Homozygous mutation in ELMO2 may cause Ramon syndrome.

We report on a girl, born to first cousin Lebanese parents, with intellectual disability, seizures, repeated gingivorrhagia, enlarged lower and upper jaws, overgrowth of the gums, high arched and narrow palate, crowded teeth, hirsutism of the back, large abdomen and a small umbilical hernia. Cysts of the mandible, fibrous dysplasia of bones, and enlarged adenoids causing around 60% narrowing of the nasopharyngeal airways were noted at radiographic examination. Her brother presented with the same features in addition to a short stature, an ostium secundum, and more pronounced intellectual disability. He died at the age of 8 years from a severe pulmonary infection and repeated bleeding episodes. A clinical diagnosis of Ramon syndrome was made. Whole exome sequencing studies performed on the family revealed the presence of a novel homozygous missense mutation in ELMO2 gene, p.I606S in the affected individuals. Loss of function mutations in ELMO2 have been recently described in another clinically distinct condition: primary intraosseous vascular malformation or intraosseous hemangioma, called VMOS. Review of the literature and differential diagnoses are discussed.

Mild Campomelic Dysplasia: Report on a Case and Review.

We report on a 10.5-year-old girl with a mild form of campomelic dysplasia. She presented with short stature of prenatal onset, dysmorphic facial features, limitation of supination and pronation of the forearms, dysplastic nails, and bone abnormalities consisting especially of cone-shaped epiphyses of the middle phalanx of the 2nd fingers, brachydactyly and clinodactyly of the middle phalanx of both 5th fingers, short 4th metacarpals, radial and femoral head subluxation, hypoplastic scapulae, humeral and ulnar epiphyseal abnormalities, unossified symphysis pubis, and a significant delay in bone age. Molecular analysis of the SOX9 gene revealed the presence of a de novo missense mutation: p.P170L (c.509C>T). Mild and surviving cases of campomelic dysplasia are reviewed.

Stüve-Wiedemann syndrome: long-term follow-up and genetic heterogeneity.

Stüve-Wiedemann syndrome (SWS, OMIM 601559) is a severe autosomal recessive condition caused by mutations in the leukemia inhibitory receptor (LIFR) gene. The main characteristic features are bowing of the long bones, neonatal respiratory distress, swallowing/sucking difficulties and dysautonomia symptoms including temperature instability often leading to death in the first years of life. We report here four patients with SWS who have survived beyond 36 months of age with no LIFR mutation. These patients have been compared with six unreported SWS survivors carrying null LIFR mutations. We provide evidence of clinical homogeneity of the syndrome in spite of the genetic heterogeneity.

Expanding the clinical and neuroradiologic phenotype of primary microcephaly due to ASPM mutations.

OBJECTIVE: To determine the spectrum of clinical, neuropsychological, and neuroradiologic features in patients with autosomal recessive primary microcephaly (MCPH) due to ASPM gene mutations. METHODS: ASPM was sequenced in 52 unrelated MCPH probands. In patients with ASPM mutations, we evaluated the clinical phenotype, cognition, behavior, brain MRI, and family. RESULTS: We found homozygous or compound heterozygous ASPM loss-of-function mutations in 11 (22%) probands and 5 siblings. The probands harbored 18 different mutations, of which 16 were new. Microcephaly was severe after 1 year of age in all 16 patients, although in 4 patients the occipital-frontal circumference (OFC) at birth was decreased by only 2 SD. The OFC Z score consistently decreased after birth. Late-onset seizures occurred in 3 patients and significant pyramidal tract involvement in 1 patient. Intellectual quotients ranged from borderline-normal to severe mental retardation. Mild motor delay was noted in 7/16 patients. Language development was delayed in all patients older than 3 years. Brain MRI (n = 12) showed a simplified gyral pattern in 9 patients and several malformations including ventricle enlargement (n = 7), partial corpus callosum agenesis (n = 3), mild cerebellar hypoplasia (n = 1), focal cortical dysplasia (n = 1), and unilateral polymicrogyria (n = 1). Non-neurologic abnormalities consisted of short stature (n = 1), idiopathic premature puberty (n = 1), and renal dysplasia (n = 1). CONCLUSIONS: We provide a detailed description of features associated with ASPM mutations. Borderline microcephaly at birth, borderline-normal intellectual efficiency, and brain malformations can occur in ASPM-related primary hereditary microcephaly.

[Mirror hand deformity: a new phenotype with literature review]. / Main en miroir: une nouvelle forme avec revue de la littérature.

