their phenotype if a recessive cause exists. METHODS: Ophthalmic examination and candidate gene direct sequencing (KIF21A, paired-like homeobox 2A [PHOX2A], tubulin beta-3 [TUBB3]) of CFEOM1 patients from consanguineous families referred for counseling from 2005 to 2010. RESULTS: All 5 probands had classic CFEOM1 as defined above. Three had siblings with CFEOM. None of the probands had mutations in KIF21A, PHOX2A, or TUBB3. CONCLUSIONS: The lack of KIF21A mutations in CFEOM1 patients exclusively from consanguineous families, most of whom had siblings with CFEOM, is strong evidence for a recessive form of CFEOM1. Further studies of such families will hopefully uncover the specific locus(loci).

One-year soy protein supplementation does not improve lipid profile in postmenopausal women.

OBJECTIVE: The risk of heart disease increases significantly in women after menopause mostly because of estrogen deficiency. Soy protein, a good source of isoflavones that are known to bind estrogen receptors, has also been promoted as a dietary means for reducing the risk of heart disease. The aim of this study was to examine the effects of soy protein consumption on heart disease risk in postmenopausal women. METHODS: Moderately hypercholesterolemic postmenopausal women were randomly assigned to consume soy or control foods daily for 1 year. Serum samples were analyzed for total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, apolipoprotein (Apo) A, and Apo B. Sixty-two women completed the study. RESULTS: There was a trend for total cholesterol and high-density lipoprotein cholesterol levels to increase after 1 year of soy protein supplementation (230.04 +/- 6.1 vs 242.57 +/- 6.2 mg/dL, P < 0.1, and 56.87 +/- 2.5 vs 60.33 +/- 2.5 mg/dL, P < 0.1, respectively). There were no significant differences in low-density lipoprotein cholesterol or triglyceride levels; however, a significant increase in Apo B levels (105.5 +/- 5.9 vs 120.21 +/- 5.9 mg/dL; P = 0.002) and a significant decrease in Apo A levels (189.36 +/- 10 vs 173.21 +/- 10 mg/dL; P = 0.009) were seen. CONCLUSIONS: Our data indicate that 1-year soy protein supplementation did not confer cardiovascular benefits, in terms of favorable alterations in the lipid profile, in this cohort of postmenopausal women. These findings, as well as those from other studies, lend credence to the decision of the Food and Drug Administration to reevaluate the soy protein health claim issued a decade ago.

Germline Mosaicism for KIF21A Mutation (p.R954L) Mimicking Recessive Inheritance for Congenital Fibrosis of the Extraocular Muscles.

OBJECTIVE: To document the genotype for familial congenital fibrosis of the extraocular muscles (CFEOM) with apparent autosomal recessive inheritance. DESIGN: Interventional family study. PARTICIPANTS: Two affected siblings, 3 asymptomatic siblings, and their 2 asymptomatic parents. METHODS: Ophthalmologic examination and candidate gene analysis (KIF21A and PHOX2A from venous blood samples) of the 2 affected siblings and their parents; confirmatory testing for 3 available asymptomatic siblings. MAIN OUTCOME MEASURES: Significant clinical observations and results of gene testing. RESULTS: The 2 affected siblings had large-angle exotropia, moderate bilateral hypotropia, moderate bilateral ptosis, sluggish pupils, and almost complete ophthalmoloplegia with some abnormal synkinesis. The asymptomatic parents were not related and had unremarkable ophthalmic examinations. Four other siblings were normal by history; 3 underwent venous blood sampling for confirmatory testing. Candidate gene testing of PHOX2A, the gene for recessive CFEOM (CFEOM2), did not reveal mutation in the 2 patients or their parents. Sequencing of KIF21A, the gene for dominant CFEOM (CFEOM1), revealed heterozygous p.R954L in both affected individuals but in not in their parents or 3 asymptomatic siblings, consistent with parental germline mosaicism. Haplotype analysis suggested paternal inheritance but was not conclusive. CONCLUSIONS: Parental germline mosaicism can mimic recessive inheritance in CFEOM and likely is underrecognized. Ophthalmologists should be aware of this phenomenon when counseling parents of children with apparent recessive (or de novo) hereditary eye disease. Unlike other reported KIF21A mutations that cause CFEOM1, the p.R954L variant seems to be associated with abnormal pupils. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Homozygous mutations in ADAMTS10 and ADAMTS17 cause lenticular myopia, ectopia lentis, glaucoma, spherophakia, and short stature.

Weill-Marchesani syndrome (WMS) is a well-characterized disorder in which patients develop eye and skeletal abnormalities. Autosomal-recessive and autosomal-dominant forms of WMS are caused by mutations in ADAMTS10 and FBN1 genes, respectively. Here we report on 13 patients from seven unrelated families from the Arabian Peninsula. These patients have a constellation of features that fall within the WMS spectrum and follow an autosomal-recessive mode of inheritance. Individuals who came from two families and met the diagnostic criteria for WMS were each found to have a different homozygous missense mutation in ADAMTS10. Linkage analysis and direct sequencing of candidate genes in another two families and a sporadic case with phenotypes best described as WMS-like led to the identification of three homozygous mutations in the closely related ADAMTS17 gene. Our clinical and genetic findings suggest that ADAMTS17 plays a role in crystalline lens zonules and connective tissue formation and that mutations in ADAMTS17 are sufficient to produce some of the main features typically described in WMS.