We report the case of a child who presented polydactyly with eight triphalangeal fingers, no thumb or radius and ulnar dimelia. Hand, wrist, forearm and elbow function was compromised, particularly due to wrist stiffness in flexion, the absence of forearm pronation supination and severe limitation of elbow motion. In addition, the child underwent surgery for pyloric hypertrophy and also presented a multicystic kidney. We present the clinical, anatomic, electromyographic, genetic and therapeutic aspects of this rare deformity and discuss data presented in the literature.

Revisiting the craniosynostosis-radial ray hypoplasia association: Baller-Gerold syndrome caused by mutations in the RECQL4 gene.

Baller-Gerold syndrome (BGS) is a rare autosomal recessive condition with radial aplasia/hypoplasia and craniosynostosis (OMIM 218600). Of >20 cases reported so far, a few appear atypical and have been reassigned to other nosologic entities, including Fanconi anaemia, Roberts SC phocomelia, and Pfeiffer syndromes after demonstration of corresponding cytogenetic or molecular abnormalities. Clinical overlap between BGS, Rothmund-Thomson syndrome (RTS), and RAPADILINO syndrome is noticeable. Because patients with RAPADILINO syndrome and a subset of patients with RTS have RECQL4 mutations, we reassessed two previously reported BGS families and found causal mutations in RECQL4 in both. In the first family, four affected offspring had craniosynostosis and radial defect and one of them developed poikiloderma. In this family, compound heterozygosity for a R1021W missense mutation and a g.2886delT frameshift mutation of exon 9 was found. In the second family, the affected male had craniosynostosis, radial ray defect, poikiloderma, and short stature. He had a homozygous splice site mutation (IVS17-2A>C). In both families, the affected offspring had craniosynostosis, radial defects, and growth retardation, and two developed poikiloderma. Our results confirm that BGS in a subgroup of patients is due to RECQL4 mutations and could be integrated into a clinical spectrum that encompasses RTS and RAPADILINO syndrome.

X-linked reticulate pigmentary layer. Report of a new patient and demonstration of a skewed X-inactivation.

We report a boy, born to healthy first cousin parents, with diffuse hyperpigmentation of the skin and guttate hypomelanotic lesions, photophobia, abnormal hair, developmental delay, and recurrent bronchitis. Skin histology showed pigmentation incontinence with numerous melanophages. Electron microscopy showed a very high number of melanosomes and some degenerating keratinocytes. These features correspond to a rare genodermatosis, the X-linked reticulate pigmentary disorder with systemic manifestations. Skewed X-inactivation patterns were detected in the mother's lymphocytes.

[Megalencephalic leucoencephalopathy with subcortical cysts: a study of a Lebanese family and a review of the literature]. / La leucoencéphalopathie mégalencéphalique avec kystes sous-corticaux: étude d'une famille libanaise et revue de la littérature.

INTRODUCTION: Megalencephalic leukoencephalopathy with subcortical cysts is a rare disease with autosomal recessive inheritance. MATERIALS AND METHODS: Two brothers born from a consanguineous marriage, presenting with the phenotype of the disease, their parents, brothers and sisters were examined. Magnetic resonance imaging of the brain was performed for the two patients. Sequence analysis of MLC1 (GenBank mRNA accession no. NM_OI5166) was performed for the patients using intronic primers. PCR restriction fragment length polymorphism analysis was done in patients, their parents and in 100 Lebanese controls in order to exclude gene polymorphism. RESULTS: The clinical features were characteristic of the disease, consisting of an early-onset macrocephaly followed by slowly progressive ataxia, pyramidal tract involvement and epileptic seizures. In one patient, the clinical manifestations were aggravated by a trivial brain trauma. In his brother and in one female cousin, a status epilepticus was precipitated by a febrile syndrome. The diffuse cerebral white matter lesions and the subcortical temporo-polar and frontal cysts, best seen on MRI, allowed making the diagnosis. Molecular genetics revealed a new mutation involving the MLC1 gene (263G-->T, exon 3). As a consequence, it affects the second transmembrane domain predict (G88V) of the MLC protein (protein sequence NP_055981). The mutation was confirmed by PCR restriction fragment length polymorphism analysis. CONCLUSION: Megalencephalic leucoencephalopathy with subcortical cysts may be individualized on clinical and radiological basis and confirmed by molecular genetics. In this Lebanese family, a new mutation of the MLC1 gene is reported.

[Pre-symptomatic diagnosis of severe hereditary diseases with late onset in Lebanon: a choice or a necessity?]. / Le diagnostic présymptomatique des maladies graves héréditaires à [corrected] révélation tardive: [corrected] un choix ou une nécessité?

Progress achieved in the field of molecular genetics has opened the door to pre-symptomatic diagnosis tests of several severe hereditary disease, a majority of which are dominant and appear later in life. Given the importance of diagnosis in some of the cases where medical supervision and prevention are possible, there are a number of ethical dilemmas with regards to most of these diseases that, unfortunately, do not have a cure or any preventive treatment available. Above and beyond the capacity for medical care provision, there is a very high level of pressure and anxiety felt by every member of a family who has someone affected by one of these diseases in that they might be a carrier of a mutated gene which could be the cause or source of illness. They carry the burden of uncertainty that they may have already transmitted this gene or could give it to any of their children, and often there is also a significant level of guilt when one is the carrier but not to be affected by the disease itself. More and more frequently in these types of cases, there is a strong desire to know--in order to better organise and plan one's life and that of one's potential future family in the instance where one wishes to found one. This article discusses these problems based upon the consideration of four examples of such diseases with late onset: Huntington's disease, the common forms of thyroid cancer, the familiar forms of a predisposition to breast and ovarian cancer, and von Hippel-Lindau syndrome. However, regardless of the type of disease, the decision to take a genetic test is solely the choice of the individual in question, and the person should be accompanied and guided in his or her reflection by a multi-disciplinary team who can advise him or her and initiate useful deliberations on the various possibilities, their advantages and their disadvantages.

Non-collagenic etiologies of muscle weakness with joint deformities: about two paradigmatic case reports.

Muscle weakness associated to marked joint deformities is not an uncommon clinical situation in daily neuromuscular clinics. These abnormalities encompass a large variety of conditions including non-primary muscle disorders. Besides well-defined and rather readily recognisable hereditary syndromes such as Bethlem myopathy or Ullrich congenital muscular dystrophy, some unusual etiologies should also be considered. We report here two paradigmatic cases in which we found mutations in two novel genes corresponding to two newly described entities (progressive pseudorheumatoid dysplasia, PPD, and infantile systemic hyalinosis, ISH) both conditions in which the clinical picture can mimick primary muscle disease.

Spondyloepimetaphyseal dysplasia with multiple dislocations, leptodactylic type: report of a new patient and review of the literature.

A 6-year-old boy with congenital hip dislocation, developmental delay, short stature, macrocephaly, low set ears, short neck, and hyperlaxity of the wrists and fingers is described. Radiographs disclosed mainly the presence of thoracic scoliosis, narrow interpedicular distances, metaphyseal vertical striations, very small irregular epiphyses, right hip dislocation, luxation of both elbows, and severe delay of ossification of the epiphyses and the carpal bones. These features are very close to the newly described entity: spondyloepimetaphyseal dysplasia and multiple dislocations. This patient brings to light the differential diagnosis and confirms the specificity of the radiological findings of this new entity.

Genetic heterogeneity of megalencephalic leukoencephalopathy and subcortical cysts.

Reported are the clinical, neuroradiologic, and molecular findings in 18 patients with megalencephalic leukoencephalopathy and subcortical cysts (MLC) syndrome. Marked clinical intrafamilial and interfamilial variability in mutation-proven cases was found. A broad spectrum of pathogenetic mutations (missense, splice site, insertion, and deletions) were identified in the MLC1 gene, enlarging the spectrum of allelic variants without a straightforward genotype-phenotype correlation. Five patients did not harbor mutations in MLC1, supporting the existence of at least one other MLC locus.

Homozygosity mapping of a Dyggve-Melchior-Clausen syndrome gene to chromosome 18q21.1.

Dyggve-Melchior-Clausen syndrome (DMC) is an autosomal recessive condition characterised by short trunk dwarfism, scoliosis, microcephaly, coarse facies, mental retardation, and characteristic radiological features. X rays show platyspondyly with double vertebral hump, epiphyseal dysplasia, irregular metaphyses, and a characteristic lacy appearance of the iliac crests. Electron microscopy of chondrocytes have shown widened cisternae of rough endoplasmic reticulum and biochemical analyses have shown accumulation of glucosaminoglycan in cartilage, but the pathogenesis of DMC remains unexplained. Here, we report on the homozygosity mapping of a DMC gene to chromosome 18q21.1 in seven inbred families (Zmax=9.65 at theta=0 at locus D18S1126) in the genetic interval (1.8 cM) defined by loci D18S455 and D18S363. Despite the various geographical origins of the families reported here (Morocco, Tunisia, Portugal, and Lebanon), this condition was genetically homogeneous in our series. Continuing studies will hopefully lead to the identification of the disease causing gene.

Congenital contractures, short stature, abnormal face, microcephaly, scoliosis, hip dislocation, and severe psychomotor retardation in two unrelated girls. a new MCA/MR syndrome?

Severe mental retardation, congenital contractures, short stature, microcephaly, ptosis, myopia, beaked nose, abnormal teeth, hip dislocation, and severe scoliosis, are described in a 16-year-old and an unrelated 24-year-old females. Results of all laboratory investigations were normal. Review of the literature, of the London Dysmorphology Data Base and POSSUM did not yield to any diagnosis. Whether these patients present a new MCA/MR syndrome is discussed.

Short stature, abnormal face, joint laxity, dislocation, hernias, delayed bone age, and severe psychomotor retardation in two brothers: previously undescribed MCA/MR syndrome.

We describe two brothers with severe psychomotor retardation, short stature, microbrachycephaly, flat occiput, ptosis, low set and prominent ears, "beaked" nose, joint hyperlaxity and dislocation, hernias, delayed bone age, and abnormalities on skin biopsy. Their parents are first cousins. To the best of our knowledge, this syndrome has not been reported before.

One novel and two recurrent missense DKC1 mutations in patients with dyskeratosis congenita (DKC).

X-linked dyskeratosis congenita (DKC) is a progressive multisystem disorder most severely affecting tissues with a high cellular turnover such as skin, mucous membranes, and blood. Most patients die of bone marrow failure, although the chances of succumbing to various types of cancer and pulmonary disease are also high. DKC is caused predominantly by missense mutations in the DKC1 gene linked to Xq28. Some of the clinical features are reminiscent of premature ageing and this agrees with recent indications that DKC could be a telomere maintenance disorder. There is considerable variability in the type, severity, and age at onset of the various anomalies. Recognition of this has increased with the finding that patients with Hoyeraal-Hreidarsson syndrome (HHS) who exhibit severe neurological problems in addition to early-onset pancytopenia, also bear mutations in the DKC1 gene. For these reasons, and compounded by the range of mutations, phenotype-genotype correlations and accurate assessments of prognosis have not been possible. To complement the present data, we here report on three new cases of DKC and their mutations. One is a novel mutation in the exon 3 (K43E). The other two represent a frequently recurring mutation in exon 11 (A353V) and a less frequently recurring mutation in the exon 3 (T49M).

A new familial syndrome with facial abnormalities, abnormal EEG, and mental retardation.

Two sisters are reported with up-slanting palpebral fissures, hypertelorism, ptosis, a broad, bifid nasal tip, a high-arched palate, mental retardation, abnormal EEG and hand malformations in one of the patients. The girls' parents originate from the same village. Although the findings resemble the recently defined neurofaciodigitorenal syndrome, some findings suggest that this is a newly recognized syndrome.

Familial Mediterranean fever in Lebanon: mutation spectrum, evidence for cases in Maronites, Greek orthodoxes, Greek catholics, Syriacs and Chiites and for an association between amyloidosis and M694V and M694I mutations.

Seventy-nine unrelated Lebanese patients were tested for 15 mutations in the MEFV gene: A761H, A744S, V726A, K695R, M694V, M694I, M694del, M6801 (G --> C), M680I (G --> A) in exon 10, F479L in exon 5, P369S in exon 3, T267I, E167D and E148Q in exon 2, using PCR digestion, ARMS, DGGE and/or sequencing. Mutations were detected in patients belonging to all communities, most interestingly the Maronite, Greek orthodox, Greek catholic, Syriac and Chiite communities. The most frequent mutations are M694V and V726A (27% and 20% of the total alleles respectively). M694I, E148Q and M680I mutations account respectively for 9%, 8% and 5%. Each of the K695R, E167D and F479L mutations was observed once and all the remaining mutations were not encountered. Of the alleles 33% do not carry any of the studied mutations. The mutation spectra, clinical features and severity of the disease differed among the Lebanese communities. The genotype-phenotype analysis showed a significant association (P < 0.001) between amyloidosis and the presence of mutations at codon 694 in exon 10 (both M694V and M694I). None of the patients carrying other mutations developed amyloidosis